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FDA Approves Ustekinumab Biosimilar Otulfi
This is the fourth ustekinumab biosimilar approved in the United States. Like the reference product, ustekinumab-aauz is indicated for:
- Patients 6 years or older with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy
- Patients 6 years or older with active psoriatic arthritis
- Adult patients with moderately to severely active Crohn’s disease
- Adult patients with moderately to severely active ulcerative colitis
Ustekinumab-aauz, produced by a partnership between Fresenius Kabi and Formycon, has two formulations: subcutaneous injection (45 mg/0.5 mL or 90 mg/mL solution in a single-dose prefilled syringe) or intravenous infusion (130 mg/26 mL solution in a single-dose vial).
The biosimilar will launch in the United States “no later than February 22, 2025,” according to the press release, “in accordance with the patent settlement between Fresenius Kabi, Formycon, and Johnson & Johnson.”
Ustekinumab-aauz is Fresenius Kabi’s fourth biosimilar granted US approval, behind adalimumab-aacf (Idacio), tocilizumab-aazg (Tyenne), and pegfilgrastim-fpgk (Stimufend).
A version of this article first appeared on Medscape.com.
This is the fourth ustekinumab biosimilar approved in the United States. Like the reference product, ustekinumab-aauz is indicated for:
- Patients 6 years or older with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy
- Patients 6 years or older with active psoriatic arthritis
- Adult patients with moderately to severely active Crohn’s disease
- Adult patients with moderately to severely active ulcerative colitis
Ustekinumab-aauz, produced by a partnership between Fresenius Kabi and Formycon, has two formulations: subcutaneous injection (45 mg/0.5 mL or 90 mg/mL solution in a single-dose prefilled syringe) or intravenous infusion (130 mg/26 mL solution in a single-dose vial).
The biosimilar will launch in the United States “no later than February 22, 2025,” according to the press release, “in accordance with the patent settlement between Fresenius Kabi, Formycon, and Johnson & Johnson.”
Ustekinumab-aauz is Fresenius Kabi’s fourth biosimilar granted US approval, behind adalimumab-aacf (Idacio), tocilizumab-aazg (Tyenne), and pegfilgrastim-fpgk (Stimufend).
A version of this article first appeared on Medscape.com.
This is the fourth ustekinumab biosimilar approved in the United States. Like the reference product, ustekinumab-aauz is indicated for:
- Patients 6 years or older with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy
- Patients 6 years or older with active psoriatic arthritis
- Adult patients with moderately to severely active Crohn’s disease
- Adult patients with moderately to severely active ulcerative colitis
Ustekinumab-aauz, produced by a partnership between Fresenius Kabi and Formycon, has two formulations: subcutaneous injection (45 mg/0.5 mL or 90 mg/mL solution in a single-dose prefilled syringe) or intravenous infusion (130 mg/26 mL solution in a single-dose vial).
The biosimilar will launch in the United States “no later than February 22, 2025,” according to the press release, “in accordance with the patent settlement between Fresenius Kabi, Formycon, and Johnson & Johnson.”
Ustekinumab-aauz is Fresenius Kabi’s fourth biosimilar granted US approval, behind adalimumab-aacf (Idacio), tocilizumab-aazg (Tyenne), and pegfilgrastim-fpgk (Stimufend).
A version of this article first appeared on Medscape.com.
New Biologic Tulisokibart Beats Placebo in Ulcerative Colitis Trial
In one cohort of 135 patients, the primary endpoint of clinical remission occurred in 26% of those given the novel antibody to tumor necrosis factor–like cytokine 1A (TL1A) vs 1% given placebo (95% CI, 14-37, P < .001). In a smaller cohort of 43 patients genetically pretested for likely response to the new biologic, remission after treatment was only slightly higher at 32% vs 11% (95% CI, 2-38, P = .02).
The incidence of adverse events was similar in both arms, and most events were mild.
The 12-week induction trial, conducted in 14 countries by the ARTEMIS-UC Study Group and led by Bruce E. Sands, MD, MS, AGAF, a professor of medicine at Icahn School of Medicine at Mount Sinai and system chief in the Division of Gastroenterology at Mount Sinai Health System in New York City, was published in The New England Journal of Medicine.
“Our results suggest that important clinical benefit may be achieved through TL1A blockade in patients with UC,” Dr. Sands said in an interview, adding that this is the first rigorous study of a drug class with an entirely new mechanism of action that may be beneficial in other immune-mediated and fibrotic diseases.
“And it is also the first prospective randomized controlled trial in IBD to incorporate a precision-medicine approach using a predictive biomarker for response in a drug development program,” he added.
Dr. Sands stressed the urgent need for new therapies since, despite the approval of multiple new classes of agents, both small molecules and biologics, “there is still a plateau of efficacy in that less than 50% of patients achieve remission at a year.”
He added that UC may progress over time owing to fibrosis of the bowel, a condition not directly or safely addressed by any existing therapies. “Identifying novel targets such as TL1A may allow us to address a different subpopulation of patients who may not respond to the targets addressed by existing therapies,” he said.
In agreement is Jason K. Hou, MD, MS, AGAF, an associate professor of medicine at Baylor College of Medicine and section chief of gastroenterology at Michael E. DeBakey VA Medical Center, both in Houston, Texas. “Although it’s a very exciting time with more options in the last few years for treating UC, even inhibitors with new agents such as JAK inhibitors and interleukin 23 antagonists, many patients have no or only a partial response,” he said in an interview. “Targeting molecules, which has been studied for decades, may offer more than a shot in the dark.”
Why Target TL1A?
Genome-wide studies have shown elevated TL1A, a member of the tumor necrosis factor superfamily, in patients with inflammatory bowel disease (IBD).
“The interaction of TL1A and its ligand, death domain receptor 3, contributes to the immune-mediated inflammation and fibrosis seen in IBD through the downstream production of proinflammatory cytokines by multiple different immune cells, and the elaboration of collagen by fibroblasts,” Dr. Sands explained.
With the intention of targeting TL1A, his group randomly assigned patients with moderate to severe active UC who were glucocorticoid dependent or had not responded to conventional or advanced therapies, with disease extending a minimum of 15 cm from the anal verge. Across arms, the age of the mainly White, non-Hispanic participants ranged from about 37 to about 42, 35%-53% were female, and disease duration was approximately 6-8 years.
The arms received either placebo or intravenous tulisokibart at 1000 mg on day 1 and 500 mg at weeks 2, 6, and 10. Cohort 1 included patients regardless of biomarker status for likelihood of response. Cohort 2 included only patients with a positive test for likelihood of response.
Dr. Hou was surprised that response to tulisokibart vs placebo was not greater in test-identified probable responders. “The biomarker didn’t make a huge difference, just a numerical one,” he said. “It may be that more genes are involved than the test could identify, and response is more complicated. Or perhaps the placebo response was particularly high in this small group. We need a deeper dive into why.”
Earlier Application?
“This was a phase 2 study, so it’s too soon to say if tulisokibart could be used as early therapy or in severe disease,” Sands said. “However, the excellent safety profile and efficacy suggest that these populations should be explored in later studies.
Further work is needed to validate the test to predict higher likelihood of response, he added, and recruiting for a phase 3 study is now underway.
The study was supported by Prometheus Biosciences, a subsidiary of Merck. Dr. Sands disclosed multiple ties to private companies, including research support, consulting, data safety monitoring, travel, a gift, and a stock option. Several coauthors reported, variously, research support from and/or consulting for multiple private companies. Others reported employment, variously, with Prometheus and/or Merck, Spyre Therapeutics, and Mirador Therapeutics, or patent holding for IBD drugs. Dr. Hou had no relevant competing interests to disclose but will participate in the phase 3 trial.
A version of this article appeared on Medscape.com.
In one cohort of 135 patients, the primary endpoint of clinical remission occurred in 26% of those given the novel antibody to tumor necrosis factor–like cytokine 1A (TL1A) vs 1% given placebo (95% CI, 14-37, P < .001). In a smaller cohort of 43 patients genetically pretested for likely response to the new biologic, remission after treatment was only slightly higher at 32% vs 11% (95% CI, 2-38, P = .02).
The incidence of adverse events was similar in both arms, and most events were mild.
The 12-week induction trial, conducted in 14 countries by the ARTEMIS-UC Study Group and led by Bruce E. Sands, MD, MS, AGAF, a professor of medicine at Icahn School of Medicine at Mount Sinai and system chief in the Division of Gastroenterology at Mount Sinai Health System in New York City, was published in The New England Journal of Medicine.
“Our results suggest that important clinical benefit may be achieved through TL1A blockade in patients with UC,” Dr. Sands said in an interview, adding that this is the first rigorous study of a drug class with an entirely new mechanism of action that may be beneficial in other immune-mediated and fibrotic diseases.
“And it is also the first prospective randomized controlled trial in IBD to incorporate a precision-medicine approach using a predictive biomarker for response in a drug development program,” he added.
Dr. Sands stressed the urgent need for new therapies since, despite the approval of multiple new classes of agents, both small molecules and biologics, “there is still a plateau of efficacy in that less than 50% of patients achieve remission at a year.”
He added that UC may progress over time owing to fibrosis of the bowel, a condition not directly or safely addressed by any existing therapies. “Identifying novel targets such as TL1A may allow us to address a different subpopulation of patients who may not respond to the targets addressed by existing therapies,” he said.
In agreement is Jason K. Hou, MD, MS, AGAF, an associate professor of medicine at Baylor College of Medicine and section chief of gastroenterology at Michael E. DeBakey VA Medical Center, both in Houston, Texas. “Although it’s a very exciting time with more options in the last few years for treating UC, even inhibitors with new agents such as JAK inhibitors and interleukin 23 antagonists, many patients have no or only a partial response,” he said in an interview. “Targeting molecules, which has been studied for decades, may offer more than a shot in the dark.”
Why Target TL1A?
Genome-wide studies have shown elevated TL1A, a member of the tumor necrosis factor superfamily, in patients with inflammatory bowel disease (IBD).
“The interaction of TL1A and its ligand, death domain receptor 3, contributes to the immune-mediated inflammation and fibrosis seen in IBD through the downstream production of proinflammatory cytokines by multiple different immune cells, and the elaboration of collagen by fibroblasts,” Dr. Sands explained.
With the intention of targeting TL1A, his group randomly assigned patients with moderate to severe active UC who were glucocorticoid dependent or had not responded to conventional or advanced therapies, with disease extending a minimum of 15 cm from the anal verge. Across arms, the age of the mainly White, non-Hispanic participants ranged from about 37 to about 42, 35%-53% were female, and disease duration was approximately 6-8 years.
The arms received either placebo or intravenous tulisokibart at 1000 mg on day 1 and 500 mg at weeks 2, 6, and 10. Cohort 1 included patients regardless of biomarker status for likelihood of response. Cohort 2 included only patients with a positive test for likelihood of response.
Dr. Hou was surprised that response to tulisokibart vs placebo was not greater in test-identified probable responders. “The biomarker didn’t make a huge difference, just a numerical one,” he said. “It may be that more genes are involved than the test could identify, and response is more complicated. Or perhaps the placebo response was particularly high in this small group. We need a deeper dive into why.”
Earlier Application?
“This was a phase 2 study, so it’s too soon to say if tulisokibart could be used as early therapy or in severe disease,” Sands said. “However, the excellent safety profile and efficacy suggest that these populations should be explored in later studies.
Further work is needed to validate the test to predict higher likelihood of response, he added, and recruiting for a phase 3 study is now underway.
The study was supported by Prometheus Biosciences, a subsidiary of Merck. Dr. Sands disclosed multiple ties to private companies, including research support, consulting, data safety monitoring, travel, a gift, and a stock option. Several coauthors reported, variously, research support from and/or consulting for multiple private companies. Others reported employment, variously, with Prometheus and/or Merck, Spyre Therapeutics, and Mirador Therapeutics, or patent holding for IBD drugs. Dr. Hou had no relevant competing interests to disclose but will participate in the phase 3 trial.
A version of this article appeared on Medscape.com.
In one cohort of 135 patients, the primary endpoint of clinical remission occurred in 26% of those given the novel antibody to tumor necrosis factor–like cytokine 1A (TL1A) vs 1% given placebo (95% CI, 14-37, P < .001). In a smaller cohort of 43 patients genetically pretested for likely response to the new biologic, remission after treatment was only slightly higher at 32% vs 11% (95% CI, 2-38, P = .02).
The incidence of adverse events was similar in both arms, and most events were mild.
The 12-week induction trial, conducted in 14 countries by the ARTEMIS-UC Study Group and led by Bruce E. Sands, MD, MS, AGAF, a professor of medicine at Icahn School of Medicine at Mount Sinai and system chief in the Division of Gastroenterology at Mount Sinai Health System in New York City, was published in The New England Journal of Medicine.
“Our results suggest that important clinical benefit may be achieved through TL1A blockade in patients with UC,” Dr. Sands said in an interview, adding that this is the first rigorous study of a drug class with an entirely new mechanism of action that may be beneficial in other immune-mediated and fibrotic diseases.
“And it is also the first prospective randomized controlled trial in IBD to incorporate a precision-medicine approach using a predictive biomarker for response in a drug development program,” he added.
Dr. Sands stressed the urgent need for new therapies since, despite the approval of multiple new classes of agents, both small molecules and biologics, “there is still a plateau of efficacy in that less than 50% of patients achieve remission at a year.”
He added that UC may progress over time owing to fibrosis of the bowel, a condition not directly or safely addressed by any existing therapies. “Identifying novel targets such as TL1A may allow us to address a different subpopulation of patients who may not respond to the targets addressed by existing therapies,” he said.
In agreement is Jason K. Hou, MD, MS, AGAF, an associate professor of medicine at Baylor College of Medicine and section chief of gastroenterology at Michael E. DeBakey VA Medical Center, both in Houston, Texas. “Although it’s a very exciting time with more options in the last few years for treating UC, even inhibitors with new agents such as JAK inhibitors and interleukin 23 antagonists, many patients have no or only a partial response,” he said in an interview. “Targeting molecules, which has been studied for decades, may offer more than a shot in the dark.”
Why Target TL1A?
Genome-wide studies have shown elevated TL1A, a member of the tumor necrosis factor superfamily, in patients with inflammatory bowel disease (IBD).
“The interaction of TL1A and its ligand, death domain receptor 3, contributes to the immune-mediated inflammation and fibrosis seen in IBD through the downstream production of proinflammatory cytokines by multiple different immune cells, and the elaboration of collagen by fibroblasts,” Dr. Sands explained.
With the intention of targeting TL1A, his group randomly assigned patients with moderate to severe active UC who were glucocorticoid dependent or had not responded to conventional or advanced therapies, with disease extending a minimum of 15 cm from the anal verge. Across arms, the age of the mainly White, non-Hispanic participants ranged from about 37 to about 42, 35%-53% were female, and disease duration was approximately 6-8 years.
The arms received either placebo or intravenous tulisokibart at 1000 mg on day 1 and 500 mg at weeks 2, 6, and 10. Cohort 1 included patients regardless of biomarker status for likelihood of response. Cohort 2 included only patients with a positive test for likelihood of response.
Dr. Hou was surprised that response to tulisokibart vs placebo was not greater in test-identified probable responders. “The biomarker didn’t make a huge difference, just a numerical one,” he said. “It may be that more genes are involved than the test could identify, and response is more complicated. Or perhaps the placebo response was particularly high in this small group. We need a deeper dive into why.”
Earlier Application?
“This was a phase 2 study, so it’s too soon to say if tulisokibart could be used as early therapy or in severe disease,” Sands said. “However, the excellent safety profile and efficacy suggest that these populations should be explored in later studies.
Further work is needed to validate the test to predict higher likelihood of response, he added, and recruiting for a phase 3 study is now underway.
The study was supported by Prometheus Biosciences, a subsidiary of Merck. Dr. Sands disclosed multiple ties to private companies, including research support, consulting, data safety monitoring, travel, a gift, and a stock option. Several coauthors reported, variously, research support from and/or consulting for multiple private companies. Others reported employment, variously, with Prometheus and/or Merck, Spyre Therapeutics, and Mirador Therapeutics, or patent holding for IBD drugs. Dr. Hou had no relevant competing interests to disclose but will participate in the phase 3 trial.
A version of this article appeared on Medscape.com.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Environmental Pollutants Play a Growing Role in IBD
The culprit environmental substances include heavy and transition metals, air pollutants, pesticides, and industrial contaminants. The latter encompass synthetic chemicals such as perfluoroalkyls and polyfluoroalkyls (PFAs), which are present in many common household products.
In contrast, zinc exposure may have a protective, anti-inflammatory effect, according to a research group led by Maria Manuela Estevinho, MD, of the Department of Gastroenterology of the Unidade Local de Saúde Gaia e Espinho in Vila Nova de Gaia, Portugal.
Published in Gut , the review also found limited data suggesting adverse IBD outcomes such as hospitalizations are more prevalent with increased exposure to air contaminants in particular.
“These data carry relevance toward counseling patients and family members,” coauthor Manasi Agrawal, MD, assistant professor of medicine at the Icahn School of Medicine, Mount Sinai, and a gastroenterologist at Mount Sinai Hospital in New York City, said in an interview. “At the individual level, we can try to decrease our exposure to chemicals; for example, to minimize use of pesticides and products containing in our homes. However, at the broader community level, health policy changes are needed to help with mitigation strategies and curb production.”
The physiological mechanisms by which pollutants raise IBD risk include an exaggerated immune response leading to systemic inflammation, loss of tight junction proteins leading to increased gut permeability, and dysbiosis of the intestinal microbiota.
The review found the following effects for various pollutants:
- Heavy and transition metals such as copper, lead, and cadmium were associated with gut dysbiosis, overgrowth of undesirable species of microorganisms, and loss of tight junction proteins leading to leaky gut. In all studies, individuals with IBD showed higher concentrations of such metals than healthy control individuals. While the specific profile of heavy metals varied across studies, lead, copper, and iron, were linked to IBD risk in more than one study.
- The particulate matter present in air pollution — including agricultural and wood dust as well as volcanic ash and hydrocarbon dioxin — was linked to dysbiosis and tight junction protein loss. Air pollution has also been linked to increased incidence of irritable bowel syndrome.
- Industrial and organic pollutants such as perfluoroalkyl and polyfluoroalkyl compounds, triclocarban, and polychlorinated biphenyls were also associated with gut permeability and/or reduced microbial diversity.
- Pesticides such as PFAs, organochloride and organophosphate compounds, and pyrethroids were associated with loss of tight junction proteins.
- Zinc was linked to an increase in tight junction proteins.
Commenting on the review but not involved in it, Ashwin N. Ananthakrishnan, MBBS, MD, MPH, AGAF, director of the Crohn’s and Colitis Center at Massachusetts General Hospital, and associate professor at Harvard Medical School in Boston, called it a very important study that expands our understanding of the role of environment in IBD.
“While traditionally studies have focused on dietary and other exposures related to personal behavior and lifestyle such as smoking, this expands consideration to exposures at the environmental level, where an individual may have less control,” he said in an interview.
“This shift could be critically important from a policy standpoint as modifying these risk factors may require more societal than individual efforts,” he added. He did offer a caveat, however. “While the review highlights several plausible associations, all of which merit further study, importantly, one should also avoid overinterpreting the results as there are very few high-quality studies that provide robust evidence of an association. So more work is needed.”
Recent research has suggested that environmental exposures affect IBD risk more than genetic predisposition.
As background to this review, the growing industrialization and consumerism of the developing world has seen the global number of IBD cases rise from 3.3 million in 1990 to an estimated 4.9 million in 2019, a jump of 47.5%. In the United States, IBD accounts for more than $25 billion in direct healthcare costs.
In terms of the near future, Dr. Agrawal said, “Next steps would be to measure various chemicals in pre-disease biological samples for objective assessment of the impact of chemicals on IBD risk, and such studies are already underway.”
That would mean using exposure biomarkers with high temporal resolution in preclinical samples, as well as advanced measurement techniques and machine-based composite data analysis to explain the IBD-pollutant relationship. “This approach may also provide insight into the role of different environmental insults in different stages of life and clarify whether the timing of exposure may be more critical than the duration,” the authors wrote.
Dr. Agrawal was supported by the National Institute of Diabetes and Digestive and Kidney Diseases, the International Organization For the Study of Inflammatory Bowel Disease, and the Crohn’s and Colitis Foundation. She reported consulting for Douglas Pharmaceuticals. Other authors reported lecture/consulting fees from multiple pharmaceutical/biomedical companies. Dr. Ananthakrishnan had no relevant conflicts of interest.
A version of this article appeared on Medscape.com.
The culprit environmental substances include heavy and transition metals, air pollutants, pesticides, and industrial contaminants. The latter encompass synthetic chemicals such as perfluoroalkyls and polyfluoroalkyls (PFAs), which are present in many common household products.
In contrast, zinc exposure may have a protective, anti-inflammatory effect, according to a research group led by Maria Manuela Estevinho, MD, of the Department of Gastroenterology of the Unidade Local de Saúde Gaia e Espinho in Vila Nova de Gaia, Portugal.
Published in Gut , the review also found limited data suggesting adverse IBD outcomes such as hospitalizations are more prevalent with increased exposure to air contaminants in particular.
“These data carry relevance toward counseling patients and family members,” coauthor Manasi Agrawal, MD, assistant professor of medicine at the Icahn School of Medicine, Mount Sinai, and a gastroenterologist at Mount Sinai Hospital in New York City, said in an interview. “At the individual level, we can try to decrease our exposure to chemicals; for example, to minimize use of pesticides and products containing in our homes. However, at the broader community level, health policy changes are needed to help with mitigation strategies and curb production.”
The physiological mechanisms by which pollutants raise IBD risk include an exaggerated immune response leading to systemic inflammation, loss of tight junction proteins leading to increased gut permeability, and dysbiosis of the intestinal microbiota.
The review found the following effects for various pollutants:
- Heavy and transition metals such as copper, lead, and cadmium were associated with gut dysbiosis, overgrowth of undesirable species of microorganisms, and loss of tight junction proteins leading to leaky gut. In all studies, individuals with IBD showed higher concentrations of such metals than healthy control individuals. While the specific profile of heavy metals varied across studies, lead, copper, and iron, were linked to IBD risk in more than one study.
- The particulate matter present in air pollution — including agricultural and wood dust as well as volcanic ash and hydrocarbon dioxin — was linked to dysbiosis and tight junction protein loss. Air pollution has also been linked to increased incidence of irritable bowel syndrome.
- Industrial and organic pollutants such as perfluoroalkyl and polyfluoroalkyl compounds, triclocarban, and polychlorinated biphenyls were also associated with gut permeability and/or reduced microbial diversity.
- Pesticides such as PFAs, organochloride and organophosphate compounds, and pyrethroids were associated with loss of tight junction proteins.
- Zinc was linked to an increase in tight junction proteins.
Commenting on the review but not involved in it, Ashwin N. Ananthakrishnan, MBBS, MD, MPH, AGAF, director of the Crohn’s and Colitis Center at Massachusetts General Hospital, and associate professor at Harvard Medical School in Boston, called it a very important study that expands our understanding of the role of environment in IBD.
“While traditionally studies have focused on dietary and other exposures related to personal behavior and lifestyle such as smoking, this expands consideration to exposures at the environmental level, where an individual may have less control,” he said in an interview.
“This shift could be critically important from a policy standpoint as modifying these risk factors may require more societal than individual efforts,” he added. He did offer a caveat, however. “While the review highlights several plausible associations, all of which merit further study, importantly, one should also avoid overinterpreting the results as there are very few high-quality studies that provide robust evidence of an association. So more work is needed.”
Recent research has suggested that environmental exposures affect IBD risk more than genetic predisposition.
As background to this review, the growing industrialization and consumerism of the developing world has seen the global number of IBD cases rise from 3.3 million in 1990 to an estimated 4.9 million in 2019, a jump of 47.5%. In the United States, IBD accounts for more than $25 billion in direct healthcare costs.
In terms of the near future, Dr. Agrawal said, “Next steps would be to measure various chemicals in pre-disease biological samples for objective assessment of the impact of chemicals on IBD risk, and such studies are already underway.”
That would mean using exposure biomarkers with high temporal resolution in preclinical samples, as well as advanced measurement techniques and machine-based composite data analysis to explain the IBD-pollutant relationship. “This approach may also provide insight into the role of different environmental insults in different stages of life and clarify whether the timing of exposure may be more critical than the duration,” the authors wrote.
Dr. Agrawal was supported by the National Institute of Diabetes and Digestive and Kidney Diseases, the International Organization For the Study of Inflammatory Bowel Disease, and the Crohn’s and Colitis Foundation. She reported consulting for Douglas Pharmaceuticals. Other authors reported lecture/consulting fees from multiple pharmaceutical/biomedical companies. Dr. Ananthakrishnan had no relevant conflicts of interest.
A version of this article appeared on Medscape.com.
The culprit environmental substances include heavy and transition metals, air pollutants, pesticides, and industrial contaminants. The latter encompass synthetic chemicals such as perfluoroalkyls and polyfluoroalkyls (PFAs), which are present in many common household products.
In contrast, zinc exposure may have a protective, anti-inflammatory effect, according to a research group led by Maria Manuela Estevinho, MD, of the Department of Gastroenterology of the Unidade Local de Saúde Gaia e Espinho in Vila Nova de Gaia, Portugal.
Published in Gut , the review also found limited data suggesting adverse IBD outcomes such as hospitalizations are more prevalent with increased exposure to air contaminants in particular.
“These data carry relevance toward counseling patients and family members,” coauthor Manasi Agrawal, MD, assistant professor of medicine at the Icahn School of Medicine, Mount Sinai, and a gastroenterologist at Mount Sinai Hospital in New York City, said in an interview. “At the individual level, we can try to decrease our exposure to chemicals; for example, to minimize use of pesticides and products containing in our homes. However, at the broader community level, health policy changes are needed to help with mitigation strategies and curb production.”
The physiological mechanisms by which pollutants raise IBD risk include an exaggerated immune response leading to systemic inflammation, loss of tight junction proteins leading to increased gut permeability, and dysbiosis of the intestinal microbiota.
The review found the following effects for various pollutants:
- Heavy and transition metals such as copper, lead, and cadmium were associated with gut dysbiosis, overgrowth of undesirable species of microorganisms, and loss of tight junction proteins leading to leaky gut. In all studies, individuals with IBD showed higher concentrations of such metals than healthy control individuals. While the specific profile of heavy metals varied across studies, lead, copper, and iron, were linked to IBD risk in more than one study.
- The particulate matter present in air pollution — including agricultural and wood dust as well as volcanic ash and hydrocarbon dioxin — was linked to dysbiosis and tight junction protein loss. Air pollution has also been linked to increased incidence of irritable bowel syndrome.
- Industrial and organic pollutants such as perfluoroalkyl and polyfluoroalkyl compounds, triclocarban, and polychlorinated biphenyls were also associated with gut permeability and/or reduced microbial diversity.
- Pesticides such as PFAs, organochloride and organophosphate compounds, and pyrethroids were associated with loss of tight junction proteins.
- Zinc was linked to an increase in tight junction proteins.
Commenting on the review but not involved in it, Ashwin N. Ananthakrishnan, MBBS, MD, MPH, AGAF, director of the Crohn’s and Colitis Center at Massachusetts General Hospital, and associate professor at Harvard Medical School in Boston, called it a very important study that expands our understanding of the role of environment in IBD.
“While traditionally studies have focused on dietary and other exposures related to personal behavior and lifestyle such as smoking, this expands consideration to exposures at the environmental level, where an individual may have less control,” he said in an interview.
“This shift could be critically important from a policy standpoint as modifying these risk factors may require more societal than individual efforts,” he added. He did offer a caveat, however. “While the review highlights several plausible associations, all of which merit further study, importantly, one should also avoid overinterpreting the results as there are very few high-quality studies that provide robust evidence of an association. So more work is needed.”
Recent research has suggested that environmental exposures affect IBD risk more than genetic predisposition.
As background to this review, the growing industrialization and consumerism of the developing world has seen the global number of IBD cases rise from 3.3 million in 1990 to an estimated 4.9 million in 2019, a jump of 47.5%. In the United States, IBD accounts for more than $25 billion in direct healthcare costs.
In terms of the near future, Dr. Agrawal said, “Next steps would be to measure various chemicals in pre-disease biological samples for objective assessment of the impact of chemicals on IBD risk, and such studies are already underway.”
That would mean using exposure biomarkers with high temporal resolution in preclinical samples, as well as advanced measurement techniques and machine-based composite data analysis to explain the IBD-pollutant relationship. “This approach may also provide insight into the role of different environmental insults in different stages of life and clarify whether the timing of exposure may be more critical than the duration,” the authors wrote.
Dr. Agrawal was supported by the National Institute of Diabetes and Digestive and Kidney Diseases, the International Organization For the Study of Inflammatory Bowel Disease, and the Crohn’s and Colitis Foundation. She reported consulting for Douglas Pharmaceuticals. Other authors reported lecture/consulting fees from multiple pharmaceutical/biomedical companies. Dr. Ananthakrishnan had no relevant conflicts of interest.
A version of this article appeared on Medscape.com.
Myth of the Month: Vitamin C vs the Common Cold
Case: A 38-year-old presents for acute onset runny nose, cough, and fever for the last 3 days. Her children at home have a similar presentation. She believes that she has been managing her symptoms well with Tylenol and rest. The patient is up to date on her COVID and flu shots and was wondering if there was anything else she could have done to prevent her symptoms. She saw a commercial about vitamin C supplements boosting the immune system and was wondering about their efficacy. How would you respond?
Studies of Vitamin C
Linus Pauling, FRS, did a summary of four relatively small published studies of vitamin C and concluded that vitamin C supplementation helped prevent and lessen colds.1 He mentioned a placebo-controlled study of vitamin C with viral inoculation which did not show any effect. His overall conclusion of efficacy for vitamin C led to the widespread belief that vitamin C was a proven effective therapy to prevent and treat the common cold. Since then, multiple trials and studies have examined the effect of vitamin C on the prevention and treatment of colds.
The Cochrane Review conducted a meta-analysis comparing 29 placebo-controlled trials involving 11,306 participants.2 Criteria included vitamin C supplementation of 0.2 g-1 g/day to study its efficacy in preventing the common cold. The analysis showed that supplemental vitamin C did not significantly reduce the incidence of colds. However, there was a statistically significant 8% reduction in adults and 14% in children in the duration of colds. In terms of treatment, there was no evidence of vitamin C’s efficacy.
A 2001 study conducted a small double-blind, randomized control trial to evaluate large doses of vitamin C as treatment for the common cold.3 Volunteers were divided and instructed to take varying doses ranging from 1 to 3 g of vitamin C vs a placebo at the onset of cold-like symptoms. Subjects were expected to assess the duration and severity of their cold. The data showed no significant difference in the severity or duration of cold symptoms between small or large vitamin C doses or placebo.
A more recent meta-analysis by Hemilä and Chalker looked at 10 placebo-controlled trials of vitamin C for the prevention and treatment of colds.4 The analysis showed a small 15% reduction in more severe cold symptoms.
Summary
While vitamin C is safe, there is no evidence for its ability to prevent the common cold. Although the Cochrane review and more a recent meta-analysis by Hemilä and Chalker demonstrated statistical significance in shortening the duration of symptoms, it was a minimal reduction with little clinical significance. .
Ms. Ibabao is a fourth year medical student at the University of Washington School of Medicine; Dr. Paauw is Professor of Medicine, Rathmann Family Foundation Endowed Chair Patient-centered Clinical Education, at the University of Washington School of Medicine, Seattle. They have no conflicts of interest.
References
1. Pauling L. The significance of the evidence about ascorbic acid and the common cold. Proc Natl Acad Sci USA. 1971;68:2678-2671.
2. Hemilä H, Chalker E. Vitamin C for preventing and treating the common cold. Cochrane Database of Systematic Reviews. 2013;1(1).
3. Audera C et al. Mega‐dose vitamin C in treatment of the common cold: a randomised controlled trial. Med J Australia. 2001;175(7):359-362.
4. Hemilä H, Chalker E. Vitamin C reduces the severity of common colds: a meta-analysis. BMC Public Health. 2023;23:2468.
Case: A 38-year-old presents for acute onset runny nose, cough, and fever for the last 3 days. Her children at home have a similar presentation. She believes that she has been managing her symptoms well with Tylenol and rest. The patient is up to date on her COVID and flu shots and was wondering if there was anything else she could have done to prevent her symptoms. She saw a commercial about vitamin C supplements boosting the immune system and was wondering about their efficacy. How would you respond?
Studies of Vitamin C
Linus Pauling, FRS, did a summary of four relatively small published studies of vitamin C and concluded that vitamin C supplementation helped prevent and lessen colds.1 He mentioned a placebo-controlled study of vitamin C with viral inoculation which did not show any effect. His overall conclusion of efficacy for vitamin C led to the widespread belief that vitamin C was a proven effective therapy to prevent and treat the common cold. Since then, multiple trials and studies have examined the effect of vitamin C on the prevention and treatment of colds.
The Cochrane Review conducted a meta-analysis comparing 29 placebo-controlled trials involving 11,306 participants.2 Criteria included vitamin C supplementation of 0.2 g-1 g/day to study its efficacy in preventing the common cold. The analysis showed that supplemental vitamin C did not significantly reduce the incidence of colds. However, there was a statistically significant 8% reduction in adults and 14% in children in the duration of colds. In terms of treatment, there was no evidence of vitamin C’s efficacy.
A 2001 study conducted a small double-blind, randomized control trial to evaluate large doses of vitamin C as treatment for the common cold.3 Volunteers were divided and instructed to take varying doses ranging from 1 to 3 g of vitamin C vs a placebo at the onset of cold-like symptoms. Subjects were expected to assess the duration and severity of their cold. The data showed no significant difference in the severity or duration of cold symptoms between small or large vitamin C doses or placebo.
A more recent meta-analysis by Hemilä and Chalker looked at 10 placebo-controlled trials of vitamin C for the prevention and treatment of colds.4 The analysis showed a small 15% reduction in more severe cold symptoms.
Summary
While vitamin C is safe, there is no evidence for its ability to prevent the common cold. Although the Cochrane review and more a recent meta-analysis by Hemilä and Chalker demonstrated statistical significance in shortening the duration of symptoms, it was a minimal reduction with little clinical significance. .
Ms. Ibabao is a fourth year medical student at the University of Washington School of Medicine; Dr. Paauw is Professor of Medicine, Rathmann Family Foundation Endowed Chair Patient-centered Clinical Education, at the University of Washington School of Medicine, Seattle. They have no conflicts of interest.
References
1. Pauling L. The significance of the evidence about ascorbic acid and the common cold. Proc Natl Acad Sci USA. 1971;68:2678-2671.
2. Hemilä H, Chalker E. Vitamin C for preventing and treating the common cold. Cochrane Database of Systematic Reviews. 2013;1(1).
3. Audera C et al. Mega‐dose vitamin C in treatment of the common cold: a randomised controlled trial. Med J Australia. 2001;175(7):359-362.
4. Hemilä H, Chalker E. Vitamin C reduces the severity of common colds: a meta-analysis. BMC Public Health. 2023;23:2468.
Case: A 38-year-old presents for acute onset runny nose, cough, and fever for the last 3 days. Her children at home have a similar presentation. She believes that she has been managing her symptoms well with Tylenol and rest. The patient is up to date on her COVID and flu shots and was wondering if there was anything else she could have done to prevent her symptoms. She saw a commercial about vitamin C supplements boosting the immune system and was wondering about their efficacy. How would you respond?
Studies of Vitamin C
Linus Pauling, FRS, did a summary of four relatively small published studies of vitamin C and concluded that vitamin C supplementation helped prevent and lessen colds.1 He mentioned a placebo-controlled study of vitamin C with viral inoculation which did not show any effect. His overall conclusion of efficacy for vitamin C led to the widespread belief that vitamin C was a proven effective therapy to prevent and treat the common cold. Since then, multiple trials and studies have examined the effect of vitamin C on the prevention and treatment of colds.
The Cochrane Review conducted a meta-analysis comparing 29 placebo-controlled trials involving 11,306 participants.2 Criteria included vitamin C supplementation of 0.2 g-1 g/day to study its efficacy in preventing the common cold. The analysis showed that supplemental vitamin C did not significantly reduce the incidence of colds. However, there was a statistically significant 8% reduction in adults and 14% in children in the duration of colds. In terms of treatment, there was no evidence of vitamin C’s efficacy.
A 2001 study conducted a small double-blind, randomized control trial to evaluate large doses of vitamin C as treatment for the common cold.3 Volunteers were divided and instructed to take varying doses ranging from 1 to 3 g of vitamin C vs a placebo at the onset of cold-like symptoms. Subjects were expected to assess the duration and severity of their cold. The data showed no significant difference in the severity or duration of cold symptoms between small or large vitamin C doses or placebo.
A more recent meta-analysis by Hemilä and Chalker looked at 10 placebo-controlled trials of vitamin C for the prevention and treatment of colds.4 The analysis showed a small 15% reduction in more severe cold symptoms.
Summary
While vitamin C is safe, there is no evidence for its ability to prevent the common cold. Although the Cochrane review and more a recent meta-analysis by Hemilä and Chalker demonstrated statistical significance in shortening the duration of symptoms, it was a minimal reduction with little clinical significance. .
Ms. Ibabao is a fourth year medical student at the University of Washington School of Medicine; Dr. Paauw is Professor of Medicine, Rathmann Family Foundation Endowed Chair Patient-centered Clinical Education, at the University of Washington School of Medicine, Seattle. They have no conflicts of interest.
References
1. Pauling L. The significance of the evidence about ascorbic acid and the common cold. Proc Natl Acad Sci USA. 1971;68:2678-2671.
2. Hemilä H, Chalker E. Vitamin C for preventing and treating the common cold. Cochrane Database of Systematic Reviews. 2013;1(1).
3. Audera C et al. Mega‐dose vitamin C in treatment of the common cold: a randomised controlled trial. Med J Australia. 2001;175(7):359-362.
4. Hemilä H, Chalker E. Vitamin C reduces the severity of common colds: a meta-analysis. BMC Public Health. 2023;23:2468.
The New Formula for Stronger, Longer-Lasting Vaccines
Vaccines work pretty well. But with a little help, they could work better.
Stanford researchers have developed a new vaccine helper that combines two kinds of adjuvants, ingredients that improve a vaccine’s efficacy, in a novel, customizable system.
In lab tests, the experimental additive improved the effectiveness of COVID-19 and HIV vaccine candidates, though it could be adapted to stimulate immune responses to a variety of pathogens, the researchers said. It could also be used one day to fine-tune vaccines for vulnerable groups like young children, older adults, and those with compromised immune systems.
“Current vaccines are not perfect,” said lead study author Ben Ou, a PhD candidate and researcher in the lab of Eric Appel, PhD, an associate professor of materials science and engineering, at Stanford University in California. “Many fail to generate long-lasting immunity or immunity against closely related strains [such as] flu or COVID vaccines. One way to improve them is to design more potent vaccine adjuvants.”
The study marks an advance in an area of growing scientific interest: Combining different adjuvants to enhance the immune-stimulating effect.
The Stanford scientists developed sphere-shaped nanoparticles, like tiny round cages, made of saponins, immune-stimulating molecules common in adjuvant development. To these nanoparticles, they attached Toll-like receptor (TLR) agonists, molecules that have become a focus in vaccine research because they stimulate a variety of immune responses.
Dr. Ou and the team tested the new adjuvant platform in COVID and HIV vaccines, comparing it to vaccines containing alum, a widely used adjuvant. (Alum is not used in COVID vaccines available in the United States.)
The nanoparticle-adjuvanted vaccines triggered stronger, longer-lasting effects.
Notably, the combination of the new adjuvant system with a SARS-CoV-2 virus vaccine was effective in mice against the original SARS-CoV-2 virus and against Delta, Omicron, and other variants that emerged in the months and years after the initial outbreak.
“Since our nanoparticle adjuvant platform is more potent than traditional/clinical vaccine adjuvants,” Dr. Ou said, “we expected mice to produce broadly neutralizing antibodies and better breadth responses.”
100 Years of Adjuvants
The first vaccine adjuvants were aluminum salts mixed into shots against pertussis, diphtheria, and tetanus in the 1920s. Today, alum is still used in many vaccines, including shots for diphtheria, tetanus, and pertussis; hepatitis A and B; human papillomavirus; and pneumococcal disease.
But since the 1990s, new adjuvants have come on the scene. Saponin-based compounds, harvested from the soapbark tree, are used in the Novavax COVID-19 Vaccine, Adjuvanted; a synthetic DNA adjuvant in the Heplisav-B vaccine against hepatitis B; and oil in water adjuvants using squalene in the Fluad and Fluad Quadrivalent influenza vaccines. Other vaccines, including those for chickenpox, cholera, measles, mumps, rubella, and mRNA-based COVID vaccines from Pfizer-BioNTech and Moderna, don’t contain adjuvants.
TLR agonists have recently become research hotspots in vaccine science.
“TLR agonists activate the innate immune system, putting it on a heightened alert state that can result in a higher antibody production and longer-lasting protection,” said David Burkhart, PhD, a research professor in biomedical and pharmaceutical sciences at the University of Montana in Missoula. He is also the chief operating officer of Inimmune, a biotech company developing vaccines and immunotherapies.
Dr. Burkhart studies TLR agonists in vaccines and other applications. “Different combinations activate different parts of the immune system,” he said. “TLR4 might activate the army, while TLR7 might activate the air force. You might need both in one vaccine.”
TLR agonists have also shown promise against Alzheimer’s disease, allergies, cancer, and even addiction. In immune’s experimental immunotherapy using TLR agonists for advanced solid tumors has just entered human trials, and the company is looking at a TLR agonist therapy for allergic rhinitis.
Combining Forces
In the new study, researchers tested five different combinations of TLR agonists hooked to the saponin nanoparticle framework. Each elicited a slightly different response from the immune cells.
“Our immune systems generate different downstream immune responses based on which TLRs are activated,” Dr. Ou said.
Ultimately, the advance could spur the development of vaccines tuned for stronger immune protection.
“We need different immune responses to fight different types of pathogens,” Dr. Ou said. “Depending on what specific virus/disease the vaccine is formulated for, activation of one specific TLR may confer better protection than another TLR.”
According to Dr. Burkhart, combining a saponin with a TLR agonist has found success before.
Biopharma company GSK (formerly GlaxoSmithKline) used the combination in its AS01 adjuvant, in the vaccine Shingrix against herpes zoster. The live-attenuated yellow fever vaccine, given to more than 600 million people around the world and considered one of the most powerful vaccines ever developed, uses several TLR agonists.
The Stanford paper, Dr. Burkhart said, “is a nice demonstration of the enhanced efficacy [that] adjuvants can provide to vaccines by exploiting the synergy different adjuvants and TLR agonists can provide when used in combination.”
Tailoring Vaccines
The customizable aspect of TLR agonists is important too, Dr. Burkhart said.
“The human immune system changes dramatically from birth to childhood into adulthood into older maturity,” he said. “It’s not a one-size-fits-all. Vaccines need to be tailored to these populations for maximum effectiveness and safety. TLRAs [TLR agonists] are a highly valuable tool in the vaccine toolbox. I think it’s inevitable we’ll have more in the future.”
That’s what the Stanford researchers hope for.
They noted in the study that the nanoparticle platform could easily be used to test different TLR agonist adjuvant combinations in vaccines.
But human studies are still a ways off. Tests in larger animals would likely come next, Dr. Ou said.
“We now have a single nanoparticle adjuvant platform with formulations containing different TLRs,” Dr. Ou said. “Scientists can pick which specific formulation is the most suitable for their needs.”
A version of this article first appeared on Medscape.com.
Vaccines work pretty well. But with a little help, they could work better.
Stanford researchers have developed a new vaccine helper that combines two kinds of adjuvants, ingredients that improve a vaccine’s efficacy, in a novel, customizable system.
In lab tests, the experimental additive improved the effectiveness of COVID-19 and HIV vaccine candidates, though it could be adapted to stimulate immune responses to a variety of pathogens, the researchers said. It could also be used one day to fine-tune vaccines for vulnerable groups like young children, older adults, and those with compromised immune systems.
“Current vaccines are not perfect,” said lead study author Ben Ou, a PhD candidate and researcher in the lab of Eric Appel, PhD, an associate professor of materials science and engineering, at Stanford University in California. “Many fail to generate long-lasting immunity or immunity against closely related strains [such as] flu or COVID vaccines. One way to improve them is to design more potent vaccine adjuvants.”
The study marks an advance in an area of growing scientific interest: Combining different adjuvants to enhance the immune-stimulating effect.
The Stanford scientists developed sphere-shaped nanoparticles, like tiny round cages, made of saponins, immune-stimulating molecules common in adjuvant development. To these nanoparticles, they attached Toll-like receptor (TLR) agonists, molecules that have become a focus in vaccine research because they stimulate a variety of immune responses.
Dr. Ou and the team tested the new adjuvant platform in COVID and HIV vaccines, comparing it to vaccines containing alum, a widely used adjuvant. (Alum is not used in COVID vaccines available in the United States.)
The nanoparticle-adjuvanted vaccines triggered stronger, longer-lasting effects.
Notably, the combination of the new adjuvant system with a SARS-CoV-2 virus vaccine was effective in mice against the original SARS-CoV-2 virus and against Delta, Omicron, and other variants that emerged in the months and years after the initial outbreak.
“Since our nanoparticle adjuvant platform is more potent than traditional/clinical vaccine adjuvants,” Dr. Ou said, “we expected mice to produce broadly neutralizing antibodies and better breadth responses.”
100 Years of Adjuvants
The first vaccine adjuvants were aluminum salts mixed into shots against pertussis, diphtheria, and tetanus in the 1920s. Today, alum is still used in many vaccines, including shots for diphtheria, tetanus, and pertussis; hepatitis A and B; human papillomavirus; and pneumococcal disease.
But since the 1990s, new adjuvants have come on the scene. Saponin-based compounds, harvested from the soapbark tree, are used in the Novavax COVID-19 Vaccine, Adjuvanted; a synthetic DNA adjuvant in the Heplisav-B vaccine against hepatitis B; and oil in water adjuvants using squalene in the Fluad and Fluad Quadrivalent influenza vaccines. Other vaccines, including those for chickenpox, cholera, measles, mumps, rubella, and mRNA-based COVID vaccines from Pfizer-BioNTech and Moderna, don’t contain adjuvants.
TLR agonists have recently become research hotspots in vaccine science.
“TLR agonists activate the innate immune system, putting it on a heightened alert state that can result in a higher antibody production and longer-lasting protection,” said David Burkhart, PhD, a research professor in biomedical and pharmaceutical sciences at the University of Montana in Missoula. He is also the chief operating officer of Inimmune, a biotech company developing vaccines and immunotherapies.
Dr. Burkhart studies TLR agonists in vaccines and other applications. “Different combinations activate different parts of the immune system,” he said. “TLR4 might activate the army, while TLR7 might activate the air force. You might need both in one vaccine.”
TLR agonists have also shown promise against Alzheimer’s disease, allergies, cancer, and even addiction. In immune’s experimental immunotherapy using TLR agonists for advanced solid tumors has just entered human trials, and the company is looking at a TLR agonist therapy for allergic rhinitis.
Combining Forces
In the new study, researchers tested five different combinations of TLR agonists hooked to the saponin nanoparticle framework. Each elicited a slightly different response from the immune cells.
“Our immune systems generate different downstream immune responses based on which TLRs are activated,” Dr. Ou said.
Ultimately, the advance could spur the development of vaccines tuned for stronger immune protection.
“We need different immune responses to fight different types of pathogens,” Dr. Ou said. “Depending on what specific virus/disease the vaccine is formulated for, activation of one specific TLR may confer better protection than another TLR.”
According to Dr. Burkhart, combining a saponin with a TLR agonist has found success before.
Biopharma company GSK (formerly GlaxoSmithKline) used the combination in its AS01 adjuvant, in the vaccine Shingrix against herpes zoster. The live-attenuated yellow fever vaccine, given to more than 600 million people around the world and considered one of the most powerful vaccines ever developed, uses several TLR agonists.
The Stanford paper, Dr. Burkhart said, “is a nice demonstration of the enhanced efficacy [that] adjuvants can provide to vaccines by exploiting the synergy different adjuvants and TLR agonists can provide when used in combination.”
Tailoring Vaccines
The customizable aspect of TLR agonists is important too, Dr. Burkhart said.
“The human immune system changes dramatically from birth to childhood into adulthood into older maturity,” he said. “It’s not a one-size-fits-all. Vaccines need to be tailored to these populations for maximum effectiveness and safety. TLRAs [TLR agonists] are a highly valuable tool in the vaccine toolbox. I think it’s inevitable we’ll have more in the future.”
That’s what the Stanford researchers hope for.
They noted in the study that the nanoparticle platform could easily be used to test different TLR agonist adjuvant combinations in vaccines.
But human studies are still a ways off. Tests in larger animals would likely come next, Dr. Ou said.
“We now have a single nanoparticle adjuvant platform with formulations containing different TLRs,” Dr. Ou said. “Scientists can pick which specific formulation is the most suitable for their needs.”
A version of this article first appeared on Medscape.com.
Vaccines work pretty well. But with a little help, they could work better.
Stanford researchers have developed a new vaccine helper that combines two kinds of adjuvants, ingredients that improve a vaccine’s efficacy, in a novel, customizable system.
In lab tests, the experimental additive improved the effectiveness of COVID-19 and HIV vaccine candidates, though it could be adapted to stimulate immune responses to a variety of pathogens, the researchers said. It could also be used one day to fine-tune vaccines for vulnerable groups like young children, older adults, and those with compromised immune systems.
“Current vaccines are not perfect,” said lead study author Ben Ou, a PhD candidate and researcher in the lab of Eric Appel, PhD, an associate professor of materials science and engineering, at Stanford University in California. “Many fail to generate long-lasting immunity or immunity against closely related strains [such as] flu or COVID vaccines. One way to improve them is to design more potent vaccine adjuvants.”
The study marks an advance in an area of growing scientific interest: Combining different adjuvants to enhance the immune-stimulating effect.
The Stanford scientists developed sphere-shaped nanoparticles, like tiny round cages, made of saponins, immune-stimulating molecules common in adjuvant development. To these nanoparticles, they attached Toll-like receptor (TLR) agonists, molecules that have become a focus in vaccine research because they stimulate a variety of immune responses.
Dr. Ou and the team tested the new adjuvant platform in COVID and HIV vaccines, comparing it to vaccines containing alum, a widely used adjuvant. (Alum is not used in COVID vaccines available in the United States.)
The nanoparticle-adjuvanted vaccines triggered stronger, longer-lasting effects.
Notably, the combination of the new adjuvant system with a SARS-CoV-2 virus vaccine was effective in mice against the original SARS-CoV-2 virus and against Delta, Omicron, and other variants that emerged in the months and years after the initial outbreak.
“Since our nanoparticle adjuvant platform is more potent than traditional/clinical vaccine adjuvants,” Dr. Ou said, “we expected mice to produce broadly neutralizing antibodies and better breadth responses.”
100 Years of Adjuvants
The first vaccine adjuvants were aluminum salts mixed into shots against pertussis, diphtheria, and tetanus in the 1920s. Today, alum is still used in many vaccines, including shots for diphtheria, tetanus, and pertussis; hepatitis A and B; human papillomavirus; and pneumococcal disease.
But since the 1990s, new adjuvants have come on the scene. Saponin-based compounds, harvested from the soapbark tree, are used in the Novavax COVID-19 Vaccine, Adjuvanted; a synthetic DNA adjuvant in the Heplisav-B vaccine against hepatitis B; and oil in water adjuvants using squalene in the Fluad and Fluad Quadrivalent influenza vaccines. Other vaccines, including those for chickenpox, cholera, measles, mumps, rubella, and mRNA-based COVID vaccines from Pfizer-BioNTech and Moderna, don’t contain adjuvants.
TLR agonists have recently become research hotspots in vaccine science.
“TLR agonists activate the innate immune system, putting it on a heightened alert state that can result in a higher antibody production and longer-lasting protection,” said David Burkhart, PhD, a research professor in biomedical and pharmaceutical sciences at the University of Montana in Missoula. He is also the chief operating officer of Inimmune, a biotech company developing vaccines and immunotherapies.
Dr. Burkhart studies TLR agonists in vaccines and other applications. “Different combinations activate different parts of the immune system,” he said. “TLR4 might activate the army, while TLR7 might activate the air force. You might need both in one vaccine.”
TLR agonists have also shown promise against Alzheimer’s disease, allergies, cancer, and even addiction. In immune’s experimental immunotherapy using TLR agonists for advanced solid tumors has just entered human trials, and the company is looking at a TLR agonist therapy for allergic rhinitis.
Combining Forces
In the new study, researchers tested five different combinations of TLR agonists hooked to the saponin nanoparticle framework. Each elicited a slightly different response from the immune cells.
“Our immune systems generate different downstream immune responses based on which TLRs are activated,” Dr. Ou said.
Ultimately, the advance could spur the development of vaccines tuned for stronger immune protection.
“We need different immune responses to fight different types of pathogens,” Dr. Ou said. “Depending on what specific virus/disease the vaccine is formulated for, activation of one specific TLR may confer better protection than another TLR.”
According to Dr. Burkhart, combining a saponin with a TLR agonist has found success before.
Biopharma company GSK (formerly GlaxoSmithKline) used the combination in its AS01 adjuvant, in the vaccine Shingrix against herpes zoster. The live-attenuated yellow fever vaccine, given to more than 600 million people around the world and considered one of the most powerful vaccines ever developed, uses several TLR agonists.
The Stanford paper, Dr. Burkhart said, “is a nice demonstration of the enhanced efficacy [that] adjuvants can provide to vaccines by exploiting the synergy different adjuvants and TLR agonists can provide when used in combination.”
Tailoring Vaccines
The customizable aspect of TLR agonists is important too, Dr. Burkhart said.
“The human immune system changes dramatically from birth to childhood into adulthood into older maturity,” he said. “It’s not a one-size-fits-all. Vaccines need to be tailored to these populations for maximum effectiveness and safety. TLRAs [TLR agonists] are a highly valuable tool in the vaccine toolbox. I think it’s inevitable we’ll have more in the future.”
That’s what the Stanford researchers hope for.
They noted in the study that the nanoparticle platform could easily be used to test different TLR agonist adjuvant combinations in vaccines.
But human studies are still a ways off. Tests in larger animals would likely come next, Dr. Ou said.
“We now have a single nanoparticle adjuvant platform with formulations containing different TLRs,” Dr. Ou said. “Scientists can pick which specific formulation is the most suitable for their needs.”
A version of this article first appeared on Medscape.com.
FROM SCIENCE ADVANCES
Celiac Disease: Five Things to Know
Celiac disease is a chronic, immune-mediated, systemic disorder caused by intolerance to gluten — a protein present in rye, barley, and wheat grains — that affects genetically predisposed individuals.
Due to its wide spectrum of clinical manifestations, celiac disease resembles a multisystemic disorder. Its most common gastrointestinal (GI) symptoms include chronic diarrhea, weight loss, and abdominal distention. However, celiac disease can also manifest in myriad extraintestinal symptoms, ranging from headache and fatigue to delayed puberty and psychiatric disorders, with differing presentations in children and adults.
To date, the only treatment is adopting a gluten-free diet (GFD). Although key to preventing persistent villous atrophy, the main cause of complications in celiac disease, lifelong adherence to GFD is challenging and may not resolve all clinical issues. These shortcomings have driven recent efforts to develop novel therapeutic options for patients with this disease.
Here are five things to know about celiac disease.
1. Rising Prevalence of Celiac Disease and Other Autoimmune Disorders Suggests Environmental Factors May Be at Play
Gluten was first identified as the cause of celiac disease in the 1950s. At that time, the condition was thought to be a relatively rare GI disease of childhood that primarily affected people of European descent, but it is now known to be a common disease affecting those of various ages, races, and ethnicities.
A 2018 meta-analysis found the pooled global prevalence of celiac disease was 1.4%. Incidence has increased by as much as 7.5% annually over the past several decades.
Increased awareness among clinicians and improved detection likely play a role in the trend. However, the growth in celiac disease is consistent with that seen for other autoimmune disorders, according to a 2024 update of evidence surrounding celiac disease. Shared environmental factors have been proposed as triggers for celiac disease and other autoimmune diseases and appear to be influencing their rise, the authors noted. These factors include migration and population growth, changing dietary patterns and food processing practices, and altered wheat consumption.
2. No-Biopsy Diagnosis Is Accepted for Children and Shows Promise for Adults
It is estimated that almost 60 million people worldwide have celiac disease, but most remain undiagnosed or misdiagnosed, or they experience significant diagnostic delays.
Prospective data indicate that children with first-degree relatives with celiac disease are at a significantly higher risk of developing the condition, which should prompt screening efforts in this population.
The 2023 updated guidelines from the American College of Gastroenterology (ACG) state that serology testing plays a central role in screening. This commonly involves serological testing for positive serological markers of the disease, including immunoglobulin A (IgA), anti-tissue transglutaminase IgA (tTG-IgA), anti-deamidated gliadin peptide, or endomysial antibodies.
To confirm diagnosis, clinicians have relied on intestinal biopsy since the late 1950s. The ACG still recommends esophagogastroduodenoscopy with multiple duodenal biopsies for confirmation of diagnosis in both children and adults with suspicion of celiac disease. However, recent years have seen a shift toward a no-biopsy approach.
For more than a decade in Europe, a no-biopsy approach has been established practice in pediatric patients, for whom the burden of obtaining a histological confirmation is understandably greater. Most guidelines now permit children to be diagnosed with celiac disease in the absence of a biopsy under specific circumstances (eg, characteristic symptoms of celiac disease and tTG-IgA levels > 10 times the upper limit of normal). The ACG guidelines state that “this approach is a reasonable alternative to the standard approach to a [celiac disease] diagnosis in selected children.”
The ACG does not recommend a no-biopsy approach in adults, noting that, in comparison with children, there is a relative lack of data indicating that serology is predictive in this population. However, it does recognize that physicians may encounter patients for whom a biopsy diagnosis may not be safe or practical. In such cases, an “after-the-fact” diagnosis of likely celiac disease can be given to symptomatic adult patients with a ≥ 10-fold elevation of tTG-IgA and a positive endomysial antibody in a second blood sample.
A 2024 meta-analysis of 18 studies involving over 12,103 adult patients from 15 countries concluded that a no-biopsy approach using tTG-IgA antibody levels ≥ 10 times the upper limit of normal was highly specific and predictive of celiac disease.
3. Celiac Disease Is Associated With Several Life-Threatening Conditions
Emerging data indicate that gastroenterologists should be vigilant in screening patients with celiac disease for several other GI conditions.
Inflammatory bowel disease and celiac disease have a strong bidirectional association, suggesting a possible genetic link between the conditions and indicating that physicians should consider the alternate diagnosis when symptoms persist after treatment.
Given the hypervigilance around food and diet inherent to celiac disease, patients are at an increased risk of developing avoidant/restrictive food intake disorder, according to a 2022 retrospective study.
In 2023, Italian investigators showed that children with celiac disease have an elevated prevalence of functional GI disorders even after adopting a GFD for a year, regardless of whether they consumed processed or natural foods. It was unclear whether this was due to a chronic inflammatory process or to nutritional factors.
Complications resulting from celiac disease are not limited to GI disorders. For a variety of underlying pathophysiological reasons, including intestinal permeability, hyposplenism, and malabsorption of nutrients, patients with celiac disease may be at a higher risk for non-GI conditions, such as osteopenia, women’s health disorders (eg, ovarian failure, endometriosis, or pregnancy loss), juvenile idiopathic arthritis in children and rheumatoid arthritis in adults, certain forms of cancer, infectious diseases, and cardiomyopathy.
4. GFD Is the Only Treatment, but It’s Imperfect and Frustrating for Patients
GFD is the only treatment for celiac disease and must be adhered to without deviation throughout a patient’s life.
Maintaining unwavering adherence reaps considerable benefits: Improved clinical symptoms, robust mucosal healing, and normalization of serological markers. Yet it also takes a considerable toll on patients. Patients with celiac disease struggle with a host of negative physical, psychological, and social impacts. They also report a higher treatment burden than those with gastroesophageal reflux disease or hypertension, and comparable with end-stage renal disease.
GFD also poses financial challenges. Although the price of gluten-free products has decreased in recent years, they still cost significantly more than items with gluten.
Adherence to GFD does not always equate to complete mucosal recovery. While mucosal recovery is achieved in 95% of children within 2 years of the diet’s adoption, only 34% and 66% of adults obtain it within 2 and 5 years, respectively.
GFD may lead to nutrient imbalances because gluten-free foods are typically low in alimentary fiber, micronutrients (eg, vitamin D, vitamin B12, or folate), and minerals (eg, iron, zinc, magnesium, or calcium). With higher sugar and fat content, GFD may leave patients susceptible to unwanted weight gain.
The pervasiveness of gluten in the food production system makes the risk for cross-contamination high. Gluten is often found in both naturally gluten-free foods and products labeled as such. Gluten-sensing technologies, some of which can be used via smartphone apps, have been developed to help patients identify possible cross-contamination. However, the ACG guidelines recommend against the use of these technologies until there is sufficient evidence supporting their ability to improve adherence and clinical outcomes.
5. Novel Therapies for Celiac Disease Are in the Pipeline
The limitations of GFD as the standard treatment for celiac disease have led to an increased focus on developing novel therapeutic interventions. They can be sorted into five key categories: Modulation of the immunostimulatory effects of toxic gluten peptides, elimination of toxic gluten peptides before they reach the intestine, induction of gluten tolerance, modulation of intestinal permeability, and restoration of gut microbiota balance.
Three therapies designed to block antigen presentation by HLA-DQ2/8, the gene alleles that predispose people to celiac disease, show promise: TPM502, an agent that contains three gluten-specific antigenic peptides with overlapping T-cell epitopes for the HLA-DQ2.5 gene; KAN-101, designed to induce gluten tolerance by targeting receptors on the liver; and DONQ52, a multi-specific antibody that targets HLA-DQ2. The KAN-101 therapy received Fast Track designation by the US Food and Drug Administration in 2022.
These and several other agents in clinical and preclinical development are discussed in detail in a 2024 review article. Although no therapies have reached phase 3 testing, when they do, it will undoubtedly be welcomed by those with celiac disease.
A version of this article first appeared on Medscape.com.
Celiac disease is a chronic, immune-mediated, systemic disorder caused by intolerance to gluten — a protein present in rye, barley, and wheat grains — that affects genetically predisposed individuals.
Due to its wide spectrum of clinical manifestations, celiac disease resembles a multisystemic disorder. Its most common gastrointestinal (GI) symptoms include chronic diarrhea, weight loss, and abdominal distention. However, celiac disease can also manifest in myriad extraintestinal symptoms, ranging from headache and fatigue to delayed puberty and psychiatric disorders, with differing presentations in children and adults.
To date, the only treatment is adopting a gluten-free diet (GFD). Although key to preventing persistent villous atrophy, the main cause of complications in celiac disease, lifelong adherence to GFD is challenging and may not resolve all clinical issues. These shortcomings have driven recent efforts to develop novel therapeutic options for patients with this disease.
Here are five things to know about celiac disease.
1. Rising Prevalence of Celiac Disease and Other Autoimmune Disorders Suggests Environmental Factors May Be at Play
Gluten was first identified as the cause of celiac disease in the 1950s. At that time, the condition was thought to be a relatively rare GI disease of childhood that primarily affected people of European descent, but it is now known to be a common disease affecting those of various ages, races, and ethnicities.
A 2018 meta-analysis found the pooled global prevalence of celiac disease was 1.4%. Incidence has increased by as much as 7.5% annually over the past several decades.
Increased awareness among clinicians and improved detection likely play a role in the trend. However, the growth in celiac disease is consistent with that seen for other autoimmune disorders, according to a 2024 update of evidence surrounding celiac disease. Shared environmental factors have been proposed as triggers for celiac disease and other autoimmune diseases and appear to be influencing their rise, the authors noted. These factors include migration and population growth, changing dietary patterns and food processing practices, and altered wheat consumption.
2. No-Biopsy Diagnosis Is Accepted for Children and Shows Promise for Adults
It is estimated that almost 60 million people worldwide have celiac disease, but most remain undiagnosed or misdiagnosed, or they experience significant diagnostic delays.
Prospective data indicate that children with first-degree relatives with celiac disease are at a significantly higher risk of developing the condition, which should prompt screening efforts in this population.
The 2023 updated guidelines from the American College of Gastroenterology (ACG) state that serology testing plays a central role in screening. This commonly involves serological testing for positive serological markers of the disease, including immunoglobulin A (IgA), anti-tissue transglutaminase IgA (tTG-IgA), anti-deamidated gliadin peptide, or endomysial antibodies.
To confirm diagnosis, clinicians have relied on intestinal biopsy since the late 1950s. The ACG still recommends esophagogastroduodenoscopy with multiple duodenal biopsies for confirmation of diagnosis in both children and adults with suspicion of celiac disease. However, recent years have seen a shift toward a no-biopsy approach.
For more than a decade in Europe, a no-biopsy approach has been established practice in pediatric patients, for whom the burden of obtaining a histological confirmation is understandably greater. Most guidelines now permit children to be diagnosed with celiac disease in the absence of a biopsy under specific circumstances (eg, characteristic symptoms of celiac disease and tTG-IgA levels > 10 times the upper limit of normal). The ACG guidelines state that “this approach is a reasonable alternative to the standard approach to a [celiac disease] diagnosis in selected children.”
The ACG does not recommend a no-biopsy approach in adults, noting that, in comparison with children, there is a relative lack of data indicating that serology is predictive in this population. However, it does recognize that physicians may encounter patients for whom a biopsy diagnosis may not be safe or practical. In such cases, an “after-the-fact” diagnosis of likely celiac disease can be given to symptomatic adult patients with a ≥ 10-fold elevation of tTG-IgA and a positive endomysial antibody in a second blood sample.
A 2024 meta-analysis of 18 studies involving over 12,103 adult patients from 15 countries concluded that a no-biopsy approach using tTG-IgA antibody levels ≥ 10 times the upper limit of normal was highly specific and predictive of celiac disease.
3. Celiac Disease Is Associated With Several Life-Threatening Conditions
Emerging data indicate that gastroenterologists should be vigilant in screening patients with celiac disease for several other GI conditions.
Inflammatory bowel disease and celiac disease have a strong bidirectional association, suggesting a possible genetic link between the conditions and indicating that physicians should consider the alternate diagnosis when symptoms persist after treatment.
Given the hypervigilance around food and diet inherent to celiac disease, patients are at an increased risk of developing avoidant/restrictive food intake disorder, according to a 2022 retrospective study.
In 2023, Italian investigators showed that children with celiac disease have an elevated prevalence of functional GI disorders even after adopting a GFD for a year, regardless of whether they consumed processed or natural foods. It was unclear whether this was due to a chronic inflammatory process or to nutritional factors.
Complications resulting from celiac disease are not limited to GI disorders. For a variety of underlying pathophysiological reasons, including intestinal permeability, hyposplenism, and malabsorption of nutrients, patients with celiac disease may be at a higher risk for non-GI conditions, such as osteopenia, women’s health disorders (eg, ovarian failure, endometriosis, or pregnancy loss), juvenile idiopathic arthritis in children and rheumatoid arthritis in adults, certain forms of cancer, infectious diseases, and cardiomyopathy.
4. GFD Is the Only Treatment, but It’s Imperfect and Frustrating for Patients
GFD is the only treatment for celiac disease and must be adhered to without deviation throughout a patient’s life.
Maintaining unwavering adherence reaps considerable benefits: Improved clinical symptoms, robust mucosal healing, and normalization of serological markers. Yet it also takes a considerable toll on patients. Patients with celiac disease struggle with a host of negative physical, psychological, and social impacts. They also report a higher treatment burden than those with gastroesophageal reflux disease or hypertension, and comparable with end-stage renal disease.
GFD also poses financial challenges. Although the price of gluten-free products has decreased in recent years, they still cost significantly more than items with gluten.
Adherence to GFD does not always equate to complete mucosal recovery. While mucosal recovery is achieved in 95% of children within 2 years of the diet’s adoption, only 34% and 66% of adults obtain it within 2 and 5 years, respectively.
GFD may lead to nutrient imbalances because gluten-free foods are typically low in alimentary fiber, micronutrients (eg, vitamin D, vitamin B12, or folate), and minerals (eg, iron, zinc, magnesium, or calcium). With higher sugar and fat content, GFD may leave patients susceptible to unwanted weight gain.
The pervasiveness of gluten in the food production system makes the risk for cross-contamination high. Gluten is often found in both naturally gluten-free foods and products labeled as such. Gluten-sensing technologies, some of which can be used via smartphone apps, have been developed to help patients identify possible cross-contamination. However, the ACG guidelines recommend against the use of these technologies until there is sufficient evidence supporting their ability to improve adherence and clinical outcomes.
5. Novel Therapies for Celiac Disease Are in the Pipeline
The limitations of GFD as the standard treatment for celiac disease have led to an increased focus on developing novel therapeutic interventions. They can be sorted into five key categories: Modulation of the immunostimulatory effects of toxic gluten peptides, elimination of toxic gluten peptides before they reach the intestine, induction of gluten tolerance, modulation of intestinal permeability, and restoration of gut microbiota balance.
Three therapies designed to block antigen presentation by HLA-DQ2/8, the gene alleles that predispose people to celiac disease, show promise: TPM502, an agent that contains three gluten-specific antigenic peptides with overlapping T-cell epitopes for the HLA-DQ2.5 gene; KAN-101, designed to induce gluten tolerance by targeting receptors on the liver; and DONQ52, a multi-specific antibody that targets HLA-DQ2. The KAN-101 therapy received Fast Track designation by the US Food and Drug Administration in 2022.
These and several other agents in clinical and preclinical development are discussed in detail in a 2024 review article. Although no therapies have reached phase 3 testing, when they do, it will undoubtedly be welcomed by those with celiac disease.
A version of this article first appeared on Medscape.com.
Celiac disease is a chronic, immune-mediated, systemic disorder caused by intolerance to gluten — a protein present in rye, barley, and wheat grains — that affects genetically predisposed individuals.
Due to its wide spectrum of clinical manifestations, celiac disease resembles a multisystemic disorder. Its most common gastrointestinal (GI) symptoms include chronic diarrhea, weight loss, and abdominal distention. However, celiac disease can also manifest in myriad extraintestinal symptoms, ranging from headache and fatigue to delayed puberty and psychiatric disorders, with differing presentations in children and adults.
To date, the only treatment is adopting a gluten-free diet (GFD). Although key to preventing persistent villous atrophy, the main cause of complications in celiac disease, lifelong adherence to GFD is challenging and may not resolve all clinical issues. These shortcomings have driven recent efforts to develop novel therapeutic options for patients with this disease.
Here are five things to know about celiac disease.
1. Rising Prevalence of Celiac Disease and Other Autoimmune Disorders Suggests Environmental Factors May Be at Play
Gluten was first identified as the cause of celiac disease in the 1950s. At that time, the condition was thought to be a relatively rare GI disease of childhood that primarily affected people of European descent, but it is now known to be a common disease affecting those of various ages, races, and ethnicities.
A 2018 meta-analysis found the pooled global prevalence of celiac disease was 1.4%. Incidence has increased by as much as 7.5% annually over the past several decades.
Increased awareness among clinicians and improved detection likely play a role in the trend. However, the growth in celiac disease is consistent with that seen for other autoimmune disorders, according to a 2024 update of evidence surrounding celiac disease. Shared environmental factors have been proposed as triggers for celiac disease and other autoimmune diseases and appear to be influencing their rise, the authors noted. These factors include migration and population growth, changing dietary patterns and food processing practices, and altered wheat consumption.
2. No-Biopsy Diagnosis Is Accepted for Children and Shows Promise for Adults
It is estimated that almost 60 million people worldwide have celiac disease, but most remain undiagnosed or misdiagnosed, or they experience significant diagnostic delays.
Prospective data indicate that children with first-degree relatives with celiac disease are at a significantly higher risk of developing the condition, which should prompt screening efforts in this population.
The 2023 updated guidelines from the American College of Gastroenterology (ACG) state that serology testing plays a central role in screening. This commonly involves serological testing for positive serological markers of the disease, including immunoglobulin A (IgA), anti-tissue transglutaminase IgA (tTG-IgA), anti-deamidated gliadin peptide, or endomysial antibodies.
To confirm diagnosis, clinicians have relied on intestinal biopsy since the late 1950s. The ACG still recommends esophagogastroduodenoscopy with multiple duodenal biopsies for confirmation of diagnosis in both children and adults with suspicion of celiac disease. However, recent years have seen a shift toward a no-biopsy approach.
For more than a decade in Europe, a no-biopsy approach has been established practice in pediatric patients, for whom the burden of obtaining a histological confirmation is understandably greater. Most guidelines now permit children to be diagnosed with celiac disease in the absence of a biopsy under specific circumstances (eg, characteristic symptoms of celiac disease and tTG-IgA levels > 10 times the upper limit of normal). The ACG guidelines state that “this approach is a reasonable alternative to the standard approach to a [celiac disease] diagnosis in selected children.”
The ACG does not recommend a no-biopsy approach in adults, noting that, in comparison with children, there is a relative lack of data indicating that serology is predictive in this population. However, it does recognize that physicians may encounter patients for whom a biopsy diagnosis may not be safe or practical. In such cases, an “after-the-fact” diagnosis of likely celiac disease can be given to symptomatic adult patients with a ≥ 10-fold elevation of tTG-IgA and a positive endomysial antibody in a second blood sample.
A 2024 meta-analysis of 18 studies involving over 12,103 adult patients from 15 countries concluded that a no-biopsy approach using tTG-IgA antibody levels ≥ 10 times the upper limit of normal was highly specific and predictive of celiac disease.
3. Celiac Disease Is Associated With Several Life-Threatening Conditions
Emerging data indicate that gastroenterologists should be vigilant in screening patients with celiac disease for several other GI conditions.
Inflammatory bowel disease and celiac disease have a strong bidirectional association, suggesting a possible genetic link between the conditions and indicating that physicians should consider the alternate diagnosis when symptoms persist after treatment.
Given the hypervigilance around food and diet inherent to celiac disease, patients are at an increased risk of developing avoidant/restrictive food intake disorder, according to a 2022 retrospective study.
In 2023, Italian investigators showed that children with celiac disease have an elevated prevalence of functional GI disorders even after adopting a GFD for a year, regardless of whether they consumed processed or natural foods. It was unclear whether this was due to a chronic inflammatory process or to nutritional factors.
Complications resulting from celiac disease are not limited to GI disorders. For a variety of underlying pathophysiological reasons, including intestinal permeability, hyposplenism, and malabsorption of nutrients, patients with celiac disease may be at a higher risk for non-GI conditions, such as osteopenia, women’s health disorders (eg, ovarian failure, endometriosis, or pregnancy loss), juvenile idiopathic arthritis in children and rheumatoid arthritis in adults, certain forms of cancer, infectious diseases, and cardiomyopathy.
4. GFD Is the Only Treatment, but It’s Imperfect and Frustrating for Patients
GFD is the only treatment for celiac disease and must be adhered to without deviation throughout a patient’s life.
Maintaining unwavering adherence reaps considerable benefits: Improved clinical symptoms, robust mucosal healing, and normalization of serological markers. Yet it also takes a considerable toll on patients. Patients with celiac disease struggle with a host of negative physical, psychological, and social impacts. They also report a higher treatment burden than those with gastroesophageal reflux disease or hypertension, and comparable with end-stage renal disease.
GFD also poses financial challenges. Although the price of gluten-free products has decreased in recent years, they still cost significantly more than items with gluten.
Adherence to GFD does not always equate to complete mucosal recovery. While mucosal recovery is achieved in 95% of children within 2 years of the diet’s adoption, only 34% and 66% of adults obtain it within 2 and 5 years, respectively.
GFD may lead to nutrient imbalances because gluten-free foods are typically low in alimentary fiber, micronutrients (eg, vitamin D, vitamin B12, or folate), and minerals (eg, iron, zinc, magnesium, or calcium). With higher sugar and fat content, GFD may leave patients susceptible to unwanted weight gain.
The pervasiveness of gluten in the food production system makes the risk for cross-contamination high. Gluten is often found in both naturally gluten-free foods and products labeled as such. Gluten-sensing technologies, some of which can be used via smartphone apps, have been developed to help patients identify possible cross-contamination. However, the ACG guidelines recommend against the use of these technologies until there is sufficient evidence supporting their ability to improve adherence and clinical outcomes.
5. Novel Therapies for Celiac Disease Are in the Pipeline
The limitations of GFD as the standard treatment for celiac disease have led to an increased focus on developing novel therapeutic interventions. They can be sorted into five key categories: Modulation of the immunostimulatory effects of toxic gluten peptides, elimination of toxic gluten peptides before they reach the intestine, induction of gluten tolerance, modulation of intestinal permeability, and restoration of gut microbiota balance.
Three therapies designed to block antigen presentation by HLA-DQ2/8, the gene alleles that predispose people to celiac disease, show promise: TPM502, an agent that contains three gluten-specific antigenic peptides with overlapping T-cell epitopes for the HLA-DQ2.5 gene; KAN-101, designed to induce gluten tolerance by targeting receptors on the liver; and DONQ52, a multi-specific antibody that targets HLA-DQ2. The KAN-101 therapy received Fast Track designation by the US Food and Drug Administration in 2022.
These and several other agents in clinical and preclinical development are discussed in detail in a 2024 review article. Although no therapies have reached phase 3 testing, when they do, it will undoubtedly be welcomed by those with celiac disease.
A version of this article first appeared on Medscape.com.
Gestational Rhinitis: How Can We Manage It?
PARIS — Allergic comorbidities such as asthma and rhinitis are common among pregnant women. During the 19th French-speaking Congress of Allergology, Dario Ebode, MD, otolaryngologist and cervicofacial surgeon at Hôpital de la Conception in Marseille, France, described gestational rhinitis and detailed its management.
A Hormonal Rhinitis
The prevalence of rhinitis during pregnancy ranges from 18% to 30%, whether it is pre-existing (eg, allergic or infectious) or newly diagnosed. About half of the cases of pre-existing rhinitis worsen during pregnancy, leading to gestational rhinitis, which has a prevalence of approximately 22%.
“The latter is characterized by its onset in the 2nd or 3rd trimester, a duration of > 6 weeks, an absence of associated allergic symptoms, and complete spontaneous resolution 2-3 weeks after delivery,” said Dr. Ebode.
Uncertainties about the pathophysiology of gestational rhinitis, a “hormonal rhinitis,” remain, he added. Beta-estradiol and progesterone hormones lead to an increase in H1 histamine receptors on epithelial and endothelial cells, which promotes the migration or degranulation of eosinophils.
Management
While gestational rhinitis is benign, its symptoms can still be bothersome and can be relieved. In addition to dietary and hygienic (nasal irrigation with large volumes) measures and allergen avoidance, local treatments include nasal corticosteroids, possibly combined with antihistamines, and systemic antihistamines. “During pregnancy, nasal corticosteroids, oral antihistamines [excluding azelastine hydrochloride before 10 weeks], and ipratropium bromide are allowed,” said Dr. Ebode. Regarding sprays that combine corticosteroids and antihistamines, the combination of mometasone furoate and olopatadine is possible but not the combination of azelastine hydrochloride and fluticasone propionate before 10 weeks.
Finally, oral vasoconstrictors (which are found in many over-the-counter medications) should be avoided, as should Kenacort (triamcinolone acetonide), “which also has no place in women outside of pregnancy due to an unfavorable risk-benefit balance in rhinitis,” said Dr. Ebode. Allergen immunotherapy plans should be postponed after delivery.
Dr. Ebode reported a financial relationship with Zambon.
This story was translated from the Medscape French edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
PARIS — Allergic comorbidities such as asthma and rhinitis are common among pregnant women. During the 19th French-speaking Congress of Allergology, Dario Ebode, MD, otolaryngologist and cervicofacial surgeon at Hôpital de la Conception in Marseille, France, described gestational rhinitis and detailed its management.
A Hormonal Rhinitis
The prevalence of rhinitis during pregnancy ranges from 18% to 30%, whether it is pre-existing (eg, allergic or infectious) or newly diagnosed. About half of the cases of pre-existing rhinitis worsen during pregnancy, leading to gestational rhinitis, which has a prevalence of approximately 22%.
“The latter is characterized by its onset in the 2nd or 3rd trimester, a duration of > 6 weeks, an absence of associated allergic symptoms, and complete spontaneous resolution 2-3 weeks after delivery,” said Dr. Ebode.
Uncertainties about the pathophysiology of gestational rhinitis, a “hormonal rhinitis,” remain, he added. Beta-estradiol and progesterone hormones lead to an increase in H1 histamine receptors on epithelial and endothelial cells, which promotes the migration or degranulation of eosinophils.
Management
While gestational rhinitis is benign, its symptoms can still be bothersome and can be relieved. In addition to dietary and hygienic (nasal irrigation with large volumes) measures and allergen avoidance, local treatments include nasal corticosteroids, possibly combined with antihistamines, and systemic antihistamines. “During pregnancy, nasal corticosteroids, oral antihistamines [excluding azelastine hydrochloride before 10 weeks], and ipratropium bromide are allowed,” said Dr. Ebode. Regarding sprays that combine corticosteroids and antihistamines, the combination of mometasone furoate and olopatadine is possible but not the combination of azelastine hydrochloride and fluticasone propionate before 10 weeks.
Finally, oral vasoconstrictors (which are found in many over-the-counter medications) should be avoided, as should Kenacort (triamcinolone acetonide), “which also has no place in women outside of pregnancy due to an unfavorable risk-benefit balance in rhinitis,” said Dr. Ebode. Allergen immunotherapy plans should be postponed after delivery.
Dr. Ebode reported a financial relationship with Zambon.
This story was translated from the Medscape French edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
PARIS — Allergic comorbidities such as asthma and rhinitis are common among pregnant women. During the 19th French-speaking Congress of Allergology, Dario Ebode, MD, otolaryngologist and cervicofacial surgeon at Hôpital de la Conception in Marseille, France, described gestational rhinitis and detailed its management.
A Hormonal Rhinitis
The prevalence of rhinitis during pregnancy ranges from 18% to 30%, whether it is pre-existing (eg, allergic or infectious) or newly diagnosed. About half of the cases of pre-existing rhinitis worsen during pregnancy, leading to gestational rhinitis, which has a prevalence of approximately 22%.
“The latter is characterized by its onset in the 2nd or 3rd trimester, a duration of > 6 weeks, an absence of associated allergic symptoms, and complete spontaneous resolution 2-3 weeks after delivery,” said Dr. Ebode.
Uncertainties about the pathophysiology of gestational rhinitis, a “hormonal rhinitis,” remain, he added. Beta-estradiol and progesterone hormones lead to an increase in H1 histamine receptors on epithelial and endothelial cells, which promotes the migration or degranulation of eosinophils.
Management
While gestational rhinitis is benign, its symptoms can still be bothersome and can be relieved. In addition to dietary and hygienic (nasal irrigation with large volumes) measures and allergen avoidance, local treatments include nasal corticosteroids, possibly combined with antihistamines, and systemic antihistamines. “During pregnancy, nasal corticosteroids, oral antihistamines [excluding azelastine hydrochloride before 10 weeks], and ipratropium bromide are allowed,” said Dr. Ebode. Regarding sprays that combine corticosteroids and antihistamines, the combination of mometasone furoate and olopatadine is possible but not the combination of azelastine hydrochloride and fluticasone propionate before 10 weeks.
Finally, oral vasoconstrictors (which are found in many over-the-counter medications) should be avoided, as should Kenacort (triamcinolone acetonide), “which also has no place in women outside of pregnancy due to an unfavorable risk-benefit balance in rhinitis,” said Dr. Ebode. Allergen immunotherapy plans should be postponed after delivery.
Dr. Ebode reported a financial relationship with Zambon.
This story was translated from the Medscape French edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
New Administration Routes for Adrenaline in Anaphylaxis
PARIS — While anaphylaxis requires immediate adrenaline administration through autoinjection, the use of this treatment is not optimal. Therefore, the development of new adrenaline formulations (such as for intranasal, sublingual, and transcutaneous routes) aims to facilitate the drug’s use and reduce persistent delays in administration by patients and caregivers. An overview of the research was presented at the 19th French-speaking Congress of Allergology.
Anaphylaxis is a severe and potentially fatal immediate hypersensitivity reaction with highly variable and dynamic clinical presentations. It requires prompt recognition for immediate treatment with intramuscular (IM) adrenaline (at the anterolateral aspect of the mid-thigh).
One might think that this reflex is acquired, but in France, while the number of prescribed adrenaline autoinjection (AAI) devices has been increasing for a decade, reaching 965,944 units in 2022, this first-line treatment is underused. Anapen (150, 300, and 500 µg), EpiPen (150 and 300 µg), Jext (150 µg and 300 µg), and Emerade (150, 300, and 500 µg) are the four products marketed in France in 2024.
“Only 17.3% of individuals presenting to the emergency department in the Lorraine region used it in 2015,” said Catherine Neukirch, MD, a pneumologist at Hôpital Bichat–Claude Bernard in Paris, France, with rates of 11.3% for children and 20.3% for adults.
Anaphylaxis Incidence Increasing
Approximately 0.3% (95% CI, 0.1-0.5) of the population will experience an anaphylaxis episode in their lifetime. Incidence in Europe, across all causes, is estimated between 1.5 and 7.9 cases per 100,000 inhabitants per year. Although anaphylaxis is on the rise, its associated mortality remains low, ranging between 0.05 and 0.51 per million per year for drugs, between 0.03 and 0.32 per million per year for foods, and between 0.09 and 0.13 per million per year for hymenopteran venoms.
Data from the European Anaphylaxis Registry indicate that anaphylaxis manifests rapidly after allergen exposure: 55% of cases occur within 10 minutes and 80% within 30 minutes. In addition, a biphasic reaction, which can occur up to 72 hours after exposure, is observed in < 5% of cases.
While a delay in adrenaline use is associated with risk for increased morbidity and mortality, AAI significantly reduces error rates compared with manual treatments involving ampoules, needles, and syringes. It also reduces the associated panic risks. However, there are multiple barriers to adrenaline use. The clinical symptoms of anaphylaxis may be misleading, especially if it occurs without cutaneous and urticarial manifestations but with only acute bronchospasm. It may present as isolated laryngeal edema without digestive involvement, hypotension, or other respiratory problems.
Other limitations to adrenaline use include technical difficulties and the possibility of incorrect administration, the need for appropriate needle sizes for patients with obesity, needle phobia, potential adverse effects of adrenaline injections, failure to carry two autoinjectors, constraints related to storage and bulky transport, as well as the need for training and practice.
“These factors contribute to underuse of adrenaline by patients and caregivers,” said Dr. Neukirch, which results in delays in necessary administration.
Adrenaline Treatment Criteria?
An analysis published in 2023 based on pharmacovigilance data from 30 regional French centers from 1984 to 2022 included 42 reported cases (average age, 33 years; 26% children) of reactions to AAI, which probably is an underestimate. About 40% of AAI uses occurred during anaphylaxis. The remaining 60% were triggered outside of reactions. The main reasons were accidental injections, mainly in the fingers, and cases of not triggering the autoinjector, underlining the importance of patient education.
In 2015, the European Medicines Agency required pharmacological studies for injectable adrenaline on healthy volunteers. These studies include ultrasound measurements of bolus injection, pharmacokinetics (ie, absorption, distribution, metabolism, and excretion), and pharmacodynamics (ie, the effect of the drug and the mechanism of action in the body), with precise evaluation of cardiovascular effects (eg, systolic and diastolic blood pressures and heart rate).
Among the information collected with the different products, ultrasound studies have shown a different localization of the adrenaline bolus (ie, in muscle in patients with normal BMI and mostly in adipose tissue in patients with BMI indicating overweight and obesity). The consequences of this finding are still unknown.
In a study with 500 µg Anapen, women with overweight or obesity showed different pharmacokinetic or pharmacodynamic profiles from those in men with normal weight, with an increase in the area under the curve (0-240 min) and marked changes in the heart rate time curve.
IM administration of 0.5 mg produces rapid pharmacokinetic effects in patients with normal weight, overweight, or obesity, with a delay for the second peak in the latter case. This delay perhaps results from initial local vasoconstriction due to adrenaline.
The early peak plasma concentration occurs at 5-10 minutes for AAI, with a faster speed for Anapen and EpiPen.
Moreover, needle size is not the most important factor. Rather, it is the strength and speed of injection, which can vary depending on the AAI.
Also, the optimal plasma concentration of adrenaline to treat anaphylaxis is not known; studies cannot be conducted during anaphylaxis. In terms of pharmacokinetics, a small series discovered that increased skin or muscle thickness delays the absorption of EpiPen AAI.
Intranasal Adrenaline
To facilitate rapid adrenaline use and convince reluctant patients to carry and use adrenaline, intranasal, sublingual, or transcutaneous forms are under development.
Three intranasal forms of adrenaline are already well advanced, including Neffy from ARS Pharma, epinephrine sprays from Bryn Pharma and Hikma, and Oxero from Oragoo, which contains dry powder.
A comparison of intranasal adrenaline Neffy and AAI shows that the former has satisfactory pharmacokinetic and pharmacodynamic effects.
In a phase 1 randomized crossover study of 42 healthy adults comparing the pharmacokinetic effects of Neffy adrenaline (2 mg) and EpiPen (0.3 mg), as well as IM epinephrine 0.3 mg, several observations were made. For a single dose, the maximum concentration (Cmax) of Neffy was lower than that of EpiPen.
However, with repeated doses administered 10 minutes apart, the Cmax of Neffy was higher than that of EpiPen. At this stage, pharmacodynamic responses to intranasal products are at least comparable with those of approved injectable products.
A comparison of the pharmacodynamic effects, such as systolic and diastolic blood pressures and heart rate, of Neffy adrenaline and AAI concluded that the profile of Neffy is comparable with that of EpiPen and superior to that of IM epinephrine.
In patients with a history of allergic rhinitis, adrenaline Cmax appears to be increased, while time to peak plasma concentration (Tmax) is reduced. Low blood pressure does not prevent Neffy absorption. Neffy is currently under review by the American and European health authorities.
Intranasal absorption of dry powder adrenaline appears to be faster than that of EpiPen, thus offering a clinical advantage in the short therapeutic window for anaphylaxis treatment.
In an open-label trial conducted on 12 adults with seasonal allergic rhinitis without asthma, the pharmacokinetics, pharmacodynamics, and safety of adrenaline were compared between FMXIN002 (1.6 and 3.2 mg), which was administered intranasally with or without nasal allergen challenge, and IM EpiPen 0.3 mg. Pharmacokinetics varied by patient. Nevertheless, nasal FMXIN002 had a shorter Tmax, a doubled Cmax after the allergen challenge peak, and a higher area under the curve in the 8 hours following administration compared with EpiPen. Pharmacodynamic effects comparable with those of EpiPen were noted at 15 minutes to 4 hours after administration. The tolerance was good, with mild and local side effects. The powder seems to deposit slightly better in the nasal cavity. It remains stable for 6 months at a temperature of 40 °C and relative humidity of 75% and for 2 years at a temperature of 25 °C and relative humidity of 60%.
Sublingual Adrenaline Film
AQST-109 is a sublingual film that is intended to allow rapid administration of epinephrine 1, which is a prodrug of adrenaline. The product is the size of a postage stamp, weighs < 30 g, and dissolves on contact with the tongue.
The EPIPHAST II study was a phase 1, multiperiod, crossover study conducted on 24 healthy adults (age, 24-49 years) who were randomly assigned to receive either 12 or 0.3 mg of AQST-109 of manual IM adrenaline in the first two periods. All participants received 0.3 mg of EpiPen in the last period.
EpiPen 0.3 mg resulted in a higher Cmax than AQST-109 12 mg. AQST-109 12 mg had the fastest median Tmax of 12 minutes. The areas under the curve of AQST-109 12 mg fell between those of EpiPen 0.3 mg and manual IM adrenaline 0.3 mg.
Early increases in systolic blood pressure, diastolic blood pressure, and heart rate were observed with AQST-109 12 mg. Changes were more pronounced with AQST-109 12 mg despite a higher Cmax with EpiPen 0.3 mg.
Part 3 of the EPIPHAST study evaluated the impact of food exposure (ie, a peanut butter sandwich) on the pharmacokinetics of AQST-109 12 mg in 24 healthy adults. Oral food residues did not significantly affect pharmacodynamic parameters, and no treatment-related adverse events were reported.
Researchers concluded that AQST-109 12 mg absorption would not be altered by “real” situations if used during meals. “These results suggest that the sublingual adrenaline film could be promising in real situations,” said Dr. Neukirch, especially in cases of food allergy with recent ingestion of the allergenic food.
Transcutaneous Adrenaline
A transcutaneous form of adrenaline that uses the Zeneo device developed by Crossject, a company based in Dijon, France, comes in the form of an AAI that requires no needle. This project, funded by the European Union, uses a gas generator to propel the drug at very high speed through the skin in 50 milliseconds. This method allows for extended drug storage.
Dr. Neukirch reported financial relationships with Viatris, Stallergènes, ALK, Astrazeneca, Sanofi, GSK, and Novartis.
This story was translated from the Medscape French edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
PARIS — While anaphylaxis requires immediate adrenaline administration through autoinjection, the use of this treatment is not optimal. Therefore, the development of new adrenaline formulations (such as for intranasal, sublingual, and transcutaneous routes) aims to facilitate the drug’s use and reduce persistent delays in administration by patients and caregivers. An overview of the research was presented at the 19th French-speaking Congress of Allergology.
Anaphylaxis is a severe and potentially fatal immediate hypersensitivity reaction with highly variable and dynamic clinical presentations. It requires prompt recognition for immediate treatment with intramuscular (IM) adrenaline (at the anterolateral aspect of the mid-thigh).
One might think that this reflex is acquired, but in France, while the number of prescribed adrenaline autoinjection (AAI) devices has been increasing for a decade, reaching 965,944 units in 2022, this first-line treatment is underused. Anapen (150, 300, and 500 µg), EpiPen (150 and 300 µg), Jext (150 µg and 300 µg), and Emerade (150, 300, and 500 µg) are the four products marketed in France in 2024.
“Only 17.3% of individuals presenting to the emergency department in the Lorraine region used it in 2015,” said Catherine Neukirch, MD, a pneumologist at Hôpital Bichat–Claude Bernard in Paris, France, with rates of 11.3% for children and 20.3% for adults.
Anaphylaxis Incidence Increasing
Approximately 0.3% (95% CI, 0.1-0.5) of the population will experience an anaphylaxis episode in their lifetime. Incidence in Europe, across all causes, is estimated between 1.5 and 7.9 cases per 100,000 inhabitants per year. Although anaphylaxis is on the rise, its associated mortality remains low, ranging between 0.05 and 0.51 per million per year for drugs, between 0.03 and 0.32 per million per year for foods, and between 0.09 and 0.13 per million per year for hymenopteran venoms.
Data from the European Anaphylaxis Registry indicate that anaphylaxis manifests rapidly after allergen exposure: 55% of cases occur within 10 minutes and 80% within 30 minutes. In addition, a biphasic reaction, which can occur up to 72 hours after exposure, is observed in < 5% of cases.
While a delay in adrenaline use is associated with risk for increased morbidity and mortality, AAI significantly reduces error rates compared with manual treatments involving ampoules, needles, and syringes. It also reduces the associated panic risks. However, there are multiple barriers to adrenaline use. The clinical symptoms of anaphylaxis may be misleading, especially if it occurs without cutaneous and urticarial manifestations but with only acute bronchospasm. It may present as isolated laryngeal edema without digestive involvement, hypotension, or other respiratory problems.
Other limitations to adrenaline use include technical difficulties and the possibility of incorrect administration, the need for appropriate needle sizes for patients with obesity, needle phobia, potential adverse effects of adrenaline injections, failure to carry two autoinjectors, constraints related to storage and bulky transport, as well as the need for training and practice.
“These factors contribute to underuse of adrenaline by patients and caregivers,” said Dr. Neukirch, which results in delays in necessary administration.
Adrenaline Treatment Criteria?
An analysis published in 2023 based on pharmacovigilance data from 30 regional French centers from 1984 to 2022 included 42 reported cases (average age, 33 years; 26% children) of reactions to AAI, which probably is an underestimate. About 40% of AAI uses occurred during anaphylaxis. The remaining 60% were triggered outside of reactions. The main reasons were accidental injections, mainly in the fingers, and cases of not triggering the autoinjector, underlining the importance of patient education.
In 2015, the European Medicines Agency required pharmacological studies for injectable adrenaline on healthy volunteers. These studies include ultrasound measurements of bolus injection, pharmacokinetics (ie, absorption, distribution, metabolism, and excretion), and pharmacodynamics (ie, the effect of the drug and the mechanism of action in the body), with precise evaluation of cardiovascular effects (eg, systolic and diastolic blood pressures and heart rate).
Among the information collected with the different products, ultrasound studies have shown a different localization of the adrenaline bolus (ie, in muscle in patients with normal BMI and mostly in adipose tissue in patients with BMI indicating overweight and obesity). The consequences of this finding are still unknown.
In a study with 500 µg Anapen, women with overweight or obesity showed different pharmacokinetic or pharmacodynamic profiles from those in men with normal weight, with an increase in the area under the curve (0-240 min) and marked changes in the heart rate time curve.
IM administration of 0.5 mg produces rapid pharmacokinetic effects in patients with normal weight, overweight, or obesity, with a delay for the second peak in the latter case. This delay perhaps results from initial local vasoconstriction due to adrenaline.
The early peak plasma concentration occurs at 5-10 minutes for AAI, with a faster speed for Anapen and EpiPen.
Moreover, needle size is not the most important factor. Rather, it is the strength and speed of injection, which can vary depending on the AAI.
Also, the optimal plasma concentration of adrenaline to treat anaphylaxis is not known; studies cannot be conducted during anaphylaxis. In terms of pharmacokinetics, a small series discovered that increased skin or muscle thickness delays the absorption of EpiPen AAI.
Intranasal Adrenaline
To facilitate rapid adrenaline use and convince reluctant patients to carry and use adrenaline, intranasal, sublingual, or transcutaneous forms are under development.
Three intranasal forms of adrenaline are already well advanced, including Neffy from ARS Pharma, epinephrine sprays from Bryn Pharma and Hikma, and Oxero from Oragoo, which contains dry powder.
A comparison of intranasal adrenaline Neffy and AAI shows that the former has satisfactory pharmacokinetic and pharmacodynamic effects.
In a phase 1 randomized crossover study of 42 healthy adults comparing the pharmacokinetic effects of Neffy adrenaline (2 mg) and EpiPen (0.3 mg), as well as IM epinephrine 0.3 mg, several observations were made. For a single dose, the maximum concentration (Cmax) of Neffy was lower than that of EpiPen.
However, with repeated doses administered 10 minutes apart, the Cmax of Neffy was higher than that of EpiPen. At this stage, pharmacodynamic responses to intranasal products are at least comparable with those of approved injectable products.
A comparison of the pharmacodynamic effects, such as systolic and diastolic blood pressures and heart rate, of Neffy adrenaline and AAI concluded that the profile of Neffy is comparable with that of EpiPen and superior to that of IM epinephrine.
In patients with a history of allergic rhinitis, adrenaline Cmax appears to be increased, while time to peak plasma concentration (Tmax) is reduced. Low blood pressure does not prevent Neffy absorption. Neffy is currently under review by the American and European health authorities.
Intranasal absorption of dry powder adrenaline appears to be faster than that of EpiPen, thus offering a clinical advantage in the short therapeutic window for anaphylaxis treatment.
In an open-label trial conducted on 12 adults with seasonal allergic rhinitis without asthma, the pharmacokinetics, pharmacodynamics, and safety of adrenaline were compared between FMXIN002 (1.6 and 3.2 mg), which was administered intranasally with or without nasal allergen challenge, and IM EpiPen 0.3 mg. Pharmacokinetics varied by patient. Nevertheless, nasal FMXIN002 had a shorter Tmax, a doubled Cmax after the allergen challenge peak, and a higher area under the curve in the 8 hours following administration compared with EpiPen. Pharmacodynamic effects comparable with those of EpiPen were noted at 15 minutes to 4 hours after administration. The tolerance was good, with mild and local side effects. The powder seems to deposit slightly better in the nasal cavity. It remains stable for 6 months at a temperature of 40 °C and relative humidity of 75% and for 2 years at a temperature of 25 °C and relative humidity of 60%.
Sublingual Adrenaline Film
AQST-109 is a sublingual film that is intended to allow rapid administration of epinephrine 1, which is a prodrug of adrenaline. The product is the size of a postage stamp, weighs < 30 g, and dissolves on contact with the tongue.
The EPIPHAST II study was a phase 1, multiperiod, crossover study conducted on 24 healthy adults (age, 24-49 years) who were randomly assigned to receive either 12 or 0.3 mg of AQST-109 of manual IM adrenaline in the first two periods. All participants received 0.3 mg of EpiPen in the last period.
EpiPen 0.3 mg resulted in a higher Cmax than AQST-109 12 mg. AQST-109 12 mg had the fastest median Tmax of 12 minutes. The areas under the curve of AQST-109 12 mg fell between those of EpiPen 0.3 mg and manual IM adrenaline 0.3 mg.
Early increases in systolic blood pressure, diastolic blood pressure, and heart rate were observed with AQST-109 12 mg. Changes were more pronounced with AQST-109 12 mg despite a higher Cmax with EpiPen 0.3 mg.
Part 3 of the EPIPHAST study evaluated the impact of food exposure (ie, a peanut butter sandwich) on the pharmacokinetics of AQST-109 12 mg in 24 healthy adults. Oral food residues did not significantly affect pharmacodynamic parameters, and no treatment-related adverse events were reported.
Researchers concluded that AQST-109 12 mg absorption would not be altered by “real” situations if used during meals. “These results suggest that the sublingual adrenaline film could be promising in real situations,” said Dr. Neukirch, especially in cases of food allergy with recent ingestion of the allergenic food.
Transcutaneous Adrenaline
A transcutaneous form of adrenaline that uses the Zeneo device developed by Crossject, a company based in Dijon, France, comes in the form of an AAI that requires no needle. This project, funded by the European Union, uses a gas generator to propel the drug at very high speed through the skin in 50 milliseconds. This method allows for extended drug storage.
Dr. Neukirch reported financial relationships with Viatris, Stallergènes, ALK, Astrazeneca, Sanofi, GSK, and Novartis.
This story was translated from the Medscape French edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
PARIS — While anaphylaxis requires immediate adrenaline administration through autoinjection, the use of this treatment is not optimal. Therefore, the development of new adrenaline formulations (such as for intranasal, sublingual, and transcutaneous routes) aims to facilitate the drug’s use and reduce persistent delays in administration by patients and caregivers. An overview of the research was presented at the 19th French-speaking Congress of Allergology.
Anaphylaxis is a severe and potentially fatal immediate hypersensitivity reaction with highly variable and dynamic clinical presentations. It requires prompt recognition for immediate treatment with intramuscular (IM) adrenaline (at the anterolateral aspect of the mid-thigh).
One might think that this reflex is acquired, but in France, while the number of prescribed adrenaline autoinjection (AAI) devices has been increasing for a decade, reaching 965,944 units in 2022, this first-line treatment is underused. Anapen (150, 300, and 500 µg), EpiPen (150 and 300 µg), Jext (150 µg and 300 µg), and Emerade (150, 300, and 500 µg) are the four products marketed in France in 2024.
“Only 17.3% of individuals presenting to the emergency department in the Lorraine region used it in 2015,” said Catherine Neukirch, MD, a pneumologist at Hôpital Bichat–Claude Bernard in Paris, France, with rates of 11.3% for children and 20.3% for adults.
Anaphylaxis Incidence Increasing
Approximately 0.3% (95% CI, 0.1-0.5) of the population will experience an anaphylaxis episode in their lifetime. Incidence in Europe, across all causes, is estimated between 1.5 and 7.9 cases per 100,000 inhabitants per year. Although anaphylaxis is on the rise, its associated mortality remains low, ranging between 0.05 and 0.51 per million per year for drugs, between 0.03 and 0.32 per million per year for foods, and between 0.09 and 0.13 per million per year for hymenopteran venoms.
Data from the European Anaphylaxis Registry indicate that anaphylaxis manifests rapidly after allergen exposure: 55% of cases occur within 10 minutes and 80% within 30 minutes. In addition, a biphasic reaction, which can occur up to 72 hours after exposure, is observed in < 5% of cases.
While a delay in adrenaline use is associated with risk for increased morbidity and mortality, AAI significantly reduces error rates compared with manual treatments involving ampoules, needles, and syringes. It also reduces the associated panic risks. However, there are multiple barriers to adrenaline use. The clinical symptoms of anaphylaxis may be misleading, especially if it occurs without cutaneous and urticarial manifestations but with only acute bronchospasm. It may present as isolated laryngeal edema without digestive involvement, hypotension, or other respiratory problems.
Other limitations to adrenaline use include technical difficulties and the possibility of incorrect administration, the need for appropriate needle sizes for patients with obesity, needle phobia, potential adverse effects of adrenaline injections, failure to carry two autoinjectors, constraints related to storage and bulky transport, as well as the need for training and practice.
“These factors contribute to underuse of adrenaline by patients and caregivers,” said Dr. Neukirch, which results in delays in necessary administration.
Adrenaline Treatment Criteria?
An analysis published in 2023 based on pharmacovigilance data from 30 regional French centers from 1984 to 2022 included 42 reported cases (average age, 33 years; 26% children) of reactions to AAI, which probably is an underestimate. About 40% of AAI uses occurred during anaphylaxis. The remaining 60% were triggered outside of reactions. The main reasons were accidental injections, mainly in the fingers, and cases of not triggering the autoinjector, underlining the importance of patient education.
In 2015, the European Medicines Agency required pharmacological studies for injectable adrenaline on healthy volunteers. These studies include ultrasound measurements of bolus injection, pharmacokinetics (ie, absorption, distribution, metabolism, and excretion), and pharmacodynamics (ie, the effect of the drug and the mechanism of action in the body), with precise evaluation of cardiovascular effects (eg, systolic and diastolic blood pressures and heart rate).
Among the information collected with the different products, ultrasound studies have shown a different localization of the adrenaline bolus (ie, in muscle in patients with normal BMI and mostly in adipose tissue in patients with BMI indicating overweight and obesity). The consequences of this finding are still unknown.
In a study with 500 µg Anapen, women with overweight or obesity showed different pharmacokinetic or pharmacodynamic profiles from those in men with normal weight, with an increase in the area under the curve (0-240 min) and marked changes in the heart rate time curve.
IM administration of 0.5 mg produces rapid pharmacokinetic effects in patients with normal weight, overweight, or obesity, with a delay for the second peak in the latter case. This delay perhaps results from initial local vasoconstriction due to adrenaline.
The early peak plasma concentration occurs at 5-10 minutes for AAI, with a faster speed for Anapen and EpiPen.
Moreover, needle size is not the most important factor. Rather, it is the strength and speed of injection, which can vary depending on the AAI.
Also, the optimal plasma concentration of adrenaline to treat anaphylaxis is not known; studies cannot be conducted during anaphylaxis. In terms of pharmacokinetics, a small series discovered that increased skin or muscle thickness delays the absorption of EpiPen AAI.
Intranasal Adrenaline
To facilitate rapid adrenaline use and convince reluctant patients to carry and use adrenaline, intranasal, sublingual, or transcutaneous forms are under development.
Three intranasal forms of adrenaline are already well advanced, including Neffy from ARS Pharma, epinephrine sprays from Bryn Pharma and Hikma, and Oxero from Oragoo, which contains dry powder.
A comparison of intranasal adrenaline Neffy and AAI shows that the former has satisfactory pharmacokinetic and pharmacodynamic effects.
In a phase 1 randomized crossover study of 42 healthy adults comparing the pharmacokinetic effects of Neffy adrenaline (2 mg) and EpiPen (0.3 mg), as well as IM epinephrine 0.3 mg, several observations were made. For a single dose, the maximum concentration (Cmax) of Neffy was lower than that of EpiPen.
However, with repeated doses administered 10 minutes apart, the Cmax of Neffy was higher than that of EpiPen. At this stage, pharmacodynamic responses to intranasal products are at least comparable with those of approved injectable products.
A comparison of the pharmacodynamic effects, such as systolic and diastolic blood pressures and heart rate, of Neffy adrenaline and AAI concluded that the profile of Neffy is comparable with that of EpiPen and superior to that of IM epinephrine.
In patients with a history of allergic rhinitis, adrenaline Cmax appears to be increased, while time to peak plasma concentration (Tmax) is reduced. Low blood pressure does not prevent Neffy absorption. Neffy is currently under review by the American and European health authorities.
Intranasal absorption of dry powder adrenaline appears to be faster than that of EpiPen, thus offering a clinical advantage in the short therapeutic window for anaphylaxis treatment.
In an open-label trial conducted on 12 adults with seasonal allergic rhinitis without asthma, the pharmacokinetics, pharmacodynamics, and safety of adrenaline were compared between FMXIN002 (1.6 and 3.2 mg), which was administered intranasally with or without nasal allergen challenge, and IM EpiPen 0.3 mg. Pharmacokinetics varied by patient. Nevertheless, nasal FMXIN002 had a shorter Tmax, a doubled Cmax after the allergen challenge peak, and a higher area under the curve in the 8 hours following administration compared with EpiPen. Pharmacodynamic effects comparable with those of EpiPen were noted at 15 minutes to 4 hours after administration. The tolerance was good, with mild and local side effects. The powder seems to deposit slightly better in the nasal cavity. It remains stable for 6 months at a temperature of 40 °C and relative humidity of 75% and for 2 years at a temperature of 25 °C and relative humidity of 60%.
Sublingual Adrenaline Film
AQST-109 is a sublingual film that is intended to allow rapid administration of epinephrine 1, which is a prodrug of adrenaline. The product is the size of a postage stamp, weighs < 30 g, and dissolves on contact with the tongue.
The EPIPHAST II study was a phase 1, multiperiod, crossover study conducted on 24 healthy adults (age, 24-49 years) who were randomly assigned to receive either 12 or 0.3 mg of AQST-109 of manual IM adrenaline in the first two periods. All participants received 0.3 mg of EpiPen in the last period.
EpiPen 0.3 mg resulted in a higher Cmax than AQST-109 12 mg. AQST-109 12 mg had the fastest median Tmax of 12 minutes. The areas under the curve of AQST-109 12 mg fell between those of EpiPen 0.3 mg and manual IM adrenaline 0.3 mg.
Early increases in systolic blood pressure, diastolic blood pressure, and heart rate were observed with AQST-109 12 mg. Changes were more pronounced with AQST-109 12 mg despite a higher Cmax with EpiPen 0.3 mg.
Part 3 of the EPIPHAST study evaluated the impact of food exposure (ie, a peanut butter sandwich) on the pharmacokinetics of AQST-109 12 mg in 24 healthy adults. Oral food residues did not significantly affect pharmacodynamic parameters, and no treatment-related adverse events were reported.
Researchers concluded that AQST-109 12 mg absorption would not be altered by “real” situations if used during meals. “These results suggest that the sublingual adrenaline film could be promising in real situations,” said Dr. Neukirch, especially in cases of food allergy with recent ingestion of the allergenic food.
Transcutaneous Adrenaline
A transcutaneous form of adrenaline that uses the Zeneo device developed by Crossject, a company based in Dijon, France, comes in the form of an AAI that requires no needle. This project, funded by the European Union, uses a gas generator to propel the drug at very high speed through the skin in 50 milliseconds. This method allows for extended drug storage.
Dr. Neukirch reported financial relationships with Viatris, Stallergènes, ALK, Astrazeneca, Sanofi, GSK, and Novartis.
This story was translated from the Medscape French edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
Ocular Microbiome May Be Dry Eye Culprit
A mix of microbes may help explain why some people develop dry eye disease, new research showed.
This finding suggests that bacteria may cause dry eye and could someday point to new treatments for the condition and related disorders, which affect an estimated 27 million Americans, according to researchers.
Current treatments aim to preserve and enhance tears and tear production to ease the grittiness and itchiness that accompany dry eye disease.
To examine the role of the ocular microbiome in dry eye disease, scientists in Texas analyzed swab samples from 30 men and women, nine of whom had dry eye.
They found Streptococcus and Pedobacter species were the most common bacteria in healthy eyes.
In people with dry eye, however, more Acinetobacter species were detected.
“We think the metabolites produced by these bacteria are responsible for dry eye conditions,” study coauthor Pallavi Sharma said in a news release about the findings.
Sharma, a graduate student at Stephen F. Austin State University in Nacogdoches, Texas, presented this research last month at the annual meeting of the American Society for Biochemistry and Molecular Biology. The research team was led by Alexandra Van Kley, PhD, a professor of biology at the university.
“Once we understand the eye microbiota properly, it will improve disease diagnosis at an early stage,” Van Kley predicted in the news release. “This knowledge can also serve as a catalyst for developing innovative therapies aimed at preventing and treating ocular disease as well as those that affect the central microbiome site: The gut.”
Investigators in Australia have conducted similar experiments in patients with meibomian gland dysfunction, a condition marked by underproduction of key oils in the eye.
One group reported in August 2023 the finding of “detectable differences in the bacterial richness, diversity, and community structure of the conjunctiva and eyelid margin between individuals with meibomian gland dysfunction with and without lacrimal dysfunction, as well as to healthy controls.”
More research is needed to confirm and understand the findings, though, and “to determine if manipulating the microbiome could be a potential treatment for the condition,” they wrote.
A version of this article appeared on Medscape.com.
A mix of microbes may help explain why some people develop dry eye disease, new research showed.
This finding suggests that bacteria may cause dry eye and could someday point to new treatments for the condition and related disorders, which affect an estimated 27 million Americans, according to researchers.
Current treatments aim to preserve and enhance tears and tear production to ease the grittiness and itchiness that accompany dry eye disease.
To examine the role of the ocular microbiome in dry eye disease, scientists in Texas analyzed swab samples from 30 men and women, nine of whom had dry eye.
They found Streptococcus and Pedobacter species were the most common bacteria in healthy eyes.
In people with dry eye, however, more Acinetobacter species were detected.
“We think the metabolites produced by these bacteria are responsible for dry eye conditions,” study coauthor Pallavi Sharma said in a news release about the findings.
Sharma, a graduate student at Stephen F. Austin State University in Nacogdoches, Texas, presented this research last month at the annual meeting of the American Society for Biochemistry and Molecular Biology. The research team was led by Alexandra Van Kley, PhD, a professor of biology at the university.
“Once we understand the eye microbiota properly, it will improve disease diagnosis at an early stage,” Van Kley predicted in the news release. “This knowledge can also serve as a catalyst for developing innovative therapies aimed at preventing and treating ocular disease as well as those that affect the central microbiome site: The gut.”
Investigators in Australia have conducted similar experiments in patients with meibomian gland dysfunction, a condition marked by underproduction of key oils in the eye.
One group reported in August 2023 the finding of “detectable differences in the bacterial richness, diversity, and community structure of the conjunctiva and eyelid margin between individuals with meibomian gland dysfunction with and without lacrimal dysfunction, as well as to healthy controls.”
More research is needed to confirm and understand the findings, though, and “to determine if manipulating the microbiome could be a potential treatment for the condition,” they wrote.
A version of this article appeared on Medscape.com.
A mix of microbes may help explain why some people develop dry eye disease, new research showed.
This finding suggests that bacteria may cause dry eye and could someday point to new treatments for the condition and related disorders, which affect an estimated 27 million Americans, according to researchers.
Current treatments aim to preserve and enhance tears and tear production to ease the grittiness and itchiness that accompany dry eye disease.
To examine the role of the ocular microbiome in dry eye disease, scientists in Texas analyzed swab samples from 30 men and women, nine of whom had dry eye.
They found Streptococcus and Pedobacter species were the most common bacteria in healthy eyes.
In people with dry eye, however, more Acinetobacter species were detected.
“We think the metabolites produced by these bacteria are responsible for dry eye conditions,” study coauthor Pallavi Sharma said in a news release about the findings.
Sharma, a graduate student at Stephen F. Austin State University in Nacogdoches, Texas, presented this research last month at the annual meeting of the American Society for Biochemistry and Molecular Biology. The research team was led by Alexandra Van Kley, PhD, a professor of biology at the university.
“Once we understand the eye microbiota properly, it will improve disease diagnosis at an early stage,” Van Kley predicted in the news release. “This knowledge can also serve as a catalyst for developing innovative therapies aimed at preventing and treating ocular disease as well as those that affect the central microbiome site: The gut.”
Investigators in Australia have conducted similar experiments in patients with meibomian gland dysfunction, a condition marked by underproduction of key oils in the eye.
One group reported in August 2023 the finding of “detectable differences in the bacterial richness, diversity, and community structure of the conjunctiva and eyelid margin between individuals with meibomian gland dysfunction with and without lacrimal dysfunction, as well as to healthy controls.”
More research is needed to confirm and understand the findings, though, and “to determine if manipulating the microbiome could be a potential treatment for the condition,” they wrote.
A version of this article appeared on Medscape.com.
Is It Time to Stop Using the Term AIDS?
The acronym AIDS is redundant, loaded with stigma, and potentially harmful, according to a group of specialists who suggest replacing the term with “advanced HIV.”
Mexico, and colleagues.
People generally associate the acronym AIDS with patients who have no available treatment options and a short life expectancy, said Dr. Núñez. That mischaracterization may affect treatment decisions by patients and clinicians and could result in exaggerated infection-control measures.
Using the HIV/AIDS combination erroneously implies equivalence and can mislead the public and clinicians, which the authors explained in their Viewpoint article published in The Lancet HIV.
Original Reason for the Term
AIDS, which stands for acquired immunodeficiency syndrome, was coined in 1982 by the US Centers for Disease Control and Prevention (CDC) to name a disease with an unknown cause that affected people with weakened cell-mediated immunity.
“When HIV was found to be the cause of the disease (labeled HIV in 1986), the term AIDS, strictly speaking, became unnecessary,” Dr. Núñez said.
AIDS was originally intended as a case definition for surveillance purposes, and treatment decisions were based on whether patients met the case definition for AIDS, he pointed out.
“The fact that some people still do so in this day and age shows that this is not only unhelpful, but misleading and even harmful,” he noted. Without the label AIDS, clinicians can focus on whether and for how long people have been on treatment, whether they recently switched treatment, and other factors that will help determine appropriate care.
Some Organizations Removed AIDS From Their Names
Some organizations have already removed AIDS from their names. For example, the International AIDS Society–USA, which issues guidelines on antiretroviral treatment, changed its name to the International Antiviral Society–USA.
In 2017, the name of AIDS.gov was changed to HIV.gov. In its explanation, the group wrote, “Today, people with HIV who are diagnosed early, linked to care, start antiretroviral therapy, and take it as prescribed can achieve life-long viral suppression that prevents HIV infection from progressing to AIDS.”
A different view on the term AIDS comes from Greg Millett, MPH, vice president at the Foundation for AIDS Research (amfAR) and the director of amfAR’s Public Policy Office.
Although he believes that AIDS is an anachronistic term, as a researcher for more than 30 years in the field; a policy director in Washington; a scientist; and a person living with HIV, “it feels like a distinction without a difference. At least from where I sit, there are far more pressing issues that we’re facing as an HIV community,” Millett shared.
For instance, “we’re seeing that global, as well as domestic, HIV funding is in, by far, the most precarious position that I’ve ever seen in the field. Calling it AIDS or HIV makes no difference in trying to alleviate that jeopardy,” he said.
Millett also said that the stigma and persecution and, in some cases, criminalization of people living with HIV or AIDS is pervasive and won’t go away with a name change, which is a point the authors also acknowledged.
“We need to focus on the social determinants of health,” he said. “That is the thing that is going to move the needle among people living with HIV, not nomenclature.”
Millett likens the argument to the one between Black and African American. “As a Black American, I remember fierce debates in the early ‘90s over whether we should be called African Americans or Blacks. Some argued that African American carried greater dignity and would help with self-esteem and address inequities by emphasizing that we are American. Many others said that it doesn’t make a difference.”
“It is clear that being called African American has not fixed intractable issues like poverty, structural racism, or inequities in incarceration,” he pointed out.
End the Epidemic, Not the Name
The authors misinterpret the impact of the term on stigma, said James W. Curran, MD, MPH, dean emeritus of the Rollins School of Public Health and professor of epidemiology and global health at Emory University, both in Atlanta, Georgia. The term AIDS “is more likely attributed to the fatal nature of the infection itself,” without treatment, he explained, and the mode of transmission, exacerbated by homophobia.
“The term has been in widespread use for 40 years and recognized worldwide,” Dr. Curran, who led the nation’s efforts in the battle against HIV and AIDS at the CDC for 15 years before joining Emory as dean, said.
He also worries about the continued trajectory of lives lost: “Over 35 million people worldwide have perished from HIV/AIDS, including over 500,000 per year now.”
Meanwhile, “global programs such as PEPFAR [the US President’s Emergency Plan for AIDS Relief] are under fire and threatened by Congress as no longer necessary. Removing AIDS from the terminology may add to confusion,” making people think “that the epidemic is over,” he said.
Although the authors argue that keeping the term may cause harm, eliminating it might worsen a different kind of harm. “There is a risk that abolishing the term will further de-emphasize the importance of the problem, with no significant impact on stigma,” Dr. Curran added.
A version of this article appeared on Medscape.com.
The acronym AIDS is redundant, loaded with stigma, and potentially harmful, according to a group of specialists who suggest replacing the term with “advanced HIV.”
Mexico, and colleagues.
People generally associate the acronym AIDS with patients who have no available treatment options and a short life expectancy, said Dr. Núñez. That mischaracterization may affect treatment decisions by patients and clinicians and could result in exaggerated infection-control measures.
Using the HIV/AIDS combination erroneously implies equivalence and can mislead the public and clinicians, which the authors explained in their Viewpoint article published in The Lancet HIV.
Original Reason for the Term
AIDS, which stands for acquired immunodeficiency syndrome, was coined in 1982 by the US Centers for Disease Control and Prevention (CDC) to name a disease with an unknown cause that affected people with weakened cell-mediated immunity.
“When HIV was found to be the cause of the disease (labeled HIV in 1986), the term AIDS, strictly speaking, became unnecessary,” Dr. Núñez said.
AIDS was originally intended as a case definition for surveillance purposes, and treatment decisions were based on whether patients met the case definition for AIDS, he pointed out.
“The fact that some people still do so in this day and age shows that this is not only unhelpful, but misleading and even harmful,” he noted. Without the label AIDS, clinicians can focus on whether and for how long people have been on treatment, whether they recently switched treatment, and other factors that will help determine appropriate care.
Some Organizations Removed AIDS From Their Names
Some organizations have already removed AIDS from their names. For example, the International AIDS Society–USA, which issues guidelines on antiretroviral treatment, changed its name to the International Antiviral Society–USA.
In 2017, the name of AIDS.gov was changed to HIV.gov. In its explanation, the group wrote, “Today, people with HIV who are diagnosed early, linked to care, start antiretroviral therapy, and take it as prescribed can achieve life-long viral suppression that prevents HIV infection from progressing to AIDS.”
A different view on the term AIDS comes from Greg Millett, MPH, vice president at the Foundation for AIDS Research (amfAR) and the director of amfAR’s Public Policy Office.
Although he believes that AIDS is an anachronistic term, as a researcher for more than 30 years in the field; a policy director in Washington; a scientist; and a person living with HIV, “it feels like a distinction without a difference. At least from where I sit, there are far more pressing issues that we’re facing as an HIV community,” Millett shared.
For instance, “we’re seeing that global, as well as domestic, HIV funding is in, by far, the most precarious position that I’ve ever seen in the field. Calling it AIDS or HIV makes no difference in trying to alleviate that jeopardy,” he said.
Millett also said that the stigma and persecution and, in some cases, criminalization of people living with HIV or AIDS is pervasive and won’t go away with a name change, which is a point the authors also acknowledged.
“We need to focus on the social determinants of health,” he said. “That is the thing that is going to move the needle among people living with HIV, not nomenclature.”
Millett likens the argument to the one between Black and African American. “As a Black American, I remember fierce debates in the early ‘90s over whether we should be called African Americans or Blacks. Some argued that African American carried greater dignity and would help with self-esteem and address inequities by emphasizing that we are American. Many others said that it doesn’t make a difference.”
“It is clear that being called African American has not fixed intractable issues like poverty, structural racism, or inequities in incarceration,” he pointed out.
End the Epidemic, Not the Name
The authors misinterpret the impact of the term on stigma, said James W. Curran, MD, MPH, dean emeritus of the Rollins School of Public Health and professor of epidemiology and global health at Emory University, both in Atlanta, Georgia. The term AIDS “is more likely attributed to the fatal nature of the infection itself,” without treatment, he explained, and the mode of transmission, exacerbated by homophobia.
“The term has been in widespread use for 40 years and recognized worldwide,” Dr. Curran, who led the nation’s efforts in the battle against HIV and AIDS at the CDC for 15 years before joining Emory as dean, said.
He also worries about the continued trajectory of lives lost: “Over 35 million people worldwide have perished from HIV/AIDS, including over 500,000 per year now.”
Meanwhile, “global programs such as PEPFAR [the US President’s Emergency Plan for AIDS Relief] are under fire and threatened by Congress as no longer necessary. Removing AIDS from the terminology may add to confusion,” making people think “that the epidemic is over,” he said.
Although the authors argue that keeping the term may cause harm, eliminating it might worsen a different kind of harm. “There is a risk that abolishing the term will further de-emphasize the importance of the problem, with no significant impact on stigma,” Dr. Curran added.
A version of this article appeared on Medscape.com.
The acronym AIDS is redundant, loaded with stigma, and potentially harmful, according to a group of specialists who suggest replacing the term with “advanced HIV.”
Mexico, and colleagues.
People generally associate the acronym AIDS with patients who have no available treatment options and a short life expectancy, said Dr. Núñez. That mischaracterization may affect treatment decisions by patients and clinicians and could result in exaggerated infection-control measures.
Using the HIV/AIDS combination erroneously implies equivalence and can mislead the public and clinicians, which the authors explained in their Viewpoint article published in The Lancet HIV.
Original Reason for the Term
AIDS, which stands for acquired immunodeficiency syndrome, was coined in 1982 by the US Centers for Disease Control and Prevention (CDC) to name a disease with an unknown cause that affected people with weakened cell-mediated immunity.
“When HIV was found to be the cause of the disease (labeled HIV in 1986), the term AIDS, strictly speaking, became unnecessary,” Dr. Núñez said.
AIDS was originally intended as a case definition for surveillance purposes, and treatment decisions were based on whether patients met the case definition for AIDS, he pointed out.
“The fact that some people still do so in this day and age shows that this is not only unhelpful, but misleading and even harmful,” he noted. Without the label AIDS, clinicians can focus on whether and for how long people have been on treatment, whether they recently switched treatment, and other factors that will help determine appropriate care.
Some Organizations Removed AIDS From Their Names
Some organizations have already removed AIDS from their names. For example, the International AIDS Society–USA, which issues guidelines on antiretroviral treatment, changed its name to the International Antiviral Society–USA.
In 2017, the name of AIDS.gov was changed to HIV.gov. In its explanation, the group wrote, “Today, people with HIV who are diagnosed early, linked to care, start antiretroviral therapy, and take it as prescribed can achieve life-long viral suppression that prevents HIV infection from progressing to AIDS.”
A different view on the term AIDS comes from Greg Millett, MPH, vice president at the Foundation for AIDS Research (amfAR) and the director of amfAR’s Public Policy Office.
Although he believes that AIDS is an anachronistic term, as a researcher for more than 30 years in the field; a policy director in Washington; a scientist; and a person living with HIV, “it feels like a distinction without a difference. At least from where I sit, there are far more pressing issues that we’re facing as an HIV community,” Millett shared.
For instance, “we’re seeing that global, as well as domestic, HIV funding is in, by far, the most precarious position that I’ve ever seen in the field. Calling it AIDS or HIV makes no difference in trying to alleviate that jeopardy,” he said.
Millett also said that the stigma and persecution and, in some cases, criminalization of people living with HIV or AIDS is pervasive and won’t go away with a name change, which is a point the authors also acknowledged.
“We need to focus on the social determinants of health,” he said. “That is the thing that is going to move the needle among people living with HIV, not nomenclature.”
Millett likens the argument to the one between Black and African American. “As a Black American, I remember fierce debates in the early ‘90s over whether we should be called African Americans or Blacks. Some argued that African American carried greater dignity and would help with self-esteem and address inequities by emphasizing that we are American. Many others said that it doesn’t make a difference.”
“It is clear that being called African American has not fixed intractable issues like poverty, structural racism, or inequities in incarceration,” he pointed out.
End the Epidemic, Not the Name
The authors misinterpret the impact of the term on stigma, said James W. Curran, MD, MPH, dean emeritus of the Rollins School of Public Health and professor of epidemiology and global health at Emory University, both in Atlanta, Georgia. The term AIDS “is more likely attributed to the fatal nature of the infection itself,” without treatment, he explained, and the mode of transmission, exacerbated by homophobia.
“The term has been in widespread use for 40 years and recognized worldwide,” Dr. Curran, who led the nation’s efforts in the battle against HIV and AIDS at the CDC for 15 years before joining Emory as dean, said.
He also worries about the continued trajectory of lives lost: “Over 35 million people worldwide have perished from HIV/AIDS, including over 500,000 per year now.”
Meanwhile, “global programs such as PEPFAR [the US President’s Emergency Plan for AIDS Relief] are under fire and threatened by Congress as no longer necessary. Removing AIDS from the terminology may add to confusion,” making people think “that the epidemic is over,” he said.
Although the authors argue that keeping the term may cause harm, eliminating it might worsen a different kind of harm. “There is a risk that abolishing the term will further de-emphasize the importance of the problem, with no significant impact on stigma,” Dr. Curran added.
A version of this article appeared on Medscape.com.
FROM THE LANCET HIV