A study of the nasal microbiome helped researchers predict recurrent polyps in chronic rhinosinusitis patients with more than 90% accuracy, based on data from 85 individuals.

Chronic rhinosinusitis with nasal polyps (CRSwNP) has a significant impact on patient quality of life, but the underlying mechanism of the disease has not been well studied, and treatment options remain limited, wrote Yan Zhao, MD, of Capital Medical University, Beijing, and study coauthors.

Previous research has shown that nasal microbiome composition differs in patients with and without asthma, and some studies suggest that changes in microbiota could contribute to CRSwNP, the authors wrote. The researchers wondered if features of the nasal microbiome can predict the recurrence of nasal polyps after endoscopic sinus surgery and serve as a potential treatment target.

In a study in Allergy, the researchers examined nasal swab samples from 85 adults with CRSwNP who underwent endoscopic sinus surgery between August 2014 and March 2016 at a single center in China. The researchers performed bacterial analysis and gene sequencing on all samples.

The patients ranged in age from 18-73 years, with a mean age of 46 years, and included 64 men and 21 women. The primary outcome was recurrence of polyps. Of the total, 39 individuals had recurrence, and 46 did not.

When the researchers compared microbiota from swab samples of recurrent and nonrecurrent patients, they found differences in composition based on bacterial genus abundance. “Campylobacter, Bdellovibrio, and Aggregatibacter, among others, were more abundant in swabs from CRSwNP recurrence samples, whereas Actinobacillus, Gemella, and Moraxella were more abundant in non-recurrence samples,” they wrote.

The researchers then tested their theory that distinct nasal microbiota could be a predictive marker of risk for future nasal polyp recurrence. They used a training set of 48 samples and constructed models from nasal microbiota alone, clinical features alone, and both together.

The regression model identified Porphyromonas, Bacteroides, Moryella, Aggregatibacter, Butyrivibrio, Shewanella, Pseudoxanthomonas, Friedmanniella, Limnobacter, and Curvibacter as the most important taxa that distinguished recurrence from nonrecurrence in the specimens. When the model was validated, the area under the curve was 0.914, yielding a predictor of nasal polyp recurrence with 91.4% accuracy.

“It is highly likely that proteins, nucleic acids, and other small molecules produced by nasal microbiota are associated with the progression of CRSwNP,” the researchers noted in their discussion of the findings. “Further, the nasal microbiota could maintain a stable community environment through the secretion of various chemical compounds and/or inflammatory factors, thus playing a central role in the development of CRSwNP.”

The study findings were limited by several factors, including the analysis of nasal flora only at the genus level in the screening phase, the use only of bioinformatic analysis for recurrence prediction, and the inclusion only of subjects from a single center, the researchers noted. Future studies should combine predictors to increase accuracy and include deeper sequencing, they said. However, the results support data from previous studies and suggest a strategy to meet the need for predictors of recurrence in CRSwNP, they concluded.

“There is a critical need to understand the role of the upper airway microbiome in different phenotypes of CRS,” said Emily K. Cope, PhD, assistant director at the Pathogen and Microbiome Institute, Northern Arizona University, Flagstaff, in an interview. “This was one of the first studies to evaluate the predictive power of the microbiome in recurrence of a common CRS phenotype – CRS with nasal polyps,” she said. “Importantly, the researchers were able to predict recurrence of polyps prior to the disease manifestation,” she noted.  

“Given the nascent state of current upper airway microbiome research, I was surprised that they were able to predict polyp recurrence prior to disease manifestation,” Dr. Cope said. “This is exciting, and I can imagine a future where we use microbiome data to understand risk for disease.”

What is the take-home message for clinicians? Although the immediate clinical implications are limited, Dr. Cope expressed enthusiasm for additional research. “At this point, there’s not a lot we can do without validation studies, but this study is promising. I hope we can understand the mechanism that an altered microbiome might drive (or be a result of) polyposis,” she said.

The study was supported by the National Natural Science Foundation of China, the program for the Changjiang scholars and innovative research team, the Beijing Bai-Qian-Wan talent project, the Public Welfare Development and Reform Pilot Project, the National Science and Technology Major Project, and the CAMS Innovation Fund for Medical Sciences. The researchers and Dr. Cope disclosed no financial conflicts.

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

A study of the nasal microbiome helped researchers predict recurrent polyps in chronic rhinosinusitis patients with more than 90% accuracy, based on data from 85 individuals.

Chronic rhinosinusitis with nasal polyps (CRSwNP) has a significant impact on patient quality of life, but the underlying mechanism of the disease has not been well studied, and treatment options remain limited, wrote Yan Zhao, MD, of Capital Medical University, Beijing, and study coauthors.

Previous research has shown that nasal microbiome composition differs in patients with and without asthma, and some studies suggest that changes in microbiota could contribute to CRSwNP, the authors wrote. The researchers wondered if features of the nasal microbiome can predict the recurrence of nasal polyps after endoscopic sinus surgery and serve as a potential treatment target.

In a study in Allergy, the researchers examined nasal swab samples from 85 adults with CRSwNP who underwent endoscopic sinus surgery between August 2014 and March 2016 at a single center in China. The researchers performed bacterial analysis and gene sequencing on all samples.

The patients ranged in age from 18-73 years, with a mean age of 46 years, and included 64 men and 21 women. The primary outcome was recurrence of polyps. Of the total, 39 individuals had recurrence, and 46 did not.

When the researchers compared microbiota from swab samples of recurrent and nonrecurrent patients, they found differences in composition based on bacterial genus abundance. “Campylobacter, Bdellovibrio, and Aggregatibacter, among others, were more abundant in swabs from CRSwNP recurrence samples, whereas Actinobacillus, Gemella, and Moraxella were more abundant in non-recurrence samples,” they wrote.

The researchers then tested their theory that distinct nasal microbiota could be a predictive marker of risk for future nasal polyp recurrence. They used a training set of 48 samples and constructed models from nasal microbiota alone, clinical features alone, and both together.

The regression model identified Porphyromonas, Bacteroides, Moryella, Aggregatibacter, Butyrivibrio, Shewanella, Pseudoxanthomonas, Friedmanniella, Limnobacter, and Curvibacter as the most important taxa that distinguished recurrence from nonrecurrence in the specimens. When the model was validated, the area under the curve was 0.914, yielding a predictor of nasal polyp recurrence with 91.4% accuracy.

“It is highly likely that proteins, nucleic acids, and other small molecules produced by nasal microbiota are associated with the progression of CRSwNP,” the researchers noted in their discussion of the findings. “Further, the nasal microbiota could maintain a stable community environment through the secretion of various chemical compounds and/or inflammatory factors, thus playing a central role in the development of CRSwNP.”

The study findings were limited by several factors, including the analysis of nasal flora only at the genus level in the screening phase, the use only of bioinformatic analysis for recurrence prediction, and the inclusion only of subjects from a single center, the researchers noted. Future studies should combine predictors to increase accuracy and include deeper sequencing, they said. However, the results support data from previous studies and suggest a strategy to meet the need for predictors of recurrence in CRSwNP, they concluded.

“There is a critical need to understand the role of the upper airway microbiome in different phenotypes of CRS,” said Emily K. Cope, PhD, assistant director at the Pathogen and Microbiome Institute, Northern Arizona University, Flagstaff, in an interview. “This was one of the first studies to evaluate the predictive power of the microbiome in recurrence of a common CRS phenotype – CRS with nasal polyps,” she said. “Importantly, the researchers were able to predict recurrence of polyps prior to the disease manifestation,” she noted.  

“Given the nascent state of current upper airway microbiome research, I was surprised that they were able to predict polyp recurrence prior to disease manifestation,” Dr. Cope said. “This is exciting, and I can imagine a future where we use microbiome data to understand risk for disease.”

What is the take-home message for clinicians? Although the immediate clinical implications are limited, Dr. Cope expressed enthusiasm for additional research. “At this point, there’s not a lot we can do without validation studies, but this study is promising. I hope we can understand the mechanism that an altered microbiome might drive (or be a result of) polyposis,” she said.

The study was supported by the National Natural Science Foundation of China, the program for the Changjiang scholars and innovative research team, the Beijing Bai-Qian-Wan talent project, the Public Welfare Development and Reform Pilot Project, the National Science and Technology Major Project, and the CAMS Innovation Fund for Medical Sciences. The researchers and Dr. Cope disclosed no financial conflicts.

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

A study of the nasal microbiome helped researchers predict recurrent polyps in chronic rhinosinusitis patients with more than 90% accuracy, based on data from 85 individuals.

Chronic rhinosinusitis with nasal polyps (CRSwNP) has a significant impact on patient quality of life, but the underlying mechanism of the disease has not been well studied, and treatment options remain limited, wrote Yan Zhao, MD, of Capital Medical University, Beijing, and study coauthors.

Previous research has shown that nasal microbiome composition differs in patients with and without asthma, and some studies suggest that changes in microbiota could contribute to CRSwNP, the authors wrote. The researchers wondered if features of the nasal microbiome can predict the recurrence of nasal polyps after endoscopic sinus surgery and serve as a potential treatment target.

In a study in Allergy, the researchers examined nasal swab samples from 85 adults with CRSwNP who underwent endoscopic sinus surgery between August 2014 and March 2016 at a single center in China. The researchers performed bacterial analysis and gene sequencing on all samples.

The patients ranged in age from 18-73 years, with a mean age of 46 years, and included 64 men and 21 women. The primary outcome was recurrence of polyps. Of the total, 39 individuals had recurrence, and 46 did not.

When the researchers compared microbiota from swab samples of recurrent and nonrecurrent patients, they found differences in composition based on bacterial genus abundance. “Campylobacter, Bdellovibrio, and Aggregatibacter, among others, were more abundant in swabs from CRSwNP recurrence samples, whereas Actinobacillus, Gemella, and Moraxella were more abundant in non-recurrence samples,” they wrote.

The researchers then tested their theory that distinct nasal microbiota could be a predictive marker of risk for future nasal polyp recurrence. They used a training set of 48 samples and constructed models from nasal microbiota alone, clinical features alone, and both together.

The regression model identified Porphyromonas, Bacteroides, Moryella, Aggregatibacter, Butyrivibrio, Shewanella, Pseudoxanthomonas, Friedmanniella, Limnobacter, and Curvibacter as the most important taxa that distinguished recurrence from nonrecurrence in the specimens. When the model was validated, the area under the curve was 0.914, yielding a predictor of nasal polyp recurrence with 91.4% accuracy.

“It is highly likely that proteins, nucleic acids, and other small molecules produced by nasal microbiota are associated with the progression of CRSwNP,” the researchers noted in their discussion of the findings. “Further, the nasal microbiota could maintain a stable community environment through the secretion of various chemical compounds and/or inflammatory factors, thus playing a central role in the development of CRSwNP.”

The study findings were limited by several factors, including the analysis of nasal flora only at the genus level in the screening phase, the use only of bioinformatic analysis for recurrence prediction, and the inclusion only of subjects from a single center, the researchers noted. Future studies should combine predictors to increase accuracy and include deeper sequencing, they said. However, the results support data from previous studies and suggest a strategy to meet the need for predictors of recurrence in CRSwNP, they concluded.

“There is a critical need to understand the role of the upper airway microbiome in different phenotypes of CRS,” said Emily K. Cope, PhD, assistant director at the Pathogen and Microbiome Institute, Northern Arizona University, Flagstaff, in an interview. “This was one of the first studies to evaluate the predictive power of the microbiome in recurrence of a common CRS phenotype – CRS with nasal polyps,” she said. “Importantly, the researchers were able to predict recurrence of polyps prior to the disease manifestation,” she noted.  

“Given the nascent state of current upper airway microbiome research, I was surprised that they were able to predict polyp recurrence prior to disease manifestation,” Dr. Cope said. “This is exciting, and I can imagine a future where we use microbiome data to understand risk for disease.”

What is the take-home message for clinicians? Although the immediate clinical implications are limited, Dr. Cope expressed enthusiasm for additional research. “At this point, there’s not a lot we can do without validation studies, but this study is promising. I hope we can understand the mechanism that an altered microbiome might drive (or be a result of) polyposis,” she said.

The study was supported by the National Natural Science Foundation of China, the program for the Changjiang scholars and innovative research team, the Beijing Bai-Qian-Wan talent project, the Public Welfare Development and Reform Pilot Project, the National Science and Technology Major Project, and the CAMS Innovation Fund for Medical Sciences. The researchers and Dr. Cope disclosed no financial conflicts.

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

Legionnaires’ disease (LD) in the United States appears to be on an upswing that started in 2003, according to a study from the Centers for Disease Control and Prevention.

The reasons for this increased incidence are unclear, the researchers write in Emerging Infectious Diseases.

“The findings revealed a rising national trend in cases, widening racial disparities between Black or African American persons and White persons, and an increasing geographic focus in the Middle Atlantic, the East North Central, and New England,” lead author Albert E. Barskey, MPH, an epidemiologist in CDC’s Division of Bacterial Diseases, Atlanta, said in an email.

“Legionnaires’ disease cannot be diagnosed based on clinical features alone, and studies estimate that it is underdiagnosed, perhaps by 50%,” he added. “Our findings may serve to heighten clinicians’ awareness of this severe pneumonia’s etiology, so with an earlier correct diagnosis, appropriate treatment can be rendered sooner.”

Mr. Barskey and his coauthors at CDC – mathematical statistician Gordana Derado, PhD, and epidemiologist Chris Edens, PhD – used surveillance data to investigate the incidence of LD in the U.S. over time. They compared LD incidence in 2018 with average incidence between 1992 and 2002. The incidence data, from over 80,000 LD cases, were age-standardized using the 2005 U.S. standard population as the reference.

The researchers analyzed LD data reported to CDC by the 50 states, New York City, and Washington, D.C., through the National Notifiable Diseases Surveillance System. They performed regression analysis to identify the optimal year when population parameters changed, and for most analyses, they compared 1992-2002 data with 2003-2018 data.
 

Legionnaires’ disease up in various groups

• The overall age-standardized average incidence grew from 0.48 per 100,000 people during 1992-2002 to 2.71 per 100,000 in 2018 (incidence risk ratio, 5.67; 95% confidence interval, 5.52-5.83).
• LD incidence more than quintupled for people over 34 years of age, with the largest relative increase in those over 85 (RR, 6.50; 95% CI, 5.82-7.27).
• Incidence in men increased slightly more (RR, 5.86; 95% CI, 5.67-6.05) than in women (RR, 5.29; 95% CI, 5.06-5.53).
• Over the years, the racial disparity in incidence grew markedly. Incidence in Black persons increased from 0.47 to 5.21 per 100,000 (RR, 11.04; 95% CI, 10.39-11.73), compared with an increase from 0.37 to 1.99 per 100,000 in White persons (RR, 5.30; 95% CI, 5.12-5.49).
• The relative increase in incidence was highest in the Northeast (RR, 7.04; 95% CI, 6.70-7.40), followed by the Midwest (RR, 6.13; 95% CI, 5.85-6.42), the South (RR, 5.97; 95% CI, 5.67-6.29), and the West (RR, 3.39; 95% CI, 3.11-3.68).

Most LD cases occurred in summer or fall, and the seasonal pattern became more pronounced over time. The average of 57.8% of cases between June and November during 1992-2002 grew to 68.9% in 2003-2018.

Although the study “was hindered by incomplete race and ethnicity data,” Mr. Barskey said, “its breadth was a strength.”
 

Consider legionella in your diagnosis

In an interview, Paul G. Auwaerter, MD, a professor of medicine and the clinical director of the Division of Infectious Diseases at Johns Hopkins University School of Medicine, Baltimore, said he was not surprised by the results. “CDC has been reporting increased incidence of Legionnaires’ disease from water source outbreaks over the years. As a clinician, I very much depend on epidemiologic trends to help me understand the patient in front of me.

“The key point is that there’s more of it around, so consider it in your diagnosis,” he advised.

“Physicians are increasingly beginning to consider Legionella. Because LD is difficult to diagnose by traditional methods such as culture, they may use a PCR test,” said Dr. Auwaerter, who was not involved in the study. “Legionella needs antibiotics that differ a bit from traditional antibiotics used to treat bacterial pneumonia, so a correct diagnosis can inform a more directed therapy.”

“Why the incidence is increasing is the big question, and the authors nicely outline a litany of things,” he said.

The authors and Dr. Auwaerter proposed a number of possible contributing factors to the increased incidence:

• an aging population
• aging municipal and residential water sources that may harbor more organisms
• racial disparities and poverty
• underlying conditions, including diabetes, end-stage renal disease, and some cancers
• occupations in transportation, repair, cleaning services, and construction
• weather patterns
• improved surveillance and reporting

“Why Legionella appears in some locations more than others has not been explained,” Dr. Auwaerter added. “For example, Pittsburgh always seemed to have much more Legionella than Baltimore.”

Mr. Barskey and his team are planning further research into racial disparities and links between weather and climate and Legionnaires’ disease.

The authors are employees of CDC. Dr. Auwaerter has disclosed no relevant financial realtionships.

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

Legionnaires’ disease (LD) in the United States appears to be on an upswing that started in 2003, according to a study from the Centers for Disease Control and Prevention.

The reasons for this increased incidence are unclear, the researchers write in Emerging Infectious Diseases.

“The findings revealed a rising national trend in cases, widening racial disparities between Black or African American persons and White persons, and an increasing geographic focus in the Middle Atlantic, the East North Central, and New England,” lead author Albert E. Barskey, MPH, an epidemiologist in CDC’s Division of Bacterial Diseases, Atlanta, said in an email.

“Legionnaires’ disease cannot be diagnosed based on clinical features alone, and studies estimate that it is underdiagnosed, perhaps by 50%,” he added. “Our findings may serve to heighten clinicians’ awareness of this severe pneumonia’s etiology, so with an earlier correct diagnosis, appropriate treatment can be rendered sooner.”

Mr. Barskey and his coauthors at CDC – mathematical statistician Gordana Derado, PhD, and epidemiologist Chris Edens, PhD – used surveillance data to investigate the incidence of LD in the U.S. over time. They compared LD incidence in 2018 with average incidence between 1992 and 2002. The incidence data, from over 80,000 LD cases, were age-standardized using the 2005 U.S. standard population as the reference.

The researchers analyzed LD data reported to CDC by the 50 states, New York City, and Washington, D.C., through the National Notifiable Diseases Surveillance System. They performed regression analysis to identify the optimal year when population parameters changed, and for most analyses, they compared 1992-2002 data with 2003-2018 data.
 

Legionnaires’ disease up in various groups

• The overall age-standardized average incidence grew from 0.48 per 100,000 people during 1992-2002 to 2.71 per 100,000 in 2018 (incidence risk ratio, 5.67; 95% confidence interval, 5.52-5.83).
• LD incidence more than quintupled for people over 34 years of age, with the largest relative increase in those over 85 (RR, 6.50; 95% CI, 5.82-7.27).
• Incidence in men increased slightly more (RR, 5.86; 95% CI, 5.67-6.05) than in women (RR, 5.29; 95% CI, 5.06-5.53).
• Over the years, the racial disparity in incidence grew markedly. Incidence in Black persons increased from 0.47 to 5.21 per 100,000 (RR, 11.04; 95% CI, 10.39-11.73), compared with an increase from 0.37 to 1.99 per 100,000 in White persons (RR, 5.30; 95% CI, 5.12-5.49).
• The relative increase in incidence was highest in the Northeast (RR, 7.04; 95% CI, 6.70-7.40), followed by the Midwest (RR, 6.13; 95% CI, 5.85-6.42), the South (RR, 5.97; 95% CI, 5.67-6.29), and the West (RR, 3.39; 95% CI, 3.11-3.68).

Most LD cases occurred in summer or fall, and the seasonal pattern became more pronounced over time. The average of 57.8% of cases between June and November during 1992-2002 grew to 68.9% in 2003-2018.

Although the study “was hindered by incomplete race and ethnicity data,” Mr. Barskey said, “its breadth was a strength.”
 

Consider legionella in your diagnosis

In an interview, Paul G. Auwaerter, MD, a professor of medicine and the clinical director of the Division of Infectious Diseases at Johns Hopkins University School of Medicine, Baltimore, said he was not surprised by the results. “CDC has been reporting increased incidence of Legionnaires’ disease from water source outbreaks over the years. As a clinician, I very much depend on epidemiologic trends to help me understand the patient in front of me.

“The key point is that there’s more of it around, so consider it in your diagnosis,” he advised.

“Physicians are increasingly beginning to consider Legionella. Because LD is difficult to diagnose by traditional methods such as culture, they may use a PCR test,” said Dr. Auwaerter, who was not involved in the study. “Legionella needs antibiotics that differ a bit from traditional antibiotics used to treat bacterial pneumonia, so a correct diagnosis can inform a more directed therapy.”

“Why the incidence is increasing is the big question, and the authors nicely outline a litany of things,” he said.

The authors and Dr. Auwaerter proposed a number of possible contributing factors to the increased incidence:

• an aging population
• aging municipal and residential water sources that may harbor more organisms
• racial disparities and poverty
• underlying conditions, including diabetes, end-stage renal disease, and some cancers
• occupations in transportation, repair, cleaning services, and construction
• weather patterns
• improved surveillance and reporting

“Why Legionella appears in some locations more than others has not been explained,” Dr. Auwaerter added. “For example, Pittsburgh always seemed to have much more Legionella than Baltimore.”

Mr. Barskey and his team are planning further research into racial disparities and links between weather and climate and Legionnaires’ disease.

The authors are employees of CDC. Dr. Auwaerter has disclosed no relevant financial realtionships.

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

Legionnaires’ disease (LD) in the United States appears to be on an upswing that started in 2003, according to a study from the Centers for Disease Control and Prevention.

The reasons for this increased incidence are unclear, the researchers write in Emerging Infectious Diseases.

“The findings revealed a rising national trend in cases, widening racial disparities between Black or African American persons and White persons, and an increasing geographic focus in the Middle Atlantic, the East North Central, and New England,” lead author Albert E. Barskey, MPH, an epidemiologist in CDC’s Division of Bacterial Diseases, Atlanta, said in an email.

“Legionnaires’ disease cannot be diagnosed based on clinical features alone, and studies estimate that it is underdiagnosed, perhaps by 50%,” he added. “Our findings may serve to heighten clinicians’ awareness of this severe pneumonia’s etiology, so with an earlier correct diagnosis, appropriate treatment can be rendered sooner.”

Mr. Barskey and his coauthors at CDC – mathematical statistician Gordana Derado, PhD, and epidemiologist Chris Edens, PhD – used surveillance data to investigate the incidence of LD in the U.S. over time. They compared LD incidence in 2018 with average incidence between 1992 and 2002. The incidence data, from over 80,000 LD cases, were age-standardized using the 2005 U.S. standard population as the reference.

The researchers analyzed LD data reported to CDC by the 50 states, New York City, and Washington, D.C., through the National Notifiable Diseases Surveillance System. They performed regression analysis to identify the optimal year when population parameters changed, and for most analyses, they compared 1992-2002 data with 2003-2018 data.
 

Legionnaires’ disease up in various groups

• The overall age-standardized average incidence grew from 0.48 per 100,000 people during 1992-2002 to 2.71 per 100,000 in 2018 (incidence risk ratio, 5.67; 95% confidence interval, 5.52-5.83).
• LD incidence more than quintupled for people over 34 years of age, with the largest relative increase in those over 85 (RR, 6.50; 95% CI, 5.82-7.27).
• Incidence in men increased slightly more (RR, 5.86; 95% CI, 5.67-6.05) than in women (RR, 5.29; 95% CI, 5.06-5.53).
• Over the years, the racial disparity in incidence grew markedly. Incidence in Black persons increased from 0.47 to 5.21 per 100,000 (RR, 11.04; 95% CI, 10.39-11.73), compared with an increase from 0.37 to 1.99 per 100,000 in White persons (RR, 5.30; 95% CI, 5.12-5.49).
• The relative increase in incidence was highest in the Northeast (RR, 7.04; 95% CI, 6.70-7.40), followed by the Midwest (RR, 6.13; 95% CI, 5.85-6.42), the South (RR, 5.97; 95% CI, 5.67-6.29), and the West (RR, 3.39; 95% CI, 3.11-3.68).

Most LD cases occurred in summer or fall, and the seasonal pattern became more pronounced over time. The average of 57.8% of cases between June and November during 1992-2002 grew to 68.9% in 2003-2018.

Although the study “was hindered by incomplete race and ethnicity data,” Mr. Barskey said, “its breadth was a strength.”
 

Consider legionella in your diagnosis

In an interview, Paul G. Auwaerter, MD, a professor of medicine and the clinical director of the Division of Infectious Diseases at Johns Hopkins University School of Medicine, Baltimore, said he was not surprised by the results. “CDC has been reporting increased incidence of Legionnaires’ disease from water source outbreaks over the years. As a clinician, I very much depend on epidemiologic trends to help me understand the patient in front of me.

“The key point is that there’s more of it around, so consider it in your diagnosis,” he advised.

“Physicians are increasingly beginning to consider Legionella. Because LD is difficult to diagnose by traditional methods such as culture, they may use a PCR test,” said Dr. Auwaerter, who was not involved in the study. “Legionella needs antibiotics that differ a bit from traditional antibiotics used to treat bacterial pneumonia, so a correct diagnosis can inform a more directed therapy.”

“Why the incidence is increasing is the big question, and the authors nicely outline a litany of things,” he said.

The authors and Dr. Auwaerter proposed a number of possible contributing factors to the increased incidence:

• an aging population
• aging municipal and residential water sources that may harbor more organisms
• racial disparities and poverty
• underlying conditions, including diabetes, end-stage renal disease, and some cancers
• occupations in transportation, repair, cleaning services, and construction
• weather patterns
• improved surveillance and reporting

“Why Legionella appears in some locations more than others has not been explained,” Dr. Auwaerter added. “For example, Pittsburgh always seemed to have much more Legionella than Baltimore.”

Mr. Barskey and his team are planning further research into racial disparities and links between weather and climate and Legionnaires’ disease.

The authors are employees of CDC. Dr. Auwaerter has disclosed no relevant financial realtionships.

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

Workers who had the highest exposure to hydrocarbons during the Deepwater Horizon oil spill disaster had a higher risk of having a hypertension diagnosis in the years following the event, a new study suggests.

Results showed that the highest exposure to total petroleum hydrocarbons during the cleanup operation was associated with a 31% higher risk of new hypertension 1-3 years later.

“What is remarkable is that we still found an increased risk of hypertension a couple of years after the cleanup had been completed. This suggests working in this environment even for a short period could have long-term health consequences,” lead author Richard Kwok, PhD, told this news organization.

The study was published online in JAMA Network Open.

For the study, Dr. Kwok, a scientist at the U.S. National Institute of Environmental Health Sciences, and colleagues estimated the levels of exposure to toxic hydrocarbons in 6,846 adults who had worked on the oil spill cleanup after the Deepwater Horizon disaster in 2010, during which 200 million gallons of oil spilled into the Gulf of Mexico. They then investigated whether there was an association with the development of hypertension 1-3 years later.

“Clean-up efforts started almost immediately and lasted over a year,” Dr. Kwok noted. “In the first few months, oil flowed freely into the Gulf of Mexico which released high levels of volatile organic compounds into the air that the workers could have been exposed to. The exposures change over time because the oil becomes weathered and starts to decompose and harden. This is associated with a lower level of volatile organic compounds but can still cause damage.”

Workers involved in the cleanup may have been there for just a few days or could have spent many months at the site and would have had different exposures depending on what types of jobs they were doing, Dr. Kwok reported.

“The highest levels of exposure to total hydrocarbons would have been to those involved in the early months of the oil spill response and cleanup when the oil was flowing freely, and those who were skimming oil off the water, burning oil, handling dispersants, or involved in the decontamination of the vessels. Others who were involved in the cleanup on land or support functions would have had lower exposures,” he said.

Each worker was interviewed and asked about their activities during the cleanup operation, the location of work, and period of work. Their level of exposure to total petroleum hydrocarbons (THCs) was estimated based on their self-reported activities, and when and where they worked.

Two measures of estimated cumulative THC were calculated: cumulative maximum daily exposure, which summed the maximum daily THC exposure level, and cumulative mean exposure, which summed the mean daily exposure levels. These THC values were categorized into quintiles based on the exposure distribution among workers.

Systolic and diastolic blood pressure measurements were collected for the workers during home exams from 2011 to 2013 using automated oscillometric monitors. Newly detected hypertension was defined as either antihypertensive medication use or elevated blood pressure since the spill.

Results showed a clear dose relationship between the level of THC exposure and the development of hypertension at follow-up.

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

Workers who had the highest exposure to hydrocarbons during the Deepwater Horizon oil spill disaster had a higher risk of having a hypertension diagnosis in the years following the event, a new study suggests.

Results showed that the highest exposure to total petroleum hydrocarbons during the cleanup operation was associated with a 31% higher risk of new hypertension 1-3 years later.

“What is remarkable is that we still found an increased risk of hypertension a couple of years after the cleanup had been completed. This suggests working in this environment even for a short period could have long-term health consequences,” lead author Richard Kwok, PhD, told this news organization.

The study was published online in JAMA Network Open.

For the study, Dr. Kwok, a scientist at the U.S. National Institute of Environmental Health Sciences, and colleagues estimated the levels of exposure to toxic hydrocarbons in 6,846 adults who had worked on the oil spill cleanup after the Deepwater Horizon disaster in 2010, during which 200 million gallons of oil spilled into the Gulf of Mexico. They then investigated whether there was an association with the development of hypertension 1-3 years later.

“Clean-up efforts started almost immediately and lasted over a year,” Dr. Kwok noted. “In the first few months, oil flowed freely into the Gulf of Mexico which released high levels of volatile organic compounds into the air that the workers could have been exposed to. The exposures change over time because the oil becomes weathered and starts to decompose and harden. This is associated with a lower level of volatile organic compounds but can still cause damage.”

Workers involved in the cleanup may have been there for just a few days or could have spent many months at the site and would have had different exposures depending on what types of jobs they were doing, Dr. Kwok reported.

“The highest levels of exposure to total hydrocarbons would have been to those involved in the early months of the oil spill response and cleanup when the oil was flowing freely, and those who were skimming oil off the water, burning oil, handling dispersants, or involved in the decontamination of the vessels. Others who were involved in the cleanup on land or support functions would have had lower exposures,” he said.

Each worker was interviewed and asked about their activities during the cleanup operation, the location of work, and period of work. Their level of exposure to total petroleum hydrocarbons (THCs) was estimated based on their self-reported activities, and when and where they worked.

Two measures of estimated cumulative THC were calculated: cumulative maximum daily exposure, which summed the maximum daily THC exposure level, and cumulative mean exposure, which summed the mean daily exposure levels. These THC values were categorized into quintiles based on the exposure distribution among workers.

Systolic and diastolic blood pressure measurements were collected for the workers during home exams from 2011 to 2013 using automated oscillometric monitors. Newly detected hypertension was defined as either antihypertensive medication use or elevated blood pressure since the spill.

Results showed a clear dose relationship between the level of THC exposure and the development of hypertension at follow-up.

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

Workers who had the highest exposure to hydrocarbons during the Deepwater Horizon oil spill disaster had a higher risk of having a hypertension diagnosis in the years following the event, a new study suggests.

Results showed that the highest exposure to total petroleum hydrocarbons during the cleanup operation was associated with a 31% higher risk of new hypertension 1-3 years later.

“What is remarkable is that we still found an increased risk of hypertension a couple of years after the cleanup had been completed. This suggests working in this environment even for a short period could have long-term health consequences,” lead author Richard Kwok, PhD, told this news organization.

The study was published online in JAMA Network Open.

For the study, Dr. Kwok, a scientist at the U.S. National Institute of Environmental Health Sciences, and colleagues estimated the levels of exposure to toxic hydrocarbons in 6,846 adults who had worked on the oil spill cleanup after the Deepwater Horizon disaster in 2010, during which 200 million gallons of oil spilled into the Gulf of Mexico. They then investigated whether there was an association with the development of hypertension 1-3 years later.

“Clean-up efforts started almost immediately and lasted over a year,” Dr. Kwok noted. “In the first few months, oil flowed freely into the Gulf of Mexico which released high levels of volatile organic compounds into the air that the workers could have been exposed to. The exposures change over time because the oil becomes weathered and starts to decompose and harden. This is associated with a lower level of volatile organic compounds but can still cause damage.”

Workers involved in the cleanup may have been there for just a few days or could have spent many months at the site and would have had different exposures depending on what types of jobs they were doing, Dr. Kwok reported.

“The highest levels of exposure to total hydrocarbons would have been to those involved in the early months of the oil spill response and cleanup when the oil was flowing freely, and those who were skimming oil off the water, burning oil, handling dispersants, or involved in the decontamination of the vessels. Others who were involved in the cleanup on land or support functions would have had lower exposures,” he said.

Each worker was interviewed and asked about their activities during the cleanup operation, the location of work, and period of work. Their level of exposure to total petroleum hydrocarbons (THCs) was estimated based on their self-reported activities, and when and where they worked.

Two measures of estimated cumulative THC were calculated: cumulative maximum daily exposure, which summed the maximum daily THC exposure level, and cumulative mean exposure, which summed the mean daily exposure levels. These THC values were categorized into quintiles based on the exposure distribution among workers.

Systolic and diastolic blood pressure measurements were collected for the workers during home exams from 2011 to 2013 using automated oscillometric monitors. Newly detected hypertension was defined as either antihypertensive medication use or elevated blood pressure since the spill.

Results showed a clear dose relationship between the level of THC exposure and the development of hypertension at follow-up.

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

Mirikizumab is the first interleukin (IL) 23p19 to report positive phase 3 results for induction therapy in patients who have moderate to severe ulcerative colitis (UC) and have already been treated with at least one prior therapy.

Compared to placebo, almost a quarter (24.2%) of patients treated with mirikizumab versus 13% of those treated with placebo were in clinical remission at the end of the 12-week LUCENT-1 study. This was the study’s primary endpoint and it was a significant result (P = .00006), study investigator Geert D’Haens, MD, PhD, reported at the 17th congress of the European Crohn’s and Colitis Organisation.

Moreover, mirikizumab met all its secondary endpoints in the trial. At the end of the study almost two-thirds (63.5%) of patients achieved a clinical response (vs. 42.2% in the placebo arm); over one-third (36.3%) exhibited endoscopic remission (vs. 21.1%), and just over a quarter (27.1% vs. 13.9%) showed histologic-endoscopic mucosal improvement, according to a press release. The P values for all comparisons were less than .00001.

Perhaps more importantly from the patient perspective, there was greater symptomatic improvement and less bowel urgency in those treated with mirikizumab versus those randomized to placebo.

“The results confirmed [the] efficacy and safety noted in the phase 2 induction [trials], and supports mirikizumab’s potential as treatment for ulcerative colitis,” said Dr. D’Haens, professor of gastroenterology and hepatology at Amsterdam University Medical Centers.

Dominik Bettenworth, MD, who was not involved in the study, said that “the positive results from the LUCENT-1 trial are an important step towards selective IL-23 inhibition as a new mode of action for the treatment of patients with UC.

“This treatment approach has been shown efficacious and launched in other immune-mediated diseases such as psoriasis,” said Dr. Bettenworth, a specialist in internal medicine and gastroenterology in Münster, Germany.

“Noteworthy, for the first time in a phase 3 trial in IBD, [bowel] urgency has been assessed as a secondary endpoint – a clinical symptom of particular importance for patients with UC,” he added, noting that regarding safety, “the LUCENT-1 trial further confirms the previously observed overall good safety profile of IL-23 inhibitors.”
 

About mirikizumab and LUCENT-1

Mirikizumab is a humanized monoclonal antibody directed against the p19 subunit of IL-23 and is one of several IL23p19 antibodies currently under investigation for the treatment of IBD.

LUCENT-1 was a multicenter, randomized, double-blind, parallel group, placebo-controlled induction study in just over 1,200 patients aged 18-80 years. For inclusion, patients had to have moderately to severely active UC and had to have received at least one prior therapy, but had an inadequate or loss of response to it or been intolerant of it. Baseline data showed that 40% of patients included had been treated with corticosteroids and 24% with immunomodulators, and any current treatment remained unchanged during the study. Biologic treatment had failed in about 40% of patients and any patient taking such therapy had to discontinue it before participating in the trial.

Patients were randomized to receive 300 mg of mirikizumab or matching placebo, given intravenously at weeks 0, 4, and 8. Dr. D’Haens noted that randomization had been in a 3:1 ratio and had been stratified according to various factors such as biologic failure status, corticosteroid use, baseline disease activity, and region of the world where the patient was recruited.
 

Better results if biologic naive

Clinical remission was stringently defined as: Mayo stool frequency subscore of zero or one, with a reduction of one point or greater from baseline; no rectal bleeding; and a Mayo endoscopic subscore of zero to one. When looking at this primary endpoint in terms of whether patients had received prior biologic treatment, there was a higher remission rate at week 12 if patients had not previously been given any biologic therapy than if they had, but rates were still higher than placebo (30.9% vs. 15.8% and 15.2% vs. 8.5%, respectively), according to the press release. The P value was less than .001 for both comparisons although the study was not powered to look at these subgroups of patients.

Similarly, for clinical response – which was a decrease in the modified Mayo score of 2 or more points and at least a 30% decrease from initial values, as well as a decrease in rectal bleeding – there were differences between patients who had (54.6% for mirikizumab vs. 29.7% for placebo) and had not (70.1% vs. 50.3%) received a biologic previously (again, P less than .001 for both comparisons).

“Control of bowel function is one of the most debilitating, or one of the most important features for patients with ulcerative colitis,” Dr. D’Haens said when presenting the data on bowel urgency. In the trial there was an improvement in urgency – which was rated by patients – starting as early as week 2, with further improvement seen as the induction period went on.
 

Mirikizumab safety consistent with other trials

Dr. D’Haens noted that the safety profile of IL23 antibodies was “extremely clean.” As with other trials of mirikizumab, he said, there were similar or lower rates to placebo for many adverse events including any infection (15.1% vs. 14%) and cerebrocardiovascular events (0.6% vs. 0.1%). The overall rate of treatment emergent adverse events was 44.5% vs. 46.1% for mirikizumab and placebo. Notably, there were fewer serious adverse events (2.8% vs. 5.3%.) and discontinuations because of side effects (1.6% vs. 7.2%) in the mirikizumab group.

Are gastroenterologists now spoiled for choice?

Lots of questions followed Dr. D’Haens presentation, many picking up on the high placebo response and remission rates.

“We’ve seen it in a number of trials now,” Dr. D’Haens said. “One of the reasons is that patients are allowed to start corticosteroids as late as 2 weeks before randomization,” he observed. In LUCENT-1, half of the patients that were using steroids were receiving a dose of 20 mg of prednisone.

“Now when you start 20 mg of prednisone 2 weeks before randomization that might have an impact on your placebo readout. So I think that’s a lesson for many more trials in the future,” Dr. D’Haens said,”

A high placebo response rate was not expected and another hypothesis is that maybe additional clinical support for fatigue that was received may have played a role.

Several delegates asked for guidance on where mirikizumab and other IL-23p19 blockers might now fit in the grand scheme of patient treatment.

“It is really nice to have expanding therapeutic options but how will we choose?” said one in the online Q&A. “Which IL23 antagonist should we be using now?” and “Is ustekinumab obsolete in UC?” asked others.

“I think it’s early days to decide where the field is going,” Dr. D’Haens said after his presentation. “We don’t have head-to-head data. In GALAXI, ustekinumab was a reference arm.”

There will be further subanalyses of LUCENT-1 to come, including results from endoscopy and histology investigations, and the maintenance trial LUCENT-2 will also report soon.

“The feeling is that IL23 blockade is more specific, [more] beneficial in inflammatory bowel disease than blocking both IL12 and IL23,” Dr. D’Haens said.

Dr. D’Haens was an investigator in the LUCENT-1 trial and has acted as an adviser to the study’s sponsor, Eli Lilly, among many other big pharma companies. Dr. Bettenworth is on the advisory board or is a consultant for AbbVie, Amgen, Arena, Atheneum, BNG Service GmbH, Bristol Myers Squibb, CED-Service GmbH, Celltrion, Else Kröner-Fresenius-Foundation, Galapagos, Guidepoint, Impulze, Falk Foundation, Ferring, Janssen Cilag, Medical Tribune, MedTriX, MSD, Mylan, Onkowissen, Pharmacosmos, Pfizer, Roche, Sandoz, Takeda, Tetrameros, Thieme, Tillotts Pharma, and Vifor Pharma.

Mirikizumab is the first interleukin (IL) 23p19 to report positive phase 3 results for induction therapy in patients who have moderate to severe ulcerative colitis (UC) and have already been treated with at least one prior therapy.

Compared to placebo, almost a quarter (24.2%) of patients treated with mirikizumab versus 13% of those treated with placebo were in clinical remission at the end of the 12-week LUCENT-1 study. This was the study’s primary endpoint and it was a significant result (P = .00006), study investigator Geert D’Haens, MD, PhD, reported at the 17th congress of the European Crohn’s and Colitis Organisation.

Moreover, mirikizumab met all its secondary endpoints in the trial. At the end of the study almost two-thirds (63.5%) of patients achieved a clinical response (vs. 42.2% in the placebo arm); over one-third (36.3%) exhibited endoscopic remission (vs. 21.1%), and just over a quarter (27.1% vs. 13.9%) showed histologic-endoscopic mucosal improvement, according to a press release. The P values for all comparisons were less than .00001.

Perhaps more importantly from the patient perspective, there was greater symptomatic improvement and less bowel urgency in those treated with mirikizumab versus those randomized to placebo.

“The results confirmed [the] efficacy and safety noted in the phase 2 induction [trials], and supports mirikizumab’s potential as treatment for ulcerative colitis,” said Dr. D’Haens, professor of gastroenterology and hepatology at Amsterdam University Medical Centers.

Dominik Bettenworth, MD, who was not involved in the study, said that “the positive results from the LUCENT-1 trial are an important step towards selective IL-23 inhibition as a new mode of action for the treatment of patients with UC.

“This treatment approach has been shown efficacious and launched in other immune-mediated diseases such as psoriasis,” said Dr. Bettenworth, a specialist in internal medicine and gastroenterology in Münster, Germany.

“Noteworthy, for the first time in a phase 3 trial in IBD, [bowel] urgency has been assessed as a secondary endpoint – a clinical symptom of particular importance for patients with UC,” he added, noting that regarding safety, “the LUCENT-1 trial further confirms the previously observed overall good safety profile of IL-23 inhibitors.”
 

About mirikizumab and LUCENT-1

Mirikizumab is a humanized monoclonal antibody directed against the p19 subunit of IL-23 and is one of several IL23p19 antibodies currently under investigation for the treatment of IBD.

LUCENT-1 was a multicenter, randomized, double-blind, parallel group, placebo-controlled induction study in just over 1,200 patients aged 18-80 years. For inclusion, patients had to have moderately to severely active UC and had to have received at least one prior therapy, but had an inadequate or loss of response to it or been intolerant of it. Baseline data showed that 40% of patients included had been treated with corticosteroids and 24% with immunomodulators, and any current treatment remained unchanged during the study. Biologic treatment had failed in about 40% of patients and any patient taking such therapy had to discontinue it before participating in the trial.

Patients were randomized to receive 300 mg of mirikizumab or matching placebo, given intravenously at weeks 0, 4, and 8. Dr. D’Haens noted that randomization had been in a 3:1 ratio and had been stratified according to various factors such as biologic failure status, corticosteroid use, baseline disease activity, and region of the world where the patient was recruited.
 

Better results if biologic naive

Clinical remission was stringently defined as: Mayo stool frequency subscore of zero or one, with a reduction of one point or greater from baseline; no rectal bleeding; and a Mayo endoscopic subscore of zero to one. When looking at this primary endpoint in terms of whether patients had received prior biologic treatment, there was a higher remission rate at week 12 if patients had not previously been given any biologic therapy than if they had, but rates were still higher than placebo (30.9% vs. 15.8% and 15.2% vs. 8.5%, respectively), according to the press release. The P value was less than .001 for both comparisons although the study was not powered to look at these subgroups of patients.

Similarly, for clinical response – which was a decrease in the modified Mayo score of 2 or more points and at least a 30% decrease from initial values, as well as a decrease in rectal bleeding – there were differences between patients who had (54.6% for mirikizumab vs. 29.7% for placebo) and had not (70.1% vs. 50.3%) received a biologic previously (again, P less than .001 for both comparisons).

“Control of bowel function is one of the most debilitating, or one of the most important features for patients with ulcerative colitis,” Dr. D’Haens said when presenting the data on bowel urgency. In the trial there was an improvement in urgency – which was rated by patients – starting as early as week 2, with further improvement seen as the induction period went on.
 

Mirikizumab safety consistent with other trials

Dr. D’Haens noted that the safety profile of IL23 antibodies was “extremely clean.” As with other trials of mirikizumab, he said, there were similar or lower rates to placebo for many adverse events including any infection (15.1% vs. 14%) and cerebrocardiovascular events (0.6% vs. 0.1%). The overall rate of treatment emergent adverse events was 44.5% vs. 46.1% for mirikizumab and placebo. Notably, there were fewer serious adverse events (2.8% vs. 5.3%.) and discontinuations because of side effects (1.6% vs. 7.2%) in the mirikizumab group.

Are gastroenterologists now spoiled for choice?

Lots of questions followed Dr. D’Haens presentation, many picking up on the high placebo response and remission rates.

“We’ve seen it in a number of trials now,” Dr. D’Haens said. “One of the reasons is that patients are allowed to start corticosteroids as late as 2 weeks before randomization,” he observed. In LUCENT-1, half of the patients that were using steroids were receiving a dose of 20 mg of prednisone.

“Now when you start 20 mg of prednisone 2 weeks before randomization that might have an impact on your placebo readout. So I think that’s a lesson for many more trials in the future,” Dr. D’Haens said,”

A high placebo response rate was not expected and another hypothesis is that maybe additional clinical support for fatigue that was received may have played a role.

Several delegates asked for guidance on where mirikizumab and other IL-23p19 blockers might now fit in the grand scheme of patient treatment.

“It is really nice to have expanding therapeutic options but how will we choose?” said one in the online Q&A. “Which IL23 antagonist should we be using now?” and “Is ustekinumab obsolete in UC?” asked others.

“I think it’s early days to decide where the field is going,” Dr. D’Haens said after his presentation. “We don’t have head-to-head data. In GALAXI, ustekinumab was a reference arm.”

There will be further subanalyses of LUCENT-1 to come, including results from endoscopy and histology investigations, and the maintenance trial LUCENT-2 will also report soon.

“The feeling is that IL23 blockade is more specific, [more] beneficial in inflammatory bowel disease than blocking both IL12 and IL23,” Dr. D’Haens said.

Dr. D’Haens was an investigator in the LUCENT-1 trial and has acted as an adviser to the study’s sponsor, Eli Lilly, among many other big pharma companies. Dr. Bettenworth is on the advisory board or is a consultant for AbbVie, Amgen, Arena, Atheneum, BNG Service GmbH, Bristol Myers Squibb, CED-Service GmbH, Celltrion, Else Kröner-Fresenius-Foundation, Galapagos, Guidepoint, Impulze, Falk Foundation, Ferring, Janssen Cilag, Medical Tribune, MedTriX, MSD, Mylan, Onkowissen, Pharmacosmos, Pfizer, Roche, Sandoz, Takeda, Tetrameros, Thieme, Tillotts Pharma, and Vifor Pharma.

Mirikizumab is the first interleukin (IL) 23p19 to report positive phase 3 results for induction therapy in patients who have moderate to severe ulcerative colitis (UC) and have already been treated with at least one prior therapy.

Compared to placebo, almost a quarter (24.2%) of patients treated with mirikizumab versus 13% of those treated with placebo were in clinical remission at the end of the 12-week LUCENT-1 study. This was the study’s primary endpoint and it was a significant result (P = .00006), study investigator Geert D’Haens, MD, PhD, reported at the 17th congress of the European Crohn’s and Colitis Organisation.

Moreover, mirikizumab met all its secondary endpoints in the trial. At the end of the study almost two-thirds (63.5%) of patients achieved a clinical response (vs. 42.2% in the placebo arm); over one-third (36.3%) exhibited endoscopic remission (vs. 21.1%), and just over a quarter (27.1% vs. 13.9%) showed histologic-endoscopic mucosal improvement, according to a press release. The P values for all comparisons were less than .00001.

Perhaps more importantly from the patient perspective, there was greater symptomatic improvement and less bowel urgency in those treated with mirikizumab versus those randomized to placebo.

“The results confirmed [the] efficacy and safety noted in the phase 2 induction [trials], and supports mirikizumab’s potential as treatment for ulcerative colitis,” said Dr. D’Haens, professor of gastroenterology and hepatology at Amsterdam University Medical Centers.

Dominik Bettenworth, MD, who was not involved in the study, said that “the positive results from the LUCENT-1 trial are an important step towards selective IL-23 inhibition as a new mode of action for the treatment of patients with UC.

“This treatment approach has been shown efficacious and launched in other immune-mediated diseases such as psoriasis,” said Dr. Bettenworth, a specialist in internal medicine and gastroenterology in Münster, Germany.

“Noteworthy, for the first time in a phase 3 trial in IBD, [bowel] urgency has been assessed as a secondary endpoint – a clinical symptom of particular importance for patients with UC,” he added, noting that regarding safety, “the LUCENT-1 trial further confirms the previously observed overall good safety profile of IL-23 inhibitors.”
 

About mirikizumab and LUCENT-1

Mirikizumab is a humanized monoclonal antibody directed against the p19 subunit of IL-23 and is one of several IL23p19 antibodies currently under investigation for the treatment of IBD.

LUCENT-1 was a multicenter, randomized, double-blind, parallel group, placebo-controlled induction study in just over 1,200 patients aged 18-80 years. For inclusion, patients had to have moderately to severely active UC and had to have received at least one prior therapy, but had an inadequate or loss of response to it or been intolerant of it. Baseline data showed that 40% of patients included had been treated with corticosteroids and 24% with immunomodulators, and any current treatment remained unchanged during the study. Biologic treatment had failed in about 40% of patients and any patient taking such therapy had to discontinue it before participating in the trial.

Patients were randomized to receive 300 mg of mirikizumab or matching placebo, given intravenously at weeks 0, 4, and 8. Dr. D’Haens noted that randomization had been in a 3:1 ratio and had been stratified according to various factors such as biologic failure status, corticosteroid use, baseline disease activity, and region of the world where the patient was recruited.
 

Better results if biologic naive

Clinical remission was stringently defined as: Mayo stool frequency subscore of zero or one, with a reduction of one point or greater from baseline; no rectal bleeding; and a Mayo endoscopic subscore of zero to one. When looking at this primary endpoint in terms of whether patients had received prior biologic treatment, there was a higher remission rate at week 12 if patients had not previously been given any biologic therapy than if they had, but rates were still higher than placebo (30.9% vs. 15.8% and 15.2% vs. 8.5%, respectively), according to the press release. The P value was less than .001 for both comparisons although the study was not powered to look at these subgroups of patients.

Similarly, for clinical response – which was a decrease in the modified Mayo score of 2 or more points and at least a 30% decrease from initial values, as well as a decrease in rectal bleeding – there were differences between patients who had (54.6% for mirikizumab vs. 29.7% for placebo) and had not (70.1% vs. 50.3%) received a biologic previously (again, P less than .001 for both comparisons).

“Control of bowel function is one of the most debilitating, or one of the most important features for patients with ulcerative colitis,” Dr. D’Haens said when presenting the data on bowel urgency. In the trial there was an improvement in urgency – which was rated by patients – starting as early as week 2, with further improvement seen as the induction period went on.
 

Mirikizumab safety consistent with other trials

Dr. D’Haens noted that the safety profile of IL23 antibodies was “extremely clean.” As with other trials of mirikizumab, he said, there were similar or lower rates to placebo for many adverse events including any infection (15.1% vs. 14%) and cerebrocardiovascular events (0.6% vs. 0.1%). The overall rate of treatment emergent adverse events was 44.5% vs. 46.1% for mirikizumab and placebo. Notably, there were fewer serious adverse events (2.8% vs. 5.3%.) and discontinuations because of side effects (1.6% vs. 7.2%) in the mirikizumab group.

Are gastroenterologists now spoiled for choice?

Lots of questions followed Dr. D’Haens presentation, many picking up on the high placebo response and remission rates.

“We’ve seen it in a number of trials now,” Dr. D’Haens said. “One of the reasons is that patients are allowed to start corticosteroids as late as 2 weeks before randomization,” he observed. In LUCENT-1, half of the patients that were using steroids were receiving a dose of 20 mg of prednisone.

“Now when you start 20 mg of prednisone 2 weeks before randomization that might have an impact on your placebo readout. So I think that’s a lesson for many more trials in the future,” Dr. D’Haens said,”

A high placebo response rate was not expected and another hypothesis is that maybe additional clinical support for fatigue that was received may have played a role.

Several delegates asked for guidance on where mirikizumab and other IL-23p19 blockers might now fit in the grand scheme of patient treatment.

“It is really nice to have expanding therapeutic options but how will we choose?” said one in the online Q&A. “Which IL23 antagonist should we be using now?” and “Is ustekinumab obsolete in UC?” asked others.

“I think it’s early days to decide where the field is going,” Dr. D’Haens said after his presentation. “We don’t have head-to-head data. In GALAXI, ustekinumab was a reference arm.”

There will be further subanalyses of LUCENT-1 to come, including results from endoscopy and histology investigations, and the maintenance trial LUCENT-2 will also report soon.

“The feeling is that IL23 blockade is more specific, [more] beneficial in inflammatory bowel disease than blocking both IL12 and IL23,” Dr. D’Haens said.

Dr. D’Haens was an investigator in the LUCENT-1 trial and has acted as an adviser to the study’s sponsor, Eli Lilly, among many other big pharma companies. Dr. Bettenworth is on the advisory board or is a consultant for AbbVie, Amgen, Arena, Atheneum, BNG Service GmbH, Bristol Myers Squibb, CED-Service GmbH, Celltrion, Else Kröner-Fresenius-Foundation, Galapagos, Guidepoint, Impulze, Falk Foundation, Ferring, Janssen Cilag, Medical Tribune, MedTriX, MSD, Mylan, Onkowissen, Pharmacosmos, Pfizer, Roche, Sandoz, Takeda, Tetrameros, Thieme, Tillotts Pharma, and Vifor Pharma.

Circulating antiphospholipid autoantibodies may contribute to endothelial cell activation and dysfunction in severe COVID-19, researchers report.

In 2020, the same researchers reported results from a preclinical study demonstrating that autoantibodies from patients with active COVID-19 caused clotting in mice.

The new study, published in Arthritis and Rheumatology, found higher-than-expected levels of antiphospholipid autoantibodies in the blood samples of 244 patients hospitalized with COVID-19.

“While endothelial dysfunction has been implicated in the widespread thromboinflammatory complications of COVID-19, the upstream mediators of endotheliopathy remain for the most part cryptic,” write Hui Shi, MD, PhD, and coauthors from the University of Michigan, Ann Arbor, and the National Heart, Lung, and Blood Institute.

When asked for comment on the study, Eline T. Luning Prak, MD, PhD, professor of pathology and laboratory medicine at the Hospital of the University of Pennsylvania in Philadelphia, said, “The autopsy cases for COVID-19 strongly point to thromboembolic complications in many individuals who succumbed to sequelae of the infection.

“Importantly, however, many factors can contribute to this pathology, including the inflammatory milieu, monocyte activation, neutrophil extracellular traps, immune complexes, complement, as well as effects on endothelial cells,” explained Dr. Luning Prak, who was not involved in the study.

“The findings in this paper nicely complement another study by Schmaier et al. that came out recently in JCI Insight that also suggests that endothelial cells can be activated by antibodies, she said.
 

‘Even stronger connection between autoantibody formation and clotting in COVID-19’

Dr. Shi and her team cultured human endothelial cells in serum or plasma from 244 patients hospitalized with COVID-19 and plasma from 100 patients with non-COVID sepsis. Using in-cell enzyme-linked immunosorbent assay, they measured levels of key cell adhesion molecules.

After analysis, the researchers found that serum from COVID-19 patients activated cultured endothelial cells to express surface adhesion molecules essential to inflammation and thrombosis, particularly E-selectin, ICAM-1, and VCAM-1.

“The presence of circulating antiphospholipid antibodies was a strong marker of the ability of COVID-19 serum to activate endothelium,” they explain.

Further analyses revealed that, for a subset of serum samples from patients with severe infection, this activation could be mitigated by depleting total immunoglobulin G.

In addition, supplementation of control serum with patient IgG was adequate to trigger endothelial activation.

On the basis of these results, the researchers hypothesize that antiphospholipid autoantibodies may characterize antibody profiles in severe COVID-19 that activate the endothelium and transition the usually quiescent blood-vessel wall interface toward inflammation and coagulation.

“[These findings] provide an even stronger connection between autoantibody formation and clotting in COVID-19,” Dr. Shi said in an accompanying press release.

Clinical implications

From a clinical perspective, Dr. Shi and her team question whether patients with severe COVID-19 should be tested for antiphospholipid antibodies to assess their risk of thrombosis and progression to respiratory failure.

Moreover, they question whether patients with high antiphospholipid antibody titers might benefit from therapies used in conventional cases of severe antiphospholipid syndrome, such as plasmapheresis, anticoagulation therapy, and complement inhibition, Dr. Shi added.

The researchers hope to answer these and other remaining questions in future studies. “Eventually, we may be able to repurpose treatments used in traditional cases of antiphospholipid syndrome for COVID-19.

“As we await definitive solutions to the pandemic, these findings add important context to the complex interplay between SARS-CoV-2 infection, the human immune system, and vascular immunobiology,” she concluded.

The study was supported by grants from the Rheumatology Research Foundation, the Michigan Medicine Frankel Cardiovascular Center, and the A. Alfred Taubman Medical Research Institute. One author is an inventor on an unrelated pending patent to the University of Michigan. The other authors and Dr. Luning Prak have disclosed no relevant financial relationships.

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

Circulating antiphospholipid autoantibodies may contribute to endothelial cell activation and dysfunction in severe COVID-19, researchers report.

In 2020, the same researchers reported results from a preclinical study demonstrating that autoantibodies from patients with active COVID-19 caused clotting in mice.

The new study, published in Arthritis and Rheumatology, found higher-than-expected levels of antiphospholipid autoantibodies in the blood samples of 244 patients hospitalized with COVID-19.

“While endothelial dysfunction has been implicated in the widespread thromboinflammatory complications of COVID-19, the upstream mediators of endotheliopathy remain for the most part cryptic,” write Hui Shi, MD, PhD, and coauthors from the University of Michigan, Ann Arbor, and the National Heart, Lung, and Blood Institute.

When asked for comment on the study, Eline T. Luning Prak, MD, PhD, professor of pathology and laboratory medicine at the Hospital of the University of Pennsylvania in Philadelphia, said, “The autopsy cases for COVID-19 strongly point to thromboembolic complications in many individuals who succumbed to sequelae of the infection.

“Importantly, however, many factors can contribute to this pathology, including the inflammatory milieu, monocyte activation, neutrophil extracellular traps, immune complexes, complement, as well as effects on endothelial cells,” explained Dr. Luning Prak, who was not involved in the study.

“The findings in this paper nicely complement another study by Schmaier et al. that came out recently in JCI Insight that also suggests that endothelial cells can be activated by antibodies, she said.
 

‘Even stronger connection between autoantibody formation and clotting in COVID-19’

Dr. Shi and her team cultured human endothelial cells in serum or plasma from 244 patients hospitalized with COVID-19 and plasma from 100 patients with non-COVID sepsis. Using in-cell enzyme-linked immunosorbent assay, they measured levels of key cell adhesion molecules.

After analysis, the researchers found that serum from COVID-19 patients activated cultured endothelial cells to express surface adhesion molecules essential to inflammation and thrombosis, particularly E-selectin, ICAM-1, and VCAM-1.

“The presence of circulating antiphospholipid antibodies was a strong marker of the ability of COVID-19 serum to activate endothelium,” they explain.

Further analyses revealed that, for a subset of serum samples from patients with severe infection, this activation could be mitigated by depleting total immunoglobulin G.

In addition, supplementation of control serum with patient IgG was adequate to trigger endothelial activation.

On the basis of these results, the researchers hypothesize that antiphospholipid autoantibodies may characterize antibody profiles in severe COVID-19 that activate the endothelium and transition the usually quiescent blood-vessel wall interface toward inflammation and coagulation.

“[These findings] provide an even stronger connection between autoantibody formation and clotting in COVID-19,” Dr. Shi said in an accompanying press release.

Clinical implications

From a clinical perspective, Dr. Shi and her team question whether patients with severe COVID-19 should be tested for antiphospholipid antibodies to assess their risk of thrombosis and progression to respiratory failure.

Moreover, they question whether patients with high antiphospholipid antibody titers might benefit from therapies used in conventional cases of severe antiphospholipid syndrome, such as plasmapheresis, anticoagulation therapy, and complement inhibition, Dr. Shi added.

The researchers hope to answer these and other remaining questions in future studies. “Eventually, we may be able to repurpose treatments used in traditional cases of antiphospholipid syndrome for COVID-19.

“As we await definitive solutions to the pandemic, these findings add important context to the complex interplay between SARS-CoV-2 infection, the human immune system, and vascular immunobiology,” she concluded.

The study was supported by grants from the Rheumatology Research Foundation, the Michigan Medicine Frankel Cardiovascular Center, and the A. Alfred Taubman Medical Research Institute. One author is an inventor on an unrelated pending patent to the University of Michigan. The other authors and Dr. Luning Prak have disclosed no relevant financial relationships.

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

Circulating antiphospholipid autoantibodies may contribute to endothelial cell activation and dysfunction in severe COVID-19, researchers report.

In 2020, the same researchers reported results from a preclinical study demonstrating that autoantibodies from patients with active COVID-19 caused clotting in mice.

The new study, published in Arthritis and Rheumatology, found higher-than-expected levels of antiphospholipid autoantibodies in the blood samples of 244 patients hospitalized with COVID-19.

“While endothelial dysfunction has been implicated in the widespread thromboinflammatory complications of COVID-19, the upstream mediators of endotheliopathy remain for the most part cryptic,” write Hui Shi, MD, PhD, and coauthors from the University of Michigan, Ann Arbor, and the National Heart, Lung, and Blood Institute.

When asked for comment on the study, Eline T. Luning Prak, MD, PhD, professor of pathology and laboratory medicine at the Hospital of the University of Pennsylvania in Philadelphia, said, “The autopsy cases for COVID-19 strongly point to thromboembolic complications in many individuals who succumbed to sequelae of the infection.

“Importantly, however, many factors can contribute to this pathology, including the inflammatory milieu, monocyte activation, neutrophil extracellular traps, immune complexes, complement, as well as effects on endothelial cells,” explained Dr. Luning Prak, who was not involved in the study.

“The findings in this paper nicely complement another study by Schmaier et al. that came out recently in JCI Insight that also suggests that endothelial cells can be activated by antibodies, she said.
 

‘Even stronger connection between autoantibody formation and clotting in COVID-19’

Dr. Shi and her team cultured human endothelial cells in serum or plasma from 244 patients hospitalized with COVID-19 and plasma from 100 patients with non-COVID sepsis. Using in-cell enzyme-linked immunosorbent assay, they measured levels of key cell adhesion molecules.

After analysis, the researchers found that serum from COVID-19 patients activated cultured endothelial cells to express surface adhesion molecules essential to inflammation and thrombosis, particularly E-selectin, ICAM-1, and VCAM-1.

“The presence of circulating antiphospholipid antibodies was a strong marker of the ability of COVID-19 serum to activate endothelium,” they explain.

Further analyses revealed that, for a subset of serum samples from patients with severe infection, this activation could be mitigated by depleting total immunoglobulin G.

In addition, supplementation of control serum with patient IgG was adequate to trigger endothelial activation.

On the basis of these results, the researchers hypothesize that antiphospholipid autoantibodies may characterize antibody profiles in severe COVID-19 that activate the endothelium and transition the usually quiescent blood-vessel wall interface toward inflammation and coagulation.

“[These findings] provide an even stronger connection between autoantibody formation and clotting in COVID-19,” Dr. Shi said in an accompanying press release.

Clinical implications

From a clinical perspective, Dr. Shi and her team question whether patients with severe COVID-19 should be tested for antiphospholipid antibodies to assess their risk of thrombosis and progression to respiratory failure.

Moreover, they question whether patients with high antiphospholipid antibody titers might benefit from therapies used in conventional cases of severe antiphospholipid syndrome, such as plasmapheresis, anticoagulation therapy, and complement inhibition, Dr. Shi added.

The researchers hope to answer these and other remaining questions in future studies. “Eventually, we may be able to repurpose treatments used in traditional cases of antiphospholipid syndrome for COVID-19.

“As we await definitive solutions to the pandemic, these findings add important context to the complex interplay between SARS-CoV-2 infection, the human immune system, and vascular immunobiology,” she concluded.

The study was supported by grants from the Rheumatology Research Foundation, the Michigan Medicine Frankel Cardiovascular Center, and the A. Alfred Taubman Medical Research Institute. One author is an inventor on an unrelated pending patent to the University of Michigan. The other authors and Dr. Luning Prak have disclosed no relevant financial relationships.

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

Universal screening for presymptomatic type 1 diabetes among schoolchildren would cost approximately 22 euros (about $25) per child screened, and about 7,000 euros (about $7,900) per child diagnosed, a new analysis of data from a German program finds.

The data come from the Fr1da study, in which a blood test for type 1 diabetes–associated islet autoantibodies is offered to all children aged 21 months to 6 years old in Bavaria.

Families of those who test positive are offered participation in a program of diabetes education, metabolic staging, psychological evaluation for stress, and prospective follow-up.

The researchers explain that, worldwide, 4 in 1,000 people under the age of 20 years have type 1 diabetes. It is the most common metabolic disease in children and adolescents. Only about 1 in 10 of those affected has a close relative with the disease. This means that type 1 diabetes can affect any child.

However, in many cases, the disease does not become known until a severe to life-threatening metabolic derailment known as diabetic ketoacidosis (DKA) occurs. This often leads to intensive medical treatment, a longer hospitalization, and poorer blood glucose control, which can result in an increased risk of secondary diseases and very high costs for the health care system.

“We want to protect as many children as possible from serious metabolic derailments. This is only possible with type 1 diabetes screenings. Therefore, we strongly support to include early detection tests in standard medical care,” Peter Achenbach, DrMed, senior author of the study, said in a statement from his institution, Helmholtz Zentrum München in Neuherberg, Germany.

The new findings were published in Diabetes Care by Florian M. Karl, also of Helmholtz Zentrum München, and colleagues.

In 2020, the Fr1da investigators reported that, of 90,632 children who participated from February 2015 to May 2019, 0.31% (280) were diagnosed with presymptomatic type 1 diabetes through the presence of two or more islet autoantibodies.

This news organization asked Brett McQueen, PhD, who led a similar study examining cost and cost-effectiveness in the Autoimmunity Screening for Kids (ASK) program, in which Denver-area children aged 2-17 years are offered autoantibody screening for both type 1 diabetes and celiac disease, for comment.

“If we have a chance to change a child’s life from when they’re 2 or 3 years old and there’s even a small chance that this thing potentially improves health outcomes for a decent price, what are we waiting for?” said Dr. McQueen, who is assistant professor in the department of clinical pharmacy at the University of Colorado, Aurora.
 

Is DKA prevention enough to justify universal screening?

Although identifying type 1 diabetes before symptoms arise could help avoid DKA, currently no therapeutic interventions are available to prevent or delay the trajectory from presymptomatic to clinical type 1 diabetes.

A possible future intervention – the anti-CD3 monoclonal antibody teplizumab (Tzield, Provention Bio) – had a setback in July 2021 when the Food and Drug Administration declined to approve it for the delay of type 1 diabetes in at-risk individuals.

However, on Feb. 22 Provention Bio announced that it has resubmitted the Biologics License Application for teplizumab for the delay of clinical type 1 diabetes in at-risk individuals. The FDA now has 30 days to review the resubmission, determine whether it is complete and acceptable for review, and provide a review goal date, according to a company statement.

But even without the ability to forestall the development of type 1 diabetes, screening proponents point to the potential benefit from educating families about early signs of diabetes onset and thereby preventing progression to DKA and both its short-term and possible long-term sequelae.

Prevention of DKA at diagnosis has been linked to improved long-term glycemic control and other potential health benefits.

And the frequency of DKA at the onset of type 1 diabetes has increased in recent years, to more than 20% in Germany and over 45% in the United States.

But, prior data have suggested that universal screening for presymptomatic type 1 diabetes is unlikely to be cost effective if only the health and economic benefits of prevention of DKA at type 1 diabetes onset is considered, unless the screening costs are exceedingly low.
 

What will it take to implement universal screening?

“What this paper does is contribute really to our understanding of more around resource utilization,” noted Dr. McQueen. “As they correctly identify, it’s really hard to compare country prices. It’s easier to compare utilization.”

In Dr. McQueen’s ASK program, the cost per child screened and per case detected in that program were similar to those found in the German study, even though the cost of the antibody testing itself was considerably lower in Germany than in the United States.

Fr1da included more components of screening and monitoring than did ASK, Dr. McQueen told this news organization.

The conclusions of the ASK study were that “presymptomatic type 1 diabetes screening may be cost effective in areas with a high prevalence of DKA and an infrastructure facilitating screening and monitoring if the benefits of avoiding DKA events and improved [hemoglobin] A1c persist over long-run time horizons.”

Nonetheless, Dr. McQueen thinks it’s unlikely that universal screening will be recommended by professional societies or covered by payers in the United States until a pharmacologic intervention to forestall disease progression is available.“Teplizumab approval could move this along. ... We’re just trying to take one factor, the economics of it, to create the most efficient scenario so that if it were to be adopted we would catch the most cases, prevent the most complications, benefit children the most in terms of their lifetime health outcomes – all at the minimum cost possible.”
 

‘A benchmark for the expected implementation cost of screening’

Mr. Karl and colleagues simulated the cost of implementation of this screening as standard care in Germany – assuming the same 0.31% prevalence found in Fr1da – the average cost per child was estimated at 21.73 euros, including 9.34 euros for laboratory costs, 12.25 euros for pediatrician costs, and 0.14 euros for local diabetes clinics to perform metabolic staging and education for children diagnosed with presymptomatic type 1 diabetes.

The model included 50% of the costs incurred in Fr1da for obtaining informed consent. Negative autoantibody results from the initial screening were not communicated to families, and all children with presymptomatic type 1 diabetes received staging and education. The estimated average cost per diagnosed child was 7,035 euros.

“Although our analyses are subject to some level of uncertainty, they provide a benchmark for the expected implementation cost of screening,” said coauthor Michael Laxy, MSc, PhD, also at Helmholtz Zentrum München.

“Next, we aim to evaluate the long-term ratio of screening costs, potential cost savings through the prevention of metabolic derailment and its consequences, and potentially increased quality of life with a type 1 diabetes screening compared to the costs and quality of life without a screening.”

Dr. McQueen is working along similar lines in Colorado, attempting to create a model that incorporates all the different possibilities including DKA monitoring, teplizumab availability, screening children at different ages, and the effect of including blood glucose monitoring in children identified with presymptomatic type 1 diabetes.

“There are so many different potential answers and avenues and no one has really put it all together,” he observed.

But he believes that economics shouldn’t be the only factor used in deciding whether to institute widespread screening.

This study was supported by grants from the German Federal Ministry of Education and Research to the German Center for Diabetes Research (DZD). The Fr1da study was supported by grants from the LifeScience-Stiftung, JDRF International, the Bavarian State Ministry of Health and Care, the Leona M. and Harry B. Helmsley Charitable Trust, Deutsche Diabetes-Stiftung, Landesverband Bayern der Betriebskrankenkassen, B. Braun-Stiftung, Deutsche Diabetes Hilfe, and the German Federal Ministry of Education and Research to the DZD. The authors disclosed no relevant financial relationships. The ASK study was funded by JDRF International, the Leona M. and Harry B. Helmsley Charitable Trust, and Janssen Research and Development. Dr. McQueen has received institutional funding for value assessment applications from the Institute for Clinical and Economic Review, the PhRMA Foundation, and PhRMA.

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

Universal screening for presymptomatic type 1 diabetes among schoolchildren would cost approximately 22 euros (about $25) per child screened, and about 7,000 euros (about $7,900) per child diagnosed, a new analysis of data from a German program finds.

The data come from the Fr1da study, in which a blood test for type 1 diabetes–associated islet autoantibodies is offered to all children aged 21 months to 6 years old in Bavaria.

Families of those who test positive are offered participation in a program of diabetes education, metabolic staging, psychological evaluation for stress, and prospective follow-up.

The researchers explain that, worldwide, 4 in 1,000 people under the age of 20 years have type 1 diabetes. It is the most common metabolic disease in children and adolescents. Only about 1 in 10 of those affected has a close relative with the disease. This means that type 1 diabetes can affect any child.

However, in many cases, the disease does not become known until a severe to life-threatening metabolic derailment known as diabetic ketoacidosis (DKA) occurs. This often leads to intensive medical treatment, a longer hospitalization, and poorer blood glucose control, which can result in an increased risk of secondary diseases and very high costs for the health care system.

“We want to protect as many children as possible from serious metabolic derailments. This is only possible with type 1 diabetes screenings. Therefore, we strongly support to include early detection tests in standard medical care,” Peter Achenbach, DrMed, senior author of the study, said in a statement from his institution, Helmholtz Zentrum München in Neuherberg, Germany.

The new findings were published in Diabetes Care by Florian M. Karl, also of Helmholtz Zentrum München, and colleagues.

In 2020, the Fr1da investigators reported that, of 90,632 children who participated from February 2015 to May 2019, 0.31% (280) were diagnosed with presymptomatic type 1 diabetes through the presence of two or more islet autoantibodies.

This news organization asked Brett McQueen, PhD, who led a similar study examining cost and cost-effectiveness in the Autoimmunity Screening for Kids (ASK) program, in which Denver-area children aged 2-17 years are offered autoantibody screening for both type 1 diabetes and celiac disease, for comment.

“If we have a chance to change a child’s life from when they’re 2 or 3 years old and there’s even a small chance that this thing potentially improves health outcomes for a decent price, what are we waiting for?” said Dr. McQueen, who is assistant professor in the department of clinical pharmacy at the University of Colorado, Aurora.
 

Is DKA prevention enough to justify universal screening?

Although identifying type 1 diabetes before symptoms arise could help avoid DKA, currently no therapeutic interventions are available to prevent or delay the trajectory from presymptomatic to clinical type 1 diabetes.

A possible future intervention – the anti-CD3 monoclonal antibody teplizumab (Tzield, Provention Bio) – had a setback in July 2021 when the Food and Drug Administration declined to approve it for the delay of type 1 diabetes in at-risk individuals.

However, on Feb. 22 Provention Bio announced that it has resubmitted the Biologics License Application for teplizumab for the delay of clinical type 1 diabetes in at-risk individuals. The FDA now has 30 days to review the resubmission, determine whether it is complete and acceptable for review, and provide a review goal date, according to a company statement.

But even without the ability to forestall the development of type 1 diabetes, screening proponents point to the potential benefit from educating families about early signs of diabetes onset and thereby preventing progression to DKA and both its short-term and possible long-term sequelae.

Prevention of DKA at diagnosis has been linked to improved long-term glycemic control and other potential health benefits.

And the frequency of DKA at the onset of type 1 diabetes has increased in recent years, to more than 20% in Germany and over 45% in the United States.

But, prior data have suggested that universal screening for presymptomatic type 1 diabetes is unlikely to be cost effective if only the health and economic benefits of prevention of DKA at type 1 diabetes onset is considered, unless the screening costs are exceedingly low.
 

What will it take to implement universal screening?

“What this paper does is contribute really to our understanding of more around resource utilization,” noted Dr. McQueen. “As they correctly identify, it’s really hard to compare country prices. It’s easier to compare utilization.”

In Dr. McQueen’s ASK program, the cost per child screened and per case detected in that program were similar to those found in the German study, even though the cost of the antibody testing itself was considerably lower in Germany than in the United States.

Fr1da included more components of screening and monitoring than did ASK, Dr. McQueen told this news organization.

The conclusions of the ASK study were that “presymptomatic type 1 diabetes screening may be cost effective in areas with a high prevalence of DKA and an infrastructure facilitating screening and monitoring if the benefits of avoiding DKA events and improved [hemoglobin] A1c persist over long-run time horizons.”

Nonetheless, Dr. McQueen thinks it’s unlikely that universal screening will be recommended by professional societies or covered by payers in the United States until a pharmacologic intervention to forestall disease progression is available.“Teplizumab approval could move this along. ... We’re just trying to take one factor, the economics of it, to create the most efficient scenario so that if it were to be adopted we would catch the most cases, prevent the most complications, benefit children the most in terms of their lifetime health outcomes – all at the minimum cost possible.”
 

‘A benchmark for the expected implementation cost of screening’

Mr. Karl and colleagues simulated the cost of implementation of this screening as standard care in Germany – assuming the same 0.31% prevalence found in Fr1da – the average cost per child was estimated at 21.73 euros, including 9.34 euros for laboratory costs, 12.25 euros for pediatrician costs, and 0.14 euros for local diabetes clinics to perform metabolic staging and education for children diagnosed with presymptomatic type 1 diabetes.

The model included 50% of the costs incurred in Fr1da for obtaining informed consent. Negative autoantibody results from the initial screening were not communicated to families, and all children with presymptomatic type 1 diabetes received staging and education. The estimated average cost per diagnosed child was 7,035 euros.

“Although our analyses are subject to some level of uncertainty, they provide a benchmark for the expected implementation cost of screening,” said coauthor Michael Laxy, MSc, PhD, also at Helmholtz Zentrum München.

“Next, we aim to evaluate the long-term ratio of screening costs, potential cost savings through the prevention of metabolic derailment and its consequences, and potentially increased quality of life with a type 1 diabetes screening compared to the costs and quality of life without a screening.”

Dr. McQueen is working along similar lines in Colorado, attempting to create a model that incorporates all the different possibilities including DKA monitoring, teplizumab availability, screening children at different ages, and the effect of including blood glucose monitoring in children identified with presymptomatic type 1 diabetes.

“There are so many different potential answers and avenues and no one has really put it all together,” he observed.

But he believes that economics shouldn’t be the only factor used in deciding whether to institute widespread screening.

This study was supported by grants from the German Federal Ministry of Education and Research to the German Center for Diabetes Research (DZD). The Fr1da study was supported by grants from the LifeScience-Stiftung, JDRF International, the Bavarian State Ministry of Health and Care, the Leona M. and Harry B. Helmsley Charitable Trust, Deutsche Diabetes-Stiftung, Landesverband Bayern der Betriebskrankenkassen, B. Braun-Stiftung, Deutsche Diabetes Hilfe, and the German Federal Ministry of Education and Research to the DZD. The authors disclosed no relevant financial relationships. The ASK study was funded by JDRF International, the Leona M. and Harry B. Helmsley Charitable Trust, and Janssen Research and Development. Dr. McQueen has received institutional funding for value assessment applications from the Institute for Clinical and Economic Review, the PhRMA Foundation, and PhRMA.

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

Universal screening for presymptomatic type 1 diabetes among schoolchildren would cost approximately 22 euros (about $25) per child screened, and about 7,000 euros (about $7,900) per child diagnosed, a new analysis of data from a German program finds.

The data come from the Fr1da study, in which a blood test for type 1 diabetes–associated islet autoantibodies is offered to all children aged 21 months to 6 years old in Bavaria.

Families of those who test positive are offered participation in a program of diabetes education, metabolic staging, psychological evaluation for stress, and prospective follow-up.

The researchers explain that, worldwide, 4 in 1,000 people under the age of 20 years have type 1 diabetes. It is the most common metabolic disease in children and adolescents. Only about 1 in 10 of those affected has a close relative with the disease. This means that type 1 diabetes can affect any child.

However, in many cases, the disease does not become known until a severe to life-threatening metabolic derailment known as diabetic ketoacidosis (DKA) occurs. This often leads to intensive medical treatment, a longer hospitalization, and poorer blood glucose control, which can result in an increased risk of secondary diseases and very high costs for the health care system.

“We want to protect as many children as possible from serious metabolic derailments. This is only possible with type 1 diabetes screenings. Therefore, we strongly support to include early detection tests in standard medical care,” Peter Achenbach, DrMed, senior author of the study, said in a statement from his institution, Helmholtz Zentrum München in Neuherberg, Germany.

The new findings were published in Diabetes Care by Florian M. Karl, also of Helmholtz Zentrum München, and colleagues.

In 2020, the Fr1da investigators reported that, of 90,632 children who participated from February 2015 to May 2019, 0.31% (280) were diagnosed with presymptomatic type 1 diabetes through the presence of two or more islet autoantibodies.

This news organization asked Brett McQueen, PhD, who led a similar study examining cost and cost-effectiveness in the Autoimmunity Screening for Kids (ASK) program, in which Denver-area children aged 2-17 years are offered autoantibody screening for both type 1 diabetes and celiac disease, for comment.

“If we have a chance to change a child’s life from when they’re 2 or 3 years old and there’s even a small chance that this thing potentially improves health outcomes for a decent price, what are we waiting for?” said Dr. McQueen, who is assistant professor in the department of clinical pharmacy at the University of Colorado, Aurora.
 

Is DKA prevention enough to justify universal screening?

Although identifying type 1 diabetes before symptoms arise could help avoid DKA, currently no therapeutic interventions are available to prevent or delay the trajectory from presymptomatic to clinical type 1 diabetes.

A possible future intervention – the anti-CD3 monoclonal antibody teplizumab (Tzield, Provention Bio) – had a setback in July 2021 when the Food and Drug Administration declined to approve it for the delay of type 1 diabetes in at-risk individuals.

However, on Feb. 22 Provention Bio announced that it has resubmitted the Biologics License Application for teplizumab for the delay of clinical type 1 diabetes in at-risk individuals. The FDA now has 30 days to review the resubmission, determine whether it is complete and acceptable for review, and provide a review goal date, according to a company statement.

But even without the ability to forestall the development of type 1 diabetes, screening proponents point to the potential benefit from educating families about early signs of diabetes onset and thereby preventing progression to DKA and both its short-term and possible long-term sequelae.

Prevention of DKA at diagnosis has been linked to improved long-term glycemic control and other potential health benefits.

And the frequency of DKA at the onset of type 1 diabetes has increased in recent years, to more than 20% in Germany and over 45% in the United States.

But, prior data have suggested that universal screening for presymptomatic type 1 diabetes is unlikely to be cost effective if only the health and economic benefits of prevention of DKA at type 1 diabetes onset is considered, unless the screening costs are exceedingly low.
 

What will it take to implement universal screening?

“What this paper does is contribute really to our understanding of more around resource utilization,” noted Dr. McQueen. “As they correctly identify, it’s really hard to compare country prices. It’s easier to compare utilization.”

In Dr. McQueen’s ASK program, the cost per child screened and per case detected in that program were similar to those found in the German study, even though the cost of the antibody testing itself was considerably lower in Germany than in the United States.

Fr1da included more components of screening and monitoring than did ASK, Dr. McQueen told this news organization.

The conclusions of the ASK study were that “presymptomatic type 1 diabetes screening may be cost effective in areas with a high prevalence of DKA and an infrastructure facilitating screening and monitoring if the benefits of avoiding DKA events and improved [hemoglobin] A1c persist over long-run time horizons.”

Nonetheless, Dr. McQueen thinks it’s unlikely that universal screening will be recommended by professional societies or covered by payers in the United States until a pharmacologic intervention to forestall disease progression is available.“Teplizumab approval could move this along. ... We’re just trying to take one factor, the economics of it, to create the most efficient scenario so that if it were to be adopted we would catch the most cases, prevent the most complications, benefit children the most in terms of their lifetime health outcomes – all at the minimum cost possible.”
 

‘A benchmark for the expected implementation cost of screening’

Mr. Karl and colleagues simulated the cost of implementation of this screening as standard care in Germany – assuming the same 0.31% prevalence found in Fr1da – the average cost per child was estimated at 21.73 euros, including 9.34 euros for laboratory costs, 12.25 euros for pediatrician costs, and 0.14 euros for local diabetes clinics to perform metabolic staging and education for children diagnosed with presymptomatic type 1 diabetes.

The model included 50% of the costs incurred in Fr1da for obtaining informed consent. Negative autoantibody results from the initial screening were not communicated to families, and all children with presymptomatic type 1 diabetes received staging and education. The estimated average cost per diagnosed child was 7,035 euros.

“Although our analyses are subject to some level of uncertainty, they provide a benchmark for the expected implementation cost of screening,” said coauthor Michael Laxy, MSc, PhD, also at Helmholtz Zentrum München.

“Next, we aim to evaluate the long-term ratio of screening costs, potential cost savings through the prevention of metabolic derailment and its consequences, and potentially increased quality of life with a type 1 diabetes screening compared to the costs and quality of life without a screening.”

Dr. McQueen is working along similar lines in Colorado, attempting to create a model that incorporates all the different possibilities including DKA monitoring, teplizumab availability, screening children at different ages, and the effect of including blood glucose monitoring in children identified with presymptomatic type 1 diabetes.

“There are so many different potential answers and avenues and no one has really put it all together,” he observed.

But he believes that economics shouldn’t be the only factor used in deciding whether to institute widespread screening.

This study was supported by grants from the German Federal Ministry of Education and Research to the German Center for Diabetes Research (DZD). The Fr1da study was supported by grants from the LifeScience-Stiftung, JDRF International, the Bavarian State Ministry of Health and Care, the Leona M. and Harry B. Helmsley Charitable Trust, Deutsche Diabetes-Stiftung, Landesverband Bayern der Betriebskrankenkassen, B. Braun-Stiftung, Deutsche Diabetes Hilfe, and the German Federal Ministry of Education and Research to the DZD. The authors disclosed no relevant financial relationships. The ASK study was funded by JDRF International, the Leona M. and Harry B. Helmsley Charitable Trust, and Janssen Research and Development. Dr. McQueen has received institutional funding for value assessment applications from the Institute for Clinical and Economic Review, the PhRMA Foundation, and PhRMA.

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

My wife and I had been married for 3 or 4 years when I became aware that a small cluster of my new in-laws had taken to referring to me as “Dr. I-don’t-know.” It wasn’t hard to figure out how I had earned this potentially derogatory moniker. As the only physician in the family it was not unusual for me to be peppered with medical questions. Most were unanswerable, at least by me. For example, “Will, how does aspirin work?” – which in the 1970s wasn’t something covered in medical school. Other questions were asked in a context that made it clear my answer was going to be so far removed from the preformed opinion of the questioner that Thanksgiving dinner didn’t feel like an appropriate occasion for my answer. “I don’t think I really know,” seemed to make the most sense.

In those early growing years of my outpatient general practice my in-laws weren’t the only people who must have thought of me as “Dr. I-don’t-know.” My training took place in well-thought-of teaching hospitals and during my senior residency and military tour I did enough moonlighting that by the time I entered private practice I had logged a lot of hours in the trenches. But, there were still a ton of things I didn’t know.

You probably remember how those first few years on the outside of the ivory towers felt with no one handy to ask. Even if there was someone a phone call away you didn’t want to appear as incompetent as you were by telling the patient or family that you needed to call the department head at your training program.

So, what did you do? You called. But you developed some clever language that could buy you time while you called your old mentor or hit the books. There was no Internet. Generally, that script would start with some version of “I don’t know, but ...”

As time passed and you gained more experience there were fewer questions and situations in which you needed to admit you were a few clues short of the answer. However, still, many times a day, you honestly didn’t know the answer. Hopefully, over time, you had perfected your delivery so that revealing your ignorance wasn’t driving patients away.

The art of saying “I don’t know” boils down to what you say after the “but” and how you say it. As long as you have offered a plan to find the answer and demonstrate that you are concerned about the patient, your ignorance will be tolerated and maybe even be appreciated.

“I don’t know the answer to that question, but let’s see if we can find a solution” could cover it. If finding that solution is going to require more time than the office visit allows – which it usually doesn’t – the promise of a timely response and a commitment to keep that promise is an absolute requirement. Repeated failure to keep promises is one of the quickest ways to sour a patient-doctor relationship and a potential practice killer.

I think my in-laws no longer refer to me as Dr. I-don’t-know. At least they have refrained from asking me any medical questions. But, my reputation as a physician unafraid to admit his ignorance continues here in town. Occasionally I encounter a parent of a former patient who fondly recalls my willingness to say “I don’t know.” If we had a family crest I would like it to include the motto “Ignoramus Sed Pertinet” (We don’t know but we care).
 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at pdnews@mdedge.com.

The headline on this article was updated on 2/28/22.

My wife and I had been married for 3 or 4 years when I became aware that a small cluster of my new in-laws had taken to referring to me as “Dr. I-don’t-know.” It wasn’t hard to figure out how I had earned this potentially derogatory moniker. As the only physician in the family it was not unusual for me to be peppered with medical questions. Most were unanswerable, at least by me. For example, “Will, how does aspirin work?” – which in the 1970s wasn’t something covered in medical school. Other questions were asked in a context that made it clear my answer was going to be so far removed from the preformed opinion of the questioner that Thanksgiving dinner didn’t feel like an appropriate occasion for my answer. “I don’t think I really know,” seemed to make the most sense.

In those early growing years of my outpatient general practice my in-laws weren’t the only people who must have thought of me as “Dr. I-don’t-know.” My training took place in well-thought-of teaching hospitals and during my senior residency and military tour I did enough moonlighting that by the time I entered private practice I had logged a lot of hours in the trenches. But, there were still a ton of things I didn’t know.

You probably remember how those first few years on the outside of the ivory towers felt with no one handy to ask. Even if there was someone a phone call away you didn’t want to appear as incompetent as you were by telling the patient or family that you needed to call the department head at your training program.

So, what did you do? You called. But you developed some clever language that could buy you time while you called your old mentor or hit the books. There was no Internet. Generally, that script would start with some version of “I don’t know, but ...”

As time passed and you gained more experience there were fewer questions and situations in which you needed to admit you were a few clues short of the answer. However, still, many times a day, you honestly didn’t know the answer. Hopefully, over time, you had perfected your delivery so that revealing your ignorance wasn’t driving patients away.

The art of saying “I don’t know” boils down to what you say after the “but” and how you say it. As long as you have offered a plan to find the answer and demonstrate that you are concerned about the patient, your ignorance will be tolerated and maybe even be appreciated.

“I don’t know the answer to that question, but let’s see if we can find a solution” could cover it. If finding that solution is going to require more time than the office visit allows – which it usually doesn’t – the promise of a timely response and a commitment to keep that promise is an absolute requirement. Repeated failure to keep promises is one of the quickest ways to sour a patient-doctor relationship and a potential practice killer.

I think my in-laws no longer refer to me as Dr. I-don’t-know. At least they have refrained from asking me any medical questions. But, my reputation as a physician unafraid to admit his ignorance continues here in town. Occasionally I encounter a parent of a former patient who fondly recalls my willingness to say “I don’t know.” If we had a family crest I would like it to include the motto “Ignoramus Sed Pertinet” (We don’t know but we care).
 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at pdnews@mdedge.com.

The headline on this article was updated on 2/28/22.

My wife and I had been married for 3 or 4 years when I became aware that a small cluster of my new in-laws had taken to referring to me as “Dr. I-don’t-know.” It wasn’t hard to figure out how I had earned this potentially derogatory moniker. As the only physician in the family it was not unusual for me to be peppered with medical questions. Most were unanswerable, at least by me. For example, “Will, how does aspirin work?” – which in the 1970s wasn’t something covered in medical school. Other questions were asked in a context that made it clear my answer was going to be so far removed from the preformed opinion of the questioner that Thanksgiving dinner didn’t feel like an appropriate occasion for my answer. “I don’t think I really know,” seemed to make the most sense.

In those early growing years of my outpatient general practice my in-laws weren’t the only people who must have thought of me as “Dr. I-don’t-know.” My training took place in well-thought-of teaching hospitals and during my senior residency and military tour I did enough moonlighting that by the time I entered private practice I had logged a lot of hours in the trenches. But, there were still a ton of things I didn’t know.

You probably remember how those first few years on the outside of the ivory towers felt with no one handy to ask. Even if there was someone a phone call away you didn’t want to appear as incompetent as you were by telling the patient or family that you needed to call the department head at your training program.

So, what did you do? You called. But you developed some clever language that could buy you time while you called your old mentor or hit the books. There was no Internet. Generally, that script would start with some version of “I don’t know, but ...”

As time passed and you gained more experience there were fewer questions and situations in which you needed to admit you were a few clues short of the answer. However, still, many times a day, you honestly didn’t know the answer. Hopefully, over time, you had perfected your delivery so that revealing your ignorance wasn’t driving patients away.

The art of saying “I don’t know” boils down to what you say after the “but” and how you say it. As long as you have offered a plan to find the answer and demonstrate that you are concerned about the patient, your ignorance will be tolerated and maybe even be appreciated.

“I don’t know the answer to that question, but let’s see if we can find a solution” could cover it. If finding that solution is going to require more time than the office visit allows – which it usually doesn’t – the promise of a timely response and a commitment to keep that promise is an absolute requirement. Repeated failure to keep promises is one of the quickest ways to sour a patient-doctor relationship and a potential practice killer.

I think my in-laws no longer refer to me as Dr. I-don’t-know. At least they have refrained from asking me any medical questions. But, my reputation as a physician unafraid to admit his ignorance continues here in town. Occasionally I encounter a parent of a former patient who fondly recalls my willingness to say “I don’t know.” If we had a family crest I would like it to include the motto “Ignoramus Sed Pertinet” (We don’t know but we care).
 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at pdnews@mdedge.com.

The headline on this article was updated on 2/28/22.

Dear colleagues,

We shift gears from discussing GI hospitalists to focusing on the treatment of inflammatory bowel disease. The introduction of anti-TNFs brought about a paradigm shift in IBD management. With the ability to measure drug and antibody levels, we are also able to alter dose and timing to increase the efficacy of these medications. Some experts have extended this reactive drug monitoring approach to a more proactive method with the expectation that this may prevent loss of efficacy and development of adverse events. Dr. Loren G. Rabinowitz and colleagues and Dr. Hans Herfarth describe these two approaches to anti-TNF management in IBD, drawing from the current data and their own experiences. I look forward to hearing your thoughts and experiences by email (ginews@gastro.org).

Gyanprakash A. Ketwaroo, MD, MSc, is an assistant professor of medicine at Baylor College of Medicine, Houston. He is an associate editor for GI & Hepatology News.

Better outcomes than reactive TDM

By Loren G. Rabinowitz, MD; Konstantinos Papamichael, PhD, MD; and Adam S. Cheifetz, MD, AGAF

Therapeutic drug monitoring (TDM), or the practice of treatment optimization based on serum drug concentrations, is used in many settings, including solid organ transplantation, infection, and immune-mediated inflammatory diseases, including inflammatory bowel disease (IBD). In IBD, the use of TDM has been an area of keen research focus, and, in our view, should be standard practice for optimization of biologic therapy, particularly in the setting of anti–tumor necrosis factor (TNF) therapy. TDM has demonstrated utility in determining the correct timing and dosage of biologics and can provide the impetus for deescalating or discontinuing a biologic in favor of an alternative one. It also allows prescribers the ability to protect patients from severe infusion reactions if they have developed anti-drug antibodies (ADAs).

Reactive TDM refers to a strategy of assessing drug concentration and presence of ADAs in the setting of primary nonresponse (PNR) and loss of response (LOR) to a biologic agent. In this context, TDM informs possible reasons for loss or lack of response to treatment – for example, insufficient drug concentration or the development of high-titer ADAs (immunogenicity) – thus better directing the management of these unwanted outcomes.¹ Insufficient anti-TNF concentrations have been associated with PNR and lack of clinical remission at 1 year in patients with IBD,2 which underscores the need for a durable strategy to ensure appropriate drug concentrations from the induction through maintenance phases of biologic administration. Reactive TDM can also be used to inform the decision to abandon a particular therapy in favor of a different biologic and to guide the selection of the next biologic agent, and has been shown to be less expensive than empiric dose escalation.² With regard to infliximab and adalimumab, it is our practice to continue dose escalation until drug concentrations are above 10-15 mcg/mL prior to abandoning therapy.1

For a significant number of patients, reactive TDM identifies at-risk patients too late, when ADAs have already formed. Because the number of medications to treat IBD remains limited, waiting for a patient to lose response to an agent, particularly anti-TNF therapies, increases the likelihood of immunogenicity, thus rendering an agent unusable. Proactive TDM or checking drug trough concentrations preemptively and at predetermined intervals, and dosing to an appropriate concentration, can improve patient outcomes. If drug concentration is determined to be not “at target,” dosage and timing of administration can be increased with or without the addition of an immunomodulator (thiopurines or methotrexate) to optimize the biologic’s efficacy and prevent immunogenicity. This approach allows the provider to anticipate and proactively guard against PNR and future LOR.

Proactive TDM of anti-TNF therapy has been associated with better patient outcomes in both pediatric and adult populations when compared with empiric dose optimization and/or reactive TDM.^2,3 In patients with immune-mediated inflammatory diseases undergoing maintenance therapy with infliximab, proactive TDM was found to be more effective than treatment without TDM in sustaining disease control without disease worsening.⁴ Proactive TDM has been associated with better patient outcomes, including increased rates of clinical remission in both pediatric and adult populations and decreased rates of IBD-related surgery, hospitalization, serious infusion reactions, and development of ADAs, when compared with reactive TDM or empiric optimization. Preliminary data suggest that proactive TDM can also be used to efficiently guide dose deescalation in patients in remission with drug concentrations markedly above target and to allow for optimization of infliximab monotherapy so that combination therapy can be employed more judiciously (that is, in a patient who developed rapid ADA to a different anti-TNF).¹ This could potentially attenuate the risks associated with long-term immunomodulator use, which include lymphomas and higher rates of serious and opportunistic infections. A recent study using a pharmacokinetic dashboard showed that the majority of patients with IBD will need accelerated dosing by the third infusion to maintain therapeutic infliximab concentrations during induction and maintenance therapy, highlighting the urgent need for widespread adoption of early proactive TDM.⁵ It is likely that proactive TDM is most important early in therapy when patients are most inflamed and have more rapid drug clearance. For this reason, proactive TDM should ideally be used for all patients during the induction phase. It is our practice to continue to follow drug concentrations one or two times per year once a patient has achieved remission. A recent literature review and consensus statement highlights the utility of TDM and what is known at this time.¹

Juan Gaertner/Science Photo Library/Getty Images

TDM should be standard of care for patients with IBD. At minimum, reactive TDM has rationalized the management of PNR, is associated with better outcomes, and is more cost effective than empiric dose escalation.^1,2 In this setting, however, many patients have already developed ADAs that cannot be overcome. At present, anti-TNF therapy remains the most effective agent for our sickest patients with IBD. Given the as-yet limited armamentarium of medications available, particularly for patients with fistulizing perianal Crohn’s disease (CD) and severe ulcerative colitis (UC), proactive TDM, which allows for improved optimization and long-term durability of biologics, is essential to the care of any IBD patient requiring these medications. Proactive TDM should ideally be used for all patients during the induction phase and at least once during maintenance therapy. There is also the potential for TDM-driven dose de-escalation for patients in remission and optimization of infliximab monotherapy, thus avoiding combination therapy with an immunomodulator in some cases. Future perspectives for a more precise application of TDM include the use of pharmacokinetic modeling dashboards and pharmacogenetics toward achieving truly individualized medicine.³

Dr. Rabinowitz, Dr. Papamichael, and Dr. Cheifetz are with the department of medicine and division of gastroenterology at Beth Israel Deaconess Medical Center and Harvard Medical School, both in Boston. Dr. Rabinowitz reports no conflicts of interest. Dr. Papamichael reports lecture fees from Mitsubishi Tanabe Pharma and Physicians’ Education Resource; consultancy fee from Prometheus Laboratories; and scientific advisory board fees from ProciseDx and Scipher Medicine Corporation. Dr. Cheifetz reports consulting for Janssen, AbbVie, Samsung, Arena Pharmaceuticals, Grifols, Prometheus, Bristol Myers Squibb, Artizan Biosciences, Artugan Therapeutics, and Equillium.
 

References

1. Cheifetz AS et al. Am J Gastroenterol. 2021 Oct 1;116(10):2014-25.

2. Kennedy NA et al. Lancet Gastroenterol Hepatol. 2019 May;4(5):341-53.

3. Papamichael K et al. Lancet Gastroenterol Hepatol. 2022;7(2):171-85.

4. Syversen SW et al. JAMA. 2021;326(23):2375-84.

5. Dubinsky MC et al. Inflamm Bowel Dis. 2022 Jan 3. doi: 10.1093/ibd/izab285.

Taking a closer look at the evidence

By Hans Herfarth, MD, PhD, AGAF

The debate of therapeutic drug monitoring (TDM) in the setting of anti–tumor necrosis factor (TNF) therapy has been ongoing for more than a decade. Reactive TDM, the measurement of drug concentrations in the context of loss of treatment response, is now generally accepted and recommended in multiple national and international inflammatory bowel disease (IBD) guidelines. Proactive TDM, defined as the systematic measurement of drug trough concentrations and anti-drug antibodies with dose adaptations to a predefined target drug concentration, seems to offer a possibility to stabilize drug levels and prevent anti-drug antibody formation due to low systemic drug levels, thus potentially preventing the well-known loss of response to anti-TNF therapy, which occurs in more than 50% of patients over time. However, proactive TDM is not endorsed by evidence-based guidelines, dividing IBD physicians into believers and nonbelievers and limiting uptake into clinical practice.

As with reactive TDM, one should assume that the framework for proactive TDM should have been reliably established based on factual data derived from prospective controlled studies and not rely on retrospective cohorts or “Expert Panel” consensus statements. And indeed, several prospective controlled studies with sizable IBD patient cohorts have been published. Of note, all TDM studies for IBD were conducted in patients on anti-TNF maintenance therapy, and currently no prospective studies in larger IBD populations are available for proactive TDM during induction therapy. Two prospective studies, the PRECISION and the NOR-DRUM trial, report that proactive TDM is better than no TDM at all.

However, in the comparison of proactive TDM and reactive TDM (including at least one drug adaptation in maintenance or drug escalation based on clinical symptoms or biomarkers), three studies have demonstrated no significant differences in drug persistence or overall maintenance of clinical remission. Only a fourth (the pediatric PAILOT study) reported a lower frequency of mild flares and less steroid exposure in the proactive TDM arm over 1 year, but it did not show differences in drug persistence or overall clinical remission compared with the reactive TDM arm. Interestingly, the differences in flare frequency were apparent only in patients on monotherapy but not in the subgroup on combination therapy with an immunomodulator, stressing the well-known beneficial effect of a combination therapy with thiopurines in CD first shown in the SONIC trial.

One problem, at least in the TDM trials with infliximab (IFX), may have been a delay in optimizing IFX levels until the next drug infusion because of the turnaround time of the drug assays. However, even the most recently published ultra-proactive TDM study with ad hoc dose adjustments based on point of care testing of drug levels during maintenance IFX therapy did not result in a significantly lower failure rate of IFX therapy or differences in sustained remission compared with reactive TDM over 1 year (19% vs. 10%; P = .08 for IFX failure; 75% vs. 83%; P = .17 for sustained remission). Compared with reactive TDM, the proactive measurement of drug levels resulted in significantly more drug measurements (8.8 vs. 1 per patient per year) and consecutive drug adjustments. Of interest would be the assessment of cost-effectiveness based on these trial data.

The value of proactive TDM in induction therapy remains an ongoing concern. There is no doubt that the severity of intestinal inflammation with subsequent loss of drug in the intestine can result in low drug serum concentrations correlating to lower clinical responses and higher rates of immunogenicity with the formation of anti-drug antibodies. A recent study including patients with chronic immune-mediated inflammatory diseases such as IBD, rheumatoid arthritis, and psoriasis did not find a value in proactive TDM of IFX in the induction phase, but more severe IBD may have been underrepresented in this study. Administration of significantly higher induction dosing of adalimumab (160 mg weeks 0, 1, 2, and 3) with significantly higher trough levels compared with a standard induction regimen in the SERENE study has not been shown to increase the short- or long-term remission rates in UC or CD patients. Therefore, higher trough levels in a patient population do not automatically result in better outcomes, but proactive TDM may still have found a few patients who may have benefited from an even higher induction regimen. The UC and CD SERENE maintenance studies also evaluated proactive TDM versus clinical adjustment based on clinical and biomarkers. After 1 year, no differences in the efficacy endpoints of clinical, endoscopic, and deep remission were found. These somewhat surprising results, which have been reported only in meeting abstracts, suggest that simply increasing trough levels to a higher target (one of the primary aims of proactive TDM) is not an effective universal approach for achieving higher remission rates in induction or better outcomes in maintenance. Instead, the SERENE data show that similar results can be achieved by regular clinical follow-up and monitoring of loss of response based on symptoms and/or biochemical markers followed by drug adaptation (which may then also be based on reactive TDM).

Relevant resources

• Syversen SW et al. JAMA. 2021;326:2375-84.
• Strik AS et al. Scand J Gastroenterol. 2021 Feb;56(2):145-54.
• Bossuyt P et al. J Crohns Colitis. 2022 Feb 23;16(2):199-206.
• D’Haens G et al. Gastroenterology. 2018;154:1343-51.e1.

Dear colleagues,

We shift gears from discussing GI hospitalists to focusing on the treatment of inflammatory bowel disease. The introduction of anti-TNFs brought about a paradigm shift in IBD management. With the ability to measure drug and antibody levels, we are also able to alter dose and timing to increase the efficacy of these medications. Some experts have extended this reactive drug monitoring approach to a more proactive method with the expectation that this may prevent loss of efficacy and development of adverse events. Dr. Loren G. Rabinowitz and colleagues and Dr. Hans Herfarth describe these two approaches to anti-TNF management in IBD, drawing from the current data and their own experiences. I look forward to hearing your thoughts and experiences by email (ginews@gastro.org).

Gyanprakash A. Ketwaroo, MD, MSc, is an assistant professor of medicine at Baylor College of Medicine, Houston. He is an associate editor for GI & Hepatology News.

Better outcomes than reactive TDM

By Loren G. Rabinowitz, MD; Konstantinos Papamichael, PhD, MD; and Adam S. Cheifetz, MD, AGAF

Therapeutic drug monitoring (TDM), or the practice of treatment optimization based on serum drug concentrations, is used in many settings, including solid organ transplantation, infection, and immune-mediated inflammatory diseases, including inflammatory bowel disease (IBD). In IBD, the use of TDM has been an area of keen research focus, and, in our view, should be standard practice for optimization of biologic therapy, particularly in the setting of anti–tumor necrosis factor (TNF) therapy. TDM has demonstrated utility in determining the correct timing and dosage of biologics and can provide the impetus for deescalating or discontinuing a biologic in favor of an alternative one. It also allows prescribers the ability to protect patients from severe infusion reactions if they have developed anti-drug antibodies (ADAs).

Reactive TDM refers to a strategy of assessing drug concentration and presence of ADAs in the setting of primary nonresponse (PNR) and loss of response (LOR) to a biologic agent. In this context, TDM informs possible reasons for loss or lack of response to treatment – for example, insufficient drug concentration or the development of high-titer ADAs (immunogenicity) – thus better directing the management of these unwanted outcomes.¹ Insufficient anti-TNF concentrations have been associated with PNR and lack of clinical remission at 1 year in patients with IBD,2 which underscores the need for a durable strategy to ensure appropriate drug concentrations from the induction through maintenance phases of biologic administration. Reactive TDM can also be used to inform the decision to abandon a particular therapy in favor of a different biologic and to guide the selection of the next biologic agent, and has been shown to be less expensive than empiric dose escalation.² With regard to infliximab and adalimumab, it is our practice to continue dose escalation until drug concentrations are above 10-15 mcg/mL prior to abandoning therapy.1

For a significant number of patients, reactive TDM identifies at-risk patients too late, when ADAs have already formed. Because the number of medications to treat IBD remains limited, waiting for a patient to lose response to an agent, particularly anti-TNF therapies, increases the likelihood of immunogenicity, thus rendering an agent unusable. Proactive TDM or checking drug trough concentrations preemptively and at predetermined intervals, and dosing to an appropriate concentration, can improve patient outcomes. If drug concentration is determined to be not “at target,” dosage and timing of administration can be increased with or without the addition of an immunomodulator (thiopurines or methotrexate) to optimize the biologic’s efficacy and prevent immunogenicity. This approach allows the provider to anticipate and proactively guard against PNR and future LOR.

Proactive TDM of anti-TNF therapy has been associated with better patient outcomes in both pediatric and adult populations when compared with empiric dose optimization and/or reactive TDM.^2,3 In patients with immune-mediated inflammatory diseases undergoing maintenance therapy with infliximab, proactive TDM was found to be more effective than treatment without TDM in sustaining disease control without disease worsening.⁴ Proactive TDM has been associated with better patient outcomes, including increased rates of clinical remission in both pediatric and adult populations and decreased rates of IBD-related surgery, hospitalization, serious infusion reactions, and development of ADAs, when compared with reactive TDM or empiric optimization. Preliminary data suggest that proactive TDM can also be used to efficiently guide dose deescalation in patients in remission with drug concentrations markedly above target and to allow for optimization of infliximab monotherapy so that combination therapy can be employed more judiciously (that is, in a patient who developed rapid ADA to a different anti-TNF).¹ This could potentially attenuate the risks associated with long-term immunomodulator use, which include lymphomas and higher rates of serious and opportunistic infections. A recent study using a pharmacokinetic dashboard showed that the majority of patients with IBD will need accelerated dosing by the third infusion to maintain therapeutic infliximab concentrations during induction and maintenance therapy, highlighting the urgent need for widespread adoption of early proactive TDM.⁵ It is likely that proactive TDM is most important early in therapy when patients are most inflamed and have more rapid drug clearance. For this reason, proactive TDM should ideally be used for all patients during the induction phase. It is our practice to continue to follow drug concentrations one or two times per year once a patient has achieved remission. A recent literature review and consensus statement highlights the utility of TDM and what is known at this time.¹

Juan Gaertner/Science Photo Library/Getty Images

TDM should be standard of care for patients with IBD. At minimum, reactive TDM has rationalized the management of PNR, is associated with better outcomes, and is more cost effective than empiric dose escalation.^1,2 In this setting, however, many patients have already developed ADAs that cannot be overcome. At present, anti-TNF therapy remains the most effective agent for our sickest patients with IBD. Given the as-yet limited armamentarium of medications available, particularly for patients with fistulizing perianal Crohn’s disease (CD) and severe ulcerative colitis (UC), proactive TDM, which allows for improved optimization and long-term durability of biologics, is essential to the care of any IBD patient requiring these medications. Proactive TDM should ideally be used for all patients during the induction phase and at least once during maintenance therapy. There is also the potential for TDM-driven dose de-escalation for patients in remission and optimization of infliximab monotherapy, thus avoiding combination therapy with an immunomodulator in some cases. Future perspectives for a more precise application of TDM include the use of pharmacokinetic modeling dashboards and pharmacogenetics toward achieving truly individualized medicine.³

Dr. Rabinowitz, Dr. Papamichael, and Dr. Cheifetz are with the department of medicine and division of gastroenterology at Beth Israel Deaconess Medical Center and Harvard Medical School, both in Boston. Dr. Rabinowitz reports no conflicts of interest. Dr. Papamichael reports lecture fees from Mitsubishi Tanabe Pharma and Physicians’ Education Resource; consultancy fee from Prometheus Laboratories; and scientific advisory board fees from ProciseDx and Scipher Medicine Corporation. Dr. Cheifetz reports consulting for Janssen, AbbVie, Samsung, Arena Pharmaceuticals, Grifols, Prometheus, Bristol Myers Squibb, Artizan Biosciences, Artugan Therapeutics, and Equillium.
 

References

1. Cheifetz AS et al. Am J Gastroenterol. 2021 Oct 1;116(10):2014-25.

2. Kennedy NA et al. Lancet Gastroenterol Hepatol. 2019 May;4(5):341-53.

3. Papamichael K et al. Lancet Gastroenterol Hepatol. 2022;7(2):171-85.

4. Syversen SW et al. JAMA. 2021;326(23):2375-84.

5. Dubinsky MC et al. Inflamm Bowel Dis. 2022 Jan 3. doi: 10.1093/ibd/izab285.

Taking a closer look at the evidence

By Hans Herfarth, MD, PhD, AGAF

The debate of therapeutic drug monitoring (TDM) in the setting of anti–tumor necrosis factor (TNF) therapy has been ongoing for more than a decade. Reactive TDM, the measurement of drug concentrations in the context of loss of treatment response, is now generally accepted and recommended in multiple national and international inflammatory bowel disease (IBD) guidelines. Proactive TDM, defined as the systematic measurement of drug trough concentrations and anti-drug antibodies with dose adaptations to a predefined target drug concentration, seems to offer a possibility to stabilize drug levels and prevent anti-drug antibody formation due to low systemic drug levels, thus potentially preventing the well-known loss of response to anti-TNF therapy, which occurs in more than 50% of patients over time. However, proactive TDM is not endorsed by evidence-based guidelines, dividing IBD physicians into believers and nonbelievers and limiting uptake into clinical practice.

As with reactive TDM, one should assume that the framework for proactive TDM should have been reliably established based on factual data derived from prospective controlled studies and not rely on retrospective cohorts or “Expert Panel” consensus statements. And indeed, several prospective controlled studies with sizable IBD patient cohorts have been published. Of note, all TDM studies for IBD were conducted in patients on anti-TNF maintenance therapy, and currently no prospective studies in larger IBD populations are available for proactive TDM during induction therapy. Two prospective studies, the PRECISION and the NOR-DRUM trial, report that proactive TDM is better than no TDM at all.

However, in the comparison of proactive TDM and reactive TDM (including at least one drug adaptation in maintenance or drug escalation based on clinical symptoms or biomarkers), three studies have demonstrated no significant differences in drug persistence or overall maintenance of clinical remission. Only a fourth (the pediatric PAILOT study) reported a lower frequency of mild flares and less steroid exposure in the proactive TDM arm over 1 year, but it did not show differences in drug persistence or overall clinical remission compared with the reactive TDM arm. Interestingly, the differences in flare frequency were apparent only in patients on monotherapy but not in the subgroup on combination therapy with an immunomodulator, stressing the well-known beneficial effect of a combination therapy with thiopurines in CD first shown in the SONIC trial.

One problem, at least in the TDM trials with infliximab (IFX), may have been a delay in optimizing IFX levels until the next drug infusion because of the turnaround time of the drug assays. However, even the most recently published ultra-proactive TDM study with ad hoc dose adjustments based on point of care testing of drug levels during maintenance IFX therapy did not result in a significantly lower failure rate of IFX therapy or differences in sustained remission compared with reactive TDM over 1 year (19% vs. 10%; P = .08 for IFX failure; 75% vs. 83%; P = .17 for sustained remission). Compared with reactive TDM, the proactive measurement of drug levels resulted in significantly more drug measurements (8.8 vs. 1 per patient per year) and consecutive drug adjustments. Of interest would be the assessment of cost-effectiveness based on these trial data.

The value of proactive TDM in induction therapy remains an ongoing concern. There is no doubt that the severity of intestinal inflammation with subsequent loss of drug in the intestine can result in low drug serum concentrations correlating to lower clinical responses and higher rates of immunogenicity with the formation of anti-drug antibodies. A recent study including patients with chronic immune-mediated inflammatory diseases such as IBD, rheumatoid arthritis, and psoriasis did not find a value in proactive TDM of IFX in the induction phase, but more severe IBD may have been underrepresented in this study. Administration of significantly higher induction dosing of adalimumab (160 mg weeks 0, 1, 2, and 3) with significantly higher trough levels compared with a standard induction regimen in the SERENE study has not been shown to increase the short- or long-term remission rates in UC or CD patients. Therefore, higher trough levels in a patient population do not automatically result in better outcomes, but proactive TDM may still have found a few patients who may have benefited from an even higher induction regimen. The UC and CD SERENE maintenance studies also evaluated proactive TDM versus clinical adjustment based on clinical and biomarkers. After 1 year, no differences in the efficacy endpoints of clinical, endoscopic, and deep remission were found. These somewhat surprising results, which have been reported only in meeting abstracts, suggest that simply increasing trough levels to a higher target (one of the primary aims of proactive TDM) is not an effective universal approach for achieving higher remission rates in induction or better outcomes in maintenance. Instead, the SERENE data show that similar results can be achieved by regular clinical follow-up and monitoring of loss of response based on symptoms and/or biochemical markers followed by drug adaptation (which may then also be based on reactive TDM).

Relevant resources

• Syversen SW et al. JAMA. 2021;326:2375-84.
• Strik AS et al. Scand J Gastroenterol. 2021 Feb;56(2):145-54.
• Bossuyt P et al. J Crohns Colitis. 2022 Feb 23;16(2):199-206.
• D’Haens G et al. Gastroenterology. 2018;154:1343-51.e1.

Dear colleagues,

We shift gears from discussing GI hospitalists to focusing on the treatment of inflammatory bowel disease. The introduction of anti-TNFs brought about a paradigm shift in IBD management. With the ability to measure drug and antibody levels, we are also able to alter dose and timing to increase the efficacy of these medications. Some experts have extended this reactive drug monitoring approach to a more proactive method with the expectation that this may prevent loss of efficacy and development of adverse events. Dr. Loren G. Rabinowitz and colleagues and Dr. Hans Herfarth describe these two approaches to anti-TNF management in IBD, drawing from the current data and their own experiences. I look forward to hearing your thoughts and experiences by email (ginews@gastro.org).

Gyanprakash A. Ketwaroo, MD, MSc, is an assistant professor of medicine at Baylor College of Medicine, Houston. He is an associate editor for GI & Hepatology News.

Better outcomes than reactive TDM

By Loren G. Rabinowitz, MD; Konstantinos Papamichael, PhD, MD; and Adam S. Cheifetz, MD, AGAF

Therapeutic drug monitoring (TDM), or the practice of treatment optimization based on serum drug concentrations, is used in many settings, including solid organ transplantation, infection, and immune-mediated inflammatory diseases, including inflammatory bowel disease (IBD). In IBD, the use of TDM has been an area of keen research focus, and, in our view, should be standard practice for optimization of biologic therapy, particularly in the setting of anti–tumor necrosis factor (TNF) therapy. TDM has demonstrated utility in determining the correct timing and dosage of biologics and can provide the impetus for deescalating or discontinuing a biologic in favor of an alternative one. It also allows prescribers the ability to protect patients from severe infusion reactions if they have developed anti-drug antibodies (ADAs).

Reactive TDM refers to a strategy of assessing drug concentration and presence of ADAs in the setting of primary nonresponse (PNR) and loss of response (LOR) to a biologic agent. In this context, TDM informs possible reasons for loss or lack of response to treatment – for example, insufficient drug concentration or the development of high-titer ADAs (immunogenicity) – thus better directing the management of these unwanted outcomes.¹ Insufficient anti-TNF concentrations have been associated with PNR and lack of clinical remission at 1 year in patients with IBD,2 which underscores the need for a durable strategy to ensure appropriate drug concentrations from the induction through maintenance phases of biologic administration. Reactive TDM can also be used to inform the decision to abandon a particular therapy in favor of a different biologic and to guide the selection of the next biologic agent, and has been shown to be less expensive than empiric dose escalation.² With regard to infliximab and adalimumab, it is our practice to continue dose escalation until drug concentrations are above 10-15 mcg/mL prior to abandoning therapy.1

For a significant number of patients, reactive TDM identifies at-risk patients too late, when ADAs have already formed. Because the number of medications to treat IBD remains limited, waiting for a patient to lose response to an agent, particularly anti-TNF therapies, increases the likelihood of immunogenicity, thus rendering an agent unusable. Proactive TDM or checking drug trough concentrations preemptively and at predetermined intervals, and dosing to an appropriate concentration, can improve patient outcomes. If drug concentration is determined to be not “at target,” dosage and timing of administration can be increased with or without the addition of an immunomodulator (thiopurines or methotrexate) to optimize the biologic’s efficacy and prevent immunogenicity. This approach allows the provider to anticipate and proactively guard against PNR and future LOR.

Proactive TDM of anti-TNF therapy has been associated with better patient outcomes in both pediatric and adult populations when compared with empiric dose optimization and/or reactive TDM.^2,3 In patients with immune-mediated inflammatory diseases undergoing maintenance therapy with infliximab, proactive TDM was found to be more effective than treatment without TDM in sustaining disease control without disease worsening.⁴ Proactive TDM has been associated with better patient outcomes, including increased rates of clinical remission in both pediatric and adult populations and decreased rates of IBD-related surgery, hospitalization, serious infusion reactions, and development of ADAs, when compared with reactive TDM or empiric optimization. Preliminary data suggest that proactive TDM can also be used to efficiently guide dose deescalation in patients in remission with drug concentrations markedly above target and to allow for optimization of infliximab monotherapy so that combination therapy can be employed more judiciously (that is, in a patient who developed rapid ADA to a different anti-TNF).¹ This could potentially attenuate the risks associated with long-term immunomodulator use, which include lymphomas and higher rates of serious and opportunistic infections. A recent study using a pharmacokinetic dashboard showed that the majority of patients with IBD will need accelerated dosing by the third infusion to maintain therapeutic infliximab concentrations during induction and maintenance therapy, highlighting the urgent need for widespread adoption of early proactive TDM.⁵ It is likely that proactive TDM is most important early in therapy when patients are most inflamed and have more rapid drug clearance. For this reason, proactive TDM should ideally be used for all patients during the induction phase. It is our practice to continue to follow drug concentrations one or two times per year once a patient has achieved remission. A recent literature review and consensus statement highlights the utility of TDM and what is known at this time.¹

Juan Gaertner/Science Photo Library/Getty Images

TDM should be standard of care for patients with IBD. At minimum, reactive TDM has rationalized the management of PNR, is associated with better outcomes, and is more cost effective than empiric dose escalation.^1,2 In this setting, however, many patients have already developed ADAs that cannot be overcome. At present, anti-TNF therapy remains the most effective agent for our sickest patients with IBD. Given the as-yet limited armamentarium of medications available, particularly for patients with fistulizing perianal Crohn’s disease (CD) and severe ulcerative colitis (UC), proactive TDM, which allows for improved optimization and long-term durability of biologics, is essential to the care of any IBD patient requiring these medications. Proactive TDM should ideally be used for all patients during the induction phase and at least once during maintenance therapy. There is also the potential for TDM-driven dose de-escalation for patients in remission and optimization of infliximab monotherapy, thus avoiding combination therapy with an immunomodulator in some cases. Future perspectives for a more precise application of TDM include the use of pharmacokinetic modeling dashboards and pharmacogenetics toward achieving truly individualized medicine.³

Dr. Rabinowitz, Dr. Papamichael, and Dr. Cheifetz are with the department of medicine and division of gastroenterology at Beth Israel Deaconess Medical Center and Harvard Medical School, both in Boston. Dr. Rabinowitz reports no conflicts of interest. Dr. Papamichael reports lecture fees from Mitsubishi Tanabe Pharma and Physicians’ Education Resource; consultancy fee from Prometheus Laboratories; and scientific advisory board fees from ProciseDx and Scipher Medicine Corporation. Dr. Cheifetz reports consulting for Janssen, AbbVie, Samsung, Arena Pharmaceuticals, Grifols, Prometheus, Bristol Myers Squibb, Artizan Biosciences, Artugan Therapeutics, and Equillium.
 

References

1. Cheifetz AS et al. Am J Gastroenterol. 2021 Oct 1;116(10):2014-25.

2. Kennedy NA et al. Lancet Gastroenterol Hepatol. 2019 May;4(5):341-53.

3. Papamichael K et al. Lancet Gastroenterol Hepatol. 2022;7(2):171-85.

4. Syversen SW et al. JAMA. 2021;326(23):2375-84.

5. Dubinsky MC et al. Inflamm Bowel Dis. 2022 Jan 3. doi: 10.1093/ibd/izab285.

Taking a closer look at the evidence

By Hans Herfarth, MD, PhD, AGAF

The debate of therapeutic drug monitoring (TDM) in the setting of anti–tumor necrosis factor (TNF) therapy has been ongoing for more than a decade. Reactive TDM, the measurement of drug concentrations in the context of loss of treatment response, is now generally accepted and recommended in multiple national and international inflammatory bowel disease (IBD) guidelines. Proactive TDM, defined as the systematic measurement of drug trough concentrations and anti-drug antibodies with dose adaptations to a predefined target drug concentration, seems to offer a possibility to stabilize drug levels and prevent anti-drug antibody formation due to low systemic drug levels, thus potentially preventing the well-known loss of response to anti-TNF therapy, which occurs in more than 50% of patients over time. However, proactive TDM is not endorsed by evidence-based guidelines, dividing IBD physicians into believers and nonbelievers and limiting uptake into clinical practice.

As with reactive TDM, one should assume that the framework for proactive TDM should have been reliably established based on factual data derived from prospective controlled studies and not rely on retrospective cohorts or “Expert Panel” consensus statements. And indeed, several prospective controlled studies with sizable IBD patient cohorts have been published. Of note, all TDM studies for IBD were conducted in patients on anti-TNF maintenance therapy, and currently no prospective studies in larger IBD populations are available for proactive TDM during induction therapy. Two prospective studies, the PRECISION and the NOR-DRUM trial, report that proactive TDM is better than no TDM at all.

However, in the comparison of proactive TDM and reactive TDM (including at least one drug adaptation in maintenance or drug escalation based on clinical symptoms or biomarkers), three studies have demonstrated no significant differences in drug persistence or overall maintenance of clinical remission. Only a fourth (the pediatric PAILOT study) reported a lower frequency of mild flares and less steroid exposure in the proactive TDM arm over 1 year, but it did not show differences in drug persistence or overall clinical remission compared with the reactive TDM arm. Interestingly, the differences in flare frequency were apparent only in patients on monotherapy but not in the subgroup on combination therapy with an immunomodulator, stressing the well-known beneficial effect of a combination therapy with thiopurines in CD first shown in the SONIC trial.

One problem, at least in the TDM trials with infliximab (IFX), may have been a delay in optimizing IFX levels until the next drug infusion because of the turnaround time of the drug assays. However, even the most recently published ultra-proactive TDM study with ad hoc dose adjustments based on point of care testing of drug levels during maintenance IFX therapy did not result in a significantly lower failure rate of IFX therapy or differences in sustained remission compared with reactive TDM over 1 year (19% vs. 10%; P = .08 for IFX failure; 75% vs. 83%; P = .17 for sustained remission). Compared with reactive TDM, the proactive measurement of drug levels resulted in significantly more drug measurements (8.8 vs. 1 per patient per year) and consecutive drug adjustments. Of interest would be the assessment of cost-effectiveness based on these trial data.

The value of proactive TDM in induction therapy remains an ongoing concern. There is no doubt that the severity of intestinal inflammation with subsequent loss of drug in the intestine can result in low drug serum concentrations correlating to lower clinical responses and higher rates of immunogenicity with the formation of anti-drug antibodies. A recent study including patients with chronic immune-mediated inflammatory diseases such as IBD, rheumatoid arthritis, and psoriasis did not find a value in proactive TDM of IFX in the induction phase, but more severe IBD may have been underrepresented in this study. Administration of significantly higher induction dosing of adalimumab (160 mg weeks 0, 1, 2, and 3) with significantly higher trough levels compared with a standard induction regimen in the SERENE study has not been shown to increase the short- or long-term remission rates in UC or CD patients. Therefore, higher trough levels in a patient population do not automatically result in better outcomes, but proactive TDM may still have found a few patients who may have benefited from an even higher induction regimen. The UC and CD SERENE maintenance studies also evaluated proactive TDM versus clinical adjustment based on clinical and biomarkers. After 1 year, no differences in the efficacy endpoints of clinical, endoscopic, and deep remission were found. These somewhat surprising results, which have been reported only in meeting abstracts, suggest that simply increasing trough levels to a higher target (one of the primary aims of proactive TDM) is not an effective universal approach for achieving higher remission rates in induction or better outcomes in maintenance. Instead, the SERENE data show that similar results can be achieved by regular clinical follow-up and monitoring of loss of response based on symptoms and/or biochemical markers followed by drug adaptation (which may then also be based on reactive TDM).

Relevant resources

• Syversen SW et al. JAMA. 2021;326:2375-84.
• Strik AS et al. Scand J Gastroenterol. 2021 Feb;56(2):145-54.
• Bossuyt P et al. J Crohns Colitis. 2022 Feb 23;16(2):199-206.
• D’Haens G et al. Gastroenterology. 2018;154:1343-51.e1.

A New York state radiation oncologist accused of gross negligence and incompetence back in 2018 has now lost his medical license.

The state Board for Professional Medical Conduct has revoked the medical license of Won Sam Yi, MD, following a lengthy review of the care he provided to seven cancer patients; six of them died.

“He is a danger to potential new patients should he be reinstated as a radiation oncologist,” board members wrote, according to a news report in the Buffalo News.

Dr. Yi’s lawyer said that he is appealing the decision.

Dr. Yi was the former CEO of the now-defunct private cancer practice CCS Oncology, located in western New York.

In 2018, the state health department brought numerous charges of professional misconduct against Dr. Yi, including charges that he had failed to “account for prior doses of radiotherapy” as well as exceeding “appropriate tissue tolerances” during the treatment.

Now, the state’s Board for Professional Medical Conduct has upheld nearly all of the departmental charges that had been levied against him, and also found that Dr. Yi failed to take responsibility or show contrition for his treatment decisions.

However, whistleblower claims from a former CSS Oncology employee were dismissed.
 

Troubled history

CCS Oncology was once one of the largest private cancer practices in Erie and Niagara counties, both in the Buffalo metropolitan area.

Dr. Yi purchased CCS Oncology in 2008 and was its sole shareholder, and in 2012 he also acquired CCS Medical. As of 2016, the practices provided care to about 30% of cancer patients in the region. CCS also began acquiring other practices as it expanded into noncancer specialties, including primary care.

However, CCS began to struggle financially in late 2016, when health insurance provider Independent Health announced it was removing CCS Oncology from its network, and several vendors and lenders subsequently sued CCS and Dr. Yi for nonpayment.

The announcement from Independent Health was “financially devastating to CCS,” and also was “the direct cause” of the practice defaulting on its Bank of America loan and of the practice’s inability to pay not only its vendors but state and federal tax agencies, the Buffalo News reported. As a result, several vendors and lenders had sued CCS and Dr. Yi for nonpayment.

The FBI raided numerous CCS locations in March 2018, seizing financial and other data as part of an investigation into possible Medicare billing fraud. The following month, CCS filed for Chapter 11 bankruptcy, citing it owed millions of dollars to Bank of America and other creditors. Shortly afterward, the practice closed.
 

Medical misconduct

The state’s charges of professional misconduct accused Dr. Yi of “gross negligence,” “gross incompetence,” and several other cases of misconduct in treating seven patients between 2009 and 2013 at various CCS locations. The patients ranged in age from 27 to 72. Six of the seven patients died.

In one case, Dr. Yi was accused of providing whole-brain radiation therapy to a 43-year-old woman for about 6 weeks in 2012, but the treatment was “contrary to medical indications” and did not take into account prior doses of such treatment. The patient died in December of that year, and the board concluded that Dr. Yi had improperly treated her with a high dose of radiation that was intended to cure her cancer even though she was at a stage where her disease was incurable.

The state board eventually concluded that for all but one of the patients in question, Dr. Yi was guilty of misconduct in his treatment decisions. They wrote that Dr. Yi had frequently administered radiation doses without taking into account how much radiation therapy the patients had received previously and without considering the risk of serious complications for them.

Dr. Yi plans to appeal the board’s decision in state court, according to his attorney, Anthony Scher.

“Dr Yi has treated over 10,000 patients in his career,” Mr. Scher told the Buffalo News. “These handful of cases don’t represent the thousands of success stories that he’s had.”

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

A New York state radiation oncologist accused of gross negligence and incompetence back in 2018 has now lost his medical license.

The state Board for Professional Medical Conduct has revoked the medical license of Won Sam Yi, MD, following a lengthy review of the care he provided to seven cancer patients; six of them died.

“He is a danger to potential new patients should he be reinstated as a radiation oncologist,” board members wrote, according to a news report in the Buffalo News.

Dr. Yi’s lawyer said that he is appealing the decision.

Dr. Yi was the former CEO of the now-defunct private cancer practice CCS Oncology, located in western New York.

In 2018, the state health department brought numerous charges of professional misconduct against Dr. Yi, including charges that he had failed to “account for prior doses of radiotherapy” as well as exceeding “appropriate tissue tolerances” during the treatment.

Now, the state’s Board for Professional Medical Conduct has upheld nearly all of the departmental charges that had been levied against him, and also found that Dr. Yi failed to take responsibility or show contrition for his treatment decisions.

However, whistleblower claims from a former CSS Oncology employee were dismissed.
 

Troubled history

CCS Oncology was once one of the largest private cancer practices in Erie and Niagara counties, both in the Buffalo metropolitan area.

Dr. Yi purchased CCS Oncology in 2008 and was its sole shareholder, and in 2012 he also acquired CCS Medical. As of 2016, the practices provided care to about 30% of cancer patients in the region. CCS also began acquiring other practices as it expanded into noncancer specialties, including primary care.

However, CCS began to struggle financially in late 2016, when health insurance provider Independent Health announced it was removing CCS Oncology from its network, and several vendors and lenders subsequently sued CCS and Dr. Yi for nonpayment.

The announcement from Independent Health was “financially devastating to CCS,” and also was “the direct cause” of the practice defaulting on its Bank of America loan and of the practice’s inability to pay not only its vendors but state and federal tax agencies, the Buffalo News reported. As a result, several vendors and lenders had sued CCS and Dr. Yi for nonpayment.

The FBI raided numerous CCS locations in March 2018, seizing financial and other data as part of an investigation into possible Medicare billing fraud. The following month, CCS filed for Chapter 11 bankruptcy, citing it owed millions of dollars to Bank of America and other creditors. Shortly afterward, the practice closed.
 

Medical misconduct

The state’s charges of professional misconduct accused Dr. Yi of “gross negligence,” “gross incompetence,” and several other cases of misconduct in treating seven patients between 2009 and 2013 at various CCS locations. The patients ranged in age from 27 to 72. Six of the seven patients died.

In one case, Dr. Yi was accused of providing whole-brain radiation therapy to a 43-year-old woman for about 6 weeks in 2012, but the treatment was “contrary to medical indications” and did not take into account prior doses of such treatment. The patient died in December of that year, and the board concluded that Dr. Yi had improperly treated her with a high dose of radiation that was intended to cure her cancer even though she was at a stage where her disease was incurable.

The state board eventually concluded that for all but one of the patients in question, Dr. Yi was guilty of misconduct in his treatment decisions. They wrote that Dr. Yi had frequently administered radiation doses without taking into account how much radiation therapy the patients had received previously and without considering the risk of serious complications for them.

Dr. Yi plans to appeal the board’s decision in state court, according to his attorney, Anthony Scher.

“Dr Yi has treated over 10,000 patients in his career,” Mr. Scher told the Buffalo News. “These handful of cases don’t represent the thousands of success stories that he’s had.”

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

A New York state radiation oncologist accused of gross negligence and incompetence back in 2018 has now lost his medical license.

The state Board for Professional Medical Conduct has revoked the medical license of Won Sam Yi, MD, following a lengthy review of the care he provided to seven cancer patients; six of them died.

“He is a danger to potential new patients should he be reinstated as a radiation oncologist,” board members wrote, according to a news report in the Buffalo News.

Dr. Yi’s lawyer said that he is appealing the decision.

Dr. Yi was the former CEO of the now-defunct private cancer practice CCS Oncology, located in western New York.

In 2018, the state health department brought numerous charges of professional misconduct against Dr. Yi, including charges that he had failed to “account for prior doses of radiotherapy” as well as exceeding “appropriate tissue tolerances” during the treatment.

Now, the state’s Board for Professional Medical Conduct has upheld nearly all of the departmental charges that had been levied against him, and also found that Dr. Yi failed to take responsibility or show contrition for his treatment decisions.

However, whistleblower claims from a former CSS Oncology employee were dismissed.
 

Troubled history

CCS Oncology was once one of the largest private cancer practices in Erie and Niagara counties, both in the Buffalo metropolitan area.

Dr. Yi purchased CCS Oncology in 2008 and was its sole shareholder, and in 2012 he also acquired CCS Medical. As of 2016, the practices provided care to about 30% of cancer patients in the region. CCS also began acquiring other practices as it expanded into noncancer specialties, including primary care.

However, CCS began to struggle financially in late 2016, when health insurance provider Independent Health announced it was removing CCS Oncology from its network, and several vendors and lenders subsequently sued CCS and Dr. Yi for nonpayment.

The announcement from Independent Health was “financially devastating to CCS,” and also was “the direct cause” of the practice defaulting on its Bank of America loan and of the practice’s inability to pay not only its vendors but state and federal tax agencies, the Buffalo News reported. As a result, several vendors and lenders had sued CCS and Dr. Yi for nonpayment.

The FBI raided numerous CCS locations in March 2018, seizing financial and other data as part of an investigation into possible Medicare billing fraud. The following month, CCS filed for Chapter 11 bankruptcy, citing it owed millions of dollars to Bank of America and other creditors. Shortly afterward, the practice closed.
 

Medical misconduct

The state’s charges of professional misconduct accused Dr. Yi of “gross negligence,” “gross incompetence,” and several other cases of misconduct in treating seven patients between 2009 and 2013 at various CCS locations. The patients ranged in age from 27 to 72. Six of the seven patients died.

In one case, Dr. Yi was accused of providing whole-brain radiation therapy to a 43-year-old woman for about 6 weeks in 2012, but the treatment was “contrary to medical indications” and did not take into account prior doses of such treatment. The patient died in December of that year, and the board concluded that Dr. Yi had improperly treated her with a high dose of radiation that was intended to cure her cancer even though she was at a stage where her disease was incurable.

The state board eventually concluded that for all but one of the patients in question, Dr. Yi was guilty of misconduct in his treatment decisions. They wrote that Dr. Yi had frequently administered radiation doses without taking into account how much radiation therapy the patients had received previously and without considering the risk of serious complications for them.

Dr. Yi plans to appeal the board’s decision in state court, according to his attorney, Anthony Scher.

“Dr Yi has treated over 10,000 patients in his career,” Mr. Scher told the Buffalo News. “These handful of cases don’t represent the thousands of success stories that he’s had.”

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

Disparities in health care exist in every specialty. In rheumatology, health disparities look like lack of access to care and lack of education on the part of rheumatologists and their patients, according to a speaker at the 2022 Rheumatology Winter Clinical Symposium.

Health disparities can affect people based on their racial or ethnic group, gender, sexual orientation, a mental or physical disability, socioeconomic status, or religion, Alvin Wells, MD, PhD, director of the department of rheumatology at Advocate Aurora Health in Franklin, Wisc., said in his presentation. But a person’s environment also plays a role – “where you live, work, play, and worship.”

Screenshot RWCS 2022

Social determinants of health can affect short-term and long-term health outcomes, functioning, and quality of life, he noted. “It’s economic stability, it’s access not only to health care, but also to education. And indeed, in my lifetime, as you know, some individuals weren’t allowed to read and write. They weren’t allowed to go to schools. You didn’t get the same type of education, and so that made a dramatic impact in moving forward with future, subsequent generations.”

In a survey of executives, clinical leaders, and clinicians in NEJM Catalyst Innovations in Care Delivery, 48% said widespread disparities in care delivery were present in their organizations. According to the social psychologist James S. House, PhD, some of these disparities like race/ethnicity, socioeconomic status, genetics, and geography are fixed, while others like psychosocial, medical care/insurance, and environmental hazards are modifiable. While factors like education, work, and location might be modifiable for some patients, others don’t have the ability to make these changes, Dr. Wells explained. “It’s not that easy when you think about it.”

Within rheumatology, racial and ethnic disparities exist in rheumatoid arthritis when it comes to disease activity and use of disease-modifying antirheumatic drugs. Disparities in outcomes based on race and geographic location have also been identified for patients with systemic lupus erythematosus, lupus nephritis, and based on race in osteoarthritis and psoriatic arthritis. “Where people live, where they reside, where their zip code is,” makes a difference for patients with rheumatic diseases, Dr. Wells said.

“We’ve heard at this meeting [about] some amazing drugs in treating our patients, both [for] skin and joint disease, but not everybody has the same kind of access,” he said.
 

What actions can medical stakeholders take?

Health equity should be a “desirable goal” for patients who experience health disparities, but it needs to be a “continuous effort,” Dr. Wells said. Focusing on the “how” of eliminating disparities should be a focus rather than checking a box.

Pharmacoequity is also a component of health equity, according to Dr. Wells. Where a person lives can affect their health based on their neighborhood’s level of air pollution, access to green space, and food deserts, but where a person lives also affects what parts of the health system they have access to, according to an editorial published in Circulation: Cardiovascular Quality and Outcomes. When patients aren’t taking their medication, it might be because that person doesn’t have easy access to a pharmacy, noted Dr. Wells. “It really kind of blows you away when you look at the data.”

Different stakeholders in medicine can tackle various aspects of this problem. For example, health care organizations and medical schools can make long-term commitments to prioritizing health equality, Dr. Wells said. “You want to make this a part of your practice, your group, or your university. And then once you get a process in place, don’t just check that box and move on. You want to see it. If you haven’t reached your goal, you need to revamp. If you met your goal, how do [you] improve upon that?”

Medical schools can also do better at improving misconceptions about patients of different races and ethnicities. Dr. Wells cited a striking paper published in Proceedings of the National Academy of Sciences of the U.S.A. that compared false beliefs in biological differences between Black and White people held by White laypeople and medical students. The study found that 58% of laypeople and 40% of first-year medical students believed that Black people have thicker skin than White people. “It’s absolutely amazing when you think about what medical schools can do,” he said.

Increased access to care is another area for improvement, Dr. Wells noted. “If you take people who are uninsured and you look at their health once they get Medicare, the gaps begin to close between the different races.”

In terms of individual actions, Dr. Wells noted that researchers and clinicians can help to make clinical trials better represent the overall population. At your practice, “treat all your patients like a VIP.” Instead of being concerned about the cost of a treatment, ask “is your patient worth it?”

“I have one of my patients on Medicaid. She’s on a biologic drug. And one of the VPs of my hospital is on the same drug. We don’t treat them any differently.”

The private sector is also acting, Dr. Wells said. He cited Novartis’ pledge to partner with 26 historically Black colleges to improve disparities in health and education. “We need to see more of that done from corporate America.”

Are there any short-term solutions?

Eric Ruderman, MD, professor of rheumatology at Northwestern University, Chicago, commented that institutions have been forming committees and focus groups, but “not a lot of action.”

“They’re checking boxes,” he said, “which is very frustrating.” What can rheumatologists do in the short term, he asked?

Dr. Wells noted that there has been some success in using a “carrot” model of using payment models to reduce racial disparities. For example, a recent study analyzing the effects of the Comprehensive Care for Joint Replacement model highlighted the need for payment reform that incentivizes clinicians to spend wisely on patient treatment. Under a payment model that rewards clinicians for treating patients cost effectively, “if I do a great job cost effectively, I could just have more of that money back to my group,” he said.

George Martin, MD, a clinical dermatologist practicing in Maui, recalled the disparity in health care he observed as a child growing up in Philadelphia. “There’s really, within the city, there’s two different levels of health care,” he said. “There’s a tremendous disparity in the quality of the physician in hospital, and way out in the community. Because that’s the point of contact. That’s when either you’re going to prescribe a biologic, or [you’re] going to give them some aspirin and tell them go home. That’s where it starts, point of contact.”

Dr. Wells agreed that it is a big challenge, noting that cities also contribute to pollution, crowding, and other factors that adversely impact health care.

“It’s a shared responsibility. How do we solve that?” Dr. Martin asked. “And if you tell me, I’m going to give you a Nobel Prize.”

Dr. Wells reported he is a reviewer for the Journal of Racial and Ethnic Disparities.

Disparities in health care exist in every specialty. In rheumatology, health disparities look like lack of access to care and lack of education on the part of rheumatologists and their patients, according to a speaker at the 2022 Rheumatology Winter Clinical Symposium.

Health disparities can affect people based on their racial or ethnic group, gender, sexual orientation, a mental or physical disability, socioeconomic status, or religion, Alvin Wells, MD, PhD, director of the department of rheumatology at Advocate Aurora Health in Franklin, Wisc., said in his presentation. But a person’s environment also plays a role – “where you live, work, play, and worship.”

Screenshot RWCS 2022

Social determinants of health can affect short-term and long-term health outcomes, functioning, and quality of life, he noted. “It’s economic stability, it’s access not only to health care, but also to education. And indeed, in my lifetime, as you know, some individuals weren’t allowed to read and write. They weren’t allowed to go to schools. You didn’t get the same type of education, and so that made a dramatic impact in moving forward with future, subsequent generations.”

In a survey of executives, clinical leaders, and clinicians in NEJM Catalyst Innovations in Care Delivery, 48% said widespread disparities in care delivery were present in their organizations. According to the social psychologist James S. House, PhD, some of these disparities like race/ethnicity, socioeconomic status, genetics, and geography are fixed, while others like psychosocial, medical care/insurance, and environmental hazards are modifiable. While factors like education, work, and location might be modifiable for some patients, others don’t have the ability to make these changes, Dr. Wells explained. “It’s not that easy when you think about it.”

Within rheumatology, racial and ethnic disparities exist in rheumatoid arthritis when it comes to disease activity and use of disease-modifying antirheumatic drugs. Disparities in outcomes based on race and geographic location have also been identified for patients with systemic lupus erythematosus, lupus nephritis, and based on race in osteoarthritis and psoriatic arthritis. “Where people live, where they reside, where their zip code is,” makes a difference for patients with rheumatic diseases, Dr. Wells said.

“We’ve heard at this meeting [about] some amazing drugs in treating our patients, both [for] skin and joint disease, but not everybody has the same kind of access,” he said.
 

What actions can medical stakeholders take?

Health equity should be a “desirable goal” for patients who experience health disparities, but it needs to be a “continuous effort,” Dr. Wells said. Focusing on the “how” of eliminating disparities should be a focus rather than checking a box.

Pharmacoequity is also a component of health equity, according to Dr. Wells. Where a person lives can affect their health based on their neighborhood’s level of air pollution, access to green space, and food deserts, but where a person lives also affects what parts of the health system they have access to, according to an editorial published in Circulation: Cardiovascular Quality and Outcomes. When patients aren’t taking their medication, it might be because that person doesn’t have easy access to a pharmacy, noted Dr. Wells. “It really kind of blows you away when you look at the data.”

Different stakeholders in medicine can tackle various aspects of this problem. For example, health care organizations and medical schools can make long-term commitments to prioritizing health equality, Dr. Wells said. “You want to make this a part of your practice, your group, or your university. And then once you get a process in place, don’t just check that box and move on. You want to see it. If you haven’t reached your goal, you need to revamp. If you met your goal, how do [you] improve upon that?”

Medical schools can also do better at improving misconceptions about patients of different races and ethnicities. Dr. Wells cited a striking paper published in Proceedings of the National Academy of Sciences of the U.S.A. that compared false beliefs in biological differences between Black and White people held by White laypeople and medical students. The study found that 58% of laypeople and 40% of first-year medical students believed that Black people have thicker skin than White people. “It’s absolutely amazing when you think about what medical schools can do,” he said.

Increased access to care is another area for improvement, Dr. Wells noted. “If you take people who are uninsured and you look at their health once they get Medicare, the gaps begin to close between the different races.”

In terms of individual actions, Dr. Wells noted that researchers and clinicians can help to make clinical trials better represent the overall population. At your practice, “treat all your patients like a VIP.” Instead of being concerned about the cost of a treatment, ask “is your patient worth it?”

“I have one of my patients on Medicaid. She’s on a biologic drug. And one of the VPs of my hospital is on the same drug. We don’t treat them any differently.”

The private sector is also acting, Dr. Wells said. He cited Novartis’ pledge to partner with 26 historically Black colleges to improve disparities in health and education. “We need to see more of that done from corporate America.”

Are there any short-term solutions?

Eric Ruderman, MD, professor of rheumatology at Northwestern University, Chicago, commented that institutions have been forming committees and focus groups, but “not a lot of action.”

“They’re checking boxes,” he said, “which is very frustrating.” What can rheumatologists do in the short term, he asked?

Dr. Wells noted that there has been some success in using a “carrot” model of using payment models to reduce racial disparities. For example, a recent study analyzing the effects of the Comprehensive Care for Joint Replacement model highlighted the need for payment reform that incentivizes clinicians to spend wisely on patient treatment. Under a payment model that rewards clinicians for treating patients cost effectively, “if I do a great job cost effectively, I could just have more of that money back to my group,” he said.

George Martin, MD, a clinical dermatologist practicing in Maui, recalled the disparity in health care he observed as a child growing up in Philadelphia. “There’s really, within the city, there’s two different levels of health care,” he said. “There’s a tremendous disparity in the quality of the physician in hospital, and way out in the community. Because that’s the point of contact. That’s when either you’re going to prescribe a biologic, or [you’re] going to give them some aspirin and tell them go home. That’s where it starts, point of contact.”

Dr. Wells agreed that it is a big challenge, noting that cities also contribute to pollution, crowding, and other factors that adversely impact health care.

“It’s a shared responsibility. How do we solve that?” Dr. Martin asked. “And if you tell me, I’m going to give you a Nobel Prize.”

Dr. Wells reported he is a reviewer for the Journal of Racial and Ethnic Disparities.

Disparities in health care exist in every specialty. In rheumatology, health disparities look like lack of access to care and lack of education on the part of rheumatologists and their patients, according to a speaker at the 2022 Rheumatology Winter Clinical Symposium.

Health disparities can affect people based on their racial or ethnic group, gender, sexual orientation, a mental or physical disability, socioeconomic status, or religion, Alvin Wells, MD, PhD, director of the department of rheumatology at Advocate Aurora Health in Franklin, Wisc., said in his presentation. But a person’s environment also plays a role – “where you live, work, play, and worship.”

Screenshot RWCS 2022

Social determinants of health can affect short-term and long-term health outcomes, functioning, and quality of life, he noted. “It’s economic stability, it’s access not only to health care, but also to education. And indeed, in my lifetime, as you know, some individuals weren’t allowed to read and write. They weren’t allowed to go to schools. You didn’t get the same type of education, and so that made a dramatic impact in moving forward with future, subsequent generations.”

In a survey of executives, clinical leaders, and clinicians in NEJM Catalyst Innovations in Care Delivery, 48% said widespread disparities in care delivery were present in their organizations. According to the social psychologist James S. House, PhD, some of these disparities like race/ethnicity, socioeconomic status, genetics, and geography are fixed, while others like psychosocial, medical care/insurance, and environmental hazards are modifiable. While factors like education, work, and location might be modifiable for some patients, others don’t have the ability to make these changes, Dr. Wells explained. “It’s not that easy when you think about it.”

Within rheumatology, racial and ethnic disparities exist in rheumatoid arthritis when it comes to disease activity and use of disease-modifying antirheumatic drugs. Disparities in outcomes based on race and geographic location have also been identified for patients with systemic lupus erythematosus, lupus nephritis, and based on race in osteoarthritis and psoriatic arthritis. “Where people live, where they reside, where their zip code is,” makes a difference for patients with rheumatic diseases, Dr. Wells said.

“We’ve heard at this meeting [about] some amazing drugs in treating our patients, both [for] skin and joint disease, but not everybody has the same kind of access,” he said.
 

What actions can medical stakeholders take?

Health equity should be a “desirable goal” for patients who experience health disparities, but it needs to be a “continuous effort,” Dr. Wells said. Focusing on the “how” of eliminating disparities should be a focus rather than checking a box.

Pharmacoequity is also a component of health equity, according to Dr. Wells. Where a person lives can affect their health based on their neighborhood’s level of air pollution, access to green space, and food deserts, but where a person lives also affects what parts of the health system they have access to, according to an editorial published in Circulation: Cardiovascular Quality and Outcomes. When patients aren’t taking their medication, it might be because that person doesn’t have easy access to a pharmacy, noted Dr. Wells. “It really kind of blows you away when you look at the data.”

Different stakeholders in medicine can tackle various aspects of this problem. For example, health care organizations and medical schools can make long-term commitments to prioritizing health equality, Dr. Wells said. “You want to make this a part of your practice, your group, or your university. And then once you get a process in place, don’t just check that box and move on. You want to see it. If you haven’t reached your goal, you need to revamp. If you met your goal, how do [you] improve upon that?”

Medical schools can also do better at improving misconceptions about patients of different races and ethnicities. Dr. Wells cited a striking paper published in Proceedings of the National Academy of Sciences of the U.S.A. that compared false beliefs in biological differences between Black and White people held by White laypeople and medical students. The study found that 58% of laypeople and 40% of first-year medical students believed that Black people have thicker skin than White people. “It’s absolutely amazing when you think about what medical schools can do,” he said.

Increased access to care is another area for improvement, Dr. Wells noted. “If you take people who are uninsured and you look at their health once they get Medicare, the gaps begin to close between the different races.”

In terms of individual actions, Dr. Wells noted that researchers and clinicians can help to make clinical trials better represent the overall population. At your practice, “treat all your patients like a VIP.” Instead of being concerned about the cost of a treatment, ask “is your patient worth it?”

“I have one of my patients on Medicaid. She’s on a biologic drug. And one of the VPs of my hospital is on the same drug. We don’t treat them any differently.”

The private sector is also acting, Dr. Wells said. He cited Novartis’ pledge to partner with 26 historically Black colleges to improve disparities in health and education. “We need to see more of that done from corporate America.”

Are there any short-term solutions?

Eric Ruderman, MD, professor of rheumatology at Northwestern University, Chicago, commented that institutions have been forming committees and focus groups, but “not a lot of action.”

“They’re checking boxes,” he said, “which is very frustrating.” What can rheumatologists do in the short term, he asked?

Dr. Wells noted that there has been some success in using a “carrot” model of using payment models to reduce racial disparities. For example, a recent study analyzing the effects of the Comprehensive Care for Joint Replacement model highlighted the need for payment reform that incentivizes clinicians to spend wisely on patient treatment. Under a payment model that rewards clinicians for treating patients cost effectively, “if I do a great job cost effectively, I could just have more of that money back to my group,” he said.

George Martin, MD, a clinical dermatologist practicing in Maui, recalled the disparity in health care he observed as a child growing up in Philadelphia. “There’s really, within the city, there’s two different levels of health care,” he said. “There’s a tremendous disparity in the quality of the physician in hospital, and way out in the community. Because that’s the point of contact. That’s when either you’re going to prescribe a biologic, or [you’re] going to give them some aspirin and tell them go home. That’s where it starts, point of contact.”

Dr. Wells agreed that it is a big challenge, noting that cities also contribute to pollution, crowding, and other factors that adversely impact health care.

“It’s a shared responsibility. How do we solve that?” Dr. Martin asked. “And if you tell me, I’m going to give you a Nobel Prize.”

Dr. Wells reported he is a reviewer for the Journal of Racial and Ethnic Disparities.