Conference Coverage

WASHINGTON – Research on standardized microbiome-based therapies designed to prevent the recurrence of Clostridioides difficile infection (CDI) is moving “with a lot of momentum,” according to one expert, and modulation of the gut microbiome may even enhance responses to immunotherapy and/or abrogate toxicity, according to another.

Several products for prevention of CDI recurrence are poised for either phase 3 trials or upcoming Food and Drug Administration approval, Sahil Khanna, MBBS, MS, professor of medicine, gastroenterology, and hepatology at the Mayo Clinic in Rochester, Minn., reported at the annual Gut Microbiota for Health World Summit.

Jennifer A. Wargo, MD, MMSc, of the University of Texas MD Anderson Cancer Center, Houston, described her investigations of microbiome modulation’s role in cancer treatment. “I used to say yes [we can do this] somewhat enthusiastically without data, but now we have data to support this,” she said at the meeting, sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility. “The answer now is totally yes.”
 

New approaches for CDI

“Based on how the field is moving, we might be able to [offer our patients] earlier microbiome restoration” than is currently afforded with fecal microbiota transplantation (FMT), he said. “Right now the [Food and Drug Administration] and our clinical guidelines say we should do FMT after three or more episodes [of CDI] – that’s heartbreaking for patients.”

Several of the microbiome-based therapies under investigation – including two poised for phase 3 trials – have shown efficacy after a second episode of CDI, and one of these two has also had positive results after one episode of CDI in patients 65 at older, a group at particularly high risk of recurrence, said Dr. Khanna.

The value of standardized, mostly pill-form microbiome therapies has been heightened during the pandemic. “We’ve been doing conventional FMT for recurrent C. difficile for over a decade now, and it’s probably the most effective treatment we have,” said Colleen R. Kelly, MD, associate professor of medicine at Brown University, Providence, R.I., and moderator of the session on microbiota-based therapies.

Prepandemic “it got really hard, with issues of identifying donors, and quality control and safety ... And then when COVID hit the stool banks shut down,” she said in an interview after the meeting. With stool testing for SARS-CoV-2 now in place, some stool is again available, “but it made me realize how fragile our current system is,” Dr. Kelly said. “The fact that companies are putting these products through the FDA pipeline and investigating them in rigorous, scientific randomized controlled trials is really good for the field.”

The products vary in composition; some are live multi-strain biotherapeutics derived from donor stool, for instance, while others are defined live bacterial consortia not from stool. Most are oral formulations, given one or multiple times, that do not require any bowel preparation.

One of the products most advanced in the pipeline, RBX2660 (Rebiotix, Ferring Pharmaceuticals) is stool derived and rectally administered. In phase 3 research, 70.5% of patients who received one active enema after having had two or more CDI recurrences and standard-of-care antibiotic treatment had no additional recurrence at 8 weeks compared to 58.1% in the placebo group, Dr. Khanna said.

The other product with positive phase 3 results, SER-109 (Seres Therapeutics), is a donor stool-derived oral formulation of purified Firmicutes spores that is administered after bowel prep. In results published earlier this year, the percentage of patients with recurrence of CDI up to 8 weeks after standard antibiotic treatment was 12% in the SER-109 group and 40% in the placebo group.

Patients in this trial were required to have had three episodes of CDI, and interestingly, Dr. Khanna said, the diagnosis of CDI was made only by toxin enzyme immunoassay (EIA). Earlier phase 2 research, which allowed either toxin EIA or polymerase chain reaction testing for the diagnosis of CDI (as other trials have done), produced negative results, leading investigators to surmise that some of the included patients had been colonized with C. difficile rather than being actively infected, Dr. Khanna said.

Researchers of these trials are documenting not only resolution of CDI but what they believe are positive shifts in the gut microbiota after microbiome-based therapy, he said. For instance, a phase 1 trial he led of the product RBX7455 (Rebiotix, Ferring Pharmaceuticals) – an oral capsule of lyophilized stool-based bacteria that can be kept for several days at room temperature – showed increases in Bacteroidia and Clostridia.

And other trials’ analyses of microbiome engraftment have demonstrated that “you can restore [species] even when these bacteria aren’t [included in the therapy],” he noted. “As the milieu of the gut improves, species that were not detected start coming back up.”

Asked about rates of efficacy in the trials’ placebo arms, Dr. Khanna said that “we’ve become smarter with our antibiotic regimens ... the placebo response rate is the response to newer guideline-based therapies.”

In addition to CDI, microbiome-based therapies are being studied, mostly in phase 1 research, for indications such as Crohn’s disease, ulcerative colitis, autism spectrum disorder, hepatitis B, and hepatic encephalopathy, Dr. Khanna noted.

Dr. Kelly, whose own research has focused on FMT for CDI, said she anticipates an expansion of research into other indications once products to prevent CDI recurrence are on the market. “There have been a couple of promising ulcerative colitis trials that haven’t gone anywhere clinically yet,” she said in the interview. “But will we now identify patients with UC who may be more sensitive to microbial manipulation, for whom we can use these microbial therapies along with a biologic?”

Some of her patients with IBD and CDI who are treated with FMT have not only had their CDI eradicated but have subsequently seen improvements in their IBD, she noted.

The role of traditional FMT and of stool banks will likely change in the future with new standardized oral microbiome-based therapies that can be approved and regulated by the FDA, she said. However, “we think the stool banks will still have some value,” she said, certainly for clinical research and probably for some treatment purposes as well. Regarding new therapies, “I just really hope they’re affordable,” she said.
 

Gut microbiome manipulation for cancer

Dr. Wargo’s research at MD Anderson has focused on metastatic breast cancer and immunotherapeutic checkpoint blockade. By sequencing microbiota samples and performing immune profiling in hundreds of patients, her team found that responders to PD-1 blockage have a greater diversity of gut bacteria and that “favorable signatures in the gut microbiome” are associated with enhanced immune responses in the tumor microenvironment.

Studies published last year in Science from investigators in Israel (2021 Feb 5;371[6529]:602-9) and Pittsburgh (2021 Feb 5;371[6529]:595-602), demonstrated that FMT promotes response in immunotherapy-refractory melanoma patients. In one study, FMT provided clinical benefit in 6 of 15 patients whose cancer had progressed on prior anti-PD-1 therapy, “which is pretty remarkable,” Dr. Wargo said.

Both research groups, she noted, saw favorable changes in the gut microbiome and immune cell infiltrates both at the level of the colon and the tumor.

Current research on FMT and other microbiome modulation strategies for cancer is guided in part by knowledge that tumors have microbial signatures – these signatures are now being identified across all tumor types – and by findings of “cross talk” between the gut and tumor microbiomes, she explained.

“Researchers are working hard to identify optimal consortia to enhance immune responses in the cancer setting, with promising work in preclinical models,” she said, and clinical trials are in progress. The role of diet in modulating the microbiome and enhancing anti-tumor immunity, with a focus on high dietary fiber intake, is also being investigated, she said.

Dr. Wargo reported that she serves on the advisory boards and is a paid speaker of numerous pharmaceutical and biotechnology companies, and is the coinventor of a patent submitted by the Texas MD Anderson Cancer Center on modulating the microbiome to enhance response to checkpoint blockade, and another related patent. Dr. Khanna reported that he is involved in research with Ferring/Rebiotix, Finch, Seres, Pfizer and Vendata, and does consulting for Immuron and several other companies. Dr. Kelly said she serves as an unpaid adviser for OpenBiome, a nonprofit stool bank, and that her site has enrolled patients in two of the trials testing products for CDI.

WASHINGTON – Research on standardized microbiome-based therapies designed to prevent the recurrence of Clostridioides difficile infection (CDI) is moving “with a lot of momentum,” according to one expert, and modulation of the gut microbiome may even enhance responses to immunotherapy and/or abrogate toxicity, according to another.

Several products for prevention of CDI recurrence are poised for either phase 3 trials or upcoming Food and Drug Administration approval, Sahil Khanna, MBBS, MS, professor of medicine, gastroenterology, and hepatology at the Mayo Clinic in Rochester, Minn., reported at the annual Gut Microbiota for Health World Summit.

Jennifer A. Wargo, MD, MMSc, of the University of Texas MD Anderson Cancer Center, Houston, described her investigations of microbiome modulation’s role in cancer treatment. “I used to say yes [we can do this] somewhat enthusiastically without data, but now we have data to support this,” she said at the meeting, sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility. “The answer now is totally yes.”
 

New approaches for CDI

“Based on how the field is moving, we might be able to [offer our patients] earlier microbiome restoration” than is currently afforded with fecal microbiota transplantation (FMT), he said. “Right now the [Food and Drug Administration] and our clinical guidelines say we should do FMT after three or more episodes [of CDI] – that’s heartbreaking for patients.”

Several of the microbiome-based therapies under investigation – including two poised for phase 3 trials – have shown efficacy after a second episode of CDI, and one of these two has also had positive results after one episode of CDI in patients 65 at older, a group at particularly high risk of recurrence, said Dr. Khanna.

The value of standardized, mostly pill-form microbiome therapies has been heightened during the pandemic. “We’ve been doing conventional FMT for recurrent C. difficile for over a decade now, and it’s probably the most effective treatment we have,” said Colleen R. Kelly, MD, associate professor of medicine at Brown University, Providence, R.I., and moderator of the session on microbiota-based therapies.

Prepandemic “it got really hard, with issues of identifying donors, and quality control and safety ... And then when COVID hit the stool banks shut down,” she said in an interview after the meeting. With stool testing for SARS-CoV-2 now in place, some stool is again available, “but it made me realize how fragile our current system is,” Dr. Kelly said. “The fact that companies are putting these products through the FDA pipeline and investigating them in rigorous, scientific randomized controlled trials is really good for the field.”

The products vary in composition; some are live multi-strain biotherapeutics derived from donor stool, for instance, while others are defined live bacterial consortia not from stool. Most are oral formulations, given one or multiple times, that do not require any bowel preparation.

One of the products most advanced in the pipeline, RBX2660 (Rebiotix, Ferring Pharmaceuticals) is stool derived and rectally administered. In phase 3 research, 70.5% of patients who received one active enema after having had two or more CDI recurrences and standard-of-care antibiotic treatment had no additional recurrence at 8 weeks compared to 58.1% in the placebo group, Dr. Khanna said.

The other product with positive phase 3 results, SER-109 (Seres Therapeutics), is a donor stool-derived oral formulation of purified Firmicutes spores that is administered after bowel prep. In results published earlier this year, the percentage of patients with recurrence of CDI up to 8 weeks after standard antibiotic treatment was 12% in the SER-109 group and 40% in the placebo group.

Patients in this trial were required to have had three episodes of CDI, and interestingly, Dr. Khanna said, the diagnosis of CDI was made only by toxin enzyme immunoassay (EIA). Earlier phase 2 research, which allowed either toxin EIA or polymerase chain reaction testing for the diagnosis of CDI (as other trials have done), produced negative results, leading investigators to surmise that some of the included patients had been colonized with C. difficile rather than being actively infected, Dr. Khanna said.

Researchers of these trials are documenting not only resolution of CDI but what they believe are positive shifts in the gut microbiota after microbiome-based therapy, he said. For instance, a phase 1 trial he led of the product RBX7455 (Rebiotix, Ferring Pharmaceuticals) – an oral capsule of lyophilized stool-based bacteria that can be kept for several days at room temperature – showed increases in Bacteroidia and Clostridia.

And other trials’ analyses of microbiome engraftment have demonstrated that “you can restore [species] even when these bacteria aren’t [included in the therapy],” he noted. “As the milieu of the gut improves, species that were not detected start coming back up.”

Asked about rates of efficacy in the trials’ placebo arms, Dr. Khanna said that “we’ve become smarter with our antibiotic regimens ... the placebo response rate is the response to newer guideline-based therapies.”

In addition to CDI, microbiome-based therapies are being studied, mostly in phase 1 research, for indications such as Crohn’s disease, ulcerative colitis, autism spectrum disorder, hepatitis B, and hepatic encephalopathy, Dr. Khanna noted.

Dr. Kelly, whose own research has focused on FMT for CDI, said she anticipates an expansion of research into other indications once products to prevent CDI recurrence are on the market. “There have been a couple of promising ulcerative colitis trials that haven’t gone anywhere clinically yet,” she said in the interview. “But will we now identify patients with UC who may be more sensitive to microbial manipulation, for whom we can use these microbial therapies along with a biologic?”

Some of her patients with IBD and CDI who are treated with FMT have not only had their CDI eradicated but have subsequently seen improvements in their IBD, she noted.

The role of traditional FMT and of stool banks will likely change in the future with new standardized oral microbiome-based therapies that can be approved and regulated by the FDA, she said. However, “we think the stool banks will still have some value,” she said, certainly for clinical research and probably for some treatment purposes as well. Regarding new therapies, “I just really hope they’re affordable,” she said.
 

Gut microbiome manipulation for cancer

Dr. Wargo’s research at MD Anderson has focused on metastatic breast cancer and immunotherapeutic checkpoint blockade. By sequencing microbiota samples and performing immune profiling in hundreds of patients, her team found that responders to PD-1 blockage have a greater diversity of gut bacteria and that “favorable signatures in the gut microbiome” are associated with enhanced immune responses in the tumor microenvironment.

Studies published last year in Science from investigators in Israel (2021 Feb 5;371[6529]:602-9) and Pittsburgh (2021 Feb 5;371[6529]:595-602), demonstrated that FMT promotes response in immunotherapy-refractory melanoma patients. In one study, FMT provided clinical benefit in 6 of 15 patients whose cancer had progressed on prior anti-PD-1 therapy, “which is pretty remarkable,” Dr. Wargo said.

Both research groups, she noted, saw favorable changes in the gut microbiome and immune cell infiltrates both at the level of the colon and the tumor.

Current research on FMT and other microbiome modulation strategies for cancer is guided in part by knowledge that tumors have microbial signatures – these signatures are now being identified across all tumor types – and by findings of “cross talk” between the gut and tumor microbiomes, she explained.

“Researchers are working hard to identify optimal consortia to enhance immune responses in the cancer setting, with promising work in preclinical models,” she said, and clinical trials are in progress. The role of diet in modulating the microbiome and enhancing anti-tumor immunity, with a focus on high dietary fiber intake, is also being investigated, she said.

Dr. Wargo reported that she serves on the advisory boards and is a paid speaker of numerous pharmaceutical and biotechnology companies, and is the coinventor of a patent submitted by the Texas MD Anderson Cancer Center on modulating the microbiome to enhance response to checkpoint blockade, and another related patent. Dr. Khanna reported that he is involved in research with Ferring/Rebiotix, Finch, Seres, Pfizer and Vendata, and does consulting for Immuron and several other companies. Dr. Kelly said she serves as an unpaid adviser for OpenBiome, a nonprofit stool bank, and that her site has enrolled patients in two of the trials testing products for CDI.

WASHINGTON – Research on standardized microbiome-based therapies designed to prevent the recurrence of Clostridioides difficile infection (CDI) is moving “with a lot of momentum,” according to one expert, and modulation of the gut microbiome may even enhance responses to immunotherapy and/or abrogate toxicity, according to another.

Several products for prevention of CDI recurrence are poised for either phase 3 trials or upcoming Food and Drug Administration approval, Sahil Khanna, MBBS, MS, professor of medicine, gastroenterology, and hepatology at the Mayo Clinic in Rochester, Minn., reported at the annual Gut Microbiota for Health World Summit.

Jennifer A. Wargo, MD, MMSc, of the University of Texas MD Anderson Cancer Center, Houston, described her investigations of microbiome modulation’s role in cancer treatment. “I used to say yes [we can do this] somewhat enthusiastically without data, but now we have data to support this,” she said at the meeting, sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility. “The answer now is totally yes.”
 

New approaches for CDI

“Based on how the field is moving, we might be able to [offer our patients] earlier microbiome restoration” than is currently afforded with fecal microbiota transplantation (FMT), he said. “Right now the [Food and Drug Administration] and our clinical guidelines say we should do FMT after three or more episodes [of CDI] – that’s heartbreaking for patients.”

Several of the microbiome-based therapies under investigation – including two poised for phase 3 trials – have shown efficacy after a second episode of CDI, and one of these two has also had positive results after one episode of CDI in patients 65 at older, a group at particularly high risk of recurrence, said Dr. Khanna.

The value of standardized, mostly pill-form microbiome therapies has been heightened during the pandemic. “We’ve been doing conventional FMT for recurrent C. difficile for over a decade now, and it’s probably the most effective treatment we have,” said Colleen R. Kelly, MD, associate professor of medicine at Brown University, Providence, R.I., and moderator of the session on microbiota-based therapies.

Prepandemic “it got really hard, with issues of identifying donors, and quality control and safety ... And then when COVID hit the stool banks shut down,” she said in an interview after the meeting. With stool testing for SARS-CoV-2 now in place, some stool is again available, “but it made me realize how fragile our current system is,” Dr. Kelly said. “The fact that companies are putting these products through the FDA pipeline and investigating them in rigorous, scientific randomized controlled trials is really good for the field.”

The products vary in composition; some are live multi-strain biotherapeutics derived from donor stool, for instance, while others are defined live bacterial consortia not from stool. Most are oral formulations, given one or multiple times, that do not require any bowel preparation.

One of the products most advanced in the pipeline, RBX2660 (Rebiotix, Ferring Pharmaceuticals) is stool derived and rectally administered. In phase 3 research, 70.5% of patients who received one active enema after having had two or more CDI recurrences and standard-of-care antibiotic treatment had no additional recurrence at 8 weeks compared to 58.1% in the placebo group, Dr. Khanna said.

The other product with positive phase 3 results, SER-109 (Seres Therapeutics), is a donor stool-derived oral formulation of purified Firmicutes spores that is administered after bowel prep. In results published earlier this year, the percentage of patients with recurrence of CDI up to 8 weeks after standard antibiotic treatment was 12% in the SER-109 group and 40% in the placebo group.

Patients in this trial were required to have had three episodes of CDI, and interestingly, Dr. Khanna said, the diagnosis of CDI was made only by toxin enzyme immunoassay (EIA). Earlier phase 2 research, which allowed either toxin EIA or polymerase chain reaction testing for the diagnosis of CDI (as other trials have done), produced negative results, leading investigators to surmise that some of the included patients had been colonized with C. difficile rather than being actively infected, Dr. Khanna said.

Researchers of these trials are documenting not only resolution of CDI but what they believe are positive shifts in the gut microbiota after microbiome-based therapy, he said. For instance, a phase 1 trial he led of the product RBX7455 (Rebiotix, Ferring Pharmaceuticals) – an oral capsule of lyophilized stool-based bacteria that can be kept for several days at room temperature – showed increases in Bacteroidia and Clostridia.

And other trials’ analyses of microbiome engraftment have demonstrated that “you can restore [species] even when these bacteria aren’t [included in the therapy],” he noted. “As the milieu of the gut improves, species that were not detected start coming back up.”

Asked about rates of efficacy in the trials’ placebo arms, Dr. Khanna said that “we’ve become smarter with our antibiotic regimens ... the placebo response rate is the response to newer guideline-based therapies.”

In addition to CDI, microbiome-based therapies are being studied, mostly in phase 1 research, for indications such as Crohn’s disease, ulcerative colitis, autism spectrum disorder, hepatitis B, and hepatic encephalopathy, Dr. Khanna noted.

Dr. Kelly, whose own research has focused on FMT for CDI, said she anticipates an expansion of research into other indications once products to prevent CDI recurrence are on the market. “There have been a couple of promising ulcerative colitis trials that haven’t gone anywhere clinically yet,” she said in the interview. “But will we now identify patients with UC who may be more sensitive to microbial manipulation, for whom we can use these microbial therapies along with a biologic?”

Some of her patients with IBD and CDI who are treated with FMT have not only had their CDI eradicated but have subsequently seen improvements in their IBD, she noted.

The role of traditional FMT and of stool banks will likely change in the future with new standardized oral microbiome-based therapies that can be approved and regulated by the FDA, she said. However, “we think the stool banks will still have some value,” she said, certainly for clinical research and probably for some treatment purposes as well. Regarding new therapies, “I just really hope they’re affordable,” she said.
 

Gut microbiome manipulation for cancer

Dr. Wargo’s research at MD Anderson has focused on metastatic breast cancer and immunotherapeutic checkpoint blockade. By sequencing microbiota samples and performing immune profiling in hundreds of patients, her team found that responders to PD-1 blockage have a greater diversity of gut bacteria and that “favorable signatures in the gut microbiome” are associated with enhanced immune responses in the tumor microenvironment.

Studies published last year in Science from investigators in Israel (2021 Feb 5;371[6529]:602-9) and Pittsburgh (2021 Feb 5;371[6529]:595-602), demonstrated that FMT promotes response in immunotherapy-refractory melanoma patients. In one study, FMT provided clinical benefit in 6 of 15 patients whose cancer had progressed on prior anti-PD-1 therapy, “which is pretty remarkable,” Dr. Wargo said.

Both research groups, she noted, saw favorable changes in the gut microbiome and immune cell infiltrates both at the level of the colon and the tumor.

Current research on FMT and other microbiome modulation strategies for cancer is guided in part by knowledge that tumors have microbial signatures – these signatures are now being identified across all tumor types – and by findings of “cross talk” between the gut and tumor microbiomes, she explained.

“Researchers are working hard to identify optimal consortia to enhance immune responses in the cancer setting, with promising work in preclinical models,” she said, and clinical trials are in progress. The role of diet in modulating the microbiome and enhancing anti-tumor immunity, with a focus on high dietary fiber intake, is also being investigated, she said.

Dr. Wargo reported that she serves on the advisory boards and is a paid speaker of numerous pharmaceutical and biotechnology companies, and is the coinventor of a patent submitted by the Texas MD Anderson Cancer Center on modulating the microbiome to enhance response to checkpoint blockade, and another related patent. Dr. Khanna reported that he is involved in research with Ferring/Rebiotix, Finch, Seres, Pfizer and Vendata, and does consulting for Immuron and several other companies. Dr. Kelly said she serves as an unpaid adviser for OpenBiome, a nonprofit stool bank, and that her site has enrolled patients in two of the trials testing products for CDI.

Scientists are trying different approaches to developing vaccines against norovirus, seeking to replicate the success seen in developing shots against rotavirus.

Speaking at the 12th World Congress of the World Society for Pediatric Infectious Diseases (WSPID), Miguel O’Ryan, MD, of the University of Chile, Santiago, presented an overview of candidate vaccines. Dr. O’Ryan has been involved for many years with research on rotavirus vaccines and has branched into work with the somewhat similar norovirus.

With advances in preventing rotavirus, norovirus has emerged in recent years as a leading cause of acute gastroenteritis (AGE) in most countries worldwide. It’s associated with almost 20% of all acute diarrheal cases globally and with an estimated 685 million episodes and 212,000 deaths annually, Dr. O’Ryan and coauthors reported in a review in the journal Viruses.

If successful, norovirus vaccines may be used someday to prevent outbreaks among military personnel, as this contagious virus has the potential to disrupt missions, Dr. O’Ryan and coauthors wrote. They also said people might consider getting norovirus vaccines ahead of trips to prevent traveler’s diarrhea. But most importantly, these kinds of vaccines could reduce diarrhea-associated hospitalizations and deaths of children. 

Takeda Pharmaceutical Company, for whom Dr. O’Ryan has done consulting, last year announced a collaboration with Frazier Healthcare Partners to launch HilleVax. Based in Boston, the company is intended to commercialize Takeda’s norovirus vaccine candidate.

The Takeda-HilleVax candidate vaccine injection has advanced as far as phase 2 studies, including a test done over two winter seasons in U.S. Navy recruits. Takeda and U.S. Navy scientists reported in 2020 in the journal Vaccine that the primary efficacy outcome for this test could not be evaluated due to an unexpectedly low number of cases of norovirus. Still, data taken from this study indicate that the vaccine induces a broad immune response, the scientists reported.

In his WSPID presentation, Dr. O’Ryan also mentioned an oral norovirus vaccine candidate that the company Vaxart is developing, referring to this as a “very interesting approach.” 
 

Betting on the gut

Based in South San Francisco, California, Vaxart is pursuing a theory that a vaccine designed to generate mucosal antibodies locally in the intestine, in addition to systemic antibodies in the blood, may better protect against norovirus infection than an injectable vaccine.

“A key ability to protect against norovirus needs to come from an intestinal immune response, and injected vaccines don’t give those very well,” Sean Tucker, PhD, the founder and chief scientific officer of Vaxart, told this news organization in an interview. “We think that’s one of the reasons why our oral approaches can have significant advantages.”

Challenges to developing a norovirus vaccine have included a lack of good animal models to use in research and a lack of an ability to grow the virus well in cell culture, Dr. Tucker said.

Vaxart experienced disruptions in its research during the early stages of the pandemic but has since picked up the pace of its efforts to develop its oral vaccine, Dr. Tucker said during the interview.

In a recent filing with the Securities and Exchange Commission, Vaxart said in early 2021 it resumed its norovirus vaccine program by initiating three clinical studies. These included a phase 1b placebo-controlled dose ranging study in healthy elderly adults aged 55-80. Data from these trials may be unveiled in the coming months.

Vaxart said that this year it has already initiated a phase 2 norovirus challenge study, which will evaluate safety, immunogenicity, and clinical efficacy of a vaccine candidate against placebo.

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

Scientists are trying different approaches to developing vaccines against norovirus, seeking to replicate the success seen in developing shots against rotavirus.

Speaking at the 12th World Congress of the World Society for Pediatric Infectious Diseases (WSPID), Miguel O’Ryan, MD, of the University of Chile, Santiago, presented an overview of candidate vaccines. Dr. O’Ryan has been involved for many years with research on rotavirus vaccines and has branched into work with the somewhat similar norovirus.

With advances in preventing rotavirus, norovirus has emerged in recent years as a leading cause of acute gastroenteritis (AGE) in most countries worldwide. It’s associated with almost 20% of all acute diarrheal cases globally and with an estimated 685 million episodes and 212,000 deaths annually, Dr. O’Ryan and coauthors reported in a review in the journal Viruses.

If successful, norovirus vaccines may be used someday to prevent outbreaks among military personnel, as this contagious virus has the potential to disrupt missions, Dr. O’Ryan and coauthors wrote. They also said people might consider getting norovirus vaccines ahead of trips to prevent traveler’s diarrhea. But most importantly, these kinds of vaccines could reduce diarrhea-associated hospitalizations and deaths of children. 

Takeda Pharmaceutical Company, for whom Dr. O’Ryan has done consulting, last year announced a collaboration with Frazier Healthcare Partners to launch HilleVax. Based in Boston, the company is intended to commercialize Takeda’s norovirus vaccine candidate.

The Takeda-HilleVax candidate vaccine injection has advanced as far as phase 2 studies, including a test done over two winter seasons in U.S. Navy recruits. Takeda and U.S. Navy scientists reported in 2020 in the journal Vaccine that the primary efficacy outcome for this test could not be evaluated due to an unexpectedly low number of cases of norovirus. Still, data taken from this study indicate that the vaccine induces a broad immune response, the scientists reported.

In his WSPID presentation, Dr. O’Ryan also mentioned an oral norovirus vaccine candidate that the company Vaxart is developing, referring to this as a “very interesting approach.” 
 

Betting on the gut

Based in South San Francisco, California, Vaxart is pursuing a theory that a vaccine designed to generate mucosal antibodies locally in the intestine, in addition to systemic antibodies in the blood, may better protect against norovirus infection than an injectable vaccine.

“A key ability to protect against norovirus needs to come from an intestinal immune response, and injected vaccines don’t give those very well,” Sean Tucker, PhD, the founder and chief scientific officer of Vaxart, told this news organization in an interview. “We think that’s one of the reasons why our oral approaches can have significant advantages.”

Challenges to developing a norovirus vaccine have included a lack of good animal models to use in research and a lack of an ability to grow the virus well in cell culture, Dr. Tucker said.

Vaxart experienced disruptions in its research during the early stages of the pandemic but has since picked up the pace of its efforts to develop its oral vaccine, Dr. Tucker said during the interview.

In a recent filing with the Securities and Exchange Commission, Vaxart said in early 2021 it resumed its norovirus vaccine program by initiating three clinical studies. These included a phase 1b placebo-controlled dose ranging study in healthy elderly adults aged 55-80. Data from these trials may be unveiled in the coming months.

Vaxart said that this year it has already initiated a phase 2 norovirus challenge study, which will evaluate safety, immunogenicity, and clinical efficacy of a vaccine candidate against placebo.

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

Scientists are trying different approaches to developing vaccines against norovirus, seeking to replicate the success seen in developing shots against rotavirus.

Speaking at the 12th World Congress of the World Society for Pediatric Infectious Diseases (WSPID), Miguel O’Ryan, MD, of the University of Chile, Santiago, presented an overview of candidate vaccines. Dr. O’Ryan has been involved for many years with research on rotavirus vaccines and has branched into work with the somewhat similar norovirus.

With advances in preventing rotavirus, norovirus has emerged in recent years as a leading cause of acute gastroenteritis (AGE) in most countries worldwide. It’s associated with almost 20% of all acute diarrheal cases globally and with an estimated 685 million episodes and 212,000 deaths annually, Dr. O’Ryan and coauthors reported in a review in the journal Viruses.

If successful, norovirus vaccines may be used someday to prevent outbreaks among military personnel, as this contagious virus has the potential to disrupt missions, Dr. O’Ryan and coauthors wrote. They also said people might consider getting norovirus vaccines ahead of trips to prevent traveler’s diarrhea. But most importantly, these kinds of vaccines could reduce diarrhea-associated hospitalizations and deaths of children. 

Takeda Pharmaceutical Company, for whom Dr. O’Ryan has done consulting, last year announced a collaboration with Frazier Healthcare Partners to launch HilleVax. Based in Boston, the company is intended to commercialize Takeda’s norovirus vaccine candidate.

The Takeda-HilleVax candidate vaccine injection has advanced as far as phase 2 studies, including a test done over two winter seasons in U.S. Navy recruits. Takeda and U.S. Navy scientists reported in 2020 in the journal Vaccine that the primary efficacy outcome for this test could not be evaluated due to an unexpectedly low number of cases of norovirus. Still, data taken from this study indicate that the vaccine induces a broad immune response, the scientists reported.

In his WSPID presentation, Dr. O’Ryan also mentioned an oral norovirus vaccine candidate that the company Vaxart is developing, referring to this as a “very interesting approach.” 
 

Betting on the gut

Based in South San Francisco, California, Vaxart is pursuing a theory that a vaccine designed to generate mucosal antibodies locally in the intestine, in addition to systemic antibodies in the blood, may better protect against norovirus infection than an injectable vaccine.

“A key ability to protect against norovirus needs to come from an intestinal immune response, and injected vaccines don’t give those very well,” Sean Tucker, PhD, the founder and chief scientific officer of Vaxart, told this news organization in an interview. “We think that’s one of the reasons why our oral approaches can have significant advantages.”

Challenges to developing a norovirus vaccine have included a lack of good animal models to use in research and a lack of an ability to grow the virus well in cell culture, Dr. Tucker said.

Vaxart experienced disruptions in its research during the early stages of the pandemic but has since picked up the pace of its efforts to develop its oral vaccine, Dr. Tucker said during the interview.

In a recent filing with the Securities and Exchange Commission, Vaxart said in early 2021 it resumed its norovirus vaccine program by initiating three clinical studies. These included a phase 1b placebo-controlled dose ranging study in healthy elderly adults aged 55-80. Data from these trials may be unveiled in the coming months.

Vaxart said that this year it has already initiated a phase 2 norovirus challenge study, which will evaluate safety, immunogenicity, and clinical efficacy of a vaccine candidate against placebo.

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

WEST PALM BEACH, FL – Including serum neurofilament light chain (sNfL) and serum glial fibrillary acidic protein (sGFAP) at multiple sclerosis (MS) onset may lead to better prediction of long-term outcomes and relapse risk, new research suggests.

The research shows that once standard clinical models can be incorporated into practice, the early measurement of these biomarkers will provide useful information in predicting who may be at risk of poorer outcomes, researcher Gauruv Bose, MD, Brigham Multiple Sclerosis Center, Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, told this news organization.

The findings were presented at annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
 

Better together?

Although higher baseline sNfL levels in MS have previously been linked to greater brain atrophy and other long-term outcomes, and sGFAP changes are also associated with inflammation and damage through the disease course, less is known about longer-term effects of the two biomarker measures combined, Dr. Bose said.

“The value of using both sNfL and sGFAP in predictive models is of interest, since one correlates with neuroaxonal damage, while the other has correlated with astrocytic glial damage/cell turnover – potentially, though differently, reflecting inflammatory damage and neurodegeneration,” he added.

To investigate the relationship, the researchers evaluated patients with MS enrolled at the Brigham Multiple Sclerosis Center. All underwent neurologic examinations every 6 months, and MRI scans and blood samples were collected every year. Some had more than 20 years of follow-up.

The first study involved 144 patients (mean age, 37.4 years) from whom two samples of sNfL and sGFAP were collected within 3 years of MS onset.

The median baseline sNfL level was 10.7 pg/mL, and 50 patients (34.7%) already showed increases in sNfL at the 1-year follow-up. Their median sGFAP level at onset was 96 pg/mL, and 59 patients (41%) showed increases in sGFAP at the 1-year follow-up.

Results showed that higher baseline sNfL levels were significantly associated with increased risk for MS relapse at 10 years (hazard ratio, 1.34; P = .04), as well as with the development of new MRI lesions (HR, 1.35; P = .022).

Of the study group, 25 (17.4%) developed secondary progressive MS (SPMS) by the 10-year follow-up. For those prognostic assessments, the investigators compared utilization of a model using well-established clinical predictors of SPMS with and without the inclusion of sNfL and sGFAP.

The clinical model included key factors such as age, sex, body mass index, Extended Disability Status Scale (EDSS), timed 25-foot walk, and other measures.

The researchers found the clinical model alone predicted 10-year outcomes with an area under the receiver operating characteristic curve (AUC) of 0.75. However, with the addition of baseline sNfL and sGFAP measures, the AUC was improved to 0.79 (P = .0008).

Furthermore, the inclusion of additional follow-up sNfL and sGFAP measurements taken after baseline further improved the model’s AUC (0.82; P = .046).

The addition of the sNfL and sGFAP measures to the clinical models also improved the prediction of disability in MS at 10 years on EDSS (P = .068), as well as prediction of 10-year brain T2 lesion volume (P = .009) and brain parenchymal fraction (P = .04).
 

Relapse predictor?

In the second study, Dr. Bose and colleagues evaluated the role of the two serum measures in predicting relapse after disease-modifying therapy (DMT) discontinuation. That study included 42 patients who discontinued DMT treatment after having been disease-activity free for 2 years while on the drugs. They were compared with 36 patients who had similar characteristics and had continued DMT treatment.

All patients (mean age, 44.5 years) had a mean of 7.4 years since prior disease activity.

Increases in sNfL following DMT discontinuation, but not before, were associated with a significantly greater risk for clinical disease worsening at a mean follow-up of 7.5 years (HR, 9.4; P = .007). Change in sGFAP was associated with new MRI lesions (HR, 8.3; P = .039), compared with no changes.

“The crux of this study” was that patients with increased biomarker levels after stopping DMTs “were at a significantly higher risk for disease activity in the future compared to those whose biomarker levels remained stable,” Dr. Bose noted.

“We think this finding, if replicated in another cohort, has the potential to be included in guidelines regarding stopping DMT in patients with MS,” he added.
 

Clinically useful?

Jeffrey Cohen, MD, current president of ACTRIMS, said the first study supports mounting evidence on how sNfL and sGFAP at onset can predict future disease and have the potential to improve current predictive models.

“Combining clinical, MRI, and serum biomarkers into a single model works better than any of the three factors individually,” said Dr. Cohen, who is director of the Mellen Center for MS Treatment and Research and professor of neurology at the Cleveland Clinic.

“For the clinician, this information may help with treatment selection,” he added.

Dr. Cohen noted that the suggestion that the biomarkers could also be helpful in predicting relapse after discontinuation is of importance.

“Increasingly, we are considering this issue in the clinical setting,” he said. However, he also noted some caveats.

“Interpretation of the results of the study is not straightforward, illustrating the complexity of the issue,” Dr. Cohen said. “One issue is that the patients in the study were relatively young, with an average age of 45, which is not a group in which we typically would consider stopping therapy.”

Dr. Bose has received a postdoctoral fellowship grant from the Multiple Sclerosis Society of Canada. Dr. Cohen reports having received personal compensation for consulting for Biogen, Bristol-Myers Squibb, Convelo, Genentech, Janssen, NervGen, Novartis, and PSI; speaking for H3 Communications; and serving as an editor of the Multiple Sclerosis Journal.

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

WEST PALM BEACH, FL – Including serum neurofilament light chain (sNfL) and serum glial fibrillary acidic protein (sGFAP) at multiple sclerosis (MS) onset may lead to better prediction of long-term outcomes and relapse risk, new research suggests.

The research shows that once standard clinical models can be incorporated into practice, the early measurement of these biomarkers will provide useful information in predicting who may be at risk of poorer outcomes, researcher Gauruv Bose, MD, Brigham Multiple Sclerosis Center, Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, told this news organization.

The findings were presented at annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
 

Better together?

Although higher baseline sNfL levels in MS have previously been linked to greater brain atrophy and other long-term outcomes, and sGFAP changes are also associated with inflammation and damage through the disease course, less is known about longer-term effects of the two biomarker measures combined, Dr. Bose said.

“The value of using both sNfL and sGFAP in predictive models is of interest, since one correlates with neuroaxonal damage, while the other has correlated with astrocytic glial damage/cell turnover – potentially, though differently, reflecting inflammatory damage and neurodegeneration,” he added.

To investigate the relationship, the researchers evaluated patients with MS enrolled at the Brigham Multiple Sclerosis Center. All underwent neurologic examinations every 6 months, and MRI scans and blood samples were collected every year. Some had more than 20 years of follow-up.

The first study involved 144 patients (mean age, 37.4 years) from whom two samples of sNfL and sGFAP were collected within 3 years of MS onset.

The median baseline sNfL level was 10.7 pg/mL, and 50 patients (34.7%) already showed increases in sNfL at the 1-year follow-up. Their median sGFAP level at onset was 96 pg/mL, and 59 patients (41%) showed increases in sGFAP at the 1-year follow-up.

Results showed that higher baseline sNfL levels were significantly associated with increased risk for MS relapse at 10 years (hazard ratio, 1.34; P = .04), as well as with the development of new MRI lesions (HR, 1.35; P = .022).

Of the study group, 25 (17.4%) developed secondary progressive MS (SPMS) by the 10-year follow-up. For those prognostic assessments, the investigators compared utilization of a model using well-established clinical predictors of SPMS with and without the inclusion of sNfL and sGFAP.

The clinical model included key factors such as age, sex, body mass index, Extended Disability Status Scale (EDSS), timed 25-foot walk, and other measures.

The researchers found the clinical model alone predicted 10-year outcomes with an area under the receiver operating characteristic curve (AUC) of 0.75. However, with the addition of baseline sNfL and sGFAP measures, the AUC was improved to 0.79 (P = .0008).

Furthermore, the inclusion of additional follow-up sNfL and sGFAP measurements taken after baseline further improved the model’s AUC (0.82; P = .046).

The addition of the sNfL and sGFAP measures to the clinical models also improved the prediction of disability in MS at 10 years on EDSS (P = .068), as well as prediction of 10-year brain T2 lesion volume (P = .009) and brain parenchymal fraction (P = .04).
 

Relapse predictor?

In the second study, Dr. Bose and colleagues evaluated the role of the two serum measures in predicting relapse after disease-modifying therapy (DMT) discontinuation. That study included 42 patients who discontinued DMT treatment after having been disease-activity free for 2 years while on the drugs. They were compared with 36 patients who had similar characteristics and had continued DMT treatment.

All patients (mean age, 44.5 years) had a mean of 7.4 years since prior disease activity.

Increases in sNfL following DMT discontinuation, but not before, were associated with a significantly greater risk for clinical disease worsening at a mean follow-up of 7.5 years (HR, 9.4; P = .007). Change in sGFAP was associated with new MRI lesions (HR, 8.3; P = .039), compared with no changes.

“The crux of this study” was that patients with increased biomarker levels after stopping DMTs “were at a significantly higher risk for disease activity in the future compared to those whose biomarker levels remained stable,” Dr. Bose noted.

“We think this finding, if replicated in another cohort, has the potential to be included in guidelines regarding stopping DMT in patients with MS,” he added.
 

Clinically useful?

Jeffrey Cohen, MD, current president of ACTRIMS, said the first study supports mounting evidence on how sNfL and sGFAP at onset can predict future disease and have the potential to improve current predictive models.

“Combining clinical, MRI, and serum biomarkers into a single model works better than any of the three factors individually,” said Dr. Cohen, who is director of the Mellen Center for MS Treatment and Research and professor of neurology at the Cleveland Clinic.

“For the clinician, this information may help with treatment selection,” he added.

Dr. Cohen noted that the suggestion that the biomarkers could also be helpful in predicting relapse after discontinuation is of importance.

“Increasingly, we are considering this issue in the clinical setting,” he said. However, he also noted some caveats.

“Interpretation of the results of the study is not straightforward, illustrating the complexity of the issue,” Dr. Cohen said. “One issue is that the patients in the study were relatively young, with an average age of 45, which is not a group in which we typically would consider stopping therapy.”

Dr. Bose has received a postdoctoral fellowship grant from the Multiple Sclerosis Society of Canada. Dr. Cohen reports having received personal compensation for consulting for Biogen, Bristol-Myers Squibb, Convelo, Genentech, Janssen, NervGen, Novartis, and PSI; speaking for H3 Communications; and serving as an editor of the Multiple Sclerosis Journal.

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

WEST PALM BEACH, FL – Including serum neurofilament light chain (sNfL) and serum glial fibrillary acidic protein (sGFAP) at multiple sclerosis (MS) onset may lead to better prediction of long-term outcomes and relapse risk, new research suggests.

The research shows that once standard clinical models can be incorporated into practice, the early measurement of these biomarkers will provide useful information in predicting who may be at risk of poorer outcomes, researcher Gauruv Bose, MD, Brigham Multiple Sclerosis Center, Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, told this news organization.

The findings were presented at annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
 

Better together?

Although higher baseline sNfL levels in MS have previously been linked to greater brain atrophy and other long-term outcomes, and sGFAP changes are also associated with inflammation and damage through the disease course, less is known about longer-term effects of the two biomarker measures combined, Dr. Bose said.

“The value of using both sNfL and sGFAP in predictive models is of interest, since one correlates with neuroaxonal damage, while the other has correlated with astrocytic glial damage/cell turnover – potentially, though differently, reflecting inflammatory damage and neurodegeneration,” he added.

To investigate the relationship, the researchers evaluated patients with MS enrolled at the Brigham Multiple Sclerosis Center. All underwent neurologic examinations every 6 months, and MRI scans and blood samples were collected every year. Some had more than 20 years of follow-up.

The first study involved 144 patients (mean age, 37.4 years) from whom two samples of sNfL and sGFAP were collected within 3 years of MS onset.

The median baseline sNfL level was 10.7 pg/mL, and 50 patients (34.7%) already showed increases in sNfL at the 1-year follow-up. Their median sGFAP level at onset was 96 pg/mL, and 59 patients (41%) showed increases in sGFAP at the 1-year follow-up.

Results showed that higher baseline sNfL levels were significantly associated with increased risk for MS relapse at 10 years (hazard ratio, 1.34; P = .04), as well as with the development of new MRI lesions (HR, 1.35; P = .022).

Of the study group, 25 (17.4%) developed secondary progressive MS (SPMS) by the 10-year follow-up. For those prognostic assessments, the investigators compared utilization of a model using well-established clinical predictors of SPMS with and without the inclusion of sNfL and sGFAP.

The clinical model included key factors such as age, sex, body mass index, Extended Disability Status Scale (EDSS), timed 25-foot walk, and other measures.

The researchers found the clinical model alone predicted 10-year outcomes with an area under the receiver operating characteristic curve (AUC) of 0.75. However, with the addition of baseline sNfL and sGFAP measures, the AUC was improved to 0.79 (P = .0008).

Furthermore, the inclusion of additional follow-up sNfL and sGFAP measurements taken after baseline further improved the model’s AUC (0.82; P = .046).

The addition of the sNfL and sGFAP measures to the clinical models also improved the prediction of disability in MS at 10 years on EDSS (P = .068), as well as prediction of 10-year brain T2 lesion volume (P = .009) and brain parenchymal fraction (P = .04).
 

Relapse predictor?

In the second study, Dr. Bose and colleagues evaluated the role of the two serum measures in predicting relapse after disease-modifying therapy (DMT) discontinuation. That study included 42 patients who discontinued DMT treatment after having been disease-activity free for 2 years while on the drugs. They were compared with 36 patients who had similar characteristics and had continued DMT treatment.

All patients (mean age, 44.5 years) had a mean of 7.4 years since prior disease activity.

Increases in sNfL following DMT discontinuation, but not before, were associated with a significantly greater risk for clinical disease worsening at a mean follow-up of 7.5 years (HR, 9.4; P = .007). Change in sGFAP was associated with new MRI lesions (HR, 8.3; P = .039), compared with no changes.

“The crux of this study” was that patients with increased biomarker levels after stopping DMTs “were at a significantly higher risk for disease activity in the future compared to those whose biomarker levels remained stable,” Dr. Bose noted.

“We think this finding, if replicated in another cohort, has the potential to be included in guidelines regarding stopping DMT in patients with MS,” he added.
 

Clinically useful?

Jeffrey Cohen, MD, current president of ACTRIMS, said the first study supports mounting evidence on how sNfL and sGFAP at onset can predict future disease and have the potential to improve current predictive models.

“Combining clinical, MRI, and serum biomarkers into a single model works better than any of the three factors individually,” said Dr. Cohen, who is director of the Mellen Center for MS Treatment and Research and professor of neurology at the Cleveland Clinic.

“For the clinician, this information may help with treatment selection,” he added.

Dr. Cohen noted that the suggestion that the biomarkers could also be helpful in predicting relapse after discontinuation is of importance.

“Increasingly, we are considering this issue in the clinical setting,” he said. However, he also noted some caveats.

“Interpretation of the results of the study is not straightforward, illustrating the complexity of the issue,” Dr. Cohen said. “One issue is that the patients in the study were relatively young, with an average age of 45, which is not a group in which we typically would consider stopping therapy.”

Dr. Bose has received a postdoctoral fellowship grant from the Multiple Sclerosis Society of Canada. Dr. Cohen reports having received personal compensation for consulting for Biogen, Bristol-Myers Squibb, Convelo, Genentech, Janssen, NervGen, Novartis, and PSI; speaking for H3 Communications; and serving as an editor of the Multiple Sclerosis Journal.

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

More than 18 months after the Watchman FLX device was licensed by the Food and Drug Administration for closure of the left atrial appendage (LAA), a prospective analysis of registry data presented at CRT 2022, sponsored by MedStar Heart & Vascular Institute, supports its safely outside of the clinical trial setting.

The data, drawn from the LAA occlusion registry of the National Cardiovascular Data Registry, showed a mortality rate at 45 days of under 1.0%, which was consistent with the acceptably low rate of other adverse events, according to Samir R. Kapadia, MD, chair of cardiovascular medicine at the Cleveland Clinic.

Only 0.5% had a pericardial effusion within 45 days of LAA closure that required intervention. Of those without effusion, 95% had a leak of less than 3 mm and 82% had no leak at all, according to Dr. Kapadia.

Patients enrolled in this analysis, called SURPASS (Surveillance Post Approval Analysis Plan), had undergone left atrial closure with the device from August 2020 to September 2022. There were no exclusion criteria. Ultimately, 2 years of follow-up is planned.

With more than 16,000 patients enrolled, the data on 14,363 patients in this initial 45-day analysis represents “the largest number of Watchman FLX patients evaluated to date,” Dr. Kapadia reported.
 

Device implantation success 97.5%

The Watchman FLX, which is delivered to the left atrial appendage by a transcatheter approach, was deployed successfully in 97.5% of all 16,048 patients enrolled in the registry. In the 398 cases without successful deployment, the anatomy was not conducive in nearly 70%. Other reasons included failure to meet device-release criteria and change in patient condition.

The outcomes of interest at 45 days were ischemic strokes, systemic emboli, device-related thrombi, device embolization, and bleeding. The primary endpoints at 2 years will be strokes and thrombotic events.

For stroke, the incidence within 45 days was 0.39%. About 25% of the strokes were hemorrhagic and the remainder were ischemic. There was 1 systemic embolism (0.01%), 5 device embolizations (0.03%), and 30 device-related thrombotic events (0.24%). Major bleeding occurred in 508 patients (3.55%).

For context, Dr. Kapadia compared these results to those observed in the PINNACLE FLX trial, which was a nonrandomized but prospective study of the Watchman FLX published about 1 year ago. In PINNACLE FLX, the enrollment was open to patients indicated for oral anticoagulation but who had an appropriate rationale for seeking a nonpharmacological alternative.

Taken from different studies, the outcomes at 45 days should not be construed as a direct comparison, but the similarity of the results can be considered reassuring, according to Dr. Kapadia.

For the composite safety endpoint of all-cause death, ischemic stroke, systemic embolism, or implantation-related events requiring intervention, the rates in SURPASS (0.4%) and PINNACLE FLX (0.5%) were nearly identical. Device leak rates (82.0% vs. 82.8%), stroke rates (0.4% vs. 0.7%), and all-cause death rates (0.9% vs. 0.5%) were also similar.

The similarity of the SURPASS and PINNACLE FLX data provides another level of reassurance.

“The SURPASS registry confirms the safety of the Watchman Flex in the real-world experience when the device is being used by many different operators in a large patient population,” Dr. Kapadia said in an interview.

In “appropriately selected patients,” the SURPASS data confirm that the Watchman FLX device “provides a safe and effective treatment option,” he added.

Relative to the PINNACLE FLX study, which enrolled 400 patients, it is noteworthy that the median age in SURPASS was older (76 vs. 73.8 years), a potential disadvantage in demonstrating comparable safety. The proportion of non-White patients was similar (6.7% vs. 6.3%). SURPASS had a higher proportion of women (40% vs. 35.5%).

Mitchel L. Zoler/MDedge News

The SURPASS data are credible, according to Vivek Y. Reddy, MD, director of cardiac arrhythmia services, Mount Sinai Health System, New York.

“While there are certainly limitations to registry data, I do feel pretty confident that these procedural complication and success rates [in SURPASS] do indeed reflect reality,” said Dr. Reddy, who was a coauthor of the PINNACLE FLX trial. In general, the SURPASS data “mirror most of our clinical experiences in routine clinical practice.”

With these registry data backing up multiple clinical studies, Dr. Reddy concluded, “I do believe that it is fair to say that Watchman-FLX implantation is a quite safe procedure.”

Dr. Kapadia reported no potential conflicts of interest. Dr. Reddy reported a financial relationship with Boston Scientific.

More than 18 months after the Watchman FLX device was licensed by the Food and Drug Administration for closure of the left atrial appendage (LAA), a prospective analysis of registry data presented at CRT 2022, sponsored by MedStar Heart & Vascular Institute, supports its safely outside of the clinical trial setting.

The data, drawn from the LAA occlusion registry of the National Cardiovascular Data Registry, showed a mortality rate at 45 days of under 1.0%, which was consistent with the acceptably low rate of other adverse events, according to Samir R. Kapadia, MD, chair of cardiovascular medicine at the Cleveland Clinic.

Only 0.5% had a pericardial effusion within 45 days of LAA closure that required intervention. Of those without effusion, 95% had a leak of less than 3 mm and 82% had no leak at all, according to Dr. Kapadia.

Patients enrolled in this analysis, called SURPASS (Surveillance Post Approval Analysis Plan), had undergone left atrial closure with the device from August 2020 to September 2022. There were no exclusion criteria. Ultimately, 2 years of follow-up is planned.

With more than 16,000 patients enrolled, the data on 14,363 patients in this initial 45-day analysis represents “the largest number of Watchman FLX patients evaluated to date,” Dr. Kapadia reported.
 

Device implantation success 97.5%

The Watchman FLX, which is delivered to the left atrial appendage by a transcatheter approach, was deployed successfully in 97.5% of all 16,048 patients enrolled in the registry. In the 398 cases without successful deployment, the anatomy was not conducive in nearly 70%. Other reasons included failure to meet device-release criteria and change in patient condition.

The outcomes of interest at 45 days were ischemic strokes, systemic emboli, device-related thrombi, device embolization, and bleeding. The primary endpoints at 2 years will be strokes and thrombotic events.

For stroke, the incidence within 45 days was 0.39%. About 25% of the strokes were hemorrhagic and the remainder were ischemic. There was 1 systemic embolism (0.01%), 5 device embolizations (0.03%), and 30 device-related thrombotic events (0.24%). Major bleeding occurred in 508 patients (3.55%).

For context, Dr. Kapadia compared these results to those observed in the PINNACLE FLX trial, which was a nonrandomized but prospective study of the Watchman FLX published about 1 year ago. In PINNACLE FLX, the enrollment was open to patients indicated for oral anticoagulation but who had an appropriate rationale for seeking a nonpharmacological alternative.

Taken from different studies, the outcomes at 45 days should not be construed as a direct comparison, but the similarity of the results can be considered reassuring, according to Dr. Kapadia.

For the composite safety endpoint of all-cause death, ischemic stroke, systemic embolism, or implantation-related events requiring intervention, the rates in SURPASS (0.4%) and PINNACLE FLX (0.5%) were nearly identical. Device leak rates (82.0% vs. 82.8%), stroke rates (0.4% vs. 0.7%), and all-cause death rates (0.9% vs. 0.5%) were also similar.

The similarity of the SURPASS and PINNACLE FLX data provides another level of reassurance.

“The SURPASS registry confirms the safety of the Watchman Flex in the real-world experience when the device is being used by many different operators in a large patient population,” Dr. Kapadia said in an interview.

In “appropriately selected patients,” the SURPASS data confirm that the Watchman FLX device “provides a safe and effective treatment option,” he added.

Relative to the PINNACLE FLX study, which enrolled 400 patients, it is noteworthy that the median age in SURPASS was older (76 vs. 73.8 years), a potential disadvantage in demonstrating comparable safety. The proportion of non-White patients was similar (6.7% vs. 6.3%). SURPASS had a higher proportion of women (40% vs. 35.5%).

Mitchel L. Zoler/MDedge News

The SURPASS data are credible, according to Vivek Y. Reddy, MD, director of cardiac arrhythmia services, Mount Sinai Health System, New York.

“While there are certainly limitations to registry data, I do feel pretty confident that these procedural complication and success rates [in SURPASS] do indeed reflect reality,” said Dr. Reddy, who was a coauthor of the PINNACLE FLX trial. In general, the SURPASS data “mirror most of our clinical experiences in routine clinical practice.”

With these registry data backing up multiple clinical studies, Dr. Reddy concluded, “I do believe that it is fair to say that Watchman-FLX implantation is a quite safe procedure.”

Dr. Kapadia reported no potential conflicts of interest. Dr. Reddy reported a financial relationship with Boston Scientific.

More than 18 months after the Watchman FLX device was licensed by the Food and Drug Administration for closure of the left atrial appendage (LAA), a prospective analysis of registry data presented at CRT 2022, sponsored by MedStar Heart & Vascular Institute, supports its safely outside of the clinical trial setting.

The data, drawn from the LAA occlusion registry of the National Cardiovascular Data Registry, showed a mortality rate at 45 days of under 1.0%, which was consistent with the acceptably low rate of other adverse events, according to Samir R. Kapadia, MD, chair of cardiovascular medicine at the Cleveland Clinic.

Only 0.5% had a pericardial effusion within 45 days of LAA closure that required intervention. Of those without effusion, 95% had a leak of less than 3 mm and 82% had no leak at all, according to Dr. Kapadia.

Patients enrolled in this analysis, called SURPASS (Surveillance Post Approval Analysis Plan), had undergone left atrial closure with the device from August 2020 to September 2022. There were no exclusion criteria. Ultimately, 2 years of follow-up is planned.

With more than 16,000 patients enrolled, the data on 14,363 patients in this initial 45-day analysis represents “the largest number of Watchman FLX patients evaluated to date,” Dr. Kapadia reported.
 

Device implantation success 97.5%

The Watchman FLX, which is delivered to the left atrial appendage by a transcatheter approach, was deployed successfully in 97.5% of all 16,048 patients enrolled in the registry. In the 398 cases without successful deployment, the anatomy was not conducive in nearly 70%. Other reasons included failure to meet device-release criteria and change in patient condition.

The outcomes of interest at 45 days were ischemic strokes, systemic emboli, device-related thrombi, device embolization, and bleeding. The primary endpoints at 2 years will be strokes and thrombotic events.

For stroke, the incidence within 45 days was 0.39%. About 25% of the strokes were hemorrhagic and the remainder were ischemic. There was 1 systemic embolism (0.01%), 5 device embolizations (0.03%), and 30 device-related thrombotic events (0.24%). Major bleeding occurred in 508 patients (3.55%).

For context, Dr. Kapadia compared these results to those observed in the PINNACLE FLX trial, which was a nonrandomized but prospective study of the Watchman FLX published about 1 year ago. In PINNACLE FLX, the enrollment was open to patients indicated for oral anticoagulation but who had an appropriate rationale for seeking a nonpharmacological alternative.

Taken from different studies, the outcomes at 45 days should not be construed as a direct comparison, but the similarity of the results can be considered reassuring, according to Dr. Kapadia.

For the composite safety endpoint of all-cause death, ischemic stroke, systemic embolism, or implantation-related events requiring intervention, the rates in SURPASS (0.4%) and PINNACLE FLX (0.5%) were nearly identical. Device leak rates (82.0% vs. 82.8%), stroke rates (0.4% vs. 0.7%), and all-cause death rates (0.9% vs. 0.5%) were also similar.

The similarity of the SURPASS and PINNACLE FLX data provides another level of reassurance.

“The SURPASS registry confirms the safety of the Watchman Flex in the real-world experience when the device is being used by many different operators in a large patient population,” Dr. Kapadia said in an interview.

In “appropriately selected patients,” the SURPASS data confirm that the Watchman FLX device “provides a safe and effective treatment option,” he added.

Relative to the PINNACLE FLX study, which enrolled 400 patients, it is noteworthy that the median age in SURPASS was older (76 vs. 73.8 years), a potential disadvantage in demonstrating comparable safety. The proportion of non-White patients was similar (6.7% vs. 6.3%). SURPASS had a higher proportion of women (40% vs. 35.5%).

Mitchel L. Zoler/MDedge News

The SURPASS data are credible, according to Vivek Y. Reddy, MD, director of cardiac arrhythmia services, Mount Sinai Health System, New York.

“While there are certainly limitations to registry data, I do feel pretty confident that these procedural complication and success rates [in SURPASS] do indeed reflect reality,” said Dr. Reddy, who was a coauthor of the PINNACLE FLX trial. In general, the SURPASS data “mirror most of our clinical experiences in routine clinical practice.”

With these registry data backing up multiple clinical studies, Dr. Reddy concluded, “I do believe that it is fair to say that Watchman-FLX implantation is a quite safe procedure.”

Dr. Kapadia reported no potential conflicts of interest. Dr. Reddy reported a financial relationship with Boston Scientific.

PHOENIX – Before considering oral steroids or biologic therapies, many people with difficult-to-control asthma can reduce symptoms by addressing medication adherence and inhaler technique – and digital monitoring devices can play a key role.

Often physicians “will approach a patient about a biologic if they’re not responding to standard therapy. But we need to sometimes go back to those basic building blocks, like, are you taking the standard therapy?” William C. Anderson, MD, codirector of the multidisciplinary asthma clinic at Children’s Hospital Colorado, Aurora, said in an interview.

At the annual meeting of the American Academy of Allergy, Asthma, and Immunology, he and others presented data highlighting the diagnostic and therapeutic potential of digital monitoring devices for difficult-to-control asthma, the theme of the 2022s meeting.

The Global Initiative for Asthma (GINA) defines asthma as “difficult to control” if it remains uncontrolled despite medium- or high-dose inhaled corticosteroids with a second controller or with maintenance oral steroids, or if the asthma requires high-dose treatment to curb symptoms and exacerbations. About 17% of adult asthma patients have difficult-to-control asthma, according to the 2021 GINA report. 

However, correcting for inhaling technique and adherence cuts the 17% down to just 3.7%, Giselle Mosnaim, MD, an allergist at NorthShore University HealthSystem outside Chicago and AAAAI immediate past president, told attendees at a Feb. 25 session on digital technologies for asthma management.

The CRITIKAL study, which reviewed data from more than 5,000 asthma patients, “showed that, if you have critical errors in inhaler technique, this leads to worse asthma outcomes and increased asthma exacerbations,” Dr. Mosnaim said. Sadly, it also shows that, from 1975 to 2014, despite new devices and new technologies, “we still have poor inhaler technique.”

As for ways to measure adherence, physician judgments tend to be inaccurate, patient self-reporting has proved unreliable, and prescription refill data doesn’t indicate whether patients actually used the medications. “The ideal measure of adherence should be objective, accurate and unobtrusive to minimize impact on patient behavior and allow reliable data collection in real-world settings,” Dr. Mosnaim said. “So electronic medication monitors are the gold standard.” 
 

Tracking adherence

A closing afternoon session featured three presentations on research tracking adherence and outcomes in difficult-to-treat asthma patients – two pediatric cohorts and one across all ages. All studies used the Propeller Health sensor, a Food and Drug Administration–cleared device that attaches to the patient’s inhaler and automatically collects information on where, when, and how often they use their medication. The sensor then sends that information to a data cloud accessible to the patient and their health care professional.

Dr. Anderson’s team scoured a nationwide Propeller Health database for 8,000 patients using the digital monitors with controller therapies for asthma or chronic obstructive pulmonary disease (COPD). The study explored whether adherence differed for once-daily versus twice-daily medications, and if adherence differed based on patient age (4-60+ years).

For both asthma and COPD patients, those on once-daily regimens had higher medication adherence, compared with those who were prescribed twice-daily therapies. Plus, a greater proportion of once-daily patients met the prespecified 80% adherence threshold.

Looking across ages, medication use in the youngest group (aged 4-11 years) looked comparable with 30-somethings, “probably because parents are the ones giving the drug,” Dr. Anderson said. Mirroring patterns from other studies, adherence levels dipped in adolescents and young adults, relative to other age subsets.

Since this population-level analysis didn’t include individualized data on exacerbations or asthma control, “we can’t relate this to outcomes,” Dr. Anderson noted. But he said the data correlating medication use with adherence suggest that once-daily formulations may be the better option.

In one of the two pediatric studies, Matt McCulloch, MD, an allergy and immunology fellow working with Dr. Anderson, and colleagues reviewed charts of 40 children who received care at the Colorado Children’s multidisciplinary asthma clinic between 2018 and 2021. Half of these patients used Propeller Health sensors with their daily inhaled controller; the other patients were matched for age, ethnicity, sex, medication level, and disease control and severity – but had no electronic monitoring device.

On the whole, children who used digital monitoring for 12 months did not fare much better than matched controls on lung function (judged by forced expiratory volume) or asthma control (measured by Asthma Control Test scores).

However, within the digital monitoring group, patients who stayed on the Propeller system for 12 months did have better asthma control, fewer exacerbations, and improved asthma severity scores (measured by the Composite Asthma Severity Index), compared with when they first began digital monitoring. These children had all received care at the clinic for a while before their families opted for the electronic sensor, so “the effect wouldn’t have just been from starting in the clinic,” Dr. McCulloch said in an interview.

The gains came despite waning medication adherence. Similar to other digital monitoring studies, use of daily controller therapies in this retrospective analysis began at 50%-80% but dropped considerably during the first 4-5 months before settling into the 20%-30% range by 1 year.

Rachelle Ramsey, PhD, a pediatric research psychologist at Cincinnati Children’s Hospital Medical Center, presented data from 20 children with difficult-to-treat asthma who received 8 weeks of a digital adherence intervention during a 12-month treatment period. They analyzed three subsets – each with interventions based on how well the patients were managing daily controller therapy at baseline.

One patient with high (>80%) baseline adherence just received digital monitoring. The seven patients who began the study with intermediate (50%-80%) adherence received digital monitoring plus prescriptive text messaging. And the 12 children with poorest (<50%) baseline adherence received digital monitoring and a telehealth session in which a behavioral health specialist helped them set goals and create strategies to overcome barriers – for example, keeping the inhaler near their toothbrush in order to pair medication use with a daily habit.

“Overall, we found that matching Propeller with a behavioral intervention really improved adherence,” Dr. Ramsey said in an interview. While patients were receiving the intervention, adherence averaged across all groups increased from 39% to 76%. However, once the intervention period ended, the group’s adherence regressed toward baseline (36%).

Although adherence did not associate with clinical gains in this small study, the use of digital monitoring to improve medication adherence has translated to better outcomes in other recent efforts.
 

Remote monitoring

In a quality improvement project in the United Kingdom, nurses asked difficult-to-control asthma patients if they understood how to use their corticosteroid/long-acting beta₂-agonist (LABA) inhalers and if they were adhering to treatment guidelines.

Those who answered yes to these questions were invited to a 28-day study that involved swapping their steroid/LABA inhalers for a different controller/bronchodilator (fluticasone/salmeterol) with INCA (Inhaler Compliance Assessment), a device that not only tracks adherence but also uses acoustics to gauge inhaler technique.

Among the 23 patients who participated, many had better clinical outcomes after 28 days of INCA monitoring. As Dr. Mosnaim told attendees, “what was amazing is so many of the patients that had been these difficult-to-control asthmatics who would have gone on to oral steroids or perhaps a biologic – lo and behold, you put them on a digital inhaler, and what do you see?” In two-thirds of the patients, “you see FeNo [a test that measures airway inflammation by detecting nitric oxide in exhalations] goes down. You see spirometry improve. You see the asthma control questionnaire improve. You see blood eosinophils go down.”

And in a 2020 randomized trial, Dr. Mosnaim and colleagues recruited 100 adults with uncontrolled asthma who had prescriptions for a daily inhaled corticosteroid and a short-acting beta-agonist (SABA) inhaler. Participants received Propeller sensors for their steroid and SABA inhalers. After a 2-week run-in period to calculate baseline corticosteroid adherence and SABA use for all participants, half the participants were randomly assigned to the control group, which had the app and sensor in silent mode, merely to collect data on medication use – whereas the treatment group received reminders, alerts, and monthly phone calls from providers who gave feedback on adherence and technique.

After 3 months of digital monitoring, patients didn’t use their rescue medication quite as often – as judged by a rise in the percentage of SABA-free days, compared with when they began the study. But the change in SABA-free days relative to baseline was more pronounced in the treatment group (19%) than in the control group (6%).

As seen in the other digital monitoring studies, adherence to daily corticosteroids fell with time, but the drop was milder in treated participants (2%) versus the control group (17%). So in this study, digital monitoring plus mobile app reminders and clinician feedback “prevented against fall in adherence to inhaled steroids over time,” Dr. Mosnaim said.

These results are “very encouraging” and offer “proof of concept that this type of remote monitoring could work,” Thanai Pongdee, MD, an allergist-immunologist with the Mayo Clinic in Rochester, Minn., said in an interview. One limitation was that the study was too short to measure exacerbation rates. A yearlong analysis would be “really fascinating because you’d catch all the seasons of the year – all the pollen seasons, all these things that could exacerbate you. Some people’s asthma can be quite seasonal.”

More important, the clinical utility of digital sensors will depend on how physicians choose to use them. If the doctor puts out a “blanket recommendation for using it but doesn’t ask you about it or doesn’t use the data to inform your care, then I think people just lose engagement and lose excitement over it,” Dr. Ramsey said. But if the health care team “asks you about the data or looks at the data with you or shows you how valuable this can be to your care, then I think that changes things.”

Building these analyses and interactions into the clinic workflow isn’t trivial. “If you have this wealth of data coming in, how are you going to look at it? Are you going to have an individual person assigned to this role? How are you going to respond to alerts?” Dr. Anderson asked.

In addition, because some digital monitors issue alerts when a patient’s asthma is not well controlled, some providers worry about liability if “something bad were to happen if you had that data but didn’t act upon it,” he said. Yet he noted that remote data monitoring is already used routinely in other areas of medicine, such as managing diabetes and heart conditions, “and it’s not like people are getting dinged for that stuff.”

Another issue is cost. Insurance only covers digital monitors in select cases, but it’s a bit of a catch-22. Insurers “don’t want to cover it until they get the data, but you can’t get the data until insurance covers it,” said Dr. Anderson, who added that “this year we finally got CPT reimbursement codes for monitoring devices.”

On the whole, studies of digital medication monitors suggest that better outcomes require “a good partnership between the health care provider and the patient,” Dr. Pongdee said. “It wasn’t like you could just put these things on and expect them to help. You still need that personal relationship to get the optimal results. We can have all this technology, but you still can’t take the people out of it.”

Dr. Mosnaim reported receiving current research grant support from GlaxoSmithKline, Novartis, Sanofi-Regeneron, and Teva; and past research grant support from AstraZeneca, Alk-Abello, and Genentech. She is immediate past president of the AAAAI, and directs the board of directors for the American Board of Allergy and Immunology. Dr. Anderson has served as a consultant for Regeneron, GlaxoSmithKline, and AstraZeneca, and has received research support from Colorado Medicaid. Dr. McCulloch and Dr. Ramsey disclosed no relevant financial relationships. Dr. Pongdee serves as an at-large director on the American Academy of Allergy, Asthma and Immunology board of directors. He receives grant funding from GlaxoSmithKline, and the Mayo Clinic is a trial site for GlaxoSmithKline and AstraZeneca.

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

PHOENIX – Before considering oral steroids or biologic therapies, many people with difficult-to-control asthma can reduce symptoms by addressing medication adherence and inhaler technique – and digital monitoring devices can play a key role.

Often physicians “will approach a patient about a biologic if they’re not responding to standard therapy. But we need to sometimes go back to those basic building blocks, like, are you taking the standard therapy?” William C. Anderson, MD, codirector of the multidisciplinary asthma clinic at Children’s Hospital Colorado, Aurora, said in an interview.

At the annual meeting of the American Academy of Allergy, Asthma, and Immunology, he and others presented data highlighting the diagnostic and therapeutic potential of digital monitoring devices for difficult-to-control asthma, the theme of the 2022s meeting.

The Global Initiative for Asthma (GINA) defines asthma as “difficult to control” if it remains uncontrolled despite medium- or high-dose inhaled corticosteroids with a second controller or with maintenance oral steroids, or if the asthma requires high-dose treatment to curb symptoms and exacerbations. About 17% of adult asthma patients have difficult-to-control asthma, according to the 2021 GINA report. 

However, correcting for inhaling technique and adherence cuts the 17% down to just 3.7%, Giselle Mosnaim, MD, an allergist at NorthShore University HealthSystem outside Chicago and AAAAI immediate past president, told attendees at a Feb. 25 session on digital technologies for asthma management.

The CRITIKAL study, which reviewed data from more than 5,000 asthma patients, “showed that, if you have critical errors in inhaler technique, this leads to worse asthma outcomes and increased asthma exacerbations,” Dr. Mosnaim said. Sadly, it also shows that, from 1975 to 2014, despite new devices and new technologies, “we still have poor inhaler technique.”

As for ways to measure adherence, physician judgments tend to be inaccurate, patient self-reporting has proved unreliable, and prescription refill data doesn’t indicate whether patients actually used the medications. “The ideal measure of adherence should be objective, accurate and unobtrusive to minimize impact on patient behavior and allow reliable data collection in real-world settings,” Dr. Mosnaim said. “So electronic medication monitors are the gold standard.” 
 

Tracking adherence

A closing afternoon session featured three presentations on research tracking adherence and outcomes in difficult-to-treat asthma patients – two pediatric cohorts and one across all ages. All studies used the Propeller Health sensor, a Food and Drug Administration–cleared device that attaches to the patient’s inhaler and automatically collects information on where, when, and how often they use their medication. The sensor then sends that information to a data cloud accessible to the patient and their health care professional.

Dr. Anderson’s team scoured a nationwide Propeller Health database for 8,000 patients using the digital monitors with controller therapies for asthma or chronic obstructive pulmonary disease (COPD). The study explored whether adherence differed for once-daily versus twice-daily medications, and if adherence differed based on patient age (4-60+ years).

For both asthma and COPD patients, those on once-daily regimens had higher medication adherence, compared with those who were prescribed twice-daily therapies. Plus, a greater proportion of once-daily patients met the prespecified 80% adherence threshold.

Looking across ages, medication use in the youngest group (aged 4-11 years) looked comparable with 30-somethings, “probably because parents are the ones giving the drug,” Dr. Anderson said. Mirroring patterns from other studies, adherence levels dipped in adolescents and young adults, relative to other age subsets.

Since this population-level analysis didn’t include individualized data on exacerbations or asthma control, “we can’t relate this to outcomes,” Dr. Anderson noted. But he said the data correlating medication use with adherence suggest that once-daily formulations may be the better option.

In one of the two pediatric studies, Matt McCulloch, MD, an allergy and immunology fellow working with Dr. Anderson, and colleagues reviewed charts of 40 children who received care at the Colorado Children’s multidisciplinary asthma clinic between 2018 and 2021. Half of these patients used Propeller Health sensors with their daily inhaled controller; the other patients were matched for age, ethnicity, sex, medication level, and disease control and severity – but had no electronic monitoring device.

On the whole, children who used digital monitoring for 12 months did not fare much better than matched controls on lung function (judged by forced expiratory volume) or asthma control (measured by Asthma Control Test scores).

However, within the digital monitoring group, patients who stayed on the Propeller system for 12 months did have better asthma control, fewer exacerbations, and improved asthma severity scores (measured by the Composite Asthma Severity Index), compared with when they first began digital monitoring. These children had all received care at the clinic for a while before their families opted for the electronic sensor, so “the effect wouldn’t have just been from starting in the clinic,” Dr. McCulloch said in an interview.

The gains came despite waning medication adherence. Similar to other digital monitoring studies, use of daily controller therapies in this retrospective analysis began at 50%-80% but dropped considerably during the first 4-5 months before settling into the 20%-30% range by 1 year.

Rachelle Ramsey, PhD, a pediatric research psychologist at Cincinnati Children’s Hospital Medical Center, presented data from 20 children with difficult-to-treat asthma who received 8 weeks of a digital adherence intervention during a 12-month treatment period. They analyzed three subsets – each with interventions based on how well the patients were managing daily controller therapy at baseline.

One patient with high (>80%) baseline adherence just received digital monitoring. The seven patients who began the study with intermediate (50%-80%) adherence received digital monitoring plus prescriptive text messaging. And the 12 children with poorest (<50%) baseline adherence received digital monitoring and a telehealth session in which a behavioral health specialist helped them set goals and create strategies to overcome barriers – for example, keeping the inhaler near their toothbrush in order to pair medication use with a daily habit.

“Overall, we found that matching Propeller with a behavioral intervention really improved adherence,” Dr. Ramsey said in an interview. While patients were receiving the intervention, adherence averaged across all groups increased from 39% to 76%. However, once the intervention period ended, the group’s adherence regressed toward baseline (36%).

Although adherence did not associate with clinical gains in this small study, the use of digital monitoring to improve medication adherence has translated to better outcomes in other recent efforts.
 

Remote monitoring

In a quality improvement project in the United Kingdom, nurses asked difficult-to-control asthma patients if they understood how to use their corticosteroid/long-acting beta₂-agonist (LABA) inhalers and if they were adhering to treatment guidelines.

Those who answered yes to these questions were invited to a 28-day study that involved swapping their steroid/LABA inhalers for a different controller/bronchodilator (fluticasone/salmeterol) with INCA (Inhaler Compliance Assessment), a device that not only tracks adherence but also uses acoustics to gauge inhaler technique.

Among the 23 patients who participated, many had better clinical outcomes after 28 days of INCA monitoring. As Dr. Mosnaim told attendees, “what was amazing is so many of the patients that had been these difficult-to-control asthmatics who would have gone on to oral steroids or perhaps a biologic – lo and behold, you put them on a digital inhaler, and what do you see?” In two-thirds of the patients, “you see FeNo [a test that measures airway inflammation by detecting nitric oxide in exhalations] goes down. You see spirometry improve. You see the asthma control questionnaire improve. You see blood eosinophils go down.”

And in a 2020 randomized trial, Dr. Mosnaim and colleagues recruited 100 adults with uncontrolled asthma who had prescriptions for a daily inhaled corticosteroid and a short-acting beta-agonist (SABA) inhaler. Participants received Propeller sensors for their steroid and SABA inhalers. After a 2-week run-in period to calculate baseline corticosteroid adherence and SABA use for all participants, half the participants were randomly assigned to the control group, which had the app and sensor in silent mode, merely to collect data on medication use – whereas the treatment group received reminders, alerts, and monthly phone calls from providers who gave feedback on adherence and technique.

After 3 months of digital monitoring, patients didn’t use their rescue medication quite as often – as judged by a rise in the percentage of SABA-free days, compared with when they began the study. But the change in SABA-free days relative to baseline was more pronounced in the treatment group (19%) than in the control group (6%).

As seen in the other digital monitoring studies, adherence to daily corticosteroids fell with time, but the drop was milder in treated participants (2%) versus the control group (17%). So in this study, digital monitoring plus mobile app reminders and clinician feedback “prevented against fall in adherence to inhaled steroids over time,” Dr. Mosnaim said.

These results are “very encouraging” and offer “proof of concept that this type of remote monitoring could work,” Thanai Pongdee, MD, an allergist-immunologist with the Mayo Clinic in Rochester, Minn., said in an interview. One limitation was that the study was too short to measure exacerbation rates. A yearlong analysis would be “really fascinating because you’d catch all the seasons of the year – all the pollen seasons, all these things that could exacerbate you. Some people’s asthma can be quite seasonal.”

More important, the clinical utility of digital sensors will depend on how physicians choose to use them. If the doctor puts out a “blanket recommendation for using it but doesn’t ask you about it or doesn’t use the data to inform your care, then I think people just lose engagement and lose excitement over it,” Dr. Ramsey said. But if the health care team “asks you about the data or looks at the data with you or shows you how valuable this can be to your care, then I think that changes things.”

Building these analyses and interactions into the clinic workflow isn’t trivial. “If you have this wealth of data coming in, how are you going to look at it? Are you going to have an individual person assigned to this role? How are you going to respond to alerts?” Dr. Anderson asked.

In addition, because some digital monitors issue alerts when a patient’s asthma is not well controlled, some providers worry about liability if “something bad were to happen if you had that data but didn’t act upon it,” he said. Yet he noted that remote data monitoring is already used routinely in other areas of medicine, such as managing diabetes and heart conditions, “and it’s not like people are getting dinged for that stuff.”

Another issue is cost. Insurance only covers digital monitors in select cases, but it’s a bit of a catch-22. Insurers “don’t want to cover it until they get the data, but you can’t get the data until insurance covers it,” said Dr. Anderson, who added that “this year we finally got CPT reimbursement codes for monitoring devices.”

On the whole, studies of digital medication monitors suggest that better outcomes require “a good partnership between the health care provider and the patient,” Dr. Pongdee said. “It wasn’t like you could just put these things on and expect them to help. You still need that personal relationship to get the optimal results. We can have all this technology, but you still can’t take the people out of it.”

Dr. Mosnaim reported receiving current research grant support from GlaxoSmithKline, Novartis, Sanofi-Regeneron, and Teva; and past research grant support from AstraZeneca, Alk-Abello, and Genentech. She is immediate past president of the AAAAI, and directs the board of directors for the American Board of Allergy and Immunology. Dr. Anderson has served as a consultant for Regeneron, GlaxoSmithKline, and AstraZeneca, and has received research support from Colorado Medicaid. Dr. McCulloch and Dr. Ramsey disclosed no relevant financial relationships. Dr. Pongdee serves as an at-large director on the American Academy of Allergy, Asthma and Immunology board of directors. He receives grant funding from GlaxoSmithKline, and the Mayo Clinic is a trial site for GlaxoSmithKline and AstraZeneca.

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

PHOENIX – Before considering oral steroids or biologic therapies, many people with difficult-to-control asthma can reduce symptoms by addressing medication adherence and inhaler technique – and digital monitoring devices can play a key role.

Often physicians “will approach a patient about a biologic if they’re not responding to standard therapy. But we need to sometimes go back to those basic building blocks, like, are you taking the standard therapy?” William C. Anderson, MD, codirector of the multidisciplinary asthma clinic at Children’s Hospital Colorado, Aurora, said in an interview.

At the annual meeting of the American Academy of Allergy, Asthma, and Immunology, he and others presented data highlighting the diagnostic and therapeutic potential of digital monitoring devices for difficult-to-control asthma, the theme of the 2022s meeting.

The Global Initiative for Asthma (GINA) defines asthma as “difficult to control” if it remains uncontrolled despite medium- or high-dose inhaled corticosteroids with a second controller or with maintenance oral steroids, or if the asthma requires high-dose treatment to curb symptoms and exacerbations. About 17% of adult asthma patients have difficult-to-control asthma, according to the 2021 GINA report. 

However, correcting for inhaling technique and adherence cuts the 17% down to just 3.7%, Giselle Mosnaim, MD, an allergist at NorthShore University HealthSystem outside Chicago and AAAAI immediate past president, told attendees at a Feb. 25 session on digital technologies for asthma management.

The CRITIKAL study, which reviewed data from more than 5,000 asthma patients, “showed that, if you have critical errors in inhaler technique, this leads to worse asthma outcomes and increased asthma exacerbations,” Dr. Mosnaim said. Sadly, it also shows that, from 1975 to 2014, despite new devices and new technologies, “we still have poor inhaler technique.”

As for ways to measure adherence, physician judgments tend to be inaccurate, patient self-reporting has proved unreliable, and prescription refill data doesn’t indicate whether patients actually used the medications. “The ideal measure of adherence should be objective, accurate and unobtrusive to minimize impact on patient behavior and allow reliable data collection in real-world settings,” Dr. Mosnaim said. “So electronic medication monitors are the gold standard.” 
 

Tracking adherence

A closing afternoon session featured three presentations on research tracking adherence and outcomes in difficult-to-treat asthma patients – two pediatric cohorts and one across all ages. All studies used the Propeller Health sensor, a Food and Drug Administration–cleared device that attaches to the patient’s inhaler and automatically collects information on where, when, and how often they use their medication. The sensor then sends that information to a data cloud accessible to the patient and their health care professional.

Dr. Anderson’s team scoured a nationwide Propeller Health database for 8,000 patients using the digital monitors with controller therapies for asthma or chronic obstructive pulmonary disease (COPD). The study explored whether adherence differed for once-daily versus twice-daily medications, and if adherence differed based on patient age (4-60+ years).

For both asthma and COPD patients, those on once-daily regimens had higher medication adherence, compared with those who were prescribed twice-daily therapies. Plus, a greater proportion of once-daily patients met the prespecified 80% adherence threshold.

Looking across ages, medication use in the youngest group (aged 4-11 years) looked comparable with 30-somethings, “probably because parents are the ones giving the drug,” Dr. Anderson said. Mirroring patterns from other studies, adherence levels dipped in adolescents and young adults, relative to other age subsets.

Since this population-level analysis didn’t include individualized data on exacerbations or asthma control, “we can’t relate this to outcomes,” Dr. Anderson noted. But he said the data correlating medication use with adherence suggest that once-daily formulations may be the better option.

In one of the two pediatric studies, Matt McCulloch, MD, an allergy and immunology fellow working with Dr. Anderson, and colleagues reviewed charts of 40 children who received care at the Colorado Children’s multidisciplinary asthma clinic between 2018 and 2021. Half of these patients used Propeller Health sensors with their daily inhaled controller; the other patients were matched for age, ethnicity, sex, medication level, and disease control and severity – but had no electronic monitoring device.

On the whole, children who used digital monitoring for 12 months did not fare much better than matched controls on lung function (judged by forced expiratory volume) or asthma control (measured by Asthma Control Test scores).

However, within the digital monitoring group, patients who stayed on the Propeller system for 12 months did have better asthma control, fewer exacerbations, and improved asthma severity scores (measured by the Composite Asthma Severity Index), compared with when they first began digital monitoring. These children had all received care at the clinic for a while before their families opted for the electronic sensor, so “the effect wouldn’t have just been from starting in the clinic,” Dr. McCulloch said in an interview.

The gains came despite waning medication adherence. Similar to other digital monitoring studies, use of daily controller therapies in this retrospective analysis began at 50%-80% but dropped considerably during the first 4-5 months before settling into the 20%-30% range by 1 year.

Rachelle Ramsey, PhD, a pediatric research psychologist at Cincinnati Children’s Hospital Medical Center, presented data from 20 children with difficult-to-treat asthma who received 8 weeks of a digital adherence intervention during a 12-month treatment period. They analyzed three subsets – each with interventions based on how well the patients were managing daily controller therapy at baseline.

One patient with high (>80%) baseline adherence just received digital monitoring. The seven patients who began the study with intermediate (50%-80%) adherence received digital monitoring plus prescriptive text messaging. And the 12 children with poorest (<50%) baseline adherence received digital monitoring and a telehealth session in which a behavioral health specialist helped them set goals and create strategies to overcome barriers – for example, keeping the inhaler near their toothbrush in order to pair medication use with a daily habit.

“Overall, we found that matching Propeller with a behavioral intervention really improved adherence,” Dr. Ramsey said in an interview. While patients were receiving the intervention, adherence averaged across all groups increased from 39% to 76%. However, once the intervention period ended, the group’s adherence regressed toward baseline (36%).

Although adherence did not associate with clinical gains in this small study, the use of digital monitoring to improve medication adherence has translated to better outcomes in other recent efforts.
 

Remote monitoring

In a quality improvement project in the United Kingdom, nurses asked difficult-to-control asthma patients if they understood how to use their corticosteroid/long-acting beta₂-agonist (LABA) inhalers and if they were adhering to treatment guidelines.

Those who answered yes to these questions were invited to a 28-day study that involved swapping their steroid/LABA inhalers for a different controller/bronchodilator (fluticasone/salmeterol) with INCA (Inhaler Compliance Assessment), a device that not only tracks adherence but also uses acoustics to gauge inhaler technique.

Among the 23 patients who participated, many had better clinical outcomes after 28 days of INCA monitoring. As Dr. Mosnaim told attendees, “what was amazing is so many of the patients that had been these difficult-to-control asthmatics who would have gone on to oral steroids or perhaps a biologic – lo and behold, you put them on a digital inhaler, and what do you see?” In two-thirds of the patients, “you see FeNo [a test that measures airway inflammation by detecting nitric oxide in exhalations] goes down. You see spirometry improve. You see the asthma control questionnaire improve. You see blood eosinophils go down.”

And in a 2020 randomized trial, Dr. Mosnaim and colleagues recruited 100 adults with uncontrolled asthma who had prescriptions for a daily inhaled corticosteroid and a short-acting beta-agonist (SABA) inhaler. Participants received Propeller sensors for their steroid and SABA inhalers. After a 2-week run-in period to calculate baseline corticosteroid adherence and SABA use for all participants, half the participants were randomly assigned to the control group, which had the app and sensor in silent mode, merely to collect data on medication use – whereas the treatment group received reminders, alerts, and monthly phone calls from providers who gave feedback on adherence and technique.

After 3 months of digital monitoring, patients didn’t use their rescue medication quite as often – as judged by a rise in the percentage of SABA-free days, compared with when they began the study. But the change in SABA-free days relative to baseline was more pronounced in the treatment group (19%) than in the control group (6%).

As seen in the other digital monitoring studies, adherence to daily corticosteroids fell with time, but the drop was milder in treated participants (2%) versus the control group (17%). So in this study, digital monitoring plus mobile app reminders and clinician feedback “prevented against fall in adherence to inhaled steroids over time,” Dr. Mosnaim said.

These results are “very encouraging” and offer “proof of concept that this type of remote monitoring could work,” Thanai Pongdee, MD, an allergist-immunologist with the Mayo Clinic in Rochester, Minn., said in an interview. One limitation was that the study was too short to measure exacerbation rates. A yearlong analysis would be “really fascinating because you’d catch all the seasons of the year – all the pollen seasons, all these things that could exacerbate you. Some people’s asthma can be quite seasonal.”

More important, the clinical utility of digital sensors will depend on how physicians choose to use them. If the doctor puts out a “blanket recommendation for using it but doesn’t ask you about it or doesn’t use the data to inform your care, then I think people just lose engagement and lose excitement over it,” Dr. Ramsey said. But if the health care team “asks you about the data or looks at the data with you or shows you how valuable this can be to your care, then I think that changes things.”

Building these analyses and interactions into the clinic workflow isn’t trivial. “If you have this wealth of data coming in, how are you going to look at it? Are you going to have an individual person assigned to this role? How are you going to respond to alerts?” Dr. Anderson asked.

In addition, because some digital monitors issue alerts when a patient’s asthma is not well controlled, some providers worry about liability if “something bad were to happen if you had that data but didn’t act upon it,” he said. Yet he noted that remote data monitoring is already used routinely in other areas of medicine, such as managing diabetes and heart conditions, “and it’s not like people are getting dinged for that stuff.”

Another issue is cost. Insurance only covers digital monitors in select cases, but it’s a bit of a catch-22. Insurers “don’t want to cover it until they get the data, but you can’t get the data until insurance covers it,” said Dr. Anderson, who added that “this year we finally got CPT reimbursement codes for monitoring devices.”

On the whole, studies of digital medication monitors suggest that better outcomes require “a good partnership between the health care provider and the patient,” Dr. Pongdee said. “It wasn’t like you could just put these things on and expect them to help. You still need that personal relationship to get the optimal results. We can have all this technology, but you still can’t take the people out of it.”

Dr. Mosnaim reported receiving current research grant support from GlaxoSmithKline, Novartis, Sanofi-Regeneron, and Teva; and past research grant support from AstraZeneca, Alk-Abello, and Genentech. She is immediate past president of the AAAAI, and directs the board of directors for the American Board of Allergy and Immunology. Dr. Anderson has served as a consultant for Regeneron, GlaxoSmithKline, and AstraZeneca, and has received research support from Colorado Medicaid. Dr. McCulloch and Dr. Ramsey disclosed no relevant financial relationships. Dr. Pongdee serves as an at-large director on the American Academy of Allergy, Asthma and Immunology board of directors. He receives grant funding from GlaxoSmithKline, and the Mayo Clinic is a trial site for GlaxoSmithKline and AstraZeneca.

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

Among patients with multiple sclerosis (MS) or neuromyelitis optica spectrum disorders (NMOSD) receiving ocrelizumab or rituximab, B cell depletion appears to last well past the 6-month dosing regimen typically used with these drugs. The results, drawn from a retrospective analysis, provide support for clinical trials to rest longer re-infusion intervals.

The study appeared online Jan. 21 in the journal Multiple Sclerosis and Related Disorders, presented by lead author Mahmoud AbdelRazek, MD, at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

Both drugs were approved based on clinical trials that investigated 6-month doses, but previous studies have suggested depletion can last longer, including a range of 9-26 months in the case of rituximab.

The initial rationale for monitoring B cell depletion was to prevent a relapse by re-infusing a patient if B cells levels rise, but the researchers noted a pattern of sustained depletion, especially in patients who had a delayed infusion for some reason – they often still had low B cell counts at the time of the next drug infusion. “That became not an unusual finding,” said Dr. AbdelRazek in an interview. He is an instructor of neurology at Harvard Medical School.

Patients also found the delay appealing, in part because they often felt unwell in the days following an infusion, and delays could mean fewer infections and other adverse effects. “Most of my patients I’ve discussed this with would be very appreciative of that delay,” said Dr. AbdelRazek. “There’s obviously an economic benefit as well,” said Dr. AbdelRazek.
 

The final answer?

The retrospective nature of the study is a key weakness, and the rationale to delay infusions based on continuing B cell depletion assumes that B cell depletion is in fact the mechanism of action for countering MS. “That is a critical question,” said Mark Gudesblatt, MD, who was asked to comment on the study. But if that is indeed the way the drugs work, then it would make sense to identify patients who repopulate B cells more slowly and tailor drug regimens. “It’s not one size fits all and blindly just re-dosing. The upsides are good: You come in less frequently for dosing, the cost to payers is less. But the bad is, maybe there are other markers. This is the putative mechanism, but what we believe may not be the final answer. There may be more to the story,” said Dr. Gutesblatt, who is Medical Director at South Shore Neurologic Associates, Patchogue, New York.

Dr. AbdelRazek also noted the study’s limitation. “I think a clinical trial is going to be warranted to really have this translated into clinical practice,” he said. His group is planning to conduct just such a trial, pending confirmation of a funding source.
 

B cell depletion beyond 6 months

The researchers analyzed data from 178 patients with MS and 10 patients with NMOSD who received ocrelizumab (n = 111) or rituximab (n = 53), or both (n = 24) at two Harvard Medical School teaching hospitals between 2010 and 2020. The data included 800 infusions and 1,054 CD19 measurements.

The researchers defined B cell depletion as an absolute count of 20 cells/uL or less, a B cell percentage of 2% or less, or if B cells were 5% or less of total lymphocytes.

Among the patient population, B cell depletion that met all 3 criteria occurred as long as 13.8 months after an initial ocrelizumab infusion cycle, and 22.8 months after second or more cycles of ocrelizumab. Following rituximab, the researchers noted B cell depletions. Following 500 mg of rituximab, B cell depletion defined by the first, second, or third criteria occurred as far out as 22.3, 26.2, and 28.5 months. For 1,000 mg doses of rituximab, B cell depletion occurred as long as 18.3, 18.3, and 29.1 months after a dose.

Examining 90 B cell measurements conducted at least 8 months after an ocrelizumab infusion, 50% were depleted by the first definition and 54% by the second definition. At 13 months, the figures were 58% and 62% among 26 B-cell measurements. Eight months or more after rituximab, 113 B-cell measurements showed rates of 43% and 52% B-cell depletion by the first two criteria.

Dr. AbdelRazek and Dr. Gudesblatt have no relevant financial disclosures.

Among patients with multiple sclerosis (MS) or neuromyelitis optica spectrum disorders (NMOSD) receiving ocrelizumab or rituximab, B cell depletion appears to last well past the 6-month dosing regimen typically used with these drugs. The results, drawn from a retrospective analysis, provide support for clinical trials to rest longer re-infusion intervals.

The study appeared online Jan. 21 in the journal Multiple Sclerosis and Related Disorders, presented by lead author Mahmoud AbdelRazek, MD, at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

Both drugs were approved based on clinical trials that investigated 6-month doses, but previous studies have suggested depletion can last longer, including a range of 9-26 months in the case of rituximab.

The initial rationale for monitoring B cell depletion was to prevent a relapse by re-infusing a patient if B cells levels rise, but the researchers noted a pattern of sustained depletion, especially in patients who had a delayed infusion for some reason – they often still had low B cell counts at the time of the next drug infusion. “That became not an unusual finding,” said Dr. AbdelRazek in an interview. He is an instructor of neurology at Harvard Medical School.

Patients also found the delay appealing, in part because they often felt unwell in the days following an infusion, and delays could mean fewer infections and other adverse effects. “Most of my patients I’ve discussed this with would be very appreciative of that delay,” said Dr. AbdelRazek. “There’s obviously an economic benefit as well,” said Dr. AbdelRazek.
 

The final answer?

The retrospective nature of the study is a key weakness, and the rationale to delay infusions based on continuing B cell depletion assumes that B cell depletion is in fact the mechanism of action for countering MS. “That is a critical question,” said Mark Gudesblatt, MD, who was asked to comment on the study. But if that is indeed the way the drugs work, then it would make sense to identify patients who repopulate B cells more slowly and tailor drug regimens. “It’s not one size fits all and blindly just re-dosing. The upsides are good: You come in less frequently for dosing, the cost to payers is less. But the bad is, maybe there are other markers. This is the putative mechanism, but what we believe may not be the final answer. There may be more to the story,” said Dr. Gutesblatt, who is Medical Director at South Shore Neurologic Associates, Patchogue, New York.

Dr. AbdelRazek also noted the study’s limitation. “I think a clinical trial is going to be warranted to really have this translated into clinical practice,” he said. His group is planning to conduct just such a trial, pending confirmation of a funding source.
 

B cell depletion beyond 6 months

The researchers analyzed data from 178 patients with MS and 10 patients with NMOSD who received ocrelizumab (n = 111) or rituximab (n = 53), or both (n = 24) at two Harvard Medical School teaching hospitals between 2010 and 2020. The data included 800 infusions and 1,054 CD19 measurements.

The researchers defined B cell depletion as an absolute count of 20 cells/uL or less, a B cell percentage of 2% or less, or if B cells were 5% or less of total lymphocytes.

Among the patient population, B cell depletion that met all 3 criteria occurred as long as 13.8 months after an initial ocrelizumab infusion cycle, and 22.8 months after second or more cycles of ocrelizumab. Following rituximab, the researchers noted B cell depletions. Following 500 mg of rituximab, B cell depletion defined by the first, second, or third criteria occurred as far out as 22.3, 26.2, and 28.5 months. For 1,000 mg doses of rituximab, B cell depletion occurred as long as 18.3, 18.3, and 29.1 months after a dose.

Examining 90 B cell measurements conducted at least 8 months after an ocrelizumab infusion, 50% were depleted by the first definition and 54% by the second definition. At 13 months, the figures were 58% and 62% among 26 B-cell measurements. Eight months or more after rituximab, 113 B-cell measurements showed rates of 43% and 52% B-cell depletion by the first two criteria.

Dr. AbdelRazek and Dr. Gudesblatt have no relevant financial disclosures.

Among patients with multiple sclerosis (MS) or neuromyelitis optica spectrum disorders (NMOSD) receiving ocrelizumab or rituximab, B cell depletion appears to last well past the 6-month dosing regimen typically used with these drugs. The results, drawn from a retrospective analysis, provide support for clinical trials to rest longer re-infusion intervals.

The study appeared online Jan. 21 in the journal Multiple Sclerosis and Related Disorders, presented by lead author Mahmoud AbdelRazek, MD, at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

Both drugs were approved based on clinical trials that investigated 6-month doses, but previous studies have suggested depletion can last longer, including a range of 9-26 months in the case of rituximab.

The initial rationale for monitoring B cell depletion was to prevent a relapse by re-infusing a patient if B cells levels rise, but the researchers noted a pattern of sustained depletion, especially in patients who had a delayed infusion for some reason – they often still had low B cell counts at the time of the next drug infusion. “That became not an unusual finding,” said Dr. AbdelRazek in an interview. He is an instructor of neurology at Harvard Medical School.

Patients also found the delay appealing, in part because they often felt unwell in the days following an infusion, and delays could mean fewer infections and other adverse effects. “Most of my patients I’ve discussed this with would be very appreciative of that delay,” said Dr. AbdelRazek. “There’s obviously an economic benefit as well,” said Dr. AbdelRazek.
 

The final answer?

The retrospective nature of the study is a key weakness, and the rationale to delay infusions based on continuing B cell depletion assumes that B cell depletion is in fact the mechanism of action for countering MS. “That is a critical question,” said Mark Gudesblatt, MD, who was asked to comment on the study. But if that is indeed the way the drugs work, then it would make sense to identify patients who repopulate B cells more slowly and tailor drug regimens. “It’s not one size fits all and blindly just re-dosing. The upsides are good: You come in less frequently for dosing, the cost to payers is less. But the bad is, maybe there are other markers. This is the putative mechanism, but what we believe may not be the final answer. There may be more to the story,” said Dr. Gutesblatt, who is Medical Director at South Shore Neurologic Associates, Patchogue, New York.

Dr. AbdelRazek also noted the study’s limitation. “I think a clinical trial is going to be warranted to really have this translated into clinical practice,” he said. His group is planning to conduct just such a trial, pending confirmation of a funding source.
 

B cell depletion beyond 6 months

The researchers analyzed data from 178 patients with MS and 10 patients with NMOSD who received ocrelizumab (n = 111) or rituximab (n = 53), or both (n = 24) at two Harvard Medical School teaching hospitals between 2010 and 2020. The data included 800 infusions and 1,054 CD19 measurements.

The researchers defined B cell depletion as an absolute count of 20 cells/uL or less, a B cell percentage of 2% or less, or if B cells were 5% or less of total lymphocytes.

Among the patient population, B cell depletion that met all 3 criteria occurred as long as 13.8 months after an initial ocrelizumab infusion cycle, and 22.8 months after second or more cycles of ocrelizumab. Following rituximab, the researchers noted B cell depletions. Following 500 mg of rituximab, B cell depletion defined by the first, second, or third criteria occurred as far out as 22.3, 26.2, and 28.5 months. For 1,000 mg doses of rituximab, B cell depletion occurred as long as 18.3, 18.3, and 29.1 months after a dose.

Examining 90 B cell measurements conducted at least 8 months after an ocrelizumab infusion, 50% were depleted by the first definition and 54% by the second definition. At 13 months, the figures were 58% and 62% among 26 B-cell measurements. Eight months or more after rituximab, 113 B-cell measurements showed rates of 43% and 52% B-cell depletion by the first two criteria.

Dr. AbdelRazek and Dr. Gudesblatt have no relevant financial disclosures.

A new report shows considerable gaps in the awareness, treatment, and control of hypertension in premenopausal women in the United States, with a key driver being regular access to health care.

In a nationally representative sample of women ages 35-54 with no prior cardiovascular disease, the prevalence of hypertension increased 8% from an estimated 15.2 million women between 2011 and 2014 to 16.4 million women between 2015 and 2018.

What’s more, the percentage of women with controlled hypertension dropped over the two time periods from 55% to 50%, which is well below the government’s Million Hearts target of 70%.

Missed opportunities for hypertension control in these premenopausal women were a lack of awareness of their hypertension in 23%, ineffective treatment in 34%, and a lack of health care access in 43%; increasing to 51% in non-Hispanic Black patients and 56% in Hispanic patients.

Notably, lack of health care access affected an estimated 3.1 million women (45%) in 2011-2014 and 3.5 million women (43%) in 2015-2018.

Equally stubborn over the two time periods was the lack of effective treatment, affecting 2.1 million (31%) versus 2.8 million (34%) women, and lack of awareness, affecting 1.6 million (24%) versus 1.9 million (23%) women.

“There’s been no improvement over the past decade, and there is evidence of race/ethnic disparities,” study author Susan Hennessy, PhD, said at the recent Epidemiology, Prevention/Lifestyle & Cardiometabolic Health (EPI|Lifestyle) 2022 conference sponsored by the American Heart Association.

The prevalence of uncontrolled hypertension among non-Hispanic Whites was less than that of the U.S. population, at 44%, and most of the missed opportunities were due to uncontrolled blood pressure (BP), noted Dr. Hennessy, a researcher with the University of California, San Francisco School of Medicine.

However, the uncontrolled prevalence was 54% in non-Hispanic Black women and 66% in Hispanic women. “In both of these subgroups, over half of the missed opportunities occur because these women have no regular access to health care,” she said.

In women who identified as “other,” which includes non-Hispanic Asian and mixed-race populations, the uncontrolled prevalence reached 70%, and the biggest missed opportunity was in those who were untreated.

Raising awareness, empowering women, and delivery of guideline-concordant care will help premenopausal women gain control of their blood pressure, Dr. Hennessy said. “But underpinning all of this is ensuring equitable health care access, because if we fail to get women into the system, then we have no opportunity to help them lower their blood pressure.”

She reminded the audience that cardiovascular disease (CVD) is the number one killer of women in the United States and that CVD risk, mediated through hypertension, increases after menopause. Thus, managing hypertension prior to this life event is an important element of primary prevention of CVD and should be a priority.

Session moderator Sadiya S. Khan, MD, Northwestern University Feinberg School of Medicine, Chicago, told this news organization that the findings should raise “alarm and concern that hypertension is not just a disease of the old but very prevalent in younger women, particularly around the time of pregnancy. And this is a clear driver of maternal morbidity and mortality as well.”

“This idea that patients should ‘Know Your Numbers’ is really important, and we talk a lot about that for hypertension, but if you don’t have a doctor, if you don’t have someone to go to, it’s very hard to know or understand what your numbers mean,” she said. “I think that’s really the main message.”

Speaking to this news organization, Dr. Hennessy said there’s no simple solution to the problem, given that some women are not even in the system, whereas others are not being treated effectively, but that increasing opportunities to screen BP would be a start. That could be through community programs, similar to the Barbershop Hypertension trial, or by making BP devices available for home monitoring.

“Again, this is about empowering ourselves to take some level of control, but, as a system, we have to be able to make it equitable for everyone and make sure they have the right equipment, the right cuff size,” she said. “The disparities arise because of the social determinants of health, so if these women are struggling to put food on the table, they aren’t going to be able to afford a blood pressure cuff.”

During a discussion of the findings, audience members noted that the National Health and Nutrition Examination Survey (NHANES) data used for the analysis were somewhat dated. Dr. Hennessy also pointed out that NHANES blood pressure is measured up to three times during a single visit, which differs from clinical practice, and that responses were based on self-report and thus subject to recall bias.

The sample included 3,343 women aged 35-54 years with no prior cardiovascular disease, representing an estimated 31.6 million American women. Hypertension was defined by a systolic BP of at least 140 mm Hg or a diastolic BP of at least 90 mm Hg or current BP medication use.

The authors and Dr. Khan report no relevant financial relationships.

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

A new report shows considerable gaps in the awareness, treatment, and control of hypertension in premenopausal women in the United States, with a key driver being regular access to health care.

In a nationally representative sample of women ages 35-54 with no prior cardiovascular disease, the prevalence of hypertension increased 8% from an estimated 15.2 million women between 2011 and 2014 to 16.4 million women between 2015 and 2018.

What’s more, the percentage of women with controlled hypertension dropped over the two time periods from 55% to 50%, which is well below the government’s Million Hearts target of 70%.

Missed opportunities for hypertension control in these premenopausal women were a lack of awareness of their hypertension in 23%, ineffective treatment in 34%, and a lack of health care access in 43%; increasing to 51% in non-Hispanic Black patients and 56% in Hispanic patients.

Notably, lack of health care access affected an estimated 3.1 million women (45%) in 2011-2014 and 3.5 million women (43%) in 2015-2018.

Equally stubborn over the two time periods was the lack of effective treatment, affecting 2.1 million (31%) versus 2.8 million (34%) women, and lack of awareness, affecting 1.6 million (24%) versus 1.9 million (23%) women.

“There’s been no improvement over the past decade, and there is evidence of race/ethnic disparities,” study author Susan Hennessy, PhD, said at the recent Epidemiology, Prevention/Lifestyle & Cardiometabolic Health (EPI|Lifestyle) 2022 conference sponsored by the American Heart Association.

The prevalence of uncontrolled hypertension among non-Hispanic Whites was less than that of the U.S. population, at 44%, and most of the missed opportunities were due to uncontrolled blood pressure (BP), noted Dr. Hennessy, a researcher with the University of California, San Francisco School of Medicine.

However, the uncontrolled prevalence was 54% in non-Hispanic Black women and 66% in Hispanic women. “In both of these subgroups, over half of the missed opportunities occur because these women have no regular access to health care,” she said.

In women who identified as “other,” which includes non-Hispanic Asian and mixed-race populations, the uncontrolled prevalence reached 70%, and the biggest missed opportunity was in those who were untreated.

Raising awareness, empowering women, and delivery of guideline-concordant care will help premenopausal women gain control of their blood pressure, Dr. Hennessy said. “But underpinning all of this is ensuring equitable health care access, because if we fail to get women into the system, then we have no opportunity to help them lower their blood pressure.”

She reminded the audience that cardiovascular disease (CVD) is the number one killer of women in the United States and that CVD risk, mediated through hypertension, increases after menopause. Thus, managing hypertension prior to this life event is an important element of primary prevention of CVD and should be a priority.

Session moderator Sadiya S. Khan, MD, Northwestern University Feinberg School of Medicine, Chicago, told this news organization that the findings should raise “alarm and concern that hypertension is not just a disease of the old but very prevalent in younger women, particularly around the time of pregnancy. And this is a clear driver of maternal morbidity and mortality as well.”

“This idea that patients should ‘Know Your Numbers’ is really important, and we talk a lot about that for hypertension, but if you don’t have a doctor, if you don’t have someone to go to, it’s very hard to know or understand what your numbers mean,” she said. “I think that’s really the main message.”

Speaking to this news organization, Dr. Hennessy said there’s no simple solution to the problem, given that some women are not even in the system, whereas others are not being treated effectively, but that increasing opportunities to screen BP would be a start. That could be through community programs, similar to the Barbershop Hypertension trial, or by making BP devices available for home monitoring.

“Again, this is about empowering ourselves to take some level of control, but, as a system, we have to be able to make it equitable for everyone and make sure they have the right equipment, the right cuff size,” she said. “The disparities arise because of the social determinants of health, so if these women are struggling to put food on the table, they aren’t going to be able to afford a blood pressure cuff.”

During a discussion of the findings, audience members noted that the National Health and Nutrition Examination Survey (NHANES) data used for the analysis were somewhat dated. Dr. Hennessy also pointed out that NHANES blood pressure is measured up to three times during a single visit, which differs from clinical practice, and that responses were based on self-report and thus subject to recall bias.

The sample included 3,343 women aged 35-54 years with no prior cardiovascular disease, representing an estimated 31.6 million American women. Hypertension was defined by a systolic BP of at least 140 mm Hg or a diastolic BP of at least 90 mm Hg or current BP medication use.

The authors and Dr. Khan report no relevant financial relationships.

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

A new report shows considerable gaps in the awareness, treatment, and control of hypertension in premenopausal women in the United States, with a key driver being regular access to health care.

In a nationally representative sample of women ages 35-54 with no prior cardiovascular disease, the prevalence of hypertension increased 8% from an estimated 15.2 million women between 2011 and 2014 to 16.4 million women between 2015 and 2018.

What’s more, the percentage of women with controlled hypertension dropped over the two time periods from 55% to 50%, which is well below the government’s Million Hearts target of 70%.

Missed opportunities for hypertension control in these premenopausal women were a lack of awareness of their hypertension in 23%, ineffective treatment in 34%, and a lack of health care access in 43%; increasing to 51% in non-Hispanic Black patients and 56% in Hispanic patients.

Notably, lack of health care access affected an estimated 3.1 million women (45%) in 2011-2014 and 3.5 million women (43%) in 2015-2018.

Equally stubborn over the two time periods was the lack of effective treatment, affecting 2.1 million (31%) versus 2.8 million (34%) women, and lack of awareness, affecting 1.6 million (24%) versus 1.9 million (23%) women.

“There’s been no improvement over the past decade, and there is evidence of race/ethnic disparities,” study author Susan Hennessy, PhD, said at the recent Epidemiology, Prevention/Lifestyle & Cardiometabolic Health (EPI|Lifestyle) 2022 conference sponsored by the American Heart Association.

The prevalence of uncontrolled hypertension among non-Hispanic Whites was less than that of the U.S. population, at 44%, and most of the missed opportunities were due to uncontrolled blood pressure (BP), noted Dr. Hennessy, a researcher with the University of California, San Francisco School of Medicine.

However, the uncontrolled prevalence was 54% in non-Hispanic Black women and 66% in Hispanic women. “In both of these subgroups, over half of the missed opportunities occur because these women have no regular access to health care,” she said.

In women who identified as “other,” which includes non-Hispanic Asian and mixed-race populations, the uncontrolled prevalence reached 70%, and the biggest missed opportunity was in those who were untreated.

Raising awareness, empowering women, and delivery of guideline-concordant care will help premenopausal women gain control of their blood pressure, Dr. Hennessy said. “But underpinning all of this is ensuring equitable health care access, because if we fail to get women into the system, then we have no opportunity to help them lower their blood pressure.”

She reminded the audience that cardiovascular disease (CVD) is the number one killer of women in the United States and that CVD risk, mediated through hypertension, increases after menopause. Thus, managing hypertension prior to this life event is an important element of primary prevention of CVD and should be a priority.

Session moderator Sadiya S. Khan, MD, Northwestern University Feinberg School of Medicine, Chicago, told this news organization that the findings should raise “alarm and concern that hypertension is not just a disease of the old but very prevalent in younger women, particularly around the time of pregnancy. And this is a clear driver of maternal morbidity and mortality as well.”

“This idea that patients should ‘Know Your Numbers’ is really important, and we talk a lot about that for hypertension, but if you don’t have a doctor, if you don’t have someone to go to, it’s very hard to know or understand what your numbers mean,” she said. “I think that’s really the main message.”

Speaking to this news organization, Dr. Hennessy said there’s no simple solution to the problem, given that some women are not even in the system, whereas others are not being treated effectively, but that increasing opportunities to screen BP would be a start. That could be through community programs, similar to the Barbershop Hypertension trial, or by making BP devices available for home monitoring.

“Again, this is about empowering ourselves to take some level of control, but, as a system, we have to be able to make it equitable for everyone and make sure they have the right equipment, the right cuff size,” she said. “The disparities arise because of the social determinants of health, so if these women are struggling to put food on the table, they aren’t going to be able to afford a blood pressure cuff.”

During a discussion of the findings, audience members noted that the National Health and Nutrition Examination Survey (NHANES) data used for the analysis were somewhat dated. Dr. Hennessy also pointed out that NHANES blood pressure is measured up to three times during a single visit, which differs from clinical practice, and that responses were based on self-report and thus subject to recall bias.

The sample included 3,343 women aged 35-54 years with no prior cardiovascular disease, representing an estimated 31.6 million American women. Hypertension was defined by a systolic BP of at least 140 mm Hg or a diastolic BP of at least 90 mm Hg or current BP medication use.

The authors and Dr. Khan report no relevant financial relationships.

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

CHICAGO – A randomized trial suggests resistance exercise promotes better sleep than other workouts among inactive adults, particularly those who are poor sleepers.

“We thought resistance exercise would be somewhere in the same neighborhood as aerobic exercise or that maybe combined exercise would be a little bit better but, no, it was consistently resistance exercise, on its own, that seemed to show the most benefits across the board,” Angelique Brellenthin, PhD, told this news organization.

The results were presented at the recent Epidemiology, Prevention/Lifestyle & Cardiometabolic Health meeting sponsored by the American Heart Association.

Even before the pandemic and bedtime “doom scrolling” took hold, research showed that a third of Americans regularly get less than 7 hours of sleep. The AHA recommends aerobic exercise to improve sleep and promote cardiovascular health, yet little is known on how it compares with other types of exercise in the general population, she said.

Dr. Brellenthin and coinvestigator Duck-chul Lee, PhD, both of Iowa State University in Ames, recruited 406 inactive adults, aged 35-70 years, who had obesity or overweight (mean body mass index, 31.2 kg/m²) and had elevated or stage 1 hypertension and randomly assigned them to no exercise or 60 minutes of supervised aerobic, resistance, or combination exercise three times per week for 12 months.

The aerobic exercise group could choose among treadmills, upright or recumbent bikes, and ellipticals, and the participants had their heart rate monitored to ensure they were continuously getting moderate- to vigorous-intensity exercise.

The resistance exercise group performed three sets of 8-16 repetitions at 50%-80% of their one-rep maximum on 12 resistance machines: a leg press, chest press, lat pulldown, leg curl, leg extension, biceps curl, triceps pushdown, shoulder press, abdominal crunch, lower back extension, torso rotation, and hip abduction.

The combination group did 30 minutes of aerobic exercise at moderate to vigorous intensity, and then two sets of 8-16 repetitions of resistance exercise on 9 machines instead of 12.

Exercise adherence over the year was 84%, 77%, and 85%, respectively.

Participants also completed the Pittsburgh Sleep Quality Index (PSQI) at baseline and 12 months. Among the 386 participants (53% women) with evaluable data, 35% had poor-quality sleep, as indicated by a global PSQI score of more than 5, and 42% regularly slept less than 7 hours per night.

In adjusted analyses, sleep duration at 12 months, on average, increased by 13 minutes in the resistance-exercise group (P = .009), decreased by 0.6 minute in the aerobic-exercise group, and increased by 2 minutes in the combined-exercise group and by 4 minutes in the control group.

Among participants who got less than 7 hours of sleep at baseline, however, sleep duration increased by 40 minutes (P < .0001), compared with increases of 23 minutes in the aerobic group, 17 minutes in the combined group, and 15 minutes in the control group.

Overall sleep efficiency, or the ratio of total sleep time to time in bed, improved in the resistance (P = .0005) and combined (P = .03) exercise groups, but not in the aerobic or control groups.

Sleep latency, or the time needed to fall asleep, decreased by 3 minutes in the resistance-exercise group, with no notable changes in the other groups.

Sleep quality and the number of sleep disturbances improved in all groups, including the control group. This could be due to simply being part of a health intervention, which included a month of lifestyle education classes, Dr. Brellenthin suggested.

It’s unclear why the aerobic-exercise group didn’t show greater gains, given the wealth of research showing it improves sleep, she said, but it had fewer poor sleepers at baseline than the resistance group (33% vs. 42%). “So it may be that people who were already getting good sleep didn’t have much room to improve.”

Among the poor-quality sleepers at baseline, resistance exercise significantly improved sleep quality (-2.4 vs. -1.0 points; P = .009) and duration (+36 vs. +3 minutes; P = .02), compared with the control group. It also improved sleep efficiency by 9.0%, compared with 0.9% in the control group (P = .002) and 8.0% for the combined-exercise group (P = .01).

“For a lot of people who know their sleep could be a bit better, this could be a place to start without resorting to medications, if they wanted to focus on a lifestyle intervention,” Dr. Brellenthin said.

It’s not fully understood how resistance exercise improves sleep, but it might contribute to better overall mental health and it might enhance the synthesis and release of certain hormones, such as testosterone and human growth hormone, which are associated with better sleep, Dr. Brellenthin said. Another hypothesis is that it causes direct microscopic damage to muscle tissue, forcing that tissue to adapt and grow over time. “So potentially that microscopic damage could provide that extra signal boost to the brain to replenish and repair, and get this person sleep.”

The study was limited by the use of self-reported sleep outcomes and a lack of detailed information on sleep medications, although 81% of participants reported taking no such medications.

The research was supported by a National Institutes of Health/National Heart, Lung, and Blood Institute grant to Dr. Lee. Dr. Brellenthin reports no relevant financial relationships.
 

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

CHICAGO – A randomized trial suggests resistance exercise promotes better sleep than other workouts among inactive adults, particularly those who are poor sleepers.

“We thought resistance exercise would be somewhere in the same neighborhood as aerobic exercise or that maybe combined exercise would be a little bit better but, no, it was consistently resistance exercise, on its own, that seemed to show the most benefits across the board,” Angelique Brellenthin, PhD, told this news organization.

The results were presented at the recent Epidemiology, Prevention/Lifestyle & Cardiometabolic Health meeting sponsored by the American Heart Association.

Even before the pandemic and bedtime “doom scrolling” took hold, research showed that a third of Americans regularly get less than 7 hours of sleep. The AHA recommends aerobic exercise to improve sleep and promote cardiovascular health, yet little is known on how it compares with other types of exercise in the general population, she said.

Dr. Brellenthin and coinvestigator Duck-chul Lee, PhD, both of Iowa State University in Ames, recruited 406 inactive adults, aged 35-70 years, who had obesity or overweight (mean body mass index, 31.2 kg/m²) and had elevated or stage 1 hypertension and randomly assigned them to no exercise or 60 minutes of supervised aerobic, resistance, or combination exercise three times per week for 12 months.

The aerobic exercise group could choose among treadmills, upright or recumbent bikes, and ellipticals, and the participants had their heart rate monitored to ensure they were continuously getting moderate- to vigorous-intensity exercise.

The resistance exercise group performed three sets of 8-16 repetitions at 50%-80% of their one-rep maximum on 12 resistance machines: a leg press, chest press, lat pulldown, leg curl, leg extension, biceps curl, triceps pushdown, shoulder press, abdominal crunch, lower back extension, torso rotation, and hip abduction.

The combination group did 30 minutes of aerobic exercise at moderate to vigorous intensity, and then two sets of 8-16 repetitions of resistance exercise on 9 machines instead of 12.

Exercise adherence over the year was 84%, 77%, and 85%, respectively.

Participants also completed the Pittsburgh Sleep Quality Index (PSQI) at baseline and 12 months. Among the 386 participants (53% women) with evaluable data, 35% had poor-quality sleep, as indicated by a global PSQI score of more than 5, and 42% regularly slept less than 7 hours per night.

In adjusted analyses, sleep duration at 12 months, on average, increased by 13 minutes in the resistance-exercise group (P = .009), decreased by 0.6 minute in the aerobic-exercise group, and increased by 2 minutes in the combined-exercise group and by 4 minutes in the control group.

Among participants who got less than 7 hours of sleep at baseline, however, sleep duration increased by 40 minutes (P < .0001), compared with increases of 23 minutes in the aerobic group, 17 minutes in the combined group, and 15 minutes in the control group.

Overall sleep efficiency, or the ratio of total sleep time to time in bed, improved in the resistance (P = .0005) and combined (P = .03) exercise groups, but not in the aerobic or control groups.

Sleep latency, or the time needed to fall asleep, decreased by 3 minutes in the resistance-exercise group, with no notable changes in the other groups.

Sleep quality and the number of sleep disturbances improved in all groups, including the control group. This could be due to simply being part of a health intervention, which included a month of lifestyle education classes, Dr. Brellenthin suggested.

It’s unclear why the aerobic-exercise group didn’t show greater gains, given the wealth of research showing it improves sleep, she said, but it had fewer poor sleepers at baseline than the resistance group (33% vs. 42%). “So it may be that people who were already getting good sleep didn’t have much room to improve.”

Among the poor-quality sleepers at baseline, resistance exercise significantly improved sleep quality (-2.4 vs. -1.0 points; P = .009) and duration (+36 vs. +3 minutes; P = .02), compared with the control group. It also improved sleep efficiency by 9.0%, compared with 0.9% in the control group (P = .002) and 8.0% for the combined-exercise group (P = .01).

“For a lot of people who know their sleep could be a bit better, this could be a place to start without resorting to medications, if they wanted to focus on a lifestyle intervention,” Dr. Brellenthin said.

It’s not fully understood how resistance exercise improves sleep, but it might contribute to better overall mental health and it might enhance the synthesis and release of certain hormones, such as testosterone and human growth hormone, which are associated with better sleep, Dr. Brellenthin said. Another hypothesis is that it causes direct microscopic damage to muscle tissue, forcing that tissue to adapt and grow over time. “So potentially that microscopic damage could provide that extra signal boost to the brain to replenish and repair, and get this person sleep.”

The study was limited by the use of self-reported sleep outcomes and a lack of detailed information on sleep medications, although 81% of participants reported taking no such medications.

The research was supported by a National Institutes of Health/National Heart, Lung, and Blood Institute grant to Dr. Lee. Dr. Brellenthin reports no relevant financial relationships.
 

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

CHICAGO – A randomized trial suggests resistance exercise promotes better sleep than other workouts among inactive adults, particularly those who are poor sleepers.

“We thought resistance exercise would be somewhere in the same neighborhood as aerobic exercise or that maybe combined exercise would be a little bit better but, no, it was consistently resistance exercise, on its own, that seemed to show the most benefits across the board,” Angelique Brellenthin, PhD, told this news organization.

The results were presented at the recent Epidemiology, Prevention/Lifestyle & Cardiometabolic Health meeting sponsored by the American Heart Association.

Even before the pandemic and bedtime “doom scrolling” took hold, research showed that a third of Americans regularly get less than 7 hours of sleep. The AHA recommends aerobic exercise to improve sleep and promote cardiovascular health, yet little is known on how it compares with other types of exercise in the general population, she said.

Dr. Brellenthin and coinvestigator Duck-chul Lee, PhD, both of Iowa State University in Ames, recruited 406 inactive adults, aged 35-70 years, who had obesity or overweight (mean body mass index, 31.2 kg/m²) and had elevated or stage 1 hypertension and randomly assigned them to no exercise or 60 minutes of supervised aerobic, resistance, or combination exercise three times per week for 12 months.

The aerobic exercise group could choose among treadmills, upright or recumbent bikes, and ellipticals, and the participants had their heart rate monitored to ensure they were continuously getting moderate- to vigorous-intensity exercise.

The resistance exercise group performed three sets of 8-16 repetitions at 50%-80% of their one-rep maximum on 12 resistance machines: a leg press, chest press, lat pulldown, leg curl, leg extension, biceps curl, triceps pushdown, shoulder press, abdominal crunch, lower back extension, torso rotation, and hip abduction.

The combination group did 30 minutes of aerobic exercise at moderate to vigorous intensity, and then two sets of 8-16 repetitions of resistance exercise on 9 machines instead of 12.

Exercise adherence over the year was 84%, 77%, and 85%, respectively.

Participants also completed the Pittsburgh Sleep Quality Index (PSQI) at baseline and 12 months. Among the 386 participants (53% women) with evaluable data, 35% had poor-quality sleep, as indicated by a global PSQI score of more than 5, and 42% regularly slept less than 7 hours per night.

In adjusted analyses, sleep duration at 12 months, on average, increased by 13 minutes in the resistance-exercise group (P = .009), decreased by 0.6 minute in the aerobic-exercise group, and increased by 2 minutes in the combined-exercise group and by 4 minutes in the control group.

Among participants who got less than 7 hours of sleep at baseline, however, sleep duration increased by 40 minutes (P < .0001), compared with increases of 23 minutes in the aerobic group, 17 minutes in the combined group, and 15 minutes in the control group.

Overall sleep efficiency, or the ratio of total sleep time to time in bed, improved in the resistance (P = .0005) and combined (P = .03) exercise groups, but not in the aerobic or control groups.

Sleep latency, or the time needed to fall asleep, decreased by 3 minutes in the resistance-exercise group, with no notable changes in the other groups.

Sleep quality and the number of sleep disturbances improved in all groups, including the control group. This could be due to simply being part of a health intervention, which included a month of lifestyle education classes, Dr. Brellenthin suggested.

It’s unclear why the aerobic-exercise group didn’t show greater gains, given the wealth of research showing it improves sleep, she said, but it had fewer poor sleepers at baseline than the resistance group (33% vs. 42%). “So it may be that people who were already getting good sleep didn’t have much room to improve.”

Among the poor-quality sleepers at baseline, resistance exercise significantly improved sleep quality (-2.4 vs. -1.0 points; P = .009) and duration (+36 vs. +3 minutes; P = .02), compared with the control group. It also improved sleep efficiency by 9.0%, compared with 0.9% in the control group (P = .002) and 8.0% for the combined-exercise group (P = .01).

“For a lot of people who know their sleep could be a bit better, this could be a place to start without resorting to medications, if they wanted to focus on a lifestyle intervention,” Dr. Brellenthin said.

It’s not fully understood how resistance exercise improves sleep, but it might contribute to better overall mental health and it might enhance the synthesis and release of certain hormones, such as testosterone and human growth hormone, which are associated with better sleep, Dr. Brellenthin said. Another hypothesis is that it causes direct microscopic damage to muscle tissue, forcing that tissue to adapt and grow over time. “So potentially that microscopic damage could provide that extra signal boost to the brain to replenish and repair, and get this person sleep.”

The study was limited by the use of self-reported sleep outcomes and a lack of detailed information on sleep medications, although 81% of participants reported taking no such medications.

The research was supported by a National Institutes of Health/National Heart, Lung, and Blood Institute grant to Dr. Lee. Dr. Brellenthin reports no relevant financial relationships.
 

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

A randomized, controlled trial of transcranial direct current stimulation (tDCS) in patients with multiple sclerosis (MS) showed improvement in a secondary outcome measure – cognition – and provided evidence that the technique can be employed outside of a physician’s office.

The primary outcome of the sham-controlled trial was fatigue, but the findings presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) focused on a secondary cognitive measure, called the Brief International Cognitive Assessment for MS (BICAMS).

The intervention may still be a work in progress as far as a treatment technique “but the more important point is that there is a path to remote cognitive rehab interventions which, as a concept, is important,” said Mark Gudesblatt, MD, medical director at South Shore Neurologic Associates in Patchogue, N.Y., who was asked to comment on the study.
 

Adaptive mechanisms

The study grew out of work done with BrainHQ, which is a brain-training program available commercially through Posit Science. It employs an algorithm to recommend and tailor exercises for participants and to adjust the difficulty of the exercises in order to maintain engagement. “We believe the key ingredient is really the adaptive mechanisms that adjust to users in real time, for instance slowing down when the user slows down or speeding up to drive the learning to maintain a level of engagement. The games are designed to target processing speed that then has a transfer effect to other aspects of cognitive function,” Leigh Charvet, PhD, said during her presentation of the study results. Dr. Charvet is director of MS research and a professor of neurology at New York University.

The researchers previously conducted a large trial in patients with MS and showed that the adaptive mechanism, used for 60 hours over 12 weeks, could improve cognitive functioning. “We had two learnings from that trial: One that the brain training in at least a very intense dose was beneficial for cognitive functioning, and the second was that at-home treatments are very popular,” said Dr. Charvet.

In the most recent trial, the researchers turned to tDCS in an effort to boost the effect of brain training. “The idea is that if you can stimulate the region of the brain that is engaged with the training activity, you can boost or potentiate the outcomes of the training,” said Dr. Charvet. The tDCS treatment applies 1.0-4.0 mA current to the scalp, where it can be placed to specifically affect a brain region of interest. The study targeted the dorsolateral prefrontal cortex, which is a key region for executive function and cognitive flexibility.

The team developed a protocol that would allow the intervention to be conducted at home, with live supervision via HIPAA-compliant teleconferencing and technology that was designed for ease of use. The tDCS devices were preprogrammed and operated on an unlock code, which initiated active or sham tDCS. “We replicated onsite lab standards, but delivered it to people at home,” said Dr. Charvet.

In the new study, 106 patients with MS who had fatigue, but not depression, underwent 30 20-minute training sessions over a 6-week period, with active or sham tDCS. The participants were tested before and after treatment using the BICAMS. The sham group had a mean change of –0.17 in the BICAMS z score, compared with a mean of +0.05 in the tDCS group (P = .027).

One of the tests that make up the BICAMS battery, the single digit modalities test (SDMT), showed a trend toward improvement in the tDCS group (z sore, +0.09 versus –0.19; P = .058). There was no significant difference between the groups In the Rey’s Auditory Verbal Learning Test or the Brief Visuospatial Memory Test–Revised.
 

What about fatigue?

The emphasis on a secondary outcome drew some criticism. “It’s odd, because the primary outcome was fatigue. They didn’t report the primary outcome, they focused on a secondary outcome of cognitive measure,” said Patricia Coyle, MD, who was asked to comment on the study.

“I think the most important finding in this study was that they were able to deliver the transcranial direct current stimulation at home, via computer. They were able to do this study by computer with their patients at home, and it was a fairly large number. You could consider it broadly as a proof of principle that this can be done,” said Dr. Coyle, professor of neurology and director of Stony Brook MS Comprehensive Care Center.

The study was funded by the National MS Society. Dr. Gudesblatt has no relevant financial disclosures. Dr. Coyle has consulted or received speaker fees from Accord-ant, Alexion, Biogen, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Horizon Therapeutics, Janssen, Mylan, Novartis, Sanofi Genzyme, TG Therapeutics, and Viela Bio. Dr. Coyle has received research funding from Actelion, Alker-mes, Celgene, CorEvitas LLC, Genentech/Roche, MedDay, Novartis, and Sanofi Genzyme.

A randomized, controlled trial of transcranial direct current stimulation (tDCS) in patients with multiple sclerosis (MS) showed improvement in a secondary outcome measure – cognition – and provided evidence that the technique can be employed outside of a physician’s office.

The primary outcome of the sham-controlled trial was fatigue, but the findings presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) focused on a secondary cognitive measure, called the Brief International Cognitive Assessment for MS (BICAMS).

The intervention may still be a work in progress as far as a treatment technique “but the more important point is that there is a path to remote cognitive rehab interventions which, as a concept, is important,” said Mark Gudesblatt, MD, medical director at South Shore Neurologic Associates in Patchogue, N.Y., who was asked to comment on the study.
 

Adaptive mechanisms

The study grew out of work done with BrainHQ, which is a brain-training program available commercially through Posit Science. It employs an algorithm to recommend and tailor exercises for participants and to adjust the difficulty of the exercises in order to maintain engagement. “We believe the key ingredient is really the adaptive mechanisms that adjust to users in real time, for instance slowing down when the user slows down or speeding up to drive the learning to maintain a level of engagement. The games are designed to target processing speed that then has a transfer effect to other aspects of cognitive function,” Leigh Charvet, PhD, said during her presentation of the study results. Dr. Charvet is director of MS research and a professor of neurology at New York University.

The researchers previously conducted a large trial in patients with MS and showed that the adaptive mechanism, used for 60 hours over 12 weeks, could improve cognitive functioning. “We had two learnings from that trial: One that the brain training in at least a very intense dose was beneficial for cognitive functioning, and the second was that at-home treatments are very popular,” said Dr. Charvet.

In the most recent trial, the researchers turned to tDCS in an effort to boost the effect of brain training. “The idea is that if you can stimulate the region of the brain that is engaged with the training activity, you can boost or potentiate the outcomes of the training,” said Dr. Charvet. The tDCS treatment applies 1.0-4.0 mA current to the scalp, where it can be placed to specifically affect a brain region of interest. The study targeted the dorsolateral prefrontal cortex, which is a key region for executive function and cognitive flexibility.

The team developed a protocol that would allow the intervention to be conducted at home, with live supervision via HIPAA-compliant teleconferencing and technology that was designed for ease of use. The tDCS devices were preprogrammed and operated on an unlock code, which initiated active or sham tDCS. “We replicated onsite lab standards, but delivered it to people at home,” said Dr. Charvet.

In the new study, 106 patients with MS who had fatigue, but not depression, underwent 30 20-minute training sessions over a 6-week period, with active or sham tDCS. The participants were tested before and after treatment using the BICAMS. The sham group had a mean change of –0.17 in the BICAMS z score, compared with a mean of +0.05 in the tDCS group (P = .027).

One of the tests that make up the BICAMS battery, the single digit modalities test (SDMT), showed a trend toward improvement in the tDCS group (z sore, +0.09 versus –0.19; P = .058). There was no significant difference between the groups In the Rey’s Auditory Verbal Learning Test or the Brief Visuospatial Memory Test–Revised.
 

What about fatigue?

The emphasis on a secondary outcome drew some criticism. “It’s odd, because the primary outcome was fatigue. They didn’t report the primary outcome, they focused on a secondary outcome of cognitive measure,” said Patricia Coyle, MD, who was asked to comment on the study.

“I think the most important finding in this study was that they were able to deliver the transcranial direct current stimulation at home, via computer. They were able to do this study by computer with their patients at home, and it was a fairly large number. You could consider it broadly as a proof of principle that this can be done,” said Dr. Coyle, professor of neurology and director of Stony Brook MS Comprehensive Care Center.

The study was funded by the National MS Society. Dr. Gudesblatt has no relevant financial disclosures. Dr. Coyle has consulted or received speaker fees from Accord-ant, Alexion, Biogen, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Horizon Therapeutics, Janssen, Mylan, Novartis, Sanofi Genzyme, TG Therapeutics, and Viela Bio. Dr. Coyle has received research funding from Actelion, Alker-mes, Celgene, CorEvitas LLC, Genentech/Roche, MedDay, Novartis, and Sanofi Genzyme.

A randomized, controlled trial of transcranial direct current stimulation (tDCS) in patients with multiple sclerosis (MS) showed improvement in a secondary outcome measure – cognition – and provided evidence that the technique can be employed outside of a physician’s office.

The primary outcome of the sham-controlled trial was fatigue, but the findings presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) focused on a secondary cognitive measure, called the Brief International Cognitive Assessment for MS (BICAMS).

The intervention may still be a work in progress as far as a treatment technique “but the more important point is that there is a path to remote cognitive rehab interventions which, as a concept, is important,” said Mark Gudesblatt, MD, medical director at South Shore Neurologic Associates in Patchogue, N.Y., who was asked to comment on the study.
 

Adaptive mechanisms

The study grew out of work done with BrainHQ, which is a brain-training program available commercially through Posit Science. It employs an algorithm to recommend and tailor exercises for participants and to adjust the difficulty of the exercises in order to maintain engagement. “We believe the key ingredient is really the adaptive mechanisms that adjust to users in real time, for instance slowing down when the user slows down or speeding up to drive the learning to maintain a level of engagement. The games are designed to target processing speed that then has a transfer effect to other aspects of cognitive function,” Leigh Charvet, PhD, said during her presentation of the study results. Dr. Charvet is director of MS research and a professor of neurology at New York University.

The researchers previously conducted a large trial in patients with MS and showed that the adaptive mechanism, used for 60 hours over 12 weeks, could improve cognitive functioning. “We had two learnings from that trial: One that the brain training in at least a very intense dose was beneficial for cognitive functioning, and the second was that at-home treatments are very popular,” said Dr. Charvet.

In the most recent trial, the researchers turned to tDCS in an effort to boost the effect of brain training. “The idea is that if you can stimulate the region of the brain that is engaged with the training activity, you can boost or potentiate the outcomes of the training,” said Dr. Charvet. The tDCS treatment applies 1.0-4.0 mA current to the scalp, where it can be placed to specifically affect a brain region of interest. The study targeted the dorsolateral prefrontal cortex, which is a key region for executive function and cognitive flexibility.

The team developed a protocol that would allow the intervention to be conducted at home, with live supervision via HIPAA-compliant teleconferencing and technology that was designed for ease of use. The tDCS devices were preprogrammed and operated on an unlock code, which initiated active or sham tDCS. “We replicated onsite lab standards, but delivered it to people at home,” said Dr. Charvet.

In the new study, 106 patients with MS who had fatigue, but not depression, underwent 30 20-minute training sessions over a 6-week period, with active or sham tDCS. The participants were tested before and after treatment using the BICAMS. The sham group had a mean change of –0.17 in the BICAMS z score, compared with a mean of +0.05 in the tDCS group (P = .027).

One of the tests that make up the BICAMS battery, the single digit modalities test (SDMT), showed a trend toward improvement in the tDCS group (z sore, +0.09 versus –0.19; P = .058). There was no significant difference between the groups In the Rey’s Auditory Verbal Learning Test or the Brief Visuospatial Memory Test–Revised.
 

What about fatigue?

The emphasis on a secondary outcome drew some criticism. “It’s odd, because the primary outcome was fatigue. They didn’t report the primary outcome, they focused on a secondary outcome of cognitive measure,” said Patricia Coyle, MD, who was asked to comment on the study.

“I think the most important finding in this study was that they were able to deliver the transcranial direct current stimulation at home, via computer. They were able to do this study by computer with their patients at home, and it was a fairly large number. You could consider it broadly as a proof of principle that this can be done,” said Dr. Coyle, professor of neurology and director of Stony Brook MS Comprehensive Care Center.

The study was funded by the National MS Society. Dr. Gudesblatt has no relevant financial disclosures. Dr. Coyle has consulted or received speaker fees from Accord-ant, Alexion, Biogen, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Horizon Therapeutics, Janssen, Mylan, Novartis, Sanofi Genzyme, TG Therapeutics, and Viela Bio. Dr. Coyle has received research funding from Actelion, Alker-mes, Celgene, CorEvitas LLC, Genentech/Roche, MedDay, Novartis, and Sanofi Genzyme.

WEST PALM BEACH, FLA. – Women with multiple sclerosis (MS) undergoing assisted reproductive technologies (ART) have an increased relapse risk if they are not treated with disease-modifying therapy (DMT), new research suggests. In a cohort study of women undergoing ART, those who did not receive DMTs had a significantly higher relapse risk than their peers who were treated with the drugs.

In addition, the likelihood of achieving pregnancy through ART while having MS appeared favorable, researchers noted.

“In this modern case series and the largest cohort to date, we identified a lower risk of relapses after ART than previously reported,” Edith L. Graham, MD, of the department of neurology, Northwestern University, Chicago, and colleagues  wrote. “Importantly, continuing DMT during ART may reduce risk of relapse during this period of marked hormonal fluctuations and stressors,” they added.

The findings were presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
 

Study details

Previous research shows a wide range of relapse risk in patients with MS undergoing ART.

To investigate the potential role of DMTs in mitigating relapse risk, the researchers evaluated data on 37 women with either relapsing-remitting MS (n = 31) or clinically isolated syndrome (CIS; n = 6) who underwent ART. The women all had low disability, with a median Expanded Disability Status Scale (EDSS) score of 1.0. All participants had undergone one to five cycles of reproductive therapy between 2010 and 2021.

Most (78%) were receiving ART because of infertility or a need for preimplantation genetic testing, whereas 22% were undergoing the treatment for the preservation of fertility. Average age of the participants was 35 years and average disease duration was 7.4 years.

Among 19 of the 37 patients who were taking DMTs prior to ART, 10 remained on the medication throughout ovarian hyperstimulation.

In those who received DMTs in the 12 months prior to ART, treatment included glatiramer acetate (n = 9), interferons (n = 3), and dimethyl fumarate (n = 1). Three participants received B-cell–depleting agents.

In addition, three women received medication in response to a rebound after discontinuation. Of these, two received fingolimod and one natalizumab.

Five patients (13.5%) experienced MS relapses in the 12 months following ART therapy. Among those experiencing relapse, none were treated with DMTs during the preceding 12 months.

Of the relapses, three occurred within 3 months of the ART treatment, one within 6 months, and one within 12 months.
 

High rate of successful pregnancy

Overall, 24 of 29 women (83%) underwent in vitro fertilization (IVF) with embryo transfer as part of ART achieved pregnancy. The remaining five patients were undergoing egg cryopreservation.

Although 14 of the 24 who achieved pregnancy were on DMTs and 2 of 5 who did not achieve pregnancy were on the therapies, Dr. Graham noted, “these numbers seem too small to draw conclusions.”

In particular, patients may benefit from treatment with rituximab or ocrelizumab 3-6 months prior to ART, “which gives better protection during ART cycle with low risk of fetal exposure,” she said.

“Treatment does not need to be discontinued if undergoing embryo banking only,” Dr. Graham added. “The risk to the fetus occurs only after embryo transfer.”

Although there is a lack of research examining whether MS relapse lowers the chance of pregnancy, Dr. Graham noted, “in theory, relapsing MS may compromise ART success because [patients] may have a narrower window to undergo ART treatments if they are trying to mitigate DMT exposure to the fetus.” 

However, the study’s results generally suggest favorable outcomes with ART among women with MS, she added. “We found that overall ART is actually very successful among people with MS. I was actually very surprised by this high rate of successful pregnancy,” Dr. Graham said.

She noted that as women with MS increasingly undergo IVF as well as egg cryopreservation, research on these issues is gaining importance for clinicians. “This is going to be something that MS specialists need to know more about, particularly the safety of ART in their patients,” said Dr. Graham.

“What’s important is there are no [formal] recommendations along these lines, so this represents an opportunity to get the word out to clinicians that you want to make sure patients with MS are protected throughout the ART cycle and that you’re not discontinuing their DMT too early,” she added.
 

Protective against relapse?

Commenting on the study, Jiwon Oh, MD, PhD, medical director of the Barlo Multiple Sclerosis Program at St. Michael’s Hospital, University of Toronto, noted that, while there are many guidelines/recommendations regarding use of older DMTs peripregnancy, data on many newer therapies is more limited.

“Often, when people do not have definitive evidence, they tend to take a conservative approach, which is why there is likely reluctance to keep patients on DMTs during ART as well as in early pregnancy,” said Dr. Oh, who was not involved in the research.

Importantly, there is also no definitive evidence of a relationship between MS relapses and ART success or pregnancy outcomes, she noted. However, “from a common-sense perspective, most clinicians worry that extreme stress or disability may negatively affect both ART and pregnancy outcomes,” she added.

Dr. Oh agreed that ocrelizumab is an appropriate choice in terms of preventing relapse during ART. “Ocrevus is one of our highest-efficacy DMTs and is only dosed every 6 months. So this allows for ART cycles and conception without worrying about fetal drug exposure and the drug affecting ART cycles,” she said.

She noted the study’s findings “are in keeping with some prior studies, but not others, demonstrating there may be a higher risk of relapse with ART” in patients who are not taking a DMT.

“However, in my mind the most important conclusion from this study is that being on a DMT seems to be protective of relapse risk, which is an important point that will be useful to provide patients with clinical guidance,” Dr. Oh said.

Dr. Graham reported having received consulting fees from Genentech. Dr. Oh reported having received consulting or speaking fees from Alexion, Biogen Idec, BMS, EMD Serono, Genzyme, Novartis, and Roche.

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

WEST PALM BEACH, FLA. – Women with multiple sclerosis (MS) undergoing assisted reproductive technologies (ART) have an increased relapse risk if they are not treated with disease-modifying therapy (DMT), new research suggests. In a cohort study of women undergoing ART, those who did not receive DMTs had a significantly higher relapse risk than their peers who were treated with the drugs.

In addition, the likelihood of achieving pregnancy through ART while having MS appeared favorable, researchers noted.

“In this modern case series and the largest cohort to date, we identified a lower risk of relapses after ART than previously reported,” Edith L. Graham, MD, of the department of neurology, Northwestern University, Chicago, and colleagues  wrote. “Importantly, continuing DMT during ART may reduce risk of relapse during this period of marked hormonal fluctuations and stressors,” they added.

The findings were presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
 

Study details

Previous research shows a wide range of relapse risk in patients with MS undergoing ART.

To investigate the potential role of DMTs in mitigating relapse risk, the researchers evaluated data on 37 women with either relapsing-remitting MS (n = 31) or clinically isolated syndrome (CIS; n = 6) who underwent ART. The women all had low disability, with a median Expanded Disability Status Scale (EDSS) score of 1.0. All participants had undergone one to five cycles of reproductive therapy between 2010 and 2021.

Most (78%) were receiving ART because of infertility or a need for preimplantation genetic testing, whereas 22% were undergoing the treatment for the preservation of fertility. Average age of the participants was 35 years and average disease duration was 7.4 years.

Among 19 of the 37 patients who were taking DMTs prior to ART, 10 remained on the medication throughout ovarian hyperstimulation.

In those who received DMTs in the 12 months prior to ART, treatment included glatiramer acetate (n = 9), interferons (n = 3), and dimethyl fumarate (n = 1). Three participants received B-cell–depleting agents.

In addition, three women received medication in response to a rebound after discontinuation. Of these, two received fingolimod and one natalizumab.

Five patients (13.5%) experienced MS relapses in the 12 months following ART therapy. Among those experiencing relapse, none were treated with DMTs during the preceding 12 months.

Of the relapses, three occurred within 3 months of the ART treatment, one within 6 months, and one within 12 months.
 

High rate of successful pregnancy

Overall, 24 of 29 women (83%) underwent in vitro fertilization (IVF) with embryo transfer as part of ART achieved pregnancy. The remaining five patients were undergoing egg cryopreservation.

Although 14 of the 24 who achieved pregnancy were on DMTs and 2 of 5 who did not achieve pregnancy were on the therapies, Dr. Graham noted, “these numbers seem too small to draw conclusions.”

In particular, patients may benefit from treatment with rituximab or ocrelizumab 3-6 months prior to ART, “which gives better protection during ART cycle with low risk of fetal exposure,” she said.

“Treatment does not need to be discontinued if undergoing embryo banking only,” Dr. Graham added. “The risk to the fetus occurs only after embryo transfer.”

Although there is a lack of research examining whether MS relapse lowers the chance of pregnancy, Dr. Graham noted, “in theory, relapsing MS may compromise ART success because [patients] may have a narrower window to undergo ART treatments if they are trying to mitigate DMT exposure to the fetus.” 

However, the study’s results generally suggest favorable outcomes with ART among women with MS, she added. “We found that overall ART is actually very successful among people with MS. I was actually very surprised by this high rate of successful pregnancy,” Dr. Graham said.

She noted that as women with MS increasingly undergo IVF as well as egg cryopreservation, research on these issues is gaining importance for clinicians. “This is going to be something that MS specialists need to know more about, particularly the safety of ART in their patients,” said Dr. Graham.

“What’s important is there are no [formal] recommendations along these lines, so this represents an opportunity to get the word out to clinicians that you want to make sure patients with MS are protected throughout the ART cycle and that you’re not discontinuing their DMT too early,” she added.
 

Protective against relapse?

Commenting on the study, Jiwon Oh, MD, PhD, medical director of the Barlo Multiple Sclerosis Program at St. Michael’s Hospital, University of Toronto, noted that, while there are many guidelines/recommendations regarding use of older DMTs peripregnancy, data on many newer therapies is more limited.

“Often, when people do not have definitive evidence, they tend to take a conservative approach, which is why there is likely reluctance to keep patients on DMTs during ART as well as in early pregnancy,” said Dr. Oh, who was not involved in the research.

Importantly, there is also no definitive evidence of a relationship between MS relapses and ART success or pregnancy outcomes, she noted. However, “from a common-sense perspective, most clinicians worry that extreme stress or disability may negatively affect both ART and pregnancy outcomes,” she added.

Dr. Oh agreed that ocrelizumab is an appropriate choice in terms of preventing relapse during ART. “Ocrevus is one of our highest-efficacy DMTs and is only dosed every 6 months. So this allows for ART cycles and conception without worrying about fetal drug exposure and the drug affecting ART cycles,” she said.

She noted the study’s findings “are in keeping with some prior studies, but not others, demonstrating there may be a higher risk of relapse with ART” in patients who are not taking a DMT.

“However, in my mind the most important conclusion from this study is that being on a DMT seems to be protective of relapse risk, which is an important point that will be useful to provide patients with clinical guidance,” Dr. Oh said.

Dr. Graham reported having received consulting fees from Genentech. Dr. Oh reported having received consulting or speaking fees from Alexion, Biogen Idec, BMS, EMD Serono, Genzyme, Novartis, and Roche.

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

WEST PALM BEACH, FLA. – Women with multiple sclerosis (MS) undergoing assisted reproductive technologies (ART) have an increased relapse risk if they are not treated with disease-modifying therapy (DMT), new research suggests. In a cohort study of women undergoing ART, those who did not receive DMTs had a significantly higher relapse risk than their peers who were treated with the drugs.

In addition, the likelihood of achieving pregnancy through ART while having MS appeared favorable, researchers noted.

“In this modern case series and the largest cohort to date, we identified a lower risk of relapses after ART than previously reported,” Edith L. Graham, MD, of the department of neurology, Northwestern University, Chicago, and colleagues  wrote. “Importantly, continuing DMT during ART may reduce risk of relapse during this period of marked hormonal fluctuations and stressors,” they added.

The findings were presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
 

Study details

Previous research shows a wide range of relapse risk in patients with MS undergoing ART.

To investigate the potential role of DMTs in mitigating relapse risk, the researchers evaluated data on 37 women with either relapsing-remitting MS (n = 31) or clinically isolated syndrome (CIS; n = 6) who underwent ART. The women all had low disability, with a median Expanded Disability Status Scale (EDSS) score of 1.0. All participants had undergone one to five cycles of reproductive therapy between 2010 and 2021.

Most (78%) were receiving ART because of infertility or a need for preimplantation genetic testing, whereas 22% were undergoing the treatment for the preservation of fertility. Average age of the participants was 35 years and average disease duration was 7.4 years.

Among 19 of the 37 patients who were taking DMTs prior to ART, 10 remained on the medication throughout ovarian hyperstimulation.

In those who received DMTs in the 12 months prior to ART, treatment included glatiramer acetate (n = 9), interferons (n = 3), and dimethyl fumarate (n = 1). Three participants received B-cell–depleting agents.

In addition, three women received medication in response to a rebound after discontinuation. Of these, two received fingolimod and one natalizumab.

Five patients (13.5%) experienced MS relapses in the 12 months following ART therapy. Among those experiencing relapse, none were treated with DMTs during the preceding 12 months.

Of the relapses, three occurred within 3 months of the ART treatment, one within 6 months, and one within 12 months.
 

High rate of successful pregnancy

Overall, 24 of 29 women (83%) underwent in vitro fertilization (IVF) with embryo transfer as part of ART achieved pregnancy. The remaining five patients were undergoing egg cryopreservation.

Although 14 of the 24 who achieved pregnancy were on DMTs and 2 of 5 who did not achieve pregnancy were on the therapies, Dr. Graham noted, “these numbers seem too small to draw conclusions.”

In particular, patients may benefit from treatment with rituximab or ocrelizumab 3-6 months prior to ART, “which gives better protection during ART cycle with low risk of fetal exposure,” she said.

“Treatment does not need to be discontinued if undergoing embryo banking only,” Dr. Graham added. “The risk to the fetus occurs only after embryo transfer.”

Although there is a lack of research examining whether MS relapse lowers the chance of pregnancy, Dr. Graham noted, “in theory, relapsing MS may compromise ART success because [patients] may have a narrower window to undergo ART treatments if they are trying to mitigate DMT exposure to the fetus.” 

However, the study’s results generally suggest favorable outcomes with ART among women with MS, she added. “We found that overall ART is actually very successful among people with MS. I was actually very surprised by this high rate of successful pregnancy,” Dr. Graham said.

She noted that as women with MS increasingly undergo IVF as well as egg cryopreservation, research on these issues is gaining importance for clinicians. “This is going to be something that MS specialists need to know more about, particularly the safety of ART in their patients,” said Dr. Graham.

“What’s important is there are no [formal] recommendations along these lines, so this represents an opportunity to get the word out to clinicians that you want to make sure patients with MS are protected throughout the ART cycle and that you’re not discontinuing their DMT too early,” she added.
 

Protective against relapse?

Commenting on the study, Jiwon Oh, MD, PhD, medical director of the Barlo Multiple Sclerosis Program at St. Michael’s Hospital, University of Toronto, noted that, while there are many guidelines/recommendations regarding use of older DMTs peripregnancy, data on many newer therapies is more limited.

“Often, when people do not have definitive evidence, they tend to take a conservative approach, which is why there is likely reluctance to keep patients on DMTs during ART as well as in early pregnancy,” said Dr. Oh, who was not involved in the research.

Importantly, there is also no definitive evidence of a relationship between MS relapses and ART success or pregnancy outcomes, she noted. However, “from a common-sense perspective, most clinicians worry that extreme stress or disability may negatively affect both ART and pregnancy outcomes,” she added.

Dr. Oh agreed that ocrelizumab is an appropriate choice in terms of preventing relapse during ART. “Ocrevus is one of our highest-efficacy DMTs and is only dosed every 6 months. So this allows for ART cycles and conception without worrying about fetal drug exposure and the drug affecting ART cycles,” she said.

She noted the study’s findings “are in keeping with some prior studies, but not others, demonstrating there may be a higher risk of relapse with ART” in patients who are not taking a DMT.

“However, in my mind the most important conclusion from this study is that being on a DMT seems to be protective of relapse risk, which is an important point that will be useful to provide patients with clinical guidance,” Dr. Oh said.

Dr. Graham reported having received consulting fees from Genentech. Dr. Oh reported having received consulting or speaking fees from Alexion, Biogen Idec, BMS, EMD Serono, Genzyme, Novartis, and Roche.

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