Liam Davenport

Measuring four circulating biomarkers through a simple blood test in patients with type 2 diabetes and kidney disease may predict their risk of heart and kidney disease progression, suggests an analysis of the CREDENCE trial.

The research, published online in the journal Circulation, also revealed that patients treated with the sodium-glucose cotransporter-2 inhibitor canagliflozin (Invokana, Invokamet) had lower levels of the biomarkers after 1 year compared with those given placebo.

Examination of biomarker levels in more than 2,600 patients from CREDENCE showed that high baseline concentrations of the individual biomarkers were able to predict the future risk for a composite endpoint of renal and heart outcomes.

The combination of all four biomarkers into a single panel revealed that patients with the highest levels were more than four times as likely to experience the composite endpoint than were those with the lowest levels.

As two of the biomarkers used in the study have yet to have established prognostic thresholds, the results remain exploratory.

Lead author James L. Januzzi, MD, director of the Heart Failure and Biomarker Trials at the Baim Institute for Clinical Research, Boston, said that further study will help refine the predictive value of the panel.

“Given that the American Heart Association/American College of Cardiology and the American Diabetes Association now all recommend measurement of biomarkers to enhance the ability to predict risk in persons with type 2 diabetes, these results may considerably extend the reach of biomarker-based testing, refining accuracy even further,” he said in a press release.

In an interview, Dr. Januzzi said that “three out of the four biomarkers are already clinically and commercially available,” while the fourth, for insulin-like growth factor binding protein 7 (IGFBP7), is “on the near horizon.”

He stressed that the “future for multiple biomarker testing, however, will be less about ordering each individual test, and ultimately will revolve around panels of blood work that are ordered as a single test.”

Dr. Januzzi added that “rather than using the rather primitive approach that we took” of looking at the individual biomarkers in adjusted models, the next stage “will be to utilize algorithms to combine the results into a single value.

“A clinician will not have to struggle with looking at individual results but will just receive one aggregated test result that informs them whether a patient is at low, medium or higher risk,” he explained.

However, this will require determining the relative importance of each biomarker and weighting them in the final model.

Consequently, the current results “set the foundation for identifying some very powerful individual tests that may ultimately, in aggregate, help us to help our patients with diabetes avoid a major complication,” Dr. Januzzi said.

By revealing that some individuals with both type 2 diabetes and kidney disease are at higher risk than others, he also hopes the findings can be leveraged to treat patients with “varying degrees of intensity with proven therapies, including weight loss, dietary adjustment, and pharmacologic intervention.”

Dr. Januzzi added: “Diabetes affects a dramatic, and growing, percentage of our population, and this type of personalized strategy to reduce the major complications of this rather common disease is an important step forward.”

The authors noted that there is a “bidirectional relationship” between cardiovascular disease and chronic kidney disease (CKD), such that either diagnosis may increase the risk of, or exacerbate, the other. 

Individuals with type 2 diabetes and CKD albuminuria, they added, are at particularly high risk for major cardiovascular events, and studies have shown that several circulating cardiorenal stress biomarkers may predict the onset and progression of CKD in type 2 diabetes, as well as predict cardiovascular events.
 

Several biomarkers associated with myocardial stress and necrosis

The recent CANVAS trial revealed that, among individuals with type 2 diabetes with and without CKD, several biomarkers were associated with myocardial stress and necrosis, and renal tubular injury, predicting the progression of CKD with albuminuria, and the risk for heart failure events.

Taking inspiration from those findings, the current researchers studied a panel of similar cardiac and renal biomarkers among participants from the CREDENCE trial, for which 4,401 patients with type 2 diabetes and CKD at high risk of progression were randomly assigned to canagliflozin or placebo.

The current analysis involved 2,627 participants who had baseline plasma samples available for analysis of four circulating biomarkers: N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin T (hs-cTnT), growth differentiation factor-15 (GDF-15), and IGFBP7.

Among those, 2,385 participants also had year 1 plasma samples available for analysis, while year 3 plasma samples were available for 895 individuals.

The results showed that, in general, median baseline concentrations of each biomarker in both treatment groups were elevated compared with healthy reference populations.

Baseline log-transformed concentrations of each biomarker were also strongly predictive of cardiac and renal outcomes, including heart failure and progression of CKD.

For example, each unit increase in baseline NT-proBNP concentrations was associated with a hazard ratio of 1.35 for the primary composite endpoint of end-stage kidney disease, doubling of serum creatinine levels, renal death, or cardiovascular disease (P < .001).

For each unit increase in hs-cTnT levels, the hazard ratio for the primary composite was 1.73 (P < .001), for GDF-15 it was 1.84 (P < .0001), and for IGFBP7 the hazard ratio was 3.14 (P < .001).

Combining the four biomarkers into a single multimarker panel revealed that, compared with individuals with a low-risk score, those with a high-risk score had a hazard ratio for the primary outcome of 4.01, whereas those with a moderate risk score had a hazard ratio of 2.39 (P < .001 for both).

For the individual outcome of heart failure hospitalization, the effect was even greater. A high-risk score was associated with a hazard ratio vs. a low-risk score of 6.04 (P < .001), whereas patients with a moderate risk score had a hazard ratio of 2.45 (P = .04).

The researchers also reported that, between baseline and year 1, concentrations of all four biomarkers rose from 6% to 29% in the placebo group, but from 3% to just 10% in those treated with canagliflozin.

“It was reassuring to discover that canagliflozin helped reduce risks the most in people with the highest chances for complications,” said Dr. Januzzi.

The CREDENCE trial and the current analysis were funded by Janssen Research & Development LLC. NT-proBNP, hs-cTnT, GDF-15, and IGFBP7 reagents were provided by Roche Diagnostics. Dr. Januzzi is funded in part by the Hutter Family Professorship. Dr. Januzzi declared relationships with Imbria Pharmaceuticals, Jana Care, Abbott, Applied Therapeutics, HeartFlow, Innolife, Roche Diagnostics, Beckman, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Merck, Novartis, Pfizer, Siemens, Abbott, AbbVie, CVRx, Intercept, and Takeda.


 

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

Measuring four circulating biomarkers through a simple blood test in patients with type 2 diabetes and kidney disease may predict their risk of heart and kidney disease progression, suggests an analysis of the CREDENCE trial.

The research, published online in the journal Circulation, also revealed that patients treated with the sodium-glucose cotransporter-2 inhibitor canagliflozin (Invokana, Invokamet) had lower levels of the biomarkers after 1 year compared with those given placebo.

Examination of biomarker levels in more than 2,600 patients from CREDENCE showed that high baseline concentrations of the individual biomarkers were able to predict the future risk for a composite endpoint of renal and heart outcomes.

The combination of all four biomarkers into a single panel revealed that patients with the highest levels were more than four times as likely to experience the composite endpoint than were those with the lowest levels.

As two of the biomarkers used in the study have yet to have established prognostic thresholds, the results remain exploratory.

Lead author James L. Januzzi, MD, director of the Heart Failure and Biomarker Trials at the Baim Institute for Clinical Research, Boston, said that further study will help refine the predictive value of the panel.

“Given that the American Heart Association/American College of Cardiology and the American Diabetes Association now all recommend measurement of biomarkers to enhance the ability to predict risk in persons with type 2 diabetes, these results may considerably extend the reach of biomarker-based testing, refining accuracy even further,” he said in a press release.

In an interview, Dr. Januzzi said that “three out of the four biomarkers are already clinically and commercially available,” while the fourth, for insulin-like growth factor binding protein 7 (IGFBP7), is “on the near horizon.”

He stressed that the “future for multiple biomarker testing, however, will be less about ordering each individual test, and ultimately will revolve around panels of blood work that are ordered as a single test.”

Dr. Januzzi added that “rather than using the rather primitive approach that we took” of looking at the individual biomarkers in adjusted models, the next stage “will be to utilize algorithms to combine the results into a single value.

“A clinician will not have to struggle with looking at individual results but will just receive one aggregated test result that informs them whether a patient is at low, medium or higher risk,” he explained.

However, this will require determining the relative importance of each biomarker and weighting them in the final model.

Consequently, the current results “set the foundation for identifying some very powerful individual tests that may ultimately, in aggregate, help us to help our patients with diabetes avoid a major complication,” Dr. Januzzi said.

By revealing that some individuals with both type 2 diabetes and kidney disease are at higher risk than others, he also hopes the findings can be leveraged to treat patients with “varying degrees of intensity with proven therapies, including weight loss, dietary adjustment, and pharmacologic intervention.”

Dr. Januzzi added: “Diabetes affects a dramatic, and growing, percentage of our population, and this type of personalized strategy to reduce the major complications of this rather common disease is an important step forward.”

The authors noted that there is a “bidirectional relationship” between cardiovascular disease and chronic kidney disease (CKD), such that either diagnosis may increase the risk of, or exacerbate, the other. 

Individuals with type 2 diabetes and CKD albuminuria, they added, are at particularly high risk for major cardiovascular events, and studies have shown that several circulating cardiorenal stress biomarkers may predict the onset and progression of CKD in type 2 diabetes, as well as predict cardiovascular events.
 

Several biomarkers associated with myocardial stress and necrosis

The recent CANVAS trial revealed that, among individuals with type 2 diabetes with and without CKD, several biomarkers were associated with myocardial stress and necrosis, and renal tubular injury, predicting the progression of CKD with albuminuria, and the risk for heart failure events.

Taking inspiration from those findings, the current researchers studied a panel of similar cardiac and renal biomarkers among participants from the CREDENCE trial, for which 4,401 patients with type 2 diabetes and CKD at high risk of progression were randomly assigned to canagliflozin or placebo.

The current analysis involved 2,627 participants who had baseline plasma samples available for analysis of four circulating biomarkers: N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin T (hs-cTnT), growth differentiation factor-15 (GDF-15), and IGFBP7.

Among those, 2,385 participants also had year 1 plasma samples available for analysis, while year 3 plasma samples were available for 895 individuals.

The results showed that, in general, median baseline concentrations of each biomarker in both treatment groups were elevated compared with healthy reference populations.

Baseline log-transformed concentrations of each biomarker were also strongly predictive of cardiac and renal outcomes, including heart failure and progression of CKD.

For example, each unit increase in baseline NT-proBNP concentrations was associated with a hazard ratio of 1.35 for the primary composite endpoint of end-stage kidney disease, doubling of serum creatinine levels, renal death, or cardiovascular disease (P < .001).

For each unit increase in hs-cTnT levels, the hazard ratio for the primary composite was 1.73 (P < .001), for GDF-15 it was 1.84 (P < .0001), and for IGFBP7 the hazard ratio was 3.14 (P < .001).

Combining the four biomarkers into a single multimarker panel revealed that, compared with individuals with a low-risk score, those with a high-risk score had a hazard ratio for the primary outcome of 4.01, whereas those with a moderate risk score had a hazard ratio of 2.39 (P < .001 for both).

For the individual outcome of heart failure hospitalization, the effect was even greater. A high-risk score was associated with a hazard ratio vs. a low-risk score of 6.04 (P < .001), whereas patients with a moderate risk score had a hazard ratio of 2.45 (P = .04).

The researchers also reported that, between baseline and year 1, concentrations of all four biomarkers rose from 6% to 29% in the placebo group, but from 3% to just 10% in those treated with canagliflozin.

“It was reassuring to discover that canagliflozin helped reduce risks the most in people with the highest chances for complications,” said Dr. Januzzi.

The CREDENCE trial and the current analysis were funded by Janssen Research & Development LLC. NT-proBNP, hs-cTnT, GDF-15, and IGFBP7 reagents were provided by Roche Diagnostics. Dr. Januzzi is funded in part by the Hutter Family Professorship. Dr. Januzzi declared relationships with Imbria Pharmaceuticals, Jana Care, Abbott, Applied Therapeutics, HeartFlow, Innolife, Roche Diagnostics, Beckman, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Merck, Novartis, Pfizer, Siemens, Abbott, AbbVie, CVRx, Intercept, and Takeda.


 

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

Measuring four circulating biomarkers through a simple blood test in patients with type 2 diabetes and kidney disease may predict their risk of heart and kidney disease progression, suggests an analysis of the CREDENCE trial.

The research, published online in the journal Circulation, also revealed that patients treated with the sodium-glucose cotransporter-2 inhibitor canagliflozin (Invokana, Invokamet) had lower levels of the biomarkers after 1 year compared with those given placebo.

Examination of biomarker levels in more than 2,600 patients from CREDENCE showed that high baseline concentrations of the individual biomarkers were able to predict the future risk for a composite endpoint of renal and heart outcomes.

The combination of all four biomarkers into a single panel revealed that patients with the highest levels were more than four times as likely to experience the composite endpoint than were those with the lowest levels.

As two of the biomarkers used in the study have yet to have established prognostic thresholds, the results remain exploratory.

Lead author James L. Januzzi, MD, director of the Heart Failure and Biomarker Trials at the Baim Institute for Clinical Research, Boston, said that further study will help refine the predictive value of the panel.

“Given that the American Heart Association/American College of Cardiology and the American Diabetes Association now all recommend measurement of biomarkers to enhance the ability to predict risk in persons with type 2 diabetes, these results may considerably extend the reach of biomarker-based testing, refining accuracy even further,” he said in a press release.

In an interview, Dr. Januzzi said that “three out of the four biomarkers are already clinically and commercially available,” while the fourth, for insulin-like growth factor binding protein 7 (IGFBP7), is “on the near horizon.”

He stressed that the “future for multiple biomarker testing, however, will be less about ordering each individual test, and ultimately will revolve around panels of blood work that are ordered as a single test.”

Dr. Januzzi added that “rather than using the rather primitive approach that we took” of looking at the individual biomarkers in adjusted models, the next stage “will be to utilize algorithms to combine the results into a single value.

“A clinician will not have to struggle with looking at individual results but will just receive one aggregated test result that informs them whether a patient is at low, medium or higher risk,” he explained.

However, this will require determining the relative importance of each biomarker and weighting them in the final model.

Consequently, the current results “set the foundation for identifying some very powerful individual tests that may ultimately, in aggregate, help us to help our patients with diabetes avoid a major complication,” Dr. Januzzi said.

By revealing that some individuals with both type 2 diabetes and kidney disease are at higher risk than others, he also hopes the findings can be leveraged to treat patients with “varying degrees of intensity with proven therapies, including weight loss, dietary adjustment, and pharmacologic intervention.”

Dr. Januzzi added: “Diabetes affects a dramatic, and growing, percentage of our population, and this type of personalized strategy to reduce the major complications of this rather common disease is an important step forward.”

The authors noted that there is a “bidirectional relationship” between cardiovascular disease and chronic kidney disease (CKD), such that either diagnosis may increase the risk of, or exacerbate, the other. 

Individuals with type 2 diabetes and CKD albuminuria, they added, are at particularly high risk for major cardiovascular events, and studies have shown that several circulating cardiorenal stress biomarkers may predict the onset and progression of CKD in type 2 diabetes, as well as predict cardiovascular events.
 

Several biomarkers associated with myocardial stress and necrosis

The recent CANVAS trial revealed that, among individuals with type 2 diabetes with and without CKD, several biomarkers were associated with myocardial stress and necrosis, and renal tubular injury, predicting the progression of CKD with albuminuria, and the risk for heart failure events.

Taking inspiration from those findings, the current researchers studied a panel of similar cardiac and renal biomarkers among participants from the CREDENCE trial, for which 4,401 patients with type 2 diabetes and CKD at high risk of progression were randomly assigned to canagliflozin or placebo.

The current analysis involved 2,627 participants who had baseline plasma samples available for analysis of four circulating biomarkers: N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin T (hs-cTnT), growth differentiation factor-15 (GDF-15), and IGFBP7.

Among those, 2,385 participants also had year 1 plasma samples available for analysis, while year 3 plasma samples were available for 895 individuals.

The results showed that, in general, median baseline concentrations of each biomarker in both treatment groups were elevated compared with healthy reference populations.

Baseline log-transformed concentrations of each biomarker were also strongly predictive of cardiac and renal outcomes, including heart failure and progression of CKD.

For example, each unit increase in baseline NT-proBNP concentrations was associated with a hazard ratio of 1.35 for the primary composite endpoint of end-stage kidney disease, doubling of serum creatinine levels, renal death, or cardiovascular disease (P < .001).

For each unit increase in hs-cTnT levels, the hazard ratio for the primary composite was 1.73 (P < .001), for GDF-15 it was 1.84 (P < .0001), and for IGFBP7 the hazard ratio was 3.14 (P < .001).

Combining the four biomarkers into a single multimarker panel revealed that, compared with individuals with a low-risk score, those with a high-risk score had a hazard ratio for the primary outcome of 4.01, whereas those with a moderate risk score had a hazard ratio of 2.39 (P < .001 for both).

For the individual outcome of heart failure hospitalization, the effect was even greater. A high-risk score was associated with a hazard ratio vs. a low-risk score of 6.04 (P < .001), whereas patients with a moderate risk score had a hazard ratio of 2.45 (P = .04).

The researchers also reported that, between baseline and year 1, concentrations of all four biomarkers rose from 6% to 29% in the placebo group, but from 3% to just 10% in those treated with canagliflozin.

“It was reassuring to discover that canagliflozin helped reduce risks the most in people with the highest chances for complications,” said Dr. Januzzi.

The CREDENCE trial and the current analysis were funded by Janssen Research & Development LLC. NT-proBNP, hs-cTnT, GDF-15, and IGFBP7 reagents were provided by Roche Diagnostics. Dr. Januzzi is funded in part by the Hutter Family Professorship. Dr. Januzzi declared relationships with Imbria Pharmaceuticals, Jana Care, Abbott, Applied Therapeutics, HeartFlow, Innolife, Roche Diagnostics, Beckman, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Merck, Novartis, Pfizer, Siemens, Abbott, AbbVie, CVRx, Intercept, and Takeda.


 

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

Acute liver failure (ALF), a rare life-threatening condition, is potentially reversible if recognized and treated early, according to the latest guidelines from the American College of Gastroenterology.

The guidelines emphasize the need for timely transfer to a transplant center for patients who are at risk for poor outcomes.

“We wanted to produce an updated set of ALF guidelines for general gastroenterologists,” said lead author Alexandra Shingina, MD, MSc, Vanderbilt University Medical Center, Nashville, Tenn.

The aim was to “provide a comprehensive review of early evaluation and management of these patients,” she added.

The new guidelines build on previous guidelines produced by the American Association for the Study of Liver Diseases in 2011. The guidelines were published in the American Journal of Gastroenterology.

In 2017, the American Gastroenterological Association issued guidelines specific to the diagnosis and management of acute liver failure.

Siddharth Singh, MD, a gastroenterologist with UC San Diego Health and an author of the AGA guidelines, said the new guidelines will help inform the treatment of ALF. “It is encouraging to see the recent ACG guidelines building on prior guidelines published by the AGA in 2017,” he said.

ALF is typically defined as severe liver impairment and rapid clinical deterioration that, with few exceptions, “occurs in patients with no pre-existing liver disease,” the authors write. It is critical to distinguish ALF from the more common acutely decompensated cirrhosis or acute on chronic liver failure, the guidelines note, because their management differs significantly.

“ALF has a multitude of etiologies and a variety of clinical presentations that can affect virtually every organ system,” the authors write.

The cause of ALF is an essential indicator for prognosis and treatment strategy, especially for liver transplantation. For example, hyperacute ALF is predominantly seen in the setting of viral hepatitis A and E, acetaminophen toxicity, and ischemic injury, they note. Although the hyperacute subtype “carries a high risk for cerebral edema, it has the best prognosis without transplantation,” compared with other forms of ALF.

Before liver transplants, nearly 80% of patients with ALF died from the condition. In the past 20 years, 1- and 5-year survival rates from liver transplants are about 80% and 75%, respectively.

The authors emphasize that it is “imperative for clinicians to recognize ALF early ... because initiation of treatment and transplant considerations could be life-saving.”
 

Notable new recommendations

To develop the new guidelines, a writing group was assembled that included hepatology experts across a range of practice settings and different stages of their clinical and research careers.

They conducted a literature search of the MEDLINE, EMBASE, and Cochrane Library databases for relevant studies published in English up to January 2022, focusing on the highest quality of evidence, where available. Owing to a lack of solid data, the recommendations are based predominantly on expert opinion, the authors note.

ALF “is a rare entity. Literature reporting on outcomes is sparse and limited to retrospective cases series, with almost no randomized controlled trials available,” Dr. Shingina said.

She and her colleagues developed the recommendations to cover all aspects of ALF management, from initial diagnosis through to system- and etiology-specific management of ALF and liver transplantation.

“One of the new recommendations is the early use of CRRT [continuous renal replacement therapy] in patients with ALF and grade 2 encephalopathy, even in the absence of conventional RRT indications,” Dr. Shingina said.

“Although the evidence is limited, we felt that it was an important point in the multidisciplinary management of complex ALF patients, which can potentially save lives by reducing cerebral edema and allowing for more time if a liver transplant is not readily available,” she said.

She also highlighted a recommendation supporting intravenous N-acetylcysteine use in patients with acetaminophen-induced ALF and pointed out that the routine use of intracranial pressure monitors is no longer recommended “given the lack of literature on improved outcomes.”

Dr. Shingina emphasized that living donor liver transplantation can be considered in patients with ALF who are listed as status 1A priority for transplantation in experienced centers, when deceased donor liver transplantation is not readily available, as can ABO-incompatible grafts in patients who are rapidly declining.

The authors also present a timeline of ALF presentation and investigations.

During the first 2-4 hours after presentation at the emergency department, the patient should undergo initial stabilization and investigations, with a transfer to the ICU for those with grade 2 or higher hepatic encephalopathy. The transplant center should also be contacted during this period, the authors write.

After transfer to the ICU or a transplant center and during hours 4-12 After the initial presentation, patients should undergo intensive monitoring.

Psychiatry, social work, and hepatobiliary surgery consults should also be undertaken to determine the patient’s transplant eligibility, and if eligible, they should be put on a list.

Those who are ineligible for transplant or who show improvements should subsequently receive supportive management.

Overall, Dr. Shingina said that risk stratification and contact with a transplant center for potential transfer is of “utmost importance” for general gastroenterologists working in the community.

She said that either the Kings College Criteria or Model for End-Stage Liver Disease score can be used for prognostication, with a MELD score of 25 indicating worse outcomes.

“These are the patients who would benefit from early transfer to the nearest transplant center,” Dr. Shingina said.
 

Guidelines valuable, offer ‘concrete advice’

Approached for comment, Michael P. Curry, MD, Beth Israel Deaconess Medical Center, Boston, welcomed the guidelines, saying they are “very well written.”

He said there have been “a lot of changes in the field” since the 2011 guidelines. The current recommendations “provide concrete advice to all physicians on the appropriate assessment of patients with ALF,” he said.

Dr. Curry singled out the new recommendation on the early use of CRRT in patients with encephalopathy. He agreed on the need for gastroenterologists outside of transplant centers to make contact for potential transfer early.

“These are not patients who should, or could, be managed in a small community hospital or in a program that does not have a transplant center with which they work in close collaboration,” he said.

“So, identifying patients who are at highest risk of progressing is really important,” he said.

Dr. Curry hopes the guidelines will be shared widely by colleagues, but he is concerned that they are “not going to make it to some of these intensive care units in community, non-tertiary care centers.”

Nikolaos Pyrsopoulos, MD, PhD, MBA, Rutgers New Jersey Medical School, Newark, said the guidelines offer a “very comprehensive review of the literature.”

He said they are also a “very thorough evaluation of the quality of the evidence-based publications.”

It was “about time” that there was a set of guidelines of this quality, he added.

As for the recommendations, Dr. Pyrsopoulos believes that they will be “really valuable for the general gastroenterologist practicing in the community,” as well as for pathologists, to help them evaluate patients with ALF “as soon as possible, and in a standardized manner.”

He also emphasized the need for the rapid transfer of patients for transplant “when they are still lucid ... so we have the opportunity to discuss with and evaluate the patient.” This can be problematic in those who have been intubated and in patients with hepatic encephalopathy because they “become really confused.”

“The window of opportunity is closing very rapidly in some of these patients ... and morbidity and mortality is really pretty high” he said, so the transplant centers “appreciate when the referral is made to them earlier.”

No funding declared. No relevant financial relationships declared.

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

Acute liver failure (ALF), a rare life-threatening condition, is potentially reversible if recognized and treated early, according to the latest guidelines from the American College of Gastroenterology.

The guidelines emphasize the need for timely transfer to a transplant center for patients who are at risk for poor outcomes.

“We wanted to produce an updated set of ALF guidelines for general gastroenterologists,” said lead author Alexandra Shingina, MD, MSc, Vanderbilt University Medical Center, Nashville, Tenn.

The aim was to “provide a comprehensive review of early evaluation and management of these patients,” she added.

The new guidelines build on previous guidelines produced by the American Association for the Study of Liver Diseases in 2011. The guidelines were published in the American Journal of Gastroenterology.

In 2017, the American Gastroenterological Association issued guidelines specific to the diagnosis and management of acute liver failure.

Siddharth Singh, MD, a gastroenterologist with UC San Diego Health and an author of the AGA guidelines, said the new guidelines will help inform the treatment of ALF. “It is encouraging to see the recent ACG guidelines building on prior guidelines published by the AGA in 2017,” he said.

ALF is typically defined as severe liver impairment and rapid clinical deterioration that, with few exceptions, “occurs in patients with no pre-existing liver disease,” the authors write. It is critical to distinguish ALF from the more common acutely decompensated cirrhosis or acute on chronic liver failure, the guidelines note, because their management differs significantly.

“ALF has a multitude of etiologies and a variety of clinical presentations that can affect virtually every organ system,” the authors write.

The cause of ALF is an essential indicator for prognosis and treatment strategy, especially for liver transplantation. For example, hyperacute ALF is predominantly seen in the setting of viral hepatitis A and E, acetaminophen toxicity, and ischemic injury, they note. Although the hyperacute subtype “carries a high risk for cerebral edema, it has the best prognosis without transplantation,” compared with other forms of ALF.

Before liver transplants, nearly 80% of patients with ALF died from the condition. In the past 20 years, 1- and 5-year survival rates from liver transplants are about 80% and 75%, respectively.

The authors emphasize that it is “imperative for clinicians to recognize ALF early ... because initiation of treatment and transplant considerations could be life-saving.”
 

Notable new recommendations

To develop the new guidelines, a writing group was assembled that included hepatology experts across a range of practice settings and different stages of their clinical and research careers.

They conducted a literature search of the MEDLINE, EMBASE, and Cochrane Library databases for relevant studies published in English up to January 2022, focusing on the highest quality of evidence, where available. Owing to a lack of solid data, the recommendations are based predominantly on expert opinion, the authors note.

ALF “is a rare entity. Literature reporting on outcomes is sparse and limited to retrospective cases series, with almost no randomized controlled trials available,” Dr. Shingina said.

She and her colleagues developed the recommendations to cover all aspects of ALF management, from initial diagnosis through to system- and etiology-specific management of ALF and liver transplantation.

“One of the new recommendations is the early use of CRRT [continuous renal replacement therapy] in patients with ALF and grade 2 encephalopathy, even in the absence of conventional RRT indications,” Dr. Shingina said.

“Although the evidence is limited, we felt that it was an important point in the multidisciplinary management of complex ALF patients, which can potentially save lives by reducing cerebral edema and allowing for more time if a liver transplant is not readily available,” she said.

She also highlighted a recommendation supporting intravenous N-acetylcysteine use in patients with acetaminophen-induced ALF and pointed out that the routine use of intracranial pressure monitors is no longer recommended “given the lack of literature on improved outcomes.”

Dr. Shingina emphasized that living donor liver transplantation can be considered in patients with ALF who are listed as status 1A priority for transplantation in experienced centers, when deceased donor liver transplantation is not readily available, as can ABO-incompatible grafts in patients who are rapidly declining.

The authors also present a timeline of ALF presentation and investigations.

During the first 2-4 hours after presentation at the emergency department, the patient should undergo initial stabilization and investigations, with a transfer to the ICU for those with grade 2 or higher hepatic encephalopathy. The transplant center should also be contacted during this period, the authors write.

After transfer to the ICU or a transplant center and during hours 4-12 After the initial presentation, patients should undergo intensive monitoring.

Psychiatry, social work, and hepatobiliary surgery consults should also be undertaken to determine the patient’s transplant eligibility, and if eligible, they should be put on a list.

Those who are ineligible for transplant or who show improvements should subsequently receive supportive management.

Overall, Dr. Shingina said that risk stratification and contact with a transplant center for potential transfer is of “utmost importance” for general gastroenterologists working in the community.

She said that either the Kings College Criteria or Model for End-Stage Liver Disease score can be used for prognostication, with a MELD score of 25 indicating worse outcomes.

“These are the patients who would benefit from early transfer to the nearest transplant center,” Dr. Shingina said.
 

Guidelines valuable, offer ‘concrete advice’

Approached for comment, Michael P. Curry, MD, Beth Israel Deaconess Medical Center, Boston, welcomed the guidelines, saying they are “very well written.”

He said there have been “a lot of changes in the field” since the 2011 guidelines. The current recommendations “provide concrete advice to all physicians on the appropriate assessment of patients with ALF,” he said.

Dr. Curry singled out the new recommendation on the early use of CRRT in patients with encephalopathy. He agreed on the need for gastroenterologists outside of transplant centers to make contact for potential transfer early.

“These are not patients who should, or could, be managed in a small community hospital or in a program that does not have a transplant center with which they work in close collaboration,” he said.

“So, identifying patients who are at highest risk of progressing is really important,” he said.

Dr. Curry hopes the guidelines will be shared widely by colleagues, but he is concerned that they are “not going to make it to some of these intensive care units in community, non-tertiary care centers.”

Nikolaos Pyrsopoulos, MD, PhD, MBA, Rutgers New Jersey Medical School, Newark, said the guidelines offer a “very comprehensive review of the literature.”

He said they are also a “very thorough evaluation of the quality of the evidence-based publications.”

It was “about time” that there was a set of guidelines of this quality, he added.

As for the recommendations, Dr. Pyrsopoulos believes that they will be “really valuable for the general gastroenterologist practicing in the community,” as well as for pathologists, to help them evaluate patients with ALF “as soon as possible, and in a standardized manner.”

He also emphasized the need for the rapid transfer of patients for transplant “when they are still lucid ... so we have the opportunity to discuss with and evaluate the patient.” This can be problematic in those who have been intubated and in patients with hepatic encephalopathy because they “become really confused.”

“The window of opportunity is closing very rapidly in some of these patients ... and morbidity and mortality is really pretty high” he said, so the transplant centers “appreciate when the referral is made to them earlier.”

No funding declared. No relevant financial relationships declared.

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

Acute liver failure (ALF), a rare life-threatening condition, is potentially reversible if recognized and treated early, according to the latest guidelines from the American College of Gastroenterology.

The guidelines emphasize the need for timely transfer to a transplant center for patients who are at risk for poor outcomes.

“We wanted to produce an updated set of ALF guidelines for general gastroenterologists,” said lead author Alexandra Shingina, MD, MSc, Vanderbilt University Medical Center, Nashville, Tenn.

The aim was to “provide a comprehensive review of early evaluation and management of these patients,” she added.

The new guidelines build on previous guidelines produced by the American Association for the Study of Liver Diseases in 2011. The guidelines were published in the American Journal of Gastroenterology.

In 2017, the American Gastroenterological Association issued guidelines specific to the diagnosis and management of acute liver failure.

Siddharth Singh, MD, a gastroenterologist with UC San Diego Health and an author of the AGA guidelines, said the new guidelines will help inform the treatment of ALF. “It is encouraging to see the recent ACG guidelines building on prior guidelines published by the AGA in 2017,” he said.

ALF is typically defined as severe liver impairment and rapid clinical deterioration that, with few exceptions, “occurs in patients with no pre-existing liver disease,” the authors write. It is critical to distinguish ALF from the more common acutely decompensated cirrhosis or acute on chronic liver failure, the guidelines note, because their management differs significantly.

“ALF has a multitude of etiologies and a variety of clinical presentations that can affect virtually every organ system,” the authors write.

The cause of ALF is an essential indicator for prognosis and treatment strategy, especially for liver transplantation. For example, hyperacute ALF is predominantly seen in the setting of viral hepatitis A and E, acetaminophen toxicity, and ischemic injury, they note. Although the hyperacute subtype “carries a high risk for cerebral edema, it has the best prognosis without transplantation,” compared with other forms of ALF.

Before liver transplants, nearly 80% of patients with ALF died from the condition. In the past 20 years, 1- and 5-year survival rates from liver transplants are about 80% and 75%, respectively.

The authors emphasize that it is “imperative for clinicians to recognize ALF early ... because initiation of treatment and transplant considerations could be life-saving.”
 

Notable new recommendations

To develop the new guidelines, a writing group was assembled that included hepatology experts across a range of practice settings and different stages of their clinical and research careers.

They conducted a literature search of the MEDLINE, EMBASE, and Cochrane Library databases for relevant studies published in English up to January 2022, focusing on the highest quality of evidence, where available. Owing to a lack of solid data, the recommendations are based predominantly on expert opinion, the authors note.

ALF “is a rare entity. Literature reporting on outcomes is sparse and limited to retrospective cases series, with almost no randomized controlled trials available,” Dr. Shingina said.

She and her colleagues developed the recommendations to cover all aspects of ALF management, from initial diagnosis through to system- and etiology-specific management of ALF and liver transplantation.

“One of the new recommendations is the early use of CRRT [continuous renal replacement therapy] in patients with ALF and grade 2 encephalopathy, even in the absence of conventional RRT indications,” Dr. Shingina said.

“Although the evidence is limited, we felt that it was an important point in the multidisciplinary management of complex ALF patients, which can potentially save lives by reducing cerebral edema and allowing for more time if a liver transplant is not readily available,” she said.

She also highlighted a recommendation supporting intravenous N-acetylcysteine use in patients with acetaminophen-induced ALF and pointed out that the routine use of intracranial pressure monitors is no longer recommended “given the lack of literature on improved outcomes.”

Dr. Shingina emphasized that living donor liver transplantation can be considered in patients with ALF who are listed as status 1A priority for transplantation in experienced centers, when deceased donor liver transplantation is not readily available, as can ABO-incompatible grafts in patients who are rapidly declining.

The authors also present a timeline of ALF presentation and investigations.

During the first 2-4 hours after presentation at the emergency department, the patient should undergo initial stabilization and investigations, with a transfer to the ICU for those with grade 2 or higher hepatic encephalopathy. The transplant center should also be contacted during this period, the authors write.

After transfer to the ICU or a transplant center and during hours 4-12 After the initial presentation, patients should undergo intensive monitoring.

Psychiatry, social work, and hepatobiliary surgery consults should also be undertaken to determine the patient’s transplant eligibility, and if eligible, they should be put on a list.

Those who are ineligible for transplant or who show improvements should subsequently receive supportive management.

Overall, Dr. Shingina said that risk stratification and contact with a transplant center for potential transfer is of “utmost importance” for general gastroenterologists working in the community.

She said that either the Kings College Criteria or Model for End-Stage Liver Disease score can be used for prognostication, with a MELD score of 25 indicating worse outcomes.

“These are the patients who would benefit from early transfer to the nearest transplant center,” Dr. Shingina said.
 

Guidelines valuable, offer ‘concrete advice’

Approached for comment, Michael P. Curry, MD, Beth Israel Deaconess Medical Center, Boston, welcomed the guidelines, saying they are “very well written.”

He said there have been “a lot of changes in the field” since the 2011 guidelines. The current recommendations “provide concrete advice to all physicians on the appropriate assessment of patients with ALF,” he said.

Dr. Curry singled out the new recommendation on the early use of CRRT in patients with encephalopathy. He agreed on the need for gastroenterologists outside of transplant centers to make contact for potential transfer early.

“These are not patients who should, or could, be managed in a small community hospital or in a program that does not have a transplant center with which they work in close collaboration,” he said.

“So, identifying patients who are at highest risk of progressing is really important,” he said.

Dr. Curry hopes the guidelines will be shared widely by colleagues, but he is concerned that they are “not going to make it to some of these intensive care units in community, non-tertiary care centers.”

Nikolaos Pyrsopoulos, MD, PhD, MBA, Rutgers New Jersey Medical School, Newark, said the guidelines offer a “very comprehensive review of the literature.”

He said they are also a “very thorough evaluation of the quality of the evidence-based publications.”

It was “about time” that there was a set of guidelines of this quality, he added.

As for the recommendations, Dr. Pyrsopoulos believes that they will be “really valuable for the general gastroenterologist practicing in the community,” as well as for pathologists, to help them evaluate patients with ALF “as soon as possible, and in a standardized manner.”

He also emphasized the need for the rapid transfer of patients for transplant “when they are still lucid ... so we have the opportunity to discuss with and evaluate the patient.” This can be problematic in those who have been intubated and in patients with hepatic encephalopathy because they “become really confused.”

“The window of opportunity is closing very rapidly in some of these patients ... and morbidity and mortality is really pretty high” he said, so the transplant centers “appreciate when the referral is made to them earlier.”

No funding declared. No relevant financial relationships declared.

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

Patients with severe alcohol-associated hepatitis (AH) need treatment for both their liver disease and their underlying alcohol use disorder (AUD), concludes a review discussing care for patients recently hospitalized.

“Probably the biggest thing I would want providers to take away from the review is to remember that these patients are likely to carry a dual diagnosis,” said lead author Akshay Shetty, MD, Pfleger Liver Institute, UCLA Medical Center.

“It is important to address the liver disease, because it probably carries the biggest mortality and morbidity risk in the short term, but we have to remember to treat their alcohol use disorder simultaneously,” Dr. Shetty said.

The guidance by Dr. Shetty and coauthors was published online in the Journal of Clinical Gastroenterology.
 

More alcohol misuse means more liver disease

AH is a “unique, severe form of alcohol-associated steatohepatitis that is seen in the background of recent heavy alcohol use,” the team writes. Patients with severe AH have faced mortality rates as high as 20%-50%. A recent study reported a drop in 30-day mortality rates to 17%, which the authors credit to improved supportive medical management.

Alcohol misuse has surged over the past two decades, which experts believe will lead to a rise in alcohol-related liver disease, including AH hospitalization, the authors note. Rates of high-risk drinking in the United States (four or more drinks daily for women, five or more for men) increased by almost 30% between 2002 and 2012, particularly among women and ethnic minorities.

At the same time, rates of AUD rose 25% among young adults. In 2019, a U.S. survey found 14.5 million people aged 12 years and older in the United States carried an AUD diagnosis.

Meanwhile, the U.S. National Inpatient Sample revealed a 28.3% rise in AH-related hospitalizations between 2007 and 2014.

“AH patients carry a high short-term mortality [and] require close outpatient monitoring and significant care coordination,” write the authors. Despite the rising rates of severe AH, there is a lack of standardized guidance on post-discharge management, which motivated their clinical care review.
 

Liver disease shapes short-term outcomes

The management of patients with a recent episode of severe AH requires a two-pronged approach and shared patient management between gastroenterologists/hepatologists and addiction specialists. The multidisciplinary management both improves outcomes and is linked to reduced health care costs, the authors write.

While abstinence from alcohol remains essential to recovery, the authors note, it is the “severity of hepatic decompensation that has been shown to dictate short-term mortality in the initial 6 months” following discharge.

The team created an outpatient algorithm that divides patient care into two main areas: hepatic decompensation and AUD.

For the risk of hepatic decompensation, patients should undergo close monitoring for infections and frequent laboratory tests in the months following discharge.

Moreover, the “majority of patients with severe AH usually have background cirrhosis and are at risk of portal hypertensive decompensations similar to cirrhosis,” the authors write, and so patients should be assessed for hepatic encephalopathy, as well as for ascites and variceal bleeding.

For HE, the authors recommend a low threshold for treatment initiation with lactulose (a colonic acidifier) and the antibiotic rifaximin, but they suggest that ascites management “should be conservative ... with strict adherence to a low-sodium diet as the first-line approach.”

A key problem among severe AH patients post-discharge is malnutrition, which reaches 100% prevalence and is associated with the severity of liver disease, including decompensation and mortality, they note.

Patients with malnutrition are at risk of entering a catabolic starvation state. The authors recommend avoiding long fasting periods with multiple small meals and late evening snacks.

Long-term, severe AH patients should be assessed for advanced fibrosis, although early diagnosis is often challenging, as the clinical and laboratory results typically mimic findings of liver cirrhosis, the authors write.

Crucially, patients should be considered for early referral for liver transplantation, because early liver transplantation is associated with “excellent transplant outcomes and is noninferior when compared with other etiologies of chronic liver disease,” they write.
 

Long-term risk rests on preventing alcohol relapse

Turning to AUD, the team notes that long-term outcomes among AH patients depend on the prevention of alcohol relapse, because alcohol use among these patients is directly linked to higher rates of mortality and decompensation.

The authors concede that the “definition of relapse remains a matter of contention, especially in the post-liver transplant population,” but they recommend complete abstinence for patients recovering from AH and define relapse as any use of alcohol.

Dr. Shetty explained that “often, the focus tends to be on the acute threats to a patient’s life, so their liver disease tends to be emphasized, and we often forget why patients present with the liver disease in the first place.”

He continued: “So we do our best to address the liver disease and not a lot gets done for the alcohol-use disorder that the patient may have in the background. The expectation is that, if the doctors help patients with their liver disease, the patients will learn that lesson on their own and stop drinking.”

Instead, Dr. Shetty and his colleagues advise, all patients should be screened for AUD and undergo surveillance with alcohol biomarkers monthly at first. Patients should also be referred to an addiction specialist, where some combination of psychotherapy, mutual support groups, and pharmacotherapy can be tailored to individual patient needs and access.

Multidisciplinary management, comprising hepatology, psychiatry, psychologist, nurse, and social worker consults, has shown “promising results in the management of AUD, improvement in liver disease, and decrease in health care burden,” the authors write, although “multidisciplinary clinics often carry financial and administrative barriers to broad application.”

Moreover, these interventions require a commitment from the patient, at least in the short term, to allow the establishment of a therapeutic relationship between the clinician and the patient and aid compliance over the longer term.

“Patients with AUD remain reluctant to pursue treatment,” the authors write, “and a large-scale effort to improve knowledge gaps in regard to AUD treatment and its success is needed, both from patients’ primary care providers and their consultants.”

Dr. Shetty explained that patient engagement is “probably the most challenging aspect of the disease, especially the alcohol use disorder part.”

This is partly because patients often lack insight, and alcohol addiction carries stigma and shame, as well as self-blame, he said, and so patients will “often delay pursuing any therapy ... even when they are sick.”

Dr. Shetty believes that reducing the stigma around alcohol addiction will require better education of patients and health care providers. To that end, he noted that the scientific literature now avoids the pejorative “alcoholic” and instead describes alcohol use as a disorder rather than having it define the patient.

“But this educational aspect is going to take a long time to really take effect, so from a provider perspective ... it is important to be open-minded when seeing these patients,” he said. This means not focusing on “the medical aspect alone but trying to really see the person who’s come to you for help and understand their motivations for pursing medical care.”

“Despite all these things, some patients may still find it very challenging and awkward. It takes several visits to really establish a rapport with them and get a sense of how to get them to share the challenging aspects of the disease,” Dr. Shetty added.
 

Multidisciplinary management for optimal outcomes

In a comment, Nancy S. Reau, MD, chair of hepatology, Rush Medical College, Chicago, agreed with the need to address both the risk for hepatic decompensation and AUD, the benefits of multidisciplinary management of patients, and the importance of patient engagement to successful outcomes.

“As hepatologists, we are often best at managing liver disease, but if you don’t also address the alcohol use disorder, the patient will not have the optimal outcome,” she said in an interview. “Most patients with severe AH have cirrhosis, [which] makes longitudinal follow-up imperative.”

“They are at risk for liver complications but also need aggressive nutritional support and management of their addiction,” she said. “As they improve, they can usually continue intensive treatment.”

Akhil Anand, MD, an addiction psychiatrist and co-director of the Multidisciplinary Alcohol Program at the Cleveland Clinic, also noted the increase in cases of alcohol-associated hepatitis from rising alcohol use.

The review “provides a timely, comprehensive, and impartial overview” of how to manage the condition, he said, as well as “how to treat co-occurring alcohol use disorder in this life-threatening situation.”

No funding was declared. The authors report no relevant financial relationships.

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

Patients with severe alcohol-associated hepatitis (AH) need treatment for both their liver disease and their underlying alcohol use disorder (AUD), concludes a review discussing care for patients recently hospitalized.

“Probably the biggest thing I would want providers to take away from the review is to remember that these patients are likely to carry a dual diagnosis,” said lead author Akshay Shetty, MD, Pfleger Liver Institute, UCLA Medical Center.

“It is important to address the liver disease, because it probably carries the biggest mortality and morbidity risk in the short term, but we have to remember to treat their alcohol use disorder simultaneously,” Dr. Shetty said.

The guidance by Dr. Shetty and coauthors was published online in the Journal of Clinical Gastroenterology.
 

More alcohol misuse means more liver disease

AH is a “unique, severe form of alcohol-associated steatohepatitis that is seen in the background of recent heavy alcohol use,” the team writes. Patients with severe AH have faced mortality rates as high as 20%-50%. A recent study reported a drop in 30-day mortality rates to 17%, which the authors credit to improved supportive medical management.

Alcohol misuse has surged over the past two decades, which experts believe will lead to a rise in alcohol-related liver disease, including AH hospitalization, the authors note. Rates of high-risk drinking in the United States (four or more drinks daily for women, five or more for men) increased by almost 30% between 2002 and 2012, particularly among women and ethnic minorities.

At the same time, rates of AUD rose 25% among young adults. In 2019, a U.S. survey found 14.5 million people aged 12 years and older in the United States carried an AUD diagnosis.

Meanwhile, the U.S. National Inpatient Sample revealed a 28.3% rise in AH-related hospitalizations between 2007 and 2014.

“AH patients carry a high short-term mortality [and] require close outpatient monitoring and significant care coordination,” write the authors. Despite the rising rates of severe AH, there is a lack of standardized guidance on post-discharge management, which motivated their clinical care review.
 

Liver disease shapes short-term outcomes

The management of patients with a recent episode of severe AH requires a two-pronged approach and shared patient management between gastroenterologists/hepatologists and addiction specialists. The multidisciplinary management both improves outcomes and is linked to reduced health care costs, the authors write.

While abstinence from alcohol remains essential to recovery, the authors note, it is the “severity of hepatic decompensation that has been shown to dictate short-term mortality in the initial 6 months” following discharge.

The team created an outpatient algorithm that divides patient care into two main areas: hepatic decompensation and AUD.

For the risk of hepatic decompensation, patients should undergo close monitoring for infections and frequent laboratory tests in the months following discharge.

Moreover, the “majority of patients with severe AH usually have background cirrhosis and are at risk of portal hypertensive decompensations similar to cirrhosis,” the authors write, and so patients should be assessed for hepatic encephalopathy, as well as for ascites and variceal bleeding.

For HE, the authors recommend a low threshold for treatment initiation with lactulose (a colonic acidifier) and the antibiotic rifaximin, but they suggest that ascites management “should be conservative ... with strict adherence to a low-sodium diet as the first-line approach.”

A key problem among severe AH patients post-discharge is malnutrition, which reaches 100% prevalence and is associated with the severity of liver disease, including decompensation and mortality, they note.

Patients with malnutrition are at risk of entering a catabolic starvation state. The authors recommend avoiding long fasting periods with multiple small meals and late evening snacks.

Long-term, severe AH patients should be assessed for advanced fibrosis, although early diagnosis is often challenging, as the clinical and laboratory results typically mimic findings of liver cirrhosis, the authors write.

Crucially, patients should be considered for early referral for liver transplantation, because early liver transplantation is associated with “excellent transplant outcomes and is noninferior when compared with other etiologies of chronic liver disease,” they write.
 

Long-term risk rests on preventing alcohol relapse

Turning to AUD, the team notes that long-term outcomes among AH patients depend on the prevention of alcohol relapse, because alcohol use among these patients is directly linked to higher rates of mortality and decompensation.

The authors concede that the “definition of relapse remains a matter of contention, especially in the post-liver transplant population,” but they recommend complete abstinence for patients recovering from AH and define relapse as any use of alcohol.

Dr. Shetty explained that “often, the focus tends to be on the acute threats to a patient’s life, so their liver disease tends to be emphasized, and we often forget why patients present with the liver disease in the first place.”

He continued: “So we do our best to address the liver disease and not a lot gets done for the alcohol-use disorder that the patient may have in the background. The expectation is that, if the doctors help patients with their liver disease, the patients will learn that lesson on their own and stop drinking.”

Instead, Dr. Shetty and his colleagues advise, all patients should be screened for AUD and undergo surveillance with alcohol biomarkers monthly at first. Patients should also be referred to an addiction specialist, where some combination of psychotherapy, mutual support groups, and pharmacotherapy can be tailored to individual patient needs and access.

Multidisciplinary management, comprising hepatology, psychiatry, psychologist, nurse, and social worker consults, has shown “promising results in the management of AUD, improvement in liver disease, and decrease in health care burden,” the authors write, although “multidisciplinary clinics often carry financial and administrative barriers to broad application.”

Moreover, these interventions require a commitment from the patient, at least in the short term, to allow the establishment of a therapeutic relationship between the clinician and the patient and aid compliance over the longer term.

“Patients with AUD remain reluctant to pursue treatment,” the authors write, “and a large-scale effort to improve knowledge gaps in regard to AUD treatment and its success is needed, both from patients’ primary care providers and their consultants.”

Dr. Shetty explained that patient engagement is “probably the most challenging aspect of the disease, especially the alcohol use disorder part.”

This is partly because patients often lack insight, and alcohol addiction carries stigma and shame, as well as self-blame, he said, and so patients will “often delay pursuing any therapy ... even when they are sick.”

Dr. Shetty believes that reducing the stigma around alcohol addiction will require better education of patients and health care providers. To that end, he noted that the scientific literature now avoids the pejorative “alcoholic” and instead describes alcohol use as a disorder rather than having it define the patient.

“But this educational aspect is going to take a long time to really take effect, so from a provider perspective ... it is important to be open-minded when seeing these patients,” he said. This means not focusing on “the medical aspect alone but trying to really see the person who’s come to you for help and understand their motivations for pursing medical care.”

“Despite all these things, some patients may still find it very challenging and awkward. It takes several visits to really establish a rapport with them and get a sense of how to get them to share the challenging aspects of the disease,” Dr. Shetty added.
 

Multidisciplinary management for optimal outcomes

In a comment, Nancy S. Reau, MD, chair of hepatology, Rush Medical College, Chicago, agreed with the need to address both the risk for hepatic decompensation and AUD, the benefits of multidisciplinary management of patients, and the importance of patient engagement to successful outcomes.

“As hepatologists, we are often best at managing liver disease, but if you don’t also address the alcohol use disorder, the patient will not have the optimal outcome,” she said in an interview. “Most patients with severe AH have cirrhosis, [which] makes longitudinal follow-up imperative.”

“They are at risk for liver complications but also need aggressive nutritional support and management of their addiction,” she said. “As they improve, they can usually continue intensive treatment.”

Akhil Anand, MD, an addiction psychiatrist and co-director of the Multidisciplinary Alcohol Program at the Cleveland Clinic, also noted the increase in cases of alcohol-associated hepatitis from rising alcohol use.

The review “provides a timely, comprehensive, and impartial overview” of how to manage the condition, he said, as well as “how to treat co-occurring alcohol use disorder in this life-threatening situation.”

No funding was declared. The authors report no relevant financial relationships.

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

Patients with severe alcohol-associated hepatitis (AH) need treatment for both their liver disease and their underlying alcohol use disorder (AUD), concludes a review discussing care for patients recently hospitalized.

“Probably the biggest thing I would want providers to take away from the review is to remember that these patients are likely to carry a dual diagnosis,” said lead author Akshay Shetty, MD, Pfleger Liver Institute, UCLA Medical Center.

“It is important to address the liver disease, because it probably carries the biggest mortality and morbidity risk in the short term, but we have to remember to treat their alcohol use disorder simultaneously,” Dr. Shetty said.

The guidance by Dr. Shetty and coauthors was published online in the Journal of Clinical Gastroenterology.
 

More alcohol misuse means more liver disease

AH is a “unique, severe form of alcohol-associated steatohepatitis that is seen in the background of recent heavy alcohol use,” the team writes. Patients with severe AH have faced mortality rates as high as 20%-50%. A recent study reported a drop in 30-day mortality rates to 17%, which the authors credit to improved supportive medical management.

Alcohol misuse has surged over the past two decades, which experts believe will lead to a rise in alcohol-related liver disease, including AH hospitalization, the authors note. Rates of high-risk drinking in the United States (four or more drinks daily for women, five or more for men) increased by almost 30% between 2002 and 2012, particularly among women and ethnic minorities.

At the same time, rates of AUD rose 25% among young adults. In 2019, a U.S. survey found 14.5 million people aged 12 years and older in the United States carried an AUD diagnosis.

Meanwhile, the U.S. National Inpatient Sample revealed a 28.3% rise in AH-related hospitalizations between 2007 and 2014.

“AH patients carry a high short-term mortality [and] require close outpatient monitoring and significant care coordination,” write the authors. Despite the rising rates of severe AH, there is a lack of standardized guidance on post-discharge management, which motivated their clinical care review.
 

Liver disease shapes short-term outcomes

The management of patients with a recent episode of severe AH requires a two-pronged approach and shared patient management between gastroenterologists/hepatologists and addiction specialists. The multidisciplinary management both improves outcomes and is linked to reduced health care costs, the authors write.

While abstinence from alcohol remains essential to recovery, the authors note, it is the “severity of hepatic decompensation that has been shown to dictate short-term mortality in the initial 6 months” following discharge.

The team created an outpatient algorithm that divides patient care into two main areas: hepatic decompensation and AUD.

For the risk of hepatic decompensation, patients should undergo close monitoring for infections and frequent laboratory tests in the months following discharge.

Moreover, the “majority of patients with severe AH usually have background cirrhosis and are at risk of portal hypertensive decompensations similar to cirrhosis,” the authors write, and so patients should be assessed for hepatic encephalopathy, as well as for ascites and variceal bleeding.

For HE, the authors recommend a low threshold for treatment initiation with lactulose (a colonic acidifier) and the antibiotic rifaximin, but they suggest that ascites management “should be conservative ... with strict adherence to a low-sodium diet as the first-line approach.”

A key problem among severe AH patients post-discharge is malnutrition, which reaches 100% prevalence and is associated with the severity of liver disease, including decompensation and mortality, they note.

Patients with malnutrition are at risk of entering a catabolic starvation state. The authors recommend avoiding long fasting periods with multiple small meals and late evening snacks.

Long-term, severe AH patients should be assessed for advanced fibrosis, although early diagnosis is often challenging, as the clinical and laboratory results typically mimic findings of liver cirrhosis, the authors write.

Crucially, patients should be considered for early referral for liver transplantation, because early liver transplantation is associated with “excellent transplant outcomes and is noninferior when compared with other etiologies of chronic liver disease,” they write.
 

Long-term risk rests on preventing alcohol relapse

Turning to AUD, the team notes that long-term outcomes among AH patients depend on the prevention of alcohol relapse, because alcohol use among these patients is directly linked to higher rates of mortality and decompensation.

The authors concede that the “definition of relapse remains a matter of contention, especially in the post-liver transplant population,” but they recommend complete abstinence for patients recovering from AH and define relapse as any use of alcohol.

Dr. Shetty explained that “often, the focus tends to be on the acute threats to a patient’s life, so their liver disease tends to be emphasized, and we often forget why patients present with the liver disease in the first place.”

He continued: “So we do our best to address the liver disease and not a lot gets done for the alcohol-use disorder that the patient may have in the background. The expectation is that, if the doctors help patients with their liver disease, the patients will learn that lesson on their own and stop drinking.”

Instead, Dr. Shetty and his colleagues advise, all patients should be screened for AUD and undergo surveillance with alcohol biomarkers monthly at first. Patients should also be referred to an addiction specialist, where some combination of psychotherapy, mutual support groups, and pharmacotherapy can be tailored to individual patient needs and access.

Multidisciplinary management, comprising hepatology, psychiatry, psychologist, nurse, and social worker consults, has shown “promising results in the management of AUD, improvement in liver disease, and decrease in health care burden,” the authors write, although “multidisciplinary clinics often carry financial and administrative barriers to broad application.”

Moreover, these interventions require a commitment from the patient, at least in the short term, to allow the establishment of a therapeutic relationship between the clinician and the patient and aid compliance over the longer term.

“Patients with AUD remain reluctant to pursue treatment,” the authors write, “and a large-scale effort to improve knowledge gaps in regard to AUD treatment and its success is needed, both from patients’ primary care providers and their consultants.”

Dr. Shetty explained that patient engagement is “probably the most challenging aspect of the disease, especially the alcohol use disorder part.”

This is partly because patients often lack insight, and alcohol addiction carries stigma and shame, as well as self-blame, he said, and so patients will “often delay pursuing any therapy ... even when they are sick.”

Dr. Shetty believes that reducing the stigma around alcohol addiction will require better education of patients and health care providers. To that end, he noted that the scientific literature now avoids the pejorative “alcoholic” and instead describes alcohol use as a disorder rather than having it define the patient.

“But this educational aspect is going to take a long time to really take effect, so from a provider perspective ... it is important to be open-minded when seeing these patients,” he said. This means not focusing on “the medical aspect alone but trying to really see the person who’s come to you for help and understand their motivations for pursing medical care.”

“Despite all these things, some patients may still find it very challenging and awkward. It takes several visits to really establish a rapport with them and get a sense of how to get them to share the challenging aspects of the disease,” Dr. Shetty added.
 

Multidisciplinary management for optimal outcomes

In a comment, Nancy S. Reau, MD, chair of hepatology, Rush Medical College, Chicago, agreed with the need to address both the risk for hepatic decompensation and AUD, the benefits of multidisciplinary management of patients, and the importance of patient engagement to successful outcomes.

“As hepatologists, we are often best at managing liver disease, but if you don’t also address the alcohol use disorder, the patient will not have the optimal outcome,” she said in an interview. “Most patients with severe AH have cirrhosis, [which] makes longitudinal follow-up imperative.”

“They are at risk for liver complications but also need aggressive nutritional support and management of their addiction,” she said. “As they improve, they can usually continue intensive treatment.”

Akhil Anand, MD, an addiction psychiatrist and co-director of the Multidisciplinary Alcohol Program at the Cleveland Clinic, also noted the increase in cases of alcohol-associated hepatitis from rising alcohol use.

The review “provides a timely, comprehensive, and impartial overview” of how to manage the condition, he said, as well as “how to treat co-occurring alcohol use disorder in this life-threatening situation.”

No funding was declared. The authors report no relevant financial relationships.

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

TOPLINE:

Direct oral anticoagulants (DOACs) are associated with a reduced risk of venous thromboembolism (VTE), major bleeding, and mortality for cancer patients with VTE in comparison with low-molecular-weight heparin (LMWH), according to a recent analysis of U.S. claims data.

METHODOLOGY:

• This retrospective cohort study of electronic records claims data from OptumLabs included adults with an active primary cancer and acute VTE.
• Patients had filled an anticoagulation prescription within 30 days of VTE onset and were categorized on the basis of the anticoagulant prescribed: DOAC, LMWH, or warfarin.
• Patients were followed until the end of treatment. VTE recurrence and all-cause mortality were the main efficacy endpoints, and major bleeding episodes and bleeding sites were the main safety endpoints.
• Overall, 5,100 patients were included (mean age, 66.3 years); a majority (69.8%) were White, 15.7% were Black, and 7.6% were Hispanic. The patients had a range of cancer types, including lung, colorectal, gynecologic, and urologic.
• Nearly half of patients (49.3%) filled prescriptions for DOACs, 29.2% for LMWH, and 28.6% for warfarin.

TAKEAWAY:

• Compared with DOACs, LMWH and warfarin were associated with an increased risk of VTE recurrence (hazard ratio, 1.47 and 1.46, respectively).
• LMWH use was associated with an increased risk of major bleeding (HR, 2.27) and all-cause mortality (HR, 1.61), compared with DOAC use; mortality rates did not differ significantly between warfarin and DOACs (HR, 1.19; 95% confidence interval, 0.85-1.68).
• Patients who received LMWH were at increased risk of hospitalization for major bleeding, GI bleeding, and intracranial bleeding, compared with those who received DOACs (HR, 2.27, 1.72, 2.72, respectively).
• The risks of hospitalization for major bleeding, GI bleeding, and intracranial bleeding among patients who received warfarin and DOACs were similar (HR, 1.12, 1.03, 1.04, respectively).

IN PRACTICE:

Consistent with recent trials, “these data reinforce the general efficacy and safety of DOACs in this patient population” and reveal an association between DOACs and reduced all-cause mortality, the study authors wrote. These data may “help facilitate shared decision-marking and inform clinical guidelines for the treatment of such patients.”

SOURCE:

The study, led by Irbaz Bin Riaz, MD, PhD, of Mayo Clinic, Phoenix, Ariz., was published online in JAMA Network Open on July 24.

LIMITATIONS:

The study is limited by the potential for information bias in the database, the use of ICD codes to identify VTE patients, and the lack of radiologic evidence for VTE, as well as the lack of assessment for clinically relevant nonmajor bleeding.

The use of U.S. claims data limits the applicability of the results to other populations, including the uninsured.
 

DISCLOSURES:

No funding was declared. The authors have disclosed no relevant financial relationships.

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

TOPLINE:

Direct oral anticoagulants (DOACs) are associated with a reduced risk of venous thromboembolism (VTE), major bleeding, and mortality for cancer patients with VTE in comparison with low-molecular-weight heparin (LMWH), according to a recent analysis of U.S. claims data.

METHODOLOGY:

• This retrospective cohort study of electronic records claims data from OptumLabs included adults with an active primary cancer and acute VTE.
• Patients had filled an anticoagulation prescription within 30 days of VTE onset and were categorized on the basis of the anticoagulant prescribed: DOAC, LMWH, or warfarin.
• Patients were followed until the end of treatment. VTE recurrence and all-cause mortality were the main efficacy endpoints, and major bleeding episodes and bleeding sites were the main safety endpoints.
• Overall, 5,100 patients were included (mean age, 66.3 years); a majority (69.8%) were White, 15.7% were Black, and 7.6% were Hispanic. The patients had a range of cancer types, including lung, colorectal, gynecologic, and urologic.
• Nearly half of patients (49.3%) filled prescriptions for DOACs, 29.2% for LMWH, and 28.6% for warfarin.

TAKEAWAY:

• Compared with DOACs, LMWH and warfarin were associated with an increased risk of VTE recurrence (hazard ratio, 1.47 and 1.46, respectively).
• LMWH use was associated with an increased risk of major bleeding (HR, 2.27) and all-cause mortality (HR, 1.61), compared with DOAC use; mortality rates did not differ significantly between warfarin and DOACs (HR, 1.19; 95% confidence interval, 0.85-1.68).
• Patients who received LMWH were at increased risk of hospitalization for major bleeding, GI bleeding, and intracranial bleeding, compared with those who received DOACs (HR, 2.27, 1.72, 2.72, respectively).
• The risks of hospitalization for major bleeding, GI bleeding, and intracranial bleeding among patients who received warfarin and DOACs were similar (HR, 1.12, 1.03, 1.04, respectively).

IN PRACTICE:

Consistent with recent trials, “these data reinforce the general efficacy and safety of DOACs in this patient population” and reveal an association between DOACs and reduced all-cause mortality, the study authors wrote. These data may “help facilitate shared decision-marking and inform clinical guidelines for the treatment of such patients.”

SOURCE:

The study, led by Irbaz Bin Riaz, MD, PhD, of Mayo Clinic, Phoenix, Ariz., was published online in JAMA Network Open on July 24.

LIMITATIONS:

The study is limited by the potential for information bias in the database, the use of ICD codes to identify VTE patients, and the lack of radiologic evidence for VTE, as well as the lack of assessment for clinically relevant nonmajor bleeding.

The use of U.S. claims data limits the applicability of the results to other populations, including the uninsured.
 

DISCLOSURES:

No funding was declared. The authors have disclosed no relevant financial relationships.

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

TOPLINE:

Direct oral anticoagulants (DOACs) are associated with a reduced risk of venous thromboembolism (VTE), major bleeding, and mortality for cancer patients with VTE in comparison with low-molecular-weight heparin (LMWH), according to a recent analysis of U.S. claims data.

METHODOLOGY:

• This retrospective cohort study of electronic records claims data from OptumLabs included adults with an active primary cancer and acute VTE.
• Patients had filled an anticoagulation prescription within 30 days of VTE onset and were categorized on the basis of the anticoagulant prescribed: DOAC, LMWH, or warfarin.
• Patients were followed until the end of treatment. VTE recurrence and all-cause mortality were the main efficacy endpoints, and major bleeding episodes and bleeding sites were the main safety endpoints.
• Overall, 5,100 patients were included (mean age, 66.3 years); a majority (69.8%) were White, 15.7% were Black, and 7.6% were Hispanic. The patients had a range of cancer types, including lung, colorectal, gynecologic, and urologic.
• Nearly half of patients (49.3%) filled prescriptions for DOACs, 29.2% for LMWH, and 28.6% for warfarin.

TAKEAWAY:

• Compared with DOACs, LMWH and warfarin were associated with an increased risk of VTE recurrence (hazard ratio, 1.47 and 1.46, respectively).
• LMWH use was associated with an increased risk of major bleeding (HR, 2.27) and all-cause mortality (HR, 1.61), compared with DOAC use; mortality rates did not differ significantly between warfarin and DOACs (HR, 1.19; 95% confidence interval, 0.85-1.68).
• Patients who received LMWH were at increased risk of hospitalization for major bleeding, GI bleeding, and intracranial bleeding, compared with those who received DOACs (HR, 2.27, 1.72, 2.72, respectively).
• The risks of hospitalization for major bleeding, GI bleeding, and intracranial bleeding among patients who received warfarin and DOACs were similar (HR, 1.12, 1.03, 1.04, respectively).

IN PRACTICE:

Consistent with recent trials, “these data reinforce the general efficacy and safety of DOACs in this patient population” and reveal an association between DOACs and reduced all-cause mortality, the study authors wrote. These data may “help facilitate shared decision-marking and inform clinical guidelines for the treatment of such patients.”

SOURCE:

The study, led by Irbaz Bin Riaz, MD, PhD, of Mayo Clinic, Phoenix, Ariz., was published online in JAMA Network Open on July 24.

LIMITATIONS:

The study is limited by the potential for information bias in the database, the use of ICD codes to identify VTE patients, and the lack of radiologic evidence for VTE, as well as the lack of assessment for clinically relevant nonmajor bleeding.

The use of U.S. claims data limits the applicability of the results to other populations, including the uninsured.
 

DISCLOSURES:

No funding was declared. The authors have disclosed no relevant financial relationships.

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

Retinal thickness may be a potential biomarker for predicting disability for patients newly diagnosed with relapsing multiple sclerosis (MS), new research suggests.

The researchers measured retinal thickness using optical coherence tomography (OCT) within 3 months of diagnosis for more than 230 patients with MS and found that thinning of the retina was associated with a more than fourfold increased risk of Expanded Disability Status Scale (EDSS) scores of at least 3.0.

The OCT “basically tells you how much nerve layer is left in the glass,” said study investigator Gabriel Bsteh, MD, PhD, department of neurology, Medical University of Vienna.

This “could potentially inform treatment strategies, but that is another direction which will be investigated hopefully in the near future,” he added. However, the imaging technique cannot be used for all patients and is currently not widely available.

Dr. Bsteh presented the results at the annual meeting of the European Academy of Neurology.


 

Retinal layers of interest

OCT produces images of the retina and measures its thickness, Dr. Bsteh explained. Of greatest interest and relevance to patients with MS are two layers – the peripapillary retinal nerve fiber layer (pRNFL) and the ganglion cell and inner plexiform layer (GCL), which are associated with “future physical and cognitive disability and brain atrophy, and are reliable biomarkers of axonal damage.”

However, he said, what is not yet known is whether the baseline thickness of these two layers independently predicts progression of disability in patients with newly diagnosed disease within the framework of all of the other known risk factors.

To investigate, the team used data from ViennOCTiMS, an ongoing prospective observational cohort study conducted in Vienna and Innsbruck. For the analysis, they included patients newly diagnosed with relapsing MS using the 2017 McDonald criteria.

Study participants were required to undergo a spectral-domain OCT scan within 90 days of diagnosis and within 270 days of symptom onset. They also had to undergo follow-up of at least 12 months.

Among 231 patients included in the study, 74 were female, and the mean age was 30.3 years.

Dr. Bsteh noted that disease duration was short. There was a median of 45 days between initial diagnosis and the OCT scan. The median number of T2 lesions on MRI was 11, with 59.3% of patients had at least 10 lesions.

At baseline, 13.0% of patients were not receiving drug therapy, although they were advised to do so, said Dr. Bsteh. A total of 59.7% of patients received “moderately effective” disease-modifying treatments, while 27.3% were treated with “highly effective” DMTs.
 

Independent predictors of disability

To determine the contribution of retinal thickness to the risk of developing EDSS of 3.0 or more, the researchers conducted a multivariate analysis that accounted for patient age and sex, the type of first relapse, the remission of first relapse symptoms, the presence of oligoclonal bands, the baseline number of T2 lesions, and the use and type of DMT.

After approximately 96 months of follow-up, a pRNFL thickness of 88 mcm or less at baseline was associated with a hazard ratio for EDSS of at least 3.0 versus a thickness of greater than 88 mcm of 4.0 (P < .001), Dr. Bsteh reported.

Similarly, a GCL thickness of less than 77 mcm at baseline was associated with a HR for EDSS of at least 3.0 of 5.1 (P < .001).

Subgroup analysis indicated that both measures of retinal thickness were indeed independent predictors of EDSS. Dr. Bsteh said: “It was encouraging to see that all the unknown prognostic factor factors performed within the expected framework.”

For example, there was a notable association between the risk of EDSS of at least 3.0 and patient age, as well as with incomplete remission and a greater number of lesions on MRI.

Dr. Bsteh said it was also “very encouraging” to find that high-efficacy DMT was associated with a reduced risk of EDSS of at least 3.0.
 

Strengths, limitations

Turning to the relatively recently described progression independent of relapse activity, Dr. Bsteh showed that both pRNFL of 88 mcm or less and GCL less than 77 mcm were significantly associated with the development of PIRA, compared with greater thickness, at HRs of 3.1 and 4.1, respectively (P < .001 for both).

Subgroup analysis again supported the independent contribution of retinal thickness to the risk of PIRA and revealed similar associations with known risk factors, although the contribution of highly effective DMT was of borderline significance for this outcome.

Interestingly, neither pRNFL of 88 mcm or less nor GCL less than 77 mcm was significantly associated with the time to second clinical attack, “which is basically the correlation of the inflammatory activity” in MS, said Dr. Bsteh.

This, he continued, “goes back to the basic theory that EDSS, PIRA, and neurodegenerative problems are associated with the OCT but not the degree of inflammatory activity.

“As good as all that sounds, there are of course, some limitations” to the study, Dr. Bsteh acknowledged.

The most important limitation is that the changes measured on OCT were “not specific to multiple sclerosis,” and the thickness of the layers “can be influenced by a lot of other factors,” in particular by eye conditions such as glaucoma and diabetes mellitus.

In addition, OCT is not reliable for patients with myopia of more than four to six diopters and for those with retinal comorbidities, such as optic drusen. Dr. Bsteh also pointed out that automatic segmentation in OCT requires stringent quality control.

However, the “biggest problem for the deployment of OCT in the clinical routine is its lack of availability. It’s not very easy for neurologists to procure an OCT,” said Dr. Bsteh.

“You can always create it with your ophthalmologist of trust, but you have to know what you’re looking for,” he added.
 

Important research

Commenting on the study, Giancarlo Comi, MD, honorary professor of neurology at the Università Vita Salute San Raffaele and founder and director of the Institute of Experimental Neurology at the Scientific Institute San Raffaele, both in Milan, characterized the research as “very, very important and interesting.”

However, he said that he was a “bit surprised” that it showed no association between OCT measures and the second clinical attack, noting that longitudinal research by his team found such an association.

Dr. Comi added that the “key point” from the current study is that there was no such association in the early phase of the disease, which suggests that the amount of inflammatory activity “is not so relevant” in determining the degree of damage seen on OCT at that point.

Dr. Bsteh said he partially agreed with Dr. Comi, adding that “it depends on what you adjust for.

“If we did the same analysis without adjusting for the number of MRI lesions, we would see an association with second clinical attack,” he said. However, the aim of the current study was to determine the independent contribution of retinal thickness, “and that’s why we tried to adjust to everything which was available to us.”

Dr. Bsteh also underlined that it was a cross-sectional analysis conducted “very, very early” in the MS disease course, and “so the inflammatory activity did not yet have a chance to influence the thickness on the OCT.”

Had OCT been performed later in the disease course, inflammatory activity might have influenced the findings, but the intention of the study was to use it “as an early marker to try to stratify patients who are at risk, and [those] who are maybe a little less at risk, and inform the treatment strategy.”

Maria Assunta Rocca, MD, associate professor of neurology at Università Vita Salute San Raffaele, and head of neuroimaging of the CNS white matter unit at IRCCS San Raffaele Scientific Institute, Milan, who cochaired the session in which the study was presented, asked whether the researchers analyzed patients with optic neuritis separately from those without and whether it affected the predictive factors.

Dr. Bsteh said that OCT cannot be used for patients with bilateral optic neuritis and so they were excluded from the study, but for patients who were affected unilaterally, the contralateral eye was assessed.

This underlines why OCT contributes the most when used early on the disease course. “The longer the disease has time, the higher the likelihood that optic neuritis has developed,” he said.

Funding for the study was provided by Mindset Technologies. All authors are, or were, employees and/or shareholders of Mindset Technologies. Dr. Bsteh has relationships with Biogen, Celgene/Bristol-Myers Squibb, Lilly, Merck, Novartis, Roche, Sanofi Genzyme, and Teva.

A version of this article appeared on Medscape.com.

Retinal thickness may be a potential biomarker for predicting disability for patients newly diagnosed with relapsing multiple sclerosis (MS), new research suggests.

The researchers measured retinal thickness using optical coherence tomography (OCT) within 3 months of diagnosis for more than 230 patients with MS and found that thinning of the retina was associated with a more than fourfold increased risk of Expanded Disability Status Scale (EDSS) scores of at least 3.0.

The OCT “basically tells you how much nerve layer is left in the glass,” said study investigator Gabriel Bsteh, MD, PhD, department of neurology, Medical University of Vienna.

This “could potentially inform treatment strategies, but that is another direction which will be investigated hopefully in the near future,” he added. However, the imaging technique cannot be used for all patients and is currently not widely available.

Dr. Bsteh presented the results at the annual meeting of the European Academy of Neurology.


 

Retinal layers of interest

OCT produces images of the retina and measures its thickness, Dr. Bsteh explained. Of greatest interest and relevance to patients with MS are two layers – the peripapillary retinal nerve fiber layer (pRNFL) and the ganglion cell and inner plexiform layer (GCL), which are associated with “future physical and cognitive disability and brain atrophy, and are reliable biomarkers of axonal damage.”

However, he said, what is not yet known is whether the baseline thickness of these two layers independently predicts progression of disability in patients with newly diagnosed disease within the framework of all of the other known risk factors.

To investigate, the team used data from ViennOCTiMS, an ongoing prospective observational cohort study conducted in Vienna and Innsbruck. For the analysis, they included patients newly diagnosed with relapsing MS using the 2017 McDonald criteria.

Study participants were required to undergo a spectral-domain OCT scan within 90 days of diagnosis and within 270 days of symptom onset. They also had to undergo follow-up of at least 12 months.

Among 231 patients included in the study, 74 were female, and the mean age was 30.3 years.

Dr. Bsteh noted that disease duration was short. There was a median of 45 days between initial diagnosis and the OCT scan. The median number of T2 lesions on MRI was 11, with 59.3% of patients had at least 10 lesions.

At baseline, 13.0% of patients were not receiving drug therapy, although they were advised to do so, said Dr. Bsteh. A total of 59.7% of patients received “moderately effective” disease-modifying treatments, while 27.3% were treated with “highly effective” DMTs.
 

Independent predictors of disability

To determine the contribution of retinal thickness to the risk of developing EDSS of 3.0 or more, the researchers conducted a multivariate analysis that accounted for patient age and sex, the type of first relapse, the remission of first relapse symptoms, the presence of oligoclonal bands, the baseline number of T2 lesions, and the use and type of DMT.

After approximately 96 months of follow-up, a pRNFL thickness of 88 mcm or less at baseline was associated with a hazard ratio for EDSS of at least 3.0 versus a thickness of greater than 88 mcm of 4.0 (P < .001), Dr. Bsteh reported.

Similarly, a GCL thickness of less than 77 mcm at baseline was associated with a HR for EDSS of at least 3.0 of 5.1 (P < .001).

Subgroup analysis indicated that both measures of retinal thickness were indeed independent predictors of EDSS. Dr. Bsteh said: “It was encouraging to see that all the unknown prognostic factor factors performed within the expected framework.”

For example, there was a notable association between the risk of EDSS of at least 3.0 and patient age, as well as with incomplete remission and a greater number of lesions on MRI.

Dr. Bsteh said it was also “very encouraging” to find that high-efficacy DMT was associated with a reduced risk of EDSS of at least 3.0.
 

Strengths, limitations

Turning to the relatively recently described progression independent of relapse activity, Dr. Bsteh showed that both pRNFL of 88 mcm or less and GCL less than 77 mcm were significantly associated with the development of PIRA, compared with greater thickness, at HRs of 3.1 and 4.1, respectively (P < .001 for both).

Subgroup analysis again supported the independent contribution of retinal thickness to the risk of PIRA and revealed similar associations with known risk factors, although the contribution of highly effective DMT was of borderline significance for this outcome.

Interestingly, neither pRNFL of 88 mcm or less nor GCL less than 77 mcm was significantly associated with the time to second clinical attack, “which is basically the correlation of the inflammatory activity” in MS, said Dr. Bsteh.

This, he continued, “goes back to the basic theory that EDSS, PIRA, and neurodegenerative problems are associated with the OCT but not the degree of inflammatory activity.

“As good as all that sounds, there are of course, some limitations” to the study, Dr. Bsteh acknowledged.

The most important limitation is that the changes measured on OCT were “not specific to multiple sclerosis,” and the thickness of the layers “can be influenced by a lot of other factors,” in particular by eye conditions such as glaucoma and diabetes mellitus.

In addition, OCT is not reliable for patients with myopia of more than four to six diopters and for those with retinal comorbidities, such as optic drusen. Dr. Bsteh also pointed out that automatic segmentation in OCT requires stringent quality control.

However, the “biggest problem for the deployment of OCT in the clinical routine is its lack of availability. It’s not very easy for neurologists to procure an OCT,” said Dr. Bsteh.

“You can always create it with your ophthalmologist of trust, but you have to know what you’re looking for,” he added.
 

Important research

Commenting on the study, Giancarlo Comi, MD, honorary professor of neurology at the Università Vita Salute San Raffaele and founder and director of the Institute of Experimental Neurology at the Scientific Institute San Raffaele, both in Milan, characterized the research as “very, very important and interesting.”

However, he said that he was a “bit surprised” that it showed no association between OCT measures and the second clinical attack, noting that longitudinal research by his team found such an association.

Dr. Comi added that the “key point” from the current study is that there was no such association in the early phase of the disease, which suggests that the amount of inflammatory activity “is not so relevant” in determining the degree of damage seen on OCT at that point.

Dr. Bsteh said he partially agreed with Dr. Comi, adding that “it depends on what you adjust for.

“If we did the same analysis without adjusting for the number of MRI lesions, we would see an association with second clinical attack,” he said. However, the aim of the current study was to determine the independent contribution of retinal thickness, “and that’s why we tried to adjust to everything which was available to us.”

Dr. Bsteh also underlined that it was a cross-sectional analysis conducted “very, very early” in the MS disease course, and “so the inflammatory activity did not yet have a chance to influence the thickness on the OCT.”

Had OCT been performed later in the disease course, inflammatory activity might have influenced the findings, but the intention of the study was to use it “as an early marker to try to stratify patients who are at risk, and [those] who are maybe a little less at risk, and inform the treatment strategy.”

Maria Assunta Rocca, MD, associate professor of neurology at Università Vita Salute San Raffaele, and head of neuroimaging of the CNS white matter unit at IRCCS San Raffaele Scientific Institute, Milan, who cochaired the session in which the study was presented, asked whether the researchers analyzed patients with optic neuritis separately from those without and whether it affected the predictive factors.

Dr. Bsteh said that OCT cannot be used for patients with bilateral optic neuritis and so they were excluded from the study, but for patients who were affected unilaterally, the contralateral eye was assessed.

This underlines why OCT contributes the most when used early on the disease course. “The longer the disease has time, the higher the likelihood that optic neuritis has developed,” he said.

Funding for the study was provided by Mindset Technologies. All authors are, or were, employees and/or shareholders of Mindset Technologies. Dr. Bsteh has relationships with Biogen, Celgene/Bristol-Myers Squibb, Lilly, Merck, Novartis, Roche, Sanofi Genzyme, and Teva.

A version of this article appeared on Medscape.com.

Retinal thickness may be a potential biomarker for predicting disability for patients newly diagnosed with relapsing multiple sclerosis (MS), new research suggests.

The researchers measured retinal thickness using optical coherence tomography (OCT) within 3 months of diagnosis for more than 230 patients with MS and found that thinning of the retina was associated with a more than fourfold increased risk of Expanded Disability Status Scale (EDSS) scores of at least 3.0.

The OCT “basically tells you how much nerve layer is left in the glass,” said study investigator Gabriel Bsteh, MD, PhD, department of neurology, Medical University of Vienna.

This “could potentially inform treatment strategies, but that is another direction which will be investigated hopefully in the near future,” he added. However, the imaging technique cannot be used for all patients and is currently not widely available.

Dr. Bsteh presented the results at the annual meeting of the European Academy of Neurology.


 

Retinal layers of interest

OCT produces images of the retina and measures its thickness, Dr. Bsteh explained. Of greatest interest and relevance to patients with MS are two layers – the peripapillary retinal nerve fiber layer (pRNFL) and the ganglion cell and inner plexiform layer (GCL), which are associated with “future physical and cognitive disability and brain atrophy, and are reliable biomarkers of axonal damage.”

However, he said, what is not yet known is whether the baseline thickness of these two layers independently predicts progression of disability in patients with newly diagnosed disease within the framework of all of the other known risk factors.

To investigate, the team used data from ViennOCTiMS, an ongoing prospective observational cohort study conducted in Vienna and Innsbruck. For the analysis, they included patients newly diagnosed with relapsing MS using the 2017 McDonald criteria.

Study participants were required to undergo a spectral-domain OCT scan within 90 days of diagnosis and within 270 days of symptom onset. They also had to undergo follow-up of at least 12 months.

Among 231 patients included in the study, 74 were female, and the mean age was 30.3 years.

Dr. Bsteh noted that disease duration was short. There was a median of 45 days between initial diagnosis and the OCT scan. The median number of T2 lesions on MRI was 11, with 59.3% of patients had at least 10 lesions.

At baseline, 13.0% of patients were not receiving drug therapy, although they were advised to do so, said Dr. Bsteh. A total of 59.7% of patients received “moderately effective” disease-modifying treatments, while 27.3% were treated with “highly effective” DMTs.
 

Independent predictors of disability

To determine the contribution of retinal thickness to the risk of developing EDSS of 3.0 or more, the researchers conducted a multivariate analysis that accounted for patient age and sex, the type of first relapse, the remission of first relapse symptoms, the presence of oligoclonal bands, the baseline number of T2 lesions, and the use and type of DMT.

After approximately 96 months of follow-up, a pRNFL thickness of 88 mcm or less at baseline was associated with a hazard ratio for EDSS of at least 3.0 versus a thickness of greater than 88 mcm of 4.0 (P < .001), Dr. Bsteh reported.

Similarly, a GCL thickness of less than 77 mcm at baseline was associated with a HR for EDSS of at least 3.0 of 5.1 (P < .001).

Subgroup analysis indicated that both measures of retinal thickness were indeed independent predictors of EDSS. Dr. Bsteh said: “It was encouraging to see that all the unknown prognostic factor factors performed within the expected framework.”

For example, there was a notable association between the risk of EDSS of at least 3.0 and patient age, as well as with incomplete remission and a greater number of lesions on MRI.

Dr. Bsteh said it was also “very encouraging” to find that high-efficacy DMT was associated with a reduced risk of EDSS of at least 3.0.
 

Strengths, limitations

Turning to the relatively recently described progression independent of relapse activity, Dr. Bsteh showed that both pRNFL of 88 mcm or less and GCL less than 77 mcm were significantly associated with the development of PIRA, compared with greater thickness, at HRs of 3.1 and 4.1, respectively (P < .001 for both).

Subgroup analysis again supported the independent contribution of retinal thickness to the risk of PIRA and revealed similar associations with known risk factors, although the contribution of highly effective DMT was of borderline significance for this outcome.

Interestingly, neither pRNFL of 88 mcm or less nor GCL less than 77 mcm was significantly associated with the time to second clinical attack, “which is basically the correlation of the inflammatory activity” in MS, said Dr. Bsteh.

This, he continued, “goes back to the basic theory that EDSS, PIRA, and neurodegenerative problems are associated with the OCT but not the degree of inflammatory activity.

“As good as all that sounds, there are of course, some limitations” to the study, Dr. Bsteh acknowledged.

The most important limitation is that the changes measured on OCT were “not specific to multiple sclerosis,” and the thickness of the layers “can be influenced by a lot of other factors,” in particular by eye conditions such as glaucoma and diabetes mellitus.

In addition, OCT is not reliable for patients with myopia of more than four to six diopters and for those with retinal comorbidities, such as optic drusen. Dr. Bsteh also pointed out that automatic segmentation in OCT requires stringent quality control.

However, the “biggest problem for the deployment of OCT in the clinical routine is its lack of availability. It’s not very easy for neurologists to procure an OCT,” said Dr. Bsteh.

“You can always create it with your ophthalmologist of trust, but you have to know what you’re looking for,” he added.
 

Important research

Commenting on the study, Giancarlo Comi, MD, honorary professor of neurology at the Università Vita Salute San Raffaele and founder and director of the Institute of Experimental Neurology at the Scientific Institute San Raffaele, both in Milan, characterized the research as “very, very important and interesting.”

However, he said that he was a “bit surprised” that it showed no association between OCT measures and the second clinical attack, noting that longitudinal research by his team found such an association.

Dr. Comi added that the “key point” from the current study is that there was no such association in the early phase of the disease, which suggests that the amount of inflammatory activity “is not so relevant” in determining the degree of damage seen on OCT at that point.

Dr. Bsteh said he partially agreed with Dr. Comi, adding that “it depends on what you adjust for.

“If we did the same analysis without adjusting for the number of MRI lesions, we would see an association with second clinical attack,” he said. However, the aim of the current study was to determine the independent contribution of retinal thickness, “and that’s why we tried to adjust to everything which was available to us.”

Dr. Bsteh also underlined that it was a cross-sectional analysis conducted “very, very early” in the MS disease course, and “so the inflammatory activity did not yet have a chance to influence the thickness on the OCT.”

Had OCT been performed later in the disease course, inflammatory activity might have influenced the findings, but the intention of the study was to use it “as an early marker to try to stratify patients who are at risk, and [those] who are maybe a little less at risk, and inform the treatment strategy.”

Maria Assunta Rocca, MD, associate professor of neurology at Università Vita Salute San Raffaele, and head of neuroimaging of the CNS white matter unit at IRCCS San Raffaele Scientific Institute, Milan, who cochaired the session in which the study was presented, asked whether the researchers analyzed patients with optic neuritis separately from those without and whether it affected the predictive factors.

Dr. Bsteh said that OCT cannot be used for patients with bilateral optic neuritis and so they were excluded from the study, but for patients who were affected unilaterally, the contralateral eye was assessed.

This underlines why OCT contributes the most when used early on the disease course. “The longer the disease has time, the higher the likelihood that optic neuritis has developed,” he said.

Funding for the study was provided by Mindset Technologies. All authors are, or were, employees and/or shareholders of Mindset Technologies. Dr. Bsteh has relationships with Biogen, Celgene/Bristol-Myers Squibb, Lilly, Merck, Novartis, Roche, Sanofi Genzyme, and Teva.

A version of this article appeared on Medscape.com.

An unapproved gene therapy for Leber hereditary optic neuropathy (LHON) led to a marked improvement in the eyesight of patients with a severe, progressive form of the disease who received the therapy as part of an early access program.

Results of a study of more than 60 patients who received lenadogene nolparvovec (Lumevoq, GenSight Biologics) as a unilateral or bilateral intravitreal injection showed that at 2-year follow-up, 60% had experienced a clinically relevant improvement in the number of letters they could read on a visual acuity chart.

The results, said study presenter Chiara La Morgia, MD, PhD, IRCCS Istituto delle Scienze Neurologiche di Bologna (Italy), confirm in a “real-life setting” the efficacy and safety of the treatment as previously shown in clinical trials.

The findings were presented at the Congress of the European Academy of Neurology (EAN) 2023.
 

Severe disease

LHON is a maternally inherited genetic condition that leads to rapid loss of vision. It is caused by alterations in mitochondrial DNA that increase oxidative stress in retinal ganglion cells, leading to cell damage and death. The m.11778G>A MT-ND4 mutation (MT-ND4-LHON) is the most common and is seen in approximately 75% of LHON patients in Europe and North America.

It also leads to the most severe form of the disease, in which patients experience rapid, progressive, and painless bilateral loss of vision, either simultaneously or sequentially in both eyes. Within 1 year of onset, 97% of patients have bilateral involvement.

Lenadogene nolparvovec uses an adeno-associated virus vector to deliver the wild-type ND4 gene directly to the mitochondrial membrane of the retinal ganglion cells. This compensates for the mutation and leads to protein synthesis and restoration of energy production.

Dr. La Morgia said that, so far, five clinical studies are or have been conducted with the gene therapy with patients in France, Italy, the United Kingdom, and the United States.

In the current analysis, patients who received the therapy as part of an early access program underwent unilateral or bilateral intravitreal injection at a dose of 9x10¹⁰ viral genomes per eye. Efficacy and safety data, as well as patient baseline characteristics, were collected.

Between August 2018 and March 2022, 63 patients with MT-ND4-LHON received lenadogene nolparvovec. Individual-level data were pooled and analyzed. The mean age at first injection was 33.7 years; 90.5% of participants were aged 60 years or younger. The majority (77.8%) were male; just over half (55.6%) were from France, while 28.6% were from the United States.

The average disease duration at first injection was 11.3 years. Sixty-seven percent of patients were injected in both eyes, and 81.0% had previously received idebenone, a short-chain benzoquinone, the only treatment for LHON that has marketing authorization.

At 2-year follow-up, there was a marked improvement in best-corrected visual acuity (BCVA) scores. Moreover, among all 90 treated eyes for which data were available, the mean change in BCVA from nadir at 1 year was –0.45 log of the minimum angle of resolution (LogMAR), or +22.5 Early Treatment Diabetic Retinopathy Study (ETDRS) letters on a chart.

Among 58 bilaterally treated eyes, the mean improvement was –0.49 LogMAR, or +24.5 ETDRS letters, over the same period. In 32 unilaterally treated eyes, mean improvement was –0.39 LogMAR, or +19.5 ETDRS letters.

Overall, 64.4% of treated eyes showed an improvement from nadir of ≥ 0.3 LogMAR. A clinically relevant response, defined as an improvement of ≥ 10 ETDRS letters, was achieved by 60.0% of patients.

Regarding safety, Dr. La Morgia showed that 42.9% of eyes had at least one episode of intraocular inflammation, a rate she described as “quite high.” The episodes lasted for an average of 155.8 days.

“But all of this inflammation was very easily treatable in a majority of cases without using oral steroids,” she added, “just topical steroids.”

She also noted that in most cases, the inflammation was not severe.
 

Approval status

Session cochair Gianfranco De Stefano, MD, department of human neuroscience, Sapienza University of Rome, asked Dr. La Morgia about the current approval status of lenadogene nolparvovec.

She said that it was presented to the European Medicines Agency for approval, but the application was withdrawn earlier this year. The “main criticism” was that bilateral improvement was seen even in patients who received only a unilateral injection.

This is “not easily explainable,” said Dr. La Morgia, although it was found that the viral vector was present in the uninjected eye.

There was also a question regarding the heterogeneity of the patient data, which it is hoped will be addressed in future clinical trials.

Commenting after the session, De Stefano said in an interview that the results are “very interesting” and “very promising.”

He pointed out that idebenone may be the only currently available therapy for LHON, but it is “not very effective, and it’s something you give the patient just for the sake of doing something” in light of the possibility that he or she might have “even a small improvement” in eyesight.

However, he believes that lenadogene nolparvovec is a long way from becoming available in the clinic, primarily because longer follow-up is required to determine whether just one injection is enough.

“It may be likely that this gene therapy does not have a long-lasting effect,” he explained.

Currently, the longest follow-up is just 2 years; “I don’t know if there will be a need for repeat injection,” De Stefano said.

No funding was declared. Dr. La Morgia has relationships with Chiesi Farmaceutici, GenSight Biologics, Regulatory Pharma Net, Thenewway, Santhera Pharmaceuticals, First Class srl, Biologix, Stoke Therapeutics, and Reneo.

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

An unapproved gene therapy for Leber hereditary optic neuropathy (LHON) led to a marked improvement in the eyesight of patients with a severe, progressive form of the disease who received the therapy as part of an early access program.

Results of a study of more than 60 patients who received lenadogene nolparvovec (Lumevoq, GenSight Biologics) as a unilateral or bilateral intravitreal injection showed that at 2-year follow-up, 60% had experienced a clinically relevant improvement in the number of letters they could read on a visual acuity chart.

The results, said study presenter Chiara La Morgia, MD, PhD, IRCCS Istituto delle Scienze Neurologiche di Bologna (Italy), confirm in a “real-life setting” the efficacy and safety of the treatment as previously shown in clinical trials.

The findings were presented at the Congress of the European Academy of Neurology (EAN) 2023.
 

Severe disease

LHON is a maternally inherited genetic condition that leads to rapid loss of vision. It is caused by alterations in mitochondrial DNA that increase oxidative stress in retinal ganglion cells, leading to cell damage and death. The m.11778G>A MT-ND4 mutation (MT-ND4-LHON) is the most common and is seen in approximately 75% of LHON patients in Europe and North America.

It also leads to the most severe form of the disease, in which patients experience rapid, progressive, and painless bilateral loss of vision, either simultaneously or sequentially in both eyes. Within 1 year of onset, 97% of patients have bilateral involvement.

Lenadogene nolparvovec uses an adeno-associated virus vector to deliver the wild-type ND4 gene directly to the mitochondrial membrane of the retinal ganglion cells. This compensates for the mutation and leads to protein synthesis and restoration of energy production.

Dr. La Morgia said that, so far, five clinical studies are or have been conducted with the gene therapy with patients in France, Italy, the United Kingdom, and the United States.

In the current analysis, patients who received the therapy as part of an early access program underwent unilateral or bilateral intravitreal injection at a dose of 9x10¹⁰ viral genomes per eye. Efficacy and safety data, as well as patient baseline characteristics, were collected.

Between August 2018 and March 2022, 63 patients with MT-ND4-LHON received lenadogene nolparvovec. Individual-level data were pooled and analyzed. The mean age at first injection was 33.7 years; 90.5% of participants were aged 60 years or younger. The majority (77.8%) were male; just over half (55.6%) were from France, while 28.6% were from the United States.

The average disease duration at first injection was 11.3 years. Sixty-seven percent of patients were injected in both eyes, and 81.0% had previously received idebenone, a short-chain benzoquinone, the only treatment for LHON that has marketing authorization.

At 2-year follow-up, there was a marked improvement in best-corrected visual acuity (BCVA) scores. Moreover, among all 90 treated eyes for which data were available, the mean change in BCVA from nadir at 1 year was –0.45 log of the minimum angle of resolution (LogMAR), or +22.5 Early Treatment Diabetic Retinopathy Study (ETDRS) letters on a chart.

Among 58 bilaterally treated eyes, the mean improvement was –0.49 LogMAR, or +24.5 ETDRS letters, over the same period. In 32 unilaterally treated eyes, mean improvement was –0.39 LogMAR, or +19.5 ETDRS letters.

Overall, 64.4% of treated eyes showed an improvement from nadir of ≥ 0.3 LogMAR. A clinically relevant response, defined as an improvement of ≥ 10 ETDRS letters, was achieved by 60.0% of patients.

Regarding safety, Dr. La Morgia showed that 42.9% of eyes had at least one episode of intraocular inflammation, a rate she described as “quite high.” The episodes lasted for an average of 155.8 days.

“But all of this inflammation was very easily treatable in a majority of cases without using oral steroids,” she added, “just topical steroids.”

She also noted that in most cases, the inflammation was not severe.
 

Approval status

Session cochair Gianfranco De Stefano, MD, department of human neuroscience, Sapienza University of Rome, asked Dr. La Morgia about the current approval status of lenadogene nolparvovec.

She said that it was presented to the European Medicines Agency for approval, but the application was withdrawn earlier this year. The “main criticism” was that bilateral improvement was seen even in patients who received only a unilateral injection.

This is “not easily explainable,” said Dr. La Morgia, although it was found that the viral vector was present in the uninjected eye.

There was also a question regarding the heterogeneity of the patient data, which it is hoped will be addressed in future clinical trials.

Commenting after the session, De Stefano said in an interview that the results are “very interesting” and “very promising.”

He pointed out that idebenone may be the only currently available therapy for LHON, but it is “not very effective, and it’s something you give the patient just for the sake of doing something” in light of the possibility that he or she might have “even a small improvement” in eyesight.

However, he believes that lenadogene nolparvovec is a long way from becoming available in the clinic, primarily because longer follow-up is required to determine whether just one injection is enough.

“It may be likely that this gene therapy does not have a long-lasting effect,” he explained.

Currently, the longest follow-up is just 2 years; “I don’t know if there will be a need for repeat injection,” De Stefano said.

No funding was declared. Dr. La Morgia has relationships with Chiesi Farmaceutici, GenSight Biologics, Regulatory Pharma Net, Thenewway, Santhera Pharmaceuticals, First Class srl, Biologix, Stoke Therapeutics, and Reneo.

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

An unapproved gene therapy for Leber hereditary optic neuropathy (LHON) led to a marked improvement in the eyesight of patients with a severe, progressive form of the disease who received the therapy as part of an early access program.

Results of a study of more than 60 patients who received lenadogene nolparvovec (Lumevoq, GenSight Biologics) as a unilateral or bilateral intravitreal injection showed that at 2-year follow-up, 60% had experienced a clinically relevant improvement in the number of letters they could read on a visual acuity chart.

The results, said study presenter Chiara La Morgia, MD, PhD, IRCCS Istituto delle Scienze Neurologiche di Bologna (Italy), confirm in a “real-life setting” the efficacy and safety of the treatment as previously shown in clinical trials.

The findings were presented at the Congress of the European Academy of Neurology (EAN) 2023.
 

Severe disease

LHON is a maternally inherited genetic condition that leads to rapid loss of vision. It is caused by alterations in mitochondrial DNA that increase oxidative stress in retinal ganglion cells, leading to cell damage and death. The m.11778G>A MT-ND4 mutation (MT-ND4-LHON) is the most common and is seen in approximately 75% of LHON patients in Europe and North America.

It also leads to the most severe form of the disease, in which patients experience rapid, progressive, and painless bilateral loss of vision, either simultaneously or sequentially in both eyes. Within 1 year of onset, 97% of patients have bilateral involvement.

Lenadogene nolparvovec uses an adeno-associated virus vector to deliver the wild-type ND4 gene directly to the mitochondrial membrane of the retinal ganglion cells. This compensates for the mutation and leads to protein synthesis and restoration of energy production.

Dr. La Morgia said that, so far, five clinical studies are or have been conducted with the gene therapy with patients in France, Italy, the United Kingdom, and the United States.

In the current analysis, patients who received the therapy as part of an early access program underwent unilateral or bilateral intravitreal injection at a dose of 9x10¹⁰ viral genomes per eye. Efficacy and safety data, as well as patient baseline characteristics, were collected.

Between August 2018 and March 2022, 63 patients with MT-ND4-LHON received lenadogene nolparvovec. Individual-level data were pooled and analyzed. The mean age at first injection was 33.7 years; 90.5% of participants were aged 60 years or younger. The majority (77.8%) were male; just over half (55.6%) were from France, while 28.6% were from the United States.

The average disease duration at first injection was 11.3 years. Sixty-seven percent of patients were injected in both eyes, and 81.0% had previously received idebenone, a short-chain benzoquinone, the only treatment for LHON that has marketing authorization.

At 2-year follow-up, there was a marked improvement in best-corrected visual acuity (BCVA) scores. Moreover, among all 90 treated eyes for which data were available, the mean change in BCVA from nadir at 1 year was –0.45 log of the minimum angle of resolution (LogMAR), or +22.5 Early Treatment Diabetic Retinopathy Study (ETDRS) letters on a chart.

Among 58 bilaterally treated eyes, the mean improvement was –0.49 LogMAR, or +24.5 ETDRS letters, over the same period. In 32 unilaterally treated eyes, mean improvement was –0.39 LogMAR, or +19.5 ETDRS letters.

Overall, 64.4% of treated eyes showed an improvement from nadir of ≥ 0.3 LogMAR. A clinically relevant response, defined as an improvement of ≥ 10 ETDRS letters, was achieved by 60.0% of patients.

Regarding safety, Dr. La Morgia showed that 42.9% of eyes had at least one episode of intraocular inflammation, a rate she described as “quite high.” The episodes lasted for an average of 155.8 days.

“But all of this inflammation was very easily treatable in a majority of cases without using oral steroids,” she added, “just topical steroids.”

She also noted that in most cases, the inflammation was not severe.
 

Approval status

Session cochair Gianfranco De Stefano, MD, department of human neuroscience, Sapienza University of Rome, asked Dr. La Morgia about the current approval status of lenadogene nolparvovec.

She said that it was presented to the European Medicines Agency for approval, but the application was withdrawn earlier this year. The “main criticism” was that bilateral improvement was seen even in patients who received only a unilateral injection.

This is “not easily explainable,” said Dr. La Morgia, although it was found that the viral vector was present in the uninjected eye.

There was also a question regarding the heterogeneity of the patient data, which it is hoped will be addressed in future clinical trials.

Commenting after the session, De Stefano said in an interview that the results are “very interesting” and “very promising.”

He pointed out that idebenone may be the only currently available therapy for LHON, but it is “not very effective, and it’s something you give the patient just for the sake of doing something” in light of the possibility that he or she might have “even a small improvement” in eyesight.

However, he believes that lenadogene nolparvovec is a long way from becoming available in the clinic, primarily because longer follow-up is required to determine whether just one injection is enough.

“It may be likely that this gene therapy does not have a long-lasting effect,” he explained.

Currently, the longest follow-up is just 2 years; “I don’t know if there will be a need for repeat injection,” De Stefano said.

No funding was declared. Dr. La Morgia has relationships with Chiesi Farmaceutici, GenSight Biologics, Regulatory Pharma Net, Thenewway, Santhera Pharmaceuticals, First Class srl, Biologix, Stoke Therapeutics, and Reneo.

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

TOPLINE:

Patients with early-stage breast cancer who do not adhere to adjuvant endocrine therapy as prescribed or stop early may face as much as a twofold higher risk of relapse or death, a new systematic review found.

METHODOLOGY:

• The investigators conducted a systematic literature search of five databases, looking for studies involving patients with nonmetastatic hormone receptor–positive breast cancer that were published between 2010 and 2020.
• Adequate adherence was defined as a medical possession ratio – the percentage of days the prescribed treatment dose of adjuvant endocrine therapy was available to the patient – of at least 80%.
• Medication nonpersistence was defined as a period in which no new adjuvant endocrine therapy prescriptions were filled before the scheduled end of treatment of 90-180 days, depending on the study.
• The impact of both parameters on event-free survival, which included breast cancer recurrence, disease-free survival, breast cancer–specific survival, and overall survival cancer was calculated.
• Of 2,026 articles retrieved, 14 studies, with sample sizes ranging from 857 to 30,573 patients, met the eligibility and quality criteria; 11 examined patient adherence, and 6 examined patient persistence.

TAKEAWAY:

• Of 10 studies that assessed event-free survival, 7 showed significantly worse survival for nonadherent or nonpersistent patients, at hazard ratios of 1.39-2.44.
• Of nine studies that examined overall survival, seven demonstrated a significantly higher risk for mortality in the groups with nonadherence and nonpersistence, at HRs of 1.26-2.18.
• The largest study, which included data on more than 30,000 patients in Taiwan, found that nonadherence and nonpersistence were associated with a significantly increased risk for mortality, at HRs of 1.98 and 2.18, respectively.

IN PRACTICE:

“The available data highlight the dangers of nonadherence and nonpersistence, showing an up to twofold higher risk of relapse or death for patients who do not use endocrine treatment as prescribed,” the researchers said. “Importantly, improving adherence and persistence represents a low-hanging fruit for increasing survival in luminal breast cancer.”

SOURCE:

The study, led by Finn Magnus Eliassen, MD, department of surgery, Stavanger (Norway) University Hospital, was published online on July 4 in BMC Cancer.

LIMITATIONS:

• The review is limited by the relatively small number of studies that met the eligibility criteria and by their heterogeneity, which ruled out a meta-analysis.
• There are no gold-standard definitions of adherence and persistence.

DISCLOSURES:

• No funding was declared. No relevant financial relationships were declared.
• A version of this article first appeared on Medscape.com.

TOPLINE:

Patients with early-stage breast cancer who do not adhere to adjuvant endocrine therapy as prescribed or stop early may face as much as a twofold higher risk of relapse or death, a new systematic review found.

METHODOLOGY:

• The investigators conducted a systematic literature search of five databases, looking for studies involving patients with nonmetastatic hormone receptor–positive breast cancer that were published between 2010 and 2020.
• Adequate adherence was defined as a medical possession ratio – the percentage of days the prescribed treatment dose of adjuvant endocrine therapy was available to the patient – of at least 80%.
• Medication nonpersistence was defined as a period in which no new adjuvant endocrine therapy prescriptions were filled before the scheduled end of treatment of 90-180 days, depending on the study.
• The impact of both parameters on event-free survival, which included breast cancer recurrence, disease-free survival, breast cancer–specific survival, and overall survival cancer was calculated.
• Of 2,026 articles retrieved, 14 studies, with sample sizes ranging from 857 to 30,573 patients, met the eligibility and quality criteria; 11 examined patient adherence, and 6 examined patient persistence.

TAKEAWAY:

• Of 10 studies that assessed event-free survival, 7 showed significantly worse survival for nonadherent or nonpersistent patients, at hazard ratios of 1.39-2.44.
• Of nine studies that examined overall survival, seven demonstrated a significantly higher risk for mortality in the groups with nonadherence and nonpersistence, at HRs of 1.26-2.18.
• The largest study, which included data on more than 30,000 patients in Taiwan, found that nonadherence and nonpersistence were associated with a significantly increased risk for mortality, at HRs of 1.98 and 2.18, respectively.

IN PRACTICE:

“The available data highlight the dangers of nonadherence and nonpersistence, showing an up to twofold higher risk of relapse or death for patients who do not use endocrine treatment as prescribed,” the researchers said. “Importantly, improving adherence and persistence represents a low-hanging fruit for increasing survival in luminal breast cancer.”

SOURCE:

The study, led by Finn Magnus Eliassen, MD, department of surgery, Stavanger (Norway) University Hospital, was published online on July 4 in BMC Cancer.

LIMITATIONS:

• The review is limited by the relatively small number of studies that met the eligibility criteria and by their heterogeneity, which ruled out a meta-analysis.
• There are no gold-standard definitions of adherence and persistence.

DISCLOSURES:

• No funding was declared. No relevant financial relationships were declared.
• A version of this article first appeared on Medscape.com.

TOPLINE:

Patients with early-stage breast cancer who do not adhere to adjuvant endocrine therapy as prescribed or stop early may face as much as a twofold higher risk of relapse or death, a new systematic review found.

METHODOLOGY:

• The investigators conducted a systematic literature search of five databases, looking for studies involving patients with nonmetastatic hormone receptor–positive breast cancer that were published between 2010 and 2020.
• Adequate adherence was defined as a medical possession ratio – the percentage of days the prescribed treatment dose of adjuvant endocrine therapy was available to the patient – of at least 80%.
• Medication nonpersistence was defined as a period in which no new adjuvant endocrine therapy prescriptions were filled before the scheduled end of treatment of 90-180 days, depending on the study.
• The impact of both parameters on event-free survival, which included breast cancer recurrence, disease-free survival, breast cancer–specific survival, and overall survival cancer was calculated.
• Of 2,026 articles retrieved, 14 studies, with sample sizes ranging from 857 to 30,573 patients, met the eligibility and quality criteria; 11 examined patient adherence, and 6 examined patient persistence.

TAKEAWAY:

• Of 10 studies that assessed event-free survival, 7 showed significantly worse survival for nonadherent or nonpersistent patients, at hazard ratios of 1.39-2.44.
• Of nine studies that examined overall survival, seven demonstrated a significantly higher risk for mortality in the groups with nonadherence and nonpersistence, at HRs of 1.26-2.18.
• The largest study, which included data on more than 30,000 patients in Taiwan, found that nonadherence and nonpersistence were associated with a significantly increased risk for mortality, at HRs of 1.98 and 2.18, respectively.

IN PRACTICE:

“The available data highlight the dangers of nonadherence and nonpersistence, showing an up to twofold higher risk of relapse or death for patients who do not use endocrine treatment as prescribed,” the researchers said. “Importantly, improving adherence and persistence represents a low-hanging fruit for increasing survival in luminal breast cancer.”

SOURCE:

The study, led by Finn Magnus Eliassen, MD, department of surgery, Stavanger (Norway) University Hospital, was published online on July 4 in BMC Cancer.

LIMITATIONS:

• The review is limited by the relatively small number of studies that met the eligibility criteria and by their heterogeneity, which ruled out a meta-analysis.
• There are no gold-standard definitions of adherence and persistence.

DISCLOSURES:

• No funding was declared. No relevant financial relationships were declared.
• A version of this article first appeared on Medscape.com.

Brain disorders, including mental illness, neurologic conditions, and stroke, account for more than 15% of all health loss worldwide – more than either cardiovascular disease or cancer – at huge cost to health care systems and society, an analysis of data from the most recent Global Burden of Disease (GBD) study shows.

“The burden of brain conditions will increase as populations continue to grow and age,” said study presenter Shayla Smith, MPH, an epidemiologist at the Institute for Health Metrics and Evaluation, the University of Washington, Seattle, in a press release.

“By 2050, more than 50 million people will be aged 65-79,” she explained, adding that the COVID-19 pandemic “has also influenced the prevalence of mental disorders globally, as people were forced to isolate and social networks broke down.”

Other factors related to brain disorders, she noted, include education level, obesity, and smoking.

“There’s still research to be done on what is the most effective way to maintain brain health, but some literature suggests a healthy brain can be achieved through a healthy lifestyle of managing conditions such as high blood pressure and diabetes, limiting alcohol consumption and smoking, prioritizing sleep, eating healthy, and staying physically and mentally active,” said Ms. Smith.

The findings were presented at the annual meeting of the Congress of the European Academy of Neurology.
 

An ‘ambitious exercise’

Coinvestigator Xaviera Steele, also from the IHME, told press conference attendees that the institute was established at the University of Washington in 2007 with the aim of “standardizing the measurement of health outcomes around the world and for all health conditions.”

A central part of that is the GBD study, “which is a very ambitious exercise in descriptive epidemiology in an effort to systematically quantify health loss” due to disease, injury, and risk factors over time, stratified by country, region, age, and sex. In addition, researchers are mapping and projecting trends over the next century and are estimating disease expenditure by country, by type of expense, and by condition “to derive a health care access and quality score for each health system in the world,” Ms. Steele said.

They are also estimating exposure to risk factors, how those risk factors contribute to health burden, and associated health outcomes by race and ethnicity to reflect the “disparities that we know are very prevalent in countries such as the United States.” From that work, Ms. Steele said that brain health and related conditions “do emerge as one of the more pressing challenges of the 21st century.”
 

Increase in dementia, mental health conditions

The data, which were gathered from 200,000 sources by the IHME, indicate that the number of individuals aged 65 years or older will increase by 350% by 2100. Ms. Steele underlined that “policy action will be needed to help families, who will struggle to provide high-quality care for their loved ones with dementia at a reasonable cost.”

The IHME calculates that in Europe health care spending on Alzheimer’s disease will increase by 226% between 2015 and 2040.

Turning to other conditions, Ms. Steele showed that since 1990, the number of individuals living with anxiety in the European region has increased by 14%, while the number living with depressive disorders has gone up by 13%.

Worldwide, the figures are even starker. Depression is estimated to affect 300 million people across the globe, which represents a 71% increase since 1990. The number of strokes increased by 95% over the same period.

Nevertheless, the “impact of brain conditions such as stroke has decreased since the 1990s due to improved treatments available,” Ms. Smith noted in the press release.

To estimate the toll caused by brain conditions, including neurologic disorders, mental disorders, cerebrovascular disease, brain cancer, brain injuries, and select infectious conditions, the researchers calculated disability-adjusted life years (DALYs).

This, Ms. Smith explained in her presentation, “captures the morbidity and mortality associated with brain conditions” and is adjusted for patient location, age, and sex.

The investigators found that, globally, brain conditions accounted for more than 15% of all health loss in 2021, at 406 DALYs – more than the 206 million DALYs that were associated with cancer, and the 402 million that were linked to cardiovascular disease.

This health loss is associated with a $1.22 trillion loss in income for people living with health disorders worldwide and accounts for $1.14 trillion in direct health care costs.

The burden of mental disorders, neurologic conditions, and stroke is expected to increase dramatically between now and 2050, said Ms. Smith, who noted that health loss linked to brain conditions is higher in younger patients. This will create “new challenges for health systems, employers, patients, and families,” she said in the press release.

“Our goal is to see an improved prevention and treatment landscape for other brain conditions and reverse the growing health loss that we are currently forecasting.”
 

Worrying increase in stroke

Jurgita Valaikiene, MD, PhD, center of neurology, clinic of neurology and neurosurgery, Vilnius (Lithuania) University Faculty of Medicine, who chaired the session, was taken aback by the findings, particularly by the worldwide increase in stroke cases.

“I work in stroke,” she said, and “we spend a lot of time on the diagnosis of stroke” and its prevention. “We try to be faster, to catch asymptomatic stenosis in the neck or head, and to apply the best medical treatment to avoid a stroke. But despite that, the numbers are increasing. I understand the population is getting older ... but still it’s a huge number.”

Dr. Valaikiene pointed out that stroke is not necessarily a condition of aging, insofar as increasing age “is not related directly to stenosis in the neck. “For example, we can have healthier vessels in older age and unhealthy vessels, with high-grade stenosis, in someone aged 30 or 40 years.”

“There are a lot of risk factors, such as smoking, physical activity, and so on. It depends on the individual,” she added.

The study was funded by the Institute for Health Metrics and Evaluation at the University of Washington. The authors have disclosed no relevant financial relationships.

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

Brain disorders, including mental illness, neurologic conditions, and stroke, account for more than 15% of all health loss worldwide – more than either cardiovascular disease or cancer – at huge cost to health care systems and society, an analysis of data from the most recent Global Burden of Disease (GBD) study shows.

“The burden of brain conditions will increase as populations continue to grow and age,” said study presenter Shayla Smith, MPH, an epidemiologist at the Institute for Health Metrics and Evaluation, the University of Washington, Seattle, in a press release.

“By 2050, more than 50 million people will be aged 65-79,” she explained, adding that the COVID-19 pandemic “has also influenced the prevalence of mental disorders globally, as people were forced to isolate and social networks broke down.”

Other factors related to brain disorders, she noted, include education level, obesity, and smoking.

“There’s still research to be done on what is the most effective way to maintain brain health, but some literature suggests a healthy brain can be achieved through a healthy lifestyle of managing conditions such as high blood pressure and diabetes, limiting alcohol consumption and smoking, prioritizing sleep, eating healthy, and staying physically and mentally active,” said Ms. Smith.

The findings were presented at the annual meeting of the Congress of the European Academy of Neurology.
 

An ‘ambitious exercise’

Coinvestigator Xaviera Steele, also from the IHME, told press conference attendees that the institute was established at the University of Washington in 2007 with the aim of “standardizing the measurement of health outcomes around the world and for all health conditions.”

A central part of that is the GBD study, “which is a very ambitious exercise in descriptive epidemiology in an effort to systematically quantify health loss” due to disease, injury, and risk factors over time, stratified by country, region, age, and sex. In addition, researchers are mapping and projecting trends over the next century and are estimating disease expenditure by country, by type of expense, and by condition “to derive a health care access and quality score for each health system in the world,” Ms. Steele said.

They are also estimating exposure to risk factors, how those risk factors contribute to health burden, and associated health outcomes by race and ethnicity to reflect the “disparities that we know are very prevalent in countries such as the United States.” From that work, Ms. Steele said that brain health and related conditions “do emerge as one of the more pressing challenges of the 21st century.”
 

Increase in dementia, mental health conditions

The data, which were gathered from 200,000 sources by the IHME, indicate that the number of individuals aged 65 years or older will increase by 350% by 2100. Ms. Steele underlined that “policy action will be needed to help families, who will struggle to provide high-quality care for their loved ones with dementia at a reasonable cost.”

The IHME calculates that in Europe health care spending on Alzheimer’s disease will increase by 226% between 2015 and 2040.

Turning to other conditions, Ms. Steele showed that since 1990, the number of individuals living with anxiety in the European region has increased by 14%, while the number living with depressive disorders has gone up by 13%.

Worldwide, the figures are even starker. Depression is estimated to affect 300 million people across the globe, which represents a 71% increase since 1990. The number of strokes increased by 95% over the same period.

Nevertheless, the “impact of brain conditions such as stroke has decreased since the 1990s due to improved treatments available,” Ms. Smith noted in the press release.

To estimate the toll caused by brain conditions, including neurologic disorders, mental disorders, cerebrovascular disease, brain cancer, brain injuries, and select infectious conditions, the researchers calculated disability-adjusted life years (DALYs).

This, Ms. Smith explained in her presentation, “captures the morbidity and mortality associated with brain conditions” and is adjusted for patient location, age, and sex.

The investigators found that, globally, brain conditions accounted for more than 15% of all health loss in 2021, at 406 DALYs – more than the 206 million DALYs that were associated with cancer, and the 402 million that were linked to cardiovascular disease.

This health loss is associated with a $1.22 trillion loss in income for people living with health disorders worldwide and accounts for $1.14 trillion in direct health care costs.

The burden of mental disorders, neurologic conditions, and stroke is expected to increase dramatically between now and 2050, said Ms. Smith, who noted that health loss linked to brain conditions is higher in younger patients. This will create “new challenges for health systems, employers, patients, and families,” she said in the press release.

“Our goal is to see an improved prevention and treatment landscape for other brain conditions and reverse the growing health loss that we are currently forecasting.”
 

Worrying increase in stroke

Jurgita Valaikiene, MD, PhD, center of neurology, clinic of neurology and neurosurgery, Vilnius (Lithuania) University Faculty of Medicine, who chaired the session, was taken aback by the findings, particularly by the worldwide increase in stroke cases.

“I work in stroke,” she said, and “we spend a lot of time on the diagnosis of stroke” and its prevention. “We try to be faster, to catch asymptomatic stenosis in the neck or head, and to apply the best medical treatment to avoid a stroke. But despite that, the numbers are increasing. I understand the population is getting older ... but still it’s a huge number.”

Dr. Valaikiene pointed out that stroke is not necessarily a condition of aging, insofar as increasing age “is not related directly to stenosis in the neck. “For example, we can have healthier vessels in older age and unhealthy vessels, with high-grade stenosis, in someone aged 30 or 40 years.”

“There are a lot of risk factors, such as smoking, physical activity, and so on. It depends on the individual,” she added.

The study was funded by the Institute for Health Metrics and Evaluation at the University of Washington. The authors have disclosed no relevant financial relationships.

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

Brain disorders, including mental illness, neurologic conditions, and stroke, account for more than 15% of all health loss worldwide – more than either cardiovascular disease or cancer – at huge cost to health care systems and society, an analysis of data from the most recent Global Burden of Disease (GBD) study shows.

“The burden of brain conditions will increase as populations continue to grow and age,” said study presenter Shayla Smith, MPH, an epidemiologist at the Institute for Health Metrics and Evaluation, the University of Washington, Seattle, in a press release.

“By 2050, more than 50 million people will be aged 65-79,” she explained, adding that the COVID-19 pandemic “has also influenced the prevalence of mental disorders globally, as people were forced to isolate and social networks broke down.”

Other factors related to brain disorders, she noted, include education level, obesity, and smoking.

“There’s still research to be done on what is the most effective way to maintain brain health, but some literature suggests a healthy brain can be achieved through a healthy lifestyle of managing conditions such as high blood pressure and diabetes, limiting alcohol consumption and smoking, prioritizing sleep, eating healthy, and staying physically and mentally active,” said Ms. Smith.

The findings were presented at the annual meeting of the Congress of the European Academy of Neurology.
 

An ‘ambitious exercise’

Coinvestigator Xaviera Steele, also from the IHME, told press conference attendees that the institute was established at the University of Washington in 2007 with the aim of “standardizing the measurement of health outcomes around the world and for all health conditions.”

A central part of that is the GBD study, “which is a very ambitious exercise in descriptive epidemiology in an effort to systematically quantify health loss” due to disease, injury, and risk factors over time, stratified by country, region, age, and sex. In addition, researchers are mapping and projecting trends over the next century and are estimating disease expenditure by country, by type of expense, and by condition “to derive a health care access and quality score for each health system in the world,” Ms. Steele said.

They are also estimating exposure to risk factors, how those risk factors contribute to health burden, and associated health outcomes by race and ethnicity to reflect the “disparities that we know are very prevalent in countries such as the United States.” From that work, Ms. Steele said that brain health and related conditions “do emerge as one of the more pressing challenges of the 21st century.”
 

Increase in dementia, mental health conditions

The data, which were gathered from 200,000 sources by the IHME, indicate that the number of individuals aged 65 years or older will increase by 350% by 2100. Ms. Steele underlined that “policy action will be needed to help families, who will struggle to provide high-quality care for their loved ones with dementia at a reasonable cost.”

The IHME calculates that in Europe health care spending on Alzheimer’s disease will increase by 226% between 2015 and 2040.

Turning to other conditions, Ms. Steele showed that since 1990, the number of individuals living with anxiety in the European region has increased by 14%, while the number living with depressive disorders has gone up by 13%.

Worldwide, the figures are even starker. Depression is estimated to affect 300 million people across the globe, which represents a 71% increase since 1990. The number of strokes increased by 95% over the same period.

Nevertheless, the “impact of brain conditions such as stroke has decreased since the 1990s due to improved treatments available,” Ms. Smith noted in the press release.

To estimate the toll caused by brain conditions, including neurologic disorders, mental disorders, cerebrovascular disease, brain cancer, brain injuries, and select infectious conditions, the researchers calculated disability-adjusted life years (DALYs).

This, Ms. Smith explained in her presentation, “captures the morbidity and mortality associated with brain conditions” and is adjusted for patient location, age, and sex.

The investigators found that, globally, brain conditions accounted for more than 15% of all health loss in 2021, at 406 DALYs – more than the 206 million DALYs that were associated with cancer, and the 402 million that were linked to cardiovascular disease.

This health loss is associated with a $1.22 trillion loss in income for people living with health disorders worldwide and accounts for $1.14 trillion in direct health care costs.

The burden of mental disorders, neurologic conditions, and stroke is expected to increase dramatically between now and 2050, said Ms. Smith, who noted that health loss linked to brain conditions is higher in younger patients. This will create “new challenges for health systems, employers, patients, and families,” she said in the press release.

“Our goal is to see an improved prevention and treatment landscape for other brain conditions and reverse the growing health loss that we are currently forecasting.”
 

Worrying increase in stroke

Jurgita Valaikiene, MD, PhD, center of neurology, clinic of neurology and neurosurgery, Vilnius (Lithuania) University Faculty of Medicine, who chaired the session, was taken aback by the findings, particularly by the worldwide increase in stroke cases.

“I work in stroke,” she said, and “we spend a lot of time on the diagnosis of stroke” and its prevention. “We try to be faster, to catch asymptomatic stenosis in the neck or head, and to apply the best medical treatment to avoid a stroke. But despite that, the numbers are increasing. I understand the population is getting older ... but still it’s a huge number.”

Dr. Valaikiene pointed out that stroke is not necessarily a condition of aging, insofar as increasing age “is not related directly to stenosis in the neck. “For example, we can have healthier vessels in older age and unhealthy vessels, with high-grade stenosis, in someone aged 30 or 40 years.”

“There are a lot of risk factors, such as smoking, physical activity, and so on. It depends on the individual,” she added.

The study was funded by the Institute for Health Metrics and Evaluation at the University of Washington. The authors have disclosed no relevant financial relationships.

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

A new European consensus statement offers expert guidance on which biomarkers to use for patients presenting with cognitive complaints.

Led by Giovanni B. Frisoni, MD, laboratory of neuroimaging of aging, University of Geneva, and director of the memory clinic at Geneva University Hospital, the multidisciplinary task force set out to define a patient-centered diagnostic workflow for the rational and cost-effective use of biomarkers in memory clinics.

The new algorithm is part of a consensus statement presented at the Congress of the European Academy of Neurology 2023. An interim update was published in June in Alzheimer’s and Dementia.
 

Which biomarker?

Many biomarkers can aid diagnosis, said Dr. Frisoni; the challenge is choosing which biomarker to use for an individual patient.

A literature-based search, he said, yields a number of recommendations, but the vast majority of these are either disease based or biomarker based. The task force notes that “in vivo biomarkers enable early etiological diagnosis of neurocognitive disorders. While they have good analytical validity, their clinical validity and utility are uncertain.”

“When you have a patient in front of you, you don’ t know whether they have Alzheimer’s disease,” Dr. Frisoni said.

“You have a differential diagnosis to make, and you have a number of biomarkers – a number of weapons in your armamentarium – you have to choose. You can’t use all of them – we would like to, but we cannot.”

He added that trying to determine from the literature which biomarker is most appropriate given individual clinical conditions and all of the potential combinations is impossible.

“You will not find evidence of the comparative diagnostic value and the added diagnostic value” of one test vs, another, he noted.

“Is CSF [cerebrospinal fluid] better than amyloid PET in a particular clinical situation? What do I gain in terms of positive and negative predictive value in all the possible clinical conditions that I encounter in my clinical practice?”

Dr. Frisoni said the reality is that clinicians in memory clinics end up using biomarkers that are “based on clinical opportunities.”

For instance, “if you have a proficient nuclear medic, you use PET a lot.” In contrast, “if you have a proficient laboratory medic,” CSF markers will be favored – a situation that he said is “not ideal” and has resulted in large discrepancies in diagnostic approaches across Europe.
 

Harmonizing clinical practice

In a bid to harmonize clinical practice, 22 European experts from 11 European scientific societies and the executive director of Alzheimer Europe set out to develop a multidisciplinary consensus algorithm for the biomarker-based diagnosis of neurocognitive disorders in general, rather than specific neurocognitive disorders.

They used the Delphi method, in which a systematic literature review of the literature was followed by the drafting of a series of clinical statements by an executive board. These were then presented to the expert panel. If a majority consensus was reached on a given statement, it was considered closed. Questions for which there was no consensus were revised and presented to the panel again. The process was repeated until a consensus was reached.

A total of 56 statements underwent six rounds of discussion. A final online meeting led to the development of a diagnostic algorithm for patients who attend memory clinics for cognitive complaints.

The algorithm features three potential assessment waves. Wave 1 defines 11 clinical profiles that are based on the results of clinical and neuropsychological assessments, blood exams, brain imaging, and, in specific cases, electroencephalography. Wave 2 defines first-line biomarkers based on Wave 1 clinical profiles, and Wave 3 defines the second-line biomarker based on Wave 2 biomarker results.

When a patient’s clinical profile suggests Alzheimer’s disease and, in undefined cases, cerebrospinal fluid biomarkers are used first line. When CSF is inconclusive, 18-fluorodeoxyglucose positron emission tomography (FDG-PET) is used second line.

When the clinical profile suggests frontotemporal lobar degeneration or motor tauopathies, FDG-PET is first line and CSF biomarkers second line in atypical metabolic patter cases. When the clinical profile suggests Lewy body disease, dopamine transporter SPECT is first line and cardia I23I-metaiodobenzylguanidine scintigraphy is second line.

Dr. Frisoni noted that the panel strongly recommends performing biomarker tests for patients younger than 70. For those aged 70-85 years, biomarker testing is only recommended for patients with specific clinical features. For patients older than 85, biomarker testing is recommended only in “exceptional circumstances.”

Dr. Frisoni noted that the consensus document has a number of limitations.

“First of all, we could not capture all the theoretical possible combinations” of potential diagnosis and relevant biomarker tests. “There are so many that it’s virtually impossible.”

He also noted that the agreement among the panel for the use of some markers was “relatively low” at “barely 50%,” while for others, the agreement was approximately 70%.

The consensus document also does not explicitly address patients with “mixed pathologies,” which are common. In addition, it does not include emerging biomarkers, such as neurofilament light polypeptide levels, an indicator of axonal compromise.

“Last, but not least,” Dr. Frisoni said, the consensus document requires validation.

“This is a paper and pencil exercise. We, as self-appointed experts, can recommend ... whatever we want, but we must check whether what we write is applicable, feasible.”

In other words, it must be determined whether the “real patient journey” fits with the “ideal patient journey” set out in the consensus document.

This kind of validation, Dr. Frisoni said, is “usually not done for this type of exercise,” but “we want to do it in this case.”
 

Pros and cons

Bogdan Draganski, MD, consultant in neurology at the department of clinical neurosciences and director of the neuroimaging research laboratory, University Hospital of Lausanne (Switzerland), who cochaired the session, told this news organization that he was “swaying between two extremes” when considering the usefulness of the consensus document.

On one hand, the “reductionist approach” of breaking down a “complex issue into an algorithm” via the Delphi method risks introducing subjective bias.

He said machine learning and artificial intelligence could answer some of the questions posed by clinicians and, by extension, the statements included in the Delphi process by assessing the available data in a more objective manner.

On the other hand, Dr. Draganski said that reducing the options available to clinicians when making a differential diagnosis into the current algorithm is, pragmatically speaking, a “good approach.”

From this standpoint, the danger of using machine learning to answer clinical questions is that it “doesn’t take the responsibility” for the final decision, which means “we’re closing the loop of subjective decision-making for an individual doctor.”

He also applauded the idea of trying to provide more uniform patient assessment across Europe, although he believes “we have a long way to go” before it can deliver on the promise of personalized medicine.

Like Dr. Frisoni, Dr. Draganski noted the fact that patients with potential neurocognitive disorders often have multiple pathologies, which can include cardiovascular problems, depression, and cancer and that that could affect the choice of diagnostic biomarkers.

The second issue, he said, concerns implementation of the consensus document, which is a political decision that centers around “how politicians will define ‘uniformity’ and equal access to technological or nontechnological platforms.”

Achieving uniformity will require a pan-regional collaboration, he noted.

The task force was supported by unrestricted grants from F. Hoffmann-La Roche, Biogen International GmbH, Eisai Europe Limited, Life Molecular Imaging GmbH, and OM Pharma Suisse SA. The authors have disclosed no relevant financial relationships.

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

A new European consensus statement offers expert guidance on which biomarkers to use for patients presenting with cognitive complaints.

Led by Giovanni B. Frisoni, MD, laboratory of neuroimaging of aging, University of Geneva, and director of the memory clinic at Geneva University Hospital, the multidisciplinary task force set out to define a patient-centered diagnostic workflow for the rational and cost-effective use of biomarkers in memory clinics.

The new algorithm is part of a consensus statement presented at the Congress of the European Academy of Neurology 2023. An interim update was published in June in Alzheimer’s and Dementia.
 

Which biomarker?

Many biomarkers can aid diagnosis, said Dr. Frisoni; the challenge is choosing which biomarker to use for an individual patient.

A literature-based search, he said, yields a number of recommendations, but the vast majority of these are either disease based or biomarker based. The task force notes that “in vivo biomarkers enable early etiological diagnosis of neurocognitive disorders. While they have good analytical validity, their clinical validity and utility are uncertain.”

“When you have a patient in front of you, you don’ t know whether they have Alzheimer’s disease,” Dr. Frisoni said.

“You have a differential diagnosis to make, and you have a number of biomarkers – a number of weapons in your armamentarium – you have to choose. You can’t use all of them – we would like to, but we cannot.”

He added that trying to determine from the literature which biomarker is most appropriate given individual clinical conditions and all of the potential combinations is impossible.

“You will not find evidence of the comparative diagnostic value and the added diagnostic value” of one test vs, another, he noted.

“Is CSF [cerebrospinal fluid] better than amyloid PET in a particular clinical situation? What do I gain in terms of positive and negative predictive value in all the possible clinical conditions that I encounter in my clinical practice?”

Dr. Frisoni said the reality is that clinicians in memory clinics end up using biomarkers that are “based on clinical opportunities.”

For instance, “if you have a proficient nuclear medic, you use PET a lot.” In contrast, “if you have a proficient laboratory medic,” CSF markers will be favored – a situation that he said is “not ideal” and has resulted in large discrepancies in diagnostic approaches across Europe.
 

Harmonizing clinical practice

In a bid to harmonize clinical practice, 22 European experts from 11 European scientific societies and the executive director of Alzheimer Europe set out to develop a multidisciplinary consensus algorithm for the biomarker-based diagnosis of neurocognitive disorders in general, rather than specific neurocognitive disorders.

They used the Delphi method, in which a systematic literature review of the literature was followed by the drafting of a series of clinical statements by an executive board. These were then presented to the expert panel. If a majority consensus was reached on a given statement, it was considered closed. Questions for which there was no consensus were revised and presented to the panel again. The process was repeated until a consensus was reached.

A total of 56 statements underwent six rounds of discussion. A final online meeting led to the development of a diagnostic algorithm for patients who attend memory clinics for cognitive complaints.

The algorithm features three potential assessment waves. Wave 1 defines 11 clinical profiles that are based on the results of clinical and neuropsychological assessments, blood exams, brain imaging, and, in specific cases, electroencephalography. Wave 2 defines first-line biomarkers based on Wave 1 clinical profiles, and Wave 3 defines the second-line biomarker based on Wave 2 biomarker results.

When a patient’s clinical profile suggests Alzheimer’s disease and, in undefined cases, cerebrospinal fluid biomarkers are used first line. When CSF is inconclusive, 18-fluorodeoxyglucose positron emission tomography (FDG-PET) is used second line.

When the clinical profile suggests frontotemporal lobar degeneration or motor tauopathies, FDG-PET is first line and CSF biomarkers second line in atypical metabolic patter cases. When the clinical profile suggests Lewy body disease, dopamine transporter SPECT is first line and cardia I23I-metaiodobenzylguanidine scintigraphy is second line.

Dr. Frisoni noted that the panel strongly recommends performing biomarker tests for patients younger than 70. For those aged 70-85 years, biomarker testing is only recommended for patients with specific clinical features. For patients older than 85, biomarker testing is recommended only in “exceptional circumstances.”

Dr. Frisoni noted that the consensus document has a number of limitations.

“First of all, we could not capture all the theoretical possible combinations” of potential diagnosis and relevant biomarker tests. “There are so many that it’s virtually impossible.”

He also noted that the agreement among the panel for the use of some markers was “relatively low” at “barely 50%,” while for others, the agreement was approximately 70%.

The consensus document also does not explicitly address patients with “mixed pathologies,” which are common. In addition, it does not include emerging biomarkers, such as neurofilament light polypeptide levels, an indicator of axonal compromise.

“Last, but not least,” Dr. Frisoni said, the consensus document requires validation.

“This is a paper and pencil exercise. We, as self-appointed experts, can recommend ... whatever we want, but we must check whether what we write is applicable, feasible.”

In other words, it must be determined whether the “real patient journey” fits with the “ideal patient journey” set out in the consensus document.

This kind of validation, Dr. Frisoni said, is “usually not done for this type of exercise,” but “we want to do it in this case.”
 

Pros and cons

Bogdan Draganski, MD, consultant in neurology at the department of clinical neurosciences and director of the neuroimaging research laboratory, University Hospital of Lausanne (Switzerland), who cochaired the session, told this news organization that he was “swaying between two extremes” when considering the usefulness of the consensus document.

On one hand, the “reductionist approach” of breaking down a “complex issue into an algorithm” via the Delphi method risks introducing subjective bias.

He said machine learning and artificial intelligence could answer some of the questions posed by clinicians and, by extension, the statements included in the Delphi process by assessing the available data in a more objective manner.

On the other hand, Dr. Draganski said that reducing the options available to clinicians when making a differential diagnosis into the current algorithm is, pragmatically speaking, a “good approach.”

From this standpoint, the danger of using machine learning to answer clinical questions is that it “doesn’t take the responsibility” for the final decision, which means “we’re closing the loop of subjective decision-making for an individual doctor.”

He also applauded the idea of trying to provide more uniform patient assessment across Europe, although he believes “we have a long way to go” before it can deliver on the promise of personalized medicine.

Like Dr. Frisoni, Dr. Draganski noted the fact that patients with potential neurocognitive disorders often have multiple pathologies, which can include cardiovascular problems, depression, and cancer and that that could affect the choice of diagnostic biomarkers.

The second issue, he said, concerns implementation of the consensus document, which is a political decision that centers around “how politicians will define ‘uniformity’ and equal access to technological or nontechnological platforms.”

Achieving uniformity will require a pan-regional collaboration, he noted.

The task force was supported by unrestricted grants from F. Hoffmann-La Roche, Biogen International GmbH, Eisai Europe Limited, Life Molecular Imaging GmbH, and OM Pharma Suisse SA. The authors have disclosed no relevant financial relationships.

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

A new European consensus statement offers expert guidance on which biomarkers to use for patients presenting with cognitive complaints.

Led by Giovanni B. Frisoni, MD, laboratory of neuroimaging of aging, University of Geneva, and director of the memory clinic at Geneva University Hospital, the multidisciplinary task force set out to define a patient-centered diagnostic workflow for the rational and cost-effective use of biomarkers in memory clinics.

The new algorithm is part of a consensus statement presented at the Congress of the European Academy of Neurology 2023. An interim update was published in June in Alzheimer’s and Dementia.
 

Which biomarker?

Many biomarkers can aid diagnosis, said Dr. Frisoni; the challenge is choosing which biomarker to use for an individual patient.

A literature-based search, he said, yields a number of recommendations, but the vast majority of these are either disease based or biomarker based. The task force notes that “in vivo biomarkers enable early etiological diagnosis of neurocognitive disorders. While they have good analytical validity, their clinical validity and utility are uncertain.”

“When you have a patient in front of you, you don’ t know whether they have Alzheimer’s disease,” Dr. Frisoni said.

“You have a differential diagnosis to make, and you have a number of biomarkers – a number of weapons in your armamentarium – you have to choose. You can’t use all of them – we would like to, but we cannot.”

He added that trying to determine from the literature which biomarker is most appropriate given individual clinical conditions and all of the potential combinations is impossible.

“You will not find evidence of the comparative diagnostic value and the added diagnostic value” of one test vs, another, he noted.

“Is CSF [cerebrospinal fluid] better than amyloid PET in a particular clinical situation? What do I gain in terms of positive and negative predictive value in all the possible clinical conditions that I encounter in my clinical practice?”

Dr. Frisoni said the reality is that clinicians in memory clinics end up using biomarkers that are “based on clinical opportunities.”

For instance, “if you have a proficient nuclear medic, you use PET a lot.” In contrast, “if you have a proficient laboratory medic,” CSF markers will be favored – a situation that he said is “not ideal” and has resulted in large discrepancies in diagnostic approaches across Europe.
 

Harmonizing clinical practice

In a bid to harmonize clinical practice, 22 European experts from 11 European scientific societies and the executive director of Alzheimer Europe set out to develop a multidisciplinary consensus algorithm for the biomarker-based diagnosis of neurocognitive disorders in general, rather than specific neurocognitive disorders.

They used the Delphi method, in which a systematic literature review of the literature was followed by the drafting of a series of clinical statements by an executive board. These were then presented to the expert panel. If a majority consensus was reached on a given statement, it was considered closed. Questions for which there was no consensus were revised and presented to the panel again. The process was repeated until a consensus was reached.

A total of 56 statements underwent six rounds of discussion. A final online meeting led to the development of a diagnostic algorithm for patients who attend memory clinics for cognitive complaints.

The algorithm features three potential assessment waves. Wave 1 defines 11 clinical profiles that are based on the results of clinical and neuropsychological assessments, blood exams, brain imaging, and, in specific cases, electroencephalography. Wave 2 defines first-line biomarkers based on Wave 1 clinical profiles, and Wave 3 defines the second-line biomarker based on Wave 2 biomarker results.

When a patient’s clinical profile suggests Alzheimer’s disease and, in undefined cases, cerebrospinal fluid biomarkers are used first line. When CSF is inconclusive, 18-fluorodeoxyglucose positron emission tomography (FDG-PET) is used second line.

When the clinical profile suggests frontotemporal lobar degeneration or motor tauopathies, FDG-PET is first line and CSF biomarkers second line in atypical metabolic patter cases. When the clinical profile suggests Lewy body disease, dopamine transporter SPECT is first line and cardia I23I-metaiodobenzylguanidine scintigraphy is second line.

Dr. Frisoni noted that the panel strongly recommends performing biomarker tests for patients younger than 70. For those aged 70-85 years, biomarker testing is only recommended for patients with specific clinical features. For patients older than 85, biomarker testing is recommended only in “exceptional circumstances.”

Dr. Frisoni noted that the consensus document has a number of limitations.

“First of all, we could not capture all the theoretical possible combinations” of potential diagnosis and relevant biomarker tests. “There are so many that it’s virtually impossible.”

He also noted that the agreement among the panel for the use of some markers was “relatively low” at “barely 50%,” while for others, the agreement was approximately 70%.

The consensus document also does not explicitly address patients with “mixed pathologies,” which are common. In addition, it does not include emerging biomarkers, such as neurofilament light polypeptide levels, an indicator of axonal compromise.

“Last, but not least,” Dr. Frisoni said, the consensus document requires validation.

“This is a paper and pencil exercise. We, as self-appointed experts, can recommend ... whatever we want, but we must check whether what we write is applicable, feasible.”

In other words, it must be determined whether the “real patient journey” fits with the “ideal patient journey” set out in the consensus document.

This kind of validation, Dr. Frisoni said, is “usually not done for this type of exercise,” but “we want to do it in this case.”
 

Pros and cons

Bogdan Draganski, MD, consultant in neurology at the department of clinical neurosciences and director of the neuroimaging research laboratory, University Hospital of Lausanne (Switzerland), who cochaired the session, told this news organization that he was “swaying between two extremes” when considering the usefulness of the consensus document.

On one hand, the “reductionist approach” of breaking down a “complex issue into an algorithm” via the Delphi method risks introducing subjective bias.

He said machine learning and artificial intelligence could answer some of the questions posed by clinicians and, by extension, the statements included in the Delphi process by assessing the available data in a more objective manner.

On the other hand, Dr. Draganski said that reducing the options available to clinicians when making a differential diagnosis into the current algorithm is, pragmatically speaking, a “good approach.”

From this standpoint, the danger of using machine learning to answer clinical questions is that it “doesn’t take the responsibility” for the final decision, which means “we’re closing the loop of subjective decision-making for an individual doctor.”

He also applauded the idea of trying to provide more uniform patient assessment across Europe, although he believes “we have a long way to go” before it can deliver on the promise of personalized medicine.

Like Dr. Frisoni, Dr. Draganski noted the fact that patients with potential neurocognitive disorders often have multiple pathologies, which can include cardiovascular problems, depression, and cancer and that that could affect the choice of diagnostic biomarkers.

The second issue, he said, concerns implementation of the consensus document, which is a political decision that centers around “how politicians will define ‘uniformity’ and equal access to technological or nontechnological platforms.”

Achieving uniformity will require a pan-regional collaboration, he noted.

The task force was supported by unrestricted grants from F. Hoffmann-La Roche, Biogen International GmbH, Eisai Europe Limited, Life Molecular Imaging GmbH, and OM Pharma Suisse SA. The authors have disclosed no relevant financial relationships.

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

CHICAGO – Fewer than 7% of patients newly diagnosed with cancer are tested for germline genetic mutations, and the percentage tested was even lower among racial and ethnic minorities, a huge study has found.

Information from germline genetic testing could affect a patient’s cancer care. For example, such testing could indicate that targeted therapies would be beneficial, and it would have implications for close relatives who may carry the same genes.

The finding that so few patients with newly diagnosed cancer were tested comes from an analysis of data on more than 1.3 million individuals across two U.S. states. The data were taken from the Surveillance, Epidemiology, and End Results (SEER) registry.

The rate is “well below guideline recommendations,” said study presenter Allison W. Kurian, MD, department of medicine, Stanford (Calif.) University.

“Innovative care delivery” is needed to tackle the problem, including the streamlining of pretest counseling, making posttest counseling more widely available, and employing long-term follow-up to track patient outcomes, she suggested.

“I do think this is a time for creative solutions of a number of different kinds,” she said. She suggested that lessons could be learned from the use of telemedicine during the COVID-19 pandemic. She also noted that “there have been some interesting studies on embedding genetic counselors in oncology clinics.”

Dr. Kurian presented the study at the annual meeting of the American Society of Clinical Oncology (ASCO). The study was simultaneously published in the Journal of the American Medical Association.

The current results represent a “missed opportunity for decrease the population-level burden of cancer,” experts noted in an accompanying editorial.

“Clinicians should recommend testing to their patients and provide them with the information necessary to make informed decisions about whether to undergo testing,” Zsofia K. Stadler, MD, and Deborah Schrag, MD, MPH, of Memorial Sloan Kettering Cancer Center, New York, wrote in their editorial.

They suggested novel approaches to widen access, such as use of point-of-care testing, telecounseling, and, in the future, chatbots to respond to patient questions.

“With greater emphasis on overcoming both health system and patient-level barriers to genetic cancer susceptibility testing for patients with cancer, treatment outcomes will improve and cancer diagnoses and related deaths in family members will be prevented,” they concluded.

At the meeting, invited discussant Erin Frances Cobain, MD, assistant professor of medical oncology, University of Michigan Health, Ann Arbor, referring to breast cancer as an example, said that progress has “stagnated” in recent years.

The study found a higher rate of gene testing among patients with newly diagnosed breast cancer, at just over 20%.

Dr. Cobain argued that this was still too low. She pointed out that “a recent study suggested that over 60% of individuals with an incident cancer diagnosis would meet criteria for genetic testing by National Comprehensive Cancer Network guidelines.

“This may be because testing is not offered, there may be poor access to genetic counseling resources, or patients may be offered testing but decline it,” she suggested.

One compelling reason to conduct genetic testing for patients newly diagnosed with breast cancer is that it may show that they are candidates for treatment with PARP (poly[ADP]-ribose polymerase) inhibitors, which “may have a direct impact on cancer-related mortality,” she pointed out.

“We need increased awareness and access to genetic testing resources for patients with breast cancer, particularly for racial and ethnic minorities,” she said.

Dr. Cobain also noted that finding variants of uncertain significance (VUS) was more likely among patients from racial and ethnic minorities than among White patients. She said such a finding “increases patient and physician anxiety,” and there may be “unclear optimal management recommendations for these patients.”
 

Details of the study

Germline genetic testing is “increasingly essential for cancer care,” Dr. Kurian said.

It is central to risk-adapted screening and secondary prevention, the use of targeted therapies, including PARP and checkpoint inhibitors, and cascade testing to identify at-risk relatives.

She pointed out that in clinical practice, testing has “evolved rapidly.” Panels include more and more genes. In addition, the cost of these tests is falling, and guidelines have become “more expansive.”

However, “little is known about genetic testing use and results,” Dr. Kurian noted.

The team therefore undertook the SEER-GeneLINK initiative, which involved patients aged ≥ 20 years who were diagnosed with cancer between Jan. 1, 2013, and March 31, 2019, and who were reported to statewide SEER registries in California and Georgia.

The team looked for patients for whom germline genetic test results had been reported by the four laboratories that performed the majority of patient testing in the two states. Results were categorized as pathogenic, benign, or VUS.

The results were classified on the basis of current guidelines for testing and/or management as related to breast/ovarian cancer, gastrointestinal cancer, other hereditary cancers, or those with no guidelines for testing or management.

Dr. Kurian reported that from an overall population of 1,412,388 patients diagnosed with cancer, 1,369,660 were eligible for inclusion. Of those, about half (51.9%) were women, and the majority (86.3%) were aged 50 years or older.

Many of these patients (61.4%) were non-Hispanic White persons, and slightly fewer than half (49.8%) were deemed to be in medium or high poverty, as determined using U.S. Census tract levels.

Overall, germline genetic testing was performed in 93,052 (6.8%) of patients over the study period.

Women were more likely to have undergone germline mutation testing than men, at 13.9% vs. 2.2%, as were patients aged 20-49 years, at 22.1% vs. 8.2% for those aged 50-69 years, and 3.3% for those aged 70 years and older.

The number of genes for which testing was conducted increased from a median of 2 in 2013 to 34 in 2019. Rates of VUS increased more than that for pathologic variants and substantially more so in non-White patients.

By 2019, the ratio of VUS to pathologic variants stood at 1.7 among White patients, vs. 3.9 among Asian patients, 3.6 among Black patients, and 2.2 among Hispanic patients.

The majority of identified pathologic variants that were related to the diagnosed cancer and genes with testing and/or management guidelines accounted for 67.5% to 94.9% of such variants.

Regarding specific cancer diagnoses, Dr. Kurian said that over the course of the study period, testing rates consistently exceeded 50% only among male breast cancer patients.

There were rapid increases in testing for ovarian cancer, from 28.0% of cases in 2013 to 54.0% in 2019. For pancreatic cancer, rates increased from 1.0% to 19.0% over the same period, and for prostate cancer, rates increased from 0.1% to 4.0%. She suggested that these increases in rates may be related to the approval of PARP inhibitors for use in these indications.

However, there was little change in the rates of germline mutation testing for lung cancer patients, from 01% in 2013 to 0.8% in 2019, and for other cancers, from 0.3% to 2.0%.

The results also revealed racial and ethnic differences in testing after controlling for age, cancer type, and year. Over the course of the study period, 8.0% of White patients underwent genetic testing, compared with 6.0% each for Asian, Black, and Hispanic patients and 5.0% for other patients (P < .001).

With regard specifically to male and female breast cancer and ovarian cancer, testing rates were 31% among White patients, 22% for Asian patients, 25% for Black patients, and 23% for Hispanic patients (P < .001).

Dr. Kurian acknowledged that the study is limited by a lack of testing from other laboratories and direct-to-consumer test data, although a recent survey suggested that this represents fewer than 5% of all germline genetic tests.

She also noted that the SEER registries do not collect data on family history or tumor sequencing.

The study was funded by the National Institutes of Health, and the Centers for Disease Control and Prevention. Dr. Kurian has relationships with Adela, Ambry Genetics, Color Genomics, GeneDx/BioReference, Genentech, InVitae, and Myriad Genetics. Other authors report numerous relationships with industry. Dr. Cobain has ties with AstraZeneca, Daiichi Sankyo, Athenex, Ayala Pharmaceuticals, bioTheranostics, and Immunomedics. Dr. Schrag has relationships with Merck, JAMA, AACR, and Grail. Dr. Stadler has ties with Adverum Biotechnologies, Genentech, Neurogene, Novartis, Optos Plc, Outlook Therapeutics, and Regeneron Pharmaceuticals.

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

CHICAGO – Fewer than 7% of patients newly diagnosed with cancer are tested for germline genetic mutations, and the percentage tested was even lower among racial and ethnic minorities, a huge study has found.

Information from germline genetic testing could affect a patient’s cancer care. For example, such testing could indicate that targeted therapies would be beneficial, and it would have implications for close relatives who may carry the same genes.

The finding that so few patients with newly diagnosed cancer were tested comes from an analysis of data on more than 1.3 million individuals across two U.S. states. The data were taken from the Surveillance, Epidemiology, and End Results (SEER) registry.

The rate is “well below guideline recommendations,” said study presenter Allison W. Kurian, MD, department of medicine, Stanford (Calif.) University.

“Innovative care delivery” is needed to tackle the problem, including the streamlining of pretest counseling, making posttest counseling more widely available, and employing long-term follow-up to track patient outcomes, she suggested.

“I do think this is a time for creative solutions of a number of different kinds,” she said. She suggested that lessons could be learned from the use of telemedicine during the COVID-19 pandemic. She also noted that “there have been some interesting studies on embedding genetic counselors in oncology clinics.”

Dr. Kurian presented the study at the annual meeting of the American Society of Clinical Oncology (ASCO). The study was simultaneously published in the Journal of the American Medical Association.

The current results represent a “missed opportunity for decrease the population-level burden of cancer,” experts noted in an accompanying editorial.

“Clinicians should recommend testing to their patients and provide them with the information necessary to make informed decisions about whether to undergo testing,” Zsofia K. Stadler, MD, and Deborah Schrag, MD, MPH, of Memorial Sloan Kettering Cancer Center, New York, wrote in their editorial.

They suggested novel approaches to widen access, such as use of point-of-care testing, telecounseling, and, in the future, chatbots to respond to patient questions.

“With greater emphasis on overcoming both health system and patient-level barriers to genetic cancer susceptibility testing for patients with cancer, treatment outcomes will improve and cancer diagnoses and related deaths in family members will be prevented,” they concluded.

At the meeting, invited discussant Erin Frances Cobain, MD, assistant professor of medical oncology, University of Michigan Health, Ann Arbor, referring to breast cancer as an example, said that progress has “stagnated” in recent years.

The study found a higher rate of gene testing among patients with newly diagnosed breast cancer, at just over 20%.

Dr. Cobain argued that this was still too low. She pointed out that “a recent study suggested that over 60% of individuals with an incident cancer diagnosis would meet criteria for genetic testing by National Comprehensive Cancer Network guidelines.

“This may be because testing is not offered, there may be poor access to genetic counseling resources, or patients may be offered testing but decline it,” she suggested.

One compelling reason to conduct genetic testing for patients newly diagnosed with breast cancer is that it may show that they are candidates for treatment with PARP (poly[ADP]-ribose polymerase) inhibitors, which “may have a direct impact on cancer-related mortality,” she pointed out.

“We need increased awareness and access to genetic testing resources for patients with breast cancer, particularly for racial and ethnic minorities,” she said.

Dr. Cobain also noted that finding variants of uncertain significance (VUS) was more likely among patients from racial and ethnic minorities than among White patients. She said such a finding “increases patient and physician anxiety,” and there may be “unclear optimal management recommendations for these patients.”
 

Details of the study

Germline genetic testing is “increasingly essential for cancer care,” Dr. Kurian said.

It is central to risk-adapted screening and secondary prevention, the use of targeted therapies, including PARP and checkpoint inhibitors, and cascade testing to identify at-risk relatives.

She pointed out that in clinical practice, testing has “evolved rapidly.” Panels include more and more genes. In addition, the cost of these tests is falling, and guidelines have become “more expansive.”

However, “little is known about genetic testing use and results,” Dr. Kurian noted.

The team therefore undertook the SEER-GeneLINK initiative, which involved patients aged ≥ 20 years who were diagnosed with cancer between Jan. 1, 2013, and March 31, 2019, and who were reported to statewide SEER registries in California and Georgia.

The team looked for patients for whom germline genetic test results had been reported by the four laboratories that performed the majority of patient testing in the two states. Results were categorized as pathogenic, benign, or VUS.

The results were classified on the basis of current guidelines for testing and/or management as related to breast/ovarian cancer, gastrointestinal cancer, other hereditary cancers, or those with no guidelines for testing or management.

Dr. Kurian reported that from an overall population of 1,412,388 patients diagnosed with cancer, 1,369,660 were eligible for inclusion. Of those, about half (51.9%) were women, and the majority (86.3%) were aged 50 years or older.

Many of these patients (61.4%) were non-Hispanic White persons, and slightly fewer than half (49.8%) were deemed to be in medium or high poverty, as determined using U.S. Census tract levels.

Overall, germline genetic testing was performed in 93,052 (6.8%) of patients over the study period.

Women were more likely to have undergone germline mutation testing than men, at 13.9% vs. 2.2%, as were patients aged 20-49 years, at 22.1% vs. 8.2% for those aged 50-69 years, and 3.3% for those aged 70 years and older.

The number of genes for which testing was conducted increased from a median of 2 in 2013 to 34 in 2019. Rates of VUS increased more than that for pathologic variants and substantially more so in non-White patients.

By 2019, the ratio of VUS to pathologic variants stood at 1.7 among White patients, vs. 3.9 among Asian patients, 3.6 among Black patients, and 2.2 among Hispanic patients.

The majority of identified pathologic variants that were related to the diagnosed cancer and genes with testing and/or management guidelines accounted for 67.5% to 94.9% of such variants.

Regarding specific cancer diagnoses, Dr. Kurian said that over the course of the study period, testing rates consistently exceeded 50% only among male breast cancer patients.

There were rapid increases in testing for ovarian cancer, from 28.0% of cases in 2013 to 54.0% in 2019. For pancreatic cancer, rates increased from 1.0% to 19.0% over the same period, and for prostate cancer, rates increased from 0.1% to 4.0%. She suggested that these increases in rates may be related to the approval of PARP inhibitors for use in these indications.

However, there was little change in the rates of germline mutation testing for lung cancer patients, from 01% in 2013 to 0.8% in 2019, and for other cancers, from 0.3% to 2.0%.

The results also revealed racial and ethnic differences in testing after controlling for age, cancer type, and year. Over the course of the study period, 8.0% of White patients underwent genetic testing, compared with 6.0% each for Asian, Black, and Hispanic patients and 5.0% for other patients (P < .001).

With regard specifically to male and female breast cancer and ovarian cancer, testing rates were 31% among White patients, 22% for Asian patients, 25% for Black patients, and 23% for Hispanic patients (P < .001).

Dr. Kurian acknowledged that the study is limited by a lack of testing from other laboratories and direct-to-consumer test data, although a recent survey suggested that this represents fewer than 5% of all germline genetic tests.

She also noted that the SEER registries do not collect data on family history or tumor sequencing.

The study was funded by the National Institutes of Health, and the Centers for Disease Control and Prevention. Dr. Kurian has relationships with Adela, Ambry Genetics, Color Genomics, GeneDx/BioReference, Genentech, InVitae, and Myriad Genetics. Other authors report numerous relationships with industry. Dr. Cobain has ties with AstraZeneca, Daiichi Sankyo, Athenex, Ayala Pharmaceuticals, bioTheranostics, and Immunomedics. Dr. Schrag has relationships with Merck, JAMA, AACR, and Grail. Dr. Stadler has ties with Adverum Biotechnologies, Genentech, Neurogene, Novartis, Optos Plc, Outlook Therapeutics, and Regeneron Pharmaceuticals.

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

CHICAGO – Fewer than 7% of patients newly diagnosed with cancer are tested for germline genetic mutations, and the percentage tested was even lower among racial and ethnic minorities, a huge study has found.

Information from germline genetic testing could affect a patient’s cancer care. For example, such testing could indicate that targeted therapies would be beneficial, and it would have implications for close relatives who may carry the same genes.

The finding that so few patients with newly diagnosed cancer were tested comes from an analysis of data on more than 1.3 million individuals across two U.S. states. The data were taken from the Surveillance, Epidemiology, and End Results (SEER) registry.

The rate is “well below guideline recommendations,” said study presenter Allison W. Kurian, MD, department of medicine, Stanford (Calif.) University.

“Innovative care delivery” is needed to tackle the problem, including the streamlining of pretest counseling, making posttest counseling more widely available, and employing long-term follow-up to track patient outcomes, she suggested.

“I do think this is a time for creative solutions of a number of different kinds,” she said. She suggested that lessons could be learned from the use of telemedicine during the COVID-19 pandemic. She also noted that “there have been some interesting studies on embedding genetic counselors in oncology clinics.”

Dr. Kurian presented the study at the annual meeting of the American Society of Clinical Oncology (ASCO). The study was simultaneously published in the Journal of the American Medical Association.

The current results represent a “missed opportunity for decrease the population-level burden of cancer,” experts noted in an accompanying editorial.

“Clinicians should recommend testing to their patients and provide them with the information necessary to make informed decisions about whether to undergo testing,” Zsofia K. Stadler, MD, and Deborah Schrag, MD, MPH, of Memorial Sloan Kettering Cancer Center, New York, wrote in their editorial.

They suggested novel approaches to widen access, such as use of point-of-care testing, telecounseling, and, in the future, chatbots to respond to patient questions.

“With greater emphasis on overcoming both health system and patient-level barriers to genetic cancer susceptibility testing for patients with cancer, treatment outcomes will improve and cancer diagnoses and related deaths in family members will be prevented,” they concluded.

At the meeting, invited discussant Erin Frances Cobain, MD, assistant professor of medical oncology, University of Michigan Health, Ann Arbor, referring to breast cancer as an example, said that progress has “stagnated” in recent years.

The study found a higher rate of gene testing among patients with newly diagnosed breast cancer, at just over 20%.

Dr. Cobain argued that this was still too low. She pointed out that “a recent study suggested that over 60% of individuals with an incident cancer diagnosis would meet criteria for genetic testing by National Comprehensive Cancer Network guidelines.

“This may be because testing is not offered, there may be poor access to genetic counseling resources, or patients may be offered testing but decline it,” she suggested.

One compelling reason to conduct genetic testing for patients newly diagnosed with breast cancer is that it may show that they are candidates for treatment with PARP (poly[ADP]-ribose polymerase) inhibitors, which “may have a direct impact on cancer-related mortality,” she pointed out.

“We need increased awareness and access to genetic testing resources for patients with breast cancer, particularly for racial and ethnic minorities,” she said.

Dr. Cobain also noted that finding variants of uncertain significance (VUS) was more likely among patients from racial and ethnic minorities than among White patients. She said such a finding “increases patient and physician anxiety,” and there may be “unclear optimal management recommendations for these patients.”
 

Details of the study

Germline genetic testing is “increasingly essential for cancer care,” Dr. Kurian said.

It is central to risk-adapted screening and secondary prevention, the use of targeted therapies, including PARP and checkpoint inhibitors, and cascade testing to identify at-risk relatives.

She pointed out that in clinical practice, testing has “evolved rapidly.” Panels include more and more genes. In addition, the cost of these tests is falling, and guidelines have become “more expansive.”

However, “little is known about genetic testing use and results,” Dr. Kurian noted.

The team therefore undertook the SEER-GeneLINK initiative, which involved patients aged ≥ 20 years who were diagnosed with cancer between Jan. 1, 2013, and March 31, 2019, and who were reported to statewide SEER registries in California and Georgia.

The team looked for patients for whom germline genetic test results had been reported by the four laboratories that performed the majority of patient testing in the two states. Results were categorized as pathogenic, benign, or VUS.

The results were classified on the basis of current guidelines for testing and/or management as related to breast/ovarian cancer, gastrointestinal cancer, other hereditary cancers, or those with no guidelines for testing or management.

Dr. Kurian reported that from an overall population of 1,412,388 patients diagnosed with cancer, 1,369,660 were eligible for inclusion. Of those, about half (51.9%) were women, and the majority (86.3%) were aged 50 years or older.

Many of these patients (61.4%) were non-Hispanic White persons, and slightly fewer than half (49.8%) were deemed to be in medium or high poverty, as determined using U.S. Census tract levels.

Overall, germline genetic testing was performed in 93,052 (6.8%) of patients over the study period.

Women were more likely to have undergone germline mutation testing than men, at 13.9% vs. 2.2%, as were patients aged 20-49 years, at 22.1% vs. 8.2% for those aged 50-69 years, and 3.3% for those aged 70 years and older.

The number of genes for which testing was conducted increased from a median of 2 in 2013 to 34 in 2019. Rates of VUS increased more than that for pathologic variants and substantially more so in non-White patients.

By 2019, the ratio of VUS to pathologic variants stood at 1.7 among White patients, vs. 3.9 among Asian patients, 3.6 among Black patients, and 2.2 among Hispanic patients.

The majority of identified pathologic variants that were related to the diagnosed cancer and genes with testing and/or management guidelines accounted for 67.5% to 94.9% of such variants.

Regarding specific cancer diagnoses, Dr. Kurian said that over the course of the study period, testing rates consistently exceeded 50% only among male breast cancer patients.

There were rapid increases in testing for ovarian cancer, from 28.0% of cases in 2013 to 54.0% in 2019. For pancreatic cancer, rates increased from 1.0% to 19.0% over the same period, and for prostate cancer, rates increased from 0.1% to 4.0%. She suggested that these increases in rates may be related to the approval of PARP inhibitors for use in these indications.

However, there was little change in the rates of germline mutation testing for lung cancer patients, from 01% in 2013 to 0.8% in 2019, and for other cancers, from 0.3% to 2.0%.

The results also revealed racial and ethnic differences in testing after controlling for age, cancer type, and year. Over the course of the study period, 8.0% of White patients underwent genetic testing, compared with 6.0% each for Asian, Black, and Hispanic patients and 5.0% for other patients (P < .001).

With regard specifically to male and female breast cancer and ovarian cancer, testing rates were 31% among White patients, 22% for Asian patients, 25% for Black patients, and 23% for Hispanic patients (P < .001).

Dr. Kurian acknowledged that the study is limited by a lack of testing from other laboratories and direct-to-consumer test data, although a recent survey suggested that this represents fewer than 5% of all germline genetic tests.

She also noted that the SEER registries do not collect data on family history or tumor sequencing.

The study was funded by the National Institutes of Health, and the Centers for Disease Control and Prevention. Dr. Kurian has relationships with Adela, Ambry Genetics, Color Genomics, GeneDx/BioReference, Genentech, InVitae, and Myriad Genetics. Other authors report numerous relationships with industry. Dr. Cobain has ties with AstraZeneca, Daiichi Sankyo, Athenex, Ayala Pharmaceuticals, bioTheranostics, and Immunomedics. Dr. Schrag has relationships with Merck, JAMA, AACR, and Grail. Dr. Stadler has ties with Adverum Biotechnologies, Genentech, Neurogene, Novartis, Optos Plc, Outlook Therapeutics, and Regeneron Pharmaceuticals.

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