Federal Practitioner

MILAN – Two independent efforts to use artificial intelligence (AI) to predict the development of early rheumatoid arthritis (RA) from patients with signs and symptoms not meeting full disease criteria showed good, near expert-level accuracy, according to findings from two studies presented at the annual European Congress of Rheumatology.

In one study, researchers from Leiden University Medical Center in the Netherlands developed an AI-based method to automatically analyze MR scans of extremities in order to predict early rheumatoid arthritis. The second study involved a Japanese research team that used machine learning to create a model capable of predicting progression from undifferentiated arthritis (UA) to RA. Both approaches would facilitate early diagnosis of RA, enabling timely treatment and improved clinical outcomes.

Dr. Lennart Jans

Lennart Jans, MD, PhD, who was not involved in either study but works with AI-assisted imaging analysis on a daily basis as head of clinics in musculoskeletal radiology at Ghent University Hospital and a professor of radiology at Ghent University in Belgium, said that integrating AI into health care poses several challenging aspects that need to be addressed. “There are three main challenges associated with the development and implementation of AI-based tools in clinical practice,” he said. “Firstly, obtaining heterogeneous datasets from different image hardware vendors, diverse racial and ethnic backgrounds, and various ages and genders is crucial for training and testing the AI algorithms. Secondly, AI algorithms need to achieve a predetermined performance level depending on the specific use case. Finally, a regulatory pathway must be followed to obtain the necessary FDA or MDR [medical devices regulation] certification before applying an AI use case in clinical practice.”
 

RA prediction

Yanli Li, the first author of the study and a member of the division of image processing at Leiden University Medical Center, explained the potential benefits of early RA prediction. “If we could determine whether a patient presenting with clinically suspected arthralgia (CSA) or early onset arthritis (EAC) is likely to develop RA in the near future, physicians could initiate treatment earlier, reducing the risk of disease progression.”

Currently, rheumatologists estimate the likelihood of developing RA by visually scoring MR scans using the RAMRIS scoring system. “We decided to explore the use of AI,” Dr. Li explained, “because it could save time, reduce costs and labor, eliminate the need for scoring training, and allow for hypothesis-free discoveries.”

The research team collected MR scans of the hands and feet from Leiden University Medical Center’s radiology department. The dataset consisted of images from 177 healthy individuals, 692 subjects with CSA (including 113 who developed RA), and 969 with EAC (including 447 who developed RA). The images underwent automated preprocessing to remove artifacts and standardize the input for the computer. Subsequently, a deep learning model was trained to predict RA development within a 2-year time frame.

The training process involved several steps. Initially, the researchers pretrained the model to learn anatomy by masking parts of the images and tasking the computer with reconstructing them. Subsequently, the AI was trained to differentiate between the groups (EAC vs. healthy and CSA vs. healthy), then between RA and other disorders. Finally, the AI model was trained to predict RA.

The accuracy of the model was evaluated using the area under the receiver operator characteristic curve (AUROC). The model that was trained using MR scans of the hands (including the wrist and metacarpophalangeal joints) achieved a mean AUROC of 0.84 for distinguishing EAC from healthy subjects and 0.83 for distinguishing CSA from healthy subjects. The model trained using MR scans of both the hands and feet achieved a mean AUROC of 0.71 for distinguishing RA from non-RA cases in EAC. The accuracy of the model in predicting RA using MR scans of the hands was 0.73, which closely matches the reported accuracy of visual scoring by human experts (0.74). Importantly, the generation and analysis of heat maps suggested that the deep learning model predicts RA based on known inflammatory signals.

“Automatic RA prediction using AI interpretation of MR scans is feasible,” Dr. Li said. “Incorporating additional clinical data will likely further enhance the AI prediction, and the heat maps may contribute to the discovery of new MRI biomarkers for RA development.”

“AI models and engines have achieved near-expertise levels for various use cases, including the early detection of RA on MRI scans of the hands,” said Dr. Jans, the Ghent University radiologist. “We are observing the same progress in AI detection of rheumatic diseases in other imaging modalities, such as radiography, CT, and ultrasound. However, it is important to note that the reported performances often apply to selected cohorts with standardized imaging protocols. The next challenge [for Dr. Li and colleagues, and others] will be to train and test these algorithms using more heterogeneous datasets to make them applicable in real-world settings.”
 

A ‘transitional phase’ of applying AI techniques

“In a medical setting, as computer scientists, we face unique challenges,” pointed out Berend C. Stoel, MSc, PhD, the senior author of the Leiden study. “Our team consists of approximately 30-35 researchers, primarily electrical engineers or computer scientists, situated within the radiology department of Leiden University Medical Center. Our focus is on image processing, seeking AI-based solutions for image analysis, particularly utilizing deep learning techniques.”

Their objective is to validate this method more broadly, and to achieve that, they require collaboration with other hospitals. Up until now, they have primarily worked with a specific type of MR images, extremity MR scans. These scans are conducted in only a few centers equipped with extremity MR scanners, which can accommodate only hands or feet.

“We are currently in a transitional phase, aiming to apply our methods to standard MR scans, which are more widely available,” Dr. Stoel informed this news organization. “We are engaged in various projects. One project, nearing completion, involves the scoring of early RA, where we train the computer to imitate the actions of rheumatologists or radiologists. We started with a relatively straightforward approach, but AI offers a multitude of possibilities. In the project presented at EULAR, we manipulated the images in a different manner, attempting to predict future events. We also have a parallel project where we employ AI to detect inflammatory changes over time by analyzing sequences of images (MR scans). Furthermore, we have developed AI models to distinguish between treatment and placebo groups. Once the neural network has been trained for this task, we can inquire about the location and timing of changes, thereby gaining insights into the therapy’s response.

“When considering the history of AI, it has experienced both ups and downs. We are currently in a promising phase, but if certain projects fail, expectations might diminish. My hope is that we will indeed revolutionize and enhance disease diagnosis, monitoring, and prediction. Additionally, AI may provide us with additional information that we, as humans, may not be able to extract from these images. However, it is difficult to predict where we will stand in 5-10 years,” he concluded.
 

Predicting disease progression

The second study, which explored the application of AI in predicting the progression of undifferentiated arthritis (UA) to RA, was presented by Takayuki Fujii, MD, PhD, assistant professor in the department of advanced medicine for rheumatic diseases at Kyoto University’s Graduate School of Medicine in Japan. “Predicting the progression of RA from UA remains an unmet medical need,” he reminded the audience.

Dr. Takayuki Fujii

Dr. Fujii’s team used data from the KURAMA cohort, a large observational RA cohort from a single center, to develop a machine learning model. The study included a total of 322 patients initially diagnosed with UA. The deep neural network (DNN) model was trained using 24 clinical features that are easily obtainable in routine clinical practice, such as age, sex, C-reactive protein (CRP) levels, and disease activity score in 28 joints using erythrocyte sedimentation rate (DAS28-ESR). The DNN model achieved a prediction accuracy of 85.1% in the training cohort. When the model was applied to validation data from an external dataset consisting of 88 patients from the ANSWER cohort, a large multicenter observational RA cohort, the prediction accuracy was 80%.

“We have developed a machine learning model that can predict the progression of RA from UA using clinical parameters,” Dr. Fujii concluded. “This model has the potential to assist rheumatologists in providing appropriate care and timely intervention for patients with UA.”

“Dr. Fujii presented a fascinating study,” Dr. Jans said. “They achieved an accuracy of 80% when applying a DNN model to predict progression from UA to RA. This level of accuracy is relatively high and certainly promising. However, it is important to consider that a pre-test probability of 30% [for progressing from UA to RA]  is also relatively high, which partially explains the high accuracy. Nonetheless, this study represents a significant step forward in the clinical management of patients with UA, as it helps identify those who may benefit the most from regular clinical follow-up.”

Dr. Li and Dr. Stoel report no relevant financial relationships with industry. Dr. Fujii has received speaking fees from Asahi Kasei, AbbVie, Chugai, and Tanabe Mitsubishi Pharma. Dr. Jans has received speaking fees from AbbVie, UCB, Lilly, and Novartis; he is cofounder of RheumaFinder. The Leiden study was funded by the Dutch Research Council and the China Scholarship Council. The study by Dr. Fujii and colleagues had no outside funding.

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

MILAN – Two independent efforts to use artificial intelligence (AI) to predict the development of early rheumatoid arthritis (RA) from patients with signs and symptoms not meeting full disease criteria showed good, near expert-level accuracy, according to findings from two studies presented at the annual European Congress of Rheumatology.

In one study, researchers from Leiden University Medical Center in the Netherlands developed an AI-based method to automatically analyze MR scans of extremities in order to predict early rheumatoid arthritis. The second study involved a Japanese research team that used machine learning to create a model capable of predicting progression from undifferentiated arthritis (UA) to RA. Both approaches would facilitate early diagnosis of RA, enabling timely treatment and improved clinical outcomes.

Dr. Lennart Jans

Lennart Jans, MD, PhD, who was not involved in either study but works with AI-assisted imaging analysis on a daily basis as head of clinics in musculoskeletal radiology at Ghent University Hospital and a professor of radiology at Ghent University in Belgium, said that integrating AI into health care poses several challenging aspects that need to be addressed. “There are three main challenges associated with the development and implementation of AI-based tools in clinical practice,” he said. “Firstly, obtaining heterogeneous datasets from different image hardware vendors, diverse racial and ethnic backgrounds, and various ages and genders is crucial for training and testing the AI algorithms. Secondly, AI algorithms need to achieve a predetermined performance level depending on the specific use case. Finally, a regulatory pathway must be followed to obtain the necessary FDA or MDR [medical devices regulation] certification before applying an AI use case in clinical practice.”
 

RA prediction

Yanli Li, the first author of the study and a member of the division of image processing at Leiden University Medical Center, explained the potential benefits of early RA prediction. “If we could determine whether a patient presenting with clinically suspected arthralgia (CSA) or early onset arthritis (EAC) is likely to develop RA in the near future, physicians could initiate treatment earlier, reducing the risk of disease progression.”

Currently, rheumatologists estimate the likelihood of developing RA by visually scoring MR scans using the RAMRIS scoring system. “We decided to explore the use of AI,” Dr. Li explained, “because it could save time, reduce costs and labor, eliminate the need for scoring training, and allow for hypothesis-free discoveries.”

The research team collected MR scans of the hands and feet from Leiden University Medical Center’s radiology department. The dataset consisted of images from 177 healthy individuals, 692 subjects with CSA (including 113 who developed RA), and 969 with EAC (including 447 who developed RA). The images underwent automated preprocessing to remove artifacts and standardize the input for the computer. Subsequently, a deep learning model was trained to predict RA development within a 2-year time frame.

The training process involved several steps. Initially, the researchers pretrained the model to learn anatomy by masking parts of the images and tasking the computer with reconstructing them. Subsequently, the AI was trained to differentiate between the groups (EAC vs. healthy and CSA vs. healthy), then between RA and other disorders. Finally, the AI model was trained to predict RA.

The accuracy of the model was evaluated using the area under the receiver operator characteristic curve (AUROC). The model that was trained using MR scans of the hands (including the wrist and metacarpophalangeal joints) achieved a mean AUROC of 0.84 for distinguishing EAC from healthy subjects and 0.83 for distinguishing CSA from healthy subjects. The model trained using MR scans of both the hands and feet achieved a mean AUROC of 0.71 for distinguishing RA from non-RA cases in EAC. The accuracy of the model in predicting RA using MR scans of the hands was 0.73, which closely matches the reported accuracy of visual scoring by human experts (0.74). Importantly, the generation and analysis of heat maps suggested that the deep learning model predicts RA based on known inflammatory signals.

“Automatic RA prediction using AI interpretation of MR scans is feasible,” Dr. Li said. “Incorporating additional clinical data will likely further enhance the AI prediction, and the heat maps may contribute to the discovery of new MRI biomarkers for RA development.”

“AI models and engines have achieved near-expertise levels for various use cases, including the early detection of RA on MRI scans of the hands,” said Dr. Jans, the Ghent University radiologist. “We are observing the same progress in AI detection of rheumatic diseases in other imaging modalities, such as radiography, CT, and ultrasound. However, it is important to note that the reported performances often apply to selected cohorts with standardized imaging protocols. The next challenge [for Dr. Li and colleagues, and others] will be to train and test these algorithms using more heterogeneous datasets to make them applicable in real-world settings.”
 

A ‘transitional phase’ of applying AI techniques

“In a medical setting, as computer scientists, we face unique challenges,” pointed out Berend C. Stoel, MSc, PhD, the senior author of the Leiden study. “Our team consists of approximately 30-35 researchers, primarily electrical engineers or computer scientists, situated within the radiology department of Leiden University Medical Center. Our focus is on image processing, seeking AI-based solutions for image analysis, particularly utilizing deep learning techniques.”

Their objective is to validate this method more broadly, and to achieve that, they require collaboration with other hospitals. Up until now, they have primarily worked with a specific type of MR images, extremity MR scans. These scans are conducted in only a few centers equipped with extremity MR scanners, which can accommodate only hands or feet.

“We are currently in a transitional phase, aiming to apply our methods to standard MR scans, which are more widely available,” Dr. Stoel informed this news organization. “We are engaged in various projects. One project, nearing completion, involves the scoring of early RA, where we train the computer to imitate the actions of rheumatologists or radiologists. We started with a relatively straightforward approach, but AI offers a multitude of possibilities. In the project presented at EULAR, we manipulated the images in a different manner, attempting to predict future events. We also have a parallel project where we employ AI to detect inflammatory changes over time by analyzing sequences of images (MR scans). Furthermore, we have developed AI models to distinguish between treatment and placebo groups. Once the neural network has been trained for this task, we can inquire about the location and timing of changes, thereby gaining insights into the therapy’s response.

“When considering the history of AI, it has experienced both ups and downs. We are currently in a promising phase, but if certain projects fail, expectations might diminish. My hope is that we will indeed revolutionize and enhance disease diagnosis, monitoring, and prediction. Additionally, AI may provide us with additional information that we, as humans, may not be able to extract from these images. However, it is difficult to predict where we will stand in 5-10 years,” he concluded.
 

Predicting disease progression

The second study, which explored the application of AI in predicting the progression of undifferentiated arthritis (UA) to RA, was presented by Takayuki Fujii, MD, PhD, assistant professor in the department of advanced medicine for rheumatic diseases at Kyoto University’s Graduate School of Medicine in Japan. “Predicting the progression of RA from UA remains an unmet medical need,” he reminded the audience.

Dr. Takayuki Fujii

Dr. Fujii’s team used data from the KURAMA cohort, a large observational RA cohort from a single center, to develop a machine learning model. The study included a total of 322 patients initially diagnosed with UA. The deep neural network (DNN) model was trained using 24 clinical features that are easily obtainable in routine clinical practice, such as age, sex, C-reactive protein (CRP) levels, and disease activity score in 28 joints using erythrocyte sedimentation rate (DAS28-ESR). The DNN model achieved a prediction accuracy of 85.1% in the training cohort. When the model was applied to validation data from an external dataset consisting of 88 patients from the ANSWER cohort, a large multicenter observational RA cohort, the prediction accuracy was 80%.

“We have developed a machine learning model that can predict the progression of RA from UA using clinical parameters,” Dr. Fujii concluded. “This model has the potential to assist rheumatologists in providing appropriate care and timely intervention for patients with UA.”

“Dr. Fujii presented a fascinating study,” Dr. Jans said. “They achieved an accuracy of 80% when applying a DNN model to predict progression from UA to RA. This level of accuracy is relatively high and certainly promising. However, it is important to consider that a pre-test probability of 30% [for progressing from UA to RA]  is also relatively high, which partially explains the high accuracy. Nonetheless, this study represents a significant step forward in the clinical management of patients with UA, as it helps identify those who may benefit the most from regular clinical follow-up.”

Dr. Li and Dr. Stoel report no relevant financial relationships with industry. Dr. Fujii has received speaking fees from Asahi Kasei, AbbVie, Chugai, and Tanabe Mitsubishi Pharma. Dr. Jans has received speaking fees from AbbVie, UCB, Lilly, and Novartis; he is cofounder of RheumaFinder. The Leiden study was funded by the Dutch Research Council and the China Scholarship Council. The study by Dr. Fujii and colleagues had no outside funding.

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

MILAN – Two independent efforts to use artificial intelligence (AI) to predict the development of early rheumatoid arthritis (RA) from patients with signs and symptoms not meeting full disease criteria showed good, near expert-level accuracy, according to findings from two studies presented at the annual European Congress of Rheumatology.

In one study, researchers from Leiden University Medical Center in the Netherlands developed an AI-based method to automatically analyze MR scans of extremities in order to predict early rheumatoid arthritis. The second study involved a Japanese research team that used machine learning to create a model capable of predicting progression from undifferentiated arthritis (UA) to RA. Both approaches would facilitate early diagnosis of RA, enabling timely treatment and improved clinical outcomes.

Dr. Lennart Jans

Lennart Jans, MD, PhD, who was not involved in either study but works with AI-assisted imaging analysis on a daily basis as head of clinics in musculoskeletal radiology at Ghent University Hospital and a professor of radiology at Ghent University in Belgium, said that integrating AI into health care poses several challenging aspects that need to be addressed. “There are three main challenges associated with the development and implementation of AI-based tools in clinical practice,” he said. “Firstly, obtaining heterogeneous datasets from different image hardware vendors, diverse racial and ethnic backgrounds, and various ages and genders is crucial for training and testing the AI algorithms. Secondly, AI algorithms need to achieve a predetermined performance level depending on the specific use case. Finally, a regulatory pathway must be followed to obtain the necessary FDA or MDR [medical devices regulation] certification before applying an AI use case in clinical practice.”
 

RA prediction

Yanli Li, the first author of the study and a member of the division of image processing at Leiden University Medical Center, explained the potential benefits of early RA prediction. “If we could determine whether a patient presenting with clinically suspected arthralgia (CSA) or early onset arthritis (EAC) is likely to develop RA in the near future, physicians could initiate treatment earlier, reducing the risk of disease progression.”

Currently, rheumatologists estimate the likelihood of developing RA by visually scoring MR scans using the RAMRIS scoring system. “We decided to explore the use of AI,” Dr. Li explained, “because it could save time, reduce costs and labor, eliminate the need for scoring training, and allow for hypothesis-free discoveries.”

The research team collected MR scans of the hands and feet from Leiden University Medical Center’s radiology department. The dataset consisted of images from 177 healthy individuals, 692 subjects with CSA (including 113 who developed RA), and 969 with EAC (including 447 who developed RA). The images underwent automated preprocessing to remove artifacts and standardize the input for the computer. Subsequently, a deep learning model was trained to predict RA development within a 2-year time frame.

The training process involved several steps. Initially, the researchers pretrained the model to learn anatomy by masking parts of the images and tasking the computer with reconstructing them. Subsequently, the AI was trained to differentiate between the groups (EAC vs. healthy and CSA vs. healthy), then between RA and other disorders. Finally, the AI model was trained to predict RA.

The accuracy of the model was evaluated using the area under the receiver operator characteristic curve (AUROC). The model that was trained using MR scans of the hands (including the wrist and metacarpophalangeal joints) achieved a mean AUROC of 0.84 for distinguishing EAC from healthy subjects and 0.83 for distinguishing CSA from healthy subjects. The model trained using MR scans of both the hands and feet achieved a mean AUROC of 0.71 for distinguishing RA from non-RA cases in EAC. The accuracy of the model in predicting RA using MR scans of the hands was 0.73, which closely matches the reported accuracy of visual scoring by human experts (0.74). Importantly, the generation and analysis of heat maps suggested that the deep learning model predicts RA based on known inflammatory signals.

“Automatic RA prediction using AI interpretation of MR scans is feasible,” Dr. Li said. “Incorporating additional clinical data will likely further enhance the AI prediction, and the heat maps may contribute to the discovery of new MRI biomarkers for RA development.”

“AI models and engines have achieved near-expertise levels for various use cases, including the early detection of RA on MRI scans of the hands,” said Dr. Jans, the Ghent University radiologist. “We are observing the same progress in AI detection of rheumatic diseases in other imaging modalities, such as radiography, CT, and ultrasound. However, it is important to note that the reported performances often apply to selected cohorts with standardized imaging protocols. The next challenge [for Dr. Li and colleagues, and others] will be to train and test these algorithms using more heterogeneous datasets to make them applicable in real-world settings.”
 

A ‘transitional phase’ of applying AI techniques

“In a medical setting, as computer scientists, we face unique challenges,” pointed out Berend C. Stoel, MSc, PhD, the senior author of the Leiden study. “Our team consists of approximately 30-35 researchers, primarily electrical engineers or computer scientists, situated within the radiology department of Leiden University Medical Center. Our focus is on image processing, seeking AI-based solutions for image analysis, particularly utilizing deep learning techniques.”

Their objective is to validate this method more broadly, and to achieve that, they require collaboration with other hospitals. Up until now, they have primarily worked with a specific type of MR images, extremity MR scans. These scans are conducted in only a few centers equipped with extremity MR scanners, which can accommodate only hands or feet.

“We are currently in a transitional phase, aiming to apply our methods to standard MR scans, which are more widely available,” Dr. Stoel informed this news organization. “We are engaged in various projects. One project, nearing completion, involves the scoring of early RA, where we train the computer to imitate the actions of rheumatologists or radiologists. We started with a relatively straightforward approach, but AI offers a multitude of possibilities. In the project presented at EULAR, we manipulated the images in a different manner, attempting to predict future events. We also have a parallel project where we employ AI to detect inflammatory changes over time by analyzing sequences of images (MR scans). Furthermore, we have developed AI models to distinguish between treatment and placebo groups. Once the neural network has been trained for this task, we can inquire about the location and timing of changes, thereby gaining insights into the therapy’s response.

“When considering the history of AI, it has experienced both ups and downs. We are currently in a promising phase, but if certain projects fail, expectations might diminish. My hope is that we will indeed revolutionize and enhance disease diagnosis, monitoring, and prediction. Additionally, AI may provide us with additional information that we, as humans, may not be able to extract from these images. However, it is difficult to predict where we will stand in 5-10 years,” he concluded.
 

Predicting disease progression

The second study, which explored the application of AI in predicting the progression of undifferentiated arthritis (UA) to RA, was presented by Takayuki Fujii, MD, PhD, assistant professor in the department of advanced medicine for rheumatic diseases at Kyoto University’s Graduate School of Medicine in Japan. “Predicting the progression of RA from UA remains an unmet medical need,” he reminded the audience.

Dr. Takayuki Fujii

Dr. Fujii’s team used data from the KURAMA cohort, a large observational RA cohort from a single center, to develop a machine learning model. The study included a total of 322 patients initially diagnosed with UA. The deep neural network (DNN) model was trained using 24 clinical features that are easily obtainable in routine clinical practice, such as age, sex, C-reactive protein (CRP) levels, and disease activity score in 28 joints using erythrocyte sedimentation rate (DAS28-ESR). The DNN model achieved a prediction accuracy of 85.1% in the training cohort. When the model was applied to validation data from an external dataset consisting of 88 patients from the ANSWER cohort, a large multicenter observational RA cohort, the prediction accuracy was 80%.

“We have developed a machine learning model that can predict the progression of RA from UA using clinical parameters,” Dr. Fujii concluded. “This model has the potential to assist rheumatologists in providing appropriate care and timely intervention for patients with UA.”

“Dr. Fujii presented a fascinating study,” Dr. Jans said. “They achieved an accuracy of 80% when applying a DNN model to predict progression from UA to RA. This level of accuracy is relatively high and certainly promising. However, it is important to consider that a pre-test probability of 30% [for progressing from UA to RA]  is also relatively high, which partially explains the high accuracy. Nonetheless, this study represents a significant step forward in the clinical management of patients with UA, as it helps identify those who may benefit the most from regular clinical follow-up.”

Dr. Li and Dr. Stoel report no relevant financial relationships with industry. Dr. Fujii has received speaking fees from Asahi Kasei, AbbVie, Chugai, and Tanabe Mitsubishi Pharma. Dr. Jans has received speaking fees from AbbVie, UCB, Lilly, and Novartis; he is cofounder of RheumaFinder. The Leiden study was funded by the Dutch Research Council and the China Scholarship Council. The study by Dr. Fujii and colleagues had no outside funding.

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

Scientists think that a person in Ohio who has been infected with COVID-19 for 2 years is shedding thousands of times more of the virus than normal, according to wastewater monitoring data. The strain of the virus appears to be unique, the researchers said. 

The mutated version of the virus was discovered by a team of researchers, led by University of Missouri–Columbia virologist Marc Johnson, PhD, that has been studying standalone mutations identified in wastewater. On Twitter, Dr. Johnson said their work could help warn people of a potential risk.

“If you knew of an exposure of a group of people to a deadly disease, there would be an obligation to inform them,” he wrote.

He believes the infected person lives in Columbus, works at a courthouse in a nearby county, and has gut health problems. The county where the person works has a population of just 15,000 people but had record COVID wastewater levels in May, The Columbus Dispatch reported. The unique COVID strain that Dr. Johnson is researching was the only COVID strain found in Fayette County’s wastewater.

“This person was shedding thousands of times more material than a normal person ever would,” Dr. Johnson told the Dispatch. “I think this person isn’t well. ... I’m guessing they have GI issues.”

Monitoring wastewater for COVID-19 is only used to inform public health officials of community levels and spread of the virus. People with COVID are not tracked down using such information.

The Centers for Disease Control and Prevention told the Dispatch that the findings do not mean there’s a public health threat.

“Unusual or ‘cryptic’ sequences identified in wastewater may represent viruses that can replicate in particular individuals, but not in the general population,” the CDC wrote in a statement to the newspaper. “This can be because of a compromised immune system. CDC and other institutions conduct studies in immunocompromised individuals to understand persistent infection and virus evolution.”

Ohio health officials told the newspaper that they don’t consider the situation a public health threat because the cryptic strain hasn’t spread beyond two sewer sheds for those 2  years.

Dr. Johnson and colleagues have been researching other unique COVID strains found in wastewater. They wrote a paper about a case in Wisconsin currently in preprint.

In the paper, the researchers suggest some people are persistently infected, calling them “prolonged shedders.” The researchers wrote that prolonged shedders could be human or “nonhuman,” and that “increased global monitoring of such lineages in wastewater could help anticipate future circulating mutations and/or variants of concern.”

Earlier in 2023, the CDC announced it was ending its community-level reporting of COVID test data and would rely more heavily on hospitalization reports and wastewater monitoring. COVID hospitalizations dipped to 7,212 nationally for the week of June 1-8, which is a 6% decline from the week prior, according to the CDC. That number of hospitalizations equals about two hospitalizations per 100,000 people.

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

Scientists think that a person in Ohio who has been infected with COVID-19 for 2 years is shedding thousands of times more of the virus than normal, according to wastewater monitoring data. The strain of the virus appears to be unique, the researchers said. 

The mutated version of the virus was discovered by a team of researchers, led by University of Missouri–Columbia virologist Marc Johnson, PhD, that has been studying standalone mutations identified in wastewater. On Twitter, Dr. Johnson said their work could help warn people of a potential risk.

“If you knew of an exposure of a group of people to a deadly disease, there would be an obligation to inform them,” he wrote.

He believes the infected person lives in Columbus, works at a courthouse in a nearby county, and has gut health problems. The county where the person works has a population of just 15,000 people but had record COVID wastewater levels in May, The Columbus Dispatch reported. The unique COVID strain that Dr. Johnson is researching was the only COVID strain found in Fayette County’s wastewater.

“This person was shedding thousands of times more material than a normal person ever would,” Dr. Johnson told the Dispatch. “I think this person isn’t well. ... I’m guessing they have GI issues.”

Monitoring wastewater for COVID-19 is only used to inform public health officials of community levels and spread of the virus. People with COVID are not tracked down using such information.

The Centers for Disease Control and Prevention told the Dispatch that the findings do not mean there’s a public health threat.

“Unusual or ‘cryptic’ sequences identified in wastewater may represent viruses that can replicate in particular individuals, but not in the general population,” the CDC wrote in a statement to the newspaper. “This can be because of a compromised immune system. CDC and other institutions conduct studies in immunocompromised individuals to understand persistent infection and virus evolution.”

Ohio health officials told the newspaper that they don’t consider the situation a public health threat because the cryptic strain hasn’t spread beyond two sewer sheds for those 2  years.

Dr. Johnson and colleagues have been researching other unique COVID strains found in wastewater. They wrote a paper about a case in Wisconsin currently in preprint.

In the paper, the researchers suggest some people are persistently infected, calling them “prolonged shedders.” The researchers wrote that prolonged shedders could be human or “nonhuman,” and that “increased global monitoring of such lineages in wastewater could help anticipate future circulating mutations and/or variants of concern.”

Earlier in 2023, the CDC announced it was ending its community-level reporting of COVID test data and would rely more heavily on hospitalization reports and wastewater monitoring. COVID hospitalizations dipped to 7,212 nationally for the week of June 1-8, which is a 6% decline from the week prior, according to the CDC. That number of hospitalizations equals about two hospitalizations per 100,000 people.

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

Scientists think that a person in Ohio who has been infected with COVID-19 for 2 years is shedding thousands of times more of the virus than normal, according to wastewater monitoring data. The strain of the virus appears to be unique, the researchers said. 

The mutated version of the virus was discovered by a team of researchers, led by University of Missouri–Columbia virologist Marc Johnson, PhD, that has been studying standalone mutations identified in wastewater. On Twitter, Dr. Johnson said their work could help warn people of a potential risk.

“If you knew of an exposure of a group of people to a deadly disease, there would be an obligation to inform them,” he wrote.

He believes the infected person lives in Columbus, works at a courthouse in a nearby county, and has gut health problems. The county where the person works has a population of just 15,000 people but had record COVID wastewater levels in May, The Columbus Dispatch reported. The unique COVID strain that Dr. Johnson is researching was the only COVID strain found in Fayette County’s wastewater.

“This person was shedding thousands of times more material than a normal person ever would,” Dr. Johnson told the Dispatch. “I think this person isn’t well. ... I’m guessing they have GI issues.”

Monitoring wastewater for COVID-19 is only used to inform public health officials of community levels and spread of the virus. People with COVID are not tracked down using such information.

The Centers for Disease Control and Prevention told the Dispatch that the findings do not mean there’s a public health threat.

“Unusual or ‘cryptic’ sequences identified in wastewater may represent viruses that can replicate in particular individuals, but not in the general population,” the CDC wrote in a statement to the newspaper. “This can be because of a compromised immune system. CDC and other institutions conduct studies in immunocompromised individuals to understand persistent infection and virus evolution.”

Ohio health officials told the newspaper that they don’t consider the situation a public health threat because the cryptic strain hasn’t spread beyond two sewer sheds for those 2  years.

Dr. Johnson and colleagues have been researching other unique COVID strains found in wastewater. They wrote a paper about a case in Wisconsin currently in preprint.

In the paper, the researchers suggest some people are persistently infected, calling them “prolonged shedders.” The researchers wrote that prolonged shedders could be human or “nonhuman,” and that “increased global monitoring of such lineages in wastewater could help anticipate future circulating mutations and/or variants of concern.”

Earlier in 2023, the CDC announced it was ending its community-level reporting of COVID test data and would rely more heavily on hospitalization reports and wastewater monitoring. COVID hospitalizations dipped to 7,212 nationally for the week of June 1-8, which is a 6% decline from the week prior, according to the CDC. That number of hospitalizations equals about two hospitalizations per 100,000 people.

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

MILAN – Treatment of rheumatoid arthritis with tumor necrosis factor inhibitors (TNFi) does not appear to demonstrate a consistent and significant risk for demyelinating disease, according to a systematic literature review presented at the annual European Congress of Rheumatology.

The review was conducted by Isabel Castrejon, MD, of the rheumatology department at Gregorio Marañón General University Hospital, Madrid, and colleagues. “In male RA patients, a marginal and slight increase in risk was found. The low number of events provides reassurance regarding the use of these drugs. However, careful consideration is recommended for individuals at the highest risk of demyelinating diseases,” Dr. Castrejon said in an interview. “Health care providers should evaluate the potential benefits and risks of TNFi treatment on a case-by-case basis and closely monitor patients for any signs or symptoms of demyelinating events.”

The researchers performed the review because early data from biologic registries did not provide sufficient clarity, and the association between TNFi exposure and inflammatory central nervous system events remains poorly understood.
 

Key findings from the analyzed data

Dr. Castrejon and colleagues’ review considered 368 studies that included patients with RA, treatment with any biologic including TNFi and synthetic disease-modifying antirheumatic drugs (DMARDs), and demyelinating event.

The studies focused on assessing the risk of demyelinating events following treatment with biologics, particularly TNFi. Some studies included only patients with RA, while others examined mixed forms of arthritis. In cases involving mixed populations, patients with RA were analyzed separately. Additionally, certain studies solely considered multiple sclerosis, while others encompassed various types of demyelinating events. Dr. Castrejon said that a meta-analysis of the studies could not be performed because of their heterogeneity.

Among the 368 studies, four observational cohort studies and three nested case-control studies reported a risk of demyelinating events following treatment with biologics. Two nested case-control studies indicated an increased risk in mixed populations but did not separately analyze the subgroup of patients with RA. Two observational cohort studies revealed a marginally increased risk in men with RA who undergo TNFi treatment. In the first study, the incidence was 19.7/100,000 patient-years (95% confidence interval, 13.7-27.3) with a standardized incidence ratio of 1.38 (95% CI, 0.96-1.92), a definite case risk ratio of 0.83 (95% CI, 0.51-1.26), and an RR for male patients of 2.75 (95% CI, 1.31-5.06). The second study had an SIR of 1.11 (95% CI, 0.63-1.93), a RR for patients with RA of 0.65 (95% CI, 0.24-1.72), and male RR of 3.48 (95% CI, 1.45-8.37).

An unresolved question is whether demyelinating events are attributable to the underlying disease itself, which may not have been recognized at the time of diagnosis, or whether they are caused by DMARDs. Additionally, the articles that the reviewers analyzed did not consider patient characteristics that could interact with other factors, such as comorbidities or smoking, that might influence their susceptibility to the development of demyelinating events.

How should clinicians manage patients with RA who are at high risk of developing demyelinating diseases? “Typically, we initiate treatment with conventional synthetic disease-modifying methotrexate and then progress to other drugs,” Maya H. Buch, MBChB, PhD, professor of rheumatology at the University of Leeds (England), said in an interview. “For patients in high-risk groups, there are alternative treatment strategies, especially in comparison to TNFi, where there may be a rationale for their use.” Dr. Buch was not involved in the review.

Dr. Castrejon and colleagues reported no relevant financial relationships.

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

MILAN – Treatment of rheumatoid arthritis with tumor necrosis factor inhibitors (TNFi) does not appear to demonstrate a consistent and significant risk for demyelinating disease, according to a systematic literature review presented at the annual European Congress of Rheumatology.

The review was conducted by Isabel Castrejon, MD, of the rheumatology department at Gregorio Marañón General University Hospital, Madrid, and colleagues. “In male RA patients, a marginal and slight increase in risk was found. The low number of events provides reassurance regarding the use of these drugs. However, careful consideration is recommended for individuals at the highest risk of demyelinating diseases,” Dr. Castrejon said in an interview. “Health care providers should evaluate the potential benefits and risks of TNFi treatment on a case-by-case basis and closely monitor patients for any signs or symptoms of demyelinating events.”

The researchers performed the review because early data from biologic registries did not provide sufficient clarity, and the association between TNFi exposure and inflammatory central nervous system events remains poorly understood.
 

Key findings from the analyzed data

Dr. Castrejon and colleagues’ review considered 368 studies that included patients with RA, treatment with any biologic including TNFi and synthetic disease-modifying antirheumatic drugs (DMARDs), and demyelinating event.

The studies focused on assessing the risk of demyelinating events following treatment with biologics, particularly TNFi. Some studies included only patients with RA, while others examined mixed forms of arthritis. In cases involving mixed populations, patients with RA were analyzed separately. Additionally, certain studies solely considered multiple sclerosis, while others encompassed various types of demyelinating events. Dr. Castrejon said that a meta-analysis of the studies could not be performed because of their heterogeneity.

Among the 368 studies, four observational cohort studies and three nested case-control studies reported a risk of demyelinating events following treatment with biologics. Two nested case-control studies indicated an increased risk in mixed populations but did not separately analyze the subgroup of patients with RA. Two observational cohort studies revealed a marginally increased risk in men with RA who undergo TNFi treatment. In the first study, the incidence was 19.7/100,000 patient-years (95% confidence interval, 13.7-27.3) with a standardized incidence ratio of 1.38 (95% CI, 0.96-1.92), a definite case risk ratio of 0.83 (95% CI, 0.51-1.26), and an RR for male patients of 2.75 (95% CI, 1.31-5.06). The second study had an SIR of 1.11 (95% CI, 0.63-1.93), a RR for patients with RA of 0.65 (95% CI, 0.24-1.72), and male RR of 3.48 (95% CI, 1.45-8.37).

An unresolved question is whether demyelinating events are attributable to the underlying disease itself, which may not have been recognized at the time of diagnosis, or whether they are caused by DMARDs. Additionally, the articles that the reviewers analyzed did not consider patient characteristics that could interact with other factors, such as comorbidities or smoking, that might influence their susceptibility to the development of demyelinating events.

How should clinicians manage patients with RA who are at high risk of developing demyelinating diseases? “Typically, we initiate treatment with conventional synthetic disease-modifying methotrexate and then progress to other drugs,” Maya H. Buch, MBChB, PhD, professor of rheumatology at the University of Leeds (England), said in an interview. “For patients in high-risk groups, there are alternative treatment strategies, especially in comparison to TNFi, where there may be a rationale for their use.” Dr. Buch was not involved in the review.

Dr. Castrejon and colleagues reported no relevant financial relationships.

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

MILAN – Treatment of rheumatoid arthritis with tumor necrosis factor inhibitors (TNFi) does not appear to demonstrate a consistent and significant risk for demyelinating disease, according to a systematic literature review presented at the annual European Congress of Rheumatology.

The review was conducted by Isabel Castrejon, MD, of the rheumatology department at Gregorio Marañón General University Hospital, Madrid, and colleagues. “In male RA patients, a marginal and slight increase in risk was found. The low number of events provides reassurance regarding the use of these drugs. However, careful consideration is recommended for individuals at the highest risk of demyelinating diseases,” Dr. Castrejon said in an interview. “Health care providers should evaluate the potential benefits and risks of TNFi treatment on a case-by-case basis and closely monitor patients for any signs or symptoms of demyelinating events.”

The researchers performed the review because early data from biologic registries did not provide sufficient clarity, and the association between TNFi exposure and inflammatory central nervous system events remains poorly understood.
 

Key findings from the analyzed data

Dr. Castrejon and colleagues’ review considered 368 studies that included patients with RA, treatment with any biologic including TNFi and synthetic disease-modifying antirheumatic drugs (DMARDs), and demyelinating event.

The studies focused on assessing the risk of demyelinating events following treatment with biologics, particularly TNFi. Some studies included only patients with RA, while others examined mixed forms of arthritis. In cases involving mixed populations, patients with RA were analyzed separately. Additionally, certain studies solely considered multiple sclerosis, while others encompassed various types of demyelinating events. Dr. Castrejon said that a meta-analysis of the studies could not be performed because of their heterogeneity.

Among the 368 studies, four observational cohort studies and three nested case-control studies reported a risk of demyelinating events following treatment with biologics. Two nested case-control studies indicated an increased risk in mixed populations but did not separately analyze the subgroup of patients with RA. Two observational cohort studies revealed a marginally increased risk in men with RA who undergo TNFi treatment. In the first study, the incidence was 19.7/100,000 patient-years (95% confidence interval, 13.7-27.3) with a standardized incidence ratio of 1.38 (95% CI, 0.96-1.92), a definite case risk ratio of 0.83 (95% CI, 0.51-1.26), and an RR for male patients of 2.75 (95% CI, 1.31-5.06). The second study had an SIR of 1.11 (95% CI, 0.63-1.93), a RR for patients with RA of 0.65 (95% CI, 0.24-1.72), and male RR of 3.48 (95% CI, 1.45-8.37).

An unresolved question is whether demyelinating events are attributable to the underlying disease itself, which may not have been recognized at the time of diagnosis, or whether they are caused by DMARDs. Additionally, the articles that the reviewers analyzed did not consider patient characteristics that could interact with other factors, such as comorbidities or smoking, that might influence their susceptibility to the development of demyelinating events.

How should clinicians manage patients with RA who are at high risk of developing demyelinating diseases? “Typically, we initiate treatment with conventional synthetic disease-modifying methotrexate and then progress to other drugs,” Maya H. Buch, MBChB, PhD, professor of rheumatology at the University of Leeds (England), said in an interview. “For patients in high-risk groups, there are alternative treatment strategies, especially in comparison to TNFi, where there may be a rationale for their use.” Dr. Buch was not involved in the review.

Dr. Castrejon and colleagues reported no relevant financial relationships.

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

MILAN – High-intensity interval training (HIIT) has been shown to enhance cardiorespiratory fitness (CRF) and mitigate cardiovascular disease (CVD) risk factors in patients with inflammatory joint diseases (IJD) in a randomized trial. Notably, the positive response in CRF did not coincide with changes in pain or fatigue.

Kristine Norden, of the Center for Treatment of Rheumatic and Musculoskeletal Diseases, Norwegian National Advisory Unit on Rehabilitation in Rheumatology, Diakonhjemmet Hospital, Oslo, presented the late-breaking results of the ExeHeart trial at the annual European Congress of Rheumatology. The trial aimed to evaluate the short- and long-term effects of 12 weeks of supervised HIIT in patients with IJD.

Viktor Cap/Thinkstock

Ms. Norden said in an interview that “HIIT is a feasible physiotherapeutic intervention with sustainable effects in patients with IJD. It does not exacerbate symptoms of IJD and can be implemented in primary care settings.”
 

The trial

The ExeHeart trial is a randomized controlled trial designed to assess the effects of HIIT on CRF, CVD risk, and disease activity in patients with IJD. The trial is a collaborative effort with patient research partners and aligns with patients’ requests for effective nonpharmacologic treatments. The outcomes being evaluated include CRF (primary outcome), CVD risk factors, anthropometric measures, disease activity, and patient-reported outcomes related to pain, fatigue, disease, physical activity, and exercise.

A total of 60 patients with IJD were recruited from the Preventive Cardio-Rheuma clinic at Diakonhjemmet. They were randomly assigned to receive either standard care (including relevant lifestyle advice and cardiopreventive medication) or standard care along with a 12-week HIIT intervention supervised by physiotherapists. Assessments were conducted at baseline, at 3 months (primary endpoint), and at 6 months post baseline. There was no supervised intervention between the 3- and 6-month time points.

The median age of the participants was 59 years, with 34 participants (57%) being women. The types of IJD among the participants included rheumatoid arthritis in 45%, spondyloarthritis in 32%, and psoriatic arthritis in 23%. Furthermore, 49 patients (82%) had a high risk for CVD.

The participants were divided into two groups: a control group (n = 30) and a HIIT group (n = 30). The HIIT group underwent a 12-week intervention consisting of twice-a-week supervised 4x4-minute HIIT sessions at 90%-95% of peak heart rate, alternated with moderate activity at 70%. The control group engaged in unsupervised moderate-intensity exercise sessions. The primary outcome measured was the change in CRF, assessed through peak oxygen uptake (VO_{2 max}) using a cardiopulmonary exercise test. Secondary outcomes – pain and fatigue – were evaluated using a questionnaire (Numeric Rating Scale 0-10, where 0 represents no pain or fatigue).

Following HIIT, a statistically significant difference was observed in VO_{2 max} (2.5 mL/kg per min; P < .01) in favor of the exercise group at 3 months, while no significant differences were found in pain and fatigue. This discrepancy in VO_{2 max} between the groups was maintained at 6 months (2.6 mL/kg per min; P < .01), with no notable disparities in pain and fatigue. A per-protocol analysis at 3 months demonstrated a difference in VO_{2 max} between the groups (3.2 mL/kg per min; P < .01).

Ms. Norden concluded that the clinical implications of these findings are significant, as increased CRF achieved through HIIT reflects an improvement in the body’s ability to deliver oxygen to working muscles. Consequently, this enhancement in CRF can lead to overall health improvements and a reduced risk for CVD.
 

Long-lasting effects

Christopher Edwards, MBBS, MD, honorary consultant rheumatologist at University Hospital Southampton (England) NHS Foundation Trust Medicine, University of Southampton, was concerned about future maintenance of increased CRF. “I really wish we had data on these patients at 12 months as well, so we could see if the effects last even longer. Regarding intensity, there are clear indications that engaging in moderate and high-intensity workouts is more beneficial,” Dr. Norden said. “So, I would certainly recommend at least one high-intensity exercise session per week for those patients, while also incorporating lower and moderate-intensity exercises if desired. However, for individuals aiming to maximize their oxygen uptake, high-intensity exercise is considered the most effective approach.”

There is compelling evidence supporting the benefits of physical activity in improving disease activity among patients with IJD, making it a critical component of nonpharmacologic treatment. However, individuals with rheumatic and musculoskeletal conditions generally exhibit lower levels of physical activity, compared with their healthy counterparts. Recognizing the importance of CVD prevention in patients with IJD, EULAR recommends routine CVD screening for individuals diagnosed with IJD.

Ms. Norden and coauthors report no relevant financial relationships.

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

MILAN – High-intensity interval training (HIIT) has been shown to enhance cardiorespiratory fitness (CRF) and mitigate cardiovascular disease (CVD) risk factors in patients with inflammatory joint diseases (IJD) in a randomized trial. Notably, the positive response in CRF did not coincide with changes in pain or fatigue.

Kristine Norden, of the Center for Treatment of Rheumatic and Musculoskeletal Diseases, Norwegian National Advisory Unit on Rehabilitation in Rheumatology, Diakonhjemmet Hospital, Oslo, presented the late-breaking results of the ExeHeart trial at the annual European Congress of Rheumatology. The trial aimed to evaluate the short- and long-term effects of 12 weeks of supervised HIIT in patients with IJD.

Viktor Cap/Thinkstock

Ms. Norden said in an interview that “HIIT is a feasible physiotherapeutic intervention with sustainable effects in patients with IJD. It does not exacerbate symptoms of IJD and can be implemented in primary care settings.”
 

The trial

The ExeHeart trial is a randomized controlled trial designed to assess the effects of HIIT on CRF, CVD risk, and disease activity in patients with IJD. The trial is a collaborative effort with patient research partners and aligns with patients’ requests for effective nonpharmacologic treatments. The outcomes being evaluated include CRF (primary outcome), CVD risk factors, anthropometric measures, disease activity, and patient-reported outcomes related to pain, fatigue, disease, physical activity, and exercise.

A total of 60 patients with IJD were recruited from the Preventive Cardio-Rheuma clinic at Diakonhjemmet. They were randomly assigned to receive either standard care (including relevant lifestyle advice and cardiopreventive medication) or standard care along with a 12-week HIIT intervention supervised by physiotherapists. Assessments were conducted at baseline, at 3 months (primary endpoint), and at 6 months post baseline. There was no supervised intervention between the 3- and 6-month time points.

The median age of the participants was 59 years, with 34 participants (57%) being women. The types of IJD among the participants included rheumatoid arthritis in 45%, spondyloarthritis in 32%, and psoriatic arthritis in 23%. Furthermore, 49 patients (82%) had a high risk for CVD.

The participants were divided into two groups: a control group (n = 30) and a HIIT group (n = 30). The HIIT group underwent a 12-week intervention consisting of twice-a-week supervised 4x4-minute HIIT sessions at 90%-95% of peak heart rate, alternated with moderate activity at 70%. The control group engaged in unsupervised moderate-intensity exercise sessions. The primary outcome measured was the change in CRF, assessed through peak oxygen uptake (VO_{2 max}) using a cardiopulmonary exercise test. Secondary outcomes – pain and fatigue – were evaluated using a questionnaire (Numeric Rating Scale 0-10, where 0 represents no pain or fatigue).

Following HIIT, a statistically significant difference was observed in VO_{2 max} (2.5 mL/kg per min; P < .01) in favor of the exercise group at 3 months, while no significant differences were found in pain and fatigue. This discrepancy in VO_{2 max} between the groups was maintained at 6 months (2.6 mL/kg per min; P < .01), with no notable disparities in pain and fatigue. A per-protocol analysis at 3 months demonstrated a difference in VO_{2 max} between the groups (3.2 mL/kg per min; P < .01).

Ms. Norden concluded that the clinical implications of these findings are significant, as increased CRF achieved through HIIT reflects an improvement in the body’s ability to deliver oxygen to working muscles. Consequently, this enhancement in CRF can lead to overall health improvements and a reduced risk for CVD.
 

Long-lasting effects

Christopher Edwards, MBBS, MD, honorary consultant rheumatologist at University Hospital Southampton (England) NHS Foundation Trust Medicine, University of Southampton, was concerned about future maintenance of increased CRF. “I really wish we had data on these patients at 12 months as well, so we could see if the effects last even longer. Regarding intensity, there are clear indications that engaging in moderate and high-intensity workouts is more beneficial,” Dr. Norden said. “So, I would certainly recommend at least one high-intensity exercise session per week for those patients, while also incorporating lower and moderate-intensity exercises if desired. However, for individuals aiming to maximize their oxygen uptake, high-intensity exercise is considered the most effective approach.”

There is compelling evidence supporting the benefits of physical activity in improving disease activity among patients with IJD, making it a critical component of nonpharmacologic treatment. However, individuals with rheumatic and musculoskeletal conditions generally exhibit lower levels of physical activity, compared with their healthy counterparts. Recognizing the importance of CVD prevention in patients with IJD, EULAR recommends routine CVD screening for individuals diagnosed with IJD.

Ms. Norden and coauthors report no relevant financial relationships.

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

MILAN – High-intensity interval training (HIIT) has been shown to enhance cardiorespiratory fitness (CRF) and mitigate cardiovascular disease (CVD) risk factors in patients with inflammatory joint diseases (IJD) in a randomized trial. Notably, the positive response in CRF did not coincide with changes in pain or fatigue.

Kristine Norden, of the Center for Treatment of Rheumatic and Musculoskeletal Diseases, Norwegian National Advisory Unit on Rehabilitation in Rheumatology, Diakonhjemmet Hospital, Oslo, presented the late-breaking results of the ExeHeart trial at the annual European Congress of Rheumatology. The trial aimed to evaluate the short- and long-term effects of 12 weeks of supervised HIIT in patients with IJD.

Viktor Cap/Thinkstock

Ms. Norden said in an interview that “HIIT is a feasible physiotherapeutic intervention with sustainable effects in patients with IJD. It does not exacerbate symptoms of IJD and can be implemented in primary care settings.”
 

The trial

The ExeHeart trial is a randomized controlled trial designed to assess the effects of HIIT on CRF, CVD risk, and disease activity in patients with IJD. The trial is a collaborative effort with patient research partners and aligns with patients’ requests for effective nonpharmacologic treatments. The outcomes being evaluated include CRF (primary outcome), CVD risk factors, anthropometric measures, disease activity, and patient-reported outcomes related to pain, fatigue, disease, physical activity, and exercise.

A total of 60 patients with IJD were recruited from the Preventive Cardio-Rheuma clinic at Diakonhjemmet. They were randomly assigned to receive either standard care (including relevant lifestyle advice and cardiopreventive medication) or standard care along with a 12-week HIIT intervention supervised by physiotherapists. Assessments were conducted at baseline, at 3 months (primary endpoint), and at 6 months post baseline. There was no supervised intervention between the 3- and 6-month time points.

The median age of the participants was 59 years, with 34 participants (57%) being women. The types of IJD among the participants included rheumatoid arthritis in 45%, spondyloarthritis in 32%, and psoriatic arthritis in 23%. Furthermore, 49 patients (82%) had a high risk for CVD.

The participants were divided into two groups: a control group (n = 30) and a HIIT group (n = 30). The HIIT group underwent a 12-week intervention consisting of twice-a-week supervised 4x4-minute HIIT sessions at 90%-95% of peak heart rate, alternated with moderate activity at 70%. The control group engaged in unsupervised moderate-intensity exercise sessions. The primary outcome measured was the change in CRF, assessed through peak oxygen uptake (VO_{2 max}) using a cardiopulmonary exercise test. Secondary outcomes – pain and fatigue – were evaluated using a questionnaire (Numeric Rating Scale 0-10, where 0 represents no pain or fatigue).

Following HIIT, a statistically significant difference was observed in VO_{2 max} (2.5 mL/kg per min; P < .01) in favor of the exercise group at 3 months, while no significant differences were found in pain and fatigue. This discrepancy in VO_{2 max} between the groups was maintained at 6 months (2.6 mL/kg per min; P < .01), with no notable disparities in pain and fatigue. A per-protocol analysis at 3 months demonstrated a difference in VO_{2 max} between the groups (3.2 mL/kg per min; P < .01).

Ms. Norden concluded that the clinical implications of these findings are significant, as increased CRF achieved through HIIT reflects an improvement in the body’s ability to deliver oxygen to working muscles. Consequently, this enhancement in CRF can lead to overall health improvements and a reduced risk for CVD.
 

Long-lasting effects

Christopher Edwards, MBBS, MD, honorary consultant rheumatologist at University Hospital Southampton (England) NHS Foundation Trust Medicine, University of Southampton, was concerned about future maintenance of increased CRF. “I really wish we had data on these patients at 12 months as well, so we could see if the effects last even longer. Regarding intensity, there are clear indications that engaging in moderate and high-intensity workouts is more beneficial,” Dr. Norden said. “So, I would certainly recommend at least one high-intensity exercise session per week for those patients, while also incorporating lower and moderate-intensity exercises if desired. However, for individuals aiming to maximize their oxygen uptake, high-intensity exercise is considered the most effective approach.”

There is compelling evidence supporting the benefits of physical activity in improving disease activity among patients with IJD, making it a critical component of nonpharmacologic treatment. However, individuals with rheumatic and musculoskeletal conditions generally exhibit lower levels of physical activity, compared with their healthy counterparts. Recognizing the importance of CVD prevention in patients with IJD, EULAR recommends routine CVD screening for individuals diagnosed with IJD.

Ms. Norden and coauthors report no relevant financial relationships.

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

TOPLINE:

Among Korean women younger than 50 years, hysterectomy is associated with an increased risk of cardiovascular disease (CVD), especially stroke, a new cohort study shows.

METHODOLOGY:

• Risk of CVD rapidly increases after menopause, possibly owing to loss of protective effects of female sex hormones and hemorheologic changes.
• Results of previous studies of the association between hysterectomy and CVD were mixed.
• Using national health insurance data, this cohort study included 55,539 South Korean women (median age, 45 years) who underwent a hysterectomy and a propensity-matched group of women.
• The primary outcome was CVD, including myocardial infarction (MI), coronary artery revascularization, and stroke.

TAKEAWAY:

• During follow-up of just under 8 years, the hysterectomy group had an increased risk of CVD compared with the non-hysterectomy group (hazard ratio [HR] 1.25; 95% confidence interval [CI], 1.09-1.44; P = .002)
• The incidence of MI and coronary revascularization was comparable between groups, but the risk of stroke was significantly higher among those who had had a hysterectomy (HR, 1.31; 95% CI, 1.12-1.53; P < .001)
• This increase in risk was similar after excluding patients who also underwent adnexal surgery.

IN PRACTICE:

Early hysterectomy was linked to higher CVD risk, especially stroke, but since the CVD incidence wasn’t high, a change in clinical practice may not be needed, said the authors.

STUDY DETAILS:

The study was conducted by Jin-Sung Yuk, MD, PhD, Department of Obstetrics and Gynecology, Sanggye Paik Hospital, Inje University College of Medicine, Seoul, Republic of Korea, and colleagues. It was published online June 12 in JAMA Network Open.

LIMITATIONS:

The study was retrospective and observational and used administrative databases that may be prone to inaccurate coding. The findings may not be generalizable outside Korea.

DISCLOSURES:

The study was supported by a National Research Foundation of Korea grant funded by the Korea government. The authors report no conflicts of interest.

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

TOPLINE:

Among Korean women younger than 50 years, hysterectomy is associated with an increased risk of cardiovascular disease (CVD), especially stroke, a new cohort study shows.

METHODOLOGY:

• Risk of CVD rapidly increases after menopause, possibly owing to loss of protective effects of female sex hormones and hemorheologic changes.
• Results of previous studies of the association between hysterectomy and CVD were mixed.
• Using national health insurance data, this cohort study included 55,539 South Korean women (median age, 45 years) who underwent a hysterectomy and a propensity-matched group of women.
• The primary outcome was CVD, including myocardial infarction (MI), coronary artery revascularization, and stroke.

TAKEAWAY:

• During follow-up of just under 8 years, the hysterectomy group had an increased risk of CVD compared with the non-hysterectomy group (hazard ratio [HR] 1.25; 95% confidence interval [CI], 1.09-1.44; P = .002)
• The incidence of MI and coronary revascularization was comparable between groups, but the risk of stroke was significantly higher among those who had had a hysterectomy (HR, 1.31; 95% CI, 1.12-1.53; P < .001)
• This increase in risk was similar after excluding patients who also underwent adnexal surgery.

IN PRACTICE:

Early hysterectomy was linked to higher CVD risk, especially stroke, but since the CVD incidence wasn’t high, a change in clinical practice may not be needed, said the authors.

STUDY DETAILS:

The study was conducted by Jin-Sung Yuk, MD, PhD, Department of Obstetrics and Gynecology, Sanggye Paik Hospital, Inje University College of Medicine, Seoul, Republic of Korea, and colleagues. It was published online June 12 in JAMA Network Open.

LIMITATIONS:

The study was retrospective and observational and used administrative databases that may be prone to inaccurate coding. The findings may not be generalizable outside Korea.

DISCLOSURES:

The study was supported by a National Research Foundation of Korea grant funded by the Korea government. The authors report no conflicts of interest.

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

TOPLINE:

Among Korean women younger than 50 years, hysterectomy is associated with an increased risk of cardiovascular disease (CVD), especially stroke, a new cohort study shows.

METHODOLOGY:

• Risk of CVD rapidly increases after menopause, possibly owing to loss of protective effects of female sex hormones and hemorheologic changes.
• Results of previous studies of the association between hysterectomy and CVD were mixed.
• Using national health insurance data, this cohort study included 55,539 South Korean women (median age, 45 years) who underwent a hysterectomy and a propensity-matched group of women.
• The primary outcome was CVD, including myocardial infarction (MI), coronary artery revascularization, and stroke.

TAKEAWAY:

• During follow-up of just under 8 years, the hysterectomy group had an increased risk of CVD compared with the non-hysterectomy group (hazard ratio [HR] 1.25; 95% confidence interval [CI], 1.09-1.44; P = .002)
• The incidence of MI and coronary revascularization was comparable between groups, but the risk of stroke was significantly higher among those who had had a hysterectomy (HR, 1.31; 95% CI, 1.12-1.53; P < .001)
• This increase in risk was similar after excluding patients who also underwent adnexal surgery.

IN PRACTICE:

Early hysterectomy was linked to higher CVD risk, especially stroke, but since the CVD incidence wasn’t high, a change in clinical practice may not be needed, said the authors.

STUDY DETAILS:

The study was conducted by Jin-Sung Yuk, MD, PhD, Department of Obstetrics and Gynecology, Sanggye Paik Hospital, Inje University College of Medicine, Seoul, Republic of Korea, and colleagues. It was published online June 12 in JAMA Network Open.

LIMITATIONS:

The study was retrospective and observational and used administrative databases that may be prone to inaccurate coding. The findings may not be generalizable outside Korea.

DISCLOSURES:

The study was supported by a National Research Foundation of Korea grant funded by the Korea government. The authors report no conflicts of interest.

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

Findings from a landmark clinical trial in pediatric Crohn’s disease show a clear benefit of adding methotrexate to treatment with the tumor necrosis factor inhibitor (TNFi) adalimumab (Humira), but not to infliximab therapy.

Children initiating treatment with adalimumab plus a low dose of methotrexate experienced a twofold reduction in treatment failure, note the authors of the largest, double-blind, randomized trial to date in pediatric Crohn’s disease. However, children initiating infliximab, another TNFi, had similar outcomes with or without methotrexate.

“We believe these results are practice changing,” said principal investigator Michael Kappelman, MD, MPH, professor of pediatrics at University of North Carolina.

All patients with pediatric Crohn’s disease starting on adalimumab, and their parents, should be informed that combining the drug with low-dose oral methotrexate improves treatment effectiveness, he said.

“Those without contraindications should be offered combination therapy, and shared decision-making should be incorporated into final treatment decisions. In contrast, most patients starting infliximab are not likely to experience added benefits from low-dose oral methotrexate,” Dr. Kappelman added.

The study was published online in Gastroenterology and was presented in May in Chicago at the annual Digestive Disease Week® (DDW).

Impactful study

“This is an important study, published in a very high-ranking journal, that will have a huge impact on how we practice,” Jacob Kurowski, MD, department of pediatric gastroenterology, hepatology and nutrition, Cleveland Clinic Children’s, who wasn’t involved in the study, said.

Treatment with a TNFi, including infliximab and adalimumab, is a mainstay of pediatric Crohn’s disease therapy. However, not all patients achieve remission, and many lose response over time.

The current trial compared the effectiveness and safety of adding a low-dose of oral methotrexate to adalimumab or infliximab vs. TNFi therapy alone in 297 children with Crohn’s disease. The mean age was 13.9 years, and about two-thirds were boys. None had a prior history of TNFi therapy.

Participants initiating infliximab or adalimumab were randomly allocated (1:1) to oral methotrexate or placebo. Of them, 110 infliximab initiators and 46 adalimumab initiators received methotrexate, while 102 infliximab initiators and 39 adalimumab initiators were given placebo. Methotrexate was administered as a weekly dose of 15 mg for children weighing 40 kg or more, 12.5 mg for children 30 kg to less than 40 kg, and 10 mg for children 20 kg to less than 30 kg. All participants received pretreatment with ondansetron 4 mg (or placebo) to prevent nausea and folic acid (1 mg per day). Participants were followed for 12-36 months.

The primary outcome was a failure to achieve or maintain steroid-free remission defined by occurrence of any of the following:

• Short Pediatric Crohn’s Disease Activity Index (SPCDAI) score of less than 15 by week 26.
• Failure to complete a steroid taper by week 16.
• SPCDAI score of 15 or higher as a result of active Crohn’s disease at two or more consecutive visits beyond week 26.
• Hospitalization or surgery for Crohn’s disease beyond week 26.
• Use of corticosteroids for Crohn’s disease for 10 or more weeks cumulatively beyond week 16.
• Discontinuation of anti-TNF and/or study drug for lack of effectiveness or toxicity.

Overall, 88 of 297 children (30%) experienced treatment failure, including 57 of 212 (27%) on infliximab and 31 of 85 (36%) on adalimumab. Overall, 40 of 156 children (26%) on combination therapy and 48 of 141 (34%) on monotherapy experienced treatment failure.

Kaplan Meier analysis of the overall population showed a nonsignificant trend toward lower event rates with combination therapy (hazard ratio, 0.69; 95% confidence interval, 0.45-1.05; P = .08).

After stratification by TNFi, there was no difference in time to treatment failure among infliximab initiators between combination and monotherapy (HR, 0.93; 95% CI, 0.55-1.56; P = .78). In contrast, among adalimumab initiators, combination therapy was significantly associated with a longer time to treatment failure (HR, 0.40; 95% CI 0.19-0.81; P = .01).

There was a nonsignificant trend toward lower development of antidrug antibodies with combination therapy (risk ratio 0.72 with infliximab and 0.71 with adalimumab). This trend is in line with adult studies and adds substantially to the pediatric literature on this topic, the researchers note.

No differences in patient-reported outcomes were observed. There were slightly more adverse events with combination therapy, as expected, but fewer serious adverse events.
 

Shared decision-making

Dr. Kappelman noted that the study was not designed to answer the question of which is better – adalimumab plus methotrexate or infliximab alone.

“This is an area for future research. At this point, we believe it is an individualized decision, and appropriate counseling is needed to support shared decision-making,” he said.

The trial was not designed to evaluate the role of proactive therapeutic drug monitoring. However, proactive TDM is endorsed in the ImproveCareNow Model IBD Care guidelines and was considered standard of care at the 35 study sites.

The findings “suggest strong consideration of using combination therapy for pediatric Crohn’s disease patients initiating adalimumab, but not infliximab,” Dr. Kappelman and colleagues say.

“Dissemination and implementation of these findings should lead to improved outcomes in this patient population, including consideration of deimplementation of combination therapy in infliximab-treated patients,” they add.

The decision about which approach to use is still very dependent on patients and their providers, Dr. Kurowski said.

“The study shows that you can safely use infliximab as monotherapy, with low risk of antibody formation, while utilizing proactive therapeutic drug monitoring and dose optimization,” he said. “The study also shows that adalimumab in combination with low-dose methotrexate can be strongly considered when needed.”

The researchers’ standardization of methotrexate doses by weight “is another significant contribution and provides a guide for clinicians,” Dr. Kurowski added.

The study was funded by grants from the Patient-Centered Outcomes Research Institute, the Helmsley Charitable Trust, and National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Kappelman has consulted for AbbVie, Janssen, Pfizer, Takeda, and Lilly; holds shares in Johnson & Johnson; and has received research support from Pfizer, Takeda, Janssen, AbbVie, Lilly, Genentech, Boehringer Ingelheim, Bristol-Myers Squibb, Celtrion, and Arena Pharmaceuticals. Dr. Kurowski reports no relevant financial relationships.

DDW is sponsored by the American Association for the Study of Liver Diseases, the American Gastroenterological Association, the American Society for Gastrointestinal Endoscopy, and the Society for Surgery of the Alimentary Tract.

Findings from a landmark clinical trial in pediatric Crohn’s disease show a clear benefit of adding methotrexate to treatment with the tumor necrosis factor inhibitor (TNFi) adalimumab (Humira), but not to infliximab therapy.

Children initiating treatment with adalimumab plus a low dose of methotrexate experienced a twofold reduction in treatment failure, note the authors of the largest, double-blind, randomized trial to date in pediatric Crohn’s disease. However, children initiating infliximab, another TNFi, had similar outcomes with or without methotrexate.

“We believe these results are practice changing,” said principal investigator Michael Kappelman, MD, MPH, professor of pediatrics at University of North Carolina.

All patients with pediatric Crohn’s disease starting on adalimumab, and their parents, should be informed that combining the drug with low-dose oral methotrexate improves treatment effectiveness, he said.

“Those without contraindications should be offered combination therapy, and shared decision-making should be incorporated into final treatment decisions. In contrast, most patients starting infliximab are not likely to experience added benefits from low-dose oral methotrexate,” Dr. Kappelman added.

The study was published online in Gastroenterology and was presented in May in Chicago at the annual Digestive Disease Week® (DDW).

Impactful study

“This is an important study, published in a very high-ranking journal, that will have a huge impact on how we practice,” Jacob Kurowski, MD, department of pediatric gastroenterology, hepatology and nutrition, Cleveland Clinic Children’s, who wasn’t involved in the study, said.

Treatment with a TNFi, including infliximab and adalimumab, is a mainstay of pediatric Crohn’s disease therapy. However, not all patients achieve remission, and many lose response over time.

The current trial compared the effectiveness and safety of adding a low-dose of oral methotrexate to adalimumab or infliximab vs. TNFi therapy alone in 297 children with Crohn’s disease. The mean age was 13.9 years, and about two-thirds were boys. None had a prior history of TNFi therapy.

Participants initiating infliximab or adalimumab were randomly allocated (1:1) to oral methotrexate or placebo. Of them, 110 infliximab initiators and 46 adalimumab initiators received methotrexate, while 102 infliximab initiators and 39 adalimumab initiators were given placebo. Methotrexate was administered as a weekly dose of 15 mg for children weighing 40 kg or more, 12.5 mg for children 30 kg to less than 40 kg, and 10 mg for children 20 kg to less than 30 kg. All participants received pretreatment with ondansetron 4 mg (or placebo) to prevent nausea and folic acid (1 mg per day). Participants were followed for 12-36 months.

The primary outcome was a failure to achieve or maintain steroid-free remission defined by occurrence of any of the following:

• Short Pediatric Crohn’s Disease Activity Index (SPCDAI) score of less than 15 by week 26.
• Failure to complete a steroid taper by week 16.
• SPCDAI score of 15 or higher as a result of active Crohn’s disease at two or more consecutive visits beyond week 26.
• Hospitalization or surgery for Crohn’s disease beyond week 26.
• Use of corticosteroids for Crohn’s disease for 10 or more weeks cumulatively beyond week 16.
• Discontinuation of anti-TNF and/or study drug for lack of effectiveness or toxicity.

Overall, 88 of 297 children (30%) experienced treatment failure, including 57 of 212 (27%) on infliximab and 31 of 85 (36%) on adalimumab. Overall, 40 of 156 children (26%) on combination therapy and 48 of 141 (34%) on monotherapy experienced treatment failure.

Kaplan Meier analysis of the overall population showed a nonsignificant trend toward lower event rates with combination therapy (hazard ratio, 0.69; 95% confidence interval, 0.45-1.05; P = .08).

After stratification by TNFi, there was no difference in time to treatment failure among infliximab initiators between combination and monotherapy (HR, 0.93; 95% CI, 0.55-1.56; P = .78). In contrast, among adalimumab initiators, combination therapy was significantly associated with a longer time to treatment failure (HR, 0.40; 95% CI 0.19-0.81; P = .01).

There was a nonsignificant trend toward lower development of antidrug antibodies with combination therapy (risk ratio 0.72 with infliximab and 0.71 with adalimumab). This trend is in line with adult studies and adds substantially to the pediatric literature on this topic, the researchers note.

No differences in patient-reported outcomes were observed. There were slightly more adverse events with combination therapy, as expected, but fewer serious adverse events.
 

Shared decision-making

Dr. Kappelman noted that the study was not designed to answer the question of which is better – adalimumab plus methotrexate or infliximab alone.

“This is an area for future research. At this point, we believe it is an individualized decision, and appropriate counseling is needed to support shared decision-making,” he said.

The trial was not designed to evaluate the role of proactive therapeutic drug monitoring. However, proactive TDM is endorsed in the ImproveCareNow Model IBD Care guidelines and was considered standard of care at the 35 study sites.

The findings “suggest strong consideration of using combination therapy for pediatric Crohn’s disease patients initiating adalimumab, but not infliximab,” Dr. Kappelman and colleagues say.

“Dissemination and implementation of these findings should lead to improved outcomes in this patient population, including consideration of deimplementation of combination therapy in infliximab-treated patients,” they add.

The decision about which approach to use is still very dependent on patients and their providers, Dr. Kurowski said.

“The study shows that you can safely use infliximab as monotherapy, with low risk of antibody formation, while utilizing proactive therapeutic drug monitoring and dose optimization,” he said. “The study also shows that adalimumab in combination with low-dose methotrexate can be strongly considered when needed.”

The researchers’ standardization of methotrexate doses by weight “is another significant contribution and provides a guide for clinicians,” Dr. Kurowski added.

The study was funded by grants from the Patient-Centered Outcomes Research Institute, the Helmsley Charitable Trust, and National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Kappelman has consulted for AbbVie, Janssen, Pfizer, Takeda, and Lilly; holds shares in Johnson & Johnson; and has received research support from Pfizer, Takeda, Janssen, AbbVie, Lilly, Genentech, Boehringer Ingelheim, Bristol-Myers Squibb, Celtrion, and Arena Pharmaceuticals. Dr. Kurowski reports no relevant financial relationships.

DDW is sponsored by the American Association for the Study of Liver Diseases, the American Gastroenterological Association, the American Society for Gastrointestinal Endoscopy, and the Society for Surgery of the Alimentary Tract.

Findings from a landmark clinical trial in pediatric Crohn’s disease show a clear benefit of adding methotrexate to treatment with the tumor necrosis factor inhibitor (TNFi) adalimumab (Humira), but not to infliximab therapy.

Children initiating treatment with adalimumab plus a low dose of methotrexate experienced a twofold reduction in treatment failure, note the authors of the largest, double-blind, randomized trial to date in pediatric Crohn’s disease. However, children initiating infliximab, another TNFi, had similar outcomes with or without methotrexate.

“We believe these results are practice changing,” said principal investigator Michael Kappelman, MD, MPH, professor of pediatrics at University of North Carolina.

All patients with pediatric Crohn’s disease starting on adalimumab, and their parents, should be informed that combining the drug with low-dose oral methotrexate improves treatment effectiveness, he said.

“Those without contraindications should be offered combination therapy, and shared decision-making should be incorporated into final treatment decisions. In contrast, most patients starting infliximab are not likely to experience added benefits from low-dose oral methotrexate,” Dr. Kappelman added.

The study was published online in Gastroenterology and was presented in May in Chicago at the annual Digestive Disease Week® (DDW).

Impactful study

“This is an important study, published in a very high-ranking journal, that will have a huge impact on how we practice,” Jacob Kurowski, MD, department of pediatric gastroenterology, hepatology and nutrition, Cleveland Clinic Children’s, who wasn’t involved in the study, said.

Treatment with a TNFi, including infliximab and adalimumab, is a mainstay of pediatric Crohn’s disease therapy. However, not all patients achieve remission, and many lose response over time.

The current trial compared the effectiveness and safety of adding a low-dose of oral methotrexate to adalimumab or infliximab vs. TNFi therapy alone in 297 children with Crohn’s disease. The mean age was 13.9 years, and about two-thirds were boys. None had a prior history of TNFi therapy.

Participants initiating infliximab or adalimumab were randomly allocated (1:1) to oral methotrexate or placebo. Of them, 110 infliximab initiators and 46 adalimumab initiators received methotrexate, while 102 infliximab initiators and 39 adalimumab initiators were given placebo. Methotrexate was administered as a weekly dose of 15 mg for children weighing 40 kg or more, 12.5 mg for children 30 kg to less than 40 kg, and 10 mg for children 20 kg to less than 30 kg. All participants received pretreatment with ondansetron 4 mg (or placebo) to prevent nausea and folic acid (1 mg per day). Participants were followed for 12-36 months.

The primary outcome was a failure to achieve or maintain steroid-free remission defined by occurrence of any of the following:

• Short Pediatric Crohn’s Disease Activity Index (SPCDAI) score of less than 15 by week 26.
• Failure to complete a steroid taper by week 16.
• SPCDAI score of 15 or higher as a result of active Crohn’s disease at two or more consecutive visits beyond week 26.
• Hospitalization or surgery for Crohn’s disease beyond week 26.
• Use of corticosteroids for Crohn’s disease for 10 or more weeks cumulatively beyond week 16.
• Discontinuation of anti-TNF and/or study drug for lack of effectiveness or toxicity.

Overall, 88 of 297 children (30%) experienced treatment failure, including 57 of 212 (27%) on infliximab and 31 of 85 (36%) on adalimumab. Overall, 40 of 156 children (26%) on combination therapy and 48 of 141 (34%) on monotherapy experienced treatment failure.

Kaplan Meier analysis of the overall population showed a nonsignificant trend toward lower event rates with combination therapy (hazard ratio, 0.69; 95% confidence interval, 0.45-1.05; P = .08).

After stratification by TNFi, there was no difference in time to treatment failure among infliximab initiators between combination and monotherapy (HR, 0.93; 95% CI, 0.55-1.56; P = .78). In contrast, among adalimumab initiators, combination therapy was significantly associated with a longer time to treatment failure (HR, 0.40; 95% CI 0.19-0.81; P = .01).

There was a nonsignificant trend toward lower development of antidrug antibodies with combination therapy (risk ratio 0.72 with infliximab and 0.71 with adalimumab). This trend is in line with adult studies and adds substantially to the pediatric literature on this topic, the researchers note.

No differences in patient-reported outcomes were observed. There were slightly more adverse events with combination therapy, as expected, but fewer serious adverse events.
 

Shared decision-making

Dr. Kappelman noted that the study was not designed to answer the question of which is better – adalimumab plus methotrexate or infliximab alone.

“This is an area for future research. At this point, we believe it is an individualized decision, and appropriate counseling is needed to support shared decision-making,” he said.

The trial was not designed to evaluate the role of proactive therapeutic drug monitoring. However, proactive TDM is endorsed in the ImproveCareNow Model IBD Care guidelines and was considered standard of care at the 35 study sites.

The findings “suggest strong consideration of using combination therapy for pediatric Crohn’s disease patients initiating adalimumab, but not infliximab,” Dr. Kappelman and colleagues say.

“Dissemination and implementation of these findings should lead to improved outcomes in this patient population, including consideration of deimplementation of combination therapy in infliximab-treated patients,” they add.

The decision about which approach to use is still very dependent on patients and their providers, Dr. Kurowski said.

“The study shows that you can safely use infliximab as monotherapy, with low risk of antibody formation, while utilizing proactive therapeutic drug monitoring and dose optimization,” he said. “The study also shows that adalimumab in combination with low-dose methotrexate can be strongly considered when needed.”

The researchers’ standardization of methotrexate doses by weight “is another significant contribution and provides a guide for clinicians,” Dr. Kurowski added.

The study was funded by grants from the Patient-Centered Outcomes Research Institute, the Helmsley Charitable Trust, and National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Kappelman has consulted for AbbVie, Janssen, Pfizer, Takeda, and Lilly; holds shares in Johnson & Johnson; and has received research support from Pfizer, Takeda, Janssen, AbbVie, Lilly, Genentech, Boehringer Ingelheim, Bristol-Myers Squibb, Celtrion, and Arena Pharmaceuticals. Dr. Kurowski reports no relevant financial relationships.

DDW is sponsored by the American Association for the Study of Liver Diseases, the American Gastroenterological Association, the American Society for Gastrointestinal Endoscopy, and the Society for Surgery of the Alimentary Tract.

The Food and Drug Administration has expanded the indication for linaclotide (Linzess) to children as young as age 6 years with functional constipation, making it the first approved treatment for pediatric functional constipation.

The recommended dosage in pediatric patients is 72 mcg orally once daily.

Functional constipation is common in children and adolescents. Symptoms include infrequent bowel movements with hard stools that can be difficult or painful to pass.

Olivier Le Moal/Getty Images

There is no known underlying organic cause and there are typically multiple contributing factors, the FDA noted in a statement announcing the approval.

The efficacy of linaclotide in children with functional constipation was demonstrated in a 12-week double-blind, placebo-controlled, randomized, multicenter clinical trial (Trial 7; NCT04026113) and supported by efficacy data from trials in adults with chronic idiopathic constipation, the FDA said.

The FDA first approved linaclotide in 2012 for the treatment of chronic idiopathic constipation and irritable bowel syndrome with constipation (IBS-C) in adults.
 

Study details

To be eligible for the pediatric clinical trial, patients had to have experienced fewer than three spontaneous bowel movements (SBMs) per week.

They also had to experience one or more of the following at least once weekly, for at least 2 months prior to the trial screening visit:

• History of stool withholding or excessive voluntary stool retention.
• History of painful or hard bowel movements.
• History of large diameter stools that may obstruct the toilet.
• Presence of a large fecal mass in the rectum.
• At least one episode of fecal incontinence per week.

The primary efficacy endpoint was a 12-week change from baseline in SBM frequency rate. Children on linaclotide experienced greater improvement in the average number of SBMs per week than peers given placebo.

SBM frequency improved during the first week and was maintained throughout the remainder of the 12-week treatment period, the FDA said.

The most common adverse reaction is diarrhea. If severe diarrhea occurs, linaclotide should be discontinued and rehydration started.

The product’s boxed warning states that linaclotide is contraindicated in children younger than 2 years. In neonatal mice, linaclotide caused deaths due to dehydration.

Patients with known or suspected mechanical gastrointestinal obstruction should not take linaclotide.

Full prescribing information is available online.

The application for linaclotide in children received priority review.

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

The Food and Drug Administration has expanded the indication for linaclotide (Linzess) to children as young as age 6 years with functional constipation, making it the first approved treatment for pediatric functional constipation.

The recommended dosage in pediatric patients is 72 mcg orally once daily.

Functional constipation is common in children and adolescents. Symptoms include infrequent bowel movements with hard stools that can be difficult or painful to pass.

Olivier Le Moal/Getty Images

There is no known underlying organic cause and there are typically multiple contributing factors, the FDA noted in a statement announcing the approval.

The efficacy of linaclotide in children with functional constipation was demonstrated in a 12-week double-blind, placebo-controlled, randomized, multicenter clinical trial (Trial 7; NCT04026113) and supported by efficacy data from trials in adults with chronic idiopathic constipation, the FDA said.

The FDA first approved linaclotide in 2012 for the treatment of chronic idiopathic constipation and irritable bowel syndrome with constipation (IBS-C) in adults.
 

Study details

To be eligible for the pediatric clinical trial, patients had to have experienced fewer than three spontaneous bowel movements (SBMs) per week.

They also had to experience one or more of the following at least once weekly, for at least 2 months prior to the trial screening visit:

• History of stool withholding or excessive voluntary stool retention.
• History of painful or hard bowel movements.
• History of large diameter stools that may obstruct the toilet.
• Presence of a large fecal mass in the rectum.
• At least one episode of fecal incontinence per week.

The primary efficacy endpoint was a 12-week change from baseline in SBM frequency rate. Children on linaclotide experienced greater improvement in the average number of SBMs per week than peers given placebo.

SBM frequency improved during the first week and was maintained throughout the remainder of the 12-week treatment period, the FDA said.

The most common adverse reaction is diarrhea. If severe diarrhea occurs, linaclotide should be discontinued and rehydration started.

The product’s boxed warning states that linaclotide is contraindicated in children younger than 2 years. In neonatal mice, linaclotide caused deaths due to dehydration.

Patients with known or suspected mechanical gastrointestinal obstruction should not take linaclotide.

Full prescribing information is available online.

The application for linaclotide in children received priority review.

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

The Food and Drug Administration has expanded the indication for linaclotide (Linzess) to children as young as age 6 years with functional constipation, making it the first approved treatment for pediatric functional constipation.

The recommended dosage in pediatric patients is 72 mcg orally once daily.

Functional constipation is common in children and adolescents. Symptoms include infrequent bowel movements with hard stools that can be difficult or painful to pass.

Olivier Le Moal/Getty Images

There is no known underlying organic cause and there are typically multiple contributing factors, the FDA noted in a statement announcing the approval.

The efficacy of linaclotide in children with functional constipation was demonstrated in a 12-week double-blind, placebo-controlled, randomized, multicenter clinical trial (Trial 7; NCT04026113) and supported by efficacy data from trials in adults with chronic idiopathic constipation, the FDA said.

The FDA first approved linaclotide in 2012 for the treatment of chronic idiopathic constipation and irritable bowel syndrome with constipation (IBS-C) in adults.
 

Study details

To be eligible for the pediatric clinical trial, patients had to have experienced fewer than three spontaneous bowel movements (SBMs) per week.

They also had to experience one or more of the following at least once weekly, for at least 2 months prior to the trial screening visit:

• History of stool withholding or excessive voluntary stool retention.
• History of painful or hard bowel movements.
• History of large diameter stools that may obstruct the toilet.
• Presence of a large fecal mass in the rectum.
• At least one episode of fecal incontinence per week.

The primary efficacy endpoint was a 12-week change from baseline in SBM frequency rate. Children on linaclotide experienced greater improvement in the average number of SBMs per week than peers given placebo.

SBM frequency improved during the first week and was maintained throughout the remainder of the 12-week treatment period, the FDA said.

The most common adverse reaction is diarrhea. If severe diarrhea occurs, linaclotide should be discontinued and rehydration started.

The product’s boxed warning states that linaclotide is contraindicated in children younger than 2 years. In neonatal mice, linaclotide caused deaths due to dehydration.

Patients with known or suspected mechanical gastrointestinal obstruction should not take linaclotide.

Full prescribing information is available online.

The application for linaclotide in children received priority review.

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

DENVER – Taking ozanimod for relapsing multiple sclerosis (MS) at the same time as taking antidepressants that increase serotonin levels does not appear to increase the risk for hypertension or any other adverse events related to serotonin toxicity, according to research presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.

“Depression and anxiety are prevalent comorbidities occurring in up to 54% of patients with multiple sclerosis, and selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitors (SNRIs) are first-line treatments for depression and anxiety disorders,” Robert T. Naismith, MD, of Washington University in St. Louis, and his colleagues reported.

“Coadministration of ozanimod with drugs that increase serotonin could hypothetically lead to serotonin accumulation,” which can increase the likelihood of hypertension. U.S. prescribing information recommends that patients taking both ozanimod and medications that increase norepinephrine or serotonin be monitored for hypertension, an adverse reaction reported in 3.9% of patients receiving ozanimod in the phase 3 trials for relapsing MS.
 

Clarifying the risk

“It’s important to be aware of potential drug interactions and risks from MS disease modifying therapies,” Lauren Gluck, MD, an assistant professor and director of the division of multiple sclerosis at Montefiore Medical Center/Albert Einstein College of Medicine, New York, said in an interview. Dr. Gluck was not involved in this study but described some of the history that revealed the value of this type of research. For example, the first sphingosine-1-phosphate receptor (S1PR) modulator approved for MS, fingolimod (Gilenya), has a risk of cardiac conduction dysfunction with QTc prolongation, so people taking fingolimod with other medications that prolong QTc, such as SSRIs, need additional monitoring.

“Ozanimod is a newer, more selective S1PR modulator that initially raised concerns about interaction with serotonin-increasing drugs based on in vitro studies,” Dr. Gluck said. “This could mean that people on ozanimod and other serotonin-increasing medicine could be at risk for dangerous events like serotonin syndrome. However, in vitro studies do not always translate to how something affects the human body, so it is not clear how much risk truly exists.”
 

Examining open-label extension trial data

The researchers therefore evaluated the safety of taking ozanimod and SSRIs or SNRIs in a subset of patients with relapsing MS who participated in the DAYBREAK open-label extension trial. The phase 3 parent trials compared 30 mcg once weekly of intramuscular interferon beta-1a with 0.92 mg of once-daily oral ozanimod and 0.46 mg of once-daily oral ozanimod. In the DAYBREAK open-label extension, 2,256 participants underwent a dose escalation over one week until all reached 0.92 mg of ozanimod, where they remained for an average of just under 5 years of follow-up. Nearly all the participants (99.4%) were White, and two-thirds (66.5%) were female.

The researchers searched the study data for terms related to serotonin toxicity and compared the rates of adverse events related with those terms and the rates of hypertension in the 274 participants who were and the 2,032 participant who were not taking antidepressants at the same time as ozanimod.

They found that 13.9% of patients taking SSRIs or SNRIs experienced at least one treatment-emergent adverse event related to their search criteria, compared with 17.7% of patients not taking SSRIs or SNRIs. Similarly, 9.2% of trial participants not taking SSRIs or SNRIs had hypertension, compared with 4.7% of participants who were taking antidepressants. The authors further noted that “similar trends were observed when 6 weeks after the end date of concomitant SSRIs/SNRI use were included in the ‘on SSRI/SNRI’ analysis period.”

When the researchers searched specifically for three terms directly related to serotonin toxicity – “serotonin syndrome,” “neuroleptic malignant syndrome,” and “hyperthermia malignant” – they did not find any patients who had treatment-emergent adverse events related to those terms.

“SSRIs/SNRIs were freely allowed as concomitant medications in the DAYBREAK open-label extension, and among the patients from SUNBEAM or RADIANCE who were followed for up to 6 years, there have been no reported safety concerns during the concurrent administration of serotonergic antidepressants and ozanimod in patients with relapsing MS as of the data cutoff,” concluded the authors, though they also noted that the overall rate of SSRI and SNRI use was low in the extension trial.
 

A reassuring finding for clinicians and patients alike

“It is reassuring, if not unexpected, that there were no clinically significant rates of symptoms associated with excess serotonin in patients on ozanimod and SSRI/SNRIs,” Dr. Gluck commented. “These findings are important for both clinicians and patients – they can help [both] feel comfortable considering ozanimod if SSRI/SNRIs are already being used. There is also freedom to use SSRI/SNRIs for symptom management in patients already on ozanimod.”

The research was funded by Bristol Myers Squibb. Dr. Naismith reported consulting for Abata Therapeutics, Banner Life Sciences, BeiGene, Biogen, Bristol Myers Squibb, Celltrion, Genentech, Genzyme, GW Therapeutics, Janssen, Horizon Therapeutics, Lundbeck, NervGen, and TG Therapeutics. Six other authors reported disclosures for various pharmaceutical companies, and six other authors are employees and/or shareholders of Bristol Myers Squibb. Dr. Gluck has served on advisory boards with Genentech and EMD Serono.
 

DENVER – Taking ozanimod for relapsing multiple sclerosis (MS) at the same time as taking antidepressants that increase serotonin levels does not appear to increase the risk for hypertension or any other adverse events related to serotonin toxicity, according to research presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.

“Depression and anxiety are prevalent comorbidities occurring in up to 54% of patients with multiple sclerosis, and selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitors (SNRIs) are first-line treatments for depression and anxiety disorders,” Robert T. Naismith, MD, of Washington University in St. Louis, and his colleagues reported.

“Coadministration of ozanimod with drugs that increase serotonin could hypothetically lead to serotonin accumulation,” which can increase the likelihood of hypertension. U.S. prescribing information recommends that patients taking both ozanimod and medications that increase norepinephrine or serotonin be monitored for hypertension, an adverse reaction reported in 3.9% of patients receiving ozanimod in the phase 3 trials for relapsing MS.
 

Clarifying the risk

“It’s important to be aware of potential drug interactions and risks from MS disease modifying therapies,” Lauren Gluck, MD, an assistant professor and director of the division of multiple sclerosis at Montefiore Medical Center/Albert Einstein College of Medicine, New York, said in an interview. Dr. Gluck was not involved in this study but described some of the history that revealed the value of this type of research. For example, the first sphingosine-1-phosphate receptor (S1PR) modulator approved for MS, fingolimod (Gilenya), has a risk of cardiac conduction dysfunction with QTc prolongation, so people taking fingolimod with other medications that prolong QTc, such as SSRIs, need additional monitoring.

“Ozanimod is a newer, more selective S1PR modulator that initially raised concerns about interaction with serotonin-increasing drugs based on in vitro studies,” Dr. Gluck said. “This could mean that people on ozanimod and other serotonin-increasing medicine could be at risk for dangerous events like serotonin syndrome. However, in vitro studies do not always translate to how something affects the human body, so it is not clear how much risk truly exists.”
 

Examining open-label extension trial data

The researchers therefore evaluated the safety of taking ozanimod and SSRIs or SNRIs in a subset of patients with relapsing MS who participated in the DAYBREAK open-label extension trial. The phase 3 parent trials compared 30 mcg once weekly of intramuscular interferon beta-1a with 0.92 mg of once-daily oral ozanimod and 0.46 mg of once-daily oral ozanimod. In the DAYBREAK open-label extension, 2,256 participants underwent a dose escalation over one week until all reached 0.92 mg of ozanimod, where they remained for an average of just under 5 years of follow-up. Nearly all the participants (99.4%) were White, and two-thirds (66.5%) were female.

The researchers searched the study data for terms related to serotonin toxicity and compared the rates of adverse events related with those terms and the rates of hypertension in the 274 participants who were and the 2,032 participant who were not taking antidepressants at the same time as ozanimod.

They found that 13.9% of patients taking SSRIs or SNRIs experienced at least one treatment-emergent adverse event related to their search criteria, compared with 17.7% of patients not taking SSRIs or SNRIs. Similarly, 9.2% of trial participants not taking SSRIs or SNRIs had hypertension, compared with 4.7% of participants who were taking antidepressants. The authors further noted that “similar trends were observed when 6 weeks after the end date of concomitant SSRIs/SNRI use were included in the ‘on SSRI/SNRI’ analysis period.”

When the researchers searched specifically for three terms directly related to serotonin toxicity – “serotonin syndrome,” “neuroleptic malignant syndrome,” and “hyperthermia malignant” – they did not find any patients who had treatment-emergent adverse events related to those terms.

“SSRIs/SNRIs were freely allowed as concomitant medications in the DAYBREAK open-label extension, and among the patients from SUNBEAM or RADIANCE who were followed for up to 6 years, there have been no reported safety concerns during the concurrent administration of serotonergic antidepressants and ozanimod in patients with relapsing MS as of the data cutoff,” concluded the authors, though they also noted that the overall rate of SSRI and SNRI use was low in the extension trial.
 

A reassuring finding for clinicians and patients alike

“It is reassuring, if not unexpected, that there were no clinically significant rates of symptoms associated with excess serotonin in patients on ozanimod and SSRI/SNRIs,” Dr. Gluck commented. “These findings are important for both clinicians and patients – they can help [both] feel comfortable considering ozanimod if SSRI/SNRIs are already being used. There is also freedom to use SSRI/SNRIs for symptom management in patients already on ozanimod.”

The research was funded by Bristol Myers Squibb. Dr. Naismith reported consulting for Abata Therapeutics, Banner Life Sciences, BeiGene, Biogen, Bristol Myers Squibb, Celltrion, Genentech, Genzyme, GW Therapeutics, Janssen, Horizon Therapeutics, Lundbeck, NervGen, and TG Therapeutics. Six other authors reported disclosures for various pharmaceutical companies, and six other authors are employees and/or shareholders of Bristol Myers Squibb. Dr. Gluck has served on advisory boards with Genentech and EMD Serono.
 

DENVER – Taking ozanimod for relapsing multiple sclerosis (MS) at the same time as taking antidepressants that increase serotonin levels does not appear to increase the risk for hypertension or any other adverse events related to serotonin toxicity, according to research presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.

“Depression and anxiety are prevalent comorbidities occurring in up to 54% of patients with multiple sclerosis, and selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitors (SNRIs) are first-line treatments for depression and anxiety disorders,” Robert T. Naismith, MD, of Washington University in St. Louis, and his colleagues reported.

“Coadministration of ozanimod with drugs that increase serotonin could hypothetically lead to serotonin accumulation,” which can increase the likelihood of hypertension. U.S. prescribing information recommends that patients taking both ozanimod and medications that increase norepinephrine or serotonin be monitored for hypertension, an adverse reaction reported in 3.9% of patients receiving ozanimod in the phase 3 trials for relapsing MS.
 

Clarifying the risk

“It’s important to be aware of potential drug interactions and risks from MS disease modifying therapies,” Lauren Gluck, MD, an assistant professor and director of the division of multiple sclerosis at Montefiore Medical Center/Albert Einstein College of Medicine, New York, said in an interview. Dr. Gluck was not involved in this study but described some of the history that revealed the value of this type of research. For example, the first sphingosine-1-phosphate receptor (S1PR) modulator approved for MS, fingolimod (Gilenya), has a risk of cardiac conduction dysfunction with QTc prolongation, so people taking fingolimod with other medications that prolong QTc, such as SSRIs, need additional monitoring.

“Ozanimod is a newer, more selective S1PR modulator that initially raised concerns about interaction with serotonin-increasing drugs based on in vitro studies,” Dr. Gluck said. “This could mean that people on ozanimod and other serotonin-increasing medicine could be at risk for dangerous events like serotonin syndrome. However, in vitro studies do not always translate to how something affects the human body, so it is not clear how much risk truly exists.”
 

Examining open-label extension trial data

The researchers therefore evaluated the safety of taking ozanimod and SSRIs or SNRIs in a subset of patients with relapsing MS who participated in the DAYBREAK open-label extension trial. The phase 3 parent trials compared 30 mcg once weekly of intramuscular interferon beta-1a with 0.92 mg of once-daily oral ozanimod and 0.46 mg of once-daily oral ozanimod. In the DAYBREAK open-label extension, 2,256 participants underwent a dose escalation over one week until all reached 0.92 mg of ozanimod, where they remained for an average of just under 5 years of follow-up. Nearly all the participants (99.4%) were White, and two-thirds (66.5%) were female.

The researchers searched the study data for terms related to serotonin toxicity and compared the rates of adverse events related with those terms and the rates of hypertension in the 274 participants who were and the 2,032 participant who were not taking antidepressants at the same time as ozanimod.

They found that 13.9% of patients taking SSRIs or SNRIs experienced at least one treatment-emergent adverse event related to their search criteria, compared with 17.7% of patients not taking SSRIs or SNRIs. Similarly, 9.2% of trial participants not taking SSRIs or SNRIs had hypertension, compared with 4.7% of participants who were taking antidepressants. The authors further noted that “similar trends were observed when 6 weeks after the end date of concomitant SSRIs/SNRI use were included in the ‘on SSRI/SNRI’ analysis period.”

When the researchers searched specifically for three terms directly related to serotonin toxicity – “serotonin syndrome,” “neuroleptic malignant syndrome,” and “hyperthermia malignant” – they did not find any patients who had treatment-emergent adverse events related to those terms.

“SSRIs/SNRIs were freely allowed as concomitant medications in the DAYBREAK open-label extension, and among the patients from SUNBEAM or RADIANCE who were followed for up to 6 years, there have been no reported safety concerns during the concurrent administration of serotonergic antidepressants and ozanimod in patients with relapsing MS as of the data cutoff,” concluded the authors, though they also noted that the overall rate of SSRI and SNRI use was low in the extension trial.
 

A reassuring finding for clinicians and patients alike

“It is reassuring, if not unexpected, that there were no clinically significant rates of symptoms associated with excess serotonin in patients on ozanimod and SSRI/SNRIs,” Dr. Gluck commented. “These findings are important for both clinicians and patients – they can help [both] feel comfortable considering ozanimod if SSRI/SNRIs are already being used. There is also freedom to use SSRI/SNRIs for symptom management in patients already on ozanimod.”

The research was funded by Bristol Myers Squibb. Dr. Naismith reported consulting for Abata Therapeutics, Banner Life Sciences, BeiGene, Biogen, Bristol Myers Squibb, Celltrion, Genentech, Genzyme, GW Therapeutics, Janssen, Horizon Therapeutics, Lundbeck, NervGen, and TG Therapeutics. Six other authors reported disclosures for various pharmaceutical companies, and six other authors are employees and/or shareholders of Bristol Myers Squibb. Dr. Gluck has served on advisory boards with Genentech and EMD Serono.
 

CHICAGO – Nearly 60% of health care providers surveyed failed to choose the same treatment strategies for HER2– early breast cancer as a panel of five oncologists with expertise in breast cancer, a new study finds.

The discrepancy suggests that many providers aren’t aware of the findings of recent landmark trials that formed the basis of the panel’s opinions, said study coauthor Denise A. Yardley, MD, of Tennessee Oncology and Sarah Cannon Research Institute in Nashville, in an interview. The findings, based on responses to a treatment decision tool, were presented in a poster at the annual meeting of the American Society of Clinical Oncology.

Study methods and results

For the new study, researchers analyzed how 547 providers – and the panel – responded to 10 case scenarios in high-risk HER2– early breast cancer between June 2022 and January 2023.

Among the providers surveyed, 72% identified as physicians, including oncologists, hematologists/oncologists, surgery oncologists, radiation oncologists, and pathologists. One percent said they were nurse practitioners or physician assistants, 7% said they were pharmacists, 1% were nurses, and the specific roles of the remaining 19% were unknown, but included medical students, according to Dr. Yardley, who is a breast cancer oncologist.

The study authors developed the free decision tool – available via the medical education company Clinical Care Options – to help oncologists navigate new treatment options for high-risk HER2– early breast cancer. The Food and Drug Administration has recently approved drugs such as abemaciclib, olaparib, and pembrolizumab for the condition.

Health care providers enter details into the tool about their patients along with their intended treatment plans. The tool then shows them recommendations for treatment from a panel of five oncologists with expertise in oncology. The members of the panel based their perspectives on the findings of the KEYNOTE-522 (pembrolizumab), OlympiA (olaparib), and monarchE (abemaciclib) trials.

The oncologists with expertise in breast cancer, who provided recommendations in March 2022, generally agreed about the best treatments, Dr. Yardley said.

The other health care providers surveyed didn’t agree with the breast cancer experts about the best treatment 58.8% of the time.

For example, one scenario describes a HR+, HER2– patient with no deleterious BRCA mutation – or unknown status – who fits the monarchE high-risk criteria. All the breast cancer experts on the panel recommended abemaciclib and endocrine therapy. But 203 providers supported a variety of strategies: endocrine therapy alone (9%), chemotherapy followed by endocrine therapy (49%), and olaparib and endocrine therapy (2%). Only 37% opted for abemaciclib and endocrine therapy, and 4% were uncertain.

Another scenario describes a patient with triple-negative breast cancer with no residual disease after neoadjuvant chemotherapy. All the experts agreed on a strategy of no adjuvant therapy plus observation. Forty percent of 25 providers agreed with this approach, but 24% were uncertain, 12% chose pembrolizumab, and 24% chose capecitabine.

In many cases, providers chose more intensive treatment options than the experts did, Dr. Yardley said.

Overtreatment in cancer is often a reflex for oncologists, she said, although “we’re learning to deescalate these treatment algorithms where there is really no benefit [to extra treatment].”

“It’s a challenge for some of these oncologists who are busy and dealing with multiple solid tumor types to keep up with the nuances of a rapidly changing field,” Dr. Yardley noted.

Many community oncologists aren’t specialists in one type of cancer and must try to keep up with treatment recommendations regarding multiple types, she continued.
 

Decision tool’s value explained

According to the study, 32% of providers changed their treatment choices in clinical practice after they learned about the expert perspectives via the decision tool; 46% said the expert opinions confirmed that their choices were best practice.

The value of the tool is its ability to help providers make better decisions about patient care, Dr. Yardley said. “There seems to be a need for this kind of support.”

In an interview, University of Pittsburgh Medical Center oncologist Adam M. Brufsky, MD, PhD – who wasn’t involved with the study – said he was surprised by the amount of disagreement between the expert and provider perspectives on treatment. However, he noted that community oncologists – unlike the breast cancer experts – often don’t see just one type of cancer.

“You just have to know so much now as an oncologist,” Dr. Brufsky said. He recommended that colleagues take advantage of decision support tools, such as cancer treatment pathways.

The study was funded by AstraZeneca, Lilly, and Merck Sharp & Dohme. Dr. Yardley has no disclosures, and disclosure information from other authors was not available. Dr. Brufsky discloses consulting support from AstraZeneca, Lilly, and Merck and grants from AstraZeneca.

CHICAGO – Nearly 60% of health care providers surveyed failed to choose the same treatment strategies for HER2– early breast cancer as a panel of five oncologists with expertise in breast cancer, a new study finds.

The discrepancy suggests that many providers aren’t aware of the findings of recent landmark trials that formed the basis of the panel’s opinions, said study coauthor Denise A. Yardley, MD, of Tennessee Oncology and Sarah Cannon Research Institute in Nashville, in an interview. The findings, based on responses to a treatment decision tool, were presented in a poster at the annual meeting of the American Society of Clinical Oncology.

Study methods and results

For the new study, researchers analyzed how 547 providers – and the panel – responded to 10 case scenarios in high-risk HER2– early breast cancer between June 2022 and January 2023.

Among the providers surveyed, 72% identified as physicians, including oncologists, hematologists/oncologists, surgery oncologists, radiation oncologists, and pathologists. One percent said they were nurse practitioners or physician assistants, 7% said they were pharmacists, 1% were nurses, and the specific roles of the remaining 19% were unknown, but included medical students, according to Dr. Yardley, who is a breast cancer oncologist.

The study authors developed the free decision tool – available via the medical education company Clinical Care Options – to help oncologists navigate new treatment options for high-risk HER2– early breast cancer. The Food and Drug Administration has recently approved drugs such as abemaciclib, olaparib, and pembrolizumab for the condition.

Health care providers enter details into the tool about their patients along with their intended treatment plans. The tool then shows them recommendations for treatment from a panel of five oncologists with expertise in oncology. The members of the panel based their perspectives on the findings of the KEYNOTE-522 (pembrolizumab), OlympiA (olaparib), and monarchE (abemaciclib) trials.

The oncologists with expertise in breast cancer, who provided recommendations in March 2022, generally agreed about the best treatments, Dr. Yardley said.

The other health care providers surveyed didn’t agree with the breast cancer experts about the best treatment 58.8% of the time.

For example, one scenario describes a HR+, HER2– patient with no deleterious BRCA mutation – or unknown status – who fits the monarchE high-risk criteria. All the breast cancer experts on the panel recommended abemaciclib and endocrine therapy. But 203 providers supported a variety of strategies: endocrine therapy alone (9%), chemotherapy followed by endocrine therapy (49%), and olaparib and endocrine therapy (2%). Only 37% opted for abemaciclib and endocrine therapy, and 4% were uncertain.

Another scenario describes a patient with triple-negative breast cancer with no residual disease after neoadjuvant chemotherapy. All the experts agreed on a strategy of no adjuvant therapy plus observation. Forty percent of 25 providers agreed with this approach, but 24% were uncertain, 12% chose pembrolizumab, and 24% chose capecitabine.

In many cases, providers chose more intensive treatment options than the experts did, Dr. Yardley said.

Overtreatment in cancer is often a reflex for oncologists, she said, although “we’re learning to deescalate these treatment algorithms where there is really no benefit [to extra treatment].”

“It’s a challenge for some of these oncologists who are busy and dealing with multiple solid tumor types to keep up with the nuances of a rapidly changing field,” Dr. Yardley noted.

Many community oncologists aren’t specialists in one type of cancer and must try to keep up with treatment recommendations regarding multiple types, she continued.
 

Decision tool’s value explained

According to the study, 32% of providers changed their treatment choices in clinical practice after they learned about the expert perspectives via the decision tool; 46% said the expert opinions confirmed that their choices were best practice.

The value of the tool is its ability to help providers make better decisions about patient care, Dr. Yardley said. “There seems to be a need for this kind of support.”

In an interview, University of Pittsburgh Medical Center oncologist Adam M. Brufsky, MD, PhD – who wasn’t involved with the study – said he was surprised by the amount of disagreement between the expert and provider perspectives on treatment. However, he noted that community oncologists – unlike the breast cancer experts – often don’t see just one type of cancer.

“You just have to know so much now as an oncologist,” Dr. Brufsky said. He recommended that colleagues take advantage of decision support tools, such as cancer treatment pathways.

The study was funded by AstraZeneca, Lilly, and Merck Sharp & Dohme. Dr. Yardley has no disclosures, and disclosure information from other authors was not available. Dr. Brufsky discloses consulting support from AstraZeneca, Lilly, and Merck and grants from AstraZeneca.

CHICAGO – Nearly 60% of health care providers surveyed failed to choose the same treatment strategies for HER2– early breast cancer as a panel of five oncologists with expertise in breast cancer, a new study finds.

The discrepancy suggests that many providers aren’t aware of the findings of recent landmark trials that formed the basis of the panel’s opinions, said study coauthor Denise A. Yardley, MD, of Tennessee Oncology and Sarah Cannon Research Institute in Nashville, in an interview. The findings, based on responses to a treatment decision tool, were presented in a poster at the annual meeting of the American Society of Clinical Oncology.

Study methods and results

For the new study, researchers analyzed how 547 providers – and the panel – responded to 10 case scenarios in high-risk HER2– early breast cancer between June 2022 and January 2023.

Among the providers surveyed, 72% identified as physicians, including oncologists, hematologists/oncologists, surgery oncologists, radiation oncologists, and pathologists. One percent said they were nurse practitioners or physician assistants, 7% said they were pharmacists, 1% were nurses, and the specific roles of the remaining 19% were unknown, but included medical students, according to Dr. Yardley, who is a breast cancer oncologist.

The study authors developed the free decision tool – available via the medical education company Clinical Care Options – to help oncologists navigate new treatment options for high-risk HER2– early breast cancer. The Food and Drug Administration has recently approved drugs such as abemaciclib, olaparib, and pembrolizumab for the condition.

Health care providers enter details into the tool about their patients along with their intended treatment plans. The tool then shows them recommendations for treatment from a panel of five oncologists with expertise in oncology. The members of the panel based their perspectives on the findings of the KEYNOTE-522 (pembrolizumab), OlympiA (olaparib), and monarchE (abemaciclib) trials.

The oncologists with expertise in breast cancer, who provided recommendations in March 2022, generally agreed about the best treatments, Dr. Yardley said.

The other health care providers surveyed didn’t agree with the breast cancer experts about the best treatment 58.8% of the time.

For example, one scenario describes a HR+, HER2– patient with no deleterious BRCA mutation – or unknown status – who fits the monarchE high-risk criteria. All the breast cancer experts on the panel recommended abemaciclib and endocrine therapy. But 203 providers supported a variety of strategies: endocrine therapy alone (9%), chemotherapy followed by endocrine therapy (49%), and olaparib and endocrine therapy (2%). Only 37% opted for abemaciclib and endocrine therapy, and 4% were uncertain.

Another scenario describes a patient with triple-negative breast cancer with no residual disease after neoadjuvant chemotherapy. All the experts agreed on a strategy of no adjuvant therapy plus observation. Forty percent of 25 providers agreed with this approach, but 24% were uncertain, 12% chose pembrolizumab, and 24% chose capecitabine.

In many cases, providers chose more intensive treatment options than the experts did, Dr. Yardley said.

Overtreatment in cancer is often a reflex for oncologists, she said, although “we’re learning to deescalate these treatment algorithms where there is really no benefit [to extra treatment].”

“It’s a challenge for some of these oncologists who are busy and dealing with multiple solid tumor types to keep up with the nuances of a rapidly changing field,” Dr. Yardley noted.

Many community oncologists aren’t specialists in one type of cancer and must try to keep up with treatment recommendations regarding multiple types, she continued.
 

Decision tool’s value explained

According to the study, 32% of providers changed their treatment choices in clinical practice after they learned about the expert perspectives via the decision tool; 46% said the expert opinions confirmed that their choices were best practice.

The value of the tool is its ability to help providers make better decisions about patient care, Dr. Yardley said. “There seems to be a need for this kind of support.”

In an interview, University of Pittsburgh Medical Center oncologist Adam M. Brufsky, MD, PhD – who wasn’t involved with the study – said he was surprised by the amount of disagreement between the expert and provider perspectives on treatment. However, he noted that community oncologists – unlike the breast cancer experts – often don’t see just one type of cancer.

“You just have to know so much now as an oncologist,” Dr. Brufsky said. He recommended that colleagues take advantage of decision support tools, such as cancer treatment pathways.

The study was funded by AstraZeneca, Lilly, and Merck Sharp & Dohme. Dr. Yardley has no disclosures, and disclosure information from other authors was not available. Dr. Brufsky discloses consulting support from AstraZeneca, Lilly, and Merck and grants from AstraZeneca.

Patients with acute promyelocytic leukemia (APL) – previously considered among the most rapidly fatal forms of acute myeloid leukemia (AML) – now show survival rates exceeding 90% at 10 years after treatment with a chemotherapy-free regimen of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), with a survival advantage over ATRA plus chemotherapy in low- and intermediate-risk patients.

“In a large cohort of patients with APL, the chemo-free combination of ATRA/ATO is confirmed as the best treatment option, prolonging overall and event-free survival and reducing the relapse rate compared with ATRA/chemotherapy,” said first author Maria Teresa Voso, MD, of Tor Vergata University, in Rome, in presenting the findings at the 2023 annual meeting of the European Hematology Association.

APL, though rare, makes up about 10% of new AML cases, and the advent of the chemo-free ATRA-ATO regimen in recent years has transformed the disease, significantly improving survival.

However, with ongoing questions regarding factors associated with treatment benefits based on issues including the level of risk, Dr. Voso and colleagues turned to data from the large European Union–funded HARMONY registry, a big data project that uniquely provides real-world as well as clinical trial findings from diverse APL patient populations.

They identified 937 patients in the registry with newly diagnosed APL between 2007 and 2020 who met the study’s data quality criteria, including 536 (57.2%) patients from two clinical trials, the UK AML-17 and GIMEMA APL0406 trials, and 401 (42.8%) patients from national registries in 6 countries, representing real-world data.

The median duration of follow-up was 5.66 years, with a range of 0-14 years.

The patients had an average age of about 50, which is consistent with the lower age of diagnosis typical of APL, compared with other forms of AML.

Among them, 380 (40.6%) were treated with the ATRA-ATO regimen while 509 (54.3%) received the chemotherapy combination of ATRA-Idarubicin (AIDA).

Overall, 37.8% were determined to be low risk, as assessed by the Sanz risk-score; 42.3% were intermediate risk, and 18.7% were considered high risk. The rate of complete remission among the patients was 87.5%, and 9% had relapsed.

The results showed the 10-year overall survival (OS) rate to be 92% among the chemo-free ATRA-ATO-treated patients versus 75% in the AIDA-treated patients (P = .001).

Likewise, those treated with the chemo-free regimen had a higher event-free survival and a lower cumulative incidence of relapse (CIR) versus chemotherapy over 10 years (P < .001 for both).

In further stratifying by risk, patients who were low risk also had greater improvements with the chemo-free regimen in overall survival (P = .004), event-free survival, and CIR versus AIDA treatment (P < .001).

Among high-risk patients, however, only event-free survival was significantly improved in the chemo-free treated patients (P = .046).

Older age stood out as a significant determinant of survival, with patients in the age 50-69 and 70 or over age groups having a significantly lower rate of overall survival and event-free survival, compared with those under 50 years of age (P < .001), with those risks observed regardless of treatment type.

Age was not a significant factor in terms of the incidence of relapse (P = .159).
 

Clinical trial versus real-world outcomes

Of note, improved outcomes were reported in clinical trials versus real-world data, with overall survival higher in clinical trials among patients receiving the ATRA/ATO chemo-free treatment (P = .025), as well as in those receiving the AIDA chemotherapy (P < .001).

Early death, an uncommon but key concern with APL, usually due to bleeding complications and defined as death occurring within 30 days from APL diagnosis, occurred among 56 patients, or 5.9%, overall, and was significantly higher in the age 50-69 and over 70 groups versus those under 50 (P < .001).

Early death was more common among those with a Sanz high-risk score (15.4%), compared with low or intermediate risk (3.9%; P < .001); however, the risk was no different between the chemo-free (3.4%) and chemotherapy (5.7%) groups, regardless of whether patients had a low or high risk.

The rates of early death were significantly higher in the real-world population (10.2%), compared with patients in clinical trials (2.8%; P < .001), which Dr. Voso noted may be expected, as early deaths in some cases can occur even before a diagnosis is made.

“These patients sometimes come to the ER and if a diagnosis is not made, they may die before even receiving treatment,” she said in a press briefing.

“Indeed, the median time to death among those who had early death in the study was only 10 days, and there were even some patients dying at day 0,” she explained.

“So, it’s very important that not only hematologists but emergency doctors recognize this disease and try to reduce the early death rate.”

Overall, the results all remained consistent after adjustment in a multivariate analysis, Dr. Voso said.

“The multivariate analysis confirmed that increasing age, high Sanz risk score, the real-life treatment scenario, and the chemotherapy-based approach are independently associated with decreased survival,” she said.

The findings underscore that “elderly age and high Sanz risk score significantly impact on the rate of early deaths, irrespective of treatment,” Dr. Voso said.
 

ATRA/ATO ‘gold standard’ for low/intermediate risk

Commenting on the study, Alessandro Isidori, MD, PhD, a hematologist at AORMN Hospital, in Pesaro, Italy, who moderated the session, noted that the study underscores the greater challenges with higher-risk patients.

“The study did not show a statistical benefit for high-risk patients receiving ATRA/ATO versus AIDA,” he told this news organization, noting that “currently, there are many countries where ATRA/ATO is not approved for use in high-risk APL.”

“In high-risk APL, the AIDA combination should still be preferred to ATRA/ATO,” he said.

Dr. Isidori recommended careful efforts to stratify higher-risk patients who still may benefit from ATRA/ATO.

“The analysis of high-risk patients with white blood cell count as a continuous variable instead of a fixed variable (more or less than 10,000/mmc) may help to discriminate some high-risk patients who could benefit from ATRA/ATO,” he noted.

Overall, however, “ATRA/ATO is the gold standard for low and intermediate risk APL,” he said.

“Although promising, more data are needed to confirm the efficacy of ATRA/ATO in high-risk APL.”

Dr. Voso disclosed ties with companies including Celgene/Bristol Myers Squibb, Astellas, Jazz Pharmaceuticals, Abbvie, Novartis, and AstraZeneca. Dr. Isidori reported no disclosures.
 

Patients with acute promyelocytic leukemia (APL) – previously considered among the most rapidly fatal forms of acute myeloid leukemia (AML) – now show survival rates exceeding 90% at 10 years after treatment with a chemotherapy-free regimen of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), with a survival advantage over ATRA plus chemotherapy in low- and intermediate-risk patients.

“In a large cohort of patients with APL, the chemo-free combination of ATRA/ATO is confirmed as the best treatment option, prolonging overall and event-free survival and reducing the relapse rate compared with ATRA/chemotherapy,” said first author Maria Teresa Voso, MD, of Tor Vergata University, in Rome, in presenting the findings at the 2023 annual meeting of the European Hematology Association.

APL, though rare, makes up about 10% of new AML cases, and the advent of the chemo-free ATRA-ATO regimen in recent years has transformed the disease, significantly improving survival.

However, with ongoing questions regarding factors associated with treatment benefits based on issues including the level of risk, Dr. Voso and colleagues turned to data from the large European Union–funded HARMONY registry, a big data project that uniquely provides real-world as well as clinical trial findings from diverse APL patient populations.

They identified 937 patients in the registry with newly diagnosed APL between 2007 and 2020 who met the study’s data quality criteria, including 536 (57.2%) patients from two clinical trials, the UK AML-17 and GIMEMA APL0406 trials, and 401 (42.8%) patients from national registries in 6 countries, representing real-world data.

The median duration of follow-up was 5.66 years, with a range of 0-14 years.

The patients had an average age of about 50, which is consistent with the lower age of diagnosis typical of APL, compared with other forms of AML.

Among them, 380 (40.6%) were treated with the ATRA-ATO regimen while 509 (54.3%) received the chemotherapy combination of ATRA-Idarubicin (AIDA).

Overall, 37.8% were determined to be low risk, as assessed by the Sanz risk-score; 42.3% were intermediate risk, and 18.7% were considered high risk. The rate of complete remission among the patients was 87.5%, and 9% had relapsed.

The results showed the 10-year overall survival (OS) rate to be 92% among the chemo-free ATRA-ATO-treated patients versus 75% in the AIDA-treated patients (P = .001).

Likewise, those treated with the chemo-free regimen had a higher event-free survival and a lower cumulative incidence of relapse (CIR) versus chemotherapy over 10 years (P < .001 for both).

In further stratifying by risk, patients who were low risk also had greater improvements with the chemo-free regimen in overall survival (P = .004), event-free survival, and CIR versus AIDA treatment (P < .001).

Among high-risk patients, however, only event-free survival was significantly improved in the chemo-free treated patients (P = .046).

Older age stood out as a significant determinant of survival, with patients in the age 50-69 and 70 or over age groups having a significantly lower rate of overall survival and event-free survival, compared with those under 50 years of age (P < .001), with those risks observed regardless of treatment type.

Age was not a significant factor in terms of the incidence of relapse (P = .159).
 

Clinical trial versus real-world outcomes

Of note, improved outcomes were reported in clinical trials versus real-world data, with overall survival higher in clinical trials among patients receiving the ATRA/ATO chemo-free treatment (P = .025), as well as in those receiving the AIDA chemotherapy (P < .001).

Early death, an uncommon but key concern with APL, usually due to bleeding complications and defined as death occurring within 30 days from APL diagnosis, occurred among 56 patients, or 5.9%, overall, and was significantly higher in the age 50-69 and over 70 groups versus those under 50 (P < .001).

Early death was more common among those with a Sanz high-risk score (15.4%), compared with low or intermediate risk (3.9%; P < .001); however, the risk was no different between the chemo-free (3.4%) and chemotherapy (5.7%) groups, regardless of whether patients had a low or high risk.

The rates of early death were significantly higher in the real-world population (10.2%), compared with patients in clinical trials (2.8%; P < .001), which Dr. Voso noted may be expected, as early deaths in some cases can occur even before a diagnosis is made.

“These patients sometimes come to the ER and if a diagnosis is not made, they may die before even receiving treatment,” she said in a press briefing.

“Indeed, the median time to death among those who had early death in the study was only 10 days, and there were even some patients dying at day 0,” she explained.

“So, it’s very important that not only hematologists but emergency doctors recognize this disease and try to reduce the early death rate.”

Overall, the results all remained consistent after adjustment in a multivariate analysis, Dr. Voso said.

“The multivariate analysis confirmed that increasing age, high Sanz risk score, the real-life treatment scenario, and the chemotherapy-based approach are independently associated with decreased survival,” she said.

The findings underscore that “elderly age and high Sanz risk score significantly impact on the rate of early deaths, irrespective of treatment,” Dr. Voso said.
 

ATRA/ATO ‘gold standard’ for low/intermediate risk

Commenting on the study, Alessandro Isidori, MD, PhD, a hematologist at AORMN Hospital, in Pesaro, Italy, who moderated the session, noted that the study underscores the greater challenges with higher-risk patients.

“The study did not show a statistical benefit for high-risk patients receiving ATRA/ATO versus AIDA,” he told this news organization, noting that “currently, there are many countries where ATRA/ATO is not approved for use in high-risk APL.”

“In high-risk APL, the AIDA combination should still be preferred to ATRA/ATO,” he said.

Dr. Isidori recommended careful efforts to stratify higher-risk patients who still may benefit from ATRA/ATO.

“The analysis of high-risk patients with white blood cell count as a continuous variable instead of a fixed variable (more or less than 10,000/mmc) may help to discriminate some high-risk patients who could benefit from ATRA/ATO,” he noted.

Overall, however, “ATRA/ATO is the gold standard for low and intermediate risk APL,” he said.

“Although promising, more data are needed to confirm the efficacy of ATRA/ATO in high-risk APL.”

Dr. Voso disclosed ties with companies including Celgene/Bristol Myers Squibb, Astellas, Jazz Pharmaceuticals, Abbvie, Novartis, and AstraZeneca. Dr. Isidori reported no disclosures.
 

Patients with acute promyelocytic leukemia (APL) – previously considered among the most rapidly fatal forms of acute myeloid leukemia (AML) – now show survival rates exceeding 90% at 10 years after treatment with a chemotherapy-free regimen of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), with a survival advantage over ATRA plus chemotherapy in low- and intermediate-risk patients.

“In a large cohort of patients with APL, the chemo-free combination of ATRA/ATO is confirmed as the best treatment option, prolonging overall and event-free survival and reducing the relapse rate compared with ATRA/chemotherapy,” said first author Maria Teresa Voso, MD, of Tor Vergata University, in Rome, in presenting the findings at the 2023 annual meeting of the European Hematology Association.

APL, though rare, makes up about 10% of new AML cases, and the advent of the chemo-free ATRA-ATO regimen in recent years has transformed the disease, significantly improving survival.

However, with ongoing questions regarding factors associated with treatment benefits based on issues including the level of risk, Dr. Voso and colleagues turned to data from the large European Union–funded HARMONY registry, a big data project that uniquely provides real-world as well as clinical trial findings from diverse APL patient populations.

They identified 937 patients in the registry with newly diagnosed APL between 2007 and 2020 who met the study’s data quality criteria, including 536 (57.2%) patients from two clinical trials, the UK AML-17 and GIMEMA APL0406 trials, and 401 (42.8%) patients from national registries in 6 countries, representing real-world data.

The median duration of follow-up was 5.66 years, with a range of 0-14 years.

The patients had an average age of about 50, which is consistent with the lower age of diagnosis typical of APL, compared with other forms of AML.

Among them, 380 (40.6%) were treated with the ATRA-ATO regimen while 509 (54.3%) received the chemotherapy combination of ATRA-Idarubicin (AIDA).

Overall, 37.8% were determined to be low risk, as assessed by the Sanz risk-score; 42.3% were intermediate risk, and 18.7% were considered high risk. The rate of complete remission among the patients was 87.5%, and 9% had relapsed.

The results showed the 10-year overall survival (OS) rate to be 92% among the chemo-free ATRA-ATO-treated patients versus 75% in the AIDA-treated patients (P = .001).

Likewise, those treated with the chemo-free regimen had a higher event-free survival and a lower cumulative incidence of relapse (CIR) versus chemotherapy over 10 years (P < .001 for both).

In further stratifying by risk, patients who were low risk also had greater improvements with the chemo-free regimen in overall survival (P = .004), event-free survival, and CIR versus AIDA treatment (P < .001).

Among high-risk patients, however, only event-free survival was significantly improved in the chemo-free treated patients (P = .046).

Older age stood out as a significant determinant of survival, with patients in the age 50-69 and 70 or over age groups having a significantly lower rate of overall survival and event-free survival, compared with those under 50 years of age (P < .001), with those risks observed regardless of treatment type.

Age was not a significant factor in terms of the incidence of relapse (P = .159).
 

Clinical trial versus real-world outcomes

Of note, improved outcomes were reported in clinical trials versus real-world data, with overall survival higher in clinical trials among patients receiving the ATRA/ATO chemo-free treatment (P = .025), as well as in those receiving the AIDA chemotherapy (P < .001).

Early death, an uncommon but key concern with APL, usually due to bleeding complications and defined as death occurring within 30 days from APL diagnosis, occurred among 56 patients, or 5.9%, overall, and was significantly higher in the age 50-69 and over 70 groups versus those under 50 (P < .001).

Early death was more common among those with a Sanz high-risk score (15.4%), compared with low or intermediate risk (3.9%; P < .001); however, the risk was no different between the chemo-free (3.4%) and chemotherapy (5.7%) groups, regardless of whether patients had a low or high risk.

The rates of early death were significantly higher in the real-world population (10.2%), compared with patients in clinical trials (2.8%; P < .001), which Dr. Voso noted may be expected, as early deaths in some cases can occur even before a diagnosis is made.

“These patients sometimes come to the ER and if a diagnosis is not made, they may die before even receiving treatment,” she said in a press briefing.

“Indeed, the median time to death among those who had early death in the study was only 10 days, and there were even some patients dying at day 0,” she explained.

“So, it’s very important that not only hematologists but emergency doctors recognize this disease and try to reduce the early death rate.”

Overall, the results all remained consistent after adjustment in a multivariate analysis, Dr. Voso said.

“The multivariate analysis confirmed that increasing age, high Sanz risk score, the real-life treatment scenario, and the chemotherapy-based approach are independently associated with decreased survival,” she said.

The findings underscore that “elderly age and high Sanz risk score significantly impact on the rate of early deaths, irrespective of treatment,” Dr. Voso said.
 

ATRA/ATO ‘gold standard’ for low/intermediate risk

Commenting on the study, Alessandro Isidori, MD, PhD, a hematologist at AORMN Hospital, in Pesaro, Italy, who moderated the session, noted that the study underscores the greater challenges with higher-risk patients.

“The study did not show a statistical benefit for high-risk patients receiving ATRA/ATO versus AIDA,” he told this news organization, noting that “currently, there are many countries where ATRA/ATO is not approved for use in high-risk APL.”

“In high-risk APL, the AIDA combination should still be preferred to ATRA/ATO,” he said.

Dr. Isidori recommended careful efforts to stratify higher-risk patients who still may benefit from ATRA/ATO.

“The analysis of high-risk patients with white blood cell count as a continuous variable instead of a fixed variable (more or less than 10,000/mmc) may help to discriminate some high-risk patients who could benefit from ATRA/ATO,” he noted.

Overall, however, “ATRA/ATO is the gold standard for low and intermediate risk APL,” he said.

“Although promising, more data are needed to confirm the efficacy of ATRA/ATO in high-risk APL.”

Dr. Voso disclosed ties with companies including Celgene/Bristol Myers Squibb, Astellas, Jazz Pharmaceuticals, Abbvie, Novartis, and AstraZeneca. Dr. Isidori reported no disclosures.