A Spanish-speaking patient navigator dramatically increased the percentage of Hispanics undergoing colorectal screening with colonoscopies in Providence, R.I.

Screening colonoscopies are a well-established approach to reducing colorectal cancer mortality by identifying and removing polyps. However, Hispanics in the United States lag behind the general population in completion rates for screening colonoscopies.

“Starting colorectal cancer colonoscopy screening at age 45 saves lives. But this life-saving procedure is underutilized by certain populations, not only because of limited access to care but because of cultural, language, and educational barriers that exist,” Abdul Saied Calvino, MD, MPH, program director of the Complex General Surgical Oncology Fellowship at Roger Williams Medical Center, Providence, R.I., told this news organization.

Tailored patient navigation is effective but has not been widely adopted. The new study is one of the first to look at the ‘real-life’ impact of these types of programs in the Hispanic population, Dr. Calvino and his colleagues reported in the journal Cancer.

Colorectal cancer is the second leading cause of cancer-related death in the United States overall and the third-most diagnosed cancer site, according to the American Cancer Society. Among Hispanics, colorectal cancer is the second leading cause of cancer mortality and the second-most diagnosed site of malignancy.

Dr. Calvino and his colleagues sought to learn if a culturally tailored patient navigation program could improve rates of screening colonoscopies among Hispanic residents in Providence.

The hospital hired a dedicated Spanish-speaking navigator/coordinator and enrolled 698 men and women into the program.

The navigator sent introductory letters in Spanish to study participants, made phone calls to educate patients about the importance of cancer screening, and called again to ensure that all potential barriers to colonoscopy were overcome, Dr. Calvino said. Colonoscopy completion, cancellations, and no-shows were recorded. Participants were followed for 28 months.

The program proved highly successful, according to the researchers. At the end of the study period, 85% of patients – exceeding the national goal of 80% set by the National Colorectal Cancer Roundtable – had completed testing, with no differences between men and women; the cancellation rate was 9% and only 6% of patients failed to show up for endoscopy.  

Among the group that underwent colonoscopy, 254 (43%) had polyps removed and eight (1.3%) required colectomy, the researchers reported. Five patients (0.8%) were diagnosed with malignancy.

Dr. Calvino attributed the 15% combined rate of no-shows and cancellations to the cost of the procedure (copayment, out-of-pocket expense, and loss of wages) and the inability to follow-up with those patients. He added that 90% of those who completed the procedure said that without the patient navigation program they would not have completed the screening colonoscopies.

Aimee Afable, PhD, MPH, an expert on health disparities and immigrant health at Downstate Health Science University, New York, called the new study small but “important.”

Dr. Afable said strong evidence supports the ability of patient navigation programs to improve the reach and impact of screening programs aimed at the underserved. However, hospitals typically do not adequately fund such initiatives. (Dr. Calvino said the program at Roger Williams started with a grant from the OLDCO Foundation and is now supported by his institution.)

“In 2022, post-COVID, it is common to see health care support staff leaving institutions, hospitals because they’re not being paid well, and they are overburdened,” Dr. Afable told this news organization. “Patient navigation is not, unfortunately, a routine part of health care in the U.S. despite its central role in ensuring continuity of care.”

Funding for the study was provided by a grant from the OLDCO Foundation. Coauthor John C. Hardaway, MD, PhD, reports being a cancer liaison physician for the American College of Surgeons. The other authors have disclosed no relevant financial relationships.

Help your patients understand colorectal cancer prevention and screening options by sharing AGA’s patient education from the GI Patient Center: www.gastro.org/CRC.

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

A Spanish-speaking patient navigator dramatically increased the percentage of Hispanics undergoing colorectal screening with colonoscopies in Providence, R.I.

Screening colonoscopies are a well-established approach to reducing colorectal cancer mortality by identifying and removing polyps. However, Hispanics in the United States lag behind the general population in completion rates for screening colonoscopies.

“Starting colorectal cancer colonoscopy screening at age 45 saves lives. But this life-saving procedure is underutilized by certain populations, not only because of limited access to care but because of cultural, language, and educational barriers that exist,” Abdul Saied Calvino, MD, MPH, program director of the Complex General Surgical Oncology Fellowship at Roger Williams Medical Center, Providence, R.I., told this news organization.

Tailored patient navigation is effective but has not been widely adopted. The new study is one of the first to look at the ‘real-life’ impact of these types of programs in the Hispanic population, Dr. Calvino and his colleagues reported in the journal Cancer.

Colorectal cancer is the second leading cause of cancer-related death in the United States overall and the third-most diagnosed cancer site, according to the American Cancer Society. Among Hispanics, colorectal cancer is the second leading cause of cancer mortality and the second-most diagnosed site of malignancy.

Dr. Calvino and his colleagues sought to learn if a culturally tailored patient navigation program could improve rates of screening colonoscopies among Hispanic residents in Providence.

The hospital hired a dedicated Spanish-speaking navigator/coordinator and enrolled 698 men and women into the program.

The navigator sent introductory letters in Spanish to study participants, made phone calls to educate patients about the importance of cancer screening, and called again to ensure that all potential barriers to colonoscopy were overcome, Dr. Calvino said. Colonoscopy completion, cancellations, and no-shows were recorded. Participants were followed for 28 months.

The program proved highly successful, according to the researchers. At the end of the study period, 85% of patients – exceeding the national goal of 80% set by the National Colorectal Cancer Roundtable – had completed testing, with no differences between men and women; the cancellation rate was 9% and only 6% of patients failed to show up for endoscopy.  

Among the group that underwent colonoscopy, 254 (43%) had polyps removed and eight (1.3%) required colectomy, the researchers reported. Five patients (0.8%) were diagnosed with malignancy.

Dr. Calvino attributed the 15% combined rate of no-shows and cancellations to the cost of the procedure (copayment, out-of-pocket expense, and loss of wages) and the inability to follow-up with those patients. He added that 90% of those who completed the procedure said that without the patient navigation program they would not have completed the screening colonoscopies.

Aimee Afable, PhD, MPH, an expert on health disparities and immigrant health at Downstate Health Science University, New York, called the new study small but “important.”

Dr. Afable said strong evidence supports the ability of patient navigation programs to improve the reach and impact of screening programs aimed at the underserved. However, hospitals typically do not adequately fund such initiatives. (Dr. Calvino said the program at Roger Williams started with a grant from the OLDCO Foundation and is now supported by his institution.)

“In 2022, post-COVID, it is common to see health care support staff leaving institutions, hospitals because they’re not being paid well, and they are overburdened,” Dr. Afable told this news organization. “Patient navigation is not, unfortunately, a routine part of health care in the U.S. despite its central role in ensuring continuity of care.”

Funding for the study was provided by a grant from the OLDCO Foundation. Coauthor John C. Hardaway, MD, PhD, reports being a cancer liaison physician for the American College of Surgeons. The other authors have disclosed no relevant financial relationships.

Help your patients understand colorectal cancer prevention and screening options by sharing AGA’s patient education from the GI Patient Center: www.gastro.org/CRC.

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

A Spanish-speaking patient navigator dramatically increased the percentage of Hispanics undergoing colorectal screening with colonoscopies in Providence, R.I.

Screening colonoscopies are a well-established approach to reducing colorectal cancer mortality by identifying and removing polyps. However, Hispanics in the United States lag behind the general population in completion rates for screening colonoscopies.

“Starting colorectal cancer colonoscopy screening at age 45 saves lives. But this life-saving procedure is underutilized by certain populations, not only because of limited access to care but because of cultural, language, and educational barriers that exist,” Abdul Saied Calvino, MD, MPH, program director of the Complex General Surgical Oncology Fellowship at Roger Williams Medical Center, Providence, R.I., told this news organization.

Tailored patient navigation is effective but has not been widely adopted. The new study is one of the first to look at the ‘real-life’ impact of these types of programs in the Hispanic population, Dr. Calvino and his colleagues reported in the journal Cancer.

Colorectal cancer is the second leading cause of cancer-related death in the United States overall and the third-most diagnosed cancer site, according to the American Cancer Society. Among Hispanics, colorectal cancer is the second leading cause of cancer mortality and the second-most diagnosed site of malignancy.

Dr. Calvino and his colleagues sought to learn if a culturally tailored patient navigation program could improve rates of screening colonoscopies among Hispanic residents in Providence.

The hospital hired a dedicated Spanish-speaking navigator/coordinator and enrolled 698 men and women into the program.

The navigator sent introductory letters in Spanish to study participants, made phone calls to educate patients about the importance of cancer screening, and called again to ensure that all potential barriers to colonoscopy were overcome, Dr. Calvino said. Colonoscopy completion, cancellations, and no-shows were recorded. Participants were followed for 28 months.

The program proved highly successful, according to the researchers. At the end of the study period, 85% of patients – exceeding the national goal of 80% set by the National Colorectal Cancer Roundtable – had completed testing, with no differences between men and women; the cancellation rate was 9% and only 6% of patients failed to show up for endoscopy.  

Among the group that underwent colonoscopy, 254 (43%) had polyps removed and eight (1.3%) required colectomy, the researchers reported. Five patients (0.8%) were diagnosed with malignancy.

Dr. Calvino attributed the 15% combined rate of no-shows and cancellations to the cost of the procedure (copayment, out-of-pocket expense, and loss of wages) and the inability to follow-up with those patients. He added that 90% of those who completed the procedure said that without the patient navigation program they would not have completed the screening colonoscopies.

Aimee Afable, PhD, MPH, an expert on health disparities and immigrant health at Downstate Health Science University, New York, called the new study small but “important.”

Dr. Afable said strong evidence supports the ability of patient navigation programs to improve the reach and impact of screening programs aimed at the underserved. However, hospitals typically do not adequately fund such initiatives. (Dr. Calvino said the program at Roger Williams started with a grant from the OLDCO Foundation and is now supported by his institution.)

“In 2022, post-COVID, it is common to see health care support staff leaving institutions, hospitals because they’re not being paid well, and they are overburdened,” Dr. Afable told this news organization. “Patient navigation is not, unfortunately, a routine part of health care in the U.S. despite its central role in ensuring continuity of care.”

Funding for the study was provided by a grant from the OLDCO Foundation. Coauthor John C. Hardaway, MD, PhD, reports being a cancer liaison physician for the American College of Surgeons. The other authors have disclosed no relevant financial relationships.

Help your patients understand colorectal cancer prevention and screening options by sharing AGA’s patient education from the GI Patient Center: www.gastro.org/CRC.

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

Researchers have found a simple, low-cost way to get more adults to complete a fecal immunochemical test (FIT) to screen for colorectal cancer (CRC).

In a randomized controlled trial, patients who received an electronic “primer” message through their patient portal before the test kit arrived in their mailbox were more apt to complete and return the test than peers who didn’t get the electronic message.

ChrisChrisW/iStock/Getty Images

Heads-up message boosts compliance

CRC screening rates in the United States remain well below the national benchmark of 80%, and COVID-19 hasn’t helped. As a result, multiple medical and professional societies have emphasized the use of a mailed FIT outreach program.

As part of the outreach program, researchers at UCLA Health developed an electronic primer message within the electronic patient portal to alert patients due for CRC screening that they would be receiving a FIT kit in the mail.

They tested the impact of the primer messages in a randomized controlled trial involving 2,339 adults (mean age, 59 years, 57.5% women). Out of these, 1,157 received the standard mailed FIT kit (control group) and 1,182 received the standard mailed FIT kit plus a primer message sent through their personal patient portal.

Adding the primer message significantly increased the FIT completion rate at 6 months by 5.5%, with rates of 37.6% in the intervention group versus 32.1% in the control group.

After adjusting for patient demographics, the primer (versus no primer) led to significantly increased odds of completing CRC screening (adjusted odds ratio: 1.29; 95% confidence interval, 1.08-1.53; P = .004).

The primer message also shortened the time to FIT screening by 3 days (35 days with the primer vs. 38 days without).

Dr. Goshgarian and Dr. Croymans believe the priming messages worked well in their patient population because at the beginning of the intervention they identified a potential lack of awareness of the incoming FIT kit mailer as a barrier to uptake.

“We believe patients were receiving the kits with minimal advanced warning and discarding it as a mistake or hesitant to complete it because they did not understand the value to them,” they told this news organization.

“Therefore, a priming message helped to bridge that gap and allowed patients to be aware of the incoming FIT kits, know why it was important to do the FIT kit, and ultimately led to increasing our FIT kit return rates and thus CRC screening,” they said.

The researchers caution that their findings may be more relevant to patient populations who are more engaged in their health or who are more technologically savvy. In the UCLA Health system, roughly 84% of patients have an activated patient portal.
 

‘Good enhancement’ for health care systems

Reached for comment, Aasma Shaukat, MD, MPH, professor of medicine, NYU Langone Health, and first author of the American College of Gastroenterology (ACG) 2021 CRC screening guidelines, said the results are “interesting but not entirely surprising.”

“There’s literature supporting that a letter or notification prior to the FIT being mailed improves its uptake. Here, the authors applied it to their health care system in a quality improvement study and demonstrated it works,” Dr. Shaukat said.

“This is a good enhancement for health care systems where most of their patients are using or accessing their health chart portal,” added Dr. Shaukat.

“Caveats are that the generalizability is not known. It requires EHR [electronic health record] support tools and patients with access to a computer and enrolled and able to access their electronic chart, likely those with high literacy and English speaking.”

Funding for the study was provided by the UCLA Health Department of Medicine. Dr. Goshgarian, Dr. Croymans, and Dr. Shaukat have disclosed no relevant financial relationships.

Help your patients understand colorectal cancer prevention and screening options by sharing AGA’s patient education from the GI Patient Center: www.gastro.org/CRC.

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

Researchers have found a simple, low-cost way to get more adults to complete a fecal immunochemical test (FIT) to screen for colorectal cancer (CRC).

In a randomized controlled trial, patients who received an electronic “primer” message through their patient portal before the test kit arrived in their mailbox were more apt to complete and return the test than peers who didn’t get the electronic message.

ChrisChrisW/iStock/Getty Images

Heads-up message boosts compliance

CRC screening rates in the United States remain well below the national benchmark of 80%, and COVID-19 hasn’t helped. As a result, multiple medical and professional societies have emphasized the use of a mailed FIT outreach program.

As part of the outreach program, researchers at UCLA Health developed an electronic primer message within the electronic patient portal to alert patients due for CRC screening that they would be receiving a FIT kit in the mail.

They tested the impact of the primer messages in a randomized controlled trial involving 2,339 adults (mean age, 59 years, 57.5% women). Out of these, 1,157 received the standard mailed FIT kit (control group) and 1,182 received the standard mailed FIT kit plus a primer message sent through their personal patient portal.

Adding the primer message significantly increased the FIT completion rate at 6 months by 5.5%, with rates of 37.6% in the intervention group versus 32.1% in the control group.

After adjusting for patient demographics, the primer (versus no primer) led to significantly increased odds of completing CRC screening (adjusted odds ratio: 1.29; 95% confidence interval, 1.08-1.53; P = .004).

The primer message also shortened the time to FIT screening by 3 days (35 days with the primer vs. 38 days without).

Dr. Goshgarian and Dr. Croymans believe the priming messages worked well in their patient population because at the beginning of the intervention they identified a potential lack of awareness of the incoming FIT kit mailer as a barrier to uptake.

“We believe patients were receiving the kits with minimal advanced warning and discarding it as a mistake or hesitant to complete it because they did not understand the value to them,” they told this news organization.

“Therefore, a priming message helped to bridge that gap and allowed patients to be aware of the incoming FIT kits, know why it was important to do the FIT kit, and ultimately led to increasing our FIT kit return rates and thus CRC screening,” they said.

The researchers caution that their findings may be more relevant to patient populations who are more engaged in their health or who are more technologically savvy. In the UCLA Health system, roughly 84% of patients have an activated patient portal.
 

‘Good enhancement’ for health care systems

Reached for comment, Aasma Shaukat, MD, MPH, professor of medicine, NYU Langone Health, and first author of the American College of Gastroenterology (ACG) 2021 CRC screening guidelines, said the results are “interesting but not entirely surprising.”

“There’s literature supporting that a letter or notification prior to the FIT being mailed improves its uptake. Here, the authors applied it to their health care system in a quality improvement study and demonstrated it works,” Dr. Shaukat said.

“This is a good enhancement for health care systems where most of their patients are using or accessing their health chart portal,” added Dr. Shaukat.

“Caveats are that the generalizability is not known. It requires EHR [electronic health record] support tools and patients with access to a computer and enrolled and able to access their electronic chart, likely those with high literacy and English speaking.”

Funding for the study was provided by the UCLA Health Department of Medicine. Dr. Goshgarian, Dr. Croymans, and Dr. Shaukat have disclosed no relevant financial relationships.

Help your patients understand colorectal cancer prevention and screening options by sharing AGA’s patient education from the GI Patient Center: www.gastro.org/CRC.

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

Researchers have found a simple, low-cost way to get more adults to complete a fecal immunochemical test (FIT) to screen for colorectal cancer (CRC).

In a randomized controlled trial, patients who received an electronic “primer” message through their patient portal before the test kit arrived in their mailbox were more apt to complete and return the test than peers who didn’t get the electronic message.

ChrisChrisW/iStock/Getty Images

Heads-up message boosts compliance

CRC screening rates in the United States remain well below the national benchmark of 80%, and COVID-19 hasn’t helped. As a result, multiple medical and professional societies have emphasized the use of a mailed FIT outreach program.

As part of the outreach program, researchers at UCLA Health developed an electronic primer message within the electronic patient portal to alert patients due for CRC screening that they would be receiving a FIT kit in the mail.

They tested the impact of the primer messages in a randomized controlled trial involving 2,339 adults (mean age, 59 years, 57.5% women). Out of these, 1,157 received the standard mailed FIT kit (control group) and 1,182 received the standard mailed FIT kit plus a primer message sent through their personal patient portal.

Adding the primer message significantly increased the FIT completion rate at 6 months by 5.5%, with rates of 37.6% in the intervention group versus 32.1% in the control group.

After adjusting for patient demographics, the primer (versus no primer) led to significantly increased odds of completing CRC screening (adjusted odds ratio: 1.29; 95% confidence interval, 1.08-1.53; P = .004).

The primer message also shortened the time to FIT screening by 3 days (35 days with the primer vs. 38 days without).

Dr. Goshgarian and Dr. Croymans believe the priming messages worked well in their patient population because at the beginning of the intervention they identified a potential lack of awareness of the incoming FIT kit mailer as a barrier to uptake.

“We believe patients were receiving the kits with minimal advanced warning and discarding it as a mistake or hesitant to complete it because they did not understand the value to them,” they told this news organization.

“Therefore, a priming message helped to bridge that gap and allowed patients to be aware of the incoming FIT kits, know why it was important to do the FIT kit, and ultimately led to increasing our FIT kit return rates and thus CRC screening,” they said.

The researchers caution that their findings may be more relevant to patient populations who are more engaged in their health or who are more technologically savvy. In the UCLA Health system, roughly 84% of patients have an activated patient portal.
 

‘Good enhancement’ for health care systems

Reached for comment, Aasma Shaukat, MD, MPH, professor of medicine, NYU Langone Health, and first author of the American College of Gastroenterology (ACG) 2021 CRC screening guidelines, said the results are “interesting but not entirely surprising.”

“There’s literature supporting that a letter or notification prior to the FIT being mailed improves its uptake. Here, the authors applied it to their health care system in a quality improvement study and demonstrated it works,” Dr. Shaukat said.

“This is a good enhancement for health care systems where most of their patients are using or accessing their health chart portal,” added Dr. Shaukat.

“Caveats are that the generalizability is not known. It requires EHR [electronic health record] support tools and patients with access to a computer and enrolled and able to access their electronic chart, likely those with high literacy and English speaking.”

Funding for the study was provided by the UCLA Health Department of Medicine. Dr. Goshgarian, Dr. Croymans, and Dr. Shaukat have disclosed no relevant financial relationships.

Help your patients understand colorectal cancer prevention and screening options by sharing AGA’s patient education from the GI Patient Center: www.gastro.org/CRC.

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

Samples from patients in the United States and Kenya show an increasing emergence of previously undetected vancomycin-resistant strains of Clostridioides difficile, sparking concern as recurrences in the treatment of C. difficile infection (CDI) continue to rise.

“Our results may help explain a decreasing effectiveness of antibiotic-based therapy in C. difficile infection, since a significant proportion of patients harboring strains with reduced susceptibility to vancomycin may not respond to treatment,” reported the authors in research published recently in Clinical Infectious Diseases.

The spread of the resistant strains “has serious public health implications, underscoring an urgent need for a comprehensive analysis of the circulating strains to help inform clinical decisions,” they added.

Commenting on the findings, Cornelius J. Clancy, MD, professor of medicine at the University of Pittsburgh, and chief of infectious diseases at the Veterans Affairs Pittsburgh Healthcare System, echoed the concern.

“The casual belief has been that [C. difficile] strains at most centers can be assumed to be vancomycin susceptible,” he told this news organization. “This study shows that this assumption can no longer be taken as a given.”

Dr. Clancy, who was not involved with this research, noted that “based on this study, there might be need for the Infectious Diseases Society of America and other organizations to offer guidance on generating good, quality surveillance data for C. difficile resistance.”

With C. difficile showing the ability to resist multiple antibiotics, drugs in the armamentarium to treat the infection have declined in recent years, and recurrences with the infection are reported in up to 25% of cases.

Oral vancomycin is recommended as the antibiotic of choice by the IDSA and the Society for Healthcare Epidemiology of America for severe as well as nonsevere cases of CDI, and although there are reports of nine vancomycin-resistant gene clusters, most involve Enterococcus.

To take a closer look at the prevalence of vancomycin-resistant C. difficile strains, first author Charles Darkoh, PhD, with the Center for Infectious Diseases at the University of Texas Health Science Center, Houston, and colleagues analyzed stool samples from patients with CDI, including 438 patients in Houston, taken between 2012 and 2017, and 98 in Nairobi, Kenya, taken in 2017.

They found that, among samples from patients in Houston, over the time period, 26% showed vancomycin nonsusceptible C. difficile isolates and 29% had isolates that were metronidazole resistant.

And among samples from the Nairobi patients, 67% harbored vancomycin-resistant isolates and 85% had isolates resistant to metronidazole.

Of note, the proportion of samples containing vancomycin-resistant C. difficile in the Houston patients showed a marked increase over time, from «complete absence» in 2012 to approximately 35% in 2017, the authors reported.

“These nonsusceptibility rates significantly exceeded prior reports from other studies conducted in the United States and Europe from 2011 to 2014, suggesting a lower percentage of resistance to both metronidazole and vancomycin,” the authors wrote.

Further experiments on mouse models infected with one of the vancomycin-resistant isolates showed that treatment with vancomycin failed to eradicate the infection, and 5-day survival was significantly lower after vancomycin treatment in those mice (25%) versus those infected with strains known to be vancomycin sensitive (50%).
 

Unrecognized genetic strains

Whole-genome sequencing of 10 of the resistant isolates showed no matches with gene clusters that have been previously recognized as being vancomycin resistant, suggesting the emergence of new clusters.

“Together, these results suggest unknown genetic elements associated with vancomycin nonsusceptibility in isolates circulating in the patient population,” the authors wrote.

Dr. Darkoh told this news organization that the research team is currently working to further investigate the patterns and mechanisms.

“We are currently working on a follow-up study for the next 5 years to find out how widespread this is,” he said. “We want to make sure it’s not necessarily just occurring in the settings we studied, and we also need to establish the mechanism of resistance.”

Further commenting on the results, Dr. Clancy noted that “the extent of resistance caught many in the field a bit off guard, as they are higher than previously reported.”

“The data are also concerning because most centers do not routinely test C. difficile for drug susceptibility.”

Dr. Clancy noted that “another immediately pressing need is to understand mechanisms of resistance. It was quite striking that vancomycin-resistant strains in this study did not carry vanA genes, pointing to previously unrecognized mechanisms of resistance.”

“As is often the case, antibiotic overuse was likely a factor in the resistances, with overtesting often leading to overtreatment of C. difficile,” Dr. Clancy said. “The situation may have been compounded by failure to appreciate how entrenched C. difficile resistance may be at certain hospitals, since widespread susceptibility testing is generally not routinely performed.”

As alternative treatments, Dr. Clancy pointed to the recent IDSA update, which included a stronger endorsement of fidaxomicin.

“Of course, there is also the need to assure that data on resistance to agents like fidaxomicin are generated going forward,” he noted.

The study was supported by was supported by National Institutes of Health, the National Institute of Allergy and Infectious Diseases, the Texas Medical Center Digestive Diseases Center, and the University of Texas Health Science Center. Dr. Darkoh has disclosed no relevant financial relationships. One coauthor received grant support from Merck, Entasis Pharmaceuticals, and MeMed Diagnostics. Dr. Clancy disclosed advisory board, consulting and/or research relationships with Merck, Qpex Biopharma, Shionogi, Astellas, Cidara, Scynexis, and Needham & Associates.

Help your patients understand their C. difficile diagnosis by sharing patient education from the AGA GI Patient Center: www.gastro.org/Cdiff. 

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

Samples from patients in the United States and Kenya show an increasing emergence of previously undetected vancomycin-resistant strains of Clostridioides difficile, sparking concern as recurrences in the treatment of C. difficile infection (CDI) continue to rise.

“Our results may help explain a decreasing effectiveness of antibiotic-based therapy in C. difficile infection, since a significant proportion of patients harboring strains with reduced susceptibility to vancomycin may not respond to treatment,” reported the authors in research published recently in Clinical Infectious Diseases.

The spread of the resistant strains “has serious public health implications, underscoring an urgent need for a comprehensive analysis of the circulating strains to help inform clinical decisions,” they added.

Commenting on the findings, Cornelius J. Clancy, MD, professor of medicine at the University of Pittsburgh, and chief of infectious diseases at the Veterans Affairs Pittsburgh Healthcare System, echoed the concern.

“The casual belief has been that [C. difficile] strains at most centers can be assumed to be vancomycin susceptible,” he told this news organization. “This study shows that this assumption can no longer be taken as a given.”

Dr. Clancy, who was not involved with this research, noted that “based on this study, there might be need for the Infectious Diseases Society of America and other organizations to offer guidance on generating good, quality surveillance data for C. difficile resistance.”

With C. difficile showing the ability to resist multiple antibiotics, drugs in the armamentarium to treat the infection have declined in recent years, and recurrences with the infection are reported in up to 25% of cases.

Oral vancomycin is recommended as the antibiotic of choice by the IDSA and the Society for Healthcare Epidemiology of America for severe as well as nonsevere cases of CDI, and although there are reports of nine vancomycin-resistant gene clusters, most involve Enterococcus.

To take a closer look at the prevalence of vancomycin-resistant C. difficile strains, first author Charles Darkoh, PhD, with the Center for Infectious Diseases at the University of Texas Health Science Center, Houston, and colleagues analyzed stool samples from patients with CDI, including 438 patients in Houston, taken between 2012 and 2017, and 98 in Nairobi, Kenya, taken in 2017.

They found that, among samples from patients in Houston, over the time period, 26% showed vancomycin nonsusceptible C. difficile isolates and 29% had isolates that were metronidazole resistant.

And among samples from the Nairobi patients, 67% harbored vancomycin-resistant isolates and 85% had isolates resistant to metronidazole.

Of note, the proportion of samples containing vancomycin-resistant C. difficile in the Houston patients showed a marked increase over time, from «complete absence» in 2012 to approximately 35% in 2017, the authors reported.

“These nonsusceptibility rates significantly exceeded prior reports from other studies conducted in the United States and Europe from 2011 to 2014, suggesting a lower percentage of resistance to both metronidazole and vancomycin,” the authors wrote.

Further experiments on mouse models infected with one of the vancomycin-resistant isolates showed that treatment with vancomycin failed to eradicate the infection, and 5-day survival was significantly lower after vancomycin treatment in those mice (25%) versus those infected with strains known to be vancomycin sensitive (50%).
 

Unrecognized genetic strains

Whole-genome sequencing of 10 of the resistant isolates showed no matches with gene clusters that have been previously recognized as being vancomycin resistant, suggesting the emergence of new clusters.

“Together, these results suggest unknown genetic elements associated with vancomycin nonsusceptibility in isolates circulating in the patient population,” the authors wrote.

Dr. Darkoh told this news organization that the research team is currently working to further investigate the patterns and mechanisms.

“We are currently working on a follow-up study for the next 5 years to find out how widespread this is,” he said. “We want to make sure it’s not necessarily just occurring in the settings we studied, and we also need to establish the mechanism of resistance.”

Further commenting on the results, Dr. Clancy noted that “the extent of resistance caught many in the field a bit off guard, as they are higher than previously reported.”

“The data are also concerning because most centers do not routinely test C. difficile for drug susceptibility.”

Dr. Clancy noted that “another immediately pressing need is to understand mechanisms of resistance. It was quite striking that vancomycin-resistant strains in this study did not carry vanA genes, pointing to previously unrecognized mechanisms of resistance.”

“As is often the case, antibiotic overuse was likely a factor in the resistances, with overtesting often leading to overtreatment of C. difficile,” Dr. Clancy said. “The situation may have been compounded by failure to appreciate how entrenched C. difficile resistance may be at certain hospitals, since widespread susceptibility testing is generally not routinely performed.”

As alternative treatments, Dr. Clancy pointed to the recent IDSA update, which included a stronger endorsement of fidaxomicin.

“Of course, there is also the need to assure that data on resistance to agents like fidaxomicin are generated going forward,” he noted.

The study was supported by was supported by National Institutes of Health, the National Institute of Allergy and Infectious Diseases, the Texas Medical Center Digestive Diseases Center, and the University of Texas Health Science Center. Dr. Darkoh has disclosed no relevant financial relationships. One coauthor received grant support from Merck, Entasis Pharmaceuticals, and MeMed Diagnostics. Dr. Clancy disclosed advisory board, consulting and/or research relationships with Merck, Qpex Biopharma, Shionogi, Astellas, Cidara, Scynexis, and Needham & Associates.

Help your patients understand their C. difficile diagnosis by sharing patient education from the AGA GI Patient Center: www.gastro.org/Cdiff. 

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

Samples from patients in the United States and Kenya show an increasing emergence of previously undetected vancomycin-resistant strains of Clostridioides difficile, sparking concern as recurrences in the treatment of C. difficile infection (CDI) continue to rise.

“Our results may help explain a decreasing effectiveness of antibiotic-based therapy in C. difficile infection, since a significant proportion of patients harboring strains with reduced susceptibility to vancomycin may not respond to treatment,” reported the authors in research published recently in Clinical Infectious Diseases.

The spread of the resistant strains “has serious public health implications, underscoring an urgent need for a comprehensive analysis of the circulating strains to help inform clinical decisions,” they added.

Commenting on the findings, Cornelius J. Clancy, MD, professor of medicine at the University of Pittsburgh, and chief of infectious diseases at the Veterans Affairs Pittsburgh Healthcare System, echoed the concern.

“The casual belief has been that [C. difficile] strains at most centers can be assumed to be vancomycin susceptible,” he told this news organization. “This study shows that this assumption can no longer be taken as a given.”

Dr. Clancy, who was not involved with this research, noted that “based on this study, there might be need for the Infectious Diseases Society of America and other organizations to offer guidance on generating good, quality surveillance data for C. difficile resistance.”

With C. difficile showing the ability to resist multiple antibiotics, drugs in the armamentarium to treat the infection have declined in recent years, and recurrences with the infection are reported in up to 25% of cases.

Oral vancomycin is recommended as the antibiotic of choice by the IDSA and the Society for Healthcare Epidemiology of America for severe as well as nonsevere cases of CDI, and although there are reports of nine vancomycin-resistant gene clusters, most involve Enterococcus.

To take a closer look at the prevalence of vancomycin-resistant C. difficile strains, first author Charles Darkoh, PhD, with the Center for Infectious Diseases at the University of Texas Health Science Center, Houston, and colleagues analyzed stool samples from patients with CDI, including 438 patients in Houston, taken between 2012 and 2017, and 98 in Nairobi, Kenya, taken in 2017.

They found that, among samples from patients in Houston, over the time period, 26% showed vancomycin nonsusceptible C. difficile isolates and 29% had isolates that were metronidazole resistant.

And among samples from the Nairobi patients, 67% harbored vancomycin-resistant isolates and 85% had isolates resistant to metronidazole.

Of note, the proportion of samples containing vancomycin-resistant C. difficile in the Houston patients showed a marked increase over time, from «complete absence» in 2012 to approximately 35% in 2017, the authors reported.

“These nonsusceptibility rates significantly exceeded prior reports from other studies conducted in the United States and Europe from 2011 to 2014, suggesting a lower percentage of resistance to both metronidazole and vancomycin,” the authors wrote.

Further experiments on mouse models infected with one of the vancomycin-resistant isolates showed that treatment with vancomycin failed to eradicate the infection, and 5-day survival was significantly lower after vancomycin treatment in those mice (25%) versus those infected with strains known to be vancomycin sensitive (50%).
 

Unrecognized genetic strains

Whole-genome sequencing of 10 of the resistant isolates showed no matches with gene clusters that have been previously recognized as being vancomycin resistant, suggesting the emergence of new clusters.

“Together, these results suggest unknown genetic elements associated with vancomycin nonsusceptibility in isolates circulating in the patient population,” the authors wrote.

Dr. Darkoh told this news organization that the research team is currently working to further investigate the patterns and mechanisms.

“We are currently working on a follow-up study for the next 5 years to find out how widespread this is,” he said. “We want to make sure it’s not necessarily just occurring in the settings we studied, and we also need to establish the mechanism of resistance.”

Further commenting on the results, Dr. Clancy noted that “the extent of resistance caught many in the field a bit off guard, as they are higher than previously reported.”

“The data are also concerning because most centers do not routinely test C. difficile for drug susceptibility.”

Dr. Clancy noted that “another immediately pressing need is to understand mechanisms of resistance. It was quite striking that vancomycin-resistant strains in this study did not carry vanA genes, pointing to previously unrecognized mechanisms of resistance.”

“As is often the case, antibiotic overuse was likely a factor in the resistances, with overtesting often leading to overtreatment of C. difficile,” Dr. Clancy said. “The situation may have been compounded by failure to appreciate how entrenched C. difficile resistance may be at certain hospitals, since widespread susceptibility testing is generally not routinely performed.”

As alternative treatments, Dr. Clancy pointed to the recent IDSA update, which included a stronger endorsement of fidaxomicin.

“Of course, there is also the need to assure that data on resistance to agents like fidaxomicin are generated going forward,” he noted.

The study was supported by was supported by National Institutes of Health, the National Institute of Allergy and Infectious Diseases, the Texas Medical Center Digestive Diseases Center, and the University of Texas Health Science Center. Dr. Darkoh has disclosed no relevant financial relationships. One coauthor received grant support from Merck, Entasis Pharmaceuticals, and MeMed Diagnostics. Dr. Clancy disclosed advisory board, consulting and/or research relationships with Merck, Qpex Biopharma, Shionogi, Astellas, Cidara, Scynexis, and Needham & Associates.

Help your patients understand their C. difficile diagnosis by sharing patient education from the AGA GI Patient Center: www.gastro.org/Cdiff. 

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

Just a few changes to your diet could add years to your life, but the sooner you start the better.

Maintaining a healthy diet is important, but most people find this difficult to do daily. In a new study, researchers examined the effects of individual healthful and nonhealthful types of foods and estimated the impact by age and sex of swapping some for others.

“Sustained change from a typical to an optimized diet from early age could translate into an increase in life expectancy of more than 10 years,” say the Norwegian scientists who conducted the study, published in PLOS Medicine on Feb. 8.

Lisovskaya/iStock/Getty Images

They developed an online tool that anyone can use to get an idea of how individual food choices can affect life expectancy.

The biggest overall impact comes from eating more plant-based foods (legumes), whole grains and nuts, and less red and processed meat. Fruits and vegetables also have a positive health impact, but on average people who eat a typical Western diet are already consuming those in relatively high amounts. Fish is included on the healthful list, whereas sugar-sweetened beverages (sodas) and foods based on refined [white] grains, such as white bread, are among those to be avoided.

The study found that although it’s never too late to start, young adults can expect to see more years gained by adopting healthful eating than would older adults.

“Our results indicate that for individuals with a typical Western diet, sustained dietary changes at any age may give substantial health benefits, although the gains are the largest if changes start early in life,” said the researchers.

Depending on how many healthy dietary “switches” are made and maintained and the amounts consumed, a 20-year-old man in the United States could extend his life up to 13 years, and a 20-year old woman by 11 years.

That number drops with age but changing from a typical diet to the optimized diet at age 60 years could still increase life expectancy by 8 years for women and 9 years for men, and even an 80-year-old female could gain more than 3 years with healthier food choices.

Until now, research in this area has shown health benefits associated with separate food groups or specific diet patterns, while focusing less on the health impact of other dietary changes. The statistical ‘modeling’ approach used in this study bridges that gap, the researchers said.

“Understanding the relative health potential of different food groups could enable people to make feasible and significant health gains,” they concluded.

A version of this article was first published on WebMD.com.

Just a few changes to your diet could add years to your life, but the sooner you start the better.

Maintaining a healthy diet is important, but most people find this difficult to do daily. In a new study, researchers examined the effects of individual healthful and nonhealthful types of foods and estimated the impact by age and sex of swapping some for others.

“Sustained change from a typical to an optimized diet from early age could translate into an increase in life expectancy of more than 10 years,” say the Norwegian scientists who conducted the study, published in PLOS Medicine on Feb. 8.

Lisovskaya/iStock/Getty Images

They developed an online tool that anyone can use to get an idea of how individual food choices can affect life expectancy.

The biggest overall impact comes from eating more plant-based foods (legumes), whole grains and nuts, and less red and processed meat. Fruits and vegetables also have a positive health impact, but on average people who eat a typical Western diet are already consuming those in relatively high amounts. Fish is included on the healthful list, whereas sugar-sweetened beverages (sodas) and foods based on refined [white] grains, such as white bread, are among those to be avoided.

The study found that although it’s never too late to start, young adults can expect to see more years gained by adopting healthful eating than would older adults.

“Our results indicate that for individuals with a typical Western diet, sustained dietary changes at any age may give substantial health benefits, although the gains are the largest if changes start early in life,” said the researchers.

Depending on how many healthy dietary “switches” are made and maintained and the amounts consumed, a 20-year-old man in the United States could extend his life up to 13 years, and a 20-year old woman by 11 years.

That number drops with age but changing from a typical diet to the optimized diet at age 60 years could still increase life expectancy by 8 years for women and 9 years for men, and even an 80-year-old female could gain more than 3 years with healthier food choices.

Until now, research in this area has shown health benefits associated with separate food groups or specific diet patterns, while focusing less on the health impact of other dietary changes. The statistical ‘modeling’ approach used in this study bridges that gap, the researchers said.

“Understanding the relative health potential of different food groups could enable people to make feasible and significant health gains,” they concluded.

A version of this article was first published on WebMD.com.

Just a few changes to your diet could add years to your life, but the sooner you start the better.

Maintaining a healthy diet is important, but most people find this difficult to do daily. In a new study, researchers examined the effects of individual healthful and nonhealthful types of foods and estimated the impact by age and sex of swapping some for others.

“Sustained change from a typical to an optimized diet from early age could translate into an increase in life expectancy of more than 10 years,” say the Norwegian scientists who conducted the study, published in PLOS Medicine on Feb. 8.

Lisovskaya/iStock/Getty Images

They developed an online tool that anyone can use to get an idea of how individual food choices can affect life expectancy.

The biggest overall impact comes from eating more plant-based foods (legumes), whole grains and nuts, and less red and processed meat. Fruits and vegetables also have a positive health impact, but on average people who eat a typical Western diet are already consuming those in relatively high amounts. Fish is included on the healthful list, whereas sugar-sweetened beverages (sodas) and foods based on refined [white] grains, such as white bread, are among those to be avoided.

The study found that although it’s never too late to start, young adults can expect to see more years gained by adopting healthful eating than would older adults.

“Our results indicate that for individuals with a typical Western diet, sustained dietary changes at any age may give substantial health benefits, although the gains are the largest if changes start early in life,” said the researchers.

Depending on how many healthy dietary “switches” are made and maintained and the amounts consumed, a 20-year-old man in the United States could extend his life up to 13 years, and a 20-year old woman by 11 years.

That number drops with age but changing from a typical diet to the optimized diet at age 60 years could still increase life expectancy by 8 years for women and 9 years for men, and even an 80-year-old female could gain more than 3 years with healthier food choices.

Until now, research in this area has shown health benefits associated with separate food groups or specific diet patterns, while focusing less on the health impact of other dietary changes. The statistical ‘modeling’ approach used in this study bridges that gap, the researchers said.

“Understanding the relative health potential of different food groups could enable people to make feasible and significant health gains,” they concluded.

A version of this article was first published on WebMD.com.

When children with atopic dermatitis (AD) present to the clinic and their parents complain that no previously recommended medical therapies have worked, what’s the next step?

“Many patients who have failed topical steroids have never had adequate treatment,” Anna Yasmine Kirkorian, MD, chief of dermatology at National Children’s Hospital in Washington, said during the ODAC Dermatology, Aesthetic & Surgical Conference. “There is no lower age limit on the use of topical corticosteroids, and low potency corticosteroids are inadequate to treat severe eczema. The idea that only over-the-counter 2.5% hydrocortisone cream is necessary is not true,” she added.

“You also want to scrutinize the vehicle,” she said, noting that children are often prescribed cream formulations that hurt when applied, so parents stop applying them. “Ointments are generally the vehicles of choice in childhood,” she added.

It is generally not advised to use topical and oral antibiotics in children with AD, unless there are clear signs of infection. “If they’re just slightly oozy, don’t use them,” she continued. “Of course, every child or adult with eczema has Staph aureus on them, but most of the time, what you need to do is repair the barrier. We know that from data and common sense. When we repair their barrier, their rates of infection decrease.”

A focal area with pustules and pus should be cultured and treated, Dr. Kirkorian said. “Monotherapy with antibiotics is going to do nothing for you.” In cases of children with failure to thrive, she recommends referral to pediatric dermatology, allergy/immunology, GI, or genetics, as appropriate.

For children with severe AD, Dr. Kirkorian favors a rescue plan with a one-pound jar of triamcinolone ointment 0.1%. She recommends application of the ointment to all areas, including the face and scalp once nightly for 2 weeks, with a follow-up appointment at the end of that time. “If you just give people medicine and ask them to come back in 6 months, they are not able to comply with that and they don’t have faith that it’s going to work,” explained Dr. Kirkorian, associate professor of dermatology and pediatrics at George Washington University, Washington. At the end of 2 weeks, “the majority will have improved dramatically, and then you can implement maintenance therapy with topical calcineurin inhibitors, crisaborole, or possibly topical ruxolitinib.”

Some clinicians prescribe oral antihistamines for AD, but Dr. Kirkorian said that data supporting their use are limited and antihistamines are not approved for use in children younger than 6 months of age. Sedating antihistamines will induce sleep, “but do not provide durable night-long sleep,” and routine use may have an impact on learning and school performance. In addition, exposure to antihistamines in children under age 2 may be associated with development of ADHD at school age.

The interleukin-4 receptor alpha antagonist dupilumab (Dupixent) is approved by the Food and Drug Administration for moderate to severe AD in patients ages 6 and older. But obtaining it for patients can be tricky, she said, as this requires documented failure of corticosteroids, calcineurin inhibitors, crisaborole ointment, and phototherapy (if prescribed). Patients are often obligated to do step therapy with an off-label drug such as cyclosporine or methotrexate for 3 months, and they need to demonstrate responses with objective measures of severity such as the SCORAD (SCORing Atopic Dermatitis) and the validated Investigator Global Assessment.

“Most of my patients carry insurance that does not approve dupilumab without failure of a prior off-label systemic immunosuppressant medication,” Dr. Kirkorian said. Cyclosporine is her first choice for a systemic immunosuppressant “because it has a fast onset of action, it’s effective for treatment of atopic dermatitis, and safe for short-term use,” she said. “I don’t think that methotrexate works well for eczema. It can take weeks and weeks to work.”

She typically starts patients on a 5 mg/kg dose of cyclosporine. Baseline tests include CBC, CMP (comprehensive metabolic panel), lipids, and vitals. She repeats the labs at 1 month, and includes a blood pressure check. Potential adverse effects of cyclosporine include infections (including opportunistic infections), cytopenias, hypertension, nephrotoxicity, hepatotoxicity, neurotoxicity (including posterior reversible encephalopathy syndrome), electrolyte disturbance, lymphoma, and cutaneous malignancy.

“The good news is that we generally don’t see the adverse effects with short-term use,” Dr. Kirkorian said. “We will see some hypertrichosis and gingival hypertrophy, which resolves with cessation of therapy. There are serious side effects if you use it for long enough.”

As for methotrexate, “it is still a very important drug in pediatric dermatology, particularly in other conditions such as psoriasis,” she said. “The problem is that weekly dosing of methotrexate poses a greater risk of dosing errors. People aren’t really triggered to think of a once-weekly medication. If you do use it, give them a short supply to make sure that they come back, and that they don’t give it daily accidentally.”

Practical tips she offered for prescribing cyclosporine include supplying a patient handout with information on all adverse effects, dosing information, vaccination information, and pregnancy precautions, with contact information (a patient portal or on-call number) for the treating clinician in case a patient develops adverse effects. Administration of live vaccines while patients are on cyclosporine is not recommended.

When transitioning patients from cyclosporine or methotrexate to dupilumab, Dr. Kirkorian recommends tapering the immunosuppressant dose by half every 2 weeks to complete cessation by week 8 of treatment. For patients who experience a severe baseline flare once the immunosuppressant is tapered, despite the switch to dupilumab, she recommends restarting methotrexate at a full dose and then reducing the dose every 2 weeks until the lowest effective dose (2.5-5 mg weekly) is reached.

“Waning efficacy is real,” she said. “We can add methotrexate to recapture efficacy. Check for superimposed allergic contact dermatitis.”

With upadacitinib (Rinvoq), an oral Janus kinase (JAK) inhibitor recently approved for treating refractory, moderate to severe AD in patients 12 years of age and older, is the risk profile acceptable to parents and physicians? “I think the answer is yes,” Dr. Kirkorian said. “But we’re going to have to think through that very carefully. It’s going to be exciting to see how this drug changes management in our patients.”

Dr. Kirkorian disclosed that she is a member of the advisory board for Verrica Pharmaceuticals.

When children with atopic dermatitis (AD) present to the clinic and their parents complain that no previously recommended medical therapies have worked, what’s the next step?

“Many patients who have failed topical steroids have never had adequate treatment,” Anna Yasmine Kirkorian, MD, chief of dermatology at National Children’s Hospital in Washington, said during the ODAC Dermatology, Aesthetic & Surgical Conference. “There is no lower age limit on the use of topical corticosteroids, and low potency corticosteroids are inadequate to treat severe eczema. The idea that only over-the-counter 2.5% hydrocortisone cream is necessary is not true,” she added.

“You also want to scrutinize the vehicle,” she said, noting that children are often prescribed cream formulations that hurt when applied, so parents stop applying them. “Ointments are generally the vehicles of choice in childhood,” she added.

It is generally not advised to use topical and oral antibiotics in children with AD, unless there are clear signs of infection. “If they’re just slightly oozy, don’t use them,” she continued. “Of course, every child or adult with eczema has Staph aureus on them, but most of the time, what you need to do is repair the barrier. We know that from data and common sense. When we repair their barrier, their rates of infection decrease.”

A focal area with pustules and pus should be cultured and treated, Dr. Kirkorian said. “Monotherapy with antibiotics is going to do nothing for you.” In cases of children with failure to thrive, she recommends referral to pediatric dermatology, allergy/immunology, GI, or genetics, as appropriate.

For children with severe AD, Dr. Kirkorian favors a rescue plan with a one-pound jar of triamcinolone ointment 0.1%. She recommends application of the ointment to all areas, including the face and scalp once nightly for 2 weeks, with a follow-up appointment at the end of that time. “If you just give people medicine and ask them to come back in 6 months, they are not able to comply with that and they don’t have faith that it’s going to work,” explained Dr. Kirkorian, associate professor of dermatology and pediatrics at George Washington University, Washington. At the end of 2 weeks, “the majority will have improved dramatically, and then you can implement maintenance therapy with topical calcineurin inhibitors, crisaborole, or possibly topical ruxolitinib.”

Some clinicians prescribe oral antihistamines for AD, but Dr. Kirkorian said that data supporting their use are limited and antihistamines are not approved for use in children younger than 6 months of age. Sedating antihistamines will induce sleep, “but do not provide durable night-long sleep,” and routine use may have an impact on learning and school performance. In addition, exposure to antihistamines in children under age 2 may be associated with development of ADHD at school age.

The interleukin-4 receptor alpha antagonist dupilumab (Dupixent) is approved by the Food and Drug Administration for moderate to severe AD in patients ages 6 and older. But obtaining it for patients can be tricky, she said, as this requires documented failure of corticosteroids, calcineurin inhibitors, crisaborole ointment, and phototherapy (if prescribed). Patients are often obligated to do step therapy with an off-label drug such as cyclosporine or methotrexate for 3 months, and they need to demonstrate responses with objective measures of severity such as the SCORAD (SCORing Atopic Dermatitis) and the validated Investigator Global Assessment.

“Most of my patients carry insurance that does not approve dupilumab without failure of a prior off-label systemic immunosuppressant medication,” Dr. Kirkorian said. Cyclosporine is her first choice for a systemic immunosuppressant “because it has a fast onset of action, it’s effective for treatment of atopic dermatitis, and safe for short-term use,” she said. “I don’t think that methotrexate works well for eczema. It can take weeks and weeks to work.”

She typically starts patients on a 5 mg/kg dose of cyclosporine. Baseline tests include CBC, CMP (comprehensive metabolic panel), lipids, and vitals. She repeats the labs at 1 month, and includes a blood pressure check. Potential adverse effects of cyclosporine include infections (including opportunistic infections), cytopenias, hypertension, nephrotoxicity, hepatotoxicity, neurotoxicity (including posterior reversible encephalopathy syndrome), electrolyte disturbance, lymphoma, and cutaneous malignancy.

“The good news is that we generally don’t see the adverse effects with short-term use,” Dr. Kirkorian said. “We will see some hypertrichosis and gingival hypertrophy, which resolves with cessation of therapy. There are serious side effects if you use it for long enough.”

As for methotrexate, “it is still a very important drug in pediatric dermatology, particularly in other conditions such as psoriasis,” she said. “The problem is that weekly dosing of methotrexate poses a greater risk of dosing errors. People aren’t really triggered to think of a once-weekly medication. If you do use it, give them a short supply to make sure that they come back, and that they don’t give it daily accidentally.”

Practical tips she offered for prescribing cyclosporine include supplying a patient handout with information on all adverse effects, dosing information, vaccination information, and pregnancy precautions, with contact information (a patient portal or on-call number) for the treating clinician in case a patient develops adverse effects. Administration of live vaccines while patients are on cyclosporine is not recommended.

When transitioning patients from cyclosporine or methotrexate to dupilumab, Dr. Kirkorian recommends tapering the immunosuppressant dose by half every 2 weeks to complete cessation by week 8 of treatment. For patients who experience a severe baseline flare once the immunosuppressant is tapered, despite the switch to dupilumab, she recommends restarting methotrexate at a full dose and then reducing the dose every 2 weeks until the lowest effective dose (2.5-5 mg weekly) is reached.

“Waning efficacy is real,” she said. “We can add methotrexate to recapture efficacy. Check for superimposed allergic contact dermatitis.”

With upadacitinib (Rinvoq), an oral Janus kinase (JAK) inhibitor recently approved for treating refractory, moderate to severe AD in patients 12 years of age and older, is the risk profile acceptable to parents and physicians? “I think the answer is yes,” Dr. Kirkorian said. “But we’re going to have to think through that very carefully. It’s going to be exciting to see how this drug changes management in our patients.”

Dr. Kirkorian disclosed that she is a member of the advisory board for Verrica Pharmaceuticals.

When children with atopic dermatitis (AD) present to the clinic and their parents complain that no previously recommended medical therapies have worked, what’s the next step?

“Many patients who have failed topical steroids have never had adequate treatment,” Anna Yasmine Kirkorian, MD, chief of dermatology at National Children’s Hospital in Washington, said during the ODAC Dermatology, Aesthetic & Surgical Conference. “There is no lower age limit on the use of topical corticosteroids, and low potency corticosteroids are inadequate to treat severe eczema. The idea that only over-the-counter 2.5% hydrocortisone cream is necessary is not true,” she added.

“You also want to scrutinize the vehicle,” she said, noting that children are often prescribed cream formulations that hurt when applied, so parents stop applying them. “Ointments are generally the vehicles of choice in childhood,” she added.

It is generally not advised to use topical and oral antibiotics in children with AD, unless there are clear signs of infection. “If they’re just slightly oozy, don’t use them,” she continued. “Of course, every child or adult with eczema has Staph aureus on them, but most of the time, what you need to do is repair the barrier. We know that from data and common sense. When we repair their barrier, their rates of infection decrease.”

A focal area with pustules and pus should be cultured and treated, Dr. Kirkorian said. “Monotherapy with antibiotics is going to do nothing for you.” In cases of children with failure to thrive, she recommends referral to pediatric dermatology, allergy/immunology, GI, or genetics, as appropriate.

For children with severe AD, Dr. Kirkorian favors a rescue plan with a one-pound jar of triamcinolone ointment 0.1%. She recommends application of the ointment to all areas, including the face and scalp once nightly for 2 weeks, with a follow-up appointment at the end of that time. “If you just give people medicine and ask them to come back in 6 months, they are not able to comply with that and they don’t have faith that it’s going to work,” explained Dr. Kirkorian, associate professor of dermatology and pediatrics at George Washington University, Washington. At the end of 2 weeks, “the majority will have improved dramatically, and then you can implement maintenance therapy with topical calcineurin inhibitors, crisaborole, or possibly topical ruxolitinib.”

Some clinicians prescribe oral antihistamines for AD, but Dr. Kirkorian said that data supporting their use are limited and antihistamines are not approved for use in children younger than 6 months of age. Sedating antihistamines will induce sleep, “but do not provide durable night-long sleep,” and routine use may have an impact on learning and school performance. In addition, exposure to antihistamines in children under age 2 may be associated with development of ADHD at school age.

The interleukin-4 receptor alpha antagonist dupilumab (Dupixent) is approved by the Food and Drug Administration for moderate to severe AD in patients ages 6 and older. But obtaining it for patients can be tricky, she said, as this requires documented failure of corticosteroids, calcineurin inhibitors, crisaborole ointment, and phototherapy (if prescribed). Patients are often obligated to do step therapy with an off-label drug such as cyclosporine or methotrexate for 3 months, and they need to demonstrate responses with objective measures of severity such as the SCORAD (SCORing Atopic Dermatitis) and the validated Investigator Global Assessment.

“Most of my patients carry insurance that does not approve dupilumab without failure of a prior off-label systemic immunosuppressant medication,” Dr. Kirkorian said. Cyclosporine is her first choice for a systemic immunosuppressant “because it has a fast onset of action, it’s effective for treatment of atopic dermatitis, and safe for short-term use,” she said. “I don’t think that methotrexate works well for eczema. It can take weeks and weeks to work.”

She typically starts patients on a 5 mg/kg dose of cyclosporine. Baseline tests include CBC, CMP (comprehensive metabolic panel), lipids, and vitals. She repeats the labs at 1 month, and includes a blood pressure check. Potential adverse effects of cyclosporine include infections (including opportunistic infections), cytopenias, hypertension, nephrotoxicity, hepatotoxicity, neurotoxicity (including posterior reversible encephalopathy syndrome), electrolyte disturbance, lymphoma, and cutaneous malignancy.

“The good news is that we generally don’t see the adverse effects with short-term use,” Dr. Kirkorian said. “We will see some hypertrichosis and gingival hypertrophy, which resolves with cessation of therapy. There are serious side effects if you use it for long enough.”

As for methotrexate, “it is still a very important drug in pediatric dermatology, particularly in other conditions such as psoriasis,” she said. “The problem is that weekly dosing of methotrexate poses a greater risk of dosing errors. People aren’t really triggered to think of a once-weekly medication. If you do use it, give them a short supply to make sure that they come back, and that they don’t give it daily accidentally.”

Practical tips she offered for prescribing cyclosporine include supplying a patient handout with information on all adverse effects, dosing information, vaccination information, and pregnancy precautions, with contact information (a patient portal or on-call number) for the treating clinician in case a patient develops adverse effects. Administration of live vaccines while patients are on cyclosporine is not recommended.

When transitioning patients from cyclosporine or methotrexate to dupilumab, Dr. Kirkorian recommends tapering the immunosuppressant dose by half every 2 weeks to complete cessation by week 8 of treatment. For patients who experience a severe baseline flare once the immunosuppressant is tapered, despite the switch to dupilumab, she recommends restarting methotrexate at a full dose and then reducing the dose every 2 weeks until the lowest effective dose (2.5-5 mg weekly) is reached.

“Waning efficacy is real,” she said. “We can add methotrexate to recapture efficacy. Check for superimposed allergic contact dermatitis.”

With upadacitinib (Rinvoq), an oral Janus kinase (JAK) inhibitor recently approved for treating refractory, moderate to severe AD in patients 12 years of age and older, is the risk profile acceptable to parents and physicians? “I think the answer is yes,” Dr. Kirkorian said. “But we’re going to have to think through that very carefully. It’s going to be exciting to see how this drug changes management in our patients.”

Dr. Kirkorian disclosed that she is a member of the advisory board for Verrica Pharmaceuticals.

Early, permanent discontinuation of venetoclax in the treatment of relapsed/refractory (r/r) chronic lymphocytic leukemia (CLL) is linked to shortened survival outcomes, but temporary interruption shows no impact on survival, underscoring the importance of preventing discontinuation.

“There’s not a lot of awareness about the fact that you’re probably better off not permanently discontinuing treatment,” Anthony R. Mato, first author of the research published in Haematologica, said in an interview.

Courtsey Memorial Sloan Kettering Cancer Center

“Instead, attempting dose reductions with later resumption to complete the planned schedule for treatment probably could improve outcomes,” said Dr. Mato, who is director of the CLL Program at Memorial Sloan Kettering Cancer Center in New York.

Venetoclax, a potent B-cell lymphoma-2 (BCL2) inhibitor, provides a novel, chemotherapy-free treatment option for first-line and r/r CLL. While its safety profile is manageable, treatment interruptions are very common, and premature discontinuations are reported in about a third of patients, often because of adverse events.

Lacking data on the effects of those interruptions on survival outcomes, Dr. Mato and colleagues conducted a post hoc analysis of the phase 3 MURANO trial. In this open-label study, treatment with six cycles of venetoclax in combination with rituximab followed by venetoclax once daily for a total of 2 years showed superior progression-free survival, compared with six cycles of bendamustine plus rituximab in patients with r/r CLL (P < .0001).

The current analysis involved 194 intention-to-treat patients from the trial’s venetoclax arm, among whom 140 (72%) completed 2 years of therapy, and 54 (28%) prematurely discontinued treatment. The most common reasons for discontinuation were adverse events (53.7%) and disease progression (22.2%).

Among those with early discontinuation for any reason except disease progression, the rate of progression-free survival was significantly inferior, compared with those who completed the treatment (hazard ratio, 5.98; P < .0001), as was the rate or discontinuation caused specifically by adverse events, which most commonly involved neutropenia or thrombocytopenia (HR, 5.82; P < .0001).

Those who discontinued had a mean duration of venetoclax therapy of 11.3 months, compared with 24.4 months for all patients. For each additional month of venetoclax therapy, there was a significantly lower risk of a progression-free survival event (P = .0263) and of an overall survival event (P < .0001).

The treatment interruption rate was much higher, at 69% (134), involving neutropenia in 43% (84) of instances and requiring dose reductions in 23% (45) of cases.

However, in contrast to permanent discontinuations, the temporary interruptions and dose reductions had no significant effect on progression-free or overall survival, regardless of the duration.

“Improved progression-free and overall survival were associated with greater cumulative venetoclax treatment exposure,” the authors wrote.

“The results of these analyses highlight the importance of appropriately managing treatment modifications to ensure optimal outcomes for patients receiving targeted treatment for CLL,” they said.

Key measures including “better supportive care, use of growth factors, and more aggressive strategies for dose reduction could potentially help to improve or decrease the number of patients discontinuing due to an adverse event,” Dr. Mato added.“We can’t say definitively because this is not a randomized study – it’s a retrospective analysis from a randomized study – but those measures likely could have a positive impact on patient outcomes.”

The study received support from Genentech and AbbVie. Dr. Mato reported consulting or other relationships with AbbVie, AstraZeneca, Celgene, DTRM, Genentech, Janssen, Loxo, PCYC, Sunesis, and TG Therapeutics.

Early, permanent discontinuation of venetoclax in the treatment of relapsed/refractory (r/r) chronic lymphocytic leukemia (CLL) is linked to shortened survival outcomes, but temporary interruption shows no impact on survival, underscoring the importance of preventing discontinuation.

“There’s not a lot of awareness about the fact that you’re probably better off not permanently discontinuing treatment,” Anthony R. Mato, first author of the research published in Haematologica, said in an interview.

Courtsey Memorial Sloan Kettering Cancer Center

“Instead, attempting dose reductions with later resumption to complete the planned schedule for treatment probably could improve outcomes,” said Dr. Mato, who is director of the CLL Program at Memorial Sloan Kettering Cancer Center in New York.

Venetoclax, a potent B-cell lymphoma-2 (BCL2) inhibitor, provides a novel, chemotherapy-free treatment option for first-line and r/r CLL. While its safety profile is manageable, treatment interruptions are very common, and premature discontinuations are reported in about a third of patients, often because of adverse events.

Lacking data on the effects of those interruptions on survival outcomes, Dr. Mato and colleagues conducted a post hoc analysis of the phase 3 MURANO trial. In this open-label study, treatment with six cycles of venetoclax in combination with rituximab followed by venetoclax once daily for a total of 2 years showed superior progression-free survival, compared with six cycles of bendamustine plus rituximab in patients with r/r CLL (P < .0001).

The current analysis involved 194 intention-to-treat patients from the trial’s venetoclax arm, among whom 140 (72%) completed 2 years of therapy, and 54 (28%) prematurely discontinued treatment. The most common reasons for discontinuation were adverse events (53.7%) and disease progression (22.2%).

Among those with early discontinuation for any reason except disease progression, the rate of progression-free survival was significantly inferior, compared with those who completed the treatment (hazard ratio, 5.98; P < .0001), as was the rate or discontinuation caused specifically by adverse events, which most commonly involved neutropenia or thrombocytopenia (HR, 5.82; P < .0001).

Those who discontinued had a mean duration of venetoclax therapy of 11.3 months, compared with 24.4 months for all patients. For each additional month of venetoclax therapy, there was a significantly lower risk of a progression-free survival event (P = .0263) and of an overall survival event (P < .0001).

The treatment interruption rate was much higher, at 69% (134), involving neutropenia in 43% (84) of instances and requiring dose reductions in 23% (45) of cases.

However, in contrast to permanent discontinuations, the temporary interruptions and dose reductions had no significant effect on progression-free or overall survival, regardless of the duration.

“Improved progression-free and overall survival were associated with greater cumulative venetoclax treatment exposure,” the authors wrote.

“The results of these analyses highlight the importance of appropriately managing treatment modifications to ensure optimal outcomes for patients receiving targeted treatment for CLL,” they said.

Key measures including “better supportive care, use of growth factors, and more aggressive strategies for dose reduction could potentially help to improve or decrease the number of patients discontinuing due to an adverse event,” Dr. Mato added.“We can’t say definitively because this is not a randomized study – it’s a retrospective analysis from a randomized study – but those measures likely could have a positive impact on patient outcomes.”

The study received support from Genentech and AbbVie. Dr. Mato reported consulting or other relationships with AbbVie, AstraZeneca, Celgene, DTRM, Genentech, Janssen, Loxo, PCYC, Sunesis, and TG Therapeutics.

Early, permanent discontinuation of venetoclax in the treatment of relapsed/refractory (r/r) chronic lymphocytic leukemia (CLL) is linked to shortened survival outcomes, but temporary interruption shows no impact on survival, underscoring the importance of preventing discontinuation.

“There’s not a lot of awareness about the fact that you’re probably better off not permanently discontinuing treatment,” Anthony R. Mato, first author of the research published in Haematologica, said in an interview.

Courtsey Memorial Sloan Kettering Cancer Center

“Instead, attempting dose reductions with later resumption to complete the planned schedule for treatment probably could improve outcomes,” said Dr. Mato, who is director of the CLL Program at Memorial Sloan Kettering Cancer Center in New York.

Venetoclax, a potent B-cell lymphoma-2 (BCL2) inhibitor, provides a novel, chemotherapy-free treatment option for first-line and r/r CLL. While its safety profile is manageable, treatment interruptions are very common, and premature discontinuations are reported in about a third of patients, often because of adverse events.

Lacking data on the effects of those interruptions on survival outcomes, Dr. Mato and colleagues conducted a post hoc analysis of the phase 3 MURANO trial. In this open-label study, treatment with six cycles of venetoclax in combination with rituximab followed by venetoclax once daily for a total of 2 years showed superior progression-free survival, compared with six cycles of bendamustine plus rituximab in patients with r/r CLL (P < .0001).

The current analysis involved 194 intention-to-treat patients from the trial’s venetoclax arm, among whom 140 (72%) completed 2 years of therapy, and 54 (28%) prematurely discontinued treatment. The most common reasons for discontinuation were adverse events (53.7%) and disease progression (22.2%).

Among those with early discontinuation for any reason except disease progression, the rate of progression-free survival was significantly inferior, compared with those who completed the treatment (hazard ratio, 5.98; P < .0001), as was the rate or discontinuation caused specifically by adverse events, which most commonly involved neutropenia or thrombocytopenia (HR, 5.82; P < .0001).

Those who discontinued had a mean duration of venetoclax therapy of 11.3 months, compared with 24.4 months for all patients. For each additional month of venetoclax therapy, there was a significantly lower risk of a progression-free survival event (P = .0263) and of an overall survival event (P < .0001).

The treatment interruption rate was much higher, at 69% (134), involving neutropenia in 43% (84) of instances and requiring dose reductions in 23% (45) of cases.

However, in contrast to permanent discontinuations, the temporary interruptions and dose reductions had no significant effect on progression-free or overall survival, regardless of the duration.

“Improved progression-free and overall survival were associated with greater cumulative venetoclax treatment exposure,” the authors wrote.

“The results of these analyses highlight the importance of appropriately managing treatment modifications to ensure optimal outcomes for patients receiving targeted treatment for CLL,” they said.

Key measures including “better supportive care, use of growth factors, and more aggressive strategies for dose reduction could potentially help to improve or decrease the number of patients discontinuing due to an adverse event,” Dr. Mato added.“We can’t say definitively because this is not a randomized study – it’s a retrospective analysis from a randomized study – but those measures likely could have a positive impact on patient outcomes.”

The study received support from Genentech and AbbVie. Dr. Mato reported consulting or other relationships with AbbVie, AstraZeneca, Celgene, DTRM, Genentech, Janssen, Loxo, PCYC, Sunesis, and TG Therapeutics.

Long COVID can affect adults, young people, and children, and now for the first time, in a landmark study accepted for publication in the Archives of Disease in Childhood, formal agreement has been made on a research definition for post–acute COVID-19, or “long COVID” as it is commonly known, in children and young people.

The researchers charged themselves with a single objective – to derive a research definition for long COVID (post–acute COVID-19) in children and young people to allow comparisons between research studies. Specifically, so studies on prevalence, course, and outcome of long COVID in this age group can be reliably compared, because to date there has been no consensus. In fact, the authors pointed out how the “slew of definitions” currently used all differ in number, type, and duration of symptoms, which hampers research efforts. In addition, the lack of definition consensus has contributed to very wide reported variations in the estimated prevalence of long COVID in children of 1%-51%, with the authors saying that a “consistently applied definition of long COVID will help reduce the variability of prevalence estimates.”
 

Statements sequentially whittled down

“Using robust consensus methodology,” the authors said, “we derived a research definition for long COVID in children and young people.”

To achieve the definition consensus, a three-phase online Delphi process was used, followed by a virtual consensus meeting. The 123 participants registered to take part in the study included 23 people (19%) in a lived experience panel, 50 (42%) in the researcher or researcher/service delivery combined panel and 47 (39%) in the service delivery panel. Of 120 registered participants, 105 (88%) completed phase 1, 86 eligible participants (82% of those completing phase 1) completed phase 2 and 77 eligible participants (90% of those completing phase 2) completed phase 3. Seventeen participants attended and voted at the consensus meeting – 4 (23%) from the service delivery panel, 11 (65%) from the researcher panel, and 2 (12%) from the lived experience panel.

Presented with 49 statements in each phase, participants scored these from 1-9 based on how important they were perceived to be with regards inclusion in the research definition of long COVID in children and young people. Having been sequentially whittled down in three phases, 10 statements were discussed at the consensus meeting, and a panel of eight 11- to 17-year-olds affected by long COVID also reviewed the statements to reach a final agreement.

Five of the statements were agreed to be included in the definition, which stated that long COVID in children and young people is a condition in which a child or young person has symptoms (at least one of which is a physical symptom) that have continued or developed after a diagnosis of COVID-19 (confirmed with one or more positive COVID tests); impact their physical, mental, or social well-being; are interfering with some aspect of daily living (for example, school, work, home, or relationships); and persist for a minimum duration of 12 weeks after initial testing for COVID-19 (even if symptoms have waxed and waned over that period).

David Strain, MBChB, MD, chair of the BMA board of science and clinical senior lecturer and honorary consultant, University of Exeter (England), told the Science Media Centre: “A Delphi study builds a consensus from the world’s experts by presenting a series of statements and continuing to refine them until there is agreement as to what the definition of pediatric long COVID should be.” He added: “This is vitally important in order to align the global research effort into long COVID.”
 

Reassuringly similar

From the agreed five statements, a further research definition was proposed to align with the World Health Organization definition for adults: “Post–COVID-19 condition occurs in young people with a history of confirmed SARS CoV-2 infection, with at least one persisting physical symptom for a minimum duration of 12 weeks after initial testing that cannot be explained by an alternative diagnosis. The symptoms have an impact on everyday functioning, may continue or develop after COVID-19 infection, and may fluctuate or relapse over time.”

The authors concluded: “This is the first research definition of long COVID (post–COVID-19 condition) in children and young people and complements the clinical case definition in adults proposed by WHO,” adding that the two definitions are “reassuringly similar.”

They reiterated how widespread adoption of this definition would allow comparisons between studies such that a core outcome set can be developed and the prevalence, course and outcome of long COVID in children and young people can be reliably evaluated, which “will substantially help strengthen the evidence base on this debilitating condition.”

In addition, the authors said that a consistently applied definition of long COVID will help to provide a “more accurate picture on the true impact of the condition.”

The researchers emphasized the need to differentiate between a clinical case definition and a research definition of long COVID and explained: “It is understandable that the patient groups representing people with long COVID are concerned about a definition that could restrict access to services that are needed.”

They went on to say that in their view the decision whether a child or young person can see a health care professional, access any support needed, or be referred, investigated, or treated for long COVID should be a “shared decision involving the young person, their carers, and clinicians.”

Dr. Strain reinforced that it was important that the definition was a research one and not a clinical one, pointing out that the 12-week period in the research definition “does not necessarily mean that a child or young person should need to wait 3 months before being offered help or assistance from their health care team, indeed a 3-month delay in offering support to a child or young person, at this vitally important period of their educational development, could have lasting long-term impacts.”

A version of this article first appeared on Medscape.co.uk.

Long COVID can affect adults, young people, and children, and now for the first time, in a landmark study accepted for publication in the Archives of Disease in Childhood, formal agreement has been made on a research definition for post–acute COVID-19, or “long COVID” as it is commonly known, in children and young people.

The researchers charged themselves with a single objective – to derive a research definition for long COVID (post–acute COVID-19) in children and young people to allow comparisons between research studies. Specifically, so studies on prevalence, course, and outcome of long COVID in this age group can be reliably compared, because to date there has been no consensus. In fact, the authors pointed out how the “slew of definitions” currently used all differ in number, type, and duration of symptoms, which hampers research efforts. In addition, the lack of definition consensus has contributed to very wide reported variations in the estimated prevalence of long COVID in children of 1%-51%, with the authors saying that a “consistently applied definition of long COVID will help reduce the variability of prevalence estimates.”
 

Statements sequentially whittled down

“Using robust consensus methodology,” the authors said, “we derived a research definition for long COVID in children and young people.”

To achieve the definition consensus, a three-phase online Delphi process was used, followed by a virtual consensus meeting. The 123 participants registered to take part in the study included 23 people (19%) in a lived experience panel, 50 (42%) in the researcher or researcher/service delivery combined panel and 47 (39%) in the service delivery panel. Of 120 registered participants, 105 (88%) completed phase 1, 86 eligible participants (82% of those completing phase 1) completed phase 2 and 77 eligible participants (90% of those completing phase 2) completed phase 3. Seventeen participants attended and voted at the consensus meeting – 4 (23%) from the service delivery panel, 11 (65%) from the researcher panel, and 2 (12%) from the lived experience panel.

Presented with 49 statements in each phase, participants scored these from 1-9 based on how important they were perceived to be with regards inclusion in the research definition of long COVID in children and young people. Having been sequentially whittled down in three phases, 10 statements were discussed at the consensus meeting, and a panel of eight 11- to 17-year-olds affected by long COVID also reviewed the statements to reach a final agreement.

Five of the statements were agreed to be included in the definition, which stated that long COVID in children and young people is a condition in which a child or young person has symptoms (at least one of which is a physical symptom) that have continued or developed after a diagnosis of COVID-19 (confirmed with one or more positive COVID tests); impact their physical, mental, or social well-being; are interfering with some aspect of daily living (for example, school, work, home, or relationships); and persist for a minimum duration of 12 weeks after initial testing for COVID-19 (even if symptoms have waxed and waned over that period).

David Strain, MBChB, MD, chair of the BMA board of science and clinical senior lecturer and honorary consultant, University of Exeter (England), told the Science Media Centre: “A Delphi study builds a consensus from the world’s experts by presenting a series of statements and continuing to refine them until there is agreement as to what the definition of pediatric long COVID should be.” He added: “This is vitally important in order to align the global research effort into long COVID.”
 

Reassuringly similar

From the agreed five statements, a further research definition was proposed to align with the World Health Organization definition for adults: “Post–COVID-19 condition occurs in young people with a history of confirmed SARS CoV-2 infection, with at least one persisting physical symptom for a minimum duration of 12 weeks after initial testing that cannot be explained by an alternative diagnosis. The symptoms have an impact on everyday functioning, may continue or develop after COVID-19 infection, and may fluctuate or relapse over time.”

The authors concluded: “This is the first research definition of long COVID (post–COVID-19 condition) in children and young people and complements the clinical case definition in adults proposed by WHO,” adding that the two definitions are “reassuringly similar.”

They reiterated how widespread adoption of this definition would allow comparisons between studies such that a core outcome set can be developed and the prevalence, course and outcome of long COVID in children and young people can be reliably evaluated, which “will substantially help strengthen the evidence base on this debilitating condition.”

In addition, the authors said that a consistently applied definition of long COVID will help to provide a “more accurate picture on the true impact of the condition.”

The researchers emphasized the need to differentiate between a clinical case definition and a research definition of long COVID and explained: “It is understandable that the patient groups representing people with long COVID are concerned about a definition that could restrict access to services that are needed.”

They went on to say that in their view the decision whether a child or young person can see a health care professional, access any support needed, or be referred, investigated, or treated for long COVID should be a “shared decision involving the young person, their carers, and clinicians.”

Dr. Strain reinforced that it was important that the definition was a research one and not a clinical one, pointing out that the 12-week period in the research definition “does not necessarily mean that a child or young person should need to wait 3 months before being offered help or assistance from their health care team, indeed a 3-month delay in offering support to a child or young person, at this vitally important period of their educational development, could have lasting long-term impacts.”

A version of this article first appeared on Medscape.co.uk.

Long COVID can affect adults, young people, and children, and now for the first time, in a landmark study accepted for publication in the Archives of Disease in Childhood, formal agreement has been made on a research definition for post–acute COVID-19, or “long COVID” as it is commonly known, in children and young people.

The researchers charged themselves with a single objective – to derive a research definition for long COVID (post–acute COVID-19) in children and young people to allow comparisons between research studies. Specifically, so studies on prevalence, course, and outcome of long COVID in this age group can be reliably compared, because to date there has been no consensus. In fact, the authors pointed out how the “slew of definitions” currently used all differ in number, type, and duration of symptoms, which hampers research efforts. In addition, the lack of definition consensus has contributed to very wide reported variations in the estimated prevalence of long COVID in children of 1%-51%, with the authors saying that a “consistently applied definition of long COVID will help reduce the variability of prevalence estimates.”
 

Statements sequentially whittled down

“Using robust consensus methodology,” the authors said, “we derived a research definition for long COVID in children and young people.”

To achieve the definition consensus, a three-phase online Delphi process was used, followed by a virtual consensus meeting. The 123 participants registered to take part in the study included 23 people (19%) in a lived experience panel, 50 (42%) in the researcher or researcher/service delivery combined panel and 47 (39%) in the service delivery panel. Of 120 registered participants, 105 (88%) completed phase 1, 86 eligible participants (82% of those completing phase 1) completed phase 2 and 77 eligible participants (90% of those completing phase 2) completed phase 3. Seventeen participants attended and voted at the consensus meeting – 4 (23%) from the service delivery panel, 11 (65%) from the researcher panel, and 2 (12%) from the lived experience panel.

Presented with 49 statements in each phase, participants scored these from 1-9 based on how important they were perceived to be with regards inclusion in the research definition of long COVID in children and young people. Having been sequentially whittled down in three phases, 10 statements were discussed at the consensus meeting, and a panel of eight 11- to 17-year-olds affected by long COVID also reviewed the statements to reach a final agreement.

Five of the statements were agreed to be included in the definition, which stated that long COVID in children and young people is a condition in which a child or young person has symptoms (at least one of which is a physical symptom) that have continued or developed after a diagnosis of COVID-19 (confirmed with one or more positive COVID tests); impact their physical, mental, or social well-being; are interfering with some aspect of daily living (for example, school, work, home, or relationships); and persist for a minimum duration of 12 weeks after initial testing for COVID-19 (even if symptoms have waxed and waned over that period).

David Strain, MBChB, MD, chair of the BMA board of science and clinical senior lecturer and honorary consultant, University of Exeter (England), told the Science Media Centre: “A Delphi study builds a consensus from the world’s experts by presenting a series of statements and continuing to refine them until there is agreement as to what the definition of pediatric long COVID should be.” He added: “This is vitally important in order to align the global research effort into long COVID.”
 

Reassuringly similar

From the agreed five statements, a further research definition was proposed to align with the World Health Organization definition for adults: “Post–COVID-19 condition occurs in young people with a history of confirmed SARS CoV-2 infection, with at least one persisting physical symptom for a minimum duration of 12 weeks after initial testing that cannot be explained by an alternative diagnosis. The symptoms have an impact on everyday functioning, may continue or develop after COVID-19 infection, and may fluctuate or relapse over time.”

The authors concluded: “This is the first research definition of long COVID (post–COVID-19 condition) in children and young people and complements the clinical case definition in adults proposed by WHO,” adding that the two definitions are “reassuringly similar.”

They reiterated how widespread adoption of this definition would allow comparisons between studies such that a core outcome set can be developed and the prevalence, course and outcome of long COVID in children and young people can be reliably evaluated, which “will substantially help strengthen the evidence base on this debilitating condition.”

In addition, the authors said that a consistently applied definition of long COVID will help to provide a “more accurate picture on the true impact of the condition.”

The researchers emphasized the need to differentiate between a clinical case definition and a research definition of long COVID and explained: “It is understandable that the patient groups representing people with long COVID are concerned about a definition that could restrict access to services that are needed.”

They went on to say that in their view the decision whether a child or young person can see a health care professional, access any support needed, or be referred, investigated, or treated for long COVID should be a “shared decision involving the young person, their carers, and clinicians.”

Dr. Strain reinforced that it was important that the definition was a research one and not a clinical one, pointing out that the 12-week period in the research definition “does not necessarily mean that a child or young person should need to wait 3 months before being offered help or assistance from their health care team, indeed a 3-month delay in offering support to a child or young person, at this vitally important period of their educational development, could have lasting long-term impacts.”

A version of this article first appeared on Medscape.co.uk.

It’s a story of promise at a time of urgent need.

Scientists are optimistic about new evidence into what is causing long COVID, a panel of research experts brought together by the New York State Department of Health said.

They proposed many theories on what might be driving long COVID. A role for a virus “cryptic reservoir” that could reactivate at any time, “viral remnants” that trigger chronic inflammation, and action by “autoimmune antibodies” that cause ongoing symptoms are possibilities.

In fact, it’s likely that research will show long COVID is a condition with more than one cause, the experts said during a recent webinar.

People might experience post-infection problems, including organ damage that takes time to heal after initial COVID-19 illness. Or they may be living with post-immune factors, including ongoing immune system responses triggered by autoantibodies.

Determining the cause or causes of long COVID is essential for treatment. For example, if one person’s symptoms persist because of an overactive immune system, “we need to provide immunosuppressant therapies,” Akiko Iwasaki, PhD, said. “But we don’t want to give that to someone who has a persistent virus reservoir,” meaning remnants of the virus remain in their bodies.

Interestingly, a study preprint, which has not been peer reviewed, found dogs were accurate more than half the time in sniffing out long COVID, said Dr. Iwasaki, professor of immunobiology and developmental biology at Yale University, New Haven, Conn.

The dogs were tasked with identifying 45 people with long COVID versus 188 people without it. The findings suggest the presence of a unique chemical in the sweat of people with long COVID that could someday lead to a diagnostic test.
 

Viral persistence possible

If one of the main theories holds, it could be that the coronavirus somehow remains in the body in some form for some people after COVID-19.

Mady Hornig, MD, agreed this is a possibility that needs to be investigated further.

“A weakened immune response to an infection may mean that you have cryptic reservoirs of virus that are continuing to cause symptoms,” she said during the briefing. Dr. Hornig is a doctor-scientist specializing in epidemiology at Columbia University, New York.

“That may explain why some patients with long COVID feel better after vaccination,” because the vaccine creates a strong antibody response to fight COVID-19, Dr. Iwasaki said.

Researchers are unearthing additional potential factors contributing to long COVID.

Viral persistence could also reactivate other dormant viruses in the body, such as Epstein-Barr virus (EBV), said Lawrence Purpura, MD, MPH, an infectious disease specialist at New York Presbyterian/Columbia University. Reactivation of Epstein-Barr is one of four identifying signs of long COVID revealed in a Jan. 25 study published in the journal Cell.
 

Immune overactivation also possible?

For other people with long COVID, it’s not the virus sticking around but the body’s reaction that’s the issue.

Investigators suggest autoimmunity plays a role, and they point to the presence of autoantibodies, for example.

When these autoantibodies persist, they can cause tissue and organ damage over time.

Other investigators are proposing “immune exhaustion” in long COVID because of similarities to chronic fatigue syndrome, Dr. Hornig said.

“It should be ‘all hands on deck’ for research into long COVID,” she said. “The number of disabled individuals who will likely qualify for a diagnosis of [chronic fatigue syndrome] is growing by the second.”
 

Forging ahead on future research

It’s clear there is more work to do. There are investigators working on banking tissue samples from people with long COVID to learn more, for example.

Also, finding a biomarker unique to long COVID could vastly improve the precision of diagnosing long COVID, especially if the dog sniffing option does not pan out.

Of the thousands of biomarker possibilities, Dr. Hornig said, “maybe that’s one or two that ultimately make a real impact on patient care. So it’s going to be critical to find those quickly, translate them, and make them available.”

In the meantime, some answers might come from a large study sponsored by the National Institutes of Health. The NIH is funding the “Researching COVID to Enhance Recovery” project using $470 million from the American Rescue Plan. Investigators at NYU Langone Health are leading the effort and plan to share the wealth by funding more than 100 researchers at more than 30 institutions to create a “metacohort” to study long COVID. More information is available at recovercovid.org.

“Fortunately, through the global research effort, we are now really starting to expand our understanding of how long COVID manifests, how common it is, and what the underlying mechanisms may be,” Dr. Purpura said.

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

It’s a story of promise at a time of urgent need.

Scientists are optimistic about new evidence into what is causing long COVID, a panel of research experts brought together by the New York State Department of Health said.

They proposed many theories on what might be driving long COVID. A role for a virus “cryptic reservoir” that could reactivate at any time, “viral remnants” that trigger chronic inflammation, and action by “autoimmune antibodies” that cause ongoing symptoms are possibilities.

In fact, it’s likely that research will show long COVID is a condition with more than one cause, the experts said during a recent webinar.

People might experience post-infection problems, including organ damage that takes time to heal after initial COVID-19 illness. Or they may be living with post-immune factors, including ongoing immune system responses triggered by autoantibodies.

Determining the cause or causes of long COVID is essential for treatment. For example, if one person’s symptoms persist because of an overactive immune system, “we need to provide immunosuppressant therapies,” Akiko Iwasaki, PhD, said. “But we don’t want to give that to someone who has a persistent virus reservoir,” meaning remnants of the virus remain in their bodies.

Interestingly, a study preprint, which has not been peer reviewed, found dogs were accurate more than half the time in sniffing out long COVID, said Dr. Iwasaki, professor of immunobiology and developmental biology at Yale University, New Haven, Conn.

The dogs were tasked with identifying 45 people with long COVID versus 188 people without it. The findings suggest the presence of a unique chemical in the sweat of people with long COVID that could someday lead to a diagnostic test.
 

Viral persistence possible

If one of the main theories holds, it could be that the coronavirus somehow remains in the body in some form for some people after COVID-19.

Mady Hornig, MD, agreed this is a possibility that needs to be investigated further.

“A weakened immune response to an infection may mean that you have cryptic reservoirs of virus that are continuing to cause symptoms,” she said during the briefing. Dr. Hornig is a doctor-scientist specializing in epidemiology at Columbia University, New York.

“That may explain why some patients with long COVID feel better after vaccination,” because the vaccine creates a strong antibody response to fight COVID-19, Dr. Iwasaki said.

Researchers are unearthing additional potential factors contributing to long COVID.

Viral persistence could also reactivate other dormant viruses in the body, such as Epstein-Barr virus (EBV), said Lawrence Purpura, MD, MPH, an infectious disease specialist at New York Presbyterian/Columbia University. Reactivation of Epstein-Barr is one of four identifying signs of long COVID revealed in a Jan. 25 study published in the journal Cell.
 

Immune overactivation also possible?

For other people with long COVID, it’s not the virus sticking around but the body’s reaction that’s the issue.

Investigators suggest autoimmunity plays a role, and they point to the presence of autoantibodies, for example.

When these autoantibodies persist, they can cause tissue and organ damage over time.

Other investigators are proposing “immune exhaustion” in long COVID because of similarities to chronic fatigue syndrome, Dr. Hornig said.

“It should be ‘all hands on deck’ for research into long COVID,” she said. “The number of disabled individuals who will likely qualify for a diagnosis of [chronic fatigue syndrome] is growing by the second.”
 

Forging ahead on future research

It’s clear there is more work to do. There are investigators working on banking tissue samples from people with long COVID to learn more, for example.

Also, finding a biomarker unique to long COVID could vastly improve the precision of diagnosing long COVID, especially if the dog sniffing option does not pan out.

Of the thousands of biomarker possibilities, Dr. Hornig said, “maybe that’s one or two that ultimately make a real impact on patient care. So it’s going to be critical to find those quickly, translate them, and make them available.”

In the meantime, some answers might come from a large study sponsored by the National Institutes of Health. The NIH is funding the “Researching COVID to Enhance Recovery” project using $470 million from the American Rescue Plan. Investigators at NYU Langone Health are leading the effort and plan to share the wealth by funding more than 100 researchers at more than 30 institutions to create a “metacohort” to study long COVID. More information is available at recovercovid.org.

“Fortunately, through the global research effort, we are now really starting to expand our understanding of how long COVID manifests, how common it is, and what the underlying mechanisms may be,” Dr. Purpura said.

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

It’s a story of promise at a time of urgent need.

Scientists are optimistic about new evidence into what is causing long COVID, a panel of research experts brought together by the New York State Department of Health said.

They proposed many theories on what might be driving long COVID. A role for a virus “cryptic reservoir” that could reactivate at any time, “viral remnants” that trigger chronic inflammation, and action by “autoimmune antibodies” that cause ongoing symptoms are possibilities.

In fact, it’s likely that research will show long COVID is a condition with more than one cause, the experts said during a recent webinar.

People might experience post-infection problems, including organ damage that takes time to heal after initial COVID-19 illness. Or they may be living with post-immune factors, including ongoing immune system responses triggered by autoantibodies.

Determining the cause or causes of long COVID is essential for treatment. For example, if one person’s symptoms persist because of an overactive immune system, “we need to provide immunosuppressant therapies,” Akiko Iwasaki, PhD, said. “But we don’t want to give that to someone who has a persistent virus reservoir,” meaning remnants of the virus remain in their bodies.

Interestingly, a study preprint, which has not been peer reviewed, found dogs were accurate more than half the time in sniffing out long COVID, said Dr. Iwasaki, professor of immunobiology and developmental biology at Yale University, New Haven, Conn.

The dogs were tasked with identifying 45 people with long COVID versus 188 people without it. The findings suggest the presence of a unique chemical in the sweat of people with long COVID that could someday lead to a diagnostic test.
 

Viral persistence possible

If one of the main theories holds, it could be that the coronavirus somehow remains in the body in some form for some people after COVID-19.

Mady Hornig, MD, agreed this is a possibility that needs to be investigated further.

“A weakened immune response to an infection may mean that you have cryptic reservoirs of virus that are continuing to cause symptoms,” she said during the briefing. Dr. Hornig is a doctor-scientist specializing in epidemiology at Columbia University, New York.

“That may explain why some patients with long COVID feel better after vaccination,” because the vaccine creates a strong antibody response to fight COVID-19, Dr. Iwasaki said.

Researchers are unearthing additional potential factors contributing to long COVID.

Viral persistence could also reactivate other dormant viruses in the body, such as Epstein-Barr virus (EBV), said Lawrence Purpura, MD, MPH, an infectious disease specialist at New York Presbyterian/Columbia University. Reactivation of Epstein-Barr is one of four identifying signs of long COVID revealed in a Jan. 25 study published in the journal Cell.
 

Immune overactivation also possible?

For other people with long COVID, it’s not the virus sticking around but the body’s reaction that’s the issue.

Investigators suggest autoimmunity plays a role, and they point to the presence of autoantibodies, for example.

When these autoantibodies persist, they can cause tissue and organ damage over time.

Other investigators are proposing “immune exhaustion” in long COVID because of similarities to chronic fatigue syndrome, Dr. Hornig said.

“It should be ‘all hands on deck’ for research into long COVID,” she said. “The number of disabled individuals who will likely qualify for a diagnosis of [chronic fatigue syndrome] is growing by the second.”
 

Forging ahead on future research

It’s clear there is more work to do. There are investigators working on banking tissue samples from people with long COVID to learn more, for example.

Also, finding a biomarker unique to long COVID could vastly improve the precision of diagnosing long COVID, especially if the dog sniffing option does not pan out.

Of the thousands of biomarker possibilities, Dr. Hornig said, “maybe that’s one or two that ultimately make a real impact on patient care. So it’s going to be critical to find those quickly, translate them, and make them available.”

In the meantime, some answers might come from a large study sponsored by the National Institutes of Health. The NIH is funding the “Researching COVID to Enhance Recovery” project using $470 million from the American Rescue Plan. Investigators at NYU Langone Health are leading the effort and plan to share the wealth by funding more than 100 researchers at more than 30 institutions to create a “metacohort” to study long COVID. More information is available at recovercovid.org.

“Fortunately, through the global research effort, we are now really starting to expand our understanding of how long COVID manifests, how common it is, and what the underlying mechanisms may be,” Dr. Purpura said.

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

Widespread white matter (WM) abnormalities may offer new insight into hoarding disorder (HD).

In a neuroimaging study, investigators led by Taro Mizobe, department of neuropsychiatry, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan, compared brain scans of individuals with and without HD.

Results showed that compared with healthy family members, participants with HD had anatomically widespread abnormalities in WM tracts.

In particular, a broad range of alterations were found in frontal WM related to HD symptom severity, as well as cortical regions involved in cognitive dysfunction.

“The finding of a characteristic association between alterations in the prefrontal WM tract, which connects cortical regions involved in cognitive function and the severity of hoarding symptoms, could provide new insights into the neurobiological basis of HD,” the researchers write.

The findings were published online Jan. 18 in the Journal of Psychiatric Research.
 

Limited information to date

“Although there are no clear neurobiological models of HD, several neuroimaging studies have found specific differences in specific brain regions” between patients with and without HD, the investigators write.

Structural MRI studies and voxel-based morphometry have shown larger volumes of gray matter in several regions of the brain in patients with HD. However, there have been no reports on alterations in the WM tracts – and studies of patients with obsessive-compulsive disorder and hoarding symptoms have yielded only “limited information” regarding WM tracts, the researchers note.

Diffusion tensor imaging (DTI) studies have yielded “inconsistent” findings, “therefore little is known about the microstructure of WM in the brains of patients with HD,” they add.

The current study was designed “to investigate microstructural alterations in the WM tracts of individuals with HD” by using tract-based spatial statistics – a model typically used for whole-brain, voxel-wise analysis of DTI measures.

DTI neuroimaging can assess the microstructure of WM. In the current study, the investigators focused on the three measures yielded by DTI: fractional anisotropy (FA), which is an index of overall WM integrity; axial diffusivity (AD); and radial diffusivity (RD).

Participants underwent MRI and DTI scans. Brain images of 25 individuals with hoarding disorder (mean age, 43 years; 64% women; 96% right-handed) were compared with those of 36 healthy controls matched for age, sex, and handedness.

Participants with HD had higher scores on the Hamilton Rating Scales for depression and anxiety than those without HD (P < .001 for both).

Of the patients with HD, 10 were taking psychiatric medications such as antidepressants, tranquilizers, or nonstimulant agents for attention-deficit/hyperactivity disorder.

Most (n = 18) were concurrently diagnosed with other psychiatric conditions, including ADHD, anxiety disorder, major depressive disorder, posttraumatic stress disorder, or obsessive-compulsive disorder.

The researchers also conducted a post hoc analysis of regions of interest “to detect correlations with clinical features.”
 

Microstructural alterations

Compared with healthy controls, patients with hoarding disorder showed decreased FA and increased RD in anatomically widespread WM tracts.

Decreased FA areas included the left superior longitudinal fasciculus (SLF), left uncinate fasciculus, left inferior fronto-occipital fasciculus (IFOF), left anterior thalamic radiation (ATR), left corticospinal tract, and left anterior limb of the internal capsule (ALIC).

Increased RD areas included the bilateral SLF, right IFOF, bilateral anterior and superior corona radiata, left posterior corona radiata, right ATR, left posterior thalamic radiation, right external capsule, and right ALIC.

Post hoc analyses of “regions of interest,” revealed “significant negative correlation” between the severity of hoarding symptoms and FA, particularly in the left anterior limb of the internal capsule, and a positive correlation between HD symptom severity and radial diffusivity in the right anterior thalamic radiation.

Those with HD also showed “a broad range of alterations” in the frontal WM tracts, including the frontothalamic circuit, frontoparietal network, and frontolimbic pathway.

“We found anatomically widespread decreases in FA and increases in WD in many major WM tracts and correlations between the severity of hoarding symptoms and DTI parameters (FA and RD) in the left ALIC and right ATR, which is part of the frontothalamic circuit,” the investigators write.

These findings “suggest that patients with HD have microstructural alterations in the prefrontal WM tracts,” they add.
 

First study

The researchers say that, to their knowledge, this is the first study to find major abnormalities in WM tracts within the brain and correlations between DTI indexes and clinical features in patients with HD.

The frontothalamic circuit is “thought to play an important role in executive functions, including working memory, attention, reward processing, and decision-making,” the investigators write.

Previous research implied that frontothalamic circuit–related cognitive functions are “impaired in patients with HD” and suggested that these impairments “underlie hoarding symptoms such as acquiring, saving, and cluttering relevant to HD.”

The decreased FA in the left SLF “reflects alterations in WM in the frontoparietal network in these patients and may be associated with cognitive impairments, such as task switching and inhibition, as shown in previous studies,” the researchers write.

Additionally, changes in FA and RD often “indicate myelin pathology,” which suggest that HD pathophysiology “may include abnormalities of myelination.”

However, the investigators cite several study limitations, including the “relatively small” sample size, which kept the DTI analysis from being “robust.” Moreover, many patients with HD had comorbid psychiatric disorders, which have also been associated with microstructural abnormalities in WM, the researchers note.
 

Novel approach

Commenting for this news organization, Michael Stevens, PhD, director, CNDLAB, Olin Neuropsychiatry Research Center, and adjunct professor of psychiatry at Yale University School of Medicine, New Haven, Conn., said the study “provides useful new clues for understanding HD neurobiology” because of its novel approach in assessing microstructural properties of major WM tracts.

The study’s “main contribution is to identify specific WM pathways between brain regions as worth looking at closely in the future. Some of these regions already have been implicated by brain function neuroimaging as abnormal in patients who compulsively hoard,” said Dr. Stevens, who was not involved in the research.

He noted that, when WM pathway integrity is affected, “it is thought to have an impact on how well information is communicated” between the brain regions.

“So once these specific findings are replicated in a separate study, they hopefully can guide researchers to ask new questions to learn exactly how these WM tracts might contribute to hoarding behavior,” Dr. Stevens said.

The study had no specific funding. The investigators and Dr. Stevens have disclosed no relevant financial relationships.

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

Widespread white matter (WM) abnormalities may offer new insight into hoarding disorder (HD).

In a neuroimaging study, investigators led by Taro Mizobe, department of neuropsychiatry, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan, compared brain scans of individuals with and without HD.

Results showed that compared with healthy family members, participants with HD had anatomically widespread abnormalities in WM tracts.

In particular, a broad range of alterations were found in frontal WM related to HD symptom severity, as well as cortical regions involved in cognitive dysfunction.

“The finding of a characteristic association between alterations in the prefrontal WM tract, which connects cortical regions involved in cognitive function and the severity of hoarding symptoms, could provide new insights into the neurobiological basis of HD,” the researchers write.

The findings were published online Jan. 18 in the Journal of Psychiatric Research.
 

Limited information to date

“Although there are no clear neurobiological models of HD, several neuroimaging studies have found specific differences in specific brain regions” between patients with and without HD, the investigators write.

Structural MRI studies and voxel-based morphometry have shown larger volumes of gray matter in several regions of the brain in patients with HD. However, there have been no reports on alterations in the WM tracts – and studies of patients with obsessive-compulsive disorder and hoarding symptoms have yielded only “limited information” regarding WM tracts, the researchers note.

Diffusion tensor imaging (DTI) studies have yielded “inconsistent” findings, “therefore little is known about the microstructure of WM in the brains of patients with HD,” they add.

The current study was designed “to investigate microstructural alterations in the WM tracts of individuals with HD” by using tract-based spatial statistics – a model typically used for whole-brain, voxel-wise analysis of DTI measures.

DTI neuroimaging can assess the microstructure of WM. In the current study, the investigators focused on the three measures yielded by DTI: fractional anisotropy (FA), which is an index of overall WM integrity; axial diffusivity (AD); and radial diffusivity (RD).

Participants underwent MRI and DTI scans. Brain images of 25 individuals with hoarding disorder (mean age, 43 years; 64% women; 96% right-handed) were compared with those of 36 healthy controls matched for age, sex, and handedness.

Participants with HD had higher scores on the Hamilton Rating Scales for depression and anxiety than those without HD (P < .001 for both).

Of the patients with HD, 10 were taking psychiatric medications such as antidepressants, tranquilizers, or nonstimulant agents for attention-deficit/hyperactivity disorder.

Most (n = 18) were concurrently diagnosed with other psychiatric conditions, including ADHD, anxiety disorder, major depressive disorder, posttraumatic stress disorder, or obsessive-compulsive disorder.

The researchers also conducted a post hoc analysis of regions of interest “to detect correlations with clinical features.”
 

Microstructural alterations

Compared with healthy controls, patients with hoarding disorder showed decreased FA and increased RD in anatomically widespread WM tracts.

Decreased FA areas included the left superior longitudinal fasciculus (SLF), left uncinate fasciculus, left inferior fronto-occipital fasciculus (IFOF), left anterior thalamic radiation (ATR), left corticospinal tract, and left anterior limb of the internal capsule (ALIC).

Increased RD areas included the bilateral SLF, right IFOF, bilateral anterior and superior corona radiata, left posterior corona radiata, right ATR, left posterior thalamic radiation, right external capsule, and right ALIC.

Post hoc analyses of “regions of interest,” revealed “significant negative correlation” between the severity of hoarding symptoms and FA, particularly in the left anterior limb of the internal capsule, and a positive correlation between HD symptom severity and radial diffusivity in the right anterior thalamic radiation.

Those with HD also showed “a broad range of alterations” in the frontal WM tracts, including the frontothalamic circuit, frontoparietal network, and frontolimbic pathway.

“We found anatomically widespread decreases in FA and increases in WD in many major WM tracts and correlations between the severity of hoarding symptoms and DTI parameters (FA and RD) in the left ALIC and right ATR, which is part of the frontothalamic circuit,” the investigators write.

These findings “suggest that patients with HD have microstructural alterations in the prefrontal WM tracts,” they add.
 

First study

The researchers say that, to their knowledge, this is the first study to find major abnormalities in WM tracts within the brain and correlations between DTI indexes and clinical features in patients with HD.

The frontothalamic circuit is “thought to play an important role in executive functions, including working memory, attention, reward processing, and decision-making,” the investigators write.

Previous research implied that frontothalamic circuit–related cognitive functions are “impaired in patients with HD” and suggested that these impairments “underlie hoarding symptoms such as acquiring, saving, and cluttering relevant to HD.”

The decreased FA in the left SLF “reflects alterations in WM in the frontoparietal network in these patients and may be associated with cognitive impairments, such as task switching and inhibition, as shown in previous studies,” the researchers write.

Additionally, changes in FA and RD often “indicate myelin pathology,” which suggest that HD pathophysiology “may include abnormalities of myelination.”

However, the investigators cite several study limitations, including the “relatively small” sample size, which kept the DTI analysis from being “robust.” Moreover, many patients with HD had comorbid psychiatric disorders, which have also been associated with microstructural abnormalities in WM, the researchers note.
 

Novel approach

Commenting for this news organization, Michael Stevens, PhD, director, CNDLAB, Olin Neuropsychiatry Research Center, and adjunct professor of psychiatry at Yale University School of Medicine, New Haven, Conn., said the study “provides useful new clues for understanding HD neurobiology” because of its novel approach in assessing microstructural properties of major WM tracts.

The study’s “main contribution is to identify specific WM pathways between brain regions as worth looking at closely in the future. Some of these regions already have been implicated by brain function neuroimaging as abnormal in patients who compulsively hoard,” said Dr. Stevens, who was not involved in the research.

He noted that, when WM pathway integrity is affected, “it is thought to have an impact on how well information is communicated” between the brain regions.

“So once these specific findings are replicated in a separate study, they hopefully can guide researchers to ask new questions to learn exactly how these WM tracts might contribute to hoarding behavior,” Dr. Stevens said.

The study had no specific funding. The investigators and Dr. Stevens have disclosed no relevant financial relationships.

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

Widespread white matter (WM) abnormalities may offer new insight into hoarding disorder (HD).

In a neuroimaging study, investigators led by Taro Mizobe, department of neuropsychiatry, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan, compared brain scans of individuals with and without HD.

Results showed that compared with healthy family members, participants with HD had anatomically widespread abnormalities in WM tracts.

In particular, a broad range of alterations were found in frontal WM related to HD symptom severity, as well as cortical regions involved in cognitive dysfunction.

“The finding of a characteristic association between alterations in the prefrontal WM tract, which connects cortical regions involved in cognitive function and the severity of hoarding symptoms, could provide new insights into the neurobiological basis of HD,” the researchers write.

The findings were published online Jan. 18 in the Journal of Psychiatric Research.
 

Limited information to date

“Although there are no clear neurobiological models of HD, several neuroimaging studies have found specific differences in specific brain regions” between patients with and without HD, the investigators write.

Structural MRI studies and voxel-based morphometry have shown larger volumes of gray matter in several regions of the brain in patients with HD. However, there have been no reports on alterations in the WM tracts – and studies of patients with obsessive-compulsive disorder and hoarding symptoms have yielded only “limited information” regarding WM tracts, the researchers note.

Diffusion tensor imaging (DTI) studies have yielded “inconsistent” findings, “therefore little is known about the microstructure of WM in the brains of patients with HD,” they add.

The current study was designed “to investigate microstructural alterations in the WM tracts of individuals with HD” by using tract-based spatial statistics – a model typically used for whole-brain, voxel-wise analysis of DTI measures.

DTI neuroimaging can assess the microstructure of WM. In the current study, the investigators focused on the three measures yielded by DTI: fractional anisotropy (FA), which is an index of overall WM integrity; axial diffusivity (AD); and radial diffusivity (RD).

Participants underwent MRI and DTI scans. Brain images of 25 individuals with hoarding disorder (mean age, 43 years; 64% women; 96% right-handed) were compared with those of 36 healthy controls matched for age, sex, and handedness.

Participants with HD had higher scores on the Hamilton Rating Scales for depression and anxiety than those without HD (P < .001 for both).

Of the patients with HD, 10 were taking psychiatric medications such as antidepressants, tranquilizers, or nonstimulant agents for attention-deficit/hyperactivity disorder.

Most (n = 18) were concurrently diagnosed with other psychiatric conditions, including ADHD, anxiety disorder, major depressive disorder, posttraumatic stress disorder, or obsessive-compulsive disorder.

The researchers also conducted a post hoc analysis of regions of interest “to detect correlations with clinical features.”
 

Microstructural alterations

Compared with healthy controls, patients with hoarding disorder showed decreased FA and increased RD in anatomically widespread WM tracts.

Decreased FA areas included the left superior longitudinal fasciculus (SLF), left uncinate fasciculus, left inferior fronto-occipital fasciculus (IFOF), left anterior thalamic radiation (ATR), left corticospinal tract, and left anterior limb of the internal capsule (ALIC).

Increased RD areas included the bilateral SLF, right IFOF, bilateral anterior and superior corona radiata, left posterior corona radiata, right ATR, left posterior thalamic radiation, right external capsule, and right ALIC.

Post hoc analyses of “regions of interest,” revealed “significant negative correlation” between the severity of hoarding symptoms and FA, particularly in the left anterior limb of the internal capsule, and a positive correlation between HD symptom severity and radial diffusivity in the right anterior thalamic radiation.

Those with HD also showed “a broad range of alterations” in the frontal WM tracts, including the frontothalamic circuit, frontoparietal network, and frontolimbic pathway.

“We found anatomically widespread decreases in FA and increases in WD in many major WM tracts and correlations between the severity of hoarding symptoms and DTI parameters (FA and RD) in the left ALIC and right ATR, which is part of the frontothalamic circuit,” the investigators write.

These findings “suggest that patients with HD have microstructural alterations in the prefrontal WM tracts,” they add.
 

First study

The researchers say that, to their knowledge, this is the first study to find major abnormalities in WM tracts within the brain and correlations between DTI indexes and clinical features in patients with HD.

The frontothalamic circuit is “thought to play an important role in executive functions, including working memory, attention, reward processing, and decision-making,” the investigators write.

Previous research implied that frontothalamic circuit–related cognitive functions are “impaired in patients with HD” and suggested that these impairments “underlie hoarding symptoms such as acquiring, saving, and cluttering relevant to HD.”

The decreased FA in the left SLF “reflects alterations in WM in the frontoparietal network in these patients and may be associated with cognitive impairments, such as task switching and inhibition, as shown in previous studies,” the researchers write.

Additionally, changes in FA and RD often “indicate myelin pathology,” which suggest that HD pathophysiology “may include abnormalities of myelination.”

However, the investigators cite several study limitations, including the “relatively small” sample size, which kept the DTI analysis from being “robust.” Moreover, many patients with HD had comorbid psychiatric disorders, which have also been associated with microstructural abnormalities in WM, the researchers note.
 

Novel approach

Commenting for this news organization, Michael Stevens, PhD, director, CNDLAB, Olin Neuropsychiatry Research Center, and adjunct professor of psychiatry at Yale University School of Medicine, New Haven, Conn., said the study “provides useful new clues for understanding HD neurobiology” because of its novel approach in assessing microstructural properties of major WM tracts.

The study’s “main contribution is to identify specific WM pathways between brain regions as worth looking at closely in the future. Some of these regions already have been implicated by brain function neuroimaging as abnormal in patients who compulsively hoard,” said Dr. Stevens, who was not involved in the research.

He noted that, when WM pathway integrity is affected, “it is thought to have an impact on how well information is communicated” between the brain regions.

“So once these specific findings are replicated in a separate study, they hopefully can guide researchers to ask new questions to learn exactly how these WM tracts might contribute to hoarding behavior,” Dr. Stevens said.

The study had no specific funding. The investigators and Dr. Stevens have disclosed no relevant financial relationships.

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

Several relatively large real-world analyses of Janus kinase inhibitors (JAKi) in patients with rheumatoid arthritis appear to show that the oral small-molecule drugs are discontinued and retained at rates similar to or better than biologic disease-modifying antirheumatic drugs (bDMARDs), including tumor necrosis factor inhibitors (TNFi), according to studies presented at the annual meeting of the Canadian Rheumatology Association.

The findings of these studies, although conducted prior to the Food and Drug Administration’s September 2021 announcement of a boxed warning for JAKi, do not lend support to the warning’s message of higher risks of major adverse cardiovascular events (MACE), blood clots, cancer, and death associated with JAKi.

In one study, discontinuation of JAKi-class drugs was less common than discontinuation of bDMARD-class drugs, including tumor necrosis factor inhibitors (TNFi), according to a multicenter team of investigators led by Janet Pope, MD, a professor in the division of rheumatology at the University of Western Ontario, London.

The greater durability of the JAKi relative to TNFi “seem to be driven by a greater loss of efficacy in bDMARDs over time,” reported Samir Magdy Iskander, a medical student at the university, who presented the data.
 

JAKi rival bDMARDs for long-term retention

In a separate but larger analysis, the retention rates with the JAKi tofacitinib (Xeljanz) and TNFi in two RA registries in Canada were about the same after a mean follow-up of 23.2 months (36.9% vs. 37.5%), but the tofacitinib group was at a relative disadvantage. Relative to the bDMARD group, patients taking JAKi were more likely to have had prior treatment with a bDMARD (66.9% vs. 33.9%), to have a higher median baseline Clinical Disease Activity Index (CDAI) score (22.1 vs. 20.0; P < .05), and to be older (59.5 vs. 57.6 years).

In this study, 1,318 patients with RA enrolled in the Ontario Best Practices Research Initiative (OBRI) or a Quebec cohort called RHUMADATA were evaluated, reported Mohammad Movahedi, MD, PhD, of the Institute of Health Policy, Management, and Evaluation at the University of Toronto.

“We have not yet analyzed the reasons for discontinuation, but the data show that retention is about the same, meaning that selection of one agent over the other should be tailored according to patient characteristics,” Dr. Movahedi said.

Reasons for discontinuation were presented in the other observational study, which included 333 adult patients with RA from two centers in Ontario. The discontinuation rate for adverse events was approximately 20% in both groups (HR, 1.0005; P = .98). However, the discontinuation rate for lack of efficacy favored the JAKi, reaching statistical significance.
 

TNFi failure for lack of efficacy is higher

“For lack of efficacy, the discontinuation rate was about 35% lower on the JAKi [HR, 0.6543; P = .029],” Mr. Iskander reported. Relative to those taking a TNFi, those on a JAKi demonstrated “greater durability regardless of gender, age, disease duration, and prior lines of therapy.”

In a population of patients who have not achieved an adequate response to conventional synthetic DMARDs (csDMARDs), which describes the study population from the two Ontario centers, JAKi “may be considered as a preferable method of treatment,” Mr. Iskander said.

Pointing out that many clinicians have interpreted the boxed warning as a relative contraindication for use of JAKi as first-line therapy in patients with an inadequate response to csDMARDs, Marinka Twilt, MD, PhD, the moderator of the scientific session where these data were presented, questioned the conclusion. In the boxed warning, clinicians and patients are advised to consider an increased risk of serious infections, malignancy, and cardiovascular-related mortality in individuals older than 50 years.

In response, Mr. Iskander said that the data were collected and analyzed prior to the change in labeling. He acknowledged that this study was not designed to capture long-term risks, such as cardiovascular disease or malignancy. In this analysis, the safety and tolerability of JAKi and bDMARDs appeared comparable.
 

NEJM published study leading to boxed warning

Just a week prior to the CRA annual meeting, the New England Journal of Medicine published an FDA-mandated postmarketing trial of tofacitinib that was used by the agency to justify the boxed warning for JAKi with indications for artitis and other inflammatory diseases. In that open-label trial, more than 4,000 patients aged 50 years or older with at least one additional cardiovascular risk factor were randomized to 5 mg tofacitinib twice daily, 10 mg tofacitinib twice daily, or a TNFi (adalimumab or etanercept).

The efficacy of the therapies was similar, but tofacitinib failed to meet predefined noninferiority criteria for the co–primary endpoints of MACE or cancer (excluding nonmelanoma skin cancer). For tofacitinib relative to TNFi, the hazard ratio was 1.33 for MACE and 1.48 for cancers. The JAKi was also associated with higher incidences of opportunistic infections.

Mr. Iskander noted that Canadian clinical practice guidelines currently identify JAKi as a reasonable first-line alternative to bDMARDs after inadequate response to csDMARDs. While his data support that position, Dr. Twilt indicated that the benefit-to-risk ratio of JAKi might need recalculation based on the data that led the FDA to issue its boxed warning. She questioned whether the language regarding the relative role of JAKi and bDMARDs will change in coming RA guideline revisions.

Dr. Iskander reported no potential conflicts of interest. Dr. Movahedi did not list any personal conflicts of interest but acknowledged that OBRI received unrestricted grants from a variety of pharmaceutical companies, including those that manufacture bDMARDs and JAKi. Dr. Twilt reported no potential conflicts of interest.

Several relatively large real-world analyses of Janus kinase inhibitors (JAKi) in patients with rheumatoid arthritis appear to show that the oral small-molecule drugs are discontinued and retained at rates similar to or better than biologic disease-modifying antirheumatic drugs (bDMARDs), including tumor necrosis factor inhibitors (TNFi), according to studies presented at the annual meeting of the Canadian Rheumatology Association.

The findings of these studies, although conducted prior to the Food and Drug Administration’s September 2021 announcement of a boxed warning for JAKi, do not lend support to the warning’s message of higher risks of major adverse cardiovascular events (MACE), blood clots, cancer, and death associated with JAKi.

In one study, discontinuation of JAKi-class drugs was less common than discontinuation of bDMARD-class drugs, including tumor necrosis factor inhibitors (TNFi), according to a multicenter team of investigators led by Janet Pope, MD, a professor in the division of rheumatology at the University of Western Ontario, London.

The greater durability of the JAKi relative to TNFi “seem to be driven by a greater loss of efficacy in bDMARDs over time,” reported Samir Magdy Iskander, a medical student at the university, who presented the data.
 

JAKi rival bDMARDs for long-term retention

In a separate but larger analysis, the retention rates with the JAKi tofacitinib (Xeljanz) and TNFi in two RA registries in Canada were about the same after a mean follow-up of 23.2 months (36.9% vs. 37.5%), but the tofacitinib group was at a relative disadvantage. Relative to the bDMARD group, patients taking JAKi were more likely to have had prior treatment with a bDMARD (66.9% vs. 33.9%), to have a higher median baseline Clinical Disease Activity Index (CDAI) score (22.1 vs. 20.0; P < .05), and to be older (59.5 vs. 57.6 years).

In this study, 1,318 patients with RA enrolled in the Ontario Best Practices Research Initiative (OBRI) or a Quebec cohort called RHUMADATA were evaluated, reported Mohammad Movahedi, MD, PhD, of the Institute of Health Policy, Management, and Evaluation at the University of Toronto.

“We have not yet analyzed the reasons for discontinuation, but the data show that retention is about the same, meaning that selection of one agent over the other should be tailored according to patient characteristics,” Dr. Movahedi said.

Reasons for discontinuation were presented in the other observational study, which included 333 adult patients with RA from two centers in Ontario. The discontinuation rate for adverse events was approximately 20% in both groups (HR, 1.0005; P = .98). However, the discontinuation rate for lack of efficacy favored the JAKi, reaching statistical significance.
 

TNFi failure for lack of efficacy is higher

“For lack of efficacy, the discontinuation rate was about 35% lower on the JAKi [HR, 0.6543; P = .029],” Mr. Iskander reported. Relative to those taking a TNFi, those on a JAKi demonstrated “greater durability regardless of gender, age, disease duration, and prior lines of therapy.”

In a population of patients who have not achieved an adequate response to conventional synthetic DMARDs (csDMARDs), which describes the study population from the two Ontario centers, JAKi “may be considered as a preferable method of treatment,” Mr. Iskander said.

Pointing out that many clinicians have interpreted the boxed warning as a relative contraindication for use of JAKi as first-line therapy in patients with an inadequate response to csDMARDs, Marinka Twilt, MD, PhD, the moderator of the scientific session where these data were presented, questioned the conclusion. In the boxed warning, clinicians and patients are advised to consider an increased risk of serious infections, malignancy, and cardiovascular-related mortality in individuals older than 50 years.

In response, Mr. Iskander said that the data were collected and analyzed prior to the change in labeling. He acknowledged that this study was not designed to capture long-term risks, such as cardiovascular disease or malignancy. In this analysis, the safety and tolerability of JAKi and bDMARDs appeared comparable.
 

NEJM published study leading to boxed warning

Just a week prior to the CRA annual meeting, the New England Journal of Medicine published an FDA-mandated postmarketing trial of tofacitinib that was used by the agency to justify the boxed warning for JAKi with indications for artitis and other inflammatory diseases. In that open-label trial, more than 4,000 patients aged 50 years or older with at least one additional cardiovascular risk factor were randomized to 5 mg tofacitinib twice daily, 10 mg tofacitinib twice daily, or a TNFi (adalimumab or etanercept).

The efficacy of the therapies was similar, but tofacitinib failed to meet predefined noninferiority criteria for the co–primary endpoints of MACE or cancer (excluding nonmelanoma skin cancer). For tofacitinib relative to TNFi, the hazard ratio was 1.33 for MACE and 1.48 for cancers. The JAKi was also associated with higher incidences of opportunistic infections.

Mr. Iskander noted that Canadian clinical practice guidelines currently identify JAKi as a reasonable first-line alternative to bDMARDs after inadequate response to csDMARDs. While his data support that position, Dr. Twilt indicated that the benefit-to-risk ratio of JAKi might need recalculation based on the data that led the FDA to issue its boxed warning. She questioned whether the language regarding the relative role of JAKi and bDMARDs will change in coming RA guideline revisions.

Dr. Iskander reported no potential conflicts of interest. Dr. Movahedi did not list any personal conflicts of interest but acknowledged that OBRI received unrestricted grants from a variety of pharmaceutical companies, including those that manufacture bDMARDs and JAKi. Dr. Twilt reported no potential conflicts of interest.

Several relatively large real-world analyses of Janus kinase inhibitors (JAKi) in patients with rheumatoid arthritis appear to show that the oral small-molecule drugs are discontinued and retained at rates similar to or better than biologic disease-modifying antirheumatic drugs (bDMARDs), including tumor necrosis factor inhibitors (TNFi), according to studies presented at the annual meeting of the Canadian Rheumatology Association.

The findings of these studies, although conducted prior to the Food and Drug Administration’s September 2021 announcement of a boxed warning for JAKi, do not lend support to the warning’s message of higher risks of major adverse cardiovascular events (MACE), blood clots, cancer, and death associated with JAKi.

In one study, discontinuation of JAKi-class drugs was less common than discontinuation of bDMARD-class drugs, including tumor necrosis factor inhibitors (TNFi), according to a multicenter team of investigators led by Janet Pope, MD, a professor in the division of rheumatology at the University of Western Ontario, London.

The greater durability of the JAKi relative to TNFi “seem to be driven by a greater loss of efficacy in bDMARDs over time,” reported Samir Magdy Iskander, a medical student at the university, who presented the data.
 

JAKi rival bDMARDs for long-term retention

In a separate but larger analysis, the retention rates with the JAKi tofacitinib (Xeljanz) and TNFi in two RA registries in Canada were about the same after a mean follow-up of 23.2 months (36.9% vs. 37.5%), but the tofacitinib group was at a relative disadvantage. Relative to the bDMARD group, patients taking JAKi were more likely to have had prior treatment with a bDMARD (66.9% vs. 33.9%), to have a higher median baseline Clinical Disease Activity Index (CDAI) score (22.1 vs. 20.0; P < .05), and to be older (59.5 vs. 57.6 years).

In this study, 1,318 patients with RA enrolled in the Ontario Best Practices Research Initiative (OBRI) or a Quebec cohort called RHUMADATA were evaluated, reported Mohammad Movahedi, MD, PhD, of the Institute of Health Policy, Management, and Evaluation at the University of Toronto.

“We have not yet analyzed the reasons for discontinuation, but the data show that retention is about the same, meaning that selection of one agent over the other should be tailored according to patient characteristics,” Dr. Movahedi said.

Reasons for discontinuation were presented in the other observational study, which included 333 adult patients with RA from two centers in Ontario. The discontinuation rate for adverse events was approximately 20% in both groups (HR, 1.0005; P = .98). However, the discontinuation rate for lack of efficacy favored the JAKi, reaching statistical significance.
 

TNFi failure for lack of efficacy is higher

“For lack of efficacy, the discontinuation rate was about 35% lower on the JAKi [HR, 0.6543; P = .029],” Mr. Iskander reported. Relative to those taking a TNFi, those on a JAKi demonstrated “greater durability regardless of gender, age, disease duration, and prior lines of therapy.”

In a population of patients who have not achieved an adequate response to conventional synthetic DMARDs (csDMARDs), which describes the study population from the two Ontario centers, JAKi “may be considered as a preferable method of treatment,” Mr. Iskander said.

Pointing out that many clinicians have interpreted the boxed warning as a relative contraindication for use of JAKi as first-line therapy in patients with an inadequate response to csDMARDs, Marinka Twilt, MD, PhD, the moderator of the scientific session where these data were presented, questioned the conclusion. In the boxed warning, clinicians and patients are advised to consider an increased risk of serious infections, malignancy, and cardiovascular-related mortality in individuals older than 50 years.

In response, Mr. Iskander said that the data were collected and analyzed prior to the change in labeling. He acknowledged that this study was not designed to capture long-term risks, such as cardiovascular disease or malignancy. In this analysis, the safety and tolerability of JAKi and bDMARDs appeared comparable.
 

NEJM published study leading to boxed warning

Just a week prior to the CRA annual meeting, the New England Journal of Medicine published an FDA-mandated postmarketing trial of tofacitinib that was used by the agency to justify the boxed warning for JAKi with indications for artitis and other inflammatory diseases. In that open-label trial, more than 4,000 patients aged 50 years or older with at least one additional cardiovascular risk factor were randomized to 5 mg tofacitinib twice daily, 10 mg tofacitinib twice daily, or a TNFi (adalimumab or etanercept).

The efficacy of the therapies was similar, but tofacitinib failed to meet predefined noninferiority criteria for the co–primary endpoints of MACE or cancer (excluding nonmelanoma skin cancer). For tofacitinib relative to TNFi, the hazard ratio was 1.33 for MACE and 1.48 for cancers. The JAKi was also associated with higher incidences of opportunistic infections.

Mr. Iskander noted that Canadian clinical practice guidelines currently identify JAKi as a reasonable first-line alternative to bDMARDs after inadequate response to csDMARDs. While his data support that position, Dr. Twilt indicated that the benefit-to-risk ratio of JAKi might need recalculation based on the data that led the FDA to issue its boxed warning. She questioned whether the language regarding the relative role of JAKi and bDMARDs will change in coming RA guideline revisions.

Dr. Iskander reported no potential conflicts of interest. Dr. Movahedi did not list any personal conflicts of interest but acknowledged that OBRI received unrestricted grants from a variety of pharmaceutical companies, including those that manufacture bDMARDs and JAKi. Dr. Twilt reported no potential conflicts of interest.