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Dietary Trial Shows Benefits of a Low Emulsifier Diet for Crohn’s Disease
WASHINGTON, DC — involving 154 patients with mildly active disease living across the United Kingdom.
The findings were reported at Gut Microbiota for Health (GMFH) World Summit 2025 by Benoit Chassaing, PhD, of the Institut Pasteur, Paris, France, whose research leading up to the trial has demonstrated that food additive emulsifiers —ubiquitous in processed foods — alter microbiota composition and lead to microbiota encroachment into the mucus layer of the gut and subsequent chronic gut inflammation.
Patients in the ADDapt trial, which was also reported in an abstract earlier this year at the European Crohn’s and Colitis Organization (ECCO) 2025 Congress, had a Crohn’s disease activity index (CDAI) of 150-250 and evidence of inflammation (faecal calprotectin (FCP) ≥ 150 µg/g or endoscopy/radiology). All “had been exposed in their regular diets to emulsifiers,” said Chassaing, a co-investigator, during a GMFH session on “Dietary Drivers of Health and Disease.”
They were randomized to either a low-emulsifier diet or to a low-emulsifier diet followed by emulsifier “resupplementation” — a design meant to “account for the very strong placebo effect that is always observed with dietary studies,” he said.
All patients received dietary counseling, a smart phone app and barcode scan to support shopping, and weekly support. They also received supermarket foods for 25% of their needs that were either free of emulsifiers or contained emulsifiers, and they were provided three snacks per day that were emulsifier-free or contained carrageenan, carboxymethycellulse (CMC), and polysorbate-80 (P80) — dietary emulsifiers that are commonly added to processed foods to enhance texture and extend shelf-life.
In the intention-to-treat (ITT) analysis, 49% of patients in the intervention group reached the primary endpoint of a 70-point reduction or more in CDAI response after 8 weeks compared with 31% of those in the control group (P = .019), with an adjusted relative risk of response of 3.1 (P = .003), Chassaing shared at the GMFH meeting, convened by the American Gastroenterological Association and the European Society of Neurogastroenterology and Motility.
In the per-protocol analysis (n = 119), 61% and 47% of patients in the intervention and control groups, respectively, reached the primary outcome of CDAI response, with an adjusted relative risk of response of 3.0 (P = .018), he said.
Secondary endpoints included CDAI remission at 24 weeks, and according to the abstract for the ECCO Congress, in the ITT analysis, patients in the intervention group were more than twice as likely to experience remission.
Chassaing noted at the GMFH meeting that as part of the study, he and coinvestigators have been investigating the participants’ gut microbiota with metagenomic analyses. The study was led by Kevin Whelan, PhD, head of the Department of Nutritional Sciences at King’s College London, London, England.
Can Emulsifier-Sensitive Individuals Be Identified?
In murine model research 10 years ago, Chassaing showed that the administration of CMC and P80 results in microbiota encroachment into the mucus layer of the gut, alterations in microbiota composition — including an increase in bacteria that produce pro-inflammatory flagellin — and development of chronic inflammation.
Wild-type mice treated with these compounds developed metabolic disease, and mice that were modified to be predisposed to colitis had a higher incidence of robust colitis. Moreover, fecal transplantation from emulsifier-treated mice to germ-free mice reproduced these changes, “clearly suggesting that the microbiome itself is sufficient to drive chronic inflammation,” he said.
In recent years, in humans, analyses from the large French NutriNet-Sante prospective cohort study have shown associations between exposure to food additive emulsifiers and the risk for cardiovascular disease, the risk for cancer (overall, breast, and prostate), and the risk for type 2 diabetes.
But to explore causality and better understand the mechanisms of emulsifier-driven changes on the microbiota, Chassaing and his colleagues also launched the FRESH study (Functional Research on Emulsifier in Humans), a double-blind randomized controlled-feeding study of the emulsifier CMC. For 11 days, nine healthy patients consumed an emulsifier-free diet and 11 consumed an identical diet enriched with 15 g/d of CMC.
Patients on the CMC-containing diet had reduced microbiota diversity and depletions of an array of microbiota-related metabolites, but only a small subset had profound alterations in microbiota composition and increased microbiota encroachment into the mucus layer. “Some seemed to be resistant to CMC-induced microbiota encroachment, while some were highly susceptible,” Chassaing said.
The pilot study raised the question, he said, of whether there is an “infectivity component” — some kind of “sensitive” gut microbiota composition — that may be associated with dietary emulsifier-driven inflammation and disease.
In other murine research, Chassaing and his team found that germ-free mice colonized with Crohn’s disease-associated adherent-invasive E coli (AIEC) and subsequently given CMC or P80 developed chronic inflammation and metabolic dysregulation, “clearly demonstrating that you can convert resistant mice to sensitive mice just by adding one bacteria to the ecosystem,” he said. “The presence of AIEC alone was sufficient to drive the detrimental effects of dietary emulsifiers.”
(In vitro research with transcriptomic analysis then showed that the emulsifiers directly elicit AIEC virulence gene expression, Chassaing and his coauthors wrote in their 2020 paper, facilitating AIEC’s “penetration of the mucus layer and adherence to epithelial cells and resulting in activation of host pro-inflammatory signaling.”)
“We don’t think it’s solely the AIEC bacteria that will drive emulsifier sensitivity, though…we think it’s more complex,” Chassaing said at the meeting. Overall, the findings raise the question of whether emulsifier-sensitive individuals can be identified.
This, he said, is one of his most recent research questions. His lab has led the development of an in vitro microbiota model built to predict an individual’s sensitivity to emulsifiers. In a study published in April, the model recapitulated the differential CMC sensitivity observed in the earlier FRESH study, suggesting that an individual’s sensitivity to emulsifiers can indeed be predicted by examining their baseline microbiota.
Interpreting the Epidemiology
Chassaing’s research arch illustrates the synergy between epidemiological research, basic/translational research, and clinical interventional research that’s needed to understand the diet-microbiome intersection in inflammatory bowel disease, said Ashwin Ananthakrishnan, MBBS, MPH, AGAF, associate professor of medicine at Massachusetts General Hospital, Boston, in an interview at the meeting.
“It’s a good example of how to really span the spectrum, starting from the big picture and going deeper to understand mechanisms, and starting from mechanisms and expanding it out,” Ananthakrishnan said.
In his own talk about research on IBD, Ananthakrishnan said that epidemiological data have shown over the past 10-15 years that total dietary fiber is inversely associated with the risk for Crohn’s disease (with the strongest associations with fiber from fruits and vegetables). Studies have also shown that a higher intake of polyunsaturated fatty acids is associated with a lower risk for ulcerative colitis, whereas “an n-6-fatty acid-rich diet is associated with a higher risk of ulcerative colitis,” he said.
Dietary cohort studies, meanwhile, have shed light on the influence of dietary patterns — such as the Mediterranean diet and diets with high inflammatory potential—on IBD. A diet rich in ultra-processed foods has also been shown in a prospective cohort study to be associated with a higher risk for Crohn’s disease, with certain categories of ultra-processed foods (eg, breads and breakfast foods) having the strongest associations.
Such studies are limited in part, however, by inadequate assessment of potentially relevant variables such as emulsifiers, preservatives, and how the food is processed, he said.
And in interpreting the epidemiological research on fiber and IBD, for instance, one must appreciate that “there are a number of mechanisms by which fiber is impactful…there’s a big picture to look at,” Ananthakrishnan said. Fiber “can affect the microbiome, clearly, it can affect the gut barrier, and it can affect bile acids, and there are detailed translational studies in support of each of these.”
But there are other constituents of fruits and vegetables “that could potentially influence disease risk, such as AhR ligands and polyphenols,” he said. “And importantly, people not eating a lot of fiber may be eating a lot of ultra-processed foods.”
Most interventional studies of fiber have not shown a benefit of a high-fiber diet, Ananthakrishnan said, but there are multiple possible reasons and factors at play, including potential population differences (eg, in inflammatory status or baseline microbiota), shortcomings of the interventions, and potentially inaccurate outcomes.
Abigail Johnson, PhD, RDN, associate director of the Nutrition Coordinating Center, University of Minnesota Twin Cities, which supports dietary analysis, said during the session that the focus of dietary research is “moving toward understanding overall dietary patterns” as opposed to focusing more narrowly on vitamins, minerals, and macronutrients such as proteins, fats, and carbohydrates.
This is an improvement, though “we still don’t have good approaches for understanding [the contributions of] things like additives and emulsifiers, food preparation and cooking, and food processing,” said Johnson, assistant professor in the Division of Epidemiology and Community Health at University of Minnesota Twin Cities. “Perhaps by looking at things at the food level we can overcome some of these limitations.”
Ananthakrishnan reported being a consultant for Geneoscopy and receiving a research grant from Takeda. Chassaing did not report any financial disclosures. Johnson reported that she had no financial disclosures.
A version of this article appeared on Medscape.com.
WASHINGTON, DC — involving 154 patients with mildly active disease living across the United Kingdom.
The findings were reported at Gut Microbiota for Health (GMFH) World Summit 2025 by Benoit Chassaing, PhD, of the Institut Pasteur, Paris, France, whose research leading up to the trial has demonstrated that food additive emulsifiers —ubiquitous in processed foods — alter microbiota composition and lead to microbiota encroachment into the mucus layer of the gut and subsequent chronic gut inflammation.
Patients in the ADDapt trial, which was also reported in an abstract earlier this year at the European Crohn’s and Colitis Organization (ECCO) 2025 Congress, had a Crohn’s disease activity index (CDAI) of 150-250 and evidence of inflammation (faecal calprotectin (FCP) ≥ 150 µg/g or endoscopy/radiology). All “had been exposed in their regular diets to emulsifiers,” said Chassaing, a co-investigator, during a GMFH session on “Dietary Drivers of Health and Disease.”
They were randomized to either a low-emulsifier diet or to a low-emulsifier diet followed by emulsifier “resupplementation” — a design meant to “account for the very strong placebo effect that is always observed with dietary studies,” he said.
All patients received dietary counseling, a smart phone app and barcode scan to support shopping, and weekly support. They also received supermarket foods for 25% of their needs that were either free of emulsifiers or contained emulsifiers, and they were provided three snacks per day that were emulsifier-free or contained carrageenan, carboxymethycellulse (CMC), and polysorbate-80 (P80) — dietary emulsifiers that are commonly added to processed foods to enhance texture and extend shelf-life.
In the intention-to-treat (ITT) analysis, 49% of patients in the intervention group reached the primary endpoint of a 70-point reduction or more in CDAI response after 8 weeks compared with 31% of those in the control group (P = .019), with an adjusted relative risk of response of 3.1 (P = .003), Chassaing shared at the GMFH meeting, convened by the American Gastroenterological Association and the European Society of Neurogastroenterology and Motility.
In the per-protocol analysis (n = 119), 61% and 47% of patients in the intervention and control groups, respectively, reached the primary outcome of CDAI response, with an adjusted relative risk of response of 3.0 (P = .018), he said.
Secondary endpoints included CDAI remission at 24 weeks, and according to the abstract for the ECCO Congress, in the ITT analysis, patients in the intervention group were more than twice as likely to experience remission.
Chassaing noted at the GMFH meeting that as part of the study, he and coinvestigators have been investigating the participants’ gut microbiota with metagenomic analyses. The study was led by Kevin Whelan, PhD, head of the Department of Nutritional Sciences at King’s College London, London, England.
Can Emulsifier-Sensitive Individuals Be Identified?
In murine model research 10 years ago, Chassaing showed that the administration of CMC and P80 results in microbiota encroachment into the mucus layer of the gut, alterations in microbiota composition — including an increase in bacteria that produce pro-inflammatory flagellin — and development of chronic inflammation.
Wild-type mice treated with these compounds developed metabolic disease, and mice that were modified to be predisposed to colitis had a higher incidence of robust colitis. Moreover, fecal transplantation from emulsifier-treated mice to germ-free mice reproduced these changes, “clearly suggesting that the microbiome itself is sufficient to drive chronic inflammation,” he said.
In recent years, in humans, analyses from the large French NutriNet-Sante prospective cohort study have shown associations between exposure to food additive emulsifiers and the risk for cardiovascular disease, the risk for cancer (overall, breast, and prostate), and the risk for type 2 diabetes.
But to explore causality and better understand the mechanisms of emulsifier-driven changes on the microbiota, Chassaing and his colleagues also launched the FRESH study (Functional Research on Emulsifier in Humans), a double-blind randomized controlled-feeding study of the emulsifier CMC. For 11 days, nine healthy patients consumed an emulsifier-free diet and 11 consumed an identical diet enriched with 15 g/d of CMC.
Patients on the CMC-containing diet had reduced microbiota diversity and depletions of an array of microbiota-related metabolites, but only a small subset had profound alterations in microbiota composition and increased microbiota encroachment into the mucus layer. “Some seemed to be resistant to CMC-induced microbiota encroachment, while some were highly susceptible,” Chassaing said.
The pilot study raised the question, he said, of whether there is an “infectivity component” — some kind of “sensitive” gut microbiota composition — that may be associated with dietary emulsifier-driven inflammation and disease.
In other murine research, Chassaing and his team found that germ-free mice colonized with Crohn’s disease-associated adherent-invasive E coli (AIEC) and subsequently given CMC or P80 developed chronic inflammation and metabolic dysregulation, “clearly demonstrating that you can convert resistant mice to sensitive mice just by adding one bacteria to the ecosystem,” he said. “The presence of AIEC alone was sufficient to drive the detrimental effects of dietary emulsifiers.”
(In vitro research with transcriptomic analysis then showed that the emulsifiers directly elicit AIEC virulence gene expression, Chassaing and his coauthors wrote in their 2020 paper, facilitating AIEC’s “penetration of the mucus layer and adherence to epithelial cells and resulting in activation of host pro-inflammatory signaling.”)
“We don’t think it’s solely the AIEC bacteria that will drive emulsifier sensitivity, though…we think it’s more complex,” Chassaing said at the meeting. Overall, the findings raise the question of whether emulsifier-sensitive individuals can be identified.
This, he said, is one of his most recent research questions. His lab has led the development of an in vitro microbiota model built to predict an individual’s sensitivity to emulsifiers. In a study published in April, the model recapitulated the differential CMC sensitivity observed in the earlier FRESH study, suggesting that an individual’s sensitivity to emulsifiers can indeed be predicted by examining their baseline microbiota.
Interpreting the Epidemiology
Chassaing’s research arch illustrates the synergy between epidemiological research, basic/translational research, and clinical interventional research that’s needed to understand the diet-microbiome intersection in inflammatory bowel disease, said Ashwin Ananthakrishnan, MBBS, MPH, AGAF, associate professor of medicine at Massachusetts General Hospital, Boston, in an interview at the meeting.
“It’s a good example of how to really span the spectrum, starting from the big picture and going deeper to understand mechanisms, and starting from mechanisms and expanding it out,” Ananthakrishnan said.
In his own talk about research on IBD, Ananthakrishnan said that epidemiological data have shown over the past 10-15 years that total dietary fiber is inversely associated with the risk for Crohn’s disease (with the strongest associations with fiber from fruits and vegetables). Studies have also shown that a higher intake of polyunsaturated fatty acids is associated with a lower risk for ulcerative colitis, whereas “an n-6-fatty acid-rich diet is associated with a higher risk of ulcerative colitis,” he said.
Dietary cohort studies, meanwhile, have shed light on the influence of dietary patterns — such as the Mediterranean diet and diets with high inflammatory potential—on IBD. A diet rich in ultra-processed foods has also been shown in a prospective cohort study to be associated with a higher risk for Crohn’s disease, with certain categories of ultra-processed foods (eg, breads and breakfast foods) having the strongest associations.
Such studies are limited in part, however, by inadequate assessment of potentially relevant variables such as emulsifiers, preservatives, and how the food is processed, he said.
And in interpreting the epidemiological research on fiber and IBD, for instance, one must appreciate that “there are a number of mechanisms by which fiber is impactful…there’s a big picture to look at,” Ananthakrishnan said. Fiber “can affect the microbiome, clearly, it can affect the gut barrier, and it can affect bile acids, and there are detailed translational studies in support of each of these.”
But there are other constituents of fruits and vegetables “that could potentially influence disease risk, such as AhR ligands and polyphenols,” he said. “And importantly, people not eating a lot of fiber may be eating a lot of ultra-processed foods.”
Most interventional studies of fiber have not shown a benefit of a high-fiber diet, Ananthakrishnan said, but there are multiple possible reasons and factors at play, including potential population differences (eg, in inflammatory status or baseline microbiota), shortcomings of the interventions, and potentially inaccurate outcomes.
Abigail Johnson, PhD, RDN, associate director of the Nutrition Coordinating Center, University of Minnesota Twin Cities, which supports dietary analysis, said during the session that the focus of dietary research is “moving toward understanding overall dietary patterns” as opposed to focusing more narrowly on vitamins, minerals, and macronutrients such as proteins, fats, and carbohydrates.
This is an improvement, though “we still don’t have good approaches for understanding [the contributions of] things like additives and emulsifiers, food preparation and cooking, and food processing,” said Johnson, assistant professor in the Division of Epidemiology and Community Health at University of Minnesota Twin Cities. “Perhaps by looking at things at the food level we can overcome some of these limitations.”
Ananthakrishnan reported being a consultant for Geneoscopy and receiving a research grant from Takeda. Chassaing did not report any financial disclosures. Johnson reported that she had no financial disclosures.
A version of this article appeared on Medscape.com.
WASHINGTON, DC — involving 154 patients with mildly active disease living across the United Kingdom.
The findings were reported at Gut Microbiota for Health (GMFH) World Summit 2025 by Benoit Chassaing, PhD, of the Institut Pasteur, Paris, France, whose research leading up to the trial has demonstrated that food additive emulsifiers —ubiquitous in processed foods — alter microbiota composition and lead to microbiota encroachment into the mucus layer of the gut and subsequent chronic gut inflammation.
Patients in the ADDapt trial, which was also reported in an abstract earlier this year at the European Crohn’s and Colitis Organization (ECCO) 2025 Congress, had a Crohn’s disease activity index (CDAI) of 150-250 and evidence of inflammation (faecal calprotectin (FCP) ≥ 150 µg/g or endoscopy/radiology). All “had been exposed in their regular diets to emulsifiers,” said Chassaing, a co-investigator, during a GMFH session on “Dietary Drivers of Health and Disease.”
They were randomized to either a low-emulsifier diet or to a low-emulsifier diet followed by emulsifier “resupplementation” — a design meant to “account for the very strong placebo effect that is always observed with dietary studies,” he said.
All patients received dietary counseling, a smart phone app and barcode scan to support shopping, and weekly support. They also received supermarket foods for 25% of their needs that were either free of emulsifiers or contained emulsifiers, and they were provided three snacks per day that were emulsifier-free or contained carrageenan, carboxymethycellulse (CMC), and polysorbate-80 (P80) — dietary emulsifiers that are commonly added to processed foods to enhance texture and extend shelf-life.
In the intention-to-treat (ITT) analysis, 49% of patients in the intervention group reached the primary endpoint of a 70-point reduction or more in CDAI response after 8 weeks compared with 31% of those in the control group (P = .019), with an adjusted relative risk of response of 3.1 (P = .003), Chassaing shared at the GMFH meeting, convened by the American Gastroenterological Association and the European Society of Neurogastroenterology and Motility.
In the per-protocol analysis (n = 119), 61% and 47% of patients in the intervention and control groups, respectively, reached the primary outcome of CDAI response, with an adjusted relative risk of response of 3.0 (P = .018), he said.
Secondary endpoints included CDAI remission at 24 weeks, and according to the abstract for the ECCO Congress, in the ITT analysis, patients in the intervention group were more than twice as likely to experience remission.
Chassaing noted at the GMFH meeting that as part of the study, he and coinvestigators have been investigating the participants’ gut microbiota with metagenomic analyses. The study was led by Kevin Whelan, PhD, head of the Department of Nutritional Sciences at King’s College London, London, England.
Can Emulsifier-Sensitive Individuals Be Identified?
In murine model research 10 years ago, Chassaing showed that the administration of CMC and P80 results in microbiota encroachment into the mucus layer of the gut, alterations in microbiota composition — including an increase in bacteria that produce pro-inflammatory flagellin — and development of chronic inflammation.
Wild-type mice treated with these compounds developed metabolic disease, and mice that were modified to be predisposed to colitis had a higher incidence of robust colitis. Moreover, fecal transplantation from emulsifier-treated mice to germ-free mice reproduced these changes, “clearly suggesting that the microbiome itself is sufficient to drive chronic inflammation,” he said.
In recent years, in humans, analyses from the large French NutriNet-Sante prospective cohort study have shown associations between exposure to food additive emulsifiers and the risk for cardiovascular disease, the risk for cancer (overall, breast, and prostate), and the risk for type 2 diabetes.
But to explore causality and better understand the mechanisms of emulsifier-driven changes on the microbiota, Chassaing and his colleagues also launched the FRESH study (Functional Research on Emulsifier in Humans), a double-blind randomized controlled-feeding study of the emulsifier CMC. For 11 days, nine healthy patients consumed an emulsifier-free diet and 11 consumed an identical diet enriched with 15 g/d of CMC.
Patients on the CMC-containing diet had reduced microbiota diversity and depletions of an array of microbiota-related metabolites, but only a small subset had profound alterations in microbiota composition and increased microbiota encroachment into the mucus layer. “Some seemed to be resistant to CMC-induced microbiota encroachment, while some were highly susceptible,” Chassaing said.
The pilot study raised the question, he said, of whether there is an “infectivity component” — some kind of “sensitive” gut microbiota composition — that may be associated with dietary emulsifier-driven inflammation and disease.
In other murine research, Chassaing and his team found that germ-free mice colonized with Crohn’s disease-associated adherent-invasive E coli (AIEC) and subsequently given CMC or P80 developed chronic inflammation and metabolic dysregulation, “clearly demonstrating that you can convert resistant mice to sensitive mice just by adding one bacteria to the ecosystem,” he said. “The presence of AIEC alone was sufficient to drive the detrimental effects of dietary emulsifiers.”
(In vitro research with transcriptomic analysis then showed that the emulsifiers directly elicit AIEC virulence gene expression, Chassaing and his coauthors wrote in their 2020 paper, facilitating AIEC’s “penetration of the mucus layer and adherence to epithelial cells and resulting in activation of host pro-inflammatory signaling.”)
“We don’t think it’s solely the AIEC bacteria that will drive emulsifier sensitivity, though…we think it’s more complex,” Chassaing said at the meeting. Overall, the findings raise the question of whether emulsifier-sensitive individuals can be identified.
This, he said, is one of his most recent research questions. His lab has led the development of an in vitro microbiota model built to predict an individual’s sensitivity to emulsifiers. In a study published in April, the model recapitulated the differential CMC sensitivity observed in the earlier FRESH study, suggesting that an individual’s sensitivity to emulsifiers can indeed be predicted by examining their baseline microbiota.
Interpreting the Epidemiology
Chassaing’s research arch illustrates the synergy between epidemiological research, basic/translational research, and clinical interventional research that’s needed to understand the diet-microbiome intersection in inflammatory bowel disease, said Ashwin Ananthakrishnan, MBBS, MPH, AGAF, associate professor of medicine at Massachusetts General Hospital, Boston, in an interview at the meeting.
“It’s a good example of how to really span the spectrum, starting from the big picture and going deeper to understand mechanisms, and starting from mechanisms and expanding it out,” Ananthakrishnan said.
In his own talk about research on IBD, Ananthakrishnan said that epidemiological data have shown over the past 10-15 years that total dietary fiber is inversely associated with the risk for Crohn’s disease (with the strongest associations with fiber from fruits and vegetables). Studies have also shown that a higher intake of polyunsaturated fatty acids is associated with a lower risk for ulcerative colitis, whereas “an n-6-fatty acid-rich diet is associated with a higher risk of ulcerative colitis,” he said.
Dietary cohort studies, meanwhile, have shed light on the influence of dietary patterns — such as the Mediterranean diet and diets with high inflammatory potential—on IBD. A diet rich in ultra-processed foods has also been shown in a prospective cohort study to be associated with a higher risk for Crohn’s disease, with certain categories of ultra-processed foods (eg, breads and breakfast foods) having the strongest associations.
Such studies are limited in part, however, by inadequate assessment of potentially relevant variables such as emulsifiers, preservatives, and how the food is processed, he said.
And in interpreting the epidemiological research on fiber and IBD, for instance, one must appreciate that “there are a number of mechanisms by which fiber is impactful…there’s a big picture to look at,” Ananthakrishnan said. Fiber “can affect the microbiome, clearly, it can affect the gut barrier, and it can affect bile acids, and there are detailed translational studies in support of each of these.”
But there are other constituents of fruits and vegetables “that could potentially influence disease risk, such as AhR ligands and polyphenols,” he said. “And importantly, people not eating a lot of fiber may be eating a lot of ultra-processed foods.”
Most interventional studies of fiber have not shown a benefit of a high-fiber diet, Ananthakrishnan said, but there are multiple possible reasons and factors at play, including potential population differences (eg, in inflammatory status or baseline microbiota), shortcomings of the interventions, and potentially inaccurate outcomes.
Abigail Johnson, PhD, RDN, associate director of the Nutrition Coordinating Center, University of Minnesota Twin Cities, which supports dietary analysis, said during the session that the focus of dietary research is “moving toward understanding overall dietary patterns” as opposed to focusing more narrowly on vitamins, minerals, and macronutrients such as proteins, fats, and carbohydrates.
This is an improvement, though “we still don’t have good approaches for understanding [the contributions of] things like additives and emulsifiers, food preparation and cooking, and food processing,” said Johnson, assistant professor in the Division of Epidemiology and Community Health at University of Minnesota Twin Cities. “Perhaps by looking at things at the food level we can overcome some of these limitations.”
Ananthakrishnan reported being a consultant for Geneoscopy and receiving a research grant from Takeda. Chassaing did not report any financial disclosures. Johnson reported that she had no financial disclosures.
A version of this article appeared on Medscape.com.
FROM GMFH 2025
Can Modulation of the Microbiome Improve Cancer Immunotherapy Tolerance and Efficacy?
WASHINGTON — For years, oncologist Jonathan Peled, MD, PhD, and his colleagues at Memorial Sloan Kettering Cancer Center (MSKCC) in New York City have been documenting gut microbiota disruption during allogeneic hematopoietic stem cell transplantation (allo-HSCT) and its role in frequent and potentially fatal bloodstream infections (BSIs) in the first 100 days after transplant.
, and at the Gut Microbiota for Health (GMFH) World Summit 2025, Peled shared two new findings.
In one study, his team found that sucrose can exacerbate antibiotic-induced microbiome injury in patients undergoing allo-HSCT — a finding that “raises the question of whether our dietary recommendations [for] allo-HSCT patients are correct,” said Peled, assistant attending at MSKCC, during a session on the gut microbiome and oncology.
And in another study, they found that a rationally designed probiotic formulation may help lower the incidence of bacterial BSIs. In December 2024, the probiotic formulation (SER-155, Seres Therapeutics, Inc.) was granted breakthrough therapy designation by the FDA.
With immunotherapies more broadly, researchers are increasingly looking at diet and modulation of the microbiome to improve both treatment tolerance and efficacy, experts said at the meeting convened by the AGA and the European Society of Neurogastroenterology and Motility.
“Cancer patients and caregivers are asking, ‘What should I eat?’” said Carrie Daniel-MacDougall, PhD, MPH, a nutritional epidemiologist at the University of Texas MD Anderson Cancer Center in Houston. “They’re not just focused on side effects — they want a good outcome for their treatment, and they’re exploring a lot of dietary strategies [for which there] is not a lot of evidence.”
Clinicians are challenged by the fact that “we don’t typically collect dietary data in clinical trials of cancer drugs,” leaving them to extrapolate from evidence-based diet guidelines for cancer prevention, Daniel-MacDougall said.
But “I think that’s starting to shift,” she said, with the microbiome being increasingly recognized for its potential influences on therapeutic response and clinical trials underway looking at “a healthy dietary pattern not just for prevention but survival.”
Diet and Probiotics After allo-HSCT
The patterns of microbiota disruption during allo-HSCT — a procedure that includes antibiotic administration, chemotherapy, and sometimes irradiation — are characterized by loss of diversity and the expansion of potentially pathogenic organisms, most commonly Enterococcus, said Peled.
This has been demonstrated across transplantation centers. In a multicenter, international study published in 2020, the patterns of microbiota disruption and their impact on mortality were similar across MSK and other transplantation centers, with higher diversity of intestinal microbiota associated with lower mortality.
Other studies have shown that Enterococcus domination alone (defined arbitrarily as > 30% of fecal microbial composition) is associated with graft vs host disease and higher mortality after allo-HSCT and that intestinal domination by Proteobacteria coincides temporally with BSIs, he said.
Autologous fecal microbiota transplantation (FMT) has been shown to largely restore the microbiota composition the patient had before antibiotic treatment and allo-HSCT, he said, making fecal sample banking and posttreatment FMT a potential approach for reconstituting the gut microbiome and improving outcomes.
But “lately we’ve been very interested in diet for modulating [harmful] patterns” in the microbiome composition, Peled said.
In the new study suggesting a role for sugar avoidance, published last year as a bioRxiv preprint, Peled and his colleagues collected real-time dietary intake data (40,702 food entries) from 173 patients hospitalized for several weeks for allo-HSCT at MSK and analyzed it alongside longitudinally collected fecal samples. They used a Bayesian mixed-effects model to identify dietary components that may correlate with microbial disruption.
“What jumped out as very predictive of a low diversity fecal sample [and expansion of Enterococcus] in the 2 days prior to collection was the interaction between antibiotics and the consumption of sweets” — foods rich in simple sugars, Peled said. The relationship between sugar and the microbiome occurred only during periods of antibiotic exposure.
“And it was particularly perplexing because the foods that fall into the ‘sweets’ category are foods we encourage people to eat clinically when they’re not feeling well and food intake drops dramatically,” he said. This includes foods like nutritional drinks or shakes, Italian ice, gelatin dessert, and sports drinks.
(In a mouse model of post-antibiotic Enterococcus expansion, Peled and his co-investigators then validated the findings and ruled out the impact of any reductions in fiber.)
In addition to possibly revising dietary recommendations for patients undergoing allo-HSCT, the findings raise the question of whether avoiding sugar intake while on antibiotics, in general, is a way to mitigate antibiotic-induced dysbiosis, he said.
To test the role of probiotics, Peled and colleagues collaborated with Seres Therapeutics on a phase 1b trial of an oral combination (SER-155) of 16 fermented strains “selected rationally,” he said, for their ability to decolonize gut pathogens, improve gut barrier function (in vitro), and reduce gut inflammation and local immune activation.
After a safety lead-in, patients were randomized to receive SER-155 (20) or placebo (14) three times — prior to transplant, upon neutrophil engraftment (with vancomycin “conditioning”), and after transplant. “The strains succeeded in grafting in the [gastrointestinal] GI tract…and some of them persisted all the way through to day 100,” Peled said.
The incidence of pathogen domination was substantially lower in the probiotic recipients compared to an MSK historical control cohort, and the incidence of BSIs was significantly lower compared to the placebo arm (10% vs 43%, respectively, representing a 77% relative risk reduction), he said.
Diet and Immunotherapy Response: Trials at MD Anderson
One of the first trials Daniel-MacDougall launched at MD Anderson on diet and the microbiome randomized 55 patients who were obese and had a history of colorectal cancer or precancerous polyps to add a cup of beans to their usual diet or to continue their usual diet without beans. There was a crossover at 8 weeks in the 16-week BE GONE trial; stool and fasting blood were collected every 4 weeks.
“Beans are a prebiotic super-house in my opinion, and they’re also something this population would avoid,” said Daniel-MacDougall, associate professor in the department of epidemiology at MD Anderson and faculty director of the Bionutrition Research Core and Research Kitchen.
“We saw a modest increase in alpha diversity [in the intervention group] and similar trends with microbiota-derived metabolites” that regressed when patients returned to their usual diet, she said. The researchers also documented decreases in proteomic biomarkers of intestinal and systemic immune and inflammatory response.
The impact of diet on cancer survival was shown in subsequent research, including an observational study published in Science in 2021 of patients with melanoma receiving immune checkpoint blockade (ICB) treatment. “Patients who consumed insufficient dietary fiber at the start of therapy tended to do worse [than those reporting sufficient fiber intake],” with significantly lower progression-free survival, Daniel-MacDougall said.
“And interestingly, when we looked at dietary fiber [with and without] probiotic use, patients who had sufficient fiber but did not take probiotics did the best,” she said. [The probiotics were not endorsed or selected by their physicians.]
Now, the researchers at MD Anderson are moving into “precision nutrition” research, Daniel-MacDougall said, with a phase 2 randomized, double-blind trial of high dietary fiber intake (a target of 50 g/d from whole foods) vs a healthy control diet (20 g/d of fiber) in patients with melanoma receiving ICB.
The study, which is underway, is a fully controlled feeding study, with all meals and snacks provided by MD Anderson and macronutrients controlled. Researchers are collecting blood, stool, and tumor tissue (if available) to answer questions about the microbiome, changes in systemic and tissue immunity, disease response and immunotherapy toxicity, and other issues.
Peled disclosed IP licensing and research support from Seres Therapeutics; consulting with Da Volterra, MaaT Pharma, and CSL Behring; and advisory/equity with Postbiotics + Research LLC and Prodigy Biosciences. Daniel-MacDougall reported having no disclosures.
A version of this article appeared on Medscape.com.
WASHINGTON — For years, oncologist Jonathan Peled, MD, PhD, and his colleagues at Memorial Sloan Kettering Cancer Center (MSKCC) in New York City have been documenting gut microbiota disruption during allogeneic hematopoietic stem cell transplantation (allo-HSCT) and its role in frequent and potentially fatal bloodstream infections (BSIs) in the first 100 days after transplant.
, and at the Gut Microbiota for Health (GMFH) World Summit 2025, Peled shared two new findings.
In one study, his team found that sucrose can exacerbate antibiotic-induced microbiome injury in patients undergoing allo-HSCT — a finding that “raises the question of whether our dietary recommendations [for] allo-HSCT patients are correct,” said Peled, assistant attending at MSKCC, during a session on the gut microbiome and oncology.
And in another study, they found that a rationally designed probiotic formulation may help lower the incidence of bacterial BSIs. In December 2024, the probiotic formulation (SER-155, Seres Therapeutics, Inc.) was granted breakthrough therapy designation by the FDA.
With immunotherapies more broadly, researchers are increasingly looking at diet and modulation of the microbiome to improve both treatment tolerance and efficacy, experts said at the meeting convened by the AGA and the European Society of Neurogastroenterology and Motility.
“Cancer patients and caregivers are asking, ‘What should I eat?’” said Carrie Daniel-MacDougall, PhD, MPH, a nutritional epidemiologist at the University of Texas MD Anderson Cancer Center in Houston. “They’re not just focused on side effects — they want a good outcome for their treatment, and they’re exploring a lot of dietary strategies [for which there] is not a lot of evidence.”
Clinicians are challenged by the fact that “we don’t typically collect dietary data in clinical trials of cancer drugs,” leaving them to extrapolate from evidence-based diet guidelines for cancer prevention, Daniel-MacDougall said.
But “I think that’s starting to shift,” she said, with the microbiome being increasingly recognized for its potential influences on therapeutic response and clinical trials underway looking at “a healthy dietary pattern not just for prevention but survival.”
Diet and Probiotics After allo-HSCT
The patterns of microbiota disruption during allo-HSCT — a procedure that includes antibiotic administration, chemotherapy, and sometimes irradiation — are characterized by loss of diversity and the expansion of potentially pathogenic organisms, most commonly Enterococcus, said Peled.
This has been demonstrated across transplantation centers. In a multicenter, international study published in 2020, the patterns of microbiota disruption and their impact on mortality were similar across MSK and other transplantation centers, with higher diversity of intestinal microbiota associated with lower mortality.
Other studies have shown that Enterococcus domination alone (defined arbitrarily as > 30% of fecal microbial composition) is associated with graft vs host disease and higher mortality after allo-HSCT and that intestinal domination by Proteobacteria coincides temporally with BSIs, he said.
Autologous fecal microbiota transplantation (FMT) has been shown to largely restore the microbiota composition the patient had before antibiotic treatment and allo-HSCT, he said, making fecal sample banking and posttreatment FMT a potential approach for reconstituting the gut microbiome and improving outcomes.
But “lately we’ve been very interested in diet for modulating [harmful] patterns” in the microbiome composition, Peled said.
In the new study suggesting a role for sugar avoidance, published last year as a bioRxiv preprint, Peled and his colleagues collected real-time dietary intake data (40,702 food entries) from 173 patients hospitalized for several weeks for allo-HSCT at MSK and analyzed it alongside longitudinally collected fecal samples. They used a Bayesian mixed-effects model to identify dietary components that may correlate with microbial disruption.
“What jumped out as very predictive of a low diversity fecal sample [and expansion of Enterococcus] in the 2 days prior to collection was the interaction between antibiotics and the consumption of sweets” — foods rich in simple sugars, Peled said. The relationship between sugar and the microbiome occurred only during periods of antibiotic exposure.
“And it was particularly perplexing because the foods that fall into the ‘sweets’ category are foods we encourage people to eat clinically when they’re not feeling well and food intake drops dramatically,” he said. This includes foods like nutritional drinks or shakes, Italian ice, gelatin dessert, and sports drinks.
(In a mouse model of post-antibiotic Enterococcus expansion, Peled and his co-investigators then validated the findings and ruled out the impact of any reductions in fiber.)
In addition to possibly revising dietary recommendations for patients undergoing allo-HSCT, the findings raise the question of whether avoiding sugar intake while on antibiotics, in general, is a way to mitigate antibiotic-induced dysbiosis, he said.
To test the role of probiotics, Peled and colleagues collaborated with Seres Therapeutics on a phase 1b trial of an oral combination (SER-155) of 16 fermented strains “selected rationally,” he said, for their ability to decolonize gut pathogens, improve gut barrier function (in vitro), and reduce gut inflammation and local immune activation.
After a safety lead-in, patients were randomized to receive SER-155 (20) or placebo (14) three times — prior to transplant, upon neutrophil engraftment (with vancomycin “conditioning”), and after transplant. “The strains succeeded in grafting in the [gastrointestinal] GI tract…and some of them persisted all the way through to day 100,” Peled said.
The incidence of pathogen domination was substantially lower in the probiotic recipients compared to an MSK historical control cohort, and the incidence of BSIs was significantly lower compared to the placebo arm (10% vs 43%, respectively, representing a 77% relative risk reduction), he said.
Diet and Immunotherapy Response: Trials at MD Anderson
One of the first trials Daniel-MacDougall launched at MD Anderson on diet and the microbiome randomized 55 patients who were obese and had a history of colorectal cancer or precancerous polyps to add a cup of beans to their usual diet or to continue their usual diet without beans. There was a crossover at 8 weeks in the 16-week BE GONE trial; stool and fasting blood were collected every 4 weeks.
“Beans are a prebiotic super-house in my opinion, and they’re also something this population would avoid,” said Daniel-MacDougall, associate professor in the department of epidemiology at MD Anderson and faculty director of the Bionutrition Research Core and Research Kitchen.
“We saw a modest increase in alpha diversity [in the intervention group] and similar trends with microbiota-derived metabolites” that regressed when patients returned to their usual diet, she said. The researchers also documented decreases in proteomic biomarkers of intestinal and systemic immune and inflammatory response.
The impact of diet on cancer survival was shown in subsequent research, including an observational study published in Science in 2021 of patients with melanoma receiving immune checkpoint blockade (ICB) treatment. “Patients who consumed insufficient dietary fiber at the start of therapy tended to do worse [than those reporting sufficient fiber intake],” with significantly lower progression-free survival, Daniel-MacDougall said.
“And interestingly, when we looked at dietary fiber [with and without] probiotic use, patients who had sufficient fiber but did not take probiotics did the best,” she said. [The probiotics were not endorsed or selected by their physicians.]
Now, the researchers at MD Anderson are moving into “precision nutrition” research, Daniel-MacDougall said, with a phase 2 randomized, double-blind trial of high dietary fiber intake (a target of 50 g/d from whole foods) vs a healthy control diet (20 g/d of fiber) in patients with melanoma receiving ICB.
The study, which is underway, is a fully controlled feeding study, with all meals and snacks provided by MD Anderson and macronutrients controlled. Researchers are collecting blood, stool, and tumor tissue (if available) to answer questions about the microbiome, changes in systemic and tissue immunity, disease response and immunotherapy toxicity, and other issues.
Peled disclosed IP licensing and research support from Seres Therapeutics; consulting with Da Volterra, MaaT Pharma, and CSL Behring; and advisory/equity with Postbiotics + Research LLC and Prodigy Biosciences. Daniel-MacDougall reported having no disclosures.
A version of this article appeared on Medscape.com.
WASHINGTON — For years, oncologist Jonathan Peled, MD, PhD, and his colleagues at Memorial Sloan Kettering Cancer Center (MSKCC) in New York City have been documenting gut microbiota disruption during allogeneic hematopoietic stem cell transplantation (allo-HSCT) and its role in frequent and potentially fatal bloodstream infections (BSIs) in the first 100 days after transplant.
, and at the Gut Microbiota for Health (GMFH) World Summit 2025, Peled shared two new findings.
In one study, his team found that sucrose can exacerbate antibiotic-induced microbiome injury in patients undergoing allo-HSCT — a finding that “raises the question of whether our dietary recommendations [for] allo-HSCT patients are correct,” said Peled, assistant attending at MSKCC, during a session on the gut microbiome and oncology.
And in another study, they found that a rationally designed probiotic formulation may help lower the incidence of bacterial BSIs. In December 2024, the probiotic formulation (SER-155, Seres Therapeutics, Inc.) was granted breakthrough therapy designation by the FDA.
With immunotherapies more broadly, researchers are increasingly looking at diet and modulation of the microbiome to improve both treatment tolerance and efficacy, experts said at the meeting convened by the AGA and the European Society of Neurogastroenterology and Motility.
“Cancer patients and caregivers are asking, ‘What should I eat?’” said Carrie Daniel-MacDougall, PhD, MPH, a nutritional epidemiologist at the University of Texas MD Anderson Cancer Center in Houston. “They’re not just focused on side effects — they want a good outcome for their treatment, and they’re exploring a lot of dietary strategies [for which there] is not a lot of evidence.”
Clinicians are challenged by the fact that “we don’t typically collect dietary data in clinical trials of cancer drugs,” leaving them to extrapolate from evidence-based diet guidelines for cancer prevention, Daniel-MacDougall said.
But “I think that’s starting to shift,” she said, with the microbiome being increasingly recognized for its potential influences on therapeutic response and clinical trials underway looking at “a healthy dietary pattern not just for prevention but survival.”
Diet and Probiotics After allo-HSCT
The patterns of microbiota disruption during allo-HSCT — a procedure that includes antibiotic administration, chemotherapy, and sometimes irradiation — are characterized by loss of diversity and the expansion of potentially pathogenic organisms, most commonly Enterococcus, said Peled.
This has been demonstrated across transplantation centers. In a multicenter, international study published in 2020, the patterns of microbiota disruption and their impact on mortality were similar across MSK and other transplantation centers, with higher diversity of intestinal microbiota associated with lower mortality.
Other studies have shown that Enterococcus domination alone (defined arbitrarily as > 30% of fecal microbial composition) is associated with graft vs host disease and higher mortality after allo-HSCT and that intestinal domination by Proteobacteria coincides temporally with BSIs, he said.
Autologous fecal microbiota transplantation (FMT) has been shown to largely restore the microbiota composition the patient had before antibiotic treatment and allo-HSCT, he said, making fecal sample banking and posttreatment FMT a potential approach for reconstituting the gut microbiome and improving outcomes.
But “lately we’ve been very interested in diet for modulating [harmful] patterns” in the microbiome composition, Peled said.
In the new study suggesting a role for sugar avoidance, published last year as a bioRxiv preprint, Peled and his colleagues collected real-time dietary intake data (40,702 food entries) from 173 patients hospitalized for several weeks for allo-HSCT at MSK and analyzed it alongside longitudinally collected fecal samples. They used a Bayesian mixed-effects model to identify dietary components that may correlate with microbial disruption.
“What jumped out as very predictive of a low diversity fecal sample [and expansion of Enterococcus] in the 2 days prior to collection was the interaction between antibiotics and the consumption of sweets” — foods rich in simple sugars, Peled said. The relationship between sugar and the microbiome occurred only during periods of antibiotic exposure.
“And it was particularly perplexing because the foods that fall into the ‘sweets’ category are foods we encourage people to eat clinically when they’re not feeling well and food intake drops dramatically,” he said. This includes foods like nutritional drinks or shakes, Italian ice, gelatin dessert, and sports drinks.
(In a mouse model of post-antibiotic Enterococcus expansion, Peled and his co-investigators then validated the findings and ruled out the impact of any reductions in fiber.)
In addition to possibly revising dietary recommendations for patients undergoing allo-HSCT, the findings raise the question of whether avoiding sugar intake while on antibiotics, in general, is a way to mitigate antibiotic-induced dysbiosis, he said.
To test the role of probiotics, Peled and colleagues collaborated with Seres Therapeutics on a phase 1b trial of an oral combination (SER-155) of 16 fermented strains “selected rationally,” he said, for their ability to decolonize gut pathogens, improve gut barrier function (in vitro), and reduce gut inflammation and local immune activation.
After a safety lead-in, patients were randomized to receive SER-155 (20) or placebo (14) three times — prior to transplant, upon neutrophil engraftment (with vancomycin “conditioning”), and after transplant. “The strains succeeded in grafting in the [gastrointestinal] GI tract…and some of them persisted all the way through to day 100,” Peled said.
The incidence of pathogen domination was substantially lower in the probiotic recipients compared to an MSK historical control cohort, and the incidence of BSIs was significantly lower compared to the placebo arm (10% vs 43%, respectively, representing a 77% relative risk reduction), he said.
Diet and Immunotherapy Response: Trials at MD Anderson
One of the first trials Daniel-MacDougall launched at MD Anderson on diet and the microbiome randomized 55 patients who were obese and had a history of colorectal cancer or precancerous polyps to add a cup of beans to their usual diet or to continue their usual diet without beans. There was a crossover at 8 weeks in the 16-week BE GONE trial; stool and fasting blood were collected every 4 weeks.
“Beans are a prebiotic super-house in my opinion, and they’re also something this population would avoid,” said Daniel-MacDougall, associate professor in the department of epidemiology at MD Anderson and faculty director of the Bionutrition Research Core and Research Kitchen.
“We saw a modest increase in alpha diversity [in the intervention group] and similar trends with microbiota-derived metabolites” that regressed when patients returned to their usual diet, she said. The researchers also documented decreases in proteomic biomarkers of intestinal and systemic immune and inflammatory response.
The impact of diet on cancer survival was shown in subsequent research, including an observational study published in Science in 2021 of patients with melanoma receiving immune checkpoint blockade (ICB) treatment. “Patients who consumed insufficient dietary fiber at the start of therapy tended to do worse [than those reporting sufficient fiber intake],” with significantly lower progression-free survival, Daniel-MacDougall said.
“And interestingly, when we looked at dietary fiber [with and without] probiotic use, patients who had sufficient fiber but did not take probiotics did the best,” she said. [The probiotics were not endorsed or selected by their physicians.]
Now, the researchers at MD Anderson are moving into “precision nutrition” research, Daniel-MacDougall said, with a phase 2 randomized, double-blind trial of high dietary fiber intake (a target of 50 g/d from whole foods) vs a healthy control diet (20 g/d of fiber) in patients with melanoma receiving ICB.
The study, which is underway, is a fully controlled feeding study, with all meals and snacks provided by MD Anderson and macronutrients controlled. Researchers are collecting blood, stool, and tumor tissue (if available) to answer questions about the microbiome, changes in systemic and tissue immunity, disease response and immunotherapy toxicity, and other issues.
Peled disclosed IP licensing and research support from Seres Therapeutics; consulting with Da Volterra, MaaT Pharma, and CSL Behring; and advisory/equity with Postbiotics + Research LLC and Prodigy Biosciences. Daniel-MacDougall reported having no disclosures.
A version of this article appeared on Medscape.com.
Auto-Brewery Syndrome Explained: New Patient Cohort Identifies Culprit Bacteria, Fermentation
WASHINGTON — When a published case of auto-brewery syndrome (ABS) in China — caused by Klebsiella pneumoniae — received widespread publicity in 2019, patients reacted, sending emails to lead author Jing Yuan, in Beijing, China. Many of these inquiries were from patients in the United States who believed they might have ABS.
“Can you check to see if I have ABS?” patients asked Yuan.
For help, Yuan contacted Bernd Schnabl, MD, AGAF, at the University of California, San Diego, whose research was addressing alcohol-associated liver disease and who was also interested in the gut-liver axis and the role of gut microbiome–derived ethanol in metabolic dysfunction–associated steatotic liver disease (MASLD).
“She asked me, ‘Are you interested in looking into ABS?” Schnabl recalled at the Gut Microbiota for Health (GMFH) World Summit 2025. He dug in and formed what may be the largest research cohort thus far of patients with ABS — a group of 22 patients with their diagnosis confirmed through observed glucose challenge.
His soon-to-be-published
ABS is considered a rare condition, but “I’d argue that it’s rarely diagnosed because many physicians don’t know of the diagnosis, and many are actually very skeptical about the disease,” Schnabl said at the meeting, convened by AGA and the European Society of Neurogastroenterology and Motility.
Patients experience symptoms of intoxication when ethanol produced by dysregulated gut microbiota exceeds the capacity of the liver to metabolize it and accumulates in the blood, he explained.
“Patients constantly talk about brain fog; they can’t concentrate, and it can be very severe,” he said. “They don’t get a firm diagnosis and go from one medical center to another, and they also suffer from complications of alcohol use disorder including serious family, social, and legal problems.”
Advancing Knowledge, Findings From the Cohort
The phenomenon of ethanol production by gut microbiota has been known for over a century, Schnabl wrote with two co-authors in a 2024 review in Nature Reviews Gastroenterology & Hepatology of “endogenous ethanol production in health and disease.”
And in recent decades, he said at the meeting, research has linked endogenous ethanol production to MASLD, positioning it as a potential contributor to disease pathogenesis. In one of the most recently published studies, patients with MASLD had higher concentrations of ethanol in their systemic circulation after a mixed meal test than did healthy controls — and even higher ethanol concentrations in their portal vein blood, “suggesting that this ethanol is coming from the gut microbiome,” Schnabl said.
The paper from China that led Schnabl to establish his cohort was spurred on by a patient with both ABS and MASLD cirrhosis. The patient was found to have strains of high alcohol–producing K pneumoniae in the gut microbiome. When the researchers transplanted these strains into mice via fecal microbiota transplantation (FMT), the mice developed MASLD.
Schnabl’s study focused just on ABS, which is alternatively sometimes called gut fermentation syndrome. The 22 patients in his ABS cohort — each of whom provided stool samples corresponding to remission or flare of ABS symptoms — had a median age of 45 years and were predominantly men, slightly overweight and not obese, and without liver disease. (About 48 patients with suspected ABS were screened, and 20 were excluded after an observed glucose challenge failed to establish a diagnosis; 6 withdrew from the study.)
During remission (no symptoms), patients’ mean blood alcohol content (BAC) level was zero, but during a flare, the mean BAC level was 136 mg/dL. “To put it into perspective, the legal limit for driving in the US is 80 mg/dL,” Schnabl said. Within a mean of 4 hours after the oral glucose load used for diagnosis, patients’ mean BAC level was 73 mg/dL, he noted.
To assess ethanol production by the patients’ microbiota, Schnabl and his team cultured the stool samples — anaerobically adding glucose and measuring ethanol production — and compared the results with findings from stool samples collected from household partners who generally were of the opposite sex. Among their findings: cultures of stool from patients experiencing a flare produced significantly more ethanol than stool from household partners and samples from patients in remission.
To assess whether ethanol was produced by bacteria or fungi, the researchers measured ethanol production in cultures treated with either the antifungal amphotericin B or the antibiotic chloramphenicol. “Chloramphenicol clearly decreased the ethanol production,” Schnabl said. “So at least in this culture test, bacteria produced most of the alcohol in our patients.”
Taxonomic profiling, moreover, revealed “significantly elevated levels” of proteobacteria — with relative abundance of Escherichia coli and K pneumoniae — in patients who were flaring, he said. And functional profiling of the fecal microbiota showed much higher activity of fermentation pathways during patients’ flares than in household partners or healthy controls. (Healthy controls were incorporated into the taxonomic and functional profiling parts of the research.)
A Clinical Approach to ABS
Schnabl said at the meeting that stool cultures of both household partners and patients in long-term remission “all produced some low amount of ethanol, which was initially puzzling to us” but became less surprising as he and his colleagues reviewed more of the literature.
Asked during a discussion period whether ABS could explain chronic fatigue, a commonly reported chronic symptom in populations, Schnabl said it’s possible. And in an interview after the meeting, he elaborated. “The literature clearly says ABS is a rare disease, but I argue that more patients may have ABS; they just don’t know it. And I suspect some may have mild symptoms, like brain fog, feeling tired,” he said. “But at this point, this is complete speculation.”
Physicians should “be aware that if a patient has unexplained symptoms that could be aligned with ABS, checking the blood alcohol level” may be warranted, he said in the interview. A PEth (phosphatidylethanol) test — a biomarker test used to check for longer-term alcohol consumption — is an option, but it is important to appreciate it will not discriminate between exogenous alcohol drinking and endogenous ethanol production.
There are no standardized diagnostic tests for ABS, but at the meeting, Schnabl outlined a clinical approach, starting with a standardized oral glucose tolerance challenge test to detect elevated ethanol concentrations.
A fecal yeast test is warranted for diagnosed patients on the basis of some case reports in which ABS symptoms have improved with antifungal treatments. When the fecal yeast test is negative, “ideally you want to identify the ethanol-producing intestinal bacteria in the patient,” he said, using cultures and fecal metagenomics sequencing.
Treatment could then be tailored to the identified microbial strain, with options being selective antibiotics, probiotics and/or prebiotics, and — likely in the future — phages or FMT, he said. (These options, all aimed at restoring gut homeostasis, are also discussed in his 2024 review.)
Schnabl and his team recently performed FMT in a patient with ABS in whom E coli was determined to be producing excessive ethanol. The FMT, performed after antibiotic pretreatment, resulted in decreases in the relative abundance of proteobacteria and E coli levels, lower blood alcohol levels and fermentation enrichment pathways, and normalized liver enzymes.
After 6 months, however, the patient relapsed, and the measurements reversed. “We decided to do FMT every month, and we treated the patient for 6 months,” Schnabl said, noting that ABS had rendered the patient dysfunctional and unable to work. “He has been out of treatment for over a year now and is not flaring any longer.”
Schnabl and Elizabeth Hohmann, MD, at Massachusetts General Hospital, Boston, are currently recruiting patients with confirmed ABS for a National Institutes of Health–funded phase 1 safety and tolerability study of FMT for ABS.
Schnabl disclosed serving as an external scientific advisor/consultant to Ambys Medicines, Boehringer Ingelheim, Gelesis, Mabwell Therapeutics, Surrozen, and Takeda; and as the founder/BOD/BEO of Nterica Bio.
A version of this article appeared on Medscape.com.
WASHINGTON — When a published case of auto-brewery syndrome (ABS) in China — caused by Klebsiella pneumoniae — received widespread publicity in 2019, patients reacted, sending emails to lead author Jing Yuan, in Beijing, China. Many of these inquiries were from patients in the United States who believed they might have ABS.
“Can you check to see if I have ABS?” patients asked Yuan.
For help, Yuan contacted Bernd Schnabl, MD, AGAF, at the University of California, San Diego, whose research was addressing alcohol-associated liver disease and who was also interested in the gut-liver axis and the role of gut microbiome–derived ethanol in metabolic dysfunction–associated steatotic liver disease (MASLD).
“She asked me, ‘Are you interested in looking into ABS?” Schnabl recalled at the Gut Microbiota for Health (GMFH) World Summit 2025. He dug in and formed what may be the largest research cohort thus far of patients with ABS — a group of 22 patients with their diagnosis confirmed through observed glucose challenge.
His soon-to-be-published
ABS is considered a rare condition, but “I’d argue that it’s rarely diagnosed because many physicians don’t know of the diagnosis, and many are actually very skeptical about the disease,” Schnabl said at the meeting, convened by AGA and the European Society of Neurogastroenterology and Motility.
Patients experience symptoms of intoxication when ethanol produced by dysregulated gut microbiota exceeds the capacity of the liver to metabolize it and accumulates in the blood, he explained.
“Patients constantly talk about brain fog; they can’t concentrate, and it can be very severe,” he said. “They don’t get a firm diagnosis and go from one medical center to another, and they also suffer from complications of alcohol use disorder including serious family, social, and legal problems.”
Advancing Knowledge, Findings From the Cohort
The phenomenon of ethanol production by gut microbiota has been known for over a century, Schnabl wrote with two co-authors in a 2024 review in Nature Reviews Gastroenterology & Hepatology of “endogenous ethanol production in health and disease.”
And in recent decades, he said at the meeting, research has linked endogenous ethanol production to MASLD, positioning it as a potential contributor to disease pathogenesis. In one of the most recently published studies, patients with MASLD had higher concentrations of ethanol in their systemic circulation after a mixed meal test than did healthy controls — and even higher ethanol concentrations in their portal vein blood, “suggesting that this ethanol is coming from the gut microbiome,” Schnabl said.
The paper from China that led Schnabl to establish his cohort was spurred on by a patient with both ABS and MASLD cirrhosis. The patient was found to have strains of high alcohol–producing K pneumoniae in the gut microbiome. When the researchers transplanted these strains into mice via fecal microbiota transplantation (FMT), the mice developed MASLD.
Schnabl’s study focused just on ABS, which is alternatively sometimes called gut fermentation syndrome. The 22 patients in his ABS cohort — each of whom provided stool samples corresponding to remission or flare of ABS symptoms — had a median age of 45 years and were predominantly men, slightly overweight and not obese, and without liver disease. (About 48 patients with suspected ABS were screened, and 20 were excluded after an observed glucose challenge failed to establish a diagnosis; 6 withdrew from the study.)
During remission (no symptoms), patients’ mean blood alcohol content (BAC) level was zero, but during a flare, the mean BAC level was 136 mg/dL. “To put it into perspective, the legal limit for driving in the US is 80 mg/dL,” Schnabl said. Within a mean of 4 hours after the oral glucose load used for diagnosis, patients’ mean BAC level was 73 mg/dL, he noted.
To assess ethanol production by the patients’ microbiota, Schnabl and his team cultured the stool samples — anaerobically adding glucose and measuring ethanol production — and compared the results with findings from stool samples collected from household partners who generally were of the opposite sex. Among their findings: cultures of stool from patients experiencing a flare produced significantly more ethanol than stool from household partners and samples from patients in remission.
To assess whether ethanol was produced by bacteria or fungi, the researchers measured ethanol production in cultures treated with either the antifungal amphotericin B or the antibiotic chloramphenicol. “Chloramphenicol clearly decreased the ethanol production,” Schnabl said. “So at least in this culture test, bacteria produced most of the alcohol in our patients.”
Taxonomic profiling, moreover, revealed “significantly elevated levels” of proteobacteria — with relative abundance of Escherichia coli and K pneumoniae — in patients who were flaring, he said. And functional profiling of the fecal microbiota showed much higher activity of fermentation pathways during patients’ flares than in household partners or healthy controls. (Healthy controls were incorporated into the taxonomic and functional profiling parts of the research.)
A Clinical Approach to ABS
Schnabl said at the meeting that stool cultures of both household partners and patients in long-term remission “all produced some low amount of ethanol, which was initially puzzling to us” but became less surprising as he and his colleagues reviewed more of the literature.
Asked during a discussion period whether ABS could explain chronic fatigue, a commonly reported chronic symptom in populations, Schnabl said it’s possible. And in an interview after the meeting, he elaborated. “The literature clearly says ABS is a rare disease, but I argue that more patients may have ABS; they just don’t know it. And I suspect some may have mild symptoms, like brain fog, feeling tired,” he said. “But at this point, this is complete speculation.”
Physicians should “be aware that if a patient has unexplained symptoms that could be aligned with ABS, checking the blood alcohol level” may be warranted, he said in the interview. A PEth (phosphatidylethanol) test — a biomarker test used to check for longer-term alcohol consumption — is an option, but it is important to appreciate it will not discriminate between exogenous alcohol drinking and endogenous ethanol production.
There are no standardized diagnostic tests for ABS, but at the meeting, Schnabl outlined a clinical approach, starting with a standardized oral glucose tolerance challenge test to detect elevated ethanol concentrations.
A fecal yeast test is warranted for diagnosed patients on the basis of some case reports in which ABS symptoms have improved with antifungal treatments. When the fecal yeast test is negative, “ideally you want to identify the ethanol-producing intestinal bacteria in the patient,” he said, using cultures and fecal metagenomics sequencing.
Treatment could then be tailored to the identified microbial strain, with options being selective antibiotics, probiotics and/or prebiotics, and — likely in the future — phages or FMT, he said. (These options, all aimed at restoring gut homeostasis, are also discussed in his 2024 review.)
Schnabl and his team recently performed FMT in a patient with ABS in whom E coli was determined to be producing excessive ethanol. The FMT, performed after antibiotic pretreatment, resulted in decreases in the relative abundance of proteobacteria and E coli levels, lower blood alcohol levels and fermentation enrichment pathways, and normalized liver enzymes.
After 6 months, however, the patient relapsed, and the measurements reversed. “We decided to do FMT every month, and we treated the patient for 6 months,” Schnabl said, noting that ABS had rendered the patient dysfunctional and unable to work. “He has been out of treatment for over a year now and is not flaring any longer.”
Schnabl and Elizabeth Hohmann, MD, at Massachusetts General Hospital, Boston, are currently recruiting patients with confirmed ABS for a National Institutes of Health–funded phase 1 safety and tolerability study of FMT for ABS.
Schnabl disclosed serving as an external scientific advisor/consultant to Ambys Medicines, Boehringer Ingelheim, Gelesis, Mabwell Therapeutics, Surrozen, and Takeda; and as the founder/BOD/BEO of Nterica Bio.
A version of this article appeared on Medscape.com.
WASHINGTON — When a published case of auto-brewery syndrome (ABS) in China — caused by Klebsiella pneumoniae — received widespread publicity in 2019, patients reacted, sending emails to lead author Jing Yuan, in Beijing, China. Many of these inquiries were from patients in the United States who believed they might have ABS.
“Can you check to see if I have ABS?” patients asked Yuan.
For help, Yuan contacted Bernd Schnabl, MD, AGAF, at the University of California, San Diego, whose research was addressing alcohol-associated liver disease and who was also interested in the gut-liver axis and the role of gut microbiome–derived ethanol in metabolic dysfunction–associated steatotic liver disease (MASLD).
“She asked me, ‘Are you interested in looking into ABS?” Schnabl recalled at the Gut Microbiota for Health (GMFH) World Summit 2025. He dug in and formed what may be the largest research cohort thus far of patients with ABS — a group of 22 patients with their diagnosis confirmed through observed glucose challenge.
His soon-to-be-published
ABS is considered a rare condition, but “I’d argue that it’s rarely diagnosed because many physicians don’t know of the diagnosis, and many are actually very skeptical about the disease,” Schnabl said at the meeting, convened by AGA and the European Society of Neurogastroenterology and Motility.
Patients experience symptoms of intoxication when ethanol produced by dysregulated gut microbiota exceeds the capacity of the liver to metabolize it and accumulates in the blood, he explained.
“Patients constantly talk about brain fog; they can’t concentrate, and it can be very severe,” he said. “They don’t get a firm diagnosis and go from one medical center to another, and they also suffer from complications of alcohol use disorder including serious family, social, and legal problems.”
Advancing Knowledge, Findings From the Cohort
The phenomenon of ethanol production by gut microbiota has been known for over a century, Schnabl wrote with two co-authors in a 2024 review in Nature Reviews Gastroenterology & Hepatology of “endogenous ethanol production in health and disease.”
And in recent decades, he said at the meeting, research has linked endogenous ethanol production to MASLD, positioning it as a potential contributor to disease pathogenesis. In one of the most recently published studies, patients with MASLD had higher concentrations of ethanol in their systemic circulation after a mixed meal test than did healthy controls — and even higher ethanol concentrations in their portal vein blood, “suggesting that this ethanol is coming from the gut microbiome,” Schnabl said.
The paper from China that led Schnabl to establish his cohort was spurred on by a patient with both ABS and MASLD cirrhosis. The patient was found to have strains of high alcohol–producing K pneumoniae in the gut microbiome. When the researchers transplanted these strains into mice via fecal microbiota transplantation (FMT), the mice developed MASLD.
Schnabl’s study focused just on ABS, which is alternatively sometimes called gut fermentation syndrome. The 22 patients in his ABS cohort — each of whom provided stool samples corresponding to remission or flare of ABS symptoms — had a median age of 45 years and were predominantly men, slightly overweight and not obese, and without liver disease. (About 48 patients with suspected ABS were screened, and 20 were excluded after an observed glucose challenge failed to establish a diagnosis; 6 withdrew from the study.)
During remission (no symptoms), patients’ mean blood alcohol content (BAC) level was zero, but during a flare, the mean BAC level was 136 mg/dL. “To put it into perspective, the legal limit for driving in the US is 80 mg/dL,” Schnabl said. Within a mean of 4 hours after the oral glucose load used for diagnosis, patients’ mean BAC level was 73 mg/dL, he noted.
To assess ethanol production by the patients’ microbiota, Schnabl and his team cultured the stool samples — anaerobically adding glucose and measuring ethanol production — and compared the results with findings from stool samples collected from household partners who generally were of the opposite sex. Among their findings: cultures of stool from patients experiencing a flare produced significantly more ethanol than stool from household partners and samples from patients in remission.
To assess whether ethanol was produced by bacteria or fungi, the researchers measured ethanol production in cultures treated with either the antifungal amphotericin B or the antibiotic chloramphenicol. “Chloramphenicol clearly decreased the ethanol production,” Schnabl said. “So at least in this culture test, bacteria produced most of the alcohol in our patients.”
Taxonomic profiling, moreover, revealed “significantly elevated levels” of proteobacteria — with relative abundance of Escherichia coli and K pneumoniae — in patients who were flaring, he said. And functional profiling of the fecal microbiota showed much higher activity of fermentation pathways during patients’ flares than in household partners or healthy controls. (Healthy controls were incorporated into the taxonomic and functional profiling parts of the research.)
A Clinical Approach to ABS
Schnabl said at the meeting that stool cultures of both household partners and patients in long-term remission “all produced some low amount of ethanol, which was initially puzzling to us” but became less surprising as he and his colleagues reviewed more of the literature.
Asked during a discussion period whether ABS could explain chronic fatigue, a commonly reported chronic symptom in populations, Schnabl said it’s possible. And in an interview after the meeting, he elaborated. “The literature clearly says ABS is a rare disease, but I argue that more patients may have ABS; they just don’t know it. And I suspect some may have mild symptoms, like brain fog, feeling tired,” he said. “But at this point, this is complete speculation.”
Physicians should “be aware that if a patient has unexplained symptoms that could be aligned with ABS, checking the blood alcohol level” may be warranted, he said in the interview. A PEth (phosphatidylethanol) test — a biomarker test used to check for longer-term alcohol consumption — is an option, but it is important to appreciate it will not discriminate between exogenous alcohol drinking and endogenous ethanol production.
There are no standardized diagnostic tests for ABS, but at the meeting, Schnabl outlined a clinical approach, starting with a standardized oral glucose tolerance challenge test to detect elevated ethanol concentrations.
A fecal yeast test is warranted for diagnosed patients on the basis of some case reports in which ABS symptoms have improved with antifungal treatments. When the fecal yeast test is negative, “ideally you want to identify the ethanol-producing intestinal bacteria in the patient,” he said, using cultures and fecal metagenomics sequencing.
Treatment could then be tailored to the identified microbial strain, with options being selective antibiotics, probiotics and/or prebiotics, and — likely in the future — phages or FMT, he said. (These options, all aimed at restoring gut homeostasis, are also discussed in his 2024 review.)
Schnabl and his team recently performed FMT in a patient with ABS in whom E coli was determined to be producing excessive ethanol. The FMT, performed after antibiotic pretreatment, resulted in decreases in the relative abundance of proteobacteria and E coli levels, lower blood alcohol levels and fermentation enrichment pathways, and normalized liver enzymes.
After 6 months, however, the patient relapsed, and the measurements reversed. “We decided to do FMT every month, and we treated the patient for 6 months,” Schnabl said, noting that ABS had rendered the patient dysfunctional and unable to work. “He has been out of treatment for over a year now and is not flaring any longer.”
Schnabl and Elizabeth Hohmann, MD, at Massachusetts General Hospital, Boston, are currently recruiting patients with confirmed ABS for a National Institutes of Health–funded phase 1 safety and tolerability study of FMT for ABS.
Schnabl disclosed serving as an external scientific advisor/consultant to Ambys Medicines, Boehringer Ingelheim, Gelesis, Mabwell Therapeutics, Surrozen, and Takeda; and as the founder/BOD/BEO of Nterica Bio.
A version of this article appeared on Medscape.com.
FROM GMFH 2025
The Extra-Bacterial Gut Ecosystem: The Influence of Phages and Fungi in the Microbiome
WASHINGTON, DC — Research on the gut microbiome — and clinical attention to it — has focused mainly on bacteria, but bacteriophages and fungi play critical roles as well, with significant influences on health and disease, experts said at the Gut Microbiota for Health (GMFH) World Summit 2025.
Fungi account for < 1% of the total genetic material in the microbiome but 1%-2% of its total biomass. “Despite their relative rarity, they have an important and outsized influence on gut health” — an impact that results from their unique interface with the immune system, said Kyla Ost, PhD, of the Anschutz Medical Campus, University of Colorado, in Denver, whose research focuses on this interface.
And bacteriophages — viruses that infect and kill bacteria — are highly abundant in the gut. “Bacteriophages begin to colonize our GI [gastrointestinal] tract at the same time we develop our own microbiome shortly after birth, and from that time on, they interact with the bacteria in our GI tract, shaping [and being shaped by] the bacterial species we carry with us,” said Robert (Chip) Schooley, MD, distinguished professor of medicine at the University of California San Diego School of Medicine.
“We’ve been talking about things that affect the gut microbiome — diet, genetics, immune response — but probably the biggest influence on what grows in the GI tract are bacteriophages,” said Schooley, co-director of the Center for Innovative Phage Applications and Therapeutics, in a session on the extra-bacterial gut ecosystem.
Among the current questions:
‘New life’ for Phage Therapy
Bacteriophages represent a promising approach for the treatment of multidrug resistant bacterial pathogens in an era of increasing resistance and a dried-up antibiotic discovery pipeline, Schooley said. (In 2019, an estimated 4.95 million deaths around the world were associated with bacterial antimicrobial resistance, and by 2050, it has been forecast that this number will rise to an estimated 8.22 million deaths.)
But in addition to suppressing bacterial pathogens causing direct morbidity, phage therapy has the potential to suppress bacteria believed to contribute to chronic diseases, he said. “We have proof-of-concept studies about the ability of phage to modulate bacteria in the digestive tract,” and an increasing number of clinical trials of the use of phages in GI and other diseases are underway, he said.
Phages were discovered just over a century ago, but phage therapy was widely abandoned once antibiotics were developed, except for in Russia and the former Eastern Bloc countries, where phage therapy continued to be used.
Phage therapy “got new life” in the West, Schooley said, about 10-15 years ago with an increasing number of detailed and high-profile case reports, including one in which a UC San Diego colleague, Tom Patterson, PhD, contracted a deadly multidrug resistant bacterial infection in Egypt and was eventually saved with bacteriophage therapy. (The case was the subject of the book The Perfect Predator).
Since then, as described in case reports and studies in the literature, “hundreds of people have been treated with bacteriophages here and in Europe,” most commonly for pulmonary infections and infections in implanted vascular and orthopedic devices, said Schooley, who coauthored a review in Cell in 2023 that describes phage biology and advances and future directions in phage therapy.
The use of bacteriophages to prevent systemic infections during high-risk periods — such as during chemotherapeutic regimens for hematological regimens — is an area of interest, he said at the meeting.
In research that is making its way to a clinical trial of patients undergoing allogeneic hematopoietic stem cell transplant (HSCT), researchers screened a library of phages to identify those with broad coverage of Escherichia coli. Using tail fiber engineering and CRISPR technology, they then engineered a combination of the four most complementary bacteriophages to selectively kill E coli — including fluoroquinolone-resistant strains that, in patients whose GI tracts are colonized with these strains, can translocate from the gut into the bloodstream, causing sepsis, during chemotherapeutic regimens for HSCT.
In a mouse model, the CRISPR-enhanced four-phage cocktail (SNIPR001) led to a steady reduction in the E coli colony counts in stool, “showing you can modulate these bacteria in the gut by using bacteriophages to kill them,” Schooley said. Moreover, the CRISPR enhancement strengthened the phages’ ability to break up biofilms, he said, showing “that you can engineer bacteriophages to make them better killers.” A phase 1b/2a study is being planned.
Other Niches for Therapeutic Phages, Challenges
Bacteriophages also could be used to target a gut bacterium that has been shown to attenuate alcoholic liver disease. Patients with alcoholic hepatitis “have a gut microbiome that is different in distribution,” Schooley said, often with increased numbers of Enterococcus faecalis that produce cytolysin, an exotoxin that exacerbates liver injury and is associated with increased mortality.
In published research led by investigators at UC San Diego, stool from cytolysin-positive patients with alcoholic hepatitis was found to exacerbate ethanol-induced liver disease in gnotobiotic mice, and phage therapy against cytolytic E faecalis was found to abolish it, Schooley shared.
Research is also exploring the potential of phage therapy to selectively target adherent invasive E coli in Crohn’s disease, and Klebsiella pneumoniae in the gut microbiome as an exacerbator of inflammatory bowel disease (IBD), he said.
And investigators in Japan, he noted, have reported that bacteriophage therapy against K pneumoniae can ameliorate liver inflammation and disease severity in primary sclerosing cholangitis.
Challenges in the therapeutic use of phages include the narrow host range of phages and an uncertain predictive value of in vitro phage susceptibility testing. “We don’t know yet how to do resistance testing as well as we do with antibiotics,” he said.
In addition, most phages tend to be acid labile, requiring strategies to mitigate inactivation by gastric acid, and there are “major knowledge gaps” relating to phage pharmacology. “We also know that adaptive immune responses to phages can but often doesn’t impact therapy, and we want to understand that better in clinical trials,” Schooley said.
Phages that have a “lysogenic” lifestyle — as opposed to lytic phages which are used therapeutically — can contribute to antibiotic resistance by facilitating the interchange of bacterial resistance genes, he noted.
A Window Into the Mycobiome
The human gut mycobiome is primarily composed of fungi in the Saccharomyces, Candida, and Malassezia genera, with Candida species dominating. Fungal cells harbor distinct immune-stimulatory molecules and activate distinct immune pathways compared with bacteria and other members of the microbiome, said Ost, assistant professor in the immunology and microbiology department of CU Anschutz.
Some fungi, including those in the Candida genus, activate adaptive and innate immune responses that promote metabolic health and protect against infection. A recently published study in Science, for instance, demonstrated that colonization with C dubliniensis in very young mice who had been exposed to broad-spectrum antibiotics promoted “the expansion and development of beta cells in the pancreas” in a macrophage dependent manner, improving metabolic health and reducing diabetes incidence, she shared.
On the one hand, fungi can “exacerbate and perpetuate the pathogenic inflammation that’s found in a growing list of inflammatory diseases” such as IBD. And “in fact, a lot of the benefits and detriments are driven by the exact same species of fungi,” said Ost. “This is particularly true of Candida,” which is a “lifelong colonizer of intestinal microbiota that rarely causes disease but can be quite pathogenic when it does.”
A 2023 review in Nature Reviews Gastroenterology & Hepatology coauthored by Ost describes the role of commensal fungi in intestinal diseases, including IBD, colorectal cancer, and pancreatic cancer.
The pathogenic potential of commensal fungi is largely dependent on its strain, its morphology and its expression of virulence factors, researchers are learning. Ost has studied C albicans, which has been associated with intestinal inflammation and IBD. Like some other Candida species, C albicans are “fascinating shape shifters,” she said, transitioning between a less pathogenic “yeast” morphology and an elongated, adhesive “hyphae” shape that is more pathogenic.
It turns out, according to research by Ost and others, that the C albicans hyphal morphotype — and the adhesins (sticky proteins that facilitate adherence to epithelial cells) and a cytolytic toxin it produces — are preferentially targeted and suppressed by immunoglobulin A (IgA) in the gut.
“Our gut is protected by a large quantity of IgA antibodies…and these IgA interact with the microbiota and play a big role in what microbes are there and the biology of the microbes,” Ost said. Indeed, symptomatic IgA deficiency in humans has been shown to be associated with C albicans overgrowth.
Leveraging the hyphal-specific IgA response to protect against disease seems possible, she said, referring to an experimental anti-Candida fungal vaccine (NDV-3A) designed to induce an adhesin-specific immune response. In a mouse model of colitis, the vaccine protected against C albicans-associated damage. “We saw an immediate IgA response that targeted C albicans in the intestinal contents,” Ost said.
C glabrata, which has also been associated with intestinal inflammation and IBD, does not form hyphae but — depending on the strain — may also induce intestinal IgA responses, she said in describing her recent research.
Ost reported having no disclosures. Schooley disclosed being a consultant for SNIPR Biome, BiomX, Locus, MicrobiotiX, Amazon Data Monitoring Committee: Merck.
A version of this article appeared on Medscape.com.
WASHINGTON, DC — Research on the gut microbiome — and clinical attention to it — has focused mainly on bacteria, but bacteriophages and fungi play critical roles as well, with significant influences on health and disease, experts said at the Gut Microbiota for Health (GMFH) World Summit 2025.
Fungi account for < 1% of the total genetic material in the microbiome but 1%-2% of its total biomass. “Despite their relative rarity, they have an important and outsized influence on gut health” — an impact that results from their unique interface with the immune system, said Kyla Ost, PhD, of the Anschutz Medical Campus, University of Colorado, in Denver, whose research focuses on this interface.
And bacteriophages — viruses that infect and kill bacteria — are highly abundant in the gut. “Bacteriophages begin to colonize our GI [gastrointestinal] tract at the same time we develop our own microbiome shortly after birth, and from that time on, they interact with the bacteria in our GI tract, shaping [and being shaped by] the bacterial species we carry with us,” said Robert (Chip) Schooley, MD, distinguished professor of medicine at the University of California San Diego School of Medicine.
“We’ve been talking about things that affect the gut microbiome — diet, genetics, immune response — but probably the biggest influence on what grows in the GI tract are bacteriophages,” said Schooley, co-director of the Center for Innovative Phage Applications and Therapeutics, in a session on the extra-bacterial gut ecosystem.
Among the current questions:
‘New life’ for Phage Therapy
Bacteriophages represent a promising approach for the treatment of multidrug resistant bacterial pathogens in an era of increasing resistance and a dried-up antibiotic discovery pipeline, Schooley said. (In 2019, an estimated 4.95 million deaths around the world were associated with bacterial antimicrobial resistance, and by 2050, it has been forecast that this number will rise to an estimated 8.22 million deaths.)
But in addition to suppressing bacterial pathogens causing direct morbidity, phage therapy has the potential to suppress bacteria believed to contribute to chronic diseases, he said. “We have proof-of-concept studies about the ability of phage to modulate bacteria in the digestive tract,” and an increasing number of clinical trials of the use of phages in GI and other diseases are underway, he said.
Phages were discovered just over a century ago, but phage therapy was widely abandoned once antibiotics were developed, except for in Russia and the former Eastern Bloc countries, where phage therapy continued to be used.
Phage therapy “got new life” in the West, Schooley said, about 10-15 years ago with an increasing number of detailed and high-profile case reports, including one in which a UC San Diego colleague, Tom Patterson, PhD, contracted a deadly multidrug resistant bacterial infection in Egypt and was eventually saved with bacteriophage therapy. (The case was the subject of the book The Perfect Predator).
Since then, as described in case reports and studies in the literature, “hundreds of people have been treated with bacteriophages here and in Europe,” most commonly for pulmonary infections and infections in implanted vascular and orthopedic devices, said Schooley, who coauthored a review in Cell in 2023 that describes phage biology and advances and future directions in phage therapy.
The use of bacteriophages to prevent systemic infections during high-risk periods — such as during chemotherapeutic regimens for hematological regimens — is an area of interest, he said at the meeting.
In research that is making its way to a clinical trial of patients undergoing allogeneic hematopoietic stem cell transplant (HSCT), researchers screened a library of phages to identify those with broad coverage of Escherichia coli. Using tail fiber engineering and CRISPR technology, they then engineered a combination of the four most complementary bacteriophages to selectively kill E coli — including fluoroquinolone-resistant strains that, in patients whose GI tracts are colonized with these strains, can translocate from the gut into the bloodstream, causing sepsis, during chemotherapeutic regimens for HSCT.
In a mouse model, the CRISPR-enhanced four-phage cocktail (SNIPR001) led to a steady reduction in the E coli colony counts in stool, “showing you can modulate these bacteria in the gut by using bacteriophages to kill them,” Schooley said. Moreover, the CRISPR enhancement strengthened the phages’ ability to break up biofilms, he said, showing “that you can engineer bacteriophages to make them better killers.” A phase 1b/2a study is being planned.
Other Niches for Therapeutic Phages, Challenges
Bacteriophages also could be used to target a gut bacterium that has been shown to attenuate alcoholic liver disease. Patients with alcoholic hepatitis “have a gut microbiome that is different in distribution,” Schooley said, often with increased numbers of Enterococcus faecalis that produce cytolysin, an exotoxin that exacerbates liver injury and is associated with increased mortality.
In published research led by investigators at UC San Diego, stool from cytolysin-positive patients with alcoholic hepatitis was found to exacerbate ethanol-induced liver disease in gnotobiotic mice, and phage therapy against cytolytic E faecalis was found to abolish it, Schooley shared.
Research is also exploring the potential of phage therapy to selectively target adherent invasive E coli in Crohn’s disease, and Klebsiella pneumoniae in the gut microbiome as an exacerbator of inflammatory bowel disease (IBD), he said.
And investigators in Japan, he noted, have reported that bacteriophage therapy against K pneumoniae can ameliorate liver inflammation and disease severity in primary sclerosing cholangitis.
Challenges in the therapeutic use of phages include the narrow host range of phages and an uncertain predictive value of in vitro phage susceptibility testing. “We don’t know yet how to do resistance testing as well as we do with antibiotics,” he said.
In addition, most phages tend to be acid labile, requiring strategies to mitigate inactivation by gastric acid, and there are “major knowledge gaps” relating to phage pharmacology. “We also know that adaptive immune responses to phages can but often doesn’t impact therapy, and we want to understand that better in clinical trials,” Schooley said.
Phages that have a “lysogenic” lifestyle — as opposed to lytic phages which are used therapeutically — can contribute to antibiotic resistance by facilitating the interchange of bacterial resistance genes, he noted.
A Window Into the Mycobiome
The human gut mycobiome is primarily composed of fungi in the Saccharomyces, Candida, and Malassezia genera, with Candida species dominating. Fungal cells harbor distinct immune-stimulatory molecules and activate distinct immune pathways compared with bacteria and other members of the microbiome, said Ost, assistant professor in the immunology and microbiology department of CU Anschutz.
Some fungi, including those in the Candida genus, activate adaptive and innate immune responses that promote metabolic health and protect against infection. A recently published study in Science, for instance, demonstrated that colonization with C dubliniensis in very young mice who had been exposed to broad-spectrum antibiotics promoted “the expansion and development of beta cells in the pancreas” in a macrophage dependent manner, improving metabolic health and reducing diabetes incidence, she shared.
On the one hand, fungi can “exacerbate and perpetuate the pathogenic inflammation that’s found in a growing list of inflammatory diseases” such as IBD. And “in fact, a lot of the benefits and detriments are driven by the exact same species of fungi,” said Ost. “This is particularly true of Candida,” which is a “lifelong colonizer of intestinal microbiota that rarely causes disease but can be quite pathogenic when it does.”
A 2023 review in Nature Reviews Gastroenterology & Hepatology coauthored by Ost describes the role of commensal fungi in intestinal diseases, including IBD, colorectal cancer, and pancreatic cancer.
The pathogenic potential of commensal fungi is largely dependent on its strain, its morphology and its expression of virulence factors, researchers are learning. Ost has studied C albicans, which has been associated with intestinal inflammation and IBD. Like some other Candida species, C albicans are “fascinating shape shifters,” she said, transitioning between a less pathogenic “yeast” morphology and an elongated, adhesive “hyphae” shape that is more pathogenic.
It turns out, according to research by Ost and others, that the C albicans hyphal morphotype — and the adhesins (sticky proteins that facilitate adherence to epithelial cells) and a cytolytic toxin it produces — are preferentially targeted and suppressed by immunoglobulin A (IgA) in the gut.
“Our gut is protected by a large quantity of IgA antibodies…and these IgA interact with the microbiota and play a big role in what microbes are there and the biology of the microbes,” Ost said. Indeed, symptomatic IgA deficiency in humans has been shown to be associated with C albicans overgrowth.
Leveraging the hyphal-specific IgA response to protect against disease seems possible, she said, referring to an experimental anti-Candida fungal vaccine (NDV-3A) designed to induce an adhesin-specific immune response. In a mouse model of colitis, the vaccine protected against C albicans-associated damage. “We saw an immediate IgA response that targeted C albicans in the intestinal contents,” Ost said.
C glabrata, which has also been associated with intestinal inflammation and IBD, does not form hyphae but — depending on the strain — may also induce intestinal IgA responses, she said in describing her recent research.
Ost reported having no disclosures. Schooley disclosed being a consultant for SNIPR Biome, BiomX, Locus, MicrobiotiX, Amazon Data Monitoring Committee: Merck.
A version of this article appeared on Medscape.com.
WASHINGTON, DC — Research on the gut microbiome — and clinical attention to it — has focused mainly on bacteria, but bacteriophages and fungi play critical roles as well, with significant influences on health and disease, experts said at the Gut Microbiota for Health (GMFH) World Summit 2025.
Fungi account for < 1% of the total genetic material in the microbiome but 1%-2% of its total biomass. “Despite their relative rarity, they have an important and outsized influence on gut health” — an impact that results from their unique interface with the immune system, said Kyla Ost, PhD, of the Anschutz Medical Campus, University of Colorado, in Denver, whose research focuses on this interface.
And bacteriophages — viruses that infect and kill bacteria — are highly abundant in the gut. “Bacteriophages begin to colonize our GI [gastrointestinal] tract at the same time we develop our own microbiome shortly after birth, and from that time on, they interact with the bacteria in our GI tract, shaping [and being shaped by] the bacterial species we carry with us,” said Robert (Chip) Schooley, MD, distinguished professor of medicine at the University of California San Diego School of Medicine.
“We’ve been talking about things that affect the gut microbiome — diet, genetics, immune response — but probably the biggest influence on what grows in the GI tract are bacteriophages,” said Schooley, co-director of the Center for Innovative Phage Applications and Therapeutics, in a session on the extra-bacterial gut ecosystem.
Among the current questions:
‘New life’ for Phage Therapy
Bacteriophages represent a promising approach for the treatment of multidrug resistant bacterial pathogens in an era of increasing resistance and a dried-up antibiotic discovery pipeline, Schooley said. (In 2019, an estimated 4.95 million deaths around the world were associated with bacterial antimicrobial resistance, and by 2050, it has been forecast that this number will rise to an estimated 8.22 million deaths.)
But in addition to suppressing bacterial pathogens causing direct morbidity, phage therapy has the potential to suppress bacteria believed to contribute to chronic diseases, he said. “We have proof-of-concept studies about the ability of phage to modulate bacteria in the digestive tract,” and an increasing number of clinical trials of the use of phages in GI and other diseases are underway, he said.
Phages were discovered just over a century ago, but phage therapy was widely abandoned once antibiotics were developed, except for in Russia and the former Eastern Bloc countries, where phage therapy continued to be used.
Phage therapy “got new life” in the West, Schooley said, about 10-15 years ago with an increasing number of detailed and high-profile case reports, including one in which a UC San Diego colleague, Tom Patterson, PhD, contracted a deadly multidrug resistant bacterial infection in Egypt and was eventually saved with bacteriophage therapy. (The case was the subject of the book The Perfect Predator).
Since then, as described in case reports and studies in the literature, “hundreds of people have been treated with bacteriophages here and in Europe,” most commonly for pulmonary infections and infections in implanted vascular and orthopedic devices, said Schooley, who coauthored a review in Cell in 2023 that describes phage biology and advances and future directions in phage therapy.
The use of bacteriophages to prevent systemic infections during high-risk periods — such as during chemotherapeutic regimens for hematological regimens — is an area of interest, he said at the meeting.
In research that is making its way to a clinical trial of patients undergoing allogeneic hematopoietic stem cell transplant (HSCT), researchers screened a library of phages to identify those with broad coverage of Escherichia coli. Using tail fiber engineering and CRISPR technology, they then engineered a combination of the four most complementary bacteriophages to selectively kill E coli — including fluoroquinolone-resistant strains that, in patients whose GI tracts are colonized with these strains, can translocate from the gut into the bloodstream, causing sepsis, during chemotherapeutic regimens for HSCT.
In a mouse model, the CRISPR-enhanced four-phage cocktail (SNIPR001) led to a steady reduction in the E coli colony counts in stool, “showing you can modulate these bacteria in the gut by using bacteriophages to kill them,” Schooley said. Moreover, the CRISPR enhancement strengthened the phages’ ability to break up biofilms, he said, showing “that you can engineer bacteriophages to make them better killers.” A phase 1b/2a study is being planned.
Other Niches for Therapeutic Phages, Challenges
Bacteriophages also could be used to target a gut bacterium that has been shown to attenuate alcoholic liver disease. Patients with alcoholic hepatitis “have a gut microbiome that is different in distribution,” Schooley said, often with increased numbers of Enterococcus faecalis that produce cytolysin, an exotoxin that exacerbates liver injury and is associated with increased mortality.
In published research led by investigators at UC San Diego, stool from cytolysin-positive patients with alcoholic hepatitis was found to exacerbate ethanol-induced liver disease in gnotobiotic mice, and phage therapy against cytolytic E faecalis was found to abolish it, Schooley shared.
Research is also exploring the potential of phage therapy to selectively target adherent invasive E coli in Crohn’s disease, and Klebsiella pneumoniae in the gut microbiome as an exacerbator of inflammatory bowel disease (IBD), he said.
And investigators in Japan, he noted, have reported that bacteriophage therapy against K pneumoniae can ameliorate liver inflammation and disease severity in primary sclerosing cholangitis.
Challenges in the therapeutic use of phages include the narrow host range of phages and an uncertain predictive value of in vitro phage susceptibility testing. “We don’t know yet how to do resistance testing as well as we do with antibiotics,” he said.
In addition, most phages tend to be acid labile, requiring strategies to mitigate inactivation by gastric acid, and there are “major knowledge gaps” relating to phage pharmacology. “We also know that adaptive immune responses to phages can but often doesn’t impact therapy, and we want to understand that better in clinical trials,” Schooley said.
Phages that have a “lysogenic” lifestyle — as opposed to lytic phages which are used therapeutically — can contribute to antibiotic resistance by facilitating the interchange of bacterial resistance genes, he noted.
A Window Into the Mycobiome
The human gut mycobiome is primarily composed of fungi in the Saccharomyces, Candida, and Malassezia genera, with Candida species dominating. Fungal cells harbor distinct immune-stimulatory molecules and activate distinct immune pathways compared with bacteria and other members of the microbiome, said Ost, assistant professor in the immunology and microbiology department of CU Anschutz.
Some fungi, including those in the Candida genus, activate adaptive and innate immune responses that promote metabolic health and protect against infection. A recently published study in Science, for instance, demonstrated that colonization with C dubliniensis in very young mice who had been exposed to broad-spectrum antibiotics promoted “the expansion and development of beta cells in the pancreas” in a macrophage dependent manner, improving metabolic health and reducing diabetes incidence, she shared.
On the one hand, fungi can “exacerbate and perpetuate the pathogenic inflammation that’s found in a growing list of inflammatory diseases” such as IBD. And “in fact, a lot of the benefits and detriments are driven by the exact same species of fungi,” said Ost. “This is particularly true of Candida,” which is a “lifelong colonizer of intestinal microbiota that rarely causes disease but can be quite pathogenic when it does.”
A 2023 review in Nature Reviews Gastroenterology & Hepatology coauthored by Ost describes the role of commensal fungi in intestinal diseases, including IBD, colorectal cancer, and pancreatic cancer.
The pathogenic potential of commensal fungi is largely dependent on its strain, its morphology and its expression of virulence factors, researchers are learning. Ost has studied C albicans, which has been associated with intestinal inflammation and IBD. Like some other Candida species, C albicans are “fascinating shape shifters,” she said, transitioning between a less pathogenic “yeast” morphology and an elongated, adhesive “hyphae” shape that is more pathogenic.
It turns out, according to research by Ost and others, that the C albicans hyphal morphotype — and the adhesins (sticky proteins that facilitate adherence to epithelial cells) and a cytolytic toxin it produces — are preferentially targeted and suppressed by immunoglobulin A (IgA) in the gut.
“Our gut is protected by a large quantity of IgA antibodies…and these IgA interact with the microbiota and play a big role in what microbes are there and the biology of the microbes,” Ost said. Indeed, symptomatic IgA deficiency in humans has been shown to be associated with C albicans overgrowth.
Leveraging the hyphal-specific IgA response to protect against disease seems possible, she said, referring to an experimental anti-Candida fungal vaccine (NDV-3A) designed to induce an adhesin-specific immune response. In a mouse model of colitis, the vaccine protected against C albicans-associated damage. “We saw an immediate IgA response that targeted C albicans in the intestinal contents,” Ost said.
C glabrata, which has also been associated with intestinal inflammation and IBD, does not form hyphae but — depending on the strain — may also induce intestinal IgA responses, she said in describing her recent research.
Ost reported having no disclosures. Schooley disclosed being a consultant for SNIPR Biome, BiomX, Locus, MicrobiotiX, Amazon Data Monitoring Committee: Merck.
A version of this article appeared on Medscape.com.
FROM GMFH 2025
Gut Microbiome Influences Multiple Neurodegenerative Disorders
WASHINGTON, DC — Age-related neurodegenerative disorders — motor neuron diseases, demyelinating diseases, Alzheimer’s disease, and other proteinopathies — are at an “inflection point,” said researcher Andrea R. Merchak, PhD, with a fuller understanding of disease pathophysiology but an overall dearth of effective disease-modifying treatments.
And this, Merchak said at the Gut Microbiota for Health (GMFH) World Summit 2025, is where the gut microbiome comes in. “The gut-brain axis is important to take into consideration,” she urged, both for gut microbiome researchers — whose collaboration with neurologists and neuroscientists is essential — and for practicing gastroenterologists.
“We are the sum of our environmental exposures,” said Merchak, assistant research professor of neurology at the Indiana University School of Medicine, in Indianapolis. “So for your patient populations, remember you’re not only treating the diseases they’re coming to you with, you’re also treating them for a lifetime of healthy [brain] aging.”
At the center of a healthy aging brain are the brain-residing microglia and peripheral monocytes, she said. These immune cell populations are directly influenced by blood-brain barrier breakdown, inflammation, and gut permeability — and indirectly influenced by microbial products, gastrointestinal (GI) function, and bacterial diversity, Merchak said at the meeting, which was convened by AGA and the European Society of Neurogastroenterology and Motility.
“Many of us grew up learning that the brain is an immune-privileged site, but we’ve been establishing that this is fundamentally not true,” she said. “While the brain does have a privileged status, there are interactions with the blood, with the peripheral immune cells.”
Merchak coauthored a 2024 review in Neurotherapeutics in which she and her colleagues explained that the brain is “heavily connected with peripheral immune dynamics,” and that the gut — as the largest immune organ in the body — is a critical place for peripheral immune development, “thus influencing brain health.”
Gut microbiota interact with the brain via several mechanisms including microbiota-derived metabolites that enter circulation, direct communication via the vagus nerve, and modulation of the immune system, Merchak and her coauthors wrote. Leaky gut, they noted, can lead to an accumulation of inflammatory signals and cells that can exacerbate or induce the onset of neurodegenerative conditions.
As researchers better understand the role that GI dysfunction plays in neurodegenerative disease — as they identify microbiome signatures for predicting risk, for instance — there will be “opportunities to target the microbiome to prevent or reverse dysbiosis as a way to delay, arrest or prevent the onset and progression of neurodegenerative diseases,” they wrote.
At the GMFH meeting, Merchak described both ongoing preclinical research that is dissecting gut-brain communication, and preliminary clinical evidence for the use of gut microbiota-modulating therapies in neurodegenerative disease.
Support for a Gut-Focused Approach
Research on bile acid metabolism in multiple sclerosis (MS) and on peripheral inflammation in dementia exemplify the ongoing preclinical research uncovering the mechanisms of gut-brain communication, Merchak said.
The finding that bile acid metabolism modulates MS autoimmunity comes from research done by Merchak and a team at the University of Virginia, Charlottesville, Virginia, several years ago in which mice with experimental autoimmune encephalomyelitis (EAE) — an animal model of MS — were engineered for T cell specific knockout of the aryl hydrocarbon receptor (AHR). The AHR has been directly tied to MS, and T lymphocytes are known to play a central role in MS pathophysiology.
Blocking the activity of AHR in CD4-positive T cells significantly affected the production of bile acids and other metabolites in the microbiome — and the outcome of central nervous system autoimmunity. “Mice with high levels of bile acids, both primary and secondary, actually recovered from this EAE” and regained motor function, Merchak said at the GMFH meeting.
The potential impact of genetic manipulation on recovery was ruled out — and the role of bile acids confirmed — when, using the EAE model, gut bacteria from mice without AHR were transplanted into mice with AHR. The mice with AHR were able to recover, confirming that AHR can reprogram the gut microbiome and that “high levels of bile acid can lead to reduced autoimmunity in an MS model,” she said.
Other elements and stages of the research, which was published in PLOS Biology in 2023, showed increased apoptosis of CD4-positive immune cells in AHR-deficient mice and the ability of oral taurocholic acid — a bile acid that was especially high in mice without AHR — to reduce the severity of EAE, Merchak said.
Evidence for the role of gut and peripheral inflammation on neurodegeneration is building on numerous fronts, Merchak said. Unpublished research using spatial transcriptomics of colon biopsies from patients with inflammatory bowel disease (IBD), patients with Parkinson’s disease (PD), and neurologically healthy control individuals, for instance, showed similar cell communication patterns in patients with IBD or PD (and no history of IBD) compared with healthy control individuals.
And in research using a single-cell genomics approach and a mouse model of lipopolysaccharide (LPS)-induced system neuroinflammation, microglia were found to preferentially communicate with peripheral myeloid cells rather than other microglia after peripheral LPS exposure.
“In saline-treated mice, the microglia are talking primarily to microglia, but in LPS-treated mice, microglia spend more time communicating with monocytes and T cells,” Merchak explained. “We see communication going from inside the brain to cells coming in from the periphery.”
In another experiment, 2 months of a high-fat, high-sugar diet in mice with an engineered predisposition to frontotemporal dementia led to significant upregulation of major histocompatibility complex class II (MHC II) expression on monocytes in the brain, she said, describing unpublished research. Because MHC II handles antigen presentation in the brain, the change signals increased central-peripheral immune crosstalk and increased brain inflammation.
State of Clinical Research
On the clinical side, Merchak said studies of gut microbiome-modulating therapies are currently not longitudinal enough to accurately study neurodegenerative diseases that may develop over decades. Still, her review of the literature — part of her 2024 article — suggests there is at least some preliminary clinical evidence for the use of probiotics/prebiotics/diet and fecal microbiota transplant (FMT) in several diseases.
- Parkinson’s Disease: “There has been some evidence,” Merchak said at the meeting, “for the treatment [with probiotics, prebiotics and diet] of nonmotor symptoms — things like gastrointestinal distress and mood changes — but no real evidence that such treatments can help with the motor symptoms we see in Parkinson’s.” Over 60 patients with PD have been treated with FMT, she said, with reduced GI distress and mixed results with motor symptoms.
- Alzheimer’s and related dementias: “Diet shows promise for cognitive outcomes, but there hasn’t been much evidence for probiotics,” she said. Her review found 17 patients diagnosed with dementia who were treated with FMT, “and for many of them, maintenance of cognitive function was reported — so no further decline — which is excellent.”
- Multiple Sclerosis: “We see higher quality-of-life measures in patients getting probiotics, prebiotics, and changes in diet,” Merchak said. “Again, most of this [relates to] mood and digestion, but some studies show a slowing of neurological damage as measured by MRI.”
There are reports of 15 patients treated with FMT, and “three of these document full functional recovery,” she said, noting that longer follow-up is necessary as MS is characterized by relapsed and periods of recovery.
Merchak reported no financial disclosures.
A version of this article appeared on Medscape.com.
WASHINGTON, DC — Age-related neurodegenerative disorders — motor neuron diseases, demyelinating diseases, Alzheimer’s disease, and other proteinopathies — are at an “inflection point,” said researcher Andrea R. Merchak, PhD, with a fuller understanding of disease pathophysiology but an overall dearth of effective disease-modifying treatments.
And this, Merchak said at the Gut Microbiota for Health (GMFH) World Summit 2025, is where the gut microbiome comes in. “The gut-brain axis is important to take into consideration,” she urged, both for gut microbiome researchers — whose collaboration with neurologists and neuroscientists is essential — and for practicing gastroenterologists.
“We are the sum of our environmental exposures,” said Merchak, assistant research professor of neurology at the Indiana University School of Medicine, in Indianapolis. “So for your patient populations, remember you’re not only treating the diseases they’re coming to you with, you’re also treating them for a lifetime of healthy [brain] aging.”
At the center of a healthy aging brain are the brain-residing microglia and peripheral monocytes, she said. These immune cell populations are directly influenced by blood-brain barrier breakdown, inflammation, and gut permeability — and indirectly influenced by microbial products, gastrointestinal (GI) function, and bacterial diversity, Merchak said at the meeting, which was convened by AGA and the European Society of Neurogastroenterology and Motility.
“Many of us grew up learning that the brain is an immune-privileged site, but we’ve been establishing that this is fundamentally not true,” she said. “While the brain does have a privileged status, there are interactions with the blood, with the peripheral immune cells.”
Merchak coauthored a 2024 review in Neurotherapeutics in which she and her colleagues explained that the brain is “heavily connected with peripheral immune dynamics,” and that the gut — as the largest immune organ in the body — is a critical place for peripheral immune development, “thus influencing brain health.”
Gut microbiota interact with the brain via several mechanisms including microbiota-derived metabolites that enter circulation, direct communication via the vagus nerve, and modulation of the immune system, Merchak and her coauthors wrote. Leaky gut, they noted, can lead to an accumulation of inflammatory signals and cells that can exacerbate or induce the onset of neurodegenerative conditions.
As researchers better understand the role that GI dysfunction plays in neurodegenerative disease — as they identify microbiome signatures for predicting risk, for instance — there will be “opportunities to target the microbiome to prevent or reverse dysbiosis as a way to delay, arrest or prevent the onset and progression of neurodegenerative diseases,” they wrote.
At the GMFH meeting, Merchak described both ongoing preclinical research that is dissecting gut-brain communication, and preliminary clinical evidence for the use of gut microbiota-modulating therapies in neurodegenerative disease.
Support for a Gut-Focused Approach
Research on bile acid metabolism in multiple sclerosis (MS) and on peripheral inflammation in dementia exemplify the ongoing preclinical research uncovering the mechanisms of gut-brain communication, Merchak said.
The finding that bile acid metabolism modulates MS autoimmunity comes from research done by Merchak and a team at the University of Virginia, Charlottesville, Virginia, several years ago in which mice with experimental autoimmune encephalomyelitis (EAE) — an animal model of MS — were engineered for T cell specific knockout of the aryl hydrocarbon receptor (AHR). The AHR has been directly tied to MS, and T lymphocytes are known to play a central role in MS pathophysiology.
Blocking the activity of AHR in CD4-positive T cells significantly affected the production of bile acids and other metabolites in the microbiome — and the outcome of central nervous system autoimmunity. “Mice with high levels of bile acids, both primary and secondary, actually recovered from this EAE” and regained motor function, Merchak said at the GMFH meeting.
The potential impact of genetic manipulation on recovery was ruled out — and the role of bile acids confirmed — when, using the EAE model, gut bacteria from mice without AHR were transplanted into mice with AHR. The mice with AHR were able to recover, confirming that AHR can reprogram the gut microbiome and that “high levels of bile acid can lead to reduced autoimmunity in an MS model,” she said.
Other elements and stages of the research, which was published in PLOS Biology in 2023, showed increased apoptosis of CD4-positive immune cells in AHR-deficient mice and the ability of oral taurocholic acid — a bile acid that was especially high in mice without AHR — to reduce the severity of EAE, Merchak said.
Evidence for the role of gut and peripheral inflammation on neurodegeneration is building on numerous fronts, Merchak said. Unpublished research using spatial transcriptomics of colon biopsies from patients with inflammatory bowel disease (IBD), patients with Parkinson’s disease (PD), and neurologically healthy control individuals, for instance, showed similar cell communication patterns in patients with IBD or PD (and no history of IBD) compared with healthy control individuals.
And in research using a single-cell genomics approach and a mouse model of lipopolysaccharide (LPS)-induced system neuroinflammation, microglia were found to preferentially communicate with peripheral myeloid cells rather than other microglia after peripheral LPS exposure.
“In saline-treated mice, the microglia are talking primarily to microglia, but in LPS-treated mice, microglia spend more time communicating with monocytes and T cells,” Merchak explained. “We see communication going from inside the brain to cells coming in from the periphery.”
In another experiment, 2 months of a high-fat, high-sugar diet in mice with an engineered predisposition to frontotemporal dementia led to significant upregulation of major histocompatibility complex class II (MHC II) expression on monocytes in the brain, she said, describing unpublished research. Because MHC II handles antigen presentation in the brain, the change signals increased central-peripheral immune crosstalk and increased brain inflammation.
State of Clinical Research
On the clinical side, Merchak said studies of gut microbiome-modulating therapies are currently not longitudinal enough to accurately study neurodegenerative diseases that may develop over decades. Still, her review of the literature — part of her 2024 article — suggests there is at least some preliminary clinical evidence for the use of probiotics/prebiotics/diet and fecal microbiota transplant (FMT) in several diseases.
- Parkinson’s Disease: “There has been some evidence,” Merchak said at the meeting, “for the treatment [with probiotics, prebiotics and diet] of nonmotor symptoms — things like gastrointestinal distress and mood changes — but no real evidence that such treatments can help with the motor symptoms we see in Parkinson’s.” Over 60 patients with PD have been treated with FMT, she said, with reduced GI distress and mixed results with motor symptoms.
- Alzheimer’s and related dementias: “Diet shows promise for cognitive outcomes, but there hasn’t been much evidence for probiotics,” she said. Her review found 17 patients diagnosed with dementia who were treated with FMT, “and for many of them, maintenance of cognitive function was reported — so no further decline — which is excellent.”
- Multiple Sclerosis: “We see higher quality-of-life measures in patients getting probiotics, prebiotics, and changes in diet,” Merchak said. “Again, most of this [relates to] mood and digestion, but some studies show a slowing of neurological damage as measured by MRI.”
There are reports of 15 patients treated with FMT, and “three of these document full functional recovery,” she said, noting that longer follow-up is necessary as MS is characterized by relapsed and periods of recovery.
Merchak reported no financial disclosures.
A version of this article appeared on Medscape.com.
WASHINGTON, DC — Age-related neurodegenerative disorders — motor neuron diseases, demyelinating diseases, Alzheimer’s disease, and other proteinopathies — are at an “inflection point,” said researcher Andrea R. Merchak, PhD, with a fuller understanding of disease pathophysiology but an overall dearth of effective disease-modifying treatments.
And this, Merchak said at the Gut Microbiota for Health (GMFH) World Summit 2025, is where the gut microbiome comes in. “The gut-brain axis is important to take into consideration,” she urged, both for gut microbiome researchers — whose collaboration with neurologists and neuroscientists is essential — and for practicing gastroenterologists.
“We are the sum of our environmental exposures,” said Merchak, assistant research professor of neurology at the Indiana University School of Medicine, in Indianapolis. “So for your patient populations, remember you’re not only treating the diseases they’re coming to you with, you’re also treating them for a lifetime of healthy [brain] aging.”
At the center of a healthy aging brain are the brain-residing microglia and peripheral monocytes, she said. These immune cell populations are directly influenced by blood-brain barrier breakdown, inflammation, and gut permeability — and indirectly influenced by microbial products, gastrointestinal (GI) function, and bacterial diversity, Merchak said at the meeting, which was convened by AGA and the European Society of Neurogastroenterology and Motility.
“Many of us grew up learning that the brain is an immune-privileged site, but we’ve been establishing that this is fundamentally not true,” she said. “While the brain does have a privileged status, there are interactions with the blood, with the peripheral immune cells.”
Merchak coauthored a 2024 review in Neurotherapeutics in which she and her colleagues explained that the brain is “heavily connected with peripheral immune dynamics,” and that the gut — as the largest immune organ in the body — is a critical place for peripheral immune development, “thus influencing brain health.”
Gut microbiota interact with the brain via several mechanisms including microbiota-derived metabolites that enter circulation, direct communication via the vagus nerve, and modulation of the immune system, Merchak and her coauthors wrote. Leaky gut, they noted, can lead to an accumulation of inflammatory signals and cells that can exacerbate or induce the onset of neurodegenerative conditions.
As researchers better understand the role that GI dysfunction plays in neurodegenerative disease — as they identify microbiome signatures for predicting risk, for instance — there will be “opportunities to target the microbiome to prevent or reverse dysbiosis as a way to delay, arrest or prevent the onset and progression of neurodegenerative diseases,” they wrote.
At the GMFH meeting, Merchak described both ongoing preclinical research that is dissecting gut-brain communication, and preliminary clinical evidence for the use of gut microbiota-modulating therapies in neurodegenerative disease.
Support for a Gut-Focused Approach
Research on bile acid metabolism in multiple sclerosis (MS) and on peripheral inflammation in dementia exemplify the ongoing preclinical research uncovering the mechanisms of gut-brain communication, Merchak said.
The finding that bile acid metabolism modulates MS autoimmunity comes from research done by Merchak and a team at the University of Virginia, Charlottesville, Virginia, several years ago in which mice with experimental autoimmune encephalomyelitis (EAE) — an animal model of MS — were engineered for T cell specific knockout of the aryl hydrocarbon receptor (AHR). The AHR has been directly tied to MS, and T lymphocytes are known to play a central role in MS pathophysiology.
Blocking the activity of AHR in CD4-positive T cells significantly affected the production of bile acids and other metabolites in the microbiome — and the outcome of central nervous system autoimmunity. “Mice with high levels of bile acids, both primary and secondary, actually recovered from this EAE” and regained motor function, Merchak said at the GMFH meeting.
The potential impact of genetic manipulation on recovery was ruled out — and the role of bile acids confirmed — when, using the EAE model, gut bacteria from mice without AHR were transplanted into mice with AHR. The mice with AHR were able to recover, confirming that AHR can reprogram the gut microbiome and that “high levels of bile acid can lead to reduced autoimmunity in an MS model,” she said.
Other elements and stages of the research, which was published in PLOS Biology in 2023, showed increased apoptosis of CD4-positive immune cells in AHR-deficient mice and the ability of oral taurocholic acid — a bile acid that was especially high in mice without AHR — to reduce the severity of EAE, Merchak said.
Evidence for the role of gut and peripheral inflammation on neurodegeneration is building on numerous fronts, Merchak said. Unpublished research using spatial transcriptomics of colon biopsies from patients with inflammatory bowel disease (IBD), patients with Parkinson’s disease (PD), and neurologically healthy control individuals, for instance, showed similar cell communication patterns in patients with IBD or PD (and no history of IBD) compared with healthy control individuals.
And in research using a single-cell genomics approach and a mouse model of lipopolysaccharide (LPS)-induced system neuroinflammation, microglia were found to preferentially communicate with peripheral myeloid cells rather than other microglia after peripheral LPS exposure.
“In saline-treated mice, the microglia are talking primarily to microglia, but in LPS-treated mice, microglia spend more time communicating with monocytes and T cells,” Merchak explained. “We see communication going from inside the brain to cells coming in from the periphery.”
In another experiment, 2 months of a high-fat, high-sugar diet in mice with an engineered predisposition to frontotemporal dementia led to significant upregulation of major histocompatibility complex class II (MHC II) expression on monocytes in the brain, she said, describing unpublished research. Because MHC II handles antigen presentation in the brain, the change signals increased central-peripheral immune crosstalk and increased brain inflammation.
State of Clinical Research
On the clinical side, Merchak said studies of gut microbiome-modulating therapies are currently not longitudinal enough to accurately study neurodegenerative diseases that may develop over decades. Still, her review of the literature — part of her 2024 article — suggests there is at least some preliminary clinical evidence for the use of probiotics/prebiotics/diet and fecal microbiota transplant (FMT) in several diseases.
- Parkinson’s Disease: “There has been some evidence,” Merchak said at the meeting, “for the treatment [with probiotics, prebiotics and diet] of nonmotor symptoms — things like gastrointestinal distress and mood changes — but no real evidence that such treatments can help with the motor symptoms we see in Parkinson’s.” Over 60 patients with PD have been treated with FMT, she said, with reduced GI distress and mixed results with motor symptoms.
- Alzheimer’s and related dementias: “Diet shows promise for cognitive outcomes, but there hasn’t been much evidence for probiotics,” she said. Her review found 17 patients diagnosed with dementia who were treated with FMT, “and for many of them, maintenance of cognitive function was reported — so no further decline — which is excellent.”
- Multiple Sclerosis: “We see higher quality-of-life measures in patients getting probiotics, prebiotics, and changes in diet,” Merchak said. “Again, most of this [relates to] mood and digestion, but some studies show a slowing of neurological damage as measured by MRI.”
There are reports of 15 patients treated with FMT, and “three of these document full functional recovery,” she said, noting that longer follow-up is necessary as MS is characterized by relapsed and periods of recovery.
Merchak reported no financial disclosures.
A version of this article appeared on Medscape.com.
FROM GMFH 2025
Geriatric Dermatology: Q&A With Daniel C. Butler, MD
Daniel C. Butler, MD, is associate professor of dermatology and director of the new Inflammatory and Aging Skin Research Program in the Division of Dermatology at the University of Arizona College of Medicine, Tucson, Arizona. Before returning to Arizona, where he had attended medical school, Butler practiced and was a researcher at the University of California, San Francisco, and its geriatric dermatology clinic. He is a co-founder and continues to co-lead the American Academy of Dermatology (AAD) Geriatric Dermatology Expert Resource Group (ERG).
Butler’s interest in geriatric dermatology is rooted in his experience growing up with four grandparents and witnessing their wisdom, relationships, moments with loved ones, and other unique and desirable parts of growing old. “When I looked later at how aging was perceived in dermatology, I found it was a lot about ‘antiaging,’” he told this news organization. “I thought there was a needed voice in dermatology for healthy aging, for all the desirable things that only growing old can provide, along with all the incredible ‘antiaging’ things we can do.”
In interviews, Butler spoke about research priorities in geriatric dermatology, how the “4M” model of geriatrics should be applied within dermatology, how dermatologists can best work with older complex patients, and more. The conversation was edited for clarity and length.
What is geriatric dermatology? It is described by the AAD’s Geriatric Dermatology ERG as “an emerging subspecialty.” Yet it’s also viewed more broadly. Please speak about its various identities and meanings and its importance for dermatology.
If you’re a Mohs surgeon, you’re seeing a strong majority of over 65 patients. And in various specialty clinics, such as inflammatory skin disease, geriatric dermatology pertains to you. In many ways, it can be viewed as a mindset.
From a framework standpoint, and as a field, geriatric dermatology is a basic science initiative, a clinical initiative, an educational initiative, and an advocacy initiative. The goal is to be able to influence, grow, and learn in each of these categories for our older patients. This is happening: Research in this field has progressed, and education has progressed, which has driven some progress in clinical care.
How has research progressed in the basic science of aging skin? What are key questions for dermatology?
There has been a lot of basic science research on aging skin and on how an aging immune system, for instance, is reflected in conditions such as bullous pemphigoid, atopic dermatitis (AD), and chronic itch. But aging involves more than immunosenescence. I think of aging skin as a three-headed monster that involves changes in the skin barrier and the microbiome as well. But is there a primary piece of aging in the skin? What comes first or influences the other? More research on these questions can potentially influence our treatments.
With respect to the immune system, what we’re finding in the skin is that age-related change is not a decline in the immune system per se, but rather aberrance in response. Parts of the system tend to become overactive, with a skew toward overexpression of type 2 inflammation. This can be problematic, driving conditions such as chronic itch.
With respect to the skin barrier, we lose essential fatty acids, and we lose a lot of our recovery ability and our ability to respond quickly to environmental stressors. But are barrier changes triggering the immune system? Or is it the other way around?
The microbiome, which is a big focus of research, involves similar chicken-and-egg discussions. Is it the microbiome that changes and alters the barrier, which then entices the immune system? Which one happens first? We have a lot to learn, and there’s probably not one answer for every patient.
Please speak about research more broadly. What questions and issues need to be answered and addressed to improve the dermatologic care of older adults?
In general, research in dermatology is very disease-specific and not particularly conducive to looking at the larger demographic populations. We have a huge opportunity, therefore, to break the mold and grow geriatric dermatology as an area of population-based research — so that geriatric dermatology research encompasses not only the melanoma researcher who’s trying to understand how aging influences the melanocytes but also the epidemiologic researcher looking at how our diagnoses and coding and prescription practices are different in the 65-plus age group.
Clinically speaking, researchers want to better understand how aging influences the clinical presentations of our diseases. And there’s research to be done on best practices. For example, what are the best practices for treating basal cell carcinomas in patients with mild cognitive impairment? How should we consider the use of topicals in a patient who has severe arthritis or who lives alone? And then how should we teach practical approaches to help providers meet people where they are?
Looking at it from a healthcare system standpoint, there are many care delivery and access issues — practical pieces — to research, and we’re getting a lot better with this. We’re also advocating not only for more inclusion of older adults in clinical trials of treatments but also for the use of evaluations and outcomes that are relevant and important for older adults.
One piece of good news is that we’re seeing safer treatment options with tremendous efficacy that target known pathways for diseases like AD and chronic itch that affect older adults. Again, now we must find ways to improve access to these novel, safe options.
Our research program at the University of Arizona College of Medicine, which we’re just getting off the ground, aims to be dual-sided, looking both at the basic science of aging skin and at access and care delivery issues, such as how to ensure that patients on Medicare have access to medications that are at least on par with others with private insurance.
What are the most common dermatologic problems experienced by older adults?
Based on my experience and on research that we expect to be published soon, it’s absolutely nonmelanoma skin cancers, precancers like actinic keratoses — and on the inflammatory disease side, itch, AD, and psoriasis. Of course, also common are the age-related changes to the skin that we put in the benign category, such as solar lentigines.
How does age influence dermatologic diseases from a pathophysiological and clinical standpoint?
Diseases overall are very similar and respond to the same treatments, but age in and of itself does influence little pieces. For example, there is more crossover in the presentation of psoriasis and AD in older adults, leading to delays in the diagnosis of psoriasis.
With AD, we’ve found that itch is the predominant symptom for older adults rather than the red rash. We see higher or more severe itch scores in older adults with AD with less visual changes on the skin than in younger cohorts. And rash occurs in different locations than in young patients. Older adults typically present with it on their chest, back, and across the trunk, rather than in folded areas. They’re also more likely to get it on their legs in a nummular pattern as opposed to the more traditional flexural area presentation.
What unique considerations need to be made in treating older adults? How should the 4M model of geriatrics be applied to dermatologic care?
Our care model pushes us to be very algorithmic, but at the end of the day, what’s really important are the 4Ms: Mobility, medication, mentation, and “what matters most.” As you’re having your shared decision-making conversations with your patients and their families, these should be your priorities.
A patient with physical limitations, for instance, may not be able to apply a topical cream twice a day all over the body. They may have comorbidities and treatments for these comorbidities that may conflict with medications you’re considering.
And then mentation is so important. For a long time, we used antihistamines for older adults, but this has been proven to be bad for their mentation and risky in other ways. We need to be sure we’re prioritizing their ability to be clear mentally when we’re prescribing medications and even when we’re considering surgical approaches. Do they show capacity for that procedure or treatment, and how will they respond to that treatment later on?
Using the 4M model to drive conversations is a way to get all of us to connect to the patient and learn about what’s most important for them. In many ways, geriatrics is about taking a step back from your specialist skills and thinking about how you would want a family member treated.
We want to avoid treating just the lesion or the pathologic diagnosis. We want to avoid the “conveyor belt” from a biopsy to Mohs. I have 95-year-olds who say, “Heck yeah, if Mohs is the best treatment, that’s what I want.” And I have 70-year-olds who say, “I think I’ll go with another option,” and that’s the right decision for them. It’s having the conversation that matters.
In practice, given time constraints and other confines, how can dermatologists best work with more complex older patients? What are your practical tips?
People talk about having 45-minute “golden year” conversations with their older patients, but it doesn’t have to be this way. In pursuing geriatric dermatology, I decided early on that I wanted to make sure it was practical, so I’ve focused on maximizing shorter visits and on embracing the concept that relationships can be developed over time. Each time we meet with someone, we’re building equity to have bigger conversations later on.
I can have a 15-minute conversation about whether my patient may want to have Mohs surgery, for instance, or escalate treatment to a systemic agent for their chronic inflammatory disease. If that time isn’t enough, I can encourage further thought about treatment options, acknowledge that decisions aren’t necessarily easy, and schedule a follow-up or offer to call the patient after clinic to continue the conversation.
Sometimes, when I’m at an impasse and my patient is unsure how to proceed, I’ll use clear metrics relevant to older adults — sleep, activity level, and caregiver burden — to help my patient. If someone is not sleeping because of their lesion — if they’re so itchy or their inflammatory disease is uncontrolled, for instance — I’ll point out that the side effects of not sleeping are worse than the medications or surgery we’d pursue. If someone removes themselves from an activity due to their skin condition, that’s a red flag. And if the caregiver in the room is overwhelmed or frustrated by having to put cream on twice a day, I’ll use this to advance treatment.
What resources are available for dermatologists interested in improving their geriatric dermatology skills or advancing the area?
For those interested in investigating these issues or improving their practices, the AAD’s Geriatric Dermatology ERG is always welcoming of new members. The ERG will have an all-inclusive meeting at the 2025 annual AAD meeting in March.
The AAD also has educational modules on geriatric dermatology that were recently published as an initiative of our ERG. More information is available on the website. Also valuable is the ElderDerm conference hosted by the George Washington University School of Medicine and Health Sciences, Washington, DC; the second such conference takes place in May 2025.
Butler reported that he had no relevant financial disclosures.
A version of this article appeared on Medscape.com.
Daniel C. Butler, MD, is associate professor of dermatology and director of the new Inflammatory and Aging Skin Research Program in the Division of Dermatology at the University of Arizona College of Medicine, Tucson, Arizona. Before returning to Arizona, where he had attended medical school, Butler practiced and was a researcher at the University of California, San Francisco, and its geriatric dermatology clinic. He is a co-founder and continues to co-lead the American Academy of Dermatology (AAD) Geriatric Dermatology Expert Resource Group (ERG).
Butler’s interest in geriatric dermatology is rooted in his experience growing up with four grandparents and witnessing their wisdom, relationships, moments with loved ones, and other unique and desirable parts of growing old. “When I looked later at how aging was perceived in dermatology, I found it was a lot about ‘antiaging,’” he told this news organization. “I thought there was a needed voice in dermatology for healthy aging, for all the desirable things that only growing old can provide, along with all the incredible ‘antiaging’ things we can do.”
In interviews, Butler spoke about research priorities in geriatric dermatology, how the “4M” model of geriatrics should be applied within dermatology, how dermatologists can best work with older complex patients, and more. The conversation was edited for clarity and length.
What is geriatric dermatology? It is described by the AAD’s Geriatric Dermatology ERG as “an emerging subspecialty.” Yet it’s also viewed more broadly. Please speak about its various identities and meanings and its importance for dermatology.
If you’re a Mohs surgeon, you’re seeing a strong majority of over 65 patients. And in various specialty clinics, such as inflammatory skin disease, geriatric dermatology pertains to you. In many ways, it can be viewed as a mindset.
From a framework standpoint, and as a field, geriatric dermatology is a basic science initiative, a clinical initiative, an educational initiative, and an advocacy initiative. The goal is to be able to influence, grow, and learn in each of these categories for our older patients. This is happening: Research in this field has progressed, and education has progressed, which has driven some progress in clinical care.
How has research progressed in the basic science of aging skin? What are key questions for dermatology?
There has been a lot of basic science research on aging skin and on how an aging immune system, for instance, is reflected in conditions such as bullous pemphigoid, atopic dermatitis (AD), and chronic itch. But aging involves more than immunosenescence. I think of aging skin as a three-headed monster that involves changes in the skin barrier and the microbiome as well. But is there a primary piece of aging in the skin? What comes first or influences the other? More research on these questions can potentially influence our treatments.
With respect to the immune system, what we’re finding in the skin is that age-related change is not a decline in the immune system per se, but rather aberrance in response. Parts of the system tend to become overactive, with a skew toward overexpression of type 2 inflammation. This can be problematic, driving conditions such as chronic itch.
With respect to the skin barrier, we lose essential fatty acids, and we lose a lot of our recovery ability and our ability to respond quickly to environmental stressors. But are barrier changes triggering the immune system? Or is it the other way around?
The microbiome, which is a big focus of research, involves similar chicken-and-egg discussions. Is it the microbiome that changes and alters the barrier, which then entices the immune system? Which one happens first? We have a lot to learn, and there’s probably not one answer for every patient.
Please speak about research more broadly. What questions and issues need to be answered and addressed to improve the dermatologic care of older adults?
In general, research in dermatology is very disease-specific and not particularly conducive to looking at the larger demographic populations. We have a huge opportunity, therefore, to break the mold and grow geriatric dermatology as an area of population-based research — so that geriatric dermatology research encompasses not only the melanoma researcher who’s trying to understand how aging influences the melanocytes but also the epidemiologic researcher looking at how our diagnoses and coding and prescription practices are different in the 65-plus age group.
Clinically speaking, researchers want to better understand how aging influences the clinical presentations of our diseases. And there’s research to be done on best practices. For example, what are the best practices for treating basal cell carcinomas in patients with mild cognitive impairment? How should we consider the use of topicals in a patient who has severe arthritis or who lives alone? And then how should we teach practical approaches to help providers meet people where they are?
Looking at it from a healthcare system standpoint, there are many care delivery and access issues — practical pieces — to research, and we’re getting a lot better with this. We’re also advocating not only for more inclusion of older adults in clinical trials of treatments but also for the use of evaluations and outcomes that are relevant and important for older adults.
One piece of good news is that we’re seeing safer treatment options with tremendous efficacy that target known pathways for diseases like AD and chronic itch that affect older adults. Again, now we must find ways to improve access to these novel, safe options.
Our research program at the University of Arizona College of Medicine, which we’re just getting off the ground, aims to be dual-sided, looking both at the basic science of aging skin and at access and care delivery issues, such as how to ensure that patients on Medicare have access to medications that are at least on par with others with private insurance.
What are the most common dermatologic problems experienced by older adults?
Based on my experience and on research that we expect to be published soon, it’s absolutely nonmelanoma skin cancers, precancers like actinic keratoses — and on the inflammatory disease side, itch, AD, and psoriasis. Of course, also common are the age-related changes to the skin that we put in the benign category, such as solar lentigines.
How does age influence dermatologic diseases from a pathophysiological and clinical standpoint?
Diseases overall are very similar and respond to the same treatments, but age in and of itself does influence little pieces. For example, there is more crossover in the presentation of psoriasis and AD in older adults, leading to delays in the diagnosis of psoriasis.
With AD, we’ve found that itch is the predominant symptom for older adults rather than the red rash. We see higher or more severe itch scores in older adults with AD with less visual changes on the skin than in younger cohorts. And rash occurs in different locations than in young patients. Older adults typically present with it on their chest, back, and across the trunk, rather than in folded areas. They’re also more likely to get it on their legs in a nummular pattern as opposed to the more traditional flexural area presentation.
What unique considerations need to be made in treating older adults? How should the 4M model of geriatrics be applied to dermatologic care?
Our care model pushes us to be very algorithmic, but at the end of the day, what’s really important are the 4Ms: Mobility, medication, mentation, and “what matters most.” As you’re having your shared decision-making conversations with your patients and their families, these should be your priorities.
A patient with physical limitations, for instance, may not be able to apply a topical cream twice a day all over the body. They may have comorbidities and treatments for these comorbidities that may conflict with medications you’re considering.
And then mentation is so important. For a long time, we used antihistamines for older adults, but this has been proven to be bad for their mentation and risky in other ways. We need to be sure we’re prioritizing their ability to be clear mentally when we’re prescribing medications and even when we’re considering surgical approaches. Do they show capacity for that procedure or treatment, and how will they respond to that treatment later on?
Using the 4M model to drive conversations is a way to get all of us to connect to the patient and learn about what’s most important for them. In many ways, geriatrics is about taking a step back from your specialist skills and thinking about how you would want a family member treated.
We want to avoid treating just the lesion or the pathologic diagnosis. We want to avoid the “conveyor belt” from a biopsy to Mohs. I have 95-year-olds who say, “Heck yeah, if Mohs is the best treatment, that’s what I want.” And I have 70-year-olds who say, “I think I’ll go with another option,” and that’s the right decision for them. It’s having the conversation that matters.
In practice, given time constraints and other confines, how can dermatologists best work with more complex older patients? What are your practical tips?
People talk about having 45-minute “golden year” conversations with their older patients, but it doesn’t have to be this way. In pursuing geriatric dermatology, I decided early on that I wanted to make sure it was practical, so I’ve focused on maximizing shorter visits and on embracing the concept that relationships can be developed over time. Each time we meet with someone, we’re building equity to have bigger conversations later on.
I can have a 15-minute conversation about whether my patient may want to have Mohs surgery, for instance, or escalate treatment to a systemic agent for their chronic inflammatory disease. If that time isn’t enough, I can encourage further thought about treatment options, acknowledge that decisions aren’t necessarily easy, and schedule a follow-up or offer to call the patient after clinic to continue the conversation.
Sometimes, when I’m at an impasse and my patient is unsure how to proceed, I’ll use clear metrics relevant to older adults — sleep, activity level, and caregiver burden — to help my patient. If someone is not sleeping because of their lesion — if they’re so itchy or their inflammatory disease is uncontrolled, for instance — I’ll point out that the side effects of not sleeping are worse than the medications or surgery we’d pursue. If someone removes themselves from an activity due to their skin condition, that’s a red flag. And if the caregiver in the room is overwhelmed or frustrated by having to put cream on twice a day, I’ll use this to advance treatment.
What resources are available for dermatologists interested in improving their geriatric dermatology skills or advancing the area?
For those interested in investigating these issues or improving their practices, the AAD’s Geriatric Dermatology ERG is always welcoming of new members. The ERG will have an all-inclusive meeting at the 2025 annual AAD meeting in March.
The AAD also has educational modules on geriatric dermatology that were recently published as an initiative of our ERG. More information is available on the website. Also valuable is the ElderDerm conference hosted by the George Washington University School of Medicine and Health Sciences, Washington, DC; the second such conference takes place in May 2025.
Butler reported that he had no relevant financial disclosures.
A version of this article appeared on Medscape.com.
Daniel C. Butler, MD, is associate professor of dermatology and director of the new Inflammatory and Aging Skin Research Program in the Division of Dermatology at the University of Arizona College of Medicine, Tucson, Arizona. Before returning to Arizona, where he had attended medical school, Butler practiced and was a researcher at the University of California, San Francisco, and its geriatric dermatology clinic. He is a co-founder and continues to co-lead the American Academy of Dermatology (AAD) Geriatric Dermatology Expert Resource Group (ERG).
Butler’s interest in geriatric dermatology is rooted in his experience growing up with four grandparents and witnessing their wisdom, relationships, moments with loved ones, and other unique and desirable parts of growing old. “When I looked later at how aging was perceived in dermatology, I found it was a lot about ‘antiaging,’” he told this news organization. “I thought there was a needed voice in dermatology for healthy aging, for all the desirable things that only growing old can provide, along with all the incredible ‘antiaging’ things we can do.”
In interviews, Butler spoke about research priorities in geriatric dermatology, how the “4M” model of geriatrics should be applied within dermatology, how dermatologists can best work with older complex patients, and more. The conversation was edited for clarity and length.
What is geriatric dermatology? It is described by the AAD’s Geriatric Dermatology ERG as “an emerging subspecialty.” Yet it’s also viewed more broadly. Please speak about its various identities and meanings and its importance for dermatology.
If you’re a Mohs surgeon, you’re seeing a strong majority of over 65 patients. And in various specialty clinics, such as inflammatory skin disease, geriatric dermatology pertains to you. In many ways, it can be viewed as a mindset.
From a framework standpoint, and as a field, geriatric dermatology is a basic science initiative, a clinical initiative, an educational initiative, and an advocacy initiative. The goal is to be able to influence, grow, and learn in each of these categories for our older patients. This is happening: Research in this field has progressed, and education has progressed, which has driven some progress in clinical care.
How has research progressed in the basic science of aging skin? What are key questions for dermatology?
There has been a lot of basic science research on aging skin and on how an aging immune system, for instance, is reflected in conditions such as bullous pemphigoid, atopic dermatitis (AD), and chronic itch. But aging involves more than immunosenescence. I think of aging skin as a three-headed monster that involves changes in the skin barrier and the microbiome as well. But is there a primary piece of aging in the skin? What comes first or influences the other? More research on these questions can potentially influence our treatments.
With respect to the immune system, what we’re finding in the skin is that age-related change is not a decline in the immune system per se, but rather aberrance in response. Parts of the system tend to become overactive, with a skew toward overexpression of type 2 inflammation. This can be problematic, driving conditions such as chronic itch.
With respect to the skin barrier, we lose essential fatty acids, and we lose a lot of our recovery ability and our ability to respond quickly to environmental stressors. But are barrier changes triggering the immune system? Or is it the other way around?
The microbiome, which is a big focus of research, involves similar chicken-and-egg discussions. Is it the microbiome that changes and alters the barrier, which then entices the immune system? Which one happens first? We have a lot to learn, and there’s probably not one answer for every patient.
Please speak about research more broadly. What questions and issues need to be answered and addressed to improve the dermatologic care of older adults?
In general, research in dermatology is very disease-specific and not particularly conducive to looking at the larger demographic populations. We have a huge opportunity, therefore, to break the mold and grow geriatric dermatology as an area of population-based research — so that geriatric dermatology research encompasses not only the melanoma researcher who’s trying to understand how aging influences the melanocytes but also the epidemiologic researcher looking at how our diagnoses and coding and prescription practices are different in the 65-plus age group.
Clinically speaking, researchers want to better understand how aging influences the clinical presentations of our diseases. And there’s research to be done on best practices. For example, what are the best practices for treating basal cell carcinomas in patients with mild cognitive impairment? How should we consider the use of topicals in a patient who has severe arthritis or who lives alone? And then how should we teach practical approaches to help providers meet people where they are?
Looking at it from a healthcare system standpoint, there are many care delivery and access issues — practical pieces — to research, and we’re getting a lot better with this. We’re also advocating not only for more inclusion of older adults in clinical trials of treatments but also for the use of evaluations and outcomes that are relevant and important for older adults.
One piece of good news is that we’re seeing safer treatment options with tremendous efficacy that target known pathways for diseases like AD and chronic itch that affect older adults. Again, now we must find ways to improve access to these novel, safe options.
Our research program at the University of Arizona College of Medicine, which we’re just getting off the ground, aims to be dual-sided, looking both at the basic science of aging skin and at access and care delivery issues, such as how to ensure that patients on Medicare have access to medications that are at least on par with others with private insurance.
What are the most common dermatologic problems experienced by older adults?
Based on my experience and on research that we expect to be published soon, it’s absolutely nonmelanoma skin cancers, precancers like actinic keratoses — and on the inflammatory disease side, itch, AD, and psoriasis. Of course, also common are the age-related changes to the skin that we put in the benign category, such as solar lentigines.
How does age influence dermatologic diseases from a pathophysiological and clinical standpoint?
Diseases overall are very similar and respond to the same treatments, but age in and of itself does influence little pieces. For example, there is more crossover in the presentation of psoriasis and AD in older adults, leading to delays in the diagnosis of psoriasis.
With AD, we’ve found that itch is the predominant symptom for older adults rather than the red rash. We see higher or more severe itch scores in older adults with AD with less visual changes on the skin than in younger cohorts. And rash occurs in different locations than in young patients. Older adults typically present with it on their chest, back, and across the trunk, rather than in folded areas. They’re also more likely to get it on their legs in a nummular pattern as opposed to the more traditional flexural area presentation.
What unique considerations need to be made in treating older adults? How should the 4M model of geriatrics be applied to dermatologic care?
Our care model pushes us to be very algorithmic, but at the end of the day, what’s really important are the 4Ms: Mobility, medication, mentation, and “what matters most.” As you’re having your shared decision-making conversations with your patients and their families, these should be your priorities.
A patient with physical limitations, for instance, may not be able to apply a topical cream twice a day all over the body. They may have comorbidities and treatments for these comorbidities that may conflict with medications you’re considering.
And then mentation is so important. For a long time, we used antihistamines for older adults, but this has been proven to be bad for their mentation and risky in other ways. We need to be sure we’re prioritizing their ability to be clear mentally when we’re prescribing medications and even when we’re considering surgical approaches. Do they show capacity for that procedure or treatment, and how will they respond to that treatment later on?
Using the 4M model to drive conversations is a way to get all of us to connect to the patient and learn about what’s most important for them. In many ways, geriatrics is about taking a step back from your specialist skills and thinking about how you would want a family member treated.
We want to avoid treating just the lesion or the pathologic diagnosis. We want to avoid the “conveyor belt” from a biopsy to Mohs. I have 95-year-olds who say, “Heck yeah, if Mohs is the best treatment, that’s what I want.” And I have 70-year-olds who say, “I think I’ll go with another option,” and that’s the right decision for them. It’s having the conversation that matters.
In practice, given time constraints and other confines, how can dermatologists best work with more complex older patients? What are your practical tips?
People talk about having 45-minute “golden year” conversations with their older patients, but it doesn’t have to be this way. In pursuing geriatric dermatology, I decided early on that I wanted to make sure it was practical, so I’ve focused on maximizing shorter visits and on embracing the concept that relationships can be developed over time. Each time we meet with someone, we’re building equity to have bigger conversations later on.
I can have a 15-minute conversation about whether my patient may want to have Mohs surgery, for instance, or escalate treatment to a systemic agent for their chronic inflammatory disease. If that time isn’t enough, I can encourage further thought about treatment options, acknowledge that decisions aren’t necessarily easy, and schedule a follow-up or offer to call the patient after clinic to continue the conversation.
Sometimes, when I’m at an impasse and my patient is unsure how to proceed, I’ll use clear metrics relevant to older adults — sleep, activity level, and caregiver burden — to help my patient. If someone is not sleeping because of their lesion — if they’re so itchy or their inflammatory disease is uncontrolled, for instance — I’ll point out that the side effects of not sleeping are worse than the medications or surgery we’d pursue. If someone removes themselves from an activity due to their skin condition, that’s a red flag. And if the caregiver in the room is overwhelmed or frustrated by having to put cream on twice a day, I’ll use this to advance treatment.
What resources are available for dermatologists interested in improving their geriatric dermatology skills or advancing the area?
For those interested in investigating these issues or improving their practices, the AAD’s Geriatric Dermatology ERG is always welcoming of new members. The ERG will have an all-inclusive meeting at the 2025 annual AAD meeting in March.
The AAD also has educational modules on geriatric dermatology that were recently published as an initiative of our ERG. More information is available on the website. Also valuable is the ElderDerm conference hosted by the George Washington University School of Medicine and Health Sciences, Washington, DC; the second such conference takes place in May 2025.
Butler reported that he had no relevant financial disclosures.
A version of this article appeared on Medscape.com.
Ob.Gyn. Says Collaboration with Dermatologists Essential for Managing Vulvar Dermatoses
— and she believes collaboration with dermatologists is essential, especially for complex cases in what she calls a neglected, data-poor area of medicine.
She also recommends that dermatologists have a good understanding of the vestibule, “one of the most important structures in vulvar medicine,” and that they become equipped to recognize generalized and localized causes of vulvar pain and/or itch.
“The problem is, we don’t talk about [vulvovaginal pain and itch] ... it’s taboo and we’re not taught about it in medical school,” Cigna, assistant professor of obstetrics and gynecology at The George Washington University (GWU), Washington, DC, said in a grand rounds lecture held recently at the GWU School of Medicine and Health Sciences Department of Dermatology.
“There are dermatologists who don’t have much training in vulvar dermatology, and a lot of gyns don’t get as much training” as they should, she said in an interview after the lecture. “So who’s looking at people’s vulvar skin and figuring out what’s going on and giving them effective treatments and evidence-based education?”
Cigna and dermatologist Emily Murphy, MD, will be co-directors of a joint ob.gyn-dermatology Vulvar Dermatology Clinic at GWU that will be launched in 2025, with monthly clinics for particularly challenging cases where the etiology is unclear or treatment is ineffective. “We want to collaborate in a more systematic way and put our heads together and think creatively about what will improve patient care,” Cigna said in the interview.
Dermatologists have valuable expertise in the immunology and genetic factors involved in skin disorders, Cigna said. Moreover, Murphy, assistant professor of dermatology and director of the Vulvar Health Program at GWU, said in an interview, dermatologists “are comfortable in going to off-label systemic medications that ob.gyns may not use that often” and bring to the table expertise in various types of procedures.
Murphy recently trained with Melissa Mauskar, MD, associate of dermatology and obstetrics and gynecology at the University of Texas Southwestern, Dallas, and founder and director of the Gynecologic Dermatology Clinic there. “It’s so important for dermatologists to be involved. It just takes some extra training that residents aren’t getting right now,” said Murphy, a member of the newly formed Vulvar Dermatoses Research Consortium.
In her grand rounds lecture, Cigna offered pearls to dermatologists for approaching a history and exam and covered highlights of the diagnosis and treatment of various problems, from vulvar Candida infections and lichen simplex chronicus to vulvar lichen sclerosus (LS), vulvar lichen planus (LP), vulvar Crohn’s disease, pudendal neuralgia, and pelvic floor muscle spasm, as well as the role of mast cell proliferation in vulvar issues.
Approaching the History and Exam
A comprehensive history covers the start, duration, and location of pain and/or itching as well as a detailed timeline (such as timing of potential causes, including injuries or births) and symptoms (such as burning, cutting, aching, and stinging). The question of whether pain “is on the outside, at the entrance, or deeper inside” is “crucial, especially for those in dermatology,” Cigna emphasized.
“And if you’re seeing a patient for a vulvar condition, please ask them about sex. Ask, is this affecting your sexual or intimate life with your partner because this can also give you a clue about what’s going on and how you can help them,” she told the audience of dermatologists.
Queries about trauma history (physical and emotional/verbal), competitive sports (such as daily cycling, equestrian, and heavy weight lifting), endometriosis/gynecologic surgery, connective tissue disorders (such as Ehler-Danlos syndrome), and irritable bowel syndrome are all potentially important to consider. It is important to ask about anxiety, depression, and obsessive-compulsive disorder, which do not cause — but are highly associated with — vulvar dermatoses, she said.
A surprisingly large number of people with vulvovaginal issues are being diagnosed with Ehler-Danlos syndrome, so “I’m always asking, are you hypermobile because this might be affecting the musculoskeletal system, which might be affecting the pelvis,” Cigna said. “Anything that affects the pelvis can affect the vulva as well.”
The pelvic examination should be “offered” rather than assumed to be part of the exam, as part of a trauma-informed approach that is crucial for earning trust, she advised. “Just saying, ‘we’re going to talk, and then I can offer you an exam if you like’…patients like it. It helps them feel safer and more open.”
Many diagnoses are differentiated by eliciting pain on the anterior vs the posterior half of the vulvar vestibule — the part of the vulva that lies between the labia minora and is composed of nonkeratinized tissue with embryonic origins in the endoderm. “If you touch on the keratinized skin (of the vulva) and they don’t have pain, but on the vestibule they do have pain, and there is no pain inside the vagina, this suggests there is a vestibular problem,” said Cigna.
Pain/tenderness isolated to the posterior half of the vestibule suggests a muscular cause, and pain in both the posterior and anterior parts of the vestibule suggests a cause that is more systemic or diffuse, which could be a result of a hormonal issue such as one related to oral contraceptives or decreased testosterone, or a nerve-related process.
Cigna uses gentle swipes of a Q-tip moistened with water or gel to examine the vulva rather than a poke or touch, with the exception being the posterior vestibule, which overlies muscle insertion sites. “Make sure to get a baseline in remote areas such as the inner thigh, and always distinguish between ‘scratchy/sensitive’ sensations and pain,” she said, noting the value of having the patient hold a mirror on her inner thigh.
Causes of Vulvar Itch: Infectious and Noninfectious
With vulvar candidiasis, a common infectious cause of vulvar itch, “you have to ask if they’re also itching on the inside because if you treat them with a topical and you don’t treat the vaginal yeast infection that may be co-occurring, they’ll keep reseeding their vulvar skin,” Cigna said, “and it will never be fully treated.”
Candida albicans is the most common cause of vulvar or vulvovaginal candidiasis, and resistance to antifungals has been rising. Non-albicans Candida “tends to have even higher resistance rates,” she said. Ordering a sensitivity panel along with the culture is helpful, but “comprehensive vaginal biome” panels are generally not useful. “It’s hard to correlate the information clinically,” she said, “and there’s not always a lot of information about susceptibilities, which is what I really like to know.”
Cigna’s treatments for vaginal infections include miconazole, terconazole, and fluconazole (and occasionally, itraconazole or voriconazole — a “decision we don’t take lightly”). Vulvar treatments include nystatin ointment, clotrimazole cream, and miconazole cream. Often, optimal treatment involves addressing “both inside and out,” she said, noting the importance of also killing yeast in undergarment fabric.
“In my experience, Diflucan [oral fluconazole] doesn’t treat persistent vulvar cutaneous skin yeast well, so while I might try Diflucan, I typically use something topical as well,” she said. “And with vaginal yeast, we do use boric acid from time to time, especially for non-albicans species because it tends to be a little more effective.”
Noninfectious causes of vulvar itch include allergic, neuropathic, and muscular causes, as well as autoimmune dermatoses and mast cell activation syndrome. Well known in dermatology are acute contact dermatitis and lichen simplex chronicus — both characterized by induration, thickening, and a “puffy” erythematous appearance, and worsening of pruritus at night. What may be less appreciated is the long list of implicated allergens , including Always menstrual pads made of a plastic-containing “dry weave” material, Cigna said. There are at least several cotton-only, low-preservative feminine products available on the market, she noted.
Common Autoimmune Vulvar Dermatoses: LS and LP
Vulvar LS has traditionally been thought to affect mainly prepubertal and postmenopausal women, but the autoimmune condition is now known to affect more reproductive-age people with vulvas than previously appreciated, Cigna said.
And notably, in an observational web-based study of premenopausal women (aged 18-50 years) with biopsy-confirmed vulvar LS, the leading symptom was not itch but dyspareunia and tearing with intercourse. This means “we’re missing people,” said Cigna, an author of the study. “We think the reason we’re not seeing itch as commonly in this population is that itch is likely mediated by the low estrogen state of pre- and postmenopausal people.”
Vulvar LS also occurs in pregnancy, with symptoms that are either stable or decrease during pregnancy and increase in the postpartum period, as demonstrated in a recently published online survey.
Patients with vulvar LS can present with hypopigmentation, lichenification, and scarring and architectural changes, the latter of which can involve clitoral phimosis, labial resorption, and narrowing of the introitus. (The vaginal mucosa is unaffected.) The presentation can be subtle, especially in premenopausal women, and differentiation between LS, vitiligo, and yeast is sometimes necessary.
A timely biopsy-driven definitive diagnosis is important because vulvar LS increases the risk for cancer if it’s not adequately treated and because long-term steroid use can affect the accuracy of pathology reports. “We really care about keeping this disease in remission as much as possible,” Cigna said. Experts in the field recommend long-term maintenance therapy with a mid-ultra-potent steroid one to three times/week or an alternative. “I’ve just started using ruxolitinib cream, a Janus kinase (JAK) inhibitor, and tacrolimus, a calcineurin inhibitor,” she said.
With vulvar LP, based on current evidence, the risk for malignant transformation is low, but “it crosses into the vagina and can cause vaginal adhesions, so if you’re diagnosing someone with lichen planus, you need to make sure you’re talking with them about dilators, and if you’re not comfortable, send them to [gyn],” she said.
The use of vulvoscopy is important for one’s ability to see the fine Wickham’s striae that often characterize vulvar LP, she noted. Medical treatments for vulvar LP include topical calcineurin inhibitors, high-potency steroids, and JAK inhibitors.
Surgical treatment of vulvar granuloma fissuratum caused by vulvar LS is possible (when the patient is in complete remission, to prevent koebnerization), with daily post-op application of clobetasol and retraction of tissues, noted Cigna, the author of a study on vulvar lysis of adhesions.
With both LS and LP, Cigna said, “don’t forget (consideration of) hormones” as an adjunctive treatment, especially in postmenopausal women. “Patients in a low hormone state will have more flares.”
Vulvar Crohn’s
“We all have to know how to look for this,” Cigna said. “Unilateral or asymmetric swelling is classic, but don’t rule out the diagnosis if you see symmetric swelling.” Patients also typically have linear “knife-like” fissures or ulcerations, the vulva “is very indurated,” and “swelling is so intense, the patients are miserable,” she said.
Vulvar Crohn’s disease may precede intestinal disease in 20%-30% of patients, so referral to a gastroenterologist — and ideally subsequent collaboration — is important, as vulvar manifestations are treated with systemic medications typical for Crohn’s.
A biopsy is required for diagnosis, and the pathologist should be advised to look for lichenified squamous mucosa with the Touton giant cell reaction. “Vulvar Crohn’s is a rare enough disorder that if you don’t have an experienced or informed pathologist looking at your specimen, they may miss it because they won’t be looking for it,” Cigna added in the interview. “You should be really clear about what you’re looking for.”
Neuropathic Itch, Pelvic Floor Muscle Spasm
Patients with pudendal neuralgia — caused by an injured, entrapped, or irritated pudendal nerve (originating from S2-S4) — typically present with chronic vulvar and pelvic pain that is often unprovoked and worsens with sitting. Itching upon touch is often another symptom, and some patients describe a foreign body sensation. The cause is often trauma (such as an accident or childbirth-related) as opposed to myofascial irritation, Cigna explained in her lecture.
“Your exam will be largely normal, with no skin findings, so patients will get sent away if you don’t know to look for pudendal neuralgia by pressing on the pudendal nerve or doing (or referring for) a diagnostic nerve block,” Cigna added in the interview.
Persistent genital arousal disorder (PGAD) is “more global” in that it can also originate not only from the pudendal nerve but also from nerve roots higher in the spine or even from the brain. “People feel a sense of arousal, but some describe it as an itch,” Cigna said in her lecture, referring to a 2021 consensus document on PGAD/genito-pelvic dysesthesia by the International Society for the Study of Women’s Sexual Health as a valuable resource for understanding and managing the condition.
Diagnosis and treatment usually start with a pudendal nerve block with a combination of steroid and anesthetic. If this does not relieve arousal/itching, the next step may be an MRI to look higher in the spine.
Pelvic Floor Muscle Spasm
Vulvar pain, skin itching, and irritation can be symptoms of pelvic floor muscle spasm. “Oftentimes people come to me and say, ‘I have a dermatologic problem,’” Cigna said. “The skin may look red and erythematous, but it’s probably more likely a muscle problem when you’re not finding anything, and no amount of steroid will help the itch go away when the problem lies underneath.”
Co-occurring symptoms can include vaginal dryness, clitoral pain, urethral discomfort, bladder pain/irritation, increased urgency, constipation, and anal fissures. The first-line treatment approach is pelvic floor therapy.
“Pelvic floor therapy is not just for incontinence. It’s also for pain and discomfort from muscles,” she said, noting that most patients with vulvar disorders are referred for pelvic floor therapy. “Almost all of them end up having pelvic floor dysfunction because the pelvic floor muscles spasm whenever there’s pain or inflammation.”
A Cautionary Word on Vulvodynia, and a Mast Cell Paradigm to Explore
Vulvodynia is defined as persistent pain of at least 3 months’ duration with no clear cause. “These are the patients with no skin findings,” Cigna said. But in most cases, she said, careful investigation identifies causes that are musculoskeletal, hormonal, or nerve-related.
“It’s a term that’s thrown around a lot — it’s kind of a catchall. Yet it should be a small minority of patients who truly have a diagnosis of vulvodynia,” she said.
In the early stages of investigation is the idea that mast cell proliferation and mast cell activation may play a role in some cases of vulvar and vestibular pain and itching. “We see that some patients with vulvodynia and vestibulodynia have mast cells that are increased in number in the epithelium and beneath the epithelium, and nerve staining shows an increased number of nerve endings traveling into the epithelium,” Cigna said.
“We do diagnose some people clinically” based on urticaria and other symptoms suggestive of mast cell proliferation/activation (such as flushing, abdominal cramping, diarrhea, hypotensive syncope or near syncope, and tachycardia), and “then we send them to the allergist for testing,” Cigna said.
Cigna and Murphy have no relevant financial disclosures.
A version of this article appeared on Medscape.com.
— and she believes collaboration with dermatologists is essential, especially for complex cases in what she calls a neglected, data-poor area of medicine.
She also recommends that dermatologists have a good understanding of the vestibule, “one of the most important structures in vulvar medicine,” and that they become equipped to recognize generalized and localized causes of vulvar pain and/or itch.
“The problem is, we don’t talk about [vulvovaginal pain and itch] ... it’s taboo and we’re not taught about it in medical school,” Cigna, assistant professor of obstetrics and gynecology at The George Washington University (GWU), Washington, DC, said in a grand rounds lecture held recently at the GWU School of Medicine and Health Sciences Department of Dermatology.
“There are dermatologists who don’t have much training in vulvar dermatology, and a lot of gyns don’t get as much training” as they should, she said in an interview after the lecture. “So who’s looking at people’s vulvar skin and figuring out what’s going on and giving them effective treatments and evidence-based education?”
Cigna and dermatologist Emily Murphy, MD, will be co-directors of a joint ob.gyn-dermatology Vulvar Dermatology Clinic at GWU that will be launched in 2025, with monthly clinics for particularly challenging cases where the etiology is unclear or treatment is ineffective. “We want to collaborate in a more systematic way and put our heads together and think creatively about what will improve patient care,” Cigna said in the interview.
Dermatologists have valuable expertise in the immunology and genetic factors involved in skin disorders, Cigna said. Moreover, Murphy, assistant professor of dermatology and director of the Vulvar Health Program at GWU, said in an interview, dermatologists “are comfortable in going to off-label systemic medications that ob.gyns may not use that often” and bring to the table expertise in various types of procedures.
Murphy recently trained with Melissa Mauskar, MD, associate of dermatology and obstetrics and gynecology at the University of Texas Southwestern, Dallas, and founder and director of the Gynecologic Dermatology Clinic there. “It’s so important for dermatologists to be involved. It just takes some extra training that residents aren’t getting right now,” said Murphy, a member of the newly formed Vulvar Dermatoses Research Consortium.
In her grand rounds lecture, Cigna offered pearls to dermatologists for approaching a history and exam and covered highlights of the diagnosis and treatment of various problems, from vulvar Candida infections and lichen simplex chronicus to vulvar lichen sclerosus (LS), vulvar lichen planus (LP), vulvar Crohn’s disease, pudendal neuralgia, and pelvic floor muscle spasm, as well as the role of mast cell proliferation in vulvar issues.
Approaching the History and Exam
A comprehensive history covers the start, duration, and location of pain and/or itching as well as a detailed timeline (such as timing of potential causes, including injuries or births) and symptoms (such as burning, cutting, aching, and stinging). The question of whether pain “is on the outside, at the entrance, or deeper inside” is “crucial, especially for those in dermatology,” Cigna emphasized.
“And if you’re seeing a patient for a vulvar condition, please ask them about sex. Ask, is this affecting your sexual or intimate life with your partner because this can also give you a clue about what’s going on and how you can help them,” she told the audience of dermatologists.
Queries about trauma history (physical and emotional/verbal), competitive sports (such as daily cycling, equestrian, and heavy weight lifting), endometriosis/gynecologic surgery, connective tissue disorders (such as Ehler-Danlos syndrome), and irritable bowel syndrome are all potentially important to consider. It is important to ask about anxiety, depression, and obsessive-compulsive disorder, which do not cause — but are highly associated with — vulvar dermatoses, she said.
A surprisingly large number of people with vulvovaginal issues are being diagnosed with Ehler-Danlos syndrome, so “I’m always asking, are you hypermobile because this might be affecting the musculoskeletal system, which might be affecting the pelvis,” Cigna said. “Anything that affects the pelvis can affect the vulva as well.”
The pelvic examination should be “offered” rather than assumed to be part of the exam, as part of a trauma-informed approach that is crucial for earning trust, she advised. “Just saying, ‘we’re going to talk, and then I can offer you an exam if you like’…patients like it. It helps them feel safer and more open.”
Many diagnoses are differentiated by eliciting pain on the anterior vs the posterior half of the vulvar vestibule — the part of the vulva that lies between the labia minora and is composed of nonkeratinized tissue with embryonic origins in the endoderm. “If you touch on the keratinized skin (of the vulva) and they don’t have pain, but on the vestibule they do have pain, and there is no pain inside the vagina, this suggests there is a vestibular problem,” said Cigna.
Pain/tenderness isolated to the posterior half of the vestibule suggests a muscular cause, and pain in both the posterior and anterior parts of the vestibule suggests a cause that is more systemic or diffuse, which could be a result of a hormonal issue such as one related to oral contraceptives or decreased testosterone, or a nerve-related process.
Cigna uses gentle swipes of a Q-tip moistened with water or gel to examine the vulva rather than a poke or touch, with the exception being the posterior vestibule, which overlies muscle insertion sites. “Make sure to get a baseline in remote areas such as the inner thigh, and always distinguish between ‘scratchy/sensitive’ sensations and pain,” she said, noting the value of having the patient hold a mirror on her inner thigh.
Causes of Vulvar Itch: Infectious and Noninfectious
With vulvar candidiasis, a common infectious cause of vulvar itch, “you have to ask if they’re also itching on the inside because if you treat them with a topical and you don’t treat the vaginal yeast infection that may be co-occurring, they’ll keep reseeding their vulvar skin,” Cigna said, “and it will never be fully treated.”
Candida albicans is the most common cause of vulvar or vulvovaginal candidiasis, and resistance to antifungals has been rising. Non-albicans Candida “tends to have even higher resistance rates,” she said. Ordering a sensitivity panel along with the culture is helpful, but “comprehensive vaginal biome” panels are generally not useful. “It’s hard to correlate the information clinically,” she said, “and there’s not always a lot of information about susceptibilities, which is what I really like to know.”
Cigna’s treatments for vaginal infections include miconazole, terconazole, and fluconazole (and occasionally, itraconazole or voriconazole — a “decision we don’t take lightly”). Vulvar treatments include nystatin ointment, clotrimazole cream, and miconazole cream. Often, optimal treatment involves addressing “both inside and out,” she said, noting the importance of also killing yeast in undergarment fabric.
“In my experience, Diflucan [oral fluconazole] doesn’t treat persistent vulvar cutaneous skin yeast well, so while I might try Diflucan, I typically use something topical as well,” she said. “And with vaginal yeast, we do use boric acid from time to time, especially for non-albicans species because it tends to be a little more effective.”
Noninfectious causes of vulvar itch include allergic, neuropathic, and muscular causes, as well as autoimmune dermatoses and mast cell activation syndrome. Well known in dermatology are acute contact dermatitis and lichen simplex chronicus — both characterized by induration, thickening, and a “puffy” erythematous appearance, and worsening of pruritus at night. What may be less appreciated is the long list of implicated allergens , including Always menstrual pads made of a plastic-containing “dry weave” material, Cigna said. There are at least several cotton-only, low-preservative feminine products available on the market, she noted.
Common Autoimmune Vulvar Dermatoses: LS and LP
Vulvar LS has traditionally been thought to affect mainly prepubertal and postmenopausal women, but the autoimmune condition is now known to affect more reproductive-age people with vulvas than previously appreciated, Cigna said.
And notably, in an observational web-based study of premenopausal women (aged 18-50 years) with biopsy-confirmed vulvar LS, the leading symptom was not itch but dyspareunia and tearing with intercourse. This means “we’re missing people,” said Cigna, an author of the study. “We think the reason we’re not seeing itch as commonly in this population is that itch is likely mediated by the low estrogen state of pre- and postmenopausal people.”
Vulvar LS also occurs in pregnancy, with symptoms that are either stable or decrease during pregnancy and increase in the postpartum period, as demonstrated in a recently published online survey.
Patients with vulvar LS can present with hypopigmentation, lichenification, and scarring and architectural changes, the latter of which can involve clitoral phimosis, labial resorption, and narrowing of the introitus. (The vaginal mucosa is unaffected.) The presentation can be subtle, especially in premenopausal women, and differentiation between LS, vitiligo, and yeast is sometimes necessary.
A timely biopsy-driven definitive diagnosis is important because vulvar LS increases the risk for cancer if it’s not adequately treated and because long-term steroid use can affect the accuracy of pathology reports. “We really care about keeping this disease in remission as much as possible,” Cigna said. Experts in the field recommend long-term maintenance therapy with a mid-ultra-potent steroid one to three times/week or an alternative. “I’ve just started using ruxolitinib cream, a Janus kinase (JAK) inhibitor, and tacrolimus, a calcineurin inhibitor,” she said.
With vulvar LP, based on current evidence, the risk for malignant transformation is low, but “it crosses into the vagina and can cause vaginal adhesions, so if you’re diagnosing someone with lichen planus, you need to make sure you’re talking with them about dilators, and if you’re not comfortable, send them to [gyn],” she said.
The use of vulvoscopy is important for one’s ability to see the fine Wickham’s striae that often characterize vulvar LP, she noted. Medical treatments for vulvar LP include topical calcineurin inhibitors, high-potency steroids, and JAK inhibitors.
Surgical treatment of vulvar granuloma fissuratum caused by vulvar LS is possible (when the patient is in complete remission, to prevent koebnerization), with daily post-op application of clobetasol and retraction of tissues, noted Cigna, the author of a study on vulvar lysis of adhesions.
With both LS and LP, Cigna said, “don’t forget (consideration of) hormones” as an adjunctive treatment, especially in postmenopausal women. “Patients in a low hormone state will have more flares.”
Vulvar Crohn’s
“We all have to know how to look for this,” Cigna said. “Unilateral or asymmetric swelling is classic, but don’t rule out the diagnosis if you see symmetric swelling.” Patients also typically have linear “knife-like” fissures or ulcerations, the vulva “is very indurated,” and “swelling is so intense, the patients are miserable,” she said.
Vulvar Crohn’s disease may precede intestinal disease in 20%-30% of patients, so referral to a gastroenterologist — and ideally subsequent collaboration — is important, as vulvar manifestations are treated with systemic medications typical for Crohn’s.
A biopsy is required for diagnosis, and the pathologist should be advised to look for lichenified squamous mucosa with the Touton giant cell reaction. “Vulvar Crohn’s is a rare enough disorder that if you don’t have an experienced or informed pathologist looking at your specimen, they may miss it because they won’t be looking for it,” Cigna added in the interview. “You should be really clear about what you’re looking for.”
Neuropathic Itch, Pelvic Floor Muscle Spasm
Patients with pudendal neuralgia — caused by an injured, entrapped, or irritated pudendal nerve (originating from S2-S4) — typically present with chronic vulvar and pelvic pain that is often unprovoked and worsens with sitting. Itching upon touch is often another symptom, and some patients describe a foreign body sensation. The cause is often trauma (such as an accident or childbirth-related) as opposed to myofascial irritation, Cigna explained in her lecture.
“Your exam will be largely normal, with no skin findings, so patients will get sent away if you don’t know to look for pudendal neuralgia by pressing on the pudendal nerve or doing (or referring for) a diagnostic nerve block,” Cigna added in the interview.
Persistent genital arousal disorder (PGAD) is “more global” in that it can also originate not only from the pudendal nerve but also from nerve roots higher in the spine or even from the brain. “People feel a sense of arousal, but some describe it as an itch,” Cigna said in her lecture, referring to a 2021 consensus document on PGAD/genito-pelvic dysesthesia by the International Society for the Study of Women’s Sexual Health as a valuable resource for understanding and managing the condition.
Diagnosis and treatment usually start with a pudendal nerve block with a combination of steroid and anesthetic. If this does not relieve arousal/itching, the next step may be an MRI to look higher in the spine.
Pelvic Floor Muscle Spasm
Vulvar pain, skin itching, and irritation can be symptoms of pelvic floor muscle spasm. “Oftentimes people come to me and say, ‘I have a dermatologic problem,’” Cigna said. “The skin may look red and erythematous, but it’s probably more likely a muscle problem when you’re not finding anything, and no amount of steroid will help the itch go away when the problem lies underneath.”
Co-occurring symptoms can include vaginal dryness, clitoral pain, urethral discomfort, bladder pain/irritation, increased urgency, constipation, and anal fissures. The first-line treatment approach is pelvic floor therapy.
“Pelvic floor therapy is not just for incontinence. It’s also for pain and discomfort from muscles,” she said, noting that most patients with vulvar disorders are referred for pelvic floor therapy. “Almost all of them end up having pelvic floor dysfunction because the pelvic floor muscles spasm whenever there’s pain or inflammation.”
A Cautionary Word on Vulvodynia, and a Mast Cell Paradigm to Explore
Vulvodynia is defined as persistent pain of at least 3 months’ duration with no clear cause. “These are the patients with no skin findings,” Cigna said. But in most cases, she said, careful investigation identifies causes that are musculoskeletal, hormonal, or nerve-related.
“It’s a term that’s thrown around a lot — it’s kind of a catchall. Yet it should be a small minority of patients who truly have a diagnosis of vulvodynia,” she said.
In the early stages of investigation is the idea that mast cell proliferation and mast cell activation may play a role in some cases of vulvar and vestibular pain and itching. “We see that some patients with vulvodynia and vestibulodynia have mast cells that are increased in number in the epithelium and beneath the epithelium, and nerve staining shows an increased number of nerve endings traveling into the epithelium,” Cigna said.
“We do diagnose some people clinically” based on urticaria and other symptoms suggestive of mast cell proliferation/activation (such as flushing, abdominal cramping, diarrhea, hypotensive syncope or near syncope, and tachycardia), and “then we send them to the allergist for testing,” Cigna said.
Cigna and Murphy have no relevant financial disclosures.
A version of this article appeared on Medscape.com.
— and she believes collaboration with dermatologists is essential, especially for complex cases in what she calls a neglected, data-poor area of medicine.
She also recommends that dermatologists have a good understanding of the vestibule, “one of the most important structures in vulvar medicine,” and that they become equipped to recognize generalized and localized causes of vulvar pain and/or itch.
“The problem is, we don’t talk about [vulvovaginal pain and itch] ... it’s taboo and we’re not taught about it in medical school,” Cigna, assistant professor of obstetrics and gynecology at The George Washington University (GWU), Washington, DC, said in a grand rounds lecture held recently at the GWU School of Medicine and Health Sciences Department of Dermatology.
“There are dermatologists who don’t have much training in vulvar dermatology, and a lot of gyns don’t get as much training” as they should, she said in an interview after the lecture. “So who’s looking at people’s vulvar skin and figuring out what’s going on and giving them effective treatments and evidence-based education?”
Cigna and dermatologist Emily Murphy, MD, will be co-directors of a joint ob.gyn-dermatology Vulvar Dermatology Clinic at GWU that will be launched in 2025, with monthly clinics for particularly challenging cases where the etiology is unclear or treatment is ineffective. “We want to collaborate in a more systematic way and put our heads together and think creatively about what will improve patient care,” Cigna said in the interview.
Dermatologists have valuable expertise in the immunology and genetic factors involved in skin disorders, Cigna said. Moreover, Murphy, assistant professor of dermatology and director of the Vulvar Health Program at GWU, said in an interview, dermatologists “are comfortable in going to off-label systemic medications that ob.gyns may not use that often” and bring to the table expertise in various types of procedures.
Murphy recently trained with Melissa Mauskar, MD, associate of dermatology and obstetrics and gynecology at the University of Texas Southwestern, Dallas, and founder and director of the Gynecologic Dermatology Clinic there. “It’s so important for dermatologists to be involved. It just takes some extra training that residents aren’t getting right now,” said Murphy, a member of the newly formed Vulvar Dermatoses Research Consortium.
In her grand rounds lecture, Cigna offered pearls to dermatologists for approaching a history and exam and covered highlights of the diagnosis and treatment of various problems, from vulvar Candida infections and lichen simplex chronicus to vulvar lichen sclerosus (LS), vulvar lichen planus (LP), vulvar Crohn’s disease, pudendal neuralgia, and pelvic floor muscle spasm, as well as the role of mast cell proliferation in vulvar issues.
Approaching the History and Exam
A comprehensive history covers the start, duration, and location of pain and/or itching as well as a detailed timeline (such as timing of potential causes, including injuries or births) and symptoms (such as burning, cutting, aching, and stinging). The question of whether pain “is on the outside, at the entrance, or deeper inside” is “crucial, especially for those in dermatology,” Cigna emphasized.
“And if you’re seeing a patient for a vulvar condition, please ask them about sex. Ask, is this affecting your sexual or intimate life with your partner because this can also give you a clue about what’s going on and how you can help them,” she told the audience of dermatologists.
Queries about trauma history (physical and emotional/verbal), competitive sports (such as daily cycling, equestrian, and heavy weight lifting), endometriosis/gynecologic surgery, connective tissue disorders (such as Ehler-Danlos syndrome), and irritable bowel syndrome are all potentially important to consider. It is important to ask about anxiety, depression, and obsessive-compulsive disorder, which do not cause — but are highly associated with — vulvar dermatoses, she said.
A surprisingly large number of people with vulvovaginal issues are being diagnosed with Ehler-Danlos syndrome, so “I’m always asking, are you hypermobile because this might be affecting the musculoskeletal system, which might be affecting the pelvis,” Cigna said. “Anything that affects the pelvis can affect the vulva as well.”
The pelvic examination should be “offered” rather than assumed to be part of the exam, as part of a trauma-informed approach that is crucial for earning trust, she advised. “Just saying, ‘we’re going to talk, and then I can offer you an exam if you like’…patients like it. It helps them feel safer and more open.”
Many diagnoses are differentiated by eliciting pain on the anterior vs the posterior half of the vulvar vestibule — the part of the vulva that lies between the labia minora and is composed of nonkeratinized tissue with embryonic origins in the endoderm. “If you touch on the keratinized skin (of the vulva) and they don’t have pain, but on the vestibule they do have pain, and there is no pain inside the vagina, this suggests there is a vestibular problem,” said Cigna.
Pain/tenderness isolated to the posterior half of the vestibule suggests a muscular cause, and pain in both the posterior and anterior parts of the vestibule suggests a cause that is more systemic or diffuse, which could be a result of a hormonal issue such as one related to oral contraceptives or decreased testosterone, or a nerve-related process.
Cigna uses gentle swipes of a Q-tip moistened with water or gel to examine the vulva rather than a poke or touch, with the exception being the posterior vestibule, which overlies muscle insertion sites. “Make sure to get a baseline in remote areas such as the inner thigh, and always distinguish between ‘scratchy/sensitive’ sensations and pain,” she said, noting the value of having the patient hold a mirror on her inner thigh.
Causes of Vulvar Itch: Infectious and Noninfectious
With vulvar candidiasis, a common infectious cause of vulvar itch, “you have to ask if they’re also itching on the inside because if you treat them with a topical and you don’t treat the vaginal yeast infection that may be co-occurring, they’ll keep reseeding their vulvar skin,” Cigna said, “and it will never be fully treated.”
Candida albicans is the most common cause of vulvar or vulvovaginal candidiasis, and resistance to antifungals has been rising. Non-albicans Candida “tends to have even higher resistance rates,” she said. Ordering a sensitivity panel along with the culture is helpful, but “comprehensive vaginal biome” panels are generally not useful. “It’s hard to correlate the information clinically,” she said, “and there’s not always a lot of information about susceptibilities, which is what I really like to know.”
Cigna’s treatments for vaginal infections include miconazole, terconazole, and fluconazole (and occasionally, itraconazole or voriconazole — a “decision we don’t take lightly”). Vulvar treatments include nystatin ointment, clotrimazole cream, and miconazole cream. Often, optimal treatment involves addressing “both inside and out,” she said, noting the importance of also killing yeast in undergarment fabric.
“In my experience, Diflucan [oral fluconazole] doesn’t treat persistent vulvar cutaneous skin yeast well, so while I might try Diflucan, I typically use something topical as well,” she said. “And with vaginal yeast, we do use boric acid from time to time, especially for non-albicans species because it tends to be a little more effective.”
Noninfectious causes of vulvar itch include allergic, neuropathic, and muscular causes, as well as autoimmune dermatoses and mast cell activation syndrome. Well known in dermatology are acute contact dermatitis and lichen simplex chronicus — both characterized by induration, thickening, and a “puffy” erythematous appearance, and worsening of pruritus at night. What may be less appreciated is the long list of implicated allergens , including Always menstrual pads made of a plastic-containing “dry weave” material, Cigna said. There are at least several cotton-only, low-preservative feminine products available on the market, she noted.
Common Autoimmune Vulvar Dermatoses: LS and LP
Vulvar LS has traditionally been thought to affect mainly prepubertal and postmenopausal women, but the autoimmune condition is now known to affect more reproductive-age people with vulvas than previously appreciated, Cigna said.
And notably, in an observational web-based study of premenopausal women (aged 18-50 years) with biopsy-confirmed vulvar LS, the leading symptom was not itch but dyspareunia and tearing with intercourse. This means “we’re missing people,” said Cigna, an author of the study. “We think the reason we’re not seeing itch as commonly in this population is that itch is likely mediated by the low estrogen state of pre- and postmenopausal people.”
Vulvar LS also occurs in pregnancy, with symptoms that are either stable or decrease during pregnancy and increase in the postpartum period, as demonstrated in a recently published online survey.
Patients with vulvar LS can present with hypopigmentation, lichenification, and scarring and architectural changes, the latter of which can involve clitoral phimosis, labial resorption, and narrowing of the introitus. (The vaginal mucosa is unaffected.) The presentation can be subtle, especially in premenopausal women, and differentiation between LS, vitiligo, and yeast is sometimes necessary.
A timely biopsy-driven definitive diagnosis is important because vulvar LS increases the risk for cancer if it’s not adequately treated and because long-term steroid use can affect the accuracy of pathology reports. “We really care about keeping this disease in remission as much as possible,” Cigna said. Experts in the field recommend long-term maintenance therapy with a mid-ultra-potent steroid one to three times/week or an alternative. “I’ve just started using ruxolitinib cream, a Janus kinase (JAK) inhibitor, and tacrolimus, a calcineurin inhibitor,” she said.
With vulvar LP, based on current evidence, the risk for malignant transformation is low, but “it crosses into the vagina and can cause vaginal adhesions, so if you’re diagnosing someone with lichen planus, you need to make sure you’re talking with them about dilators, and if you’re not comfortable, send them to [gyn],” she said.
The use of vulvoscopy is important for one’s ability to see the fine Wickham’s striae that often characterize vulvar LP, she noted. Medical treatments for vulvar LP include topical calcineurin inhibitors, high-potency steroids, and JAK inhibitors.
Surgical treatment of vulvar granuloma fissuratum caused by vulvar LS is possible (when the patient is in complete remission, to prevent koebnerization), with daily post-op application of clobetasol and retraction of tissues, noted Cigna, the author of a study on vulvar lysis of adhesions.
With both LS and LP, Cigna said, “don’t forget (consideration of) hormones” as an adjunctive treatment, especially in postmenopausal women. “Patients in a low hormone state will have more flares.”
Vulvar Crohn’s
“We all have to know how to look for this,” Cigna said. “Unilateral or asymmetric swelling is classic, but don’t rule out the diagnosis if you see symmetric swelling.” Patients also typically have linear “knife-like” fissures or ulcerations, the vulva “is very indurated,” and “swelling is so intense, the patients are miserable,” she said.
Vulvar Crohn’s disease may precede intestinal disease in 20%-30% of patients, so referral to a gastroenterologist — and ideally subsequent collaboration — is important, as vulvar manifestations are treated with systemic medications typical for Crohn’s.
A biopsy is required for diagnosis, and the pathologist should be advised to look for lichenified squamous mucosa with the Touton giant cell reaction. “Vulvar Crohn’s is a rare enough disorder that if you don’t have an experienced or informed pathologist looking at your specimen, they may miss it because they won’t be looking for it,” Cigna added in the interview. “You should be really clear about what you’re looking for.”
Neuropathic Itch, Pelvic Floor Muscle Spasm
Patients with pudendal neuralgia — caused by an injured, entrapped, or irritated pudendal nerve (originating from S2-S4) — typically present with chronic vulvar and pelvic pain that is often unprovoked and worsens with sitting. Itching upon touch is often another symptom, and some patients describe a foreign body sensation. The cause is often trauma (such as an accident or childbirth-related) as opposed to myofascial irritation, Cigna explained in her lecture.
“Your exam will be largely normal, with no skin findings, so patients will get sent away if you don’t know to look for pudendal neuralgia by pressing on the pudendal nerve or doing (or referring for) a diagnostic nerve block,” Cigna added in the interview.
Persistent genital arousal disorder (PGAD) is “more global” in that it can also originate not only from the pudendal nerve but also from nerve roots higher in the spine or even from the brain. “People feel a sense of arousal, but some describe it as an itch,” Cigna said in her lecture, referring to a 2021 consensus document on PGAD/genito-pelvic dysesthesia by the International Society for the Study of Women’s Sexual Health as a valuable resource for understanding and managing the condition.
Diagnosis and treatment usually start with a pudendal nerve block with a combination of steroid and anesthetic. If this does not relieve arousal/itching, the next step may be an MRI to look higher in the spine.
Pelvic Floor Muscle Spasm
Vulvar pain, skin itching, and irritation can be symptoms of pelvic floor muscle spasm. “Oftentimes people come to me and say, ‘I have a dermatologic problem,’” Cigna said. “The skin may look red and erythematous, but it’s probably more likely a muscle problem when you’re not finding anything, and no amount of steroid will help the itch go away when the problem lies underneath.”
Co-occurring symptoms can include vaginal dryness, clitoral pain, urethral discomfort, bladder pain/irritation, increased urgency, constipation, and anal fissures. The first-line treatment approach is pelvic floor therapy.
“Pelvic floor therapy is not just for incontinence. It’s also for pain and discomfort from muscles,” she said, noting that most patients with vulvar disorders are referred for pelvic floor therapy. “Almost all of them end up having pelvic floor dysfunction because the pelvic floor muscles spasm whenever there’s pain or inflammation.”
A Cautionary Word on Vulvodynia, and a Mast Cell Paradigm to Explore
Vulvodynia is defined as persistent pain of at least 3 months’ duration with no clear cause. “These are the patients with no skin findings,” Cigna said. But in most cases, she said, careful investigation identifies causes that are musculoskeletal, hormonal, or nerve-related.
“It’s a term that’s thrown around a lot — it’s kind of a catchall. Yet it should be a small minority of patients who truly have a diagnosis of vulvodynia,” she said.
In the early stages of investigation is the idea that mast cell proliferation and mast cell activation may play a role in some cases of vulvar and vestibular pain and itching. “We see that some patients with vulvodynia and vestibulodynia have mast cells that are increased in number in the epithelium and beneath the epithelium, and nerve staining shows an increased number of nerve endings traveling into the epithelium,” Cigna said.
“We do diagnose some people clinically” based on urticaria and other symptoms suggestive of mast cell proliferation/activation (such as flushing, abdominal cramping, diarrhea, hypotensive syncope or near syncope, and tachycardia), and “then we send them to the allergist for testing,” Cigna said.
Cigna and Murphy have no relevant financial disclosures.
A version of this article appeared on Medscape.com.
Diagnosing, Treating Rashes In Patients on Immune Checkpoint Inhibitors
WASHINGTON, DC — and with judicious usage and dosing of prednisone when deemed necessary, Blair Allais, MD, said during a session on supportive oncodermatology at the ElderDerm conference on dermatology in the older patient hosted by the George Washington University School of Medicine and Health Sciences, Washington, DC.
“It’s important when you see these patients to be as specific as possible” based on morphology and histopathology, and to treat the rashes in a similar way as in the non-ICI setting,” said Dr. Allais, a dermato-oncologist at the Inova Schar Cancer Institute, Fairfax, Virginia.
cirAEs are the most frequently reported and most visible adverse effects of checkpoint inhibition — a treatment that has emerged as a standard therapy for many malignancies since the first ICI was approved in 2011 for metastatic melanoma.
And contrary to what the phenomenon of immunosenescence might suggest, older patients are no less prone to cirAEs than younger patients. “You’d think you’d have fewer rashes and side effects as you age, but that’s not true,” said Dr. Allais, who completed a fellowship in cutaneous oncology after her dermatology residency.
A 2021 multicenter international cohort study of over 900 patients aged ≥ 80 years treated with single-agent ICIs for cancer did not find any significant differences in the development of immune-related adverse events among those younger than 85, those aged 85-89 years, and those 90 and older. Neither did the ELDERS study in the United Kingdom; this prospective observational study found similar rates of high-grade and low-grade immune toxicity in its two cohorts of patients ≥ 70 and < 70 years of age.
At the meeting, Dr. Allais, who coauthored a 2023 review of cirAEs from ICIs, reviewed recent developments and provided the following advice:
New diagnostic criteria: “Really exciting” news for more precise diagnosis and optimal therapy of cirAEs, Dr. Allais said, is a position paper published in the Journal for ImmunoTherapy of Cancer that offers consensus-based diagnostic criteria for the 10 most common types of dermatologic immune-related adverse events and an overall diagnostic framework. “Luckily, through the work of a Delphi consensus group, we can now have [more diagnostic specificity],” which is important for both clinical care and research, she said.
Most cirAEs have typically been reported nonspecifically as “rash,” but diagnosing a rash subtype is “critical in tailoring appropriate therapy that it is both effective and the least detrimental to the oncology treatment plan for patients with cancer,” the group’s coauthors wrote.
The 10 core diagnoses include psoriasis, eczematous dermatitis, vitiligo, Grover disease, eruptive atypical squamous proliferation, and bullous pemphigoid. Outside of the core diagnoses are other nonspecific presentations that require evaluation to arrive at a diagnosis, if possible, or to reveal data that can allow for targeted therapy and severity grading, the group explains in its paper.
“To prednisone or not to prednisone”: The development of cirAEs is associated with reduced mortality and improved cancer outcomes, making the use of immunosuppressants such as corticosteroids a therapeutic dilemma. “Patients who get these rashes usually do better with respect to their cancer, so the concern has been, if we affect how they respond to their immunotherapy, we may minimize that improvement in mortality,” said Dr. Allais, also assistant professor at the University of Virginia, Charlottesville, and clinical assistant professor of dermatology at George Washington University.
A widely discussed study published in 2015 reported on 254 patients with melanoma who developed an immune-related adverse event during treatment with ipilimumab — approximately one third of whom required systemic corticosteroids — and concluded that systemic corticosteroids did not affect overall survival or time to (cancer) treatment failure. This study from Memorial Sloan Kettering Cancer Center, New York City, “was the first large study looking at this question,” she said, and the subsequent message for several years in conferences and the literature was that steroids do not affect the efficacy of checkpoint inhibitors.
“But the study was not without limitations,” Dr. Allais said, “because the patients who got prednisone were mainly those with higher-grade toxicities,” while those not treated with corticosteroids had either no toxicities or low-grade toxicities. “If higher-grade toxicities were associated with better (antitumor) response, the steroids may have just [blunted] that benefit.”
The current totality of data available in the literature suggests that corticosteroids may indeed have an impact on the efficacy of ICI therapy. “Subsequent studies have come out in the community that have shown that we should probably think twice about giving prednisone to some patients, particularly within the first 50 days of ICI treatment, and that we should be mindful of the dose,” Dr. Allais said.
The takeaways from these studies — all published in the past few years — are to use prednisone early and liberally for life-threatening toxicity, to use it at the lowest dose and for the shortest course when there is not an appropriate alternative, to avoid it for diagnoses that are not treated with prednisone outside the ICI setting, and to “have a plan” for a steroid-sparing agent to use after prednisone, she said.
Dr. Allais recommends heightened consideration during the first 50 days of ICI treatment based on a multicenter retrospective study that found a significant association between use of high-dose glucocorticoids (≥ 60 mg prednisone equivalent once a day) within 8 weeks of anti–programmed cell death protein 1 (PD-1) monotherapy initiation and poorer progression-free and overall survival. The study covered a cohort of 947 patients with advanced melanoma treated with anti–PD-1 monotherapy between 2009 and 2019, 54% of whom developed immune-related adverse events.
This study and other recent studies addressing the association between steroids and survival outcomes in patients with immune-related adverse events during ICI therapy are described in Dr. Allais’ 2023 review of cirAEs from ICIs.
Approach to morbilliform eruptions: This rash is “super common” in patients on ICIs, occurring generally within 2-3 weeks of starting treatment. “It tends to be self-limited and can recur with future infusions,” Dr. Allais said.
Systemic steroids should be reserved for severe or refractory eruptions. “Usually, I treat the patients with topical steroids, and I manage their expectations (that the rash may recur with subsequent infusions), but I closely follow them up” within 2-3 weeks, she said. It’s important to rule out a severe cutaneous adverse drug eruption, of course, and to start high-dose systemic steroids immediately if necessary. “Antibiotics are a big culprit” and often can be discontinued.
Soak and smear: “I’m obsessed” with this technique of a 20-minute soak in plain water followed by application of steroid ointment, said Dr. Allais, referring to a small study published in 2005 that reported a complete response after 2 weeks in 60% of patients with psoriasis, atopic dermatitis, and other inflammatory skin conditions (none had cancer), who had failed prior systemic therapy. All patients had at least a 75% response.
The method offers a way to “avoid the systemic immunosuppression we’d get with prednisone,” she said. One just needs to make sure the older patient can get in and out of their tub safely.
ICI-induced bullous pemphigoid (BP): BP occurs more frequently in the ICI setting, compared with the general population, with a median time to development of 8.5 months after ICI initiation. It is associated in this setting with improved tumor response, but “many oncologists stop anticancer treatment because of this diagnosis,” she said.
In the supportive oncodermatology space, however, ICI-induced BP exemplifies the value of tailored treatment regimens, she said. A small multi-institutional retrospective cohort study published in 2023 identified 35 cases of ICI-BP among 5636 ICI-treated patients and found that 8 out of 11 patients who received biologic therapy (rituximab, omalizumab, or dupilumab) had a complete response to ICI-BP without flares following subsequent ICI cycles. And while statistical significance was not reached, the study showed that no cancer-related outcomes were worsened.
“If you see someone with ICI-induced BP and they have a lot of involvement, you could start them on steroids and get that steroid-sparing agent initiated for approval. ... And if IgE is elevated, you might reach for omalizumab,” said Dr. Allais, noting that her favored treatment overall is dupilumab.
Risk factors for the development of ICI-induced BP include age > 70, skin cancer, and having an initial response to ICI on first imaging, the latter of which “I find fascinating ... because imaging occurs within the first 12 weeks of treatment, but we don’t see BP popping up until 8.5 months into treatment,” she noted. “So maybe there’s a baseline risk factor that could predispose them.”
Caution with antibiotics: “I try to avoid antibiotics in the ICI setting,” Dr. Allais said, in deference to the “ever-important microbiome.” Studies have demonstrated that the microbiomes of responders to ICI treatment are different from those of nonresponders, she said.
And a “fascinating” study of patients with melanoma undergoing ICI therapy showed not only a higher abundance of Ruminococcaceae bacteria in responders vs nonresponders but a significant impact of dietary fiber. High dietary fiber was associated with significantly improved overall survival in the patients on ICI, with the most pronounced benefit in patients with good fiber intake and no probiotic use. “Even wilder, their T cells changed,” she said. “They had a high expression of genes related to T-cell activation ... so more tumor-infiltrating lymphocytes.”
A retrospective study of 568 patients with stages III and IV melanoma treated with ICI showed that those exposed to antibiotics prior to ICI had significantly worse overall survival than those not exposed to antibiotics. “Think before you give them,” Dr. Allais said. “And try to tell your older patients to eat beans and greens.”
Dr. Allais reported having no relevant disclosures.
A version of this article first appeared on Medscape.com.
WASHINGTON, DC — and with judicious usage and dosing of prednisone when deemed necessary, Blair Allais, MD, said during a session on supportive oncodermatology at the ElderDerm conference on dermatology in the older patient hosted by the George Washington University School of Medicine and Health Sciences, Washington, DC.
“It’s important when you see these patients to be as specific as possible” based on morphology and histopathology, and to treat the rashes in a similar way as in the non-ICI setting,” said Dr. Allais, a dermato-oncologist at the Inova Schar Cancer Institute, Fairfax, Virginia.
cirAEs are the most frequently reported and most visible adverse effects of checkpoint inhibition — a treatment that has emerged as a standard therapy for many malignancies since the first ICI was approved in 2011 for metastatic melanoma.
And contrary to what the phenomenon of immunosenescence might suggest, older patients are no less prone to cirAEs than younger patients. “You’d think you’d have fewer rashes and side effects as you age, but that’s not true,” said Dr. Allais, who completed a fellowship in cutaneous oncology after her dermatology residency.
A 2021 multicenter international cohort study of over 900 patients aged ≥ 80 years treated with single-agent ICIs for cancer did not find any significant differences in the development of immune-related adverse events among those younger than 85, those aged 85-89 years, and those 90 and older. Neither did the ELDERS study in the United Kingdom; this prospective observational study found similar rates of high-grade and low-grade immune toxicity in its two cohorts of patients ≥ 70 and < 70 years of age.
At the meeting, Dr. Allais, who coauthored a 2023 review of cirAEs from ICIs, reviewed recent developments and provided the following advice:
New diagnostic criteria: “Really exciting” news for more precise diagnosis and optimal therapy of cirAEs, Dr. Allais said, is a position paper published in the Journal for ImmunoTherapy of Cancer that offers consensus-based diagnostic criteria for the 10 most common types of dermatologic immune-related adverse events and an overall diagnostic framework. “Luckily, through the work of a Delphi consensus group, we can now have [more diagnostic specificity],” which is important for both clinical care and research, she said.
Most cirAEs have typically been reported nonspecifically as “rash,” but diagnosing a rash subtype is “critical in tailoring appropriate therapy that it is both effective and the least detrimental to the oncology treatment plan for patients with cancer,” the group’s coauthors wrote.
The 10 core diagnoses include psoriasis, eczematous dermatitis, vitiligo, Grover disease, eruptive atypical squamous proliferation, and bullous pemphigoid. Outside of the core diagnoses are other nonspecific presentations that require evaluation to arrive at a diagnosis, if possible, or to reveal data that can allow for targeted therapy and severity grading, the group explains in its paper.
“To prednisone or not to prednisone”: The development of cirAEs is associated with reduced mortality and improved cancer outcomes, making the use of immunosuppressants such as corticosteroids a therapeutic dilemma. “Patients who get these rashes usually do better with respect to their cancer, so the concern has been, if we affect how they respond to their immunotherapy, we may minimize that improvement in mortality,” said Dr. Allais, also assistant professor at the University of Virginia, Charlottesville, and clinical assistant professor of dermatology at George Washington University.
A widely discussed study published in 2015 reported on 254 patients with melanoma who developed an immune-related adverse event during treatment with ipilimumab — approximately one third of whom required systemic corticosteroids — and concluded that systemic corticosteroids did not affect overall survival or time to (cancer) treatment failure. This study from Memorial Sloan Kettering Cancer Center, New York City, “was the first large study looking at this question,” she said, and the subsequent message for several years in conferences and the literature was that steroids do not affect the efficacy of checkpoint inhibitors.
“But the study was not without limitations,” Dr. Allais said, “because the patients who got prednisone were mainly those with higher-grade toxicities,” while those not treated with corticosteroids had either no toxicities or low-grade toxicities. “If higher-grade toxicities were associated with better (antitumor) response, the steroids may have just [blunted] that benefit.”
The current totality of data available in the literature suggests that corticosteroids may indeed have an impact on the efficacy of ICI therapy. “Subsequent studies have come out in the community that have shown that we should probably think twice about giving prednisone to some patients, particularly within the first 50 days of ICI treatment, and that we should be mindful of the dose,” Dr. Allais said.
The takeaways from these studies — all published in the past few years — are to use prednisone early and liberally for life-threatening toxicity, to use it at the lowest dose and for the shortest course when there is not an appropriate alternative, to avoid it for diagnoses that are not treated with prednisone outside the ICI setting, and to “have a plan” for a steroid-sparing agent to use after prednisone, she said.
Dr. Allais recommends heightened consideration during the first 50 days of ICI treatment based on a multicenter retrospective study that found a significant association between use of high-dose glucocorticoids (≥ 60 mg prednisone equivalent once a day) within 8 weeks of anti–programmed cell death protein 1 (PD-1) monotherapy initiation and poorer progression-free and overall survival. The study covered a cohort of 947 patients with advanced melanoma treated with anti–PD-1 monotherapy between 2009 and 2019, 54% of whom developed immune-related adverse events.
This study and other recent studies addressing the association between steroids and survival outcomes in patients with immune-related adverse events during ICI therapy are described in Dr. Allais’ 2023 review of cirAEs from ICIs.
Approach to morbilliform eruptions: This rash is “super common” in patients on ICIs, occurring generally within 2-3 weeks of starting treatment. “It tends to be self-limited and can recur with future infusions,” Dr. Allais said.
Systemic steroids should be reserved for severe or refractory eruptions. “Usually, I treat the patients with topical steroids, and I manage their expectations (that the rash may recur with subsequent infusions), but I closely follow them up” within 2-3 weeks, she said. It’s important to rule out a severe cutaneous adverse drug eruption, of course, and to start high-dose systemic steroids immediately if necessary. “Antibiotics are a big culprit” and often can be discontinued.
Soak and smear: “I’m obsessed” with this technique of a 20-minute soak in plain water followed by application of steroid ointment, said Dr. Allais, referring to a small study published in 2005 that reported a complete response after 2 weeks in 60% of patients with psoriasis, atopic dermatitis, and other inflammatory skin conditions (none had cancer), who had failed prior systemic therapy. All patients had at least a 75% response.
The method offers a way to “avoid the systemic immunosuppression we’d get with prednisone,” she said. One just needs to make sure the older patient can get in and out of their tub safely.
ICI-induced bullous pemphigoid (BP): BP occurs more frequently in the ICI setting, compared with the general population, with a median time to development of 8.5 months after ICI initiation. It is associated in this setting with improved tumor response, but “many oncologists stop anticancer treatment because of this diagnosis,” she said.
In the supportive oncodermatology space, however, ICI-induced BP exemplifies the value of tailored treatment regimens, she said. A small multi-institutional retrospective cohort study published in 2023 identified 35 cases of ICI-BP among 5636 ICI-treated patients and found that 8 out of 11 patients who received biologic therapy (rituximab, omalizumab, or dupilumab) had a complete response to ICI-BP without flares following subsequent ICI cycles. And while statistical significance was not reached, the study showed that no cancer-related outcomes were worsened.
“If you see someone with ICI-induced BP and they have a lot of involvement, you could start them on steroids and get that steroid-sparing agent initiated for approval. ... And if IgE is elevated, you might reach for omalizumab,” said Dr. Allais, noting that her favored treatment overall is dupilumab.
Risk factors for the development of ICI-induced BP include age > 70, skin cancer, and having an initial response to ICI on first imaging, the latter of which “I find fascinating ... because imaging occurs within the first 12 weeks of treatment, but we don’t see BP popping up until 8.5 months into treatment,” she noted. “So maybe there’s a baseline risk factor that could predispose them.”
Caution with antibiotics: “I try to avoid antibiotics in the ICI setting,” Dr. Allais said, in deference to the “ever-important microbiome.” Studies have demonstrated that the microbiomes of responders to ICI treatment are different from those of nonresponders, she said.
And a “fascinating” study of patients with melanoma undergoing ICI therapy showed not only a higher abundance of Ruminococcaceae bacteria in responders vs nonresponders but a significant impact of dietary fiber. High dietary fiber was associated with significantly improved overall survival in the patients on ICI, with the most pronounced benefit in patients with good fiber intake and no probiotic use. “Even wilder, their T cells changed,” she said. “They had a high expression of genes related to T-cell activation ... so more tumor-infiltrating lymphocytes.”
A retrospective study of 568 patients with stages III and IV melanoma treated with ICI showed that those exposed to antibiotics prior to ICI had significantly worse overall survival than those not exposed to antibiotics. “Think before you give them,” Dr. Allais said. “And try to tell your older patients to eat beans and greens.”
Dr. Allais reported having no relevant disclosures.
A version of this article first appeared on Medscape.com.
WASHINGTON, DC — and with judicious usage and dosing of prednisone when deemed necessary, Blair Allais, MD, said during a session on supportive oncodermatology at the ElderDerm conference on dermatology in the older patient hosted by the George Washington University School of Medicine and Health Sciences, Washington, DC.
“It’s important when you see these patients to be as specific as possible” based on morphology and histopathology, and to treat the rashes in a similar way as in the non-ICI setting,” said Dr. Allais, a dermato-oncologist at the Inova Schar Cancer Institute, Fairfax, Virginia.
cirAEs are the most frequently reported and most visible adverse effects of checkpoint inhibition — a treatment that has emerged as a standard therapy for many malignancies since the first ICI was approved in 2011 for metastatic melanoma.
And contrary to what the phenomenon of immunosenescence might suggest, older patients are no less prone to cirAEs than younger patients. “You’d think you’d have fewer rashes and side effects as you age, but that’s not true,” said Dr. Allais, who completed a fellowship in cutaneous oncology after her dermatology residency.
A 2021 multicenter international cohort study of over 900 patients aged ≥ 80 years treated with single-agent ICIs for cancer did not find any significant differences in the development of immune-related adverse events among those younger than 85, those aged 85-89 years, and those 90 and older. Neither did the ELDERS study in the United Kingdom; this prospective observational study found similar rates of high-grade and low-grade immune toxicity in its two cohorts of patients ≥ 70 and < 70 years of age.
At the meeting, Dr. Allais, who coauthored a 2023 review of cirAEs from ICIs, reviewed recent developments and provided the following advice:
New diagnostic criteria: “Really exciting” news for more precise diagnosis and optimal therapy of cirAEs, Dr. Allais said, is a position paper published in the Journal for ImmunoTherapy of Cancer that offers consensus-based diagnostic criteria for the 10 most common types of dermatologic immune-related adverse events and an overall diagnostic framework. “Luckily, through the work of a Delphi consensus group, we can now have [more diagnostic specificity],” which is important for both clinical care and research, she said.
Most cirAEs have typically been reported nonspecifically as “rash,” but diagnosing a rash subtype is “critical in tailoring appropriate therapy that it is both effective and the least detrimental to the oncology treatment plan for patients with cancer,” the group’s coauthors wrote.
The 10 core diagnoses include psoriasis, eczematous dermatitis, vitiligo, Grover disease, eruptive atypical squamous proliferation, and bullous pemphigoid. Outside of the core diagnoses are other nonspecific presentations that require evaluation to arrive at a diagnosis, if possible, or to reveal data that can allow for targeted therapy and severity grading, the group explains in its paper.
“To prednisone or not to prednisone”: The development of cirAEs is associated with reduced mortality and improved cancer outcomes, making the use of immunosuppressants such as corticosteroids a therapeutic dilemma. “Patients who get these rashes usually do better with respect to their cancer, so the concern has been, if we affect how they respond to their immunotherapy, we may minimize that improvement in mortality,” said Dr. Allais, also assistant professor at the University of Virginia, Charlottesville, and clinical assistant professor of dermatology at George Washington University.
A widely discussed study published in 2015 reported on 254 patients with melanoma who developed an immune-related adverse event during treatment with ipilimumab — approximately one third of whom required systemic corticosteroids — and concluded that systemic corticosteroids did not affect overall survival or time to (cancer) treatment failure. This study from Memorial Sloan Kettering Cancer Center, New York City, “was the first large study looking at this question,” she said, and the subsequent message for several years in conferences and the literature was that steroids do not affect the efficacy of checkpoint inhibitors.
“But the study was not without limitations,” Dr. Allais said, “because the patients who got prednisone were mainly those with higher-grade toxicities,” while those not treated with corticosteroids had either no toxicities or low-grade toxicities. “If higher-grade toxicities were associated with better (antitumor) response, the steroids may have just [blunted] that benefit.”
The current totality of data available in the literature suggests that corticosteroids may indeed have an impact on the efficacy of ICI therapy. “Subsequent studies have come out in the community that have shown that we should probably think twice about giving prednisone to some patients, particularly within the first 50 days of ICI treatment, and that we should be mindful of the dose,” Dr. Allais said.
The takeaways from these studies — all published in the past few years — are to use prednisone early and liberally for life-threatening toxicity, to use it at the lowest dose and for the shortest course when there is not an appropriate alternative, to avoid it for diagnoses that are not treated with prednisone outside the ICI setting, and to “have a plan” for a steroid-sparing agent to use after prednisone, she said.
Dr. Allais recommends heightened consideration during the first 50 days of ICI treatment based on a multicenter retrospective study that found a significant association between use of high-dose glucocorticoids (≥ 60 mg prednisone equivalent once a day) within 8 weeks of anti–programmed cell death protein 1 (PD-1) monotherapy initiation and poorer progression-free and overall survival. The study covered a cohort of 947 patients with advanced melanoma treated with anti–PD-1 monotherapy between 2009 and 2019, 54% of whom developed immune-related adverse events.
This study and other recent studies addressing the association between steroids and survival outcomes in patients with immune-related adverse events during ICI therapy are described in Dr. Allais’ 2023 review of cirAEs from ICIs.
Approach to morbilliform eruptions: This rash is “super common” in patients on ICIs, occurring generally within 2-3 weeks of starting treatment. “It tends to be self-limited and can recur with future infusions,” Dr. Allais said.
Systemic steroids should be reserved for severe or refractory eruptions. “Usually, I treat the patients with topical steroids, and I manage their expectations (that the rash may recur with subsequent infusions), but I closely follow them up” within 2-3 weeks, she said. It’s important to rule out a severe cutaneous adverse drug eruption, of course, and to start high-dose systemic steroids immediately if necessary. “Antibiotics are a big culprit” and often can be discontinued.
Soak and smear: “I’m obsessed” with this technique of a 20-minute soak in plain water followed by application of steroid ointment, said Dr. Allais, referring to a small study published in 2005 that reported a complete response after 2 weeks in 60% of patients with psoriasis, atopic dermatitis, and other inflammatory skin conditions (none had cancer), who had failed prior systemic therapy. All patients had at least a 75% response.
The method offers a way to “avoid the systemic immunosuppression we’d get with prednisone,” she said. One just needs to make sure the older patient can get in and out of their tub safely.
ICI-induced bullous pemphigoid (BP): BP occurs more frequently in the ICI setting, compared with the general population, with a median time to development of 8.5 months after ICI initiation. It is associated in this setting with improved tumor response, but “many oncologists stop anticancer treatment because of this diagnosis,” she said.
In the supportive oncodermatology space, however, ICI-induced BP exemplifies the value of tailored treatment regimens, she said. A small multi-institutional retrospective cohort study published in 2023 identified 35 cases of ICI-BP among 5636 ICI-treated patients and found that 8 out of 11 patients who received biologic therapy (rituximab, omalizumab, or dupilumab) had a complete response to ICI-BP without flares following subsequent ICI cycles. And while statistical significance was not reached, the study showed that no cancer-related outcomes were worsened.
“If you see someone with ICI-induced BP and they have a lot of involvement, you could start them on steroids and get that steroid-sparing agent initiated for approval. ... And if IgE is elevated, you might reach for omalizumab,” said Dr. Allais, noting that her favored treatment overall is dupilumab.
Risk factors for the development of ICI-induced BP include age > 70, skin cancer, and having an initial response to ICI on first imaging, the latter of which “I find fascinating ... because imaging occurs within the first 12 weeks of treatment, but we don’t see BP popping up until 8.5 months into treatment,” she noted. “So maybe there’s a baseline risk factor that could predispose them.”
Caution with antibiotics: “I try to avoid antibiotics in the ICI setting,” Dr. Allais said, in deference to the “ever-important microbiome.” Studies have demonstrated that the microbiomes of responders to ICI treatment are different from those of nonresponders, she said.
And a “fascinating” study of patients with melanoma undergoing ICI therapy showed not only a higher abundance of Ruminococcaceae bacteria in responders vs nonresponders but a significant impact of dietary fiber. High dietary fiber was associated with significantly improved overall survival in the patients on ICI, with the most pronounced benefit in patients with good fiber intake and no probiotic use. “Even wilder, their T cells changed,” she said. “They had a high expression of genes related to T-cell activation ... so more tumor-infiltrating lymphocytes.”
A retrospective study of 568 patients with stages III and IV melanoma treated with ICI showed that those exposed to antibiotics prior to ICI had significantly worse overall survival than those not exposed to antibiotics. “Think before you give them,” Dr. Allais said. “And try to tell your older patients to eat beans and greens.”
Dr. Allais reported having no relevant disclosures.
A version of this article first appeared on Medscape.com.
FROM ELDERDERM 2024
Management, Evaluation of Chronic Itch in Older Adults
WASHINGTON — , Shawn G. Kwatra, MD, said at the ElderDerm conference on dermatology in older patients hosted by the GW School of Medicine & Health Sciences.
“We found a few years ago that eosinophils seem to differentiate this group, and now we’re finding that IgE and CBC [complete blood count] differential can help you get a little better sense of who has an immune-driven itch vs something more neuropathic,” said Dr. Kwatra, professor and chair of dermatology at the University of Maryland, Baltimore, who founded and directed the Johns Hopkins Itch Center before coming to the University of Maryland in 2023. Not all patients with immune-driven itch will have these biomarkers, “but it’s a helpful tool,” he said.
CPUO is the term that is increasingly being used, he said, to describe intense, chronic pruritus without primary skin lesions or rashes and without any known systemic cause. It becomes more common as people get older and is sometimes debilitating. The initial evaluation should be kept “simple and straightforward,” he advised, with heightened concern for underlying malignancy in those who present with an itch of less than 12 months’ duration.
Biologics, JAK Inhibitors: Case Reports, Ongoing Research
Research conducted by Dr. Kwatra and Jaya Manjunath, a fourth-year medical student at The George Washington University, Washington, documented higher levels of Th2-associated cytokines and inflammatory markers in patients with CPUO who had elevated IgE or eosinophil levels, or both than in patients with itch who had low IgE and eosinophil levels. The patients with higher levels also had a greater response to off-label treatment with immunomodulatory therapy.
“Multiple Th2-related inflammatory markers, like IL [interleukin]-5 and eotaxin-3, were reduced after dupilumab” in patients who responded to the therapy, said Ms. Manjunath, who co-presented the meeting session on chronic itch with Dr. Kwatra. Other changes in the plasma cytokine profile included a reduction in the serum level of thymus and activation-regulated chemokine, which is a biomarker for atopic dermatitis. The research is under review for publication.
Meanwhile, a phase 3 trial (LIBERTY-CPUO-CHIC) of dupilumab for CPUO is currently underway, Dr. Kwatra noted. Investigators are randomizing patients with severe pruritus (Worst Itch Numeric Rating Scale [WI-NRS] ≥ 7) to dupilumab or placebo for 12 or 24 weeks.
In one of several cases shared by Dr. Kwatra and Ms. Manjunath, a 71-year-old Black woman with a 6-month history of generalized itch (WI-NRS = 10) and a history of type 2 diabetes, hypertension, and chronic kidney disease was found to have elevated eosinophil levels and a negative malignancy workup. Previous therapies included antihistamines and topical steroids. She was started on a 600-mg loading dose of subcutaneous dupilumab followed by 300 mg every 14 days. At the 2-month follow-up, her WI-NRS score was 0.
Because “dupilumab is off label right now for this form of itch, oftentimes our first line is methotrexate,” Dr. Kwatra said. Patients “can have a good response with this therapeutic.”
He also described the case of a 72-year-old Black woman with total body itch for 2 years (WI-NRS = 10) and a history of seasonal allergies, thyroid disease, and hypertension. Previous therapies included prednisone, antihistamines, topical steroids, and gabapentin. The patient was found to have high IgE (447 kU/L) and eosinophil levels (4.9%), was started on methotrexate, and had an itch score of 0 at the 8-month follow-up.
JAK inhibitors may also have a role in the management of CPUO. A phase 2 nonrandomized controlled trial of abrocitinib for adults with prurigo nodularis (PN) or CPUO, recently published in JAMA Dermatology, showed itch scores decreased by 53.7% in the CPUO group (and 78.3% in the PN group) after 12 weeks of treatment with oral abrocitinib 200 mg daily. Patients had significant improvements in quality of life and no serious adverse events, said Dr. Kwatra, the lead author of the paper.
One of these patients was a 73-year-old White man who had experienced total body itch for 1.5 years (predominantly affecting his upper extremities; WI-NRS = 10) and a history of ascending aortic aneurysm, hypertension, and hyperlipidemia. Previous failed therapies included dupilumab (> 6 months), topical steroids, tacrolimus, and antihistamines. Labs showed elevated IgE (456 kU/L) and eosinophil levels (11.7%). After 12 weeks of treatment with abrocitinib, the WI-NRS decreased to 2.
PD-1 Inhibitors As a Trigger
Chronic pruritus caused by the anticancer PD-1 inhibitors is becoming more common as the utilization of these immune checkpoint inhibitors increases, Dr. Kwatra noted. “You don’t see much in the skin, but [these patients have] very high IgE and eosinophils,” he said. “We’ve been seeing more reports recently of utilizing agents that target type 2 inflammation off label for PD-1 inhibitor–related skin manifestations.”
One such patient with PD-1 inhibitor–induced pruritus was a 65-year-old White man with metastatic melanoma who reported a 6-month history of itching that began 3 weeks after the start of treatment with the PD-1 inhibitor pembrolizumab. His WI-NRS score was 10 despite treatment with topical steroids and antihistamines. He had a history of psoriasis. Labs showed elevated IgE (1350 kU/L) and eosinophil levels (4.5%). At a 4-month follow-up after treatment with off-label dupilumab (a 600-mg subcutaneous loading dose followed by 300 mg every 14 days), his WI-NRS score was 0.
In a paper recently published in JAAD International, Dr. Kwatra, Ms. Manjunath, and coinvestigators reported on a series of 15 patients who developed chronic pruritus following an immune stimulus exposure, including immunotherapy and vaccination (2024 Apr 7:16:97-102. doi: 10.1016/j.jdin.2024.03.022). Most immunotherapy-treated patients experienced pruritus during treatment or after 21-60 days of receiving treatment, and the patients with vaccine-stimulated pruritus (after Tdap and messenger RNA COVID-19 vaccination) developed pruritus within a week of vaccination.
In addition to the elevated levels of IgE and eosinophils, plasma cytokine analysis showed elevated levels of IL-5, thymic stromal lymphopoietin, and other Th2-related cytokines and inflammatory markers in patients with immune-stimulated pruritus compared with healthy controls, Ms. Manjunath said at the meeting.
When a Malignancy Workup Becomes Important
The initial part of any diagnostic workup for CPUO should include CBC with differential, liver function tests, renal function tests, and thyroid function testing, said Kwatra, referring to a diagnostic algorithm he developed, which was published as part of a CME review in the Journal of the American Academy of Dermatology in 2022.
Then, as indicated by risk factors in the history and physical, one could order other tests such as HIV serology, hepatitis B/C serologies, bullous pemphigoid testing, chest x-rays, evaluation for gammopathies, stool examination for ova and parasites, or heavy metal testing. “Do you do everything at once? We like to keep it straightforward,” Dr. Kwatra said. “Depending on the patient’s risk factors, you could order more or less.”
A malignancy workup should be strongly considered in patients whose itch duration is less than 12 months — and especially if the duration is less than 3 months — with an emphasis on cancers more frequently associated with itch: Hematologic and hepatobiliary cancers. This is “when concern should be heightened ... when there should be a lower threshold for workup,” he said.
The 12-month recommendation stems from a Danish cohort study published in 2014 that demonstrated a twofold increased incidence of cancer among patients with pruritus in the first 3 months after the diagnosis of pruritus. The 1-year absolute cancer risk was 1.63%.
Other risk factors for underlying malignancy or malignancy development in patients with CPUO include age older than 60 years, male sex, liver disease, and current or prior smoking, according to another study, noted Dr. Kwatra.
Dr. Kwatra disclosed that he is an advisory board member/consultant for Pfizer, Regeneron, Sanofi, and other companies and an investigator for Galderma, Incyte, Pfizer, and Sanofi. Manjunath served as the codirector of the ElderDerm conference.
A version of this article first appeared on Medscape.com.
WASHINGTON — , Shawn G. Kwatra, MD, said at the ElderDerm conference on dermatology in older patients hosted by the GW School of Medicine & Health Sciences.
“We found a few years ago that eosinophils seem to differentiate this group, and now we’re finding that IgE and CBC [complete blood count] differential can help you get a little better sense of who has an immune-driven itch vs something more neuropathic,” said Dr. Kwatra, professor and chair of dermatology at the University of Maryland, Baltimore, who founded and directed the Johns Hopkins Itch Center before coming to the University of Maryland in 2023. Not all patients with immune-driven itch will have these biomarkers, “but it’s a helpful tool,” he said.
CPUO is the term that is increasingly being used, he said, to describe intense, chronic pruritus without primary skin lesions or rashes and without any known systemic cause. It becomes more common as people get older and is sometimes debilitating. The initial evaluation should be kept “simple and straightforward,” he advised, with heightened concern for underlying malignancy in those who present with an itch of less than 12 months’ duration.
Biologics, JAK Inhibitors: Case Reports, Ongoing Research
Research conducted by Dr. Kwatra and Jaya Manjunath, a fourth-year medical student at The George Washington University, Washington, documented higher levels of Th2-associated cytokines and inflammatory markers in patients with CPUO who had elevated IgE or eosinophil levels, or both than in patients with itch who had low IgE and eosinophil levels. The patients with higher levels also had a greater response to off-label treatment with immunomodulatory therapy.
“Multiple Th2-related inflammatory markers, like IL [interleukin]-5 and eotaxin-3, were reduced after dupilumab” in patients who responded to the therapy, said Ms. Manjunath, who co-presented the meeting session on chronic itch with Dr. Kwatra. Other changes in the plasma cytokine profile included a reduction in the serum level of thymus and activation-regulated chemokine, which is a biomarker for atopic dermatitis. The research is under review for publication.
Meanwhile, a phase 3 trial (LIBERTY-CPUO-CHIC) of dupilumab for CPUO is currently underway, Dr. Kwatra noted. Investigators are randomizing patients with severe pruritus (Worst Itch Numeric Rating Scale [WI-NRS] ≥ 7) to dupilumab or placebo for 12 or 24 weeks.
In one of several cases shared by Dr. Kwatra and Ms. Manjunath, a 71-year-old Black woman with a 6-month history of generalized itch (WI-NRS = 10) and a history of type 2 diabetes, hypertension, and chronic kidney disease was found to have elevated eosinophil levels and a negative malignancy workup. Previous therapies included antihistamines and topical steroids. She was started on a 600-mg loading dose of subcutaneous dupilumab followed by 300 mg every 14 days. At the 2-month follow-up, her WI-NRS score was 0.
Because “dupilumab is off label right now for this form of itch, oftentimes our first line is methotrexate,” Dr. Kwatra said. Patients “can have a good response with this therapeutic.”
He also described the case of a 72-year-old Black woman with total body itch for 2 years (WI-NRS = 10) and a history of seasonal allergies, thyroid disease, and hypertension. Previous therapies included prednisone, antihistamines, topical steroids, and gabapentin. The patient was found to have high IgE (447 kU/L) and eosinophil levels (4.9%), was started on methotrexate, and had an itch score of 0 at the 8-month follow-up.
JAK inhibitors may also have a role in the management of CPUO. A phase 2 nonrandomized controlled trial of abrocitinib for adults with prurigo nodularis (PN) or CPUO, recently published in JAMA Dermatology, showed itch scores decreased by 53.7% in the CPUO group (and 78.3% in the PN group) after 12 weeks of treatment with oral abrocitinib 200 mg daily. Patients had significant improvements in quality of life and no serious adverse events, said Dr. Kwatra, the lead author of the paper.
One of these patients was a 73-year-old White man who had experienced total body itch for 1.5 years (predominantly affecting his upper extremities; WI-NRS = 10) and a history of ascending aortic aneurysm, hypertension, and hyperlipidemia. Previous failed therapies included dupilumab (> 6 months), topical steroids, tacrolimus, and antihistamines. Labs showed elevated IgE (456 kU/L) and eosinophil levels (11.7%). After 12 weeks of treatment with abrocitinib, the WI-NRS decreased to 2.
PD-1 Inhibitors As a Trigger
Chronic pruritus caused by the anticancer PD-1 inhibitors is becoming more common as the utilization of these immune checkpoint inhibitors increases, Dr. Kwatra noted. “You don’t see much in the skin, but [these patients have] very high IgE and eosinophils,” he said. “We’ve been seeing more reports recently of utilizing agents that target type 2 inflammation off label for PD-1 inhibitor–related skin manifestations.”
One such patient with PD-1 inhibitor–induced pruritus was a 65-year-old White man with metastatic melanoma who reported a 6-month history of itching that began 3 weeks after the start of treatment with the PD-1 inhibitor pembrolizumab. His WI-NRS score was 10 despite treatment with topical steroids and antihistamines. He had a history of psoriasis. Labs showed elevated IgE (1350 kU/L) and eosinophil levels (4.5%). At a 4-month follow-up after treatment with off-label dupilumab (a 600-mg subcutaneous loading dose followed by 300 mg every 14 days), his WI-NRS score was 0.
In a paper recently published in JAAD International, Dr. Kwatra, Ms. Manjunath, and coinvestigators reported on a series of 15 patients who developed chronic pruritus following an immune stimulus exposure, including immunotherapy and vaccination (2024 Apr 7:16:97-102. doi: 10.1016/j.jdin.2024.03.022). Most immunotherapy-treated patients experienced pruritus during treatment or after 21-60 days of receiving treatment, and the patients with vaccine-stimulated pruritus (after Tdap and messenger RNA COVID-19 vaccination) developed pruritus within a week of vaccination.
In addition to the elevated levels of IgE and eosinophils, plasma cytokine analysis showed elevated levels of IL-5, thymic stromal lymphopoietin, and other Th2-related cytokines and inflammatory markers in patients with immune-stimulated pruritus compared with healthy controls, Ms. Manjunath said at the meeting.
When a Malignancy Workup Becomes Important
The initial part of any diagnostic workup for CPUO should include CBC with differential, liver function tests, renal function tests, and thyroid function testing, said Kwatra, referring to a diagnostic algorithm he developed, which was published as part of a CME review in the Journal of the American Academy of Dermatology in 2022.
Then, as indicated by risk factors in the history and physical, one could order other tests such as HIV serology, hepatitis B/C serologies, bullous pemphigoid testing, chest x-rays, evaluation for gammopathies, stool examination for ova and parasites, or heavy metal testing. “Do you do everything at once? We like to keep it straightforward,” Dr. Kwatra said. “Depending on the patient’s risk factors, you could order more or less.”
A malignancy workup should be strongly considered in patients whose itch duration is less than 12 months — and especially if the duration is less than 3 months — with an emphasis on cancers more frequently associated with itch: Hematologic and hepatobiliary cancers. This is “when concern should be heightened ... when there should be a lower threshold for workup,” he said.
The 12-month recommendation stems from a Danish cohort study published in 2014 that demonstrated a twofold increased incidence of cancer among patients with pruritus in the first 3 months after the diagnosis of pruritus. The 1-year absolute cancer risk was 1.63%.
Other risk factors for underlying malignancy or malignancy development in patients with CPUO include age older than 60 years, male sex, liver disease, and current or prior smoking, according to another study, noted Dr. Kwatra.
Dr. Kwatra disclosed that he is an advisory board member/consultant for Pfizer, Regeneron, Sanofi, and other companies and an investigator for Galderma, Incyte, Pfizer, and Sanofi. Manjunath served as the codirector of the ElderDerm conference.
A version of this article first appeared on Medscape.com.
WASHINGTON — , Shawn G. Kwatra, MD, said at the ElderDerm conference on dermatology in older patients hosted by the GW School of Medicine & Health Sciences.
“We found a few years ago that eosinophils seem to differentiate this group, and now we’re finding that IgE and CBC [complete blood count] differential can help you get a little better sense of who has an immune-driven itch vs something more neuropathic,” said Dr. Kwatra, professor and chair of dermatology at the University of Maryland, Baltimore, who founded and directed the Johns Hopkins Itch Center before coming to the University of Maryland in 2023. Not all patients with immune-driven itch will have these biomarkers, “but it’s a helpful tool,” he said.
CPUO is the term that is increasingly being used, he said, to describe intense, chronic pruritus without primary skin lesions or rashes and without any known systemic cause. It becomes more common as people get older and is sometimes debilitating. The initial evaluation should be kept “simple and straightforward,” he advised, with heightened concern for underlying malignancy in those who present with an itch of less than 12 months’ duration.
Biologics, JAK Inhibitors: Case Reports, Ongoing Research
Research conducted by Dr. Kwatra and Jaya Manjunath, a fourth-year medical student at The George Washington University, Washington, documented higher levels of Th2-associated cytokines and inflammatory markers in patients with CPUO who had elevated IgE or eosinophil levels, or both than in patients with itch who had low IgE and eosinophil levels. The patients with higher levels also had a greater response to off-label treatment with immunomodulatory therapy.
“Multiple Th2-related inflammatory markers, like IL [interleukin]-5 and eotaxin-3, were reduced after dupilumab” in patients who responded to the therapy, said Ms. Manjunath, who co-presented the meeting session on chronic itch with Dr. Kwatra. Other changes in the plasma cytokine profile included a reduction in the serum level of thymus and activation-regulated chemokine, which is a biomarker for atopic dermatitis. The research is under review for publication.
Meanwhile, a phase 3 trial (LIBERTY-CPUO-CHIC) of dupilumab for CPUO is currently underway, Dr. Kwatra noted. Investigators are randomizing patients with severe pruritus (Worst Itch Numeric Rating Scale [WI-NRS] ≥ 7) to dupilumab or placebo for 12 or 24 weeks.
In one of several cases shared by Dr. Kwatra and Ms. Manjunath, a 71-year-old Black woman with a 6-month history of generalized itch (WI-NRS = 10) and a history of type 2 diabetes, hypertension, and chronic kidney disease was found to have elevated eosinophil levels and a negative malignancy workup. Previous therapies included antihistamines and topical steroids. She was started on a 600-mg loading dose of subcutaneous dupilumab followed by 300 mg every 14 days. At the 2-month follow-up, her WI-NRS score was 0.
Because “dupilumab is off label right now for this form of itch, oftentimes our first line is methotrexate,” Dr. Kwatra said. Patients “can have a good response with this therapeutic.”
He also described the case of a 72-year-old Black woman with total body itch for 2 years (WI-NRS = 10) and a history of seasonal allergies, thyroid disease, and hypertension. Previous therapies included prednisone, antihistamines, topical steroids, and gabapentin. The patient was found to have high IgE (447 kU/L) and eosinophil levels (4.9%), was started on methotrexate, and had an itch score of 0 at the 8-month follow-up.
JAK inhibitors may also have a role in the management of CPUO. A phase 2 nonrandomized controlled trial of abrocitinib for adults with prurigo nodularis (PN) or CPUO, recently published in JAMA Dermatology, showed itch scores decreased by 53.7% in the CPUO group (and 78.3% in the PN group) after 12 weeks of treatment with oral abrocitinib 200 mg daily. Patients had significant improvements in quality of life and no serious adverse events, said Dr. Kwatra, the lead author of the paper.
One of these patients was a 73-year-old White man who had experienced total body itch for 1.5 years (predominantly affecting his upper extremities; WI-NRS = 10) and a history of ascending aortic aneurysm, hypertension, and hyperlipidemia. Previous failed therapies included dupilumab (> 6 months), topical steroids, tacrolimus, and antihistamines. Labs showed elevated IgE (456 kU/L) and eosinophil levels (11.7%). After 12 weeks of treatment with abrocitinib, the WI-NRS decreased to 2.
PD-1 Inhibitors As a Trigger
Chronic pruritus caused by the anticancer PD-1 inhibitors is becoming more common as the utilization of these immune checkpoint inhibitors increases, Dr. Kwatra noted. “You don’t see much in the skin, but [these patients have] very high IgE and eosinophils,” he said. “We’ve been seeing more reports recently of utilizing agents that target type 2 inflammation off label for PD-1 inhibitor–related skin manifestations.”
One such patient with PD-1 inhibitor–induced pruritus was a 65-year-old White man with metastatic melanoma who reported a 6-month history of itching that began 3 weeks after the start of treatment with the PD-1 inhibitor pembrolizumab. His WI-NRS score was 10 despite treatment with topical steroids and antihistamines. He had a history of psoriasis. Labs showed elevated IgE (1350 kU/L) and eosinophil levels (4.5%). At a 4-month follow-up after treatment with off-label dupilumab (a 600-mg subcutaneous loading dose followed by 300 mg every 14 days), his WI-NRS score was 0.
In a paper recently published in JAAD International, Dr. Kwatra, Ms. Manjunath, and coinvestigators reported on a series of 15 patients who developed chronic pruritus following an immune stimulus exposure, including immunotherapy and vaccination (2024 Apr 7:16:97-102. doi: 10.1016/j.jdin.2024.03.022). Most immunotherapy-treated patients experienced pruritus during treatment or after 21-60 days of receiving treatment, and the patients with vaccine-stimulated pruritus (after Tdap and messenger RNA COVID-19 vaccination) developed pruritus within a week of vaccination.
In addition to the elevated levels of IgE and eosinophils, plasma cytokine analysis showed elevated levels of IL-5, thymic stromal lymphopoietin, and other Th2-related cytokines and inflammatory markers in patients with immune-stimulated pruritus compared with healthy controls, Ms. Manjunath said at the meeting.
When a Malignancy Workup Becomes Important
The initial part of any diagnostic workup for CPUO should include CBC with differential, liver function tests, renal function tests, and thyroid function testing, said Kwatra, referring to a diagnostic algorithm he developed, which was published as part of a CME review in the Journal of the American Academy of Dermatology in 2022.
Then, as indicated by risk factors in the history and physical, one could order other tests such as HIV serology, hepatitis B/C serologies, bullous pemphigoid testing, chest x-rays, evaluation for gammopathies, stool examination for ova and parasites, or heavy metal testing. “Do you do everything at once? We like to keep it straightforward,” Dr. Kwatra said. “Depending on the patient’s risk factors, you could order more or less.”
A malignancy workup should be strongly considered in patients whose itch duration is less than 12 months — and especially if the duration is less than 3 months — with an emphasis on cancers more frequently associated with itch: Hematologic and hepatobiliary cancers. This is “when concern should be heightened ... when there should be a lower threshold for workup,” he said.
The 12-month recommendation stems from a Danish cohort study published in 2014 that demonstrated a twofold increased incidence of cancer among patients with pruritus in the first 3 months after the diagnosis of pruritus. The 1-year absolute cancer risk was 1.63%.
Other risk factors for underlying malignancy or malignancy development in patients with CPUO include age older than 60 years, male sex, liver disease, and current or prior smoking, according to another study, noted Dr. Kwatra.
Dr. Kwatra disclosed that he is an advisory board member/consultant for Pfizer, Regeneron, Sanofi, and other companies and an investigator for Galderma, Incyte, Pfizer, and Sanofi. Manjunath served as the codirector of the ElderDerm conference.
A version of this article first appeared on Medscape.com.
FROM ELDERDERM 2024
‘Doesn’t Fit Anything I Trained for’: Committee Examines Treatment for Chronic Illness After Lyme Disease
WASHINGTON — Advancing treatment for what has been variably called chronic Lyme and posttreatment Lyme disease (PTLD) is under the eyes of a National Academies of Science, Engineering, and Medicine (NASEM) committee of experts for the first time — a year after the NASEM shone a spotlight on the need to accelerate research on chronic illnesses that follow known or suspected infections.
The committee will not make recommendations on specific approaches to diagnosis and treatment when it issues a report in early 2025 but will instead present “consensus findings” on treatment for chronic illness associated with Lyme disease, including recommendations for advancing treatment.
It’s an area void of the US Food and Drug Administration–approved therapies, void of any consensus on the off-label use of medications, and without any current standard of care or proven mechanisms and pathophysiology, said John Aucott, MD, director of the Johns Hopkins Medicine Lyme Disease Clinical Research Center, Baltimore, one of the invited speakers at a public meeting held by the NASEM in Washington, DC.
“The best way to look at this illness is not from the silos of infectious disease or the silos of rheumatology; you have to look across disciplines,” Dr. Aucott, also associate professor of medicine in the Division of Rheumatology, told the committee. “The story doesn’t fit anything I trained for in my infectious disease fellowship. Even today, I’d posit that PTLD is like an island — it’s still not connected to a lot of the mainstream of medicine.”
Rhisa Parera, who wrote and directed a 2021 documentary, Your Labs Are Normal, was one of several invited speakers who amplified the patient voice. Starting around age 7, she had pain in her knees, spine, and hips and vivid nightmares. In high school, she developed gastrointestinal issues, and in college, she developed debilitating neurologic symptoms.
Depression was her eventual diagnosis after having seen “every specialist in the book,” she said. At age 29, she received a positive western blot test and a Lyme disease diagnosis, at which point “I was prescribed 4 weeks of doxycycline and left in the dark,” the 34-year-old Black patient told the committee. Her health improved only after she began working with an “LLMD,” or Lyme-literate medical doctor (a term used in the patient community), while she lived with her mother and did not work, she said.
“I don’t share my Lyme disease history with other doctors. It’s pointless when you have those who will laugh at you, say you’re fine if you were treated, or just deny the disease completely,” Ms. Parera said. “We need this to be taught in medical school. It’s a literal emergency.”
Incidence and Potential Mechanisms
Limited research has suggested that 10%-20% of patients with Lyme disease develop persistent symptoms after standard antibiotic treatment advised by the Infectious Diseases Society of America (IDSA), Dr. Aucott said. (On its web page on chronic symptoms, the Centers for Disease Control and Prevention presents a more conservative range of 5%-10%.)
His own prospective cohort study at Johns Hopkins, published in 2022, found that 13.7% of 234 patients with prior Lyme disease met symptom and functional impact criteria for PTLD, compared with 4.1% of 49 participants without a history of Lyme disease — a statistically significant difference that he said should “put to rest” the question of “is it real?”
PTLD is the research case definition proposed by the IDSA in 2006; it requires that patients have prior documented Lyme disease, no other specific comorbidities, and specific symptoms (fatigue, widespread musculoskeletal pain, and/or cognitive difficulties) causing significant functional impact at least 6 months from their initial diagnosis and treatment.
In the real world, however, where diagnostics for acute Lyme disease are often inaccurate, erythema migrans is often absent, and the symptomatology of Lyme IACI is variable (and where there is no approved laboratory test or objective biomarker for diagnosing Lyme IACI), PTLD represents only a subset of a broader, heterogeneous population with persistent symptoms.
The term “Lyme IACI,” pronounced “Lyme eye-ACK-ee” at the meeting, builds on conversations at the 2023 NASEM workshop on infection-associated chronic illnesses and “encompasses a variety of terms that are used,” including PTLD, PTLD syndrome, persistent Lyme disease, and chronic Lyme disease, according to committee documents. Symptoms are distinct from the known complications of Lyme disease, such as arthritis or carditis.
The findings from Dr. Aucott’s SLICE cohort likely represent “the best outcome,” he said. They’re “probably not generalizable to a community setting where we see lots of missed diagnoses and delayed diagnoses,” as well as other tick-borne coinfections.
One of the challenges in designing future trials, in fact, relates to enrollment criteria and whether to use strict inclusion and exclusion criteria associated with the IDSA definition or take a broader approach to trial enrollment, he and others said. “You want to enroll patients for whom there’s no controversy that they’ve had Lyme infection ... for a study people believe in,” Dr. Aucott said during a discussion period, noting that it’s typical to screen over 100 patients to find one enrollee. “But it’s a tension we’re having.”
Timothy Sellati, PhD, chief scientific officer of the Global Lyme Alliance, urged change. “It’s really important to try to figure out how to alter our thinking on identifying and diagnosing chronic Lyme patients because they need to be recruited into clinical trials,” he said during his presentation.
“We think the best way to do this is to [develop and] employ composite diagnostic testing” that looks at unique Borrelia signatures (eg, protein, DNA, RNA, or metabolites), genetic and/or epigenetic signatures, inflammation signatures, T-cell-independent antibody signatures, and other elements, Dr. Sellati said.
Researchers designing treatment trials also face unknowns, Dr. Aucott and others said, about the role of potential mechanisms of Lyme IACI, from persistent Borrelia burgdorferi (or Borrelia mayonii) infection or the persistence of bacterial remnants (eg, nucleic acids or peptidoglycans) to infection-triggered pathology such as persistent immune dysregulation, chronic inflammation, autoimmunity, microbiome alterations, and dysautonomia and other neural network alterations.
The NASEM’s spotlight on Lyme IACI follows its long COVID-driven push last year to advance a common research agenda in infection-associated chronic illnesses. Investigators see common symptoms and potential shared mechanisms between long COVID, Lyme IACI, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and other complex chronic illnesses following infections.
At the Lyme IACI meeting, invited speakers described parts of the research landscape. Avindra Nath, MD, of the National Institute of Neurological Disorders and Stroke, for instance, described a recently published deep phenotyping study of 17 patients with ME/CFS that found decreased central catecholamine synthesis, circuit dysfunction of integrative brain regions, and immune profiling differences (eg, defects in B-cell maturation or T-cell exhaustion), compared with matched controls, that suggest the persistence of microbial antigens.
And John Leong, MD, PhD, of Tufts University, Boston, described his lab’s focus on understanding the microbe-host interactions that enable bloodstream dissemination and tissue invasion of B burgdorferi to take hold, increasing the risk for persistent symptoms. Other research at Tufts, he noted during a discussion period, has demonstrated the persistence of B burgdorferi to antibiotics in microtiter dishes. “Those organisms that survive are really difficult to eradicate in vitro,” Dr. Leong said.
Other physician investigators described research on nociplastic pain — a category of pain that can be triggered by infections, causing both amplified sensory processing and augmented central nervous system pain — and on whether reactivation of the Epstein-Barr virus could potentiate autoimmunity in the context of Borrelia infection.
Researchers are ready to test therapies while pathophysiology is unraveled — provided there is funding, Dr. Aucott said. The Clinical Trials Network for Lyme and Other Tick-Borne Diseases, coordinated by Brian Fallon, MD, of Columbia University, New York City, and funded several years ago by the Steven & Alexandra Cohen Foundation, has a slate of small pilot studies underway or being planned that address potential mechanisms (eg, studies of pulse intravenous ceftriaxone, tetracycline, transauricular vagus nerve stimulation, and mast cell modulation). And should full multisite trials be designed and funded, the network is ready with an infrastructure.
Need for Patient-Centered Outcomes
Persistent symptomatology is on the NIH’s radar screen. Efforts to understand causes were part of a strategic tick-borne disease research plan developed by the NIH in 2019. And in 2023, the National Institute of Allergy and Infectious Diseases (NIAID) funded seven projects addressing persistent symptoms that will run through 2028, C. Benjamin Beard, PhD, deputy division director of the CDC’s Division of Vector-Borne Disease, said at the NASEM committee meeting.
Patient advocates maintained that too much emphasis is placed on tick biology and pathophysiology. When Wendy Adams, research grant director and advisory board member of the Bay Area Lyme Foundation, and a colleague analyzed NIAID tick-borne disease funding from 2013 to 2021, they found that 75% of the funding went toward basic research, 15% to translational research, and “only 3% went to clinical research,” Ms. Adams told the committee.
Only 3% of the basic research budget was spent on coinfections, she said, and only 1% was spent on neurologic disease associated with tick-borne infections, both of which are survey-defined patient priorities. Moreover, “12% of the overall NIAID [tick-borne diseases] budget was spent on tick biology,” she said.
Research needs to involve community physicians who are utilizing the guidelines and approaches of the International Lyme and Associated Diseases Society to treat most patients with Lyme IACI, Ms. Adams said. “They have data to be mined,” she said, as does LymeDisease.org, which maintains a patient registry, MyLymeData, with over 18,000 patients. The organization has published two treatment studies, including one on antibiotic treatment response.
Lorraine Johnson, JD, MBA, CEO of LymeDisease.org and principal investigator of MyLymeData, stressed the importance of using patient-centered outcomes that incorporate minimal clinically important differences (MCIDs). “A change in the SF-36 score [without consideration of MCIDs] is not inherently important or meaningful to patients,” she said, referring to the SF-36 survey of health-related quality of life.
“This may seem like an esoteric issue, but two of the four clinical trials done [on retreatment of] persistent Lyme disease used the SF-36 as their outcome measure, and those studies, led by [Mark] Klempner, concluded that retreatment was not effective,” Ms. Johnson said. “Patients have been and continue to be harmed by [this research] because they’re told by physicians that antibiotics don’t work.”
A 2012 biostatistical review of these four RCTs — trials that helped inform the 2006 IDSA treatment guidelines — concluded that the Klempner studies “set the bar for treatment success too high,” Ms. Johnson said. Three of the four trials were likely underpowered to detect clinically meaningful treatment effects, the review also found.
The NASEM committee will hold additional public meetings and review a wide range of literature through this year. The formation of the committee was recommended by the US Department of Health and Human Services Tick-Borne Disease Working Group that was established by Congress in 2016 and concluded its work in 2022. The committee’s work is funded by the Cohen Foundation.
A version of this article appeared on Medscape.com.
WASHINGTON — Advancing treatment for what has been variably called chronic Lyme and posttreatment Lyme disease (PTLD) is under the eyes of a National Academies of Science, Engineering, and Medicine (NASEM) committee of experts for the first time — a year after the NASEM shone a spotlight on the need to accelerate research on chronic illnesses that follow known or suspected infections.
The committee will not make recommendations on specific approaches to diagnosis and treatment when it issues a report in early 2025 but will instead present “consensus findings” on treatment for chronic illness associated with Lyme disease, including recommendations for advancing treatment.
It’s an area void of the US Food and Drug Administration–approved therapies, void of any consensus on the off-label use of medications, and without any current standard of care or proven mechanisms and pathophysiology, said John Aucott, MD, director of the Johns Hopkins Medicine Lyme Disease Clinical Research Center, Baltimore, one of the invited speakers at a public meeting held by the NASEM in Washington, DC.
“The best way to look at this illness is not from the silos of infectious disease or the silos of rheumatology; you have to look across disciplines,” Dr. Aucott, also associate professor of medicine in the Division of Rheumatology, told the committee. “The story doesn’t fit anything I trained for in my infectious disease fellowship. Even today, I’d posit that PTLD is like an island — it’s still not connected to a lot of the mainstream of medicine.”
Rhisa Parera, who wrote and directed a 2021 documentary, Your Labs Are Normal, was one of several invited speakers who amplified the patient voice. Starting around age 7, she had pain in her knees, spine, and hips and vivid nightmares. In high school, she developed gastrointestinal issues, and in college, she developed debilitating neurologic symptoms.
Depression was her eventual diagnosis after having seen “every specialist in the book,” she said. At age 29, she received a positive western blot test and a Lyme disease diagnosis, at which point “I was prescribed 4 weeks of doxycycline and left in the dark,” the 34-year-old Black patient told the committee. Her health improved only after she began working with an “LLMD,” or Lyme-literate medical doctor (a term used in the patient community), while she lived with her mother and did not work, she said.
“I don’t share my Lyme disease history with other doctors. It’s pointless when you have those who will laugh at you, say you’re fine if you were treated, or just deny the disease completely,” Ms. Parera said. “We need this to be taught in medical school. It’s a literal emergency.”
Incidence and Potential Mechanisms
Limited research has suggested that 10%-20% of patients with Lyme disease develop persistent symptoms after standard antibiotic treatment advised by the Infectious Diseases Society of America (IDSA), Dr. Aucott said. (On its web page on chronic symptoms, the Centers for Disease Control and Prevention presents a more conservative range of 5%-10%.)
His own prospective cohort study at Johns Hopkins, published in 2022, found that 13.7% of 234 patients with prior Lyme disease met symptom and functional impact criteria for PTLD, compared with 4.1% of 49 participants without a history of Lyme disease — a statistically significant difference that he said should “put to rest” the question of “is it real?”
PTLD is the research case definition proposed by the IDSA in 2006; it requires that patients have prior documented Lyme disease, no other specific comorbidities, and specific symptoms (fatigue, widespread musculoskeletal pain, and/or cognitive difficulties) causing significant functional impact at least 6 months from their initial diagnosis and treatment.
In the real world, however, where diagnostics for acute Lyme disease are often inaccurate, erythema migrans is often absent, and the symptomatology of Lyme IACI is variable (and where there is no approved laboratory test or objective biomarker for diagnosing Lyme IACI), PTLD represents only a subset of a broader, heterogeneous population with persistent symptoms.
The term “Lyme IACI,” pronounced “Lyme eye-ACK-ee” at the meeting, builds on conversations at the 2023 NASEM workshop on infection-associated chronic illnesses and “encompasses a variety of terms that are used,” including PTLD, PTLD syndrome, persistent Lyme disease, and chronic Lyme disease, according to committee documents. Symptoms are distinct from the known complications of Lyme disease, such as arthritis or carditis.
The findings from Dr. Aucott’s SLICE cohort likely represent “the best outcome,” he said. They’re “probably not generalizable to a community setting where we see lots of missed diagnoses and delayed diagnoses,” as well as other tick-borne coinfections.
One of the challenges in designing future trials, in fact, relates to enrollment criteria and whether to use strict inclusion and exclusion criteria associated with the IDSA definition or take a broader approach to trial enrollment, he and others said. “You want to enroll patients for whom there’s no controversy that they’ve had Lyme infection ... for a study people believe in,” Dr. Aucott said during a discussion period, noting that it’s typical to screen over 100 patients to find one enrollee. “But it’s a tension we’re having.”
Timothy Sellati, PhD, chief scientific officer of the Global Lyme Alliance, urged change. “It’s really important to try to figure out how to alter our thinking on identifying and diagnosing chronic Lyme patients because they need to be recruited into clinical trials,” he said during his presentation.
“We think the best way to do this is to [develop and] employ composite diagnostic testing” that looks at unique Borrelia signatures (eg, protein, DNA, RNA, or metabolites), genetic and/or epigenetic signatures, inflammation signatures, T-cell-independent antibody signatures, and other elements, Dr. Sellati said.
Researchers designing treatment trials also face unknowns, Dr. Aucott and others said, about the role of potential mechanisms of Lyme IACI, from persistent Borrelia burgdorferi (or Borrelia mayonii) infection or the persistence of bacterial remnants (eg, nucleic acids or peptidoglycans) to infection-triggered pathology such as persistent immune dysregulation, chronic inflammation, autoimmunity, microbiome alterations, and dysautonomia and other neural network alterations.
The NASEM’s spotlight on Lyme IACI follows its long COVID-driven push last year to advance a common research agenda in infection-associated chronic illnesses. Investigators see common symptoms and potential shared mechanisms between long COVID, Lyme IACI, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and other complex chronic illnesses following infections.
At the Lyme IACI meeting, invited speakers described parts of the research landscape. Avindra Nath, MD, of the National Institute of Neurological Disorders and Stroke, for instance, described a recently published deep phenotyping study of 17 patients with ME/CFS that found decreased central catecholamine synthesis, circuit dysfunction of integrative brain regions, and immune profiling differences (eg, defects in B-cell maturation or T-cell exhaustion), compared with matched controls, that suggest the persistence of microbial antigens.
And John Leong, MD, PhD, of Tufts University, Boston, described his lab’s focus on understanding the microbe-host interactions that enable bloodstream dissemination and tissue invasion of B burgdorferi to take hold, increasing the risk for persistent symptoms. Other research at Tufts, he noted during a discussion period, has demonstrated the persistence of B burgdorferi to antibiotics in microtiter dishes. “Those organisms that survive are really difficult to eradicate in vitro,” Dr. Leong said.
Other physician investigators described research on nociplastic pain — a category of pain that can be triggered by infections, causing both amplified sensory processing and augmented central nervous system pain — and on whether reactivation of the Epstein-Barr virus could potentiate autoimmunity in the context of Borrelia infection.
Researchers are ready to test therapies while pathophysiology is unraveled — provided there is funding, Dr. Aucott said. The Clinical Trials Network for Lyme and Other Tick-Borne Diseases, coordinated by Brian Fallon, MD, of Columbia University, New York City, and funded several years ago by the Steven & Alexandra Cohen Foundation, has a slate of small pilot studies underway or being planned that address potential mechanisms (eg, studies of pulse intravenous ceftriaxone, tetracycline, transauricular vagus nerve stimulation, and mast cell modulation). And should full multisite trials be designed and funded, the network is ready with an infrastructure.
Need for Patient-Centered Outcomes
Persistent symptomatology is on the NIH’s radar screen. Efforts to understand causes were part of a strategic tick-borne disease research plan developed by the NIH in 2019. And in 2023, the National Institute of Allergy and Infectious Diseases (NIAID) funded seven projects addressing persistent symptoms that will run through 2028, C. Benjamin Beard, PhD, deputy division director of the CDC’s Division of Vector-Borne Disease, said at the NASEM committee meeting.
Patient advocates maintained that too much emphasis is placed on tick biology and pathophysiology. When Wendy Adams, research grant director and advisory board member of the Bay Area Lyme Foundation, and a colleague analyzed NIAID tick-borne disease funding from 2013 to 2021, they found that 75% of the funding went toward basic research, 15% to translational research, and “only 3% went to clinical research,” Ms. Adams told the committee.
Only 3% of the basic research budget was spent on coinfections, she said, and only 1% was spent on neurologic disease associated with tick-borne infections, both of which are survey-defined patient priorities. Moreover, “12% of the overall NIAID [tick-borne diseases] budget was spent on tick biology,” she said.
Research needs to involve community physicians who are utilizing the guidelines and approaches of the International Lyme and Associated Diseases Society to treat most patients with Lyme IACI, Ms. Adams said. “They have data to be mined,” she said, as does LymeDisease.org, which maintains a patient registry, MyLymeData, with over 18,000 patients. The organization has published two treatment studies, including one on antibiotic treatment response.
Lorraine Johnson, JD, MBA, CEO of LymeDisease.org and principal investigator of MyLymeData, stressed the importance of using patient-centered outcomes that incorporate minimal clinically important differences (MCIDs). “A change in the SF-36 score [without consideration of MCIDs] is not inherently important or meaningful to patients,” she said, referring to the SF-36 survey of health-related quality of life.
“This may seem like an esoteric issue, but two of the four clinical trials done [on retreatment of] persistent Lyme disease used the SF-36 as their outcome measure, and those studies, led by [Mark] Klempner, concluded that retreatment was not effective,” Ms. Johnson said. “Patients have been and continue to be harmed by [this research] because they’re told by physicians that antibiotics don’t work.”
A 2012 biostatistical review of these four RCTs — trials that helped inform the 2006 IDSA treatment guidelines — concluded that the Klempner studies “set the bar for treatment success too high,” Ms. Johnson said. Three of the four trials were likely underpowered to detect clinically meaningful treatment effects, the review also found.
The NASEM committee will hold additional public meetings and review a wide range of literature through this year. The formation of the committee was recommended by the US Department of Health and Human Services Tick-Borne Disease Working Group that was established by Congress in 2016 and concluded its work in 2022. The committee’s work is funded by the Cohen Foundation.
A version of this article appeared on Medscape.com.
WASHINGTON — Advancing treatment for what has been variably called chronic Lyme and posttreatment Lyme disease (PTLD) is under the eyes of a National Academies of Science, Engineering, and Medicine (NASEM) committee of experts for the first time — a year after the NASEM shone a spotlight on the need to accelerate research on chronic illnesses that follow known or suspected infections.
The committee will not make recommendations on specific approaches to diagnosis and treatment when it issues a report in early 2025 but will instead present “consensus findings” on treatment for chronic illness associated with Lyme disease, including recommendations for advancing treatment.
It’s an area void of the US Food and Drug Administration–approved therapies, void of any consensus on the off-label use of medications, and without any current standard of care or proven mechanisms and pathophysiology, said John Aucott, MD, director of the Johns Hopkins Medicine Lyme Disease Clinical Research Center, Baltimore, one of the invited speakers at a public meeting held by the NASEM in Washington, DC.
“The best way to look at this illness is not from the silos of infectious disease or the silos of rheumatology; you have to look across disciplines,” Dr. Aucott, also associate professor of medicine in the Division of Rheumatology, told the committee. “The story doesn’t fit anything I trained for in my infectious disease fellowship. Even today, I’d posit that PTLD is like an island — it’s still not connected to a lot of the mainstream of medicine.”
Rhisa Parera, who wrote and directed a 2021 documentary, Your Labs Are Normal, was one of several invited speakers who amplified the patient voice. Starting around age 7, she had pain in her knees, spine, and hips and vivid nightmares. In high school, she developed gastrointestinal issues, and in college, she developed debilitating neurologic symptoms.
Depression was her eventual diagnosis after having seen “every specialist in the book,” she said. At age 29, she received a positive western blot test and a Lyme disease diagnosis, at which point “I was prescribed 4 weeks of doxycycline and left in the dark,” the 34-year-old Black patient told the committee. Her health improved only after she began working with an “LLMD,” or Lyme-literate medical doctor (a term used in the patient community), while she lived with her mother and did not work, she said.
“I don’t share my Lyme disease history with other doctors. It’s pointless when you have those who will laugh at you, say you’re fine if you were treated, or just deny the disease completely,” Ms. Parera said. “We need this to be taught in medical school. It’s a literal emergency.”
Incidence and Potential Mechanisms
Limited research has suggested that 10%-20% of patients with Lyme disease develop persistent symptoms after standard antibiotic treatment advised by the Infectious Diseases Society of America (IDSA), Dr. Aucott said. (On its web page on chronic symptoms, the Centers for Disease Control and Prevention presents a more conservative range of 5%-10%.)
His own prospective cohort study at Johns Hopkins, published in 2022, found that 13.7% of 234 patients with prior Lyme disease met symptom and functional impact criteria for PTLD, compared with 4.1% of 49 participants without a history of Lyme disease — a statistically significant difference that he said should “put to rest” the question of “is it real?”
PTLD is the research case definition proposed by the IDSA in 2006; it requires that patients have prior documented Lyme disease, no other specific comorbidities, and specific symptoms (fatigue, widespread musculoskeletal pain, and/or cognitive difficulties) causing significant functional impact at least 6 months from their initial diagnosis and treatment.
In the real world, however, where diagnostics for acute Lyme disease are often inaccurate, erythema migrans is often absent, and the symptomatology of Lyme IACI is variable (and where there is no approved laboratory test or objective biomarker for diagnosing Lyme IACI), PTLD represents only a subset of a broader, heterogeneous population with persistent symptoms.
The term “Lyme IACI,” pronounced “Lyme eye-ACK-ee” at the meeting, builds on conversations at the 2023 NASEM workshop on infection-associated chronic illnesses and “encompasses a variety of terms that are used,” including PTLD, PTLD syndrome, persistent Lyme disease, and chronic Lyme disease, according to committee documents. Symptoms are distinct from the known complications of Lyme disease, such as arthritis or carditis.
The findings from Dr. Aucott’s SLICE cohort likely represent “the best outcome,” he said. They’re “probably not generalizable to a community setting where we see lots of missed diagnoses and delayed diagnoses,” as well as other tick-borne coinfections.
One of the challenges in designing future trials, in fact, relates to enrollment criteria and whether to use strict inclusion and exclusion criteria associated with the IDSA definition or take a broader approach to trial enrollment, he and others said. “You want to enroll patients for whom there’s no controversy that they’ve had Lyme infection ... for a study people believe in,” Dr. Aucott said during a discussion period, noting that it’s typical to screen over 100 patients to find one enrollee. “But it’s a tension we’re having.”
Timothy Sellati, PhD, chief scientific officer of the Global Lyme Alliance, urged change. “It’s really important to try to figure out how to alter our thinking on identifying and diagnosing chronic Lyme patients because they need to be recruited into clinical trials,” he said during his presentation.
“We think the best way to do this is to [develop and] employ composite diagnostic testing” that looks at unique Borrelia signatures (eg, protein, DNA, RNA, or metabolites), genetic and/or epigenetic signatures, inflammation signatures, T-cell-independent antibody signatures, and other elements, Dr. Sellati said.
Researchers designing treatment trials also face unknowns, Dr. Aucott and others said, about the role of potential mechanisms of Lyme IACI, from persistent Borrelia burgdorferi (or Borrelia mayonii) infection or the persistence of bacterial remnants (eg, nucleic acids or peptidoglycans) to infection-triggered pathology such as persistent immune dysregulation, chronic inflammation, autoimmunity, microbiome alterations, and dysautonomia and other neural network alterations.
The NASEM’s spotlight on Lyme IACI follows its long COVID-driven push last year to advance a common research agenda in infection-associated chronic illnesses. Investigators see common symptoms and potential shared mechanisms between long COVID, Lyme IACI, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and other complex chronic illnesses following infections.
At the Lyme IACI meeting, invited speakers described parts of the research landscape. Avindra Nath, MD, of the National Institute of Neurological Disorders and Stroke, for instance, described a recently published deep phenotyping study of 17 patients with ME/CFS that found decreased central catecholamine synthesis, circuit dysfunction of integrative brain regions, and immune profiling differences (eg, defects in B-cell maturation or T-cell exhaustion), compared with matched controls, that suggest the persistence of microbial antigens.
And John Leong, MD, PhD, of Tufts University, Boston, described his lab’s focus on understanding the microbe-host interactions that enable bloodstream dissemination and tissue invasion of B burgdorferi to take hold, increasing the risk for persistent symptoms. Other research at Tufts, he noted during a discussion period, has demonstrated the persistence of B burgdorferi to antibiotics in microtiter dishes. “Those organisms that survive are really difficult to eradicate in vitro,” Dr. Leong said.
Other physician investigators described research on nociplastic pain — a category of pain that can be triggered by infections, causing both amplified sensory processing and augmented central nervous system pain — and on whether reactivation of the Epstein-Barr virus could potentiate autoimmunity in the context of Borrelia infection.
Researchers are ready to test therapies while pathophysiology is unraveled — provided there is funding, Dr. Aucott said. The Clinical Trials Network for Lyme and Other Tick-Borne Diseases, coordinated by Brian Fallon, MD, of Columbia University, New York City, and funded several years ago by the Steven & Alexandra Cohen Foundation, has a slate of small pilot studies underway or being planned that address potential mechanisms (eg, studies of pulse intravenous ceftriaxone, tetracycline, transauricular vagus nerve stimulation, and mast cell modulation). And should full multisite trials be designed and funded, the network is ready with an infrastructure.
Need for Patient-Centered Outcomes
Persistent symptomatology is on the NIH’s radar screen. Efforts to understand causes were part of a strategic tick-borne disease research plan developed by the NIH in 2019. And in 2023, the National Institute of Allergy and Infectious Diseases (NIAID) funded seven projects addressing persistent symptoms that will run through 2028, C. Benjamin Beard, PhD, deputy division director of the CDC’s Division of Vector-Borne Disease, said at the NASEM committee meeting.
Patient advocates maintained that too much emphasis is placed on tick biology and pathophysiology. When Wendy Adams, research grant director and advisory board member of the Bay Area Lyme Foundation, and a colleague analyzed NIAID tick-borne disease funding from 2013 to 2021, they found that 75% of the funding went toward basic research, 15% to translational research, and “only 3% went to clinical research,” Ms. Adams told the committee.
Only 3% of the basic research budget was spent on coinfections, she said, and only 1% was spent on neurologic disease associated with tick-borne infections, both of which are survey-defined patient priorities. Moreover, “12% of the overall NIAID [tick-borne diseases] budget was spent on tick biology,” she said.
Research needs to involve community physicians who are utilizing the guidelines and approaches of the International Lyme and Associated Diseases Society to treat most patients with Lyme IACI, Ms. Adams said. “They have data to be mined,” she said, as does LymeDisease.org, which maintains a patient registry, MyLymeData, with over 18,000 patients. The organization has published two treatment studies, including one on antibiotic treatment response.
Lorraine Johnson, JD, MBA, CEO of LymeDisease.org and principal investigator of MyLymeData, stressed the importance of using patient-centered outcomes that incorporate minimal clinically important differences (MCIDs). “A change in the SF-36 score [without consideration of MCIDs] is not inherently important or meaningful to patients,” she said, referring to the SF-36 survey of health-related quality of life.
“This may seem like an esoteric issue, but two of the four clinical trials done [on retreatment of] persistent Lyme disease used the SF-36 as their outcome measure, and those studies, led by [Mark] Klempner, concluded that retreatment was not effective,” Ms. Johnson said. “Patients have been and continue to be harmed by [this research] because they’re told by physicians that antibiotics don’t work.”
A 2012 biostatistical review of these four RCTs — trials that helped inform the 2006 IDSA treatment guidelines — concluded that the Klempner studies “set the bar for treatment success too high,” Ms. Johnson said. Three of the four trials were likely underpowered to detect clinically meaningful treatment effects, the review also found.
The NASEM committee will hold additional public meetings and review a wide range of literature through this year. The formation of the committee was recommended by the US Department of Health and Human Services Tick-Borne Disease Working Group that was established by Congress in 2016 and concluded its work in 2022. The committee’s work is funded by the Cohen Foundation.
A version of this article appeared on Medscape.com.