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Infection-related chronic illness: A new paradigm for research and treatment
Experience with long COVID has shone a spotlight on persistent Lyme disease and other often debilitating chronic illnesses that follow known or suspected infections – and on the urgent need for a common and well-funded research agenda, education of physicians, growth of multidisciplinary clinics, and financially supported clinical care.
“We critically need to understand the epidemiology and pathogenesis of chronic symptoms, and identify more effective ways to manage, treat, and potentially cure these illnesses,” Lyle Petersen, MD, MPH, director of the division of vector-borne diseases at the Centers for Disease Control and Prevention, said at the start of a 2-day National Academies of Science, Engineering, and Medicine (NASEM) workshop, “Toward a Common Research Agenda in Infection-Associated Chronic Illnesses.”
Thinking about infection-associated chronic illnesses as an entity – one predicated on commonalities in chronic symptoms and in leading hypotheses for causes – represents a paradigm shift that researchers and patient advocates said can avoid research redundancies and is essential to address what the NASEM calls an overlooked, growing public health problem.
An estimated 2 million people in the United States are living with what’s called posttreatment Lyme disease (PTLD) – a subset of patients with persistent or chronic Lyme disease – and an estimated 1.7-3.3 million people in the United States have diagnoses of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). More than 700,000 people are living with multiple sclerosis. And as of January 2023, 11% of people in the United States reported having long COVID symptoms; the incidence of long COVID is currently estimated at 10%-30% of nonhospitalized cases of COVID-19.
These illnesses “have come under one umbrella,” said Avindra Nath, MD, clinical director of the National Institute of Neurologic Disorders and Stroke (NINDS), Bethesda, Md.
To date, common ground in the literature has grown largely around long COVID and ME/CFS, the latter of which is often associated with a prior, often unidentified infection.
Symptoms of both have been “rigorously” studied and shown to have overlaps, and the illnesses appear to share underlying biologic abnormalities in metabolism and the gut microbiome, as well as viral reactivation and abnormalities in the immune system, central and autonomic nervous systems, and the cardiovascular and pulmonary systems, said Anthony L. Komaroff, MD, professor of medicine at Harvard Medical School and a senior physician at Brigham & Women’s Hospital, both in Boston. (An estimated half of patients with long COVID meet the diagnostic criteria for ME/CFS.)
Although less thoroughly researched, similar symptoms are experienced by a subset of people following a variety of viral, bacterial, and protozoal infections, Dr. Komaroff said. To be determined, he said, is whether the pathophysiology believed to be shared by long COVID and ME/CFS is also shared with other postinfectious syndromes following acute illness with Ebola, West Nile, dengue, mycoplasma pneumonia, enteroviruses, and other pathogens, he said.
Persistent infection, viral reactivation
RNA viral infections can lead to persistent inflammation and dysregulated immunity, with or without viral persistence over time, Timothy J. Henrich, MD, MMSc, associate professor of medicine at the University of California, San Francisco, said in a keynote address.
Research on Ebola survivors has documented long-lasting inflammation and severe immune dysfunction 2 years after infection, for instance. And it’s well known that HIV-1 leads to aberrant immune responses, inflammation, and organ damage despite antiretroviral therapy, said Dr. Henrich, who leads a laboratory/research group that studies approaches to HIV-1 cure and PET-based imaging approaches to characterize viral reservoirs and immune sequelae.
Viral persistence, which can be difficult to measure, has also been documented in Ebola survivors. And in patients living with HIV-1, HIV-1 RNA and protein expression have been shown to persist, again despite antiretroviral therapy. The UCSF Long-Term Immunological Impact of Novel Coronavirus (LIINC) study, for which Dr. Henrich is the principal investigator, found spike RNA in colorectal tissue more than 22 months post COVID, and other research documented viral protein in gut tissue for up to 6 months, he said.
“I think we’re appreciating now, in at least the scientific and treatment community, that there’s a potential for ‘acute’ infections to exhibit some degree of persistence leading to clinical morbidity,” said Dr. Henrich, one of several speakers to describe reports of pathogen persistence. Regarding long COVID, its “etiology is likely heterogeneous,” he said, but persistence of SARS-CoV-2 “may lay behind” other described mechanisms, from clotting/microvascular dysfunction to inflammation and tissue damage to immune dysregulation.
Reactivation of existing latent viral infections in the setting of new acute microbial illness may also play an etiologic role in chronic illnesses, Dr. Henrich said. Epstein-Barr virus (EBV) reactivation has been shown in some studies, including their UCSF COVID-19 cohort, to be associated with long COVID.
“Physicians have been trained to be skeptical about the role [of latent viral infections],” Michael Peluso, MD, an infectious disease physician and assistant professor at UCSF, said during a talk on viral reactivation. This skepticism needs to be “reexamined and overcome,” he said.
Herpesviruses have frequently been associated with ME/CFS, he noted. And evidence of a strong association between EBV and multiple sclerosis came recently from a prospective study of 10 million military recruits that found a 32-fold increased risk of MS after EBV infection but no increase after infection with other viruses, Dr. Peluso and Dr. Henrich both noted.
Research needs, treatment trials
Research needs are vast: The need to learn more about the mechanisms of pathogen persistence and immune evasion, for instance, and the need for more biomarker studies, more imaging studies and tissue analyses, more study of microbiome composition and activity, and continued development and application of metagenomic next-generation sequencing.
Workshop participants also spoke of the need to better understand the molecular mimicry that can occur between pathogen-produced proteins and self-antigens, for instance, and the effects of inflammation and infection-related immune changes on neuronal and microglial function in the brain.
“We should perform similar forms of analysis [across] patients with different infection-associated chronic conditions,” said Amy Proal, PhD, president of the PolyBio Research Foundation, which funds research on infection-associated chronic infections. And within individual conditions and well-characterized study groups “we should perform many different forms of analysis … so we can define endotypes and get more solid biomarkers so that industry [will have more confidence] to run clinical trials.”
In the meantime, patients need fast-moving treatment trials for long COVID, long Lyme, and other infection-associated chronic illnesses, speakers emphasized. “We all agree that treatment trials are overdue,” said the NINDS’ Dr. Nath. “We can’t afford to wait for another decade until we understand all the mechanisms, but rather we can do clinical trials based on what we understand now and study the pathophysiology in the context of the clinical trials.”
Just as was done with HIV, said Steven G. Deeks, MD, professor of medicine at UCSF, researchers must “practice experimental medicine” and select pathways and mechanisms of interest, interrupt those pathways in a controlled manner, and assess impact. “Much of this can be done by repurposing existing drugs,” he said, like antivirals for persistent viral infection, EBV-directed therapies for EBV reactivation, anti-inflammatory drugs for inflammation, B–cell-directed therapies for autoantibodies, and antiplatelet drugs for microvascular disease.
When done correctly, he said, such “probe” studies can deepen mechanistic understandings, lead to biomarkers, and provide proof-of-concept that “will encourage massive investment in developing new therapies” for long COVID and other infection-associated chronic illnesses.
Trials of treatments for long COVID “are starting, so I’m optimistic,” said Dr. Deeks, an expert on HIV pathogenesis and treatment and a principal investigator of the Researching COVID to Enhance Recovery (RECOVER) study. Among the trials: A study of intravenous immunoglobulin (IVIG) for neurologic long COVID; a study of an anti-SARS-CoV-2 monoclonal antibody that can deplete tissue/cellular reservoirs of viral particles (replicating or not); and a study evaluating baricitinib (Olumiant), a Janus kinase inhibitor, for neurocognitive impairment and cardiopulmonary symptoms of long COVID.
Alessio Fasano, MD, professor of pediatrics at Harvard Medical School and professor of nutrition at the Harvard T.H. Chan School of Public Health, Boston, described at the workshop how he began investigating the use of larazotide acetate – an inhibitor of the protein zonulin, which increases intestinal permeability – in children with COVID-19 Multisystem Inflammatory Syndrome (MIS-C) after learning that SARS-CoV-2 viral particles persist in the gastrointestinal tract, causing dysbiosis and zonulin upregulation.
In an ongoing phase 2, double-blind, placebo-controlled trial, the agent thus far has expedited the resolution of gastrointestinal symptoms and clearance of spike protein from the circulation, he said. A phase 2 trial of the agent for pediatric patients with long COVID and SARS-CoV-2 antigenemia is underway. “What if we were to stop [chains of events] by stopping the passage of elements from the virus into circulation?’ he said.
In the realm of Lyme disease, a recently launched Clinical Trials Network for Lyme and Other Tick-Borne Diseases has awarded pilot study grants to evaluate treatments aimed at a variety of possible disease mechanisms that, notably, are similar to those of other chronic illnesses: persistence of infection or remnants of infection, immune dysregulation and autoimmune reactions, neural dysfunction, and gut microbiome changes. (Microclots and mitochondrial dysfunction have not been as well studied in Lyme.)
Current and upcoming studies include evaluations of transcutaneous auricular vagus nerve stimulation for those with persistent Lyme fatigue, transcranial direct current stimulation with cognitive retraining for Lyme brain fog, and tetracycline for PTLD, said Brian Fallon, MD, MPH, professor of clinical psychiatry at Columbia University, New York, who directs the Lyme & Tick-Borne Diseases Research Center and the coordinating center of the new network.
Moving forward, he said, it is important to loosen exclusion criteria and include patients with “probable or possible” Lyme and those with suspected infections with other tick-borne pathogens. All told, these patients comprise a large portion of those with chronic symptoms and have been neglected in an already thin research space, Dr. Fallon said, noting that “there haven’t been any clinical trials of posttreatment Lyme disease in ages – in 10-15 years.”
(PTLD refers to symptoms lasting for more than 6 months after the completion of standard Infectious Diseases Society of America–recommended antibiotic protocols. It occurs in about 15% of patients, said John Aucott, MD, director of the Johns Hopkins Lyme Disease Research Center, Baltimore, a member of the new clinical trials network.)
Calls for a new NIH center and patient involvement
Patients and patient advocacy organizations have played a vital role in research thus far: They’ve documented post-COVID symptoms that academic researchers said they would not otherwise have known of. Leaders of the Patient-Led Research Collaborative have coauthored published reviews with leading long COVID experts. And patients with tick-borne illnesses have enrolled in the MyLymeData patient registry run by LymeDisease.org, which has documented patient-experienced efficacy of alternative treatments and described antibiotic responders and nonresponders.
At the workshop, they shared findings alongside academic experts, and researchers called for their continued involvement. “Patient engagement at every step of the research process is critical,” Dr. Nath said.
“We need to ensure that research is reflective of lived experiences … and [that we’re] accelerating clinical trials of therapeutics that are of priority to the patient community,” said Lisa McCorkell, cofounder of the long COVID-focused Patient-Led Research Collaborative.
Ms. McCorkell also called for the creation of an office for infection-associated chronic illnesses in the NIH director’s office. Others voiced their support. “I think it’s a great idea to have an NIH center for infection-associated chronic illnesses,” said Dr. Fallon. “I think it would have a profound impact.”
The other great need, of course, is funding. “We have ideas, we have drugs that can be repurposed, we have a highly informed and engaged community that will enroll in and be retained in studies, and we have outcomes we can measure,” Dr. Deeks said. “What we’re missing is industry engagement and funding. We need massive engagement from the NIH.”
Real-world treatment needs
In the meantime, patients are seeking treatment, and “clinicians need to have uncertainty tolerance” and try multiple treatments simultaneously, said David Putrino, PT, PhD, director of rehabilitation innovation for the Mount Sinai Health System and professor of rehabilitation and human performance at the Icahn School of Medicine at Mount Sinai, New York. He oversees a multidisciplinary hybrid clinical care research center that has seen over 1,500 patients with long COVID and is beginning to see patients with other infection-associated chronic illnesses.
It’s a model that should be replicated to help fill the “enormous unmet clinical need” of patients with infection-associated chronic illness, said Peter Rowe, MD, professor of pediatrics at the Johns Hopkins School of Medicine and an expert on ME/CFS. And “as we request [more research funding], we will also need [financial] support for clinical care,” he emphasized, to provide equitable access for patients and to attract treating physicians.
Moreover, said Linda Geng, MD, PhD, the culture of stigma needs to change. Right now, patients with long COVID often feel dismissed not only by friends, families, and coworkers, but by clinicians who find it find it hard “to grasp that this is real and a biological condition.”
And it’s not just conditions such as long COVID that are stigmatized, but treatments as well, she said. For instance, some clinicians view low-dose naltrexone, a treatment increasingly being used for inflammation, with suspicion because it is used for opioid use disorder and alcohol use disorder – or because the “low-dose” label summons mistrust of homeopathy. “Even with therapies, there are preconceived notions and biases,” said Dr. Geng, cofounder and codirector of the Stanford (Calif.) Long COVID program.
“What almost killed me,” said Meghan O’Rourke, who has ongoing effects from long-undiagnosed tick-borne illness, “was the invisibility of the illness.” Ms. O’Rourke teaches at Yale University and is the author of “The Invisible Kingdom: Reimagining Chronic Illness.”
Teaching young physicians about these illnesses would help, she and others said. During a question and answer session, Dr. Putrino shared that the Icahn School of Medicine has recently committed to “create a complex chronic illness medical curriculum” that will impact medical education from the first year of medical school through residencies. Dr. Putrino said his team is also working on materials to help other clinics develop care models similar to those at his Mount Sinai clinic.
The NASEM workshop did not collect or require disclosures of its participants.
Experience with long COVID has shone a spotlight on persistent Lyme disease and other often debilitating chronic illnesses that follow known or suspected infections – and on the urgent need for a common and well-funded research agenda, education of physicians, growth of multidisciplinary clinics, and financially supported clinical care.
“We critically need to understand the epidemiology and pathogenesis of chronic symptoms, and identify more effective ways to manage, treat, and potentially cure these illnesses,” Lyle Petersen, MD, MPH, director of the division of vector-borne diseases at the Centers for Disease Control and Prevention, said at the start of a 2-day National Academies of Science, Engineering, and Medicine (NASEM) workshop, “Toward a Common Research Agenda in Infection-Associated Chronic Illnesses.”
Thinking about infection-associated chronic illnesses as an entity – one predicated on commonalities in chronic symptoms and in leading hypotheses for causes – represents a paradigm shift that researchers and patient advocates said can avoid research redundancies and is essential to address what the NASEM calls an overlooked, growing public health problem.
An estimated 2 million people in the United States are living with what’s called posttreatment Lyme disease (PTLD) – a subset of patients with persistent or chronic Lyme disease – and an estimated 1.7-3.3 million people in the United States have diagnoses of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). More than 700,000 people are living with multiple sclerosis. And as of January 2023, 11% of people in the United States reported having long COVID symptoms; the incidence of long COVID is currently estimated at 10%-30% of nonhospitalized cases of COVID-19.
These illnesses “have come under one umbrella,” said Avindra Nath, MD, clinical director of the National Institute of Neurologic Disorders and Stroke (NINDS), Bethesda, Md.
To date, common ground in the literature has grown largely around long COVID and ME/CFS, the latter of which is often associated with a prior, often unidentified infection.
Symptoms of both have been “rigorously” studied and shown to have overlaps, and the illnesses appear to share underlying biologic abnormalities in metabolism and the gut microbiome, as well as viral reactivation and abnormalities in the immune system, central and autonomic nervous systems, and the cardiovascular and pulmonary systems, said Anthony L. Komaroff, MD, professor of medicine at Harvard Medical School and a senior physician at Brigham & Women’s Hospital, both in Boston. (An estimated half of patients with long COVID meet the diagnostic criteria for ME/CFS.)
Although less thoroughly researched, similar symptoms are experienced by a subset of people following a variety of viral, bacterial, and protozoal infections, Dr. Komaroff said. To be determined, he said, is whether the pathophysiology believed to be shared by long COVID and ME/CFS is also shared with other postinfectious syndromes following acute illness with Ebola, West Nile, dengue, mycoplasma pneumonia, enteroviruses, and other pathogens, he said.
Persistent infection, viral reactivation
RNA viral infections can lead to persistent inflammation and dysregulated immunity, with or without viral persistence over time, Timothy J. Henrich, MD, MMSc, associate professor of medicine at the University of California, San Francisco, said in a keynote address.
Research on Ebola survivors has documented long-lasting inflammation and severe immune dysfunction 2 years after infection, for instance. And it’s well known that HIV-1 leads to aberrant immune responses, inflammation, and organ damage despite antiretroviral therapy, said Dr. Henrich, who leads a laboratory/research group that studies approaches to HIV-1 cure and PET-based imaging approaches to characterize viral reservoirs and immune sequelae.
Viral persistence, which can be difficult to measure, has also been documented in Ebola survivors. And in patients living with HIV-1, HIV-1 RNA and protein expression have been shown to persist, again despite antiretroviral therapy. The UCSF Long-Term Immunological Impact of Novel Coronavirus (LIINC) study, for which Dr. Henrich is the principal investigator, found spike RNA in colorectal tissue more than 22 months post COVID, and other research documented viral protein in gut tissue for up to 6 months, he said.
“I think we’re appreciating now, in at least the scientific and treatment community, that there’s a potential for ‘acute’ infections to exhibit some degree of persistence leading to clinical morbidity,” said Dr. Henrich, one of several speakers to describe reports of pathogen persistence. Regarding long COVID, its “etiology is likely heterogeneous,” he said, but persistence of SARS-CoV-2 “may lay behind” other described mechanisms, from clotting/microvascular dysfunction to inflammation and tissue damage to immune dysregulation.
Reactivation of existing latent viral infections in the setting of new acute microbial illness may also play an etiologic role in chronic illnesses, Dr. Henrich said. Epstein-Barr virus (EBV) reactivation has been shown in some studies, including their UCSF COVID-19 cohort, to be associated with long COVID.
“Physicians have been trained to be skeptical about the role [of latent viral infections],” Michael Peluso, MD, an infectious disease physician and assistant professor at UCSF, said during a talk on viral reactivation. This skepticism needs to be “reexamined and overcome,” he said.
Herpesviruses have frequently been associated with ME/CFS, he noted. And evidence of a strong association between EBV and multiple sclerosis came recently from a prospective study of 10 million military recruits that found a 32-fold increased risk of MS after EBV infection but no increase after infection with other viruses, Dr. Peluso and Dr. Henrich both noted.
Research needs, treatment trials
Research needs are vast: The need to learn more about the mechanisms of pathogen persistence and immune evasion, for instance, and the need for more biomarker studies, more imaging studies and tissue analyses, more study of microbiome composition and activity, and continued development and application of metagenomic next-generation sequencing.
Workshop participants also spoke of the need to better understand the molecular mimicry that can occur between pathogen-produced proteins and self-antigens, for instance, and the effects of inflammation and infection-related immune changes on neuronal and microglial function in the brain.
“We should perform similar forms of analysis [across] patients with different infection-associated chronic conditions,” said Amy Proal, PhD, president of the PolyBio Research Foundation, which funds research on infection-associated chronic infections. And within individual conditions and well-characterized study groups “we should perform many different forms of analysis … so we can define endotypes and get more solid biomarkers so that industry [will have more confidence] to run clinical trials.”
In the meantime, patients need fast-moving treatment trials for long COVID, long Lyme, and other infection-associated chronic illnesses, speakers emphasized. “We all agree that treatment trials are overdue,” said the NINDS’ Dr. Nath. “We can’t afford to wait for another decade until we understand all the mechanisms, but rather we can do clinical trials based on what we understand now and study the pathophysiology in the context of the clinical trials.”
Just as was done with HIV, said Steven G. Deeks, MD, professor of medicine at UCSF, researchers must “practice experimental medicine” and select pathways and mechanisms of interest, interrupt those pathways in a controlled manner, and assess impact. “Much of this can be done by repurposing existing drugs,” he said, like antivirals for persistent viral infection, EBV-directed therapies for EBV reactivation, anti-inflammatory drugs for inflammation, B–cell-directed therapies for autoantibodies, and antiplatelet drugs for microvascular disease.
When done correctly, he said, such “probe” studies can deepen mechanistic understandings, lead to biomarkers, and provide proof-of-concept that “will encourage massive investment in developing new therapies” for long COVID and other infection-associated chronic illnesses.
Trials of treatments for long COVID “are starting, so I’m optimistic,” said Dr. Deeks, an expert on HIV pathogenesis and treatment and a principal investigator of the Researching COVID to Enhance Recovery (RECOVER) study. Among the trials: A study of intravenous immunoglobulin (IVIG) for neurologic long COVID; a study of an anti-SARS-CoV-2 monoclonal antibody that can deplete tissue/cellular reservoirs of viral particles (replicating or not); and a study evaluating baricitinib (Olumiant), a Janus kinase inhibitor, for neurocognitive impairment and cardiopulmonary symptoms of long COVID.
Alessio Fasano, MD, professor of pediatrics at Harvard Medical School and professor of nutrition at the Harvard T.H. Chan School of Public Health, Boston, described at the workshop how he began investigating the use of larazotide acetate – an inhibitor of the protein zonulin, which increases intestinal permeability – in children with COVID-19 Multisystem Inflammatory Syndrome (MIS-C) after learning that SARS-CoV-2 viral particles persist in the gastrointestinal tract, causing dysbiosis and zonulin upregulation.
In an ongoing phase 2, double-blind, placebo-controlled trial, the agent thus far has expedited the resolution of gastrointestinal symptoms and clearance of spike protein from the circulation, he said. A phase 2 trial of the agent for pediatric patients with long COVID and SARS-CoV-2 antigenemia is underway. “What if we were to stop [chains of events] by stopping the passage of elements from the virus into circulation?’ he said.
In the realm of Lyme disease, a recently launched Clinical Trials Network for Lyme and Other Tick-Borne Diseases has awarded pilot study grants to evaluate treatments aimed at a variety of possible disease mechanisms that, notably, are similar to those of other chronic illnesses: persistence of infection or remnants of infection, immune dysregulation and autoimmune reactions, neural dysfunction, and gut microbiome changes. (Microclots and mitochondrial dysfunction have not been as well studied in Lyme.)
Current and upcoming studies include evaluations of transcutaneous auricular vagus nerve stimulation for those with persistent Lyme fatigue, transcranial direct current stimulation with cognitive retraining for Lyme brain fog, and tetracycline for PTLD, said Brian Fallon, MD, MPH, professor of clinical psychiatry at Columbia University, New York, who directs the Lyme & Tick-Borne Diseases Research Center and the coordinating center of the new network.
Moving forward, he said, it is important to loosen exclusion criteria and include patients with “probable or possible” Lyme and those with suspected infections with other tick-borne pathogens. All told, these patients comprise a large portion of those with chronic symptoms and have been neglected in an already thin research space, Dr. Fallon said, noting that “there haven’t been any clinical trials of posttreatment Lyme disease in ages – in 10-15 years.”
(PTLD refers to symptoms lasting for more than 6 months after the completion of standard Infectious Diseases Society of America–recommended antibiotic protocols. It occurs in about 15% of patients, said John Aucott, MD, director of the Johns Hopkins Lyme Disease Research Center, Baltimore, a member of the new clinical trials network.)
Calls for a new NIH center and patient involvement
Patients and patient advocacy organizations have played a vital role in research thus far: They’ve documented post-COVID symptoms that academic researchers said they would not otherwise have known of. Leaders of the Patient-Led Research Collaborative have coauthored published reviews with leading long COVID experts. And patients with tick-borne illnesses have enrolled in the MyLymeData patient registry run by LymeDisease.org, which has documented patient-experienced efficacy of alternative treatments and described antibiotic responders and nonresponders.
At the workshop, they shared findings alongside academic experts, and researchers called for their continued involvement. “Patient engagement at every step of the research process is critical,” Dr. Nath said.
“We need to ensure that research is reflective of lived experiences … and [that we’re] accelerating clinical trials of therapeutics that are of priority to the patient community,” said Lisa McCorkell, cofounder of the long COVID-focused Patient-Led Research Collaborative.
Ms. McCorkell also called for the creation of an office for infection-associated chronic illnesses in the NIH director’s office. Others voiced their support. “I think it’s a great idea to have an NIH center for infection-associated chronic illnesses,” said Dr. Fallon. “I think it would have a profound impact.”
The other great need, of course, is funding. “We have ideas, we have drugs that can be repurposed, we have a highly informed and engaged community that will enroll in and be retained in studies, and we have outcomes we can measure,” Dr. Deeks said. “What we’re missing is industry engagement and funding. We need massive engagement from the NIH.”
Real-world treatment needs
In the meantime, patients are seeking treatment, and “clinicians need to have uncertainty tolerance” and try multiple treatments simultaneously, said David Putrino, PT, PhD, director of rehabilitation innovation for the Mount Sinai Health System and professor of rehabilitation and human performance at the Icahn School of Medicine at Mount Sinai, New York. He oversees a multidisciplinary hybrid clinical care research center that has seen over 1,500 patients with long COVID and is beginning to see patients with other infection-associated chronic illnesses.
It’s a model that should be replicated to help fill the “enormous unmet clinical need” of patients with infection-associated chronic illness, said Peter Rowe, MD, professor of pediatrics at the Johns Hopkins School of Medicine and an expert on ME/CFS. And “as we request [more research funding], we will also need [financial] support for clinical care,” he emphasized, to provide equitable access for patients and to attract treating physicians.
Moreover, said Linda Geng, MD, PhD, the culture of stigma needs to change. Right now, patients with long COVID often feel dismissed not only by friends, families, and coworkers, but by clinicians who find it find it hard “to grasp that this is real and a biological condition.”
And it’s not just conditions such as long COVID that are stigmatized, but treatments as well, she said. For instance, some clinicians view low-dose naltrexone, a treatment increasingly being used for inflammation, with suspicion because it is used for opioid use disorder and alcohol use disorder – or because the “low-dose” label summons mistrust of homeopathy. “Even with therapies, there are preconceived notions and biases,” said Dr. Geng, cofounder and codirector of the Stanford (Calif.) Long COVID program.
“What almost killed me,” said Meghan O’Rourke, who has ongoing effects from long-undiagnosed tick-borne illness, “was the invisibility of the illness.” Ms. O’Rourke teaches at Yale University and is the author of “The Invisible Kingdom: Reimagining Chronic Illness.”
Teaching young physicians about these illnesses would help, she and others said. During a question and answer session, Dr. Putrino shared that the Icahn School of Medicine has recently committed to “create a complex chronic illness medical curriculum” that will impact medical education from the first year of medical school through residencies. Dr. Putrino said his team is also working on materials to help other clinics develop care models similar to those at his Mount Sinai clinic.
The NASEM workshop did not collect or require disclosures of its participants.
Experience with long COVID has shone a spotlight on persistent Lyme disease and other often debilitating chronic illnesses that follow known or suspected infections – and on the urgent need for a common and well-funded research agenda, education of physicians, growth of multidisciplinary clinics, and financially supported clinical care.
“We critically need to understand the epidemiology and pathogenesis of chronic symptoms, and identify more effective ways to manage, treat, and potentially cure these illnesses,” Lyle Petersen, MD, MPH, director of the division of vector-borne diseases at the Centers for Disease Control and Prevention, said at the start of a 2-day National Academies of Science, Engineering, and Medicine (NASEM) workshop, “Toward a Common Research Agenda in Infection-Associated Chronic Illnesses.”
Thinking about infection-associated chronic illnesses as an entity – one predicated on commonalities in chronic symptoms and in leading hypotheses for causes – represents a paradigm shift that researchers and patient advocates said can avoid research redundancies and is essential to address what the NASEM calls an overlooked, growing public health problem.
An estimated 2 million people in the United States are living with what’s called posttreatment Lyme disease (PTLD) – a subset of patients with persistent or chronic Lyme disease – and an estimated 1.7-3.3 million people in the United States have diagnoses of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). More than 700,000 people are living with multiple sclerosis. And as of January 2023, 11% of people in the United States reported having long COVID symptoms; the incidence of long COVID is currently estimated at 10%-30% of nonhospitalized cases of COVID-19.
These illnesses “have come under one umbrella,” said Avindra Nath, MD, clinical director of the National Institute of Neurologic Disorders and Stroke (NINDS), Bethesda, Md.
To date, common ground in the literature has grown largely around long COVID and ME/CFS, the latter of which is often associated with a prior, often unidentified infection.
Symptoms of both have been “rigorously” studied and shown to have overlaps, and the illnesses appear to share underlying biologic abnormalities in metabolism and the gut microbiome, as well as viral reactivation and abnormalities in the immune system, central and autonomic nervous systems, and the cardiovascular and pulmonary systems, said Anthony L. Komaroff, MD, professor of medicine at Harvard Medical School and a senior physician at Brigham & Women’s Hospital, both in Boston. (An estimated half of patients with long COVID meet the diagnostic criteria for ME/CFS.)
Although less thoroughly researched, similar symptoms are experienced by a subset of people following a variety of viral, bacterial, and protozoal infections, Dr. Komaroff said. To be determined, he said, is whether the pathophysiology believed to be shared by long COVID and ME/CFS is also shared with other postinfectious syndromes following acute illness with Ebola, West Nile, dengue, mycoplasma pneumonia, enteroviruses, and other pathogens, he said.
Persistent infection, viral reactivation
RNA viral infections can lead to persistent inflammation and dysregulated immunity, with or without viral persistence over time, Timothy J. Henrich, MD, MMSc, associate professor of medicine at the University of California, San Francisco, said in a keynote address.
Research on Ebola survivors has documented long-lasting inflammation and severe immune dysfunction 2 years after infection, for instance. And it’s well known that HIV-1 leads to aberrant immune responses, inflammation, and organ damage despite antiretroviral therapy, said Dr. Henrich, who leads a laboratory/research group that studies approaches to HIV-1 cure and PET-based imaging approaches to characterize viral reservoirs and immune sequelae.
Viral persistence, which can be difficult to measure, has also been documented in Ebola survivors. And in patients living with HIV-1, HIV-1 RNA and protein expression have been shown to persist, again despite antiretroviral therapy. The UCSF Long-Term Immunological Impact of Novel Coronavirus (LIINC) study, for which Dr. Henrich is the principal investigator, found spike RNA in colorectal tissue more than 22 months post COVID, and other research documented viral protein in gut tissue for up to 6 months, he said.
“I think we’re appreciating now, in at least the scientific and treatment community, that there’s a potential for ‘acute’ infections to exhibit some degree of persistence leading to clinical morbidity,” said Dr. Henrich, one of several speakers to describe reports of pathogen persistence. Regarding long COVID, its “etiology is likely heterogeneous,” he said, but persistence of SARS-CoV-2 “may lay behind” other described mechanisms, from clotting/microvascular dysfunction to inflammation and tissue damage to immune dysregulation.
Reactivation of existing latent viral infections in the setting of new acute microbial illness may also play an etiologic role in chronic illnesses, Dr. Henrich said. Epstein-Barr virus (EBV) reactivation has been shown in some studies, including their UCSF COVID-19 cohort, to be associated with long COVID.
“Physicians have been trained to be skeptical about the role [of latent viral infections],” Michael Peluso, MD, an infectious disease physician and assistant professor at UCSF, said during a talk on viral reactivation. This skepticism needs to be “reexamined and overcome,” he said.
Herpesviruses have frequently been associated with ME/CFS, he noted. And evidence of a strong association between EBV and multiple sclerosis came recently from a prospective study of 10 million military recruits that found a 32-fold increased risk of MS after EBV infection but no increase after infection with other viruses, Dr. Peluso and Dr. Henrich both noted.
Research needs, treatment trials
Research needs are vast: The need to learn more about the mechanisms of pathogen persistence and immune evasion, for instance, and the need for more biomarker studies, more imaging studies and tissue analyses, more study of microbiome composition and activity, and continued development and application of metagenomic next-generation sequencing.
Workshop participants also spoke of the need to better understand the molecular mimicry that can occur between pathogen-produced proteins and self-antigens, for instance, and the effects of inflammation and infection-related immune changes on neuronal and microglial function in the brain.
“We should perform similar forms of analysis [across] patients with different infection-associated chronic conditions,” said Amy Proal, PhD, president of the PolyBio Research Foundation, which funds research on infection-associated chronic infections. And within individual conditions and well-characterized study groups “we should perform many different forms of analysis … so we can define endotypes and get more solid biomarkers so that industry [will have more confidence] to run clinical trials.”
In the meantime, patients need fast-moving treatment trials for long COVID, long Lyme, and other infection-associated chronic illnesses, speakers emphasized. “We all agree that treatment trials are overdue,” said the NINDS’ Dr. Nath. “We can’t afford to wait for another decade until we understand all the mechanisms, but rather we can do clinical trials based on what we understand now and study the pathophysiology in the context of the clinical trials.”
Just as was done with HIV, said Steven G. Deeks, MD, professor of medicine at UCSF, researchers must “practice experimental medicine” and select pathways and mechanisms of interest, interrupt those pathways in a controlled manner, and assess impact. “Much of this can be done by repurposing existing drugs,” he said, like antivirals for persistent viral infection, EBV-directed therapies for EBV reactivation, anti-inflammatory drugs for inflammation, B–cell-directed therapies for autoantibodies, and antiplatelet drugs for microvascular disease.
When done correctly, he said, such “probe” studies can deepen mechanistic understandings, lead to biomarkers, and provide proof-of-concept that “will encourage massive investment in developing new therapies” for long COVID and other infection-associated chronic illnesses.
Trials of treatments for long COVID “are starting, so I’m optimistic,” said Dr. Deeks, an expert on HIV pathogenesis and treatment and a principal investigator of the Researching COVID to Enhance Recovery (RECOVER) study. Among the trials: A study of intravenous immunoglobulin (IVIG) for neurologic long COVID; a study of an anti-SARS-CoV-2 monoclonal antibody that can deplete tissue/cellular reservoirs of viral particles (replicating or not); and a study evaluating baricitinib (Olumiant), a Janus kinase inhibitor, for neurocognitive impairment and cardiopulmonary symptoms of long COVID.
Alessio Fasano, MD, professor of pediatrics at Harvard Medical School and professor of nutrition at the Harvard T.H. Chan School of Public Health, Boston, described at the workshop how he began investigating the use of larazotide acetate – an inhibitor of the protein zonulin, which increases intestinal permeability – in children with COVID-19 Multisystem Inflammatory Syndrome (MIS-C) after learning that SARS-CoV-2 viral particles persist in the gastrointestinal tract, causing dysbiosis and zonulin upregulation.
In an ongoing phase 2, double-blind, placebo-controlled trial, the agent thus far has expedited the resolution of gastrointestinal symptoms and clearance of spike protein from the circulation, he said. A phase 2 trial of the agent for pediatric patients with long COVID and SARS-CoV-2 antigenemia is underway. “What if we were to stop [chains of events] by stopping the passage of elements from the virus into circulation?’ he said.
In the realm of Lyme disease, a recently launched Clinical Trials Network for Lyme and Other Tick-Borne Diseases has awarded pilot study grants to evaluate treatments aimed at a variety of possible disease mechanisms that, notably, are similar to those of other chronic illnesses: persistence of infection or remnants of infection, immune dysregulation and autoimmune reactions, neural dysfunction, and gut microbiome changes. (Microclots and mitochondrial dysfunction have not been as well studied in Lyme.)
Current and upcoming studies include evaluations of transcutaneous auricular vagus nerve stimulation for those with persistent Lyme fatigue, transcranial direct current stimulation with cognitive retraining for Lyme brain fog, and tetracycline for PTLD, said Brian Fallon, MD, MPH, professor of clinical psychiatry at Columbia University, New York, who directs the Lyme & Tick-Borne Diseases Research Center and the coordinating center of the new network.
Moving forward, he said, it is important to loosen exclusion criteria and include patients with “probable or possible” Lyme and those with suspected infections with other tick-borne pathogens. All told, these patients comprise a large portion of those with chronic symptoms and have been neglected in an already thin research space, Dr. Fallon said, noting that “there haven’t been any clinical trials of posttreatment Lyme disease in ages – in 10-15 years.”
(PTLD refers to symptoms lasting for more than 6 months after the completion of standard Infectious Diseases Society of America–recommended antibiotic protocols. It occurs in about 15% of patients, said John Aucott, MD, director of the Johns Hopkins Lyme Disease Research Center, Baltimore, a member of the new clinical trials network.)
Calls for a new NIH center and patient involvement
Patients and patient advocacy organizations have played a vital role in research thus far: They’ve documented post-COVID symptoms that academic researchers said they would not otherwise have known of. Leaders of the Patient-Led Research Collaborative have coauthored published reviews with leading long COVID experts. And patients with tick-borne illnesses have enrolled in the MyLymeData patient registry run by LymeDisease.org, which has documented patient-experienced efficacy of alternative treatments and described antibiotic responders and nonresponders.
At the workshop, they shared findings alongside academic experts, and researchers called for their continued involvement. “Patient engagement at every step of the research process is critical,” Dr. Nath said.
“We need to ensure that research is reflective of lived experiences … and [that we’re] accelerating clinical trials of therapeutics that are of priority to the patient community,” said Lisa McCorkell, cofounder of the long COVID-focused Patient-Led Research Collaborative.
Ms. McCorkell also called for the creation of an office for infection-associated chronic illnesses in the NIH director’s office. Others voiced their support. “I think it’s a great idea to have an NIH center for infection-associated chronic illnesses,” said Dr. Fallon. “I think it would have a profound impact.”
The other great need, of course, is funding. “We have ideas, we have drugs that can be repurposed, we have a highly informed and engaged community that will enroll in and be retained in studies, and we have outcomes we can measure,” Dr. Deeks said. “What we’re missing is industry engagement and funding. We need massive engagement from the NIH.”
Real-world treatment needs
In the meantime, patients are seeking treatment, and “clinicians need to have uncertainty tolerance” and try multiple treatments simultaneously, said David Putrino, PT, PhD, director of rehabilitation innovation for the Mount Sinai Health System and professor of rehabilitation and human performance at the Icahn School of Medicine at Mount Sinai, New York. He oversees a multidisciplinary hybrid clinical care research center that has seen over 1,500 patients with long COVID and is beginning to see patients with other infection-associated chronic illnesses.
It’s a model that should be replicated to help fill the “enormous unmet clinical need” of patients with infection-associated chronic illness, said Peter Rowe, MD, professor of pediatrics at the Johns Hopkins School of Medicine and an expert on ME/CFS. And “as we request [more research funding], we will also need [financial] support for clinical care,” he emphasized, to provide equitable access for patients and to attract treating physicians.
Moreover, said Linda Geng, MD, PhD, the culture of stigma needs to change. Right now, patients with long COVID often feel dismissed not only by friends, families, and coworkers, but by clinicians who find it find it hard “to grasp that this is real and a biological condition.”
And it’s not just conditions such as long COVID that are stigmatized, but treatments as well, she said. For instance, some clinicians view low-dose naltrexone, a treatment increasingly being used for inflammation, with suspicion because it is used for opioid use disorder and alcohol use disorder – or because the “low-dose” label summons mistrust of homeopathy. “Even with therapies, there are preconceived notions and biases,” said Dr. Geng, cofounder and codirector of the Stanford (Calif.) Long COVID program.
“What almost killed me,” said Meghan O’Rourke, who has ongoing effects from long-undiagnosed tick-borne illness, “was the invisibility of the illness.” Ms. O’Rourke teaches at Yale University and is the author of “The Invisible Kingdom: Reimagining Chronic Illness.”
Teaching young physicians about these illnesses would help, she and others said. During a question and answer session, Dr. Putrino shared that the Icahn School of Medicine has recently committed to “create a complex chronic illness medical curriculum” that will impact medical education from the first year of medical school through residencies. Dr. Putrino said his team is also working on materials to help other clinics develop care models similar to those at his Mount Sinai clinic.
The NASEM workshop did not collect or require disclosures of its participants.
FROM A NATIONAL ACADEMIES OF SCIENCE, ENGINEERING, AND MEDICINE WORKSHOP
Research points toward combination therapy for Lyme and improved diagnostics
Several recent developments in Lyme disease treatment and diagnosis may pave the way forward for combating disease that persists following missed or delayed diagnoses or remains following standard treatment. These include combination therapy to address “persister” bacteria and diagnostic tests that test directly for the pathogen and/or indirectly test for host response, according to experts who presented at a 2-day National Academies of Science, Engineering and Medicine workshop on infection-associated chronic illnesses.
Research has shown that 60% of people who are infected and not treated during the early or early disseminated stages of Lyme disease go on to develop late Lyme arthritis, said John Aucott, MD, director of the Johns Hopkins Lyme Disease Clinical Research Center in Baltimore. And in the real world, there’s an additional category of patients: Those who are misdiagnosed and develop infection-related persistent symptoms – such as fatigue, brain fog/cognitive dysfunction, and musculoskeletal problems – that don’t match the “textbook schematic” involving late Lyme arthritis and late neurologic disease.
Moreover, of patients who are treated with protocols recommended by the Infectious Diseases Society of America (IDSA), about 15% go on to develop persistent symptoms at 6 months – again, symptoms that don’t match textbook manifestations and do match symptoms of other infection-associated chronic illnesses. As a “research construct,” this has been coined posttreatment Lyme disease (PTLD), he said at the workshop, “Toward a Common Research Agenda in Infection-Associated Chronic Illnesses.”
(On a practical level, it is hard to know clinically who has early disseminated disease unless they have multiple erythema migrans rashes or neurologic or cardiac involvement, he said after the meeting.)
All this points to the need for tests that are sensitive and specific for diagnosis at all stages of infection and disease, he said in a talk on diagnostics. Currently available tests – those that fit into the widely used two-tiered enzyme-linked immunosorbent assay, Western Blot serology testing – have significant limitations in sensitivity and specificity, including for acute infection when the body has not generated enough antibodies, yet treatment is most likely to succeed.
Move toward combination therapy research
Lyme disease is most commonly treated with doxycycline, and that’s problematic because the antibiotic is a microstatic whose efficacy relies on immune clearance of static bacteria, said Monica E. Embers, PhD, director of vector-borne disease at the Tulane National Primate Research Center and associate professor of immunology at Tulane University, New Orleans.
“But we know that Borrelia burgdorferi has the capability to evade the host immune response in almost every way possible. Persistence is the norm in an immunocompetent host ... [and] dormant bacteria/persisters are more tolerant of microstatic antibiotics,” she said.
Other considerations for antibiotic efficacy include the fact that B. burgdorferi survives for many months inside ticks without nutrient replenishment or replication, “so dormancy is part of their life cycle,” she said. Moreover, the bacteria can be found deep in connective tissues and joints.
The efficacy of accepted regimens of antibiotic treatment has been “a very contentious issue,” she said, noting that guidelines from the International Lyme and Associated Diseases Society “leave open the possibility for antibiotic retreatment when a chronic infection is judged to be a possible cause [of ongoing symptoms].”
The development of persister B. burgdorferi in the presence of antibiotics has been well studied in vitro, which has limitations, Dr. Embers said. But her group specializes in animal models and has shown persistence of antimicrobial-tolerant B. burgdorferi in tick-inoculated rhesus macaques 8-9 months after treatment with oral doxycycline.
“We [also] saw persistence of mild-moderate inflammation in the brain, peripheral nerves, spinal cord, joints and skeletal muscle, and in the heart,” Dr. Embers said, who coauthored a 2022 review of B. burgdorferi antimicrobial-tolerant persistence in Lyme disease and PTLD.
Her work has also shown that ceftriaxone, which is recommended by IDSA for patients with clinically evident neurological and/or cardiac involvement, does not clear infection in mice. “In general, single drugs have not been capable of clearing the infection, yet combinations show promise,” she said.
Dr. Embers has combed large drug libraries looking for combinations of antibiotics that employ different mechanisms of action in hopes of eliminating persister spirochetes. Certain combinations have shown promise in mice and have been tested in her rhesus macaque model; data analyses are underway.
Other research teams, such as that of Ying Zhang, MD, PhD, at Johns Hopkins, have similarly been screening combinations of antibiotics and other compounds, identifying candidates for further testing.
During a question and answer period, Dr. Embers said her team is also investigating the pathophysiology and long-term effects of tick-borne coinfections, including Bartonella, and is pursuing a hypothesis that infection with Borrelia allows Bartonella to cause more extensive disease and persist longer. “I think Lyme is at the core because of its ability to evade and suppress the immune response so effectively.”
Diagnostic possibilities, biomarkers for PTLD
Direct diagnostic tests for microbial nucleic acid and proteins “are promising alternatives for indirect serologic tests,” Dr. Aucott said. For instance, in addition to polymerase chain reaction tests, which “are making advances,” it may be possible to target the B. burgdorferi peptidoglycan for antigen detection.
Researchers have shown that peptidoglycan, a component of the B. burgdorferi cell envelope, is a persistent antigen in the synovial fluid of patients with Lyme arthritis who have been treated with oral and intravenous antibiotics, and that it likely contributes to inflammation.
“Maybe the infection is gone but parts of the bacteria are still there that are driving inflammation,” said Dr. Aucott, also associate professor of medicine at John Hopkins.
Researchers have also been looking at the host response to B. burgdorferi – including cytokines, chemokines, and autoantibiodies – to identify biomarkers for PTLD and to identify patients during posttreatment follow-up who are at increased risk of developing PTLD, with the hope of someday intervening. Persistently high levels of interleukin-23, CCL19, and interferon-alpha have each been associated in different studies with persistent symptoms after treatment, Dr. Aucott said.
In addition, metabolomics research is showing that patients with PTLD have metabolic fingerprints that are different from those who return to good health after treatment, and it may be possible to identify an epigenetic signature for Lyme disease. A project sponsored by the Defense Advanced Research Projects Agency called ECHO (Epigenetic Characterization and Observation) aims to identify epigenetic signatures of exposures to various threats, including B. burgdorferi.
“At the very proximal end of [indirectly testing for host response], there are modifications of the DNA that can occur in response to infectious insults ... and that changed DNA changes RNA expression and protein synthesis,” Dr. Aucott explained. DARPA’s project is “exciting because their goal [at DARPA] is to have a diagnostic test quickly as a result of this epigenetics work.”
Imaging research is also fast offering diagnostic opportunities, Dr. Aucott said. Levels of microglial activation on brain PET imaging have been found to correlate with PTLD, and a study at Johns Hopkins of multimodal neuroimaging with functional MRI and diffusion tensor imaging has shown distinct changes to white matter activation within the frontal lobe of patients with PTLD, compared with controls.
The NASEM workshop did not collect or require disclosures of its participants.
Several recent developments in Lyme disease treatment and diagnosis may pave the way forward for combating disease that persists following missed or delayed diagnoses or remains following standard treatment. These include combination therapy to address “persister” bacteria and diagnostic tests that test directly for the pathogen and/or indirectly test for host response, according to experts who presented at a 2-day National Academies of Science, Engineering and Medicine workshop on infection-associated chronic illnesses.
Research has shown that 60% of people who are infected and not treated during the early or early disseminated stages of Lyme disease go on to develop late Lyme arthritis, said John Aucott, MD, director of the Johns Hopkins Lyme Disease Clinical Research Center in Baltimore. And in the real world, there’s an additional category of patients: Those who are misdiagnosed and develop infection-related persistent symptoms – such as fatigue, brain fog/cognitive dysfunction, and musculoskeletal problems – that don’t match the “textbook schematic” involving late Lyme arthritis and late neurologic disease.
Moreover, of patients who are treated with protocols recommended by the Infectious Diseases Society of America (IDSA), about 15% go on to develop persistent symptoms at 6 months – again, symptoms that don’t match textbook manifestations and do match symptoms of other infection-associated chronic illnesses. As a “research construct,” this has been coined posttreatment Lyme disease (PTLD), he said at the workshop, “Toward a Common Research Agenda in Infection-Associated Chronic Illnesses.”
(On a practical level, it is hard to know clinically who has early disseminated disease unless they have multiple erythema migrans rashes or neurologic or cardiac involvement, he said after the meeting.)
All this points to the need for tests that are sensitive and specific for diagnosis at all stages of infection and disease, he said in a talk on diagnostics. Currently available tests – those that fit into the widely used two-tiered enzyme-linked immunosorbent assay, Western Blot serology testing – have significant limitations in sensitivity and specificity, including for acute infection when the body has not generated enough antibodies, yet treatment is most likely to succeed.
Move toward combination therapy research
Lyme disease is most commonly treated with doxycycline, and that’s problematic because the antibiotic is a microstatic whose efficacy relies on immune clearance of static bacteria, said Monica E. Embers, PhD, director of vector-borne disease at the Tulane National Primate Research Center and associate professor of immunology at Tulane University, New Orleans.
“But we know that Borrelia burgdorferi has the capability to evade the host immune response in almost every way possible. Persistence is the norm in an immunocompetent host ... [and] dormant bacteria/persisters are more tolerant of microstatic antibiotics,” she said.
Other considerations for antibiotic efficacy include the fact that B. burgdorferi survives for many months inside ticks without nutrient replenishment or replication, “so dormancy is part of their life cycle,” she said. Moreover, the bacteria can be found deep in connective tissues and joints.
The efficacy of accepted regimens of antibiotic treatment has been “a very contentious issue,” she said, noting that guidelines from the International Lyme and Associated Diseases Society “leave open the possibility for antibiotic retreatment when a chronic infection is judged to be a possible cause [of ongoing symptoms].”
The development of persister B. burgdorferi in the presence of antibiotics has been well studied in vitro, which has limitations, Dr. Embers said. But her group specializes in animal models and has shown persistence of antimicrobial-tolerant B. burgdorferi in tick-inoculated rhesus macaques 8-9 months after treatment with oral doxycycline.
“We [also] saw persistence of mild-moderate inflammation in the brain, peripheral nerves, spinal cord, joints and skeletal muscle, and in the heart,” Dr. Embers said, who coauthored a 2022 review of B. burgdorferi antimicrobial-tolerant persistence in Lyme disease and PTLD.
Her work has also shown that ceftriaxone, which is recommended by IDSA for patients with clinically evident neurological and/or cardiac involvement, does not clear infection in mice. “In general, single drugs have not been capable of clearing the infection, yet combinations show promise,” she said.
Dr. Embers has combed large drug libraries looking for combinations of antibiotics that employ different mechanisms of action in hopes of eliminating persister spirochetes. Certain combinations have shown promise in mice and have been tested in her rhesus macaque model; data analyses are underway.
Other research teams, such as that of Ying Zhang, MD, PhD, at Johns Hopkins, have similarly been screening combinations of antibiotics and other compounds, identifying candidates for further testing.
During a question and answer period, Dr. Embers said her team is also investigating the pathophysiology and long-term effects of tick-borne coinfections, including Bartonella, and is pursuing a hypothesis that infection with Borrelia allows Bartonella to cause more extensive disease and persist longer. “I think Lyme is at the core because of its ability to evade and suppress the immune response so effectively.”
Diagnostic possibilities, biomarkers for PTLD
Direct diagnostic tests for microbial nucleic acid and proteins “are promising alternatives for indirect serologic tests,” Dr. Aucott said. For instance, in addition to polymerase chain reaction tests, which “are making advances,” it may be possible to target the B. burgdorferi peptidoglycan for antigen detection.
Researchers have shown that peptidoglycan, a component of the B. burgdorferi cell envelope, is a persistent antigen in the synovial fluid of patients with Lyme arthritis who have been treated with oral and intravenous antibiotics, and that it likely contributes to inflammation.
“Maybe the infection is gone but parts of the bacteria are still there that are driving inflammation,” said Dr. Aucott, also associate professor of medicine at John Hopkins.
Researchers have also been looking at the host response to B. burgdorferi – including cytokines, chemokines, and autoantibiodies – to identify biomarkers for PTLD and to identify patients during posttreatment follow-up who are at increased risk of developing PTLD, with the hope of someday intervening. Persistently high levels of interleukin-23, CCL19, and interferon-alpha have each been associated in different studies with persistent symptoms after treatment, Dr. Aucott said.
In addition, metabolomics research is showing that patients with PTLD have metabolic fingerprints that are different from those who return to good health after treatment, and it may be possible to identify an epigenetic signature for Lyme disease. A project sponsored by the Defense Advanced Research Projects Agency called ECHO (Epigenetic Characterization and Observation) aims to identify epigenetic signatures of exposures to various threats, including B. burgdorferi.
“At the very proximal end of [indirectly testing for host response], there are modifications of the DNA that can occur in response to infectious insults ... and that changed DNA changes RNA expression and protein synthesis,” Dr. Aucott explained. DARPA’s project is “exciting because their goal [at DARPA] is to have a diagnostic test quickly as a result of this epigenetics work.”
Imaging research is also fast offering diagnostic opportunities, Dr. Aucott said. Levels of microglial activation on brain PET imaging have been found to correlate with PTLD, and a study at Johns Hopkins of multimodal neuroimaging with functional MRI and diffusion tensor imaging has shown distinct changes to white matter activation within the frontal lobe of patients with PTLD, compared with controls.
The NASEM workshop did not collect or require disclosures of its participants.
Several recent developments in Lyme disease treatment and diagnosis may pave the way forward for combating disease that persists following missed or delayed diagnoses or remains following standard treatment. These include combination therapy to address “persister” bacteria and diagnostic tests that test directly for the pathogen and/or indirectly test for host response, according to experts who presented at a 2-day National Academies of Science, Engineering and Medicine workshop on infection-associated chronic illnesses.
Research has shown that 60% of people who are infected and not treated during the early or early disseminated stages of Lyme disease go on to develop late Lyme arthritis, said John Aucott, MD, director of the Johns Hopkins Lyme Disease Clinical Research Center in Baltimore. And in the real world, there’s an additional category of patients: Those who are misdiagnosed and develop infection-related persistent symptoms – such as fatigue, brain fog/cognitive dysfunction, and musculoskeletal problems – that don’t match the “textbook schematic” involving late Lyme arthritis and late neurologic disease.
Moreover, of patients who are treated with protocols recommended by the Infectious Diseases Society of America (IDSA), about 15% go on to develop persistent symptoms at 6 months – again, symptoms that don’t match textbook manifestations and do match symptoms of other infection-associated chronic illnesses. As a “research construct,” this has been coined posttreatment Lyme disease (PTLD), he said at the workshop, “Toward a Common Research Agenda in Infection-Associated Chronic Illnesses.”
(On a practical level, it is hard to know clinically who has early disseminated disease unless they have multiple erythema migrans rashes or neurologic or cardiac involvement, he said after the meeting.)
All this points to the need for tests that are sensitive and specific for diagnosis at all stages of infection and disease, he said in a talk on diagnostics. Currently available tests – those that fit into the widely used two-tiered enzyme-linked immunosorbent assay, Western Blot serology testing – have significant limitations in sensitivity and specificity, including for acute infection when the body has not generated enough antibodies, yet treatment is most likely to succeed.
Move toward combination therapy research
Lyme disease is most commonly treated with doxycycline, and that’s problematic because the antibiotic is a microstatic whose efficacy relies on immune clearance of static bacteria, said Monica E. Embers, PhD, director of vector-borne disease at the Tulane National Primate Research Center and associate professor of immunology at Tulane University, New Orleans.
“But we know that Borrelia burgdorferi has the capability to evade the host immune response in almost every way possible. Persistence is the norm in an immunocompetent host ... [and] dormant bacteria/persisters are more tolerant of microstatic antibiotics,” she said.
Other considerations for antibiotic efficacy include the fact that B. burgdorferi survives for many months inside ticks without nutrient replenishment or replication, “so dormancy is part of their life cycle,” she said. Moreover, the bacteria can be found deep in connective tissues and joints.
The efficacy of accepted regimens of antibiotic treatment has been “a very contentious issue,” she said, noting that guidelines from the International Lyme and Associated Diseases Society “leave open the possibility for antibiotic retreatment when a chronic infection is judged to be a possible cause [of ongoing symptoms].”
The development of persister B. burgdorferi in the presence of antibiotics has been well studied in vitro, which has limitations, Dr. Embers said. But her group specializes in animal models and has shown persistence of antimicrobial-tolerant B. burgdorferi in tick-inoculated rhesus macaques 8-9 months after treatment with oral doxycycline.
“We [also] saw persistence of mild-moderate inflammation in the brain, peripheral nerves, spinal cord, joints and skeletal muscle, and in the heart,” Dr. Embers said, who coauthored a 2022 review of B. burgdorferi antimicrobial-tolerant persistence in Lyme disease and PTLD.
Her work has also shown that ceftriaxone, which is recommended by IDSA for patients with clinically evident neurological and/or cardiac involvement, does not clear infection in mice. “In general, single drugs have not been capable of clearing the infection, yet combinations show promise,” she said.
Dr. Embers has combed large drug libraries looking for combinations of antibiotics that employ different mechanisms of action in hopes of eliminating persister spirochetes. Certain combinations have shown promise in mice and have been tested in her rhesus macaque model; data analyses are underway.
Other research teams, such as that of Ying Zhang, MD, PhD, at Johns Hopkins, have similarly been screening combinations of antibiotics and other compounds, identifying candidates for further testing.
During a question and answer period, Dr. Embers said her team is also investigating the pathophysiology and long-term effects of tick-borne coinfections, including Bartonella, and is pursuing a hypothesis that infection with Borrelia allows Bartonella to cause more extensive disease and persist longer. “I think Lyme is at the core because of its ability to evade and suppress the immune response so effectively.”
Diagnostic possibilities, biomarkers for PTLD
Direct diagnostic tests for microbial nucleic acid and proteins “are promising alternatives for indirect serologic tests,” Dr. Aucott said. For instance, in addition to polymerase chain reaction tests, which “are making advances,” it may be possible to target the B. burgdorferi peptidoglycan for antigen detection.
Researchers have shown that peptidoglycan, a component of the B. burgdorferi cell envelope, is a persistent antigen in the synovial fluid of patients with Lyme arthritis who have been treated with oral and intravenous antibiotics, and that it likely contributes to inflammation.
“Maybe the infection is gone but parts of the bacteria are still there that are driving inflammation,” said Dr. Aucott, also associate professor of medicine at John Hopkins.
Researchers have also been looking at the host response to B. burgdorferi – including cytokines, chemokines, and autoantibiodies – to identify biomarkers for PTLD and to identify patients during posttreatment follow-up who are at increased risk of developing PTLD, with the hope of someday intervening. Persistently high levels of interleukin-23, CCL19, and interferon-alpha have each been associated in different studies with persistent symptoms after treatment, Dr. Aucott said.
In addition, metabolomics research is showing that patients with PTLD have metabolic fingerprints that are different from those who return to good health after treatment, and it may be possible to identify an epigenetic signature for Lyme disease. A project sponsored by the Defense Advanced Research Projects Agency called ECHO (Epigenetic Characterization and Observation) aims to identify epigenetic signatures of exposures to various threats, including B. burgdorferi.
“At the very proximal end of [indirectly testing for host response], there are modifications of the DNA that can occur in response to infectious insults ... and that changed DNA changes RNA expression and protein synthesis,” Dr. Aucott explained. DARPA’s project is “exciting because their goal [at DARPA] is to have a diagnostic test quickly as a result of this epigenetics work.”
Imaging research is also fast offering diagnostic opportunities, Dr. Aucott said. Levels of microglial activation on brain PET imaging have been found to correlate with PTLD, and a study at Johns Hopkins of multimodal neuroimaging with functional MRI and diffusion tensor imaging has shown distinct changes to white matter activation within the frontal lobe of patients with PTLD, compared with controls.
The NASEM workshop did not collect or require disclosures of its participants.
FROM A NATIONAL ACADEMIES OF SCIENCE, ENGINEERING AND MEDICINE WORKSHOP
Lupus flares linked to gut bacteria overgrowth
Flares of systemic lupus erythematosus (SLE), particularly those involving severe kidney disease, were associated with growth spikes of the gut bacteria Ruminococcus blautia gnavus in a small, 4-year observational study that also demonstrated an underlying, inherent instability in the gut microbiome of patients with SLE.
Of 16 patients with SLE studied during the provision of routine care and monitoring, 5 had R. gnavus blooms that were “strikingly concordant with periods of raised disease activity,” Gregg J. Silverman, MD, of NYU Grossman School of Medicine, New York, and coinvestigators reported in Annals of the Rheumatic Diseases.
Four of the five patients with flare-associated R. gnavus blooms had lupus nephritis (LN); the other had a flare involving inflammation in multiple joints. The four patients with concurrent LN and spikes in R. gnavus also represented almost half of patients who had LN disease flares (four of nine) during the study period. The nine patients in the study with renal involvement, and the four with concurrent R. gnavus spikes and flares, represented different races and ethnicities.
The findings build upon research published by the NYU group several years ago showing that patients with SLE had more R. gnavus in the gut than similar patients without the disease, and that flares closely tracked major increases in R. gnavus growth. Evidence of R. gnavus expansions in patients with SLE now comes from several cohorts in the United States as well as cohorts in Europe and China, the researchers noted in their new paper.
An underlying, unstable microbiome
The new study at NYU took a “deeper dive” than previous research, looking at individuals over a longer period of time, Dr. Silverman, the study’s senior investigator and associate director of rheumatology at NYU Langone Health, said in an interview. Blood and a total of 44 stool samples from the 16 patients were analyzed, as were a total of 72 stool samples from 22 healthy control volunteers.
Importantly, he said, the gut microbiome in patients with SLE was found to be inherently unstable over time, compared with the microbiota communities of the controls. “There was an instability, a shifting dynamic composition of the microbiome [in patients with lupus]. ... Healthy individuals had more of a balance, with small changes over time” and a stable, low abundance of R. gnavus, Dr. Silverman said.
Transient expansions of several pathogenic species occurred in some of the patients with lupus (and not in controls), but blooms of R. gnavus were the most common. The researchers said in their paper that they “speculate that susceptibility for specific clinical features during R. gnavus blooms reflect in part differences in genetic susceptibility of the patient.”
Patients on cytotoxic agents or antibiotics were excluded from the study, but the study was not designed to disentangle the potential influence of diet or prior antibiotic exposure, they noted. Larger studies are needed that are better controlled and that include more frequent assessments, Dr. Silverman added.
A sure association and probable cause
“There seems to be a special connection [of R. gnavus] to lupus nephritis, which is an important, major subset of disease,” said Martin Kriegel, MD, PhD, chief or rheumatology and clinical immunology at the University of Munster (Germany). Dr. Kriegel also researches the gut microbiome in lupus and was asked to comment on the new findings from NYU.
The “difficult question is, is the bug driving the flare [as the NYU paper proposes], or is it the lupus nephritis that leads to overgrowth?” he said, noting that it “is well known that kidney disease, whether from lupus or other causes, creates disturbances in the microbiome.”
It’s “likely the case” that the pathobiome – with R. gnavus being an important pathobiont – helps to drive flares, he said. The new research shows only an association, but studies done in mice – including prior research by Dr. Silverman – support a mechanistic link, said Dr. Kriegel, also adjunct associate professor of immunobiology and of medicine at Yale University, New Haven, Conn.
Investigators in the microbiome space are moving toward more strain-level analysis – “not only measuring what organisms are there, but culturing them and sequencing them,” Dr. Kriegel noted, and the new study does just this.
The R. gnavus strains isolated during lupus flares were distinguishable from strains found in healthy people – and from strains found by other researchers in patients with inflammatory bowel disease – by their common expression of a novel type of cell membrane–associated lipoglycan. The lipoglycans were recognized by specific serum IgG2 antibodies that were detected concurrently with R. gnavus blooms and lupus flares, Dr. Silverman and his colleagues reported.
Dr. Silverman and Dr. Kriegel both study the paradigm of a gut-barrier breach, whereby pathogenic bacteria cause intestinal permeability, allowing bacterial leakages that trigger inflammation and immune responses. “We think that in lupus and other rheumatic diseases like rheumatoid arthritis, a leaky gut barrier is an important mechanism, even though these patients don’t have gastrointestinal symptoms,” said Dr. Kriegel, who has studied the role of another potentially pathogenic bacteria, Enterococcus gallinarum, in SLE.
Strengthening the gut barrier may be a plausible, general approach to reducing the severity of diseases like SLE and RA until more personalized approaches targeting individuals’ microbiome are developed, he noted.
Future treatments involving antibacterial agents, probiotics or dietary regimens that prevent imbalances in the gut microbiome would be “benign,” compared with currently utilized immunosuppressive medications, Dr. Silverman said.
The NYU study was funded in part by grants from the National Institutes of Health and the Lupus Research Alliance. Dr. Silverman disclosed that NYU has filed a patent application for an antibody test to detect serum antibodies to the lipoglycan made by some strains of R. gnavus. Dr. Kriegel disclosed that he holds a patent at Yale related to the Enterococcus bacteria he studies, and that he consults for Roche, Enterome, and Eligo Biosciences.
Flares of systemic lupus erythematosus (SLE), particularly those involving severe kidney disease, were associated with growth spikes of the gut bacteria Ruminococcus blautia gnavus in a small, 4-year observational study that also demonstrated an underlying, inherent instability in the gut microbiome of patients with SLE.
Of 16 patients with SLE studied during the provision of routine care and monitoring, 5 had R. gnavus blooms that were “strikingly concordant with periods of raised disease activity,” Gregg J. Silverman, MD, of NYU Grossman School of Medicine, New York, and coinvestigators reported in Annals of the Rheumatic Diseases.
Four of the five patients with flare-associated R. gnavus blooms had lupus nephritis (LN); the other had a flare involving inflammation in multiple joints. The four patients with concurrent LN and spikes in R. gnavus also represented almost half of patients who had LN disease flares (four of nine) during the study period. The nine patients in the study with renal involvement, and the four with concurrent R. gnavus spikes and flares, represented different races and ethnicities.
The findings build upon research published by the NYU group several years ago showing that patients with SLE had more R. gnavus in the gut than similar patients without the disease, and that flares closely tracked major increases in R. gnavus growth. Evidence of R. gnavus expansions in patients with SLE now comes from several cohorts in the United States as well as cohorts in Europe and China, the researchers noted in their new paper.
An underlying, unstable microbiome
The new study at NYU took a “deeper dive” than previous research, looking at individuals over a longer period of time, Dr. Silverman, the study’s senior investigator and associate director of rheumatology at NYU Langone Health, said in an interview. Blood and a total of 44 stool samples from the 16 patients were analyzed, as were a total of 72 stool samples from 22 healthy control volunteers.
Importantly, he said, the gut microbiome in patients with SLE was found to be inherently unstable over time, compared with the microbiota communities of the controls. “There was an instability, a shifting dynamic composition of the microbiome [in patients with lupus]. ... Healthy individuals had more of a balance, with small changes over time” and a stable, low abundance of R. gnavus, Dr. Silverman said.
Transient expansions of several pathogenic species occurred in some of the patients with lupus (and not in controls), but blooms of R. gnavus were the most common. The researchers said in their paper that they “speculate that susceptibility for specific clinical features during R. gnavus blooms reflect in part differences in genetic susceptibility of the patient.”
Patients on cytotoxic agents or antibiotics were excluded from the study, but the study was not designed to disentangle the potential influence of diet or prior antibiotic exposure, they noted. Larger studies are needed that are better controlled and that include more frequent assessments, Dr. Silverman added.
A sure association and probable cause
“There seems to be a special connection [of R. gnavus] to lupus nephritis, which is an important, major subset of disease,” said Martin Kriegel, MD, PhD, chief or rheumatology and clinical immunology at the University of Munster (Germany). Dr. Kriegel also researches the gut microbiome in lupus and was asked to comment on the new findings from NYU.
The “difficult question is, is the bug driving the flare [as the NYU paper proposes], or is it the lupus nephritis that leads to overgrowth?” he said, noting that it “is well known that kidney disease, whether from lupus or other causes, creates disturbances in the microbiome.”
It’s “likely the case” that the pathobiome – with R. gnavus being an important pathobiont – helps to drive flares, he said. The new research shows only an association, but studies done in mice – including prior research by Dr. Silverman – support a mechanistic link, said Dr. Kriegel, also adjunct associate professor of immunobiology and of medicine at Yale University, New Haven, Conn.
Investigators in the microbiome space are moving toward more strain-level analysis – “not only measuring what organisms are there, but culturing them and sequencing them,” Dr. Kriegel noted, and the new study does just this.
The R. gnavus strains isolated during lupus flares were distinguishable from strains found in healthy people – and from strains found by other researchers in patients with inflammatory bowel disease – by their common expression of a novel type of cell membrane–associated lipoglycan. The lipoglycans were recognized by specific serum IgG2 antibodies that were detected concurrently with R. gnavus blooms and lupus flares, Dr. Silverman and his colleagues reported.
Dr. Silverman and Dr. Kriegel both study the paradigm of a gut-barrier breach, whereby pathogenic bacteria cause intestinal permeability, allowing bacterial leakages that trigger inflammation and immune responses. “We think that in lupus and other rheumatic diseases like rheumatoid arthritis, a leaky gut barrier is an important mechanism, even though these patients don’t have gastrointestinal symptoms,” said Dr. Kriegel, who has studied the role of another potentially pathogenic bacteria, Enterococcus gallinarum, in SLE.
Strengthening the gut barrier may be a plausible, general approach to reducing the severity of diseases like SLE and RA until more personalized approaches targeting individuals’ microbiome are developed, he noted.
Future treatments involving antibacterial agents, probiotics or dietary regimens that prevent imbalances in the gut microbiome would be “benign,” compared with currently utilized immunosuppressive medications, Dr. Silverman said.
The NYU study was funded in part by grants from the National Institutes of Health and the Lupus Research Alliance. Dr. Silverman disclosed that NYU has filed a patent application for an antibody test to detect serum antibodies to the lipoglycan made by some strains of R. gnavus. Dr. Kriegel disclosed that he holds a patent at Yale related to the Enterococcus bacteria he studies, and that he consults for Roche, Enterome, and Eligo Biosciences.
Flares of systemic lupus erythematosus (SLE), particularly those involving severe kidney disease, were associated with growth spikes of the gut bacteria Ruminococcus blautia gnavus in a small, 4-year observational study that also demonstrated an underlying, inherent instability in the gut microbiome of patients with SLE.
Of 16 patients with SLE studied during the provision of routine care and monitoring, 5 had R. gnavus blooms that were “strikingly concordant with periods of raised disease activity,” Gregg J. Silverman, MD, of NYU Grossman School of Medicine, New York, and coinvestigators reported in Annals of the Rheumatic Diseases.
Four of the five patients with flare-associated R. gnavus blooms had lupus nephritis (LN); the other had a flare involving inflammation in multiple joints. The four patients with concurrent LN and spikes in R. gnavus also represented almost half of patients who had LN disease flares (four of nine) during the study period. The nine patients in the study with renal involvement, and the four with concurrent R. gnavus spikes and flares, represented different races and ethnicities.
The findings build upon research published by the NYU group several years ago showing that patients with SLE had more R. gnavus in the gut than similar patients without the disease, and that flares closely tracked major increases in R. gnavus growth. Evidence of R. gnavus expansions in patients with SLE now comes from several cohorts in the United States as well as cohorts in Europe and China, the researchers noted in their new paper.
An underlying, unstable microbiome
The new study at NYU took a “deeper dive” than previous research, looking at individuals over a longer period of time, Dr. Silverman, the study’s senior investigator and associate director of rheumatology at NYU Langone Health, said in an interview. Blood and a total of 44 stool samples from the 16 patients were analyzed, as were a total of 72 stool samples from 22 healthy control volunteers.
Importantly, he said, the gut microbiome in patients with SLE was found to be inherently unstable over time, compared with the microbiota communities of the controls. “There was an instability, a shifting dynamic composition of the microbiome [in patients with lupus]. ... Healthy individuals had more of a balance, with small changes over time” and a stable, low abundance of R. gnavus, Dr. Silverman said.
Transient expansions of several pathogenic species occurred in some of the patients with lupus (and not in controls), but blooms of R. gnavus were the most common. The researchers said in their paper that they “speculate that susceptibility for specific clinical features during R. gnavus blooms reflect in part differences in genetic susceptibility of the patient.”
Patients on cytotoxic agents or antibiotics were excluded from the study, but the study was not designed to disentangle the potential influence of diet or prior antibiotic exposure, they noted. Larger studies are needed that are better controlled and that include more frequent assessments, Dr. Silverman added.
A sure association and probable cause
“There seems to be a special connection [of R. gnavus] to lupus nephritis, which is an important, major subset of disease,” said Martin Kriegel, MD, PhD, chief or rheumatology and clinical immunology at the University of Munster (Germany). Dr. Kriegel also researches the gut microbiome in lupus and was asked to comment on the new findings from NYU.
The “difficult question is, is the bug driving the flare [as the NYU paper proposes], or is it the lupus nephritis that leads to overgrowth?” he said, noting that it “is well known that kidney disease, whether from lupus or other causes, creates disturbances in the microbiome.”
It’s “likely the case” that the pathobiome – with R. gnavus being an important pathobiont – helps to drive flares, he said. The new research shows only an association, but studies done in mice – including prior research by Dr. Silverman – support a mechanistic link, said Dr. Kriegel, also adjunct associate professor of immunobiology and of medicine at Yale University, New Haven, Conn.
Investigators in the microbiome space are moving toward more strain-level analysis – “not only measuring what organisms are there, but culturing them and sequencing them,” Dr. Kriegel noted, and the new study does just this.
The R. gnavus strains isolated during lupus flares were distinguishable from strains found in healthy people – and from strains found by other researchers in patients with inflammatory bowel disease – by their common expression of a novel type of cell membrane–associated lipoglycan. The lipoglycans were recognized by specific serum IgG2 antibodies that were detected concurrently with R. gnavus blooms and lupus flares, Dr. Silverman and his colleagues reported.
Dr. Silverman and Dr. Kriegel both study the paradigm of a gut-barrier breach, whereby pathogenic bacteria cause intestinal permeability, allowing bacterial leakages that trigger inflammation and immune responses. “We think that in lupus and other rheumatic diseases like rheumatoid arthritis, a leaky gut barrier is an important mechanism, even though these patients don’t have gastrointestinal symptoms,” said Dr. Kriegel, who has studied the role of another potentially pathogenic bacteria, Enterococcus gallinarum, in SLE.
Strengthening the gut barrier may be a plausible, general approach to reducing the severity of diseases like SLE and RA until more personalized approaches targeting individuals’ microbiome are developed, he noted.
Future treatments involving antibacterial agents, probiotics or dietary regimens that prevent imbalances in the gut microbiome would be “benign,” compared with currently utilized immunosuppressive medications, Dr. Silverman said.
The NYU study was funded in part by grants from the National Institutes of Health and the Lupus Research Alliance. Dr. Silverman disclosed that NYU has filed a patent application for an antibody test to detect serum antibodies to the lipoglycan made by some strains of R. gnavus. Dr. Kriegel disclosed that he holds a patent at Yale related to the Enterococcus bacteria he studies, and that he consults for Roche, Enterome, and Eligo Biosciences.
FROM ANNALS OF THE RHEUMATIC DISEASES
The evolving pulmonary landscape in HIV
Chronic pulmonary disease continues to be a major cause of morbidity and mortality in individuals living with the human immunodeficiency virus, even with optimal HIV control. And this is independent, as seen in many studies, of age, smoking, and pulmonary infections.
Both chronic pulmonary obstructive disease (COPD) and lung cancer occur more frequently in people living with HIV than in the general population, and at earlier ages, and with worse outcomes. The risk for emphysema and interstitial lung abnormalities also appears to be higher, research has shown. And asthma has also recently emerged as another important lung disease in people with HIV (PWH).
“There is evidence that the severity of immunocompromise associated with HIV infection is linked with chronic lung diseases. People who have a lower CD4 cell count or a higher viral load do have an increased risk of COPD and emphysema as well as potentially lung cancer. ,” said Kristina Crothers, MD, professor in the division of pulmonary, critical care, and sleep medicine at the University of Washington, Seattle.
Research has evolved from a focus on the epidemiology of HIV-related chronic lung diseases to a current emphasis on “trying to understand further the mechanisms [behind the heightened risk] through more benchwork and corollary translational studies, and then to the next level of trying to understand what this means for how we should manage people with HIV who have chronic lung diseases,” Dr. Crothers said. “Should management be tailored for people with HIV infection?”
Impairments in immune pathways, local and systemic inflammation, oxidative stress, dysbiosis, and accelerated cellular senescence are among potential mechanisms, but until ongoing mechanistic research yields more answers, pulmonologists should simply – but importantly – be aware of the increased risk and have a low threshold for investigating respiratory symptoms, she and other experts said in interviews. Referral of eligible patients for lung cancer screening is also a priority, as is smoking cessation, they said.
Notably, while spirometry has been the most commonly studied lung function measure in PWH, another noninvasive measure, diffusing capacity for carbon monoxide (DLCO), has garnered attention in the past decade and thus far appears to be the more frequent lung function abnormality.
In an analysis published in 2020 from the longitudinal Multicenter AIDS Cohort Study (MACS) – a study of a subcohort of 591 men with HIV and 476 without HIV – those with HIV were found to have a 1.6-fold increased risk of mild DLCO impairment (< 80% of predicted normal) and a 3-fold higher risk of more severe DLCO impairment (< 60% of predicted normal). There was no significant difference in spirometry findings by HIV status.
Such findings on DLCO are worthy of consideration in clinical practice, even in the absence of HIV-specific screening guidelines for noncommunicable lung diseases, Dr. Crothers said. “In thinking about screening and diagnosing chronic lung diseases in these patients, I’d not only consider spirometry, but also diffusing capacity” when possible, she said. Impaired DLCO is seen with emphysema and pulmonary vascular diseases like pulmonary hypertension and also interstitial lung diseases.
Key chronic lung diseases
Ken M. Kunisaki, MD, MS, associate professor of medicine at the University of Minnesota, Minneapolis, and the first author of the MACS analysis of lung function – one of the most recent and largest reports of DLCO impairment – points out that studies of chest computed tomography (CT) have also documented higher rates of emphysema and interstitial lung abnormalities.
A chest CT analysis from a cohort in Denmark (the Copenhagen Comorbidity in HIV Infection [COCOMO] cohort) found interstitial lung abnormalities in 10.9% of more than 700 PWH which represented a 1.8-fold increased risk compared to HIV-negative controls. And a study from an Italian sample of never-smoking PWH and controls reported emphysema in 18% and 4%, respectively. These studies, which did not measure DLCO, are among those discussed in a 2021 review by Dr. Kunisaki of advances in HIV-associated chronic lung disease research.
COPD is the best studied and most commonly encountered chronic lung disease in PWH. “Particularly for COPD, what’s both interesting and unfortunate is that we haven’t really seen any changes in the epidemiology with ART (antiretroviral therapy) – we’re still seeing the same findings, like the association of HIV with worse COPD at younger ages,” said Alison Morris, MD, MS, professor of medicine, immunology, and clinical and translational research at the University of Pittsburgh. “It doesn’t seem to have improved.”
Its prevalence has varied widely from cohort to cohort, from as low as 3% (similar to the general population) to over 40%, Dr. Kunisaki said, emphasizing that many studies, including studies showing higher rates, have controlled for current and past smoking. In evaluating patients with low or no smoking burden, “don’t discount respiratory symptoms as possibly reflecting underlying lung disease because COPD can develop with low to no smoking history in those with HIV,” he advised.
A better understanding of how a chronic viral infection like HIV leads to heightened COPD risk will not only help those with HIV, he notes, but also people without HIV who have COPD but have never smoked – a woefully underappreciated and understudied population. Ongoing research, he said, “should help us understand COPD pathogenesis generally.”
Research on asthma is relatively limited thus far, but it does appear that PWH may be more prone to developing severe asthma, just as with COPD, said Dr. Kunisaki, also a staff physician at the Minneapolis Veterans Administration Health Care System. Research has shown, for instance, that people with HIV more frequently needed aggressive respiratory support when hospitalized for asthma exacerbations.
It’s unclear how much of this potentially increased severity is attributable to the biology of HIV’s impact on the body and how much relates to social factors like disparities in income and access to care, Dr. Kunisaki said, noting that the same questions apply to the more frequent COPD exacerbations documented in PWH.
Dr. Crothers points out that, while most studies do not suggest a difference in the incidence of asthma in PWH, “there is some data from researchers looking at asthma profiles [suggesting] that the biomarkers associated with asthma may be different in people with and without HIV,” signaling potentially different molecular or biologic underpinnings of the disease.
Incidence rates of lung cancer in PWH, meanwhile, have declined over the last 2 decades, but lung cancer remains the leading cause of cancer-related mortality in PWH and occurs at a rate that is 2-2.5 times higher than that of individuals not infected with HIV, according to
Janice Leung, MD, of the division of respiratory medicine at the University of British Columbia and the Centre for Heart Lung Innovation at St. Paul’s Hospital in Vancouver.
Patients with HIV have “worse outcomes overall and a higher risk of mortality, even when presenting at the same stage,” said Dr. Leung, who reviewed trends in COPD and lung cancer in a recently published opinion piece.
Potential drivers
A bird’s eye view of potential – and likely interrelated – mechanisms for chronic lung disease includes chronic immune activation that impairs innate and adaptive immune pathways; chronic inflammation systemically and in the lung despite viral suppression; persistence of the virus in latent reservoirs in the lung, particularly in alveolar macrophages and T cells; HIV-related proteins contributing to oxidative stress; accelerated cellular aging; dysbiosis; and ongoing injury from inhaled toxins.
All are described in the literature and are being further explored. “It’s likely that multiple pathways are playing a role,” said Dr. Crothers, “and it could be that the balance of one to another leads to different manifestations of disease.”
Biomarkers that have been elevated and associated with different features of chronic lung disease – such as airflow obstruction, low DLCO, and emphysema – include markers of inflammation (e.g., C-reactive protein, interleukin-6), monocyte activation (e.g., soluble CD14), and markers of endothelial dysfunction, she noted in a 2021 commentary marking 40 years since the first reported cases of acquired immunodeficiency syndrome.
In her laboratory, Dr. Leung is using new epigenetic markers to look at the pathogenesis of accelerated aging in the lung. By profiling bronchial epithelial brushings for DNA methylation and gene expression, they have found that “people living with both HIV and COPD have the fastest epigenetic age acceleration in their airway epithelium,” she said. The findings “suggest that the HIV lung is aging faster.”
They reported their findings in 2022, describing methylation disruptions along age-related pathways such as cellular senescence, longevity regulation, and insulin signaling.
Dr. Leung and her team have also studied the lung microbiome and found lower microbial diversity in the airway epithelium in patients with HIV than those without, especially in those with HIV and COPD. The National Institutes of Health–sponsored Lung HIV Microbiome Project found that changes in the lung microbiome are most pronounced in patients who haven’t yet initiated ART, but research in her lab suggests ongoing suppression of microbial diversity even after ART, she said.
Dr. Morris is particularly interested in the oral microbiome, having found through her research that changes in the oral microbiome in PWH were more related to impaired lung function than alterations in the lung and gut microbiome. “That may be in part because of the way we measure things,” she said. “But we also think that the oral microbiome probably seeds the lung [through micro-aspiration].” A study published in 2020 from the Pittsburgh site of the MACS described alterations in oral microbial communities in PWH with abnormal lung function.
Preliminary research suggests that improved dental cleaning and periodontal work in PWH and COPD may influence the severity of COPD, she noted.
“We don’t see as much of a signal with the gut microbiome [and HIV status or lung function], though there could still be ways in which gut microbiome influences the lung,” through systemic inflammation, the release of metabolites into the bloodstream, or microbial translocation, for instance, she said.
The potential role of translocation of members of the microbiome, in fact, is an area of active research for Dr. Morris. Members of the microbiome – viruses and fungi in addition to bacteria – “can get into the bloodstream from the mouth, from the lung, from the gut, to stimulate inflammation and worsen lung disease,” she said.
Key questions in an evolving research landscape
Dr. Kunisaki looks forward to research providing a more longitudinal look at lung function decline– a move beyond a dominance of cross-sectional studies – as well as research that is more comprehensive, with simultaneous collection of various functional measures (eg., DLCO with chest imaging and fractional excretion of nitric oxide (FENO – a standardized breath measure of Th2 airway inflammation).
The several-year-old NIH-supported MACS/WIHS (Women’s Interagency HIV Study) Combined Cohort study, in which Dr. Kunisaki and Dr. Morris participate, aims in part to identity biomarkers of increased risk for chronic lung disease and other chronic disorders and to develop strategies for more effective interventions and treatments.
Researchers will also share biospecimens, “which will allow more mechanistic work,” Dr. Kunisaki noted. (The combined cohort study includes participants from the earlier, separate MACS and WIHS studies.)
Questions about treatment strategies include the risks versus benefits of inhaled corticosteroids, which may increase an already elevated risk of respiratory infections like bacterial pneumonia in PWH, Dr. Kunisaki said.
[An aside: Inhaled corticosteroids also have well-described interactions with ART regimens that contain CYP3A4 inhibitors (e.g., ritonavir and cobicistat) that can lead to hypercortisolism. In patients who require both types of drugs, he said, beclomethasone has the least interactions and is the preferred inhaled corticosteroid.]
For Dr. Crothers, unanswered critical questions include – as she wrote in her 2021 commentary – the question of how guidelines for the management of COPD and asthma should be adapted for PWH. Is COPD in PWH more or less responsive to inhaled corticosteroids, for instance? And are antifibrotic treatments for interstitial lung disease and immunotherapies for asthma or lung cancer similarly effective, and are there any increased risks for harms in people with HIV?
There’s also the question of whether PWH should be screened for lung cancer earlier and with a lower smoking exposure than is advised under current guidelines for the general population, she said in the interview. “And should the approach to shared decision-making be modified for people with HIV?” she said. “We’re doing some work on these questions” right now.
None of the researchers interviewed reported any conflicts of interest relevant to the story. Dr. Kunisaki reported that he has no relevant disclosures, and said that his comments are his personal views and not official views of the U.S. Government, Department of Veterans Affairs, the Minneapolis VA, or the University of Minnesota.
Chronic pulmonary disease continues to be a major cause of morbidity and mortality in individuals living with the human immunodeficiency virus, even with optimal HIV control. And this is independent, as seen in many studies, of age, smoking, and pulmonary infections.
Both chronic pulmonary obstructive disease (COPD) and lung cancer occur more frequently in people living with HIV than in the general population, and at earlier ages, and with worse outcomes. The risk for emphysema and interstitial lung abnormalities also appears to be higher, research has shown. And asthma has also recently emerged as another important lung disease in people with HIV (PWH).
“There is evidence that the severity of immunocompromise associated with HIV infection is linked with chronic lung diseases. People who have a lower CD4 cell count or a higher viral load do have an increased risk of COPD and emphysema as well as potentially lung cancer. ,” said Kristina Crothers, MD, professor in the division of pulmonary, critical care, and sleep medicine at the University of Washington, Seattle.
Research has evolved from a focus on the epidemiology of HIV-related chronic lung diseases to a current emphasis on “trying to understand further the mechanisms [behind the heightened risk] through more benchwork and corollary translational studies, and then to the next level of trying to understand what this means for how we should manage people with HIV who have chronic lung diseases,” Dr. Crothers said. “Should management be tailored for people with HIV infection?”
Impairments in immune pathways, local and systemic inflammation, oxidative stress, dysbiosis, and accelerated cellular senescence are among potential mechanisms, but until ongoing mechanistic research yields more answers, pulmonologists should simply – but importantly – be aware of the increased risk and have a low threshold for investigating respiratory symptoms, she and other experts said in interviews. Referral of eligible patients for lung cancer screening is also a priority, as is smoking cessation, they said.
Notably, while spirometry has been the most commonly studied lung function measure in PWH, another noninvasive measure, diffusing capacity for carbon monoxide (DLCO), has garnered attention in the past decade and thus far appears to be the more frequent lung function abnormality.
In an analysis published in 2020 from the longitudinal Multicenter AIDS Cohort Study (MACS) – a study of a subcohort of 591 men with HIV and 476 without HIV – those with HIV were found to have a 1.6-fold increased risk of mild DLCO impairment (< 80% of predicted normal) and a 3-fold higher risk of more severe DLCO impairment (< 60% of predicted normal). There was no significant difference in spirometry findings by HIV status.
Such findings on DLCO are worthy of consideration in clinical practice, even in the absence of HIV-specific screening guidelines for noncommunicable lung diseases, Dr. Crothers said. “In thinking about screening and diagnosing chronic lung diseases in these patients, I’d not only consider spirometry, but also diffusing capacity” when possible, she said. Impaired DLCO is seen with emphysema and pulmonary vascular diseases like pulmonary hypertension and also interstitial lung diseases.
Key chronic lung diseases
Ken M. Kunisaki, MD, MS, associate professor of medicine at the University of Minnesota, Minneapolis, and the first author of the MACS analysis of lung function – one of the most recent and largest reports of DLCO impairment – points out that studies of chest computed tomography (CT) have also documented higher rates of emphysema and interstitial lung abnormalities.
A chest CT analysis from a cohort in Denmark (the Copenhagen Comorbidity in HIV Infection [COCOMO] cohort) found interstitial lung abnormalities in 10.9% of more than 700 PWH which represented a 1.8-fold increased risk compared to HIV-negative controls. And a study from an Italian sample of never-smoking PWH and controls reported emphysema in 18% and 4%, respectively. These studies, which did not measure DLCO, are among those discussed in a 2021 review by Dr. Kunisaki of advances in HIV-associated chronic lung disease research.
COPD is the best studied and most commonly encountered chronic lung disease in PWH. “Particularly for COPD, what’s both interesting and unfortunate is that we haven’t really seen any changes in the epidemiology with ART (antiretroviral therapy) – we’re still seeing the same findings, like the association of HIV with worse COPD at younger ages,” said Alison Morris, MD, MS, professor of medicine, immunology, and clinical and translational research at the University of Pittsburgh. “It doesn’t seem to have improved.”
Its prevalence has varied widely from cohort to cohort, from as low as 3% (similar to the general population) to over 40%, Dr. Kunisaki said, emphasizing that many studies, including studies showing higher rates, have controlled for current and past smoking. In evaluating patients with low or no smoking burden, “don’t discount respiratory symptoms as possibly reflecting underlying lung disease because COPD can develop with low to no smoking history in those with HIV,” he advised.
A better understanding of how a chronic viral infection like HIV leads to heightened COPD risk will not only help those with HIV, he notes, but also people without HIV who have COPD but have never smoked – a woefully underappreciated and understudied population. Ongoing research, he said, “should help us understand COPD pathogenesis generally.”
Research on asthma is relatively limited thus far, but it does appear that PWH may be more prone to developing severe asthma, just as with COPD, said Dr. Kunisaki, also a staff physician at the Minneapolis Veterans Administration Health Care System. Research has shown, for instance, that people with HIV more frequently needed aggressive respiratory support when hospitalized for asthma exacerbations.
It’s unclear how much of this potentially increased severity is attributable to the biology of HIV’s impact on the body and how much relates to social factors like disparities in income and access to care, Dr. Kunisaki said, noting that the same questions apply to the more frequent COPD exacerbations documented in PWH.
Dr. Crothers points out that, while most studies do not suggest a difference in the incidence of asthma in PWH, “there is some data from researchers looking at asthma profiles [suggesting] that the biomarkers associated with asthma may be different in people with and without HIV,” signaling potentially different molecular or biologic underpinnings of the disease.
Incidence rates of lung cancer in PWH, meanwhile, have declined over the last 2 decades, but lung cancer remains the leading cause of cancer-related mortality in PWH and occurs at a rate that is 2-2.5 times higher than that of individuals not infected with HIV, according to
Janice Leung, MD, of the division of respiratory medicine at the University of British Columbia and the Centre for Heart Lung Innovation at St. Paul’s Hospital in Vancouver.
Patients with HIV have “worse outcomes overall and a higher risk of mortality, even when presenting at the same stage,” said Dr. Leung, who reviewed trends in COPD and lung cancer in a recently published opinion piece.
Potential drivers
A bird’s eye view of potential – and likely interrelated – mechanisms for chronic lung disease includes chronic immune activation that impairs innate and adaptive immune pathways; chronic inflammation systemically and in the lung despite viral suppression; persistence of the virus in latent reservoirs in the lung, particularly in alveolar macrophages and T cells; HIV-related proteins contributing to oxidative stress; accelerated cellular aging; dysbiosis; and ongoing injury from inhaled toxins.
All are described in the literature and are being further explored. “It’s likely that multiple pathways are playing a role,” said Dr. Crothers, “and it could be that the balance of one to another leads to different manifestations of disease.”
Biomarkers that have been elevated and associated with different features of chronic lung disease – such as airflow obstruction, low DLCO, and emphysema – include markers of inflammation (e.g., C-reactive protein, interleukin-6), monocyte activation (e.g., soluble CD14), and markers of endothelial dysfunction, she noted in a 2021 commentary marking 40 years since the first reported cases of acquired immunodeficiency syndrome.
In her laboratory, Dr. Leung is using new epigenetic markers to look at the pathogenesis of accelerated aging in the lung. By profiling bronchial epithelial brushings for DNA methylation and gene expression, they have found that “people living with both HIV and COPD have the fastest epigenetic age acceleration in their airway epithelium,” she said. The findings “suggest that the HIV lung is aging faster.”
They reported their findings in 2022, describing methylation disruptions along age-related pathways such as cellular senescence, longevity regulation, and insulin signaling.
Dr. Leung and her team have also studied the lung microbiome and found lower microbial diversity in the airway epithelium in patients with HIV than those without, especially in those with HIV and COPD. The National Institutes of Health–sponsored Lung HIV Microbiome Project found that changes in the lung microbiome are most pronounced in patients who haven’t yet initiated ART, but research in her lab suggests ongoing suppression of microbial diversity even after ART, she said.
Dr. Morris is particularly interested in the oral microbiome, having found through her research that changes in the oral microbiome in PWH were more related to impaired lung function than alterations in the lung and gut microbiome. “That may be in part because of the way we measure things,” she said. “But we also think that the oral microbiome probably seeds the lung [through micro-aspiration].” A study published in 2020 from the Pittsburgh site of the MACS described alterations in oral microbial communities in PWH with abnormal lung function.
Preliminary research suggests that improved dental cleaning and periodontal work in PWH and COPD may influence the severity of COPD, she noted.
“We don’t see as much of a signal with the gut microbiome [and HIV status or lung function], though there could still be ways in which gut microbiome influences the lung,” through systemic inflammation, the release of metabolites into the bloodstream, or microbial translocation, for instance, she said.
The potential role of translocation of members of the microbiome, in fact, is an area of active research for Dr. Morris. Members of the microbiome – viruses and fungi in addition to bacteria – “can get into the bloodstream from the mouth, from the lung, from the gut, to stimulate inflammation and worsen lung disease,” she said.
Key questions in an evolving research landscape
Dr. Kunisaki looks forward to research providing a more longitudinal look at lung function decline– a move beyond a dominance of cross-sectional studies – as well as research that is more comprehensive, with simultaneous collection of various functional measures (eg., DLCO with chest imaging and fractional excretion of nitric oxide (FENO – a standardized breath measure of Th2 airway inflammation).
The several-year-old NIH-supported MACS/WIHS (Women’s Interagency HIV Study) Combined Cohort study, in which Dr. Kunisaki and Dr. Morris participate, aims in part to identity biomarkers of increased risk for chronic lung disease and other chronic disorders and to develop strategies for more effective interventions and treatments.
Researchers will also share biospecimens, “which will allow more mechanistic work,” Dr. Kunisaki noted. (The combined cohort study includes participants from the earlier, separate MACS and WIHS studies.)
Questions about treatment strategies include the risks versus benefits of inhaled corticosteroids, which may increase an already elevated risk of respiratory infections like bacterial pneumonia in PWH, Dr. Kunisaki said.
[An aside: Inhaled corticosteroids also have well-described interactions with ART regimens that contain CYP3A4 inhibitors (e.g., ritonavir and cobicistat) that can lead to hypercortisolism. In patients who require both types of drugs, he said, beclomethasone has the least interactions and is the preferred inhaled corticosteroid.]
For Dr. Crothers, unanswered critical questions include – as she wrote in her 2021 commentary – the question of how guidelines for the management of COPD and asthma should be adapted for PWH. Is COPD in PWH more or less responsive to inhaled corticosteroids, for instance? And are antifibrotic treatments for interstitial lung disease and immunotherapies for asthma or lung cancer similarly effective, and are there any increased risks for harms in people with HIV?
There’s also the question of whether PWH should be screened for lung cancer earlier and with a lower smoking exposure than is advised under current guidelines for the general population, she said in the interview. “And should the approach to shared decision-making be modified for people with HIV?” she said. “We’re doing some work on these questions” right now.
None of the researchers interviewed reported any conflicts of interest relevant to the story. Dr. Kunisaki reported that he has no relevant disclosures, and said that his comments are his personal views and not official views of the U.S. Government, Department of Veterans Affairs, the Minneapolis VA, or the University of Minnesota.
Chronic pulmonary disease continues to be a major cause of morbidity and mortality in individuals living with the human immunodeficiency virus, even with optimal HIV control. And this is independent, as seen in many studies, of age, smoking, and pulmonary infections.
Both chronic pulmonary obstructive disease (COPD) and lung cancer occur more frequently in people living with HIV than in the general population, and at earlier ages, and with worse outcomes. The risk for emphysema and interstitial lung abnormalities also appears to be higher, research has shown. And asthma has also recently emerged as another important lung disease in people with HIV (PWH).
“There is evidence that the severity of immunocompromise associated with HIV infection is linked with chronic lung diseases. People who have a lower CD4 cell count or a higher viral load do have an increased risk of COPD and emphysema as well as potentially lung cancer. ,” said Kristina Crothers, MD, professor in the division of pulmonary, critical care, and sleep medicine at the University of Washington, Seattle.
Research has evolved from a focus on the epidemiology of HIV-related chronic lung diseases to a current emphasis on “trying to understand further the mechanisms [behind the heightened risk] through more benchwork and corollary translational studies, and then to the next level of trying to understand what this means for how we should manage people with HIV who have chronic lung diseases,” Dr. Crothers said. “Should management be tailored for people with HIV infection?”
Impairments in immune pathways, local and systemic inflammation, oxidative stress, dysbiosis, and accelerated cellular senescence are among potential mechanisms, but until ongoing mechanistic research yields more answers, pulmonologists should simply – but importantly – be aware of the increased risk and have a low threshold for investigating respiratory symptoms, she and other experts said in interviews. Referral of eligible patients for lung cancer screening is also a priority, as is smoking cessation, they said.
Notably, while spirometry has been the most commonly studied lung function measure in PWH, another noninvasive measure, diffusing capacity for carbon monoxide (DLCO), has garnered attention in the past decade and thus far appears to be the more frequent lung function abnormality.
In an analysis published in 2020 from the longitudinal Multicenter AIDS Cohort Study (MACS) – a study of a subcohort of 591 men with HIV and 476 without HIV – those with HIV were found to have a 1.6-fold increased risk of mild DLCO impairment (< 80% of predicted normal) and a 3-fold higher risk of more severe DLCO impairment (< 60% of predicted normal). There was no significant difference in spirometry findings by HIV status.
Such findings on DLCO are worthy of consideration in clinical practice, even in the absence of HIV-specific screening guidelines for noncommunicable lung diseases, Dr. Crothers said. “In thinking about screening and diagnosing chronic lung diseases in these patients, I’d not only consider spirometry, but also diffusing capacity” when possible, she said. Impaired DLCO is seen with emphysema and pulmonary vascular diseases like pulmonary hypertension and also interstitial lung diseases.
Key chronic lung diseases
Ken M. Kunisaki, MD, MS, associate professor of medicine at the University of Minnesota, Minneapolis, and the first author of the MACS analysis of lung function – one of the most recent and largest reports of DLCO impairment – points out that studies of chest computed tomography (CT) have also documented higher rates of emphysema and interstitial lung abnormalities.
A chest CT analysis from a cohort in Denmark (the Copenhagen Comorbidity in HIV Infection [COCOMO] cohort) found interstitial lung abnormalities in 10.9% of more than 700 PWH which represented a 1.8-fold increased risk compared to HIV-negative controls. And a study from an Italian sample of never-smoking PWH and controls reported emphysema in 18% and 4%, respectively. These studies, which did not measure DLCO, are among those discussed in a 2021 review by Dr. Kunisaki of advances in HIV-associated chronic lung disease research.
COPD is the best studied and most commonly encountered chronic lung disease in PWH. “Particularly for COPD, what’s both interesting and unfortunate is that we haven’t really seen any changes in the epidemiology with ART (antiretroviral therapy) – we’re still seeing the same findings, like the association of HIV with worse COPD at younger ages,” said Alison Morris, MD, MS, professor of medicine, immunology, and clinical and translational research at the University of Pittsburgh. “It doesn’t seem to have improved.”
Its prevalence has varied widely from cohort to cohort, from as low as 3% (similar to the general population) to over 40%, Dr. Kunisaki said, emphasizing that many studies, including studies showing higher rates, have controlled for current and past smoking. In evaluating patients with low or no smoking burden, “don’t discount respiratory symptoms as possibly reflecting underlying lung disease because COPD can develop with low to no smoking history in those with HIV,” he advised.
A better understanding of how a chronic viral infection like HIV leads to heightened COPD risk will not only help those with HIV, he notes, but also people without HIV who have COPD but have never smoked – a woefully underappreciated and understudied population. Ongoing research, he said, “should help us understand COPD pathogenesis generally.”
Research on asthma is relatively limited thus far, but it does appear that PWH may be more prone to developing severe asthma, just as with COPD, said Dr. Kunisaki, also a staff physician at the Minneapolis Veterans Administration Health Care System. Research has shown, for instance, that people with HIV more frequently needed aggressive respiratory support when hospitalized for asthma exacerbations.
It’s unclear how much of this potentially increased severity is attributable to the biology of HIV’s impact on the body and how much relates to social factors like disparities in income and access to care, Dr. Kunisaki said, noting that the same questions apply to the more frequent COPD exacerbations documented in PWH.
Dr. Crothers points out that, while most studies do not suggest a difference in the incidence of asthma in PWH, “there is some data from researchers looking at asthma profiles [suggesting] that the biomarkers associated with asthma may be different in people with and without HIV,” signaling potentially different molecular or biologic underpinnings of the disease.
Incidence rates of lung cancer in PWH, meanwhile, have declined over the last 2 decades, but lung cancer remains the leading cause of cancer-related mortality in PWH and occurs at a rate that is 2-2.5 times higher than that of individuals not infected with HIV, according to
Janice Leung, MD, of the division of respiratory medicine at the University of British Columbia and the Centre for Heart Lung Innovation at St. Paul’s Hospital in Vancouver.
Patients with HIV have “worse outcomes overall and a higher risk of mortality, even when presenting at the same stage,” said Dr. Leung, who reviewed trends in COPD and lung cancer in a recently published opinion piece.
Potential drivers
A bird’s eye view of potential – and likely interrelated – mechanisms for chronic lung disease includes chronic immune activation that impairs innate and adaptive immune pathways; chronic inflammation systemically and in the lung despite viral suppression; persistence of the virus in latent reservoirs in the lung, particularly in alveolar macrophages and T cells; HIV-related proteins contributing to oxidative stress; accelerated cellular aging; dysbiosis; and ongoing injury from inhaled toxins.
All are described in the literature and are being further explored. “It’s likely that multiple pathways are playing a role,” said Dr. Crothers, “and it could be that the balance of one to another leads to different manifestations of disease.”
Biomarkers that have been elevated and associated with different features of chronic lung disease – such as airflow obstruction, low DLCO, and emphysema – include markers of inflammation (e.g., C-reactive protein, interleukin-6), monocyte activation (e.g., soluble CD14), and markers of endothelial dysfunction, she noted in a 2021 commentary marking 40 years since the first reported cases of acquired immunodeficiency syndrome.
In her laboratory, Dr. Leung is using new epigenetic markers to look at the pathogenesis of accelerated aging in the lung. By profiling bronchial epithelial brushings for DNA methylation and gene expression, they have found that “people living with both HIV and COPD have the fastest epigenetic age acceleration in their airway epithelium,” she said. The findings “suggest that the HIV lung is aging faster.”
They reported their findings in 2022, describing methylation disruptions along age-related pathways such as cellular senescence, longevity regulation, and insulin signaling.
Dr. Leung and her team have also studied the lung microbiome and found lower microbial diversity in the airway epithelium in patients with HIV than those without, especially in those with HIV and COPD. The National Institutes of Health–sponsored Lung HIV Microbiome Project found that changes in the lung microbiome are most pronounced in patients who haven’t yet initiated ART, but research in her lab suggests ongoing suppression of microbial diversity even after ART, she said.
Dr. Morris is particularly interested in the oral microbiome, having found through her research that changes in the oral microbiome in PWH were more related to impaired lung function than alterations in the lung and gut microbiome. “That may be in part because of the way we measure things,” she said. “But we also think that the oral microbiome probably seeds the lung [through micro-aspiration].” A study published in 2020 from the Pittsburgh site of the MACS described alterations in oral microbial communities in PWH with abnormal lung function.
Preliminary research suggests that improved dental cleaning and periodontal work in PWH and COPD may influence the severity of COPD, she noted.
“We don’t see as much of a signal with the gut microbiome [and HIV status or lung function], though there could still be ways in which gut microbiome influences the lung,” through systemic inflammation, the release of metabolites into the bloodstream, or microbial translocation, for instance, she said.
The potential role of translocation of members of the microbiome, in fact, is an area of active research for Dr. Morris. Members of the microbiome – viruses and fungi in addition to bacteria – “can get into the bloodstream from the mouth, from the lung, from the gut, to stimulate inflammation and worsen lung disease,” she said.
Key questions in an evolving research landscape
Dr. Kunisaki looks forward to research providing a more longitudinal look at lung function decline– a move beyond a dominance of cross-sectional studies – as well as research that is more comprehensive, with simultaneous collection of various functional measures (eg., DLCO with chest imaging and fractional excretion of nitric oxide (FENO – a standardized breath measure of Th2 airway inflammation).
The several-year-old NIH-supported MACS/WIHS (Women’s Interagency HIV Study) Combined Cohort study, in which Dr. Kunisaki and Dr. Morris participate, aims in part to identity biomarkers of increased risk for chronic lung disease and other chronic disorders and to develop strategies for more effective interventions and treatments.
Researchers will also share biospecimens, “which will allow more mechanistic work,” Dr. Kunisaki noted. (The combined cohort study includes participants from the earlier, separate MACS and WIHS studies.)
Questions about treatment strategies include the risks versus benefits of inhaled corticosteroids, which may increase an already elevated risk of respiratory infections like bacterial pneumonia in PWH, Dr. Kunisaki said.
[An aside: Inhaled corticosteroids also have well-described interactions with ART regimens that contain CYP3A4 inhibitors (e.g., ritonavir and cobicistat) that can lead to hypercortisolism. In patients who require both types of drugs, he said, beclomethasone has the least interactions and is the preferred inhaled corticosteroid.]
For Dr. Crothers, unanswered critical questions include – as she wrote in her 2021 commentary – the question of how guidelines for the management of COPD and asthma should be adapted for PWH. Is COPD in PWH more or less responsive to inhaled corticosteroids, for instance? And are antifibrotic treatments for interstitial lung disease and immunotherapies for asthma or lung cancer similarly effective, and are there any increased risks for harms in people with HIV?
There’s also the question of whether PWH should be screened for lung cancer earlier and with a lower smoking exposure than is advised under current guidelines for the general population, she said in the interview. “And should the approach to shared decision-making be modified for people with HIV?” she said. “We’re doing some work on these questions” right now.
None of the researchers interviewed reported any conflicts of interest relevant to the story. Dr. Kunisaki reported that he has no relevant disclosures, and said that his comments are his personal views and not official views of the U.S. Government, Department of Veterans Affairs, the Minneapolis VA, or the University of Minnesota.
Advising patients on AD treatment options: Expert pearls
WASHINGTON –
The question was top of mind for experts who shared their advice during a “Tips and Tricks” session at the Revolutionizing Atopic Dermatitis meeting. Dupilumab dosing and dupilumab-associated facial redness and ocular disease, self-image issues, topical regimen adherence, and the quantification of disease were among the other topics raised by the experts.
Here are some of their practice pearls.
Treatment decisions, safety concerns
Deciding on a treatment is “kind of confusing ... particularly in the last year ... and it will only get more complicated,” said Raj J. Chovatiya, MD, PhD, assistant professor of dermatology at Northwestern University, Chicago. “We’re all about some version of shared decision-making, but if all else is equal, sometimes it pays to explicitly ask the patient, what do you want to do?”
Questions about how long a systemic treatment should be tried, both initially and in the long run, are common. “I think that oftentimes we all get antsy about making changes when we’re not getting to the endpoint we want to. And at least in my real-world experience, late responders are a real thing. Sometimes 3-4 months ... isn’t enough,” he said.
Trial extension data show that patients who were nonresponders for various endpoints at 16 weeks are “captured continuously as you go further and further out,” Dr. Chovatiya said. Regarding the long term, “realistically, there’s no perfect time to call it quits.”
Addressing fears about Janus kinase inhibitors can be challenging, he said. “When you’ve identified the right patient and labs are done ... have them take the medication in front of you and hang out,” he advised. “It may sound ridiculous, but for the extremely anxious person it can be a big stress reducer for everyone involved.”
Regarding treatment fears more generally, “asking patients ‘what is the biggest risk of not treating your disease?’ sometimes gets people thinking,” Dr. Chovatiya said.
For parents of children with AD, said Robert Sidbury, MD, MPH, risks of not treating can become apparent once treatments are started and benefits are realized. “It’s so easy to focus on the risks of any treatment because they’re right there in black and white, and the risks of not treating are not always as apparent, even though – or maybe because – they live with them every day.”
When treatment is underway, “they see [how] everyone sleeps better, how school performance gets better, how concentration gets better,” said Dr. Sidbury, professor in the department of pediatrics at the University of Washington. Seattle, and chief of dermatology at Seattle Children’s Hospital.
“Always contextualize,” he advised. “As dermatologists, we’re savvy with navigating boxed warnings.”
David Rosmarin, MD, chair of dermatology, at Indiana University, Indianapolis, and formerly vice chair for research and education at Tufts Medical Center, Boston, said he addresses questions about the length of systemic treatment by advising patients: “Why don’t we start taking [the medication] for 3 months and then we’ll take it from there.”
In some pediatric cases, Dr. Rosmarin said, having the child express “what their AD means to them – how it affects them,” and then acknowledging and validating what the child says, is helpful to parents who are concerned about systemic treatments.
Dupilumab in the real world
Some patients on dupilumab do not have a complete response with dosing every 2 weeks and may benefit from more frequent dosing, said Dr. Rosmarin.
“We know from the SOLO-1 and SOLO-2 studies that dupilumab weekly dosing was evaluated. It was only the every-other-week dosing that was approved, and we can see why – in terms of the changes in EASI [Eczema Area and Severity Index] score they’re close to overlapping,” he said.
In real life, however, “some patients benefit from different dosing. It’s important to realize that. I think we all have some patients who may dose more frequently and some who may dose less frequently,” Dr. Rosmarin said.
For a patient who “gets absolutely no response from dupilumab after 3-4 months, I’d switch them to something else. But for those who are partial responders, particularly those who tell me they’re getting itchy before their next dose, they’re the ones who benefit most from doubling the dose to dupilumab weekly,” he said.
For patients who experience dupilumab-associated head and neck dermatitis, itraconazole may help, Dr. Rosmarin added. “We’re using 200 mg daily for 2 weeks and weekly thereafter, and it helps some of our patients.” The average self-reported improvement was 52% for patients with dupilumab-associated facial redness treated with itraconazole in a retrospective medical record review that he and his colleagues published in 2022.
Dr. Rosmarin pointed to a multicenter prospective cohort study also published in 2022 showing that baseline/pretreatment levels of Malassezia-specific IgE were associated with the development of dupilumab-associated head and neck dermatitis. The median levels of Malassezia-specific IgE were 32 kUL–1 versus 2.3 kUL–1 in patients who experienced dupilumab-associated facial redness, compared with those who did not.
He said that, while there “may be multiple reasons” for dupilumab-associated head and neck dermatitis and that “plenty of patients” who don’t have Malassezia-specific IgE develop head and neck dermatitis, “this could be one cause.”
Itraconazole has been shown in his practice to be superior to fluconazole, likely because it has greater anti-inflammatory effects and provides better coverage of Malassezia because it is more lipophilic, said Dr. Rosmarin, who does not test for Malassezia-specific IgE before trying itraconazole.
For dupilumab-associated ocular surface disease, Elaine C. Siegfried, MD, offered her first-line suggestions: warm compresses (such as a microwaved bean bag), bland ocular lubricant (such as preservative-free artificial tears), oral hydration, and if needed and accessible, the prescription ophthalmic solution lifitegrast.
“It’s become an issue – what the dermatologist can do first line,” said Dr. Siegfried, professor of pediatrics and dermatology at Saint Louis University and director of the division of pediatric dermatology at Cardinal Glennon Children’s Hospital, St. Louis.
“If these don’t work, then I’ll identify an ophthalmologist who’s knowledgeable about Dupixent-related ocular surface disease,” she said. Selection is “important because they’re not all knowledgeable ... corneal specialists typically have the most knowledge.”
Topical adherence with diffuse xerosis and mild-moderate AD
For patients with diffuse xerosis and mild-moderate AD, especially those who are older and having difficulty with topical regimens, Anna De Benedetto, MD, said she tries to enhance adherence by simplifying the regimen. She asks patients to buy a pound jar of base cream (ceramide base) – “whatever emollient they like” – and mixes into it a high-potency steroid solution. They’re instructed to apply the combined cream once daily for 1-2 weeks, and then three times a week alternating with a nonmedicated cream.
“This way they’re using one [cream] to target the immune system and the skin barrier,” said Dr. De Benedetto, associate professor of dermatology and director of the dermatology clinical trial unit at the University of Rochester (N.Y.) Medical Center.
‘Wet wrap’ pajamas; self-image for children, teens
Dermatologist Melinda Gooderham, MSc, MD, assistant professor at Queen’s University, Kingston, Ont., and medical director at the SKiN Centre for Dermatology, said that, for widespread and troublesome AD, she advises patients or parents to wet a thin cotton pajama top and bottom and spin it in the dryer “so it’s almost dry but still moist.” Dry, looser pajamas or a light track suit can then be worn over the damp pajamas. “I usually tell [patients] to buy one size up,” she said.
Body dysmorphia is common with skin disease, and its incidence is six times higher in people with eczema than those without the disease, said Dr. Siegfried. “I’ve found that, for patients subjected to AD for a long time,” this is still an issue, “even when you clear their skin.”
For children, teens and their families, the nonprofit organization Made a Masterpiece can be valuable, Dr. Siegfried said. It offers resources from parents, children, psychologists, dermatologists, and others to help manage the emotional, social and spiritual aspects of living with a skin condition.
To use or not to use BSA; environmental counseling
“I think [assessing] body surface area [BSA] is very important in pediatrics and for adolescents [especially in those with moderate to severe disease] because it quantifies the disease for the family,” said Lawrence F. Eichenfield, MD, professor of dermatology and pediatrics and vice chair of the department of dermatology at the University of California, San Diego.
“Families live with the disease, but quantification really matters” for understanding the extent and impact of the disease and for motivating families to treat, said Dr. Eichenfield.
(When the disease is markedly diminished in follow-up, knowing the BSA then “helps families to register the improvement and gives positive reinforcement,” Dr. Eichenfeld said after the meeting.)
Young patients can participate, he noted at the meeting. “When I do telemedicine visits, kids can tell me how many hands of eczema they have.”
Dr. Eichenfield also said that he now routinely counsels on the environmental impacts on eczema. For example, “I explain to people that we’re probably going to have a bad wildfire season in California, and it’s the kind of environmental perturbation that may impact some eczema patients,” he said, noting the 2021 study documenting an association of wildfire air pollution from the 2018 California Camp fire with an increase in dermatology clinic visits for AD and itch in San Francisco.
“It helps to keep an eye out for that, and also to be aware of some of the environmental changes,” he said.
Dr. Chovatiya reported ties with AbbVie, Eli Lilly, Incyte, Leo Pharma, Pfizer, Regeneron, and Sanofi, among others. Dr. Sidbury reported ties with Regeneron, UCB, Pfizer, Leo Pharma, and Lilly, among others. Dr. Rosmarin reported ties with AbbVie, Incyte, Lilly, Pfizer, Regeneron, and Sanofi, among others. Dr. Siegfried reported ties with Regeneron, Sanofi Genzyme, AbbVie, Incyte, Leo, and Pfizer, among others. Dr. De Benedetto reported ties with Incyte, Pfizer, AbbVie, and Sanofi Advent, among others. Dr. Gooderham reported ties with AbbVie, Eli Lilly, Incyte, Leo Pharma, Pfizer, Regeneron, and Sanofi Genzyme, among others. Dr. Eichenfield disclosed ties with AbbVie, Eli Lilly, Incyte, Leo Pharma, Pfizer, Regeneron, and Sanofi, among others.
WASHINGTON –
The question was top of mind for experts who shared their advice during a “Tips and Tricks” session at the Revolutionizing Atopic Dermatitis meeting. Dupilumab dosing and dupilumab-associated facial redness and ocular disease, self-image issues, topical regimen adherence, and the quantification of disease were among the other topics raised by the experts.
Here are some of their practice pearls.
Treatment decisions, safety concerns
Deciding on a treatment is “kind of confusing ... particularly in the last year ... and it will only get more complicated,” said Raj J. Chovatiya, MD, PhD, assistant professor of dermatology at Northwestern University, Chicago. “We’re all about some version of shared decision-making, but if all else is equal, sometimes it pays to explicitly ask the patient, what do you want to do?”
Questions about how long a systemic treatment should be tried, both initially and in the long run, are common. “I think that oftentimes we all get antsy about making changes when we’re not getting to the endpoint we want to. And at least in my real-world experience, late responders are a real thing. Sometimes 3-4 months ... isn’t enough,” he said.
Trial extension data show that patients who were nonresponders for various endpoints at 16 weeks are “captured continuously as you go further and further out,” Dr. Chovatiya said. Regarding the long term, “realistically, there’s no perfect time to call it quits.”
Addressing fears about Janus kinase inhibitors can be challenging, he said. “When you’ve identified the right patient and labs are done ... have them take the medication in front of you and hang out,” he advised. “It may sound ridiculous, but for the extremely anxious person it can be a big stress reducer for everyone involved.”
Regarding treatment fears more generally, “asking patients ‘what is the biggest risk of not treating your disease?’ sometimes gets people thinking,” Dr. Chovatiya said.
For parents of children with AD, said Robert Sidbury, MD, MPH, risks of not treating can become apparent once treatments are started and benefits are realized. “It’s so easy to focus on the risks of any treatment because they’re right there in black and white, and the risks of not treating are not always as apparent, even though – or maybe because – they live with them every day.”
When treatment is underway, “they see [how] everyone sleeps better, how school performance gets better, how concentration gets better,” said Dr. Sidbury, professor in the department of pediatrics at the University of Washington. Seattle, and chief of dermatology at Seattle Children’s Hospital.
“Always contextualize,” he advised. “As dermatologists, we’re savvy with navigating boxed warnings.”
David Rosmarin, MD, chair of dermatology, at Indiana University, Indianapolis, and formerly vice chair for research and education at Tufts Medical Center, Boston, said he addresses questions about the length of systemic treatment by advising patients: “Why don’t we start taking [the medication] for 3 months and then we’ll take it from there.”
In some pediatric cases, Dr. Rosmarin said, having the child express “what their AD means to them – how it affects them,” and then acknowledging and validating what the child says, is helpful to parents who are concerned about systemic treatments.
Dupilumab in the real world
Some patients on dupilumab do not have a complete response with dosing every 2 weeks and may benefit from more frequent dosing, said Dr. Rosmarin.
“We know from the SOLO-1 and SOLO-2 studies that dupilumab weekly dosing was evaluated. It was only the every-other-week dosing that was approved, and we can see why – in terms of the changes in EASI [Eczema Area and Severity Index] score they’re close to overlapping,” he said.
In real life, however, “some patients benefit from different dosing. It’s important to realize that. I think we all have some patients who may dose more frequently and some who may dose less frequently,” Dr. Rosmarin said.
For a patient who “gets absolutely no response from dupilumab after 3-4 months, I’d switch them to something else. But for those who are partial responders, particularly those who tell me they’re getting itchy before their next dose, they’re the ones who benefit most from doubling the dose to dupilumab weekly,” he said.
For patients who experience dupilumab-associated head and neck dermatitis, itraconazole may help, Dr. Rosmarin added. “We’re using 200 mg daily for 2 weeks and weekly thereafter, and it helps some of our patients.” The average self-reported improvement was 52% for patients with dupilumab-associated facial redness treated with itraconazole in a retrospective medical record review that he and his colleagues published in 2022.
Dr. Rosmarin pointed to a multicenter prospective cohort study also published in 2022 showing that baseline/pretreatment levels of Malassezia-specific IgE were associated with the development of dupilumab-associated head and neck dermatitis. The median levels of Malassezia-specific IgE were 32 kUL–1 versus 2.3 kUL–1 in patients who experienced dupilumab-associated facial redness, compared with those who did not.
He said that, while there “may be multiple reasons” for dupilumab-associated head and neck dermatitis and that “plenty of patients” who don’t have Malassezia-specific IgE develop head and neck dermatitis, “this could be one cause.”
Itraconazole has been shown in his practice to be superior to fluconazole, likely because it has greater anti-inflammatory effects and provides better coverage of Malassezia because it is more lipophilic, said Dr. Rosmarin, who does not test for Malassezia-specific IgE before trying itraconazole.
For dupilumab-associated ocular surface disease, Elaine C. Siegfried, MD, offered her first-line suggestions: warm compresses (such as a microwaved bean bag), bland ocular lubricant (such as preservative-free artificial tears), oral hydration, and if needed and accessible, the prescription ophthalmic solution lifitegrast.
“It’s become an issue – what the dermatologist can do first line,” said Dr. Siegfried, professor of pediatrics and dermatology at Saint Louis University and director of the division of pediatric dermatology at Cardinal Glennon Children’s Hospital, St. Louis.
“If these don’t work, then I’ll identify an ophthalmologist who’s knowledgeable about Dupixent-related ocular surface disease,” she said. Selection is “important because they’re not all knowledgeable ... corneal specialists typically have the most knowledge.”
Topical adherence with diffuse xerosis and mild-moderate AD
For patients with diffuse xerosis and mild-moderate AD, especially those who are older and having difficulty with topical regimens, Anna De Benedetto, MD, said she tries to enhance adherence by simplifying the regimen. She asks patients to buy a pound jar of base cream (ceramide base) – “whatever emollient they like” – and mixes into it a high-potency steroid solution. They’re instructed to apply the combined cream once daily for 1-2 weeks, and then three times a week alternating with a nonmedicated cream.
“This way they’re using one [cream] to target the immune system and the skin barrier,” said Dr. De Benedetto, associate professor of dermatology and director of the dermatology clinical trial unit at the University of Rochester (N.Y.) Medical Center.
‘Wet wrap’ pajamas; self-image for children, teens
Dermatologist Melinda Gooderham, MSc, MD, assistant professor at Queen’s University, Kingston, Ont., and medical director at the SKiN Centre for Dermatology, said that, for widespread and troublesome AD, she advises patients or parents to wet a thin cotton pajama top and bottom and spin it in the dryer “so it’s almost dry but still moist.” Dry, looser pajamas or a light track suit can then be worn over the damp pajamas. “I usually tell [patients] to buy one size up,” she said.
Body dysmorphia is common with skin disease, and its incidence is six times higher in people with eczema than those without the disease, said Dr. Siegfried. “I’ve found that, for patients subjected to AD for a long time,” this is still an issue, “even when you clear their skin.”
For children, teens and their families, the nonprofit organization Made a Masterpiece can be valuable, Dr. Siegfried said. It offers resources from parents, children, psychologists, dermatologists, and others to help manage the emotional, social and spiritual aspects of living with a skin condition.
To use or not to use BSA; environmental counseling
“I think [assessing] body surface area [BSA] is very important in pediatrics and for adolescents [especially in those with moderate to severe disease] because it quantifies the disease for the family,” said Lawrence F. Eichenfield, MD, professor of dermatology and pediatrics and vice chair of the department of dermatology at the University of California, San Diego.
“Families live with the disease, but quantification really matters” for understanding the extent and impact of the disease and for motivating families to treat, said Dr. Eichenfield.
(When the disease is markedly diminished in follow-up, knowing the BSA then “helps families to register the improvement and gives positive reinforcement,” Dr. Eichenfeld said after the meeting.)
Young patients can participate, he noted at the meeting. “When I do telemedicine visits, kids can tell me how many hands of eczema they have.”
Dr. Eichenfield also said that he now routinely counsels on the environmental impacts on eczema. For example, “I explain to people that we’re probably going to have a bad wildfire season in California, and it’s the kind of environmental perturbation that may impact some eczema patients,” he said, noting the 2021 study documenting an association of wildfire air pollution from the 2018 California Camp fire with an increase in dermatology clinic visits for AD and itch in San Francisco.
“It helps to keep an eye out for that, and also to be aware of some of the environmental changes,” he said.
Dr. Chovatiya reported ties with AbbVie, Eli Lilly, Incyte, Leo Pharma, Pfizer, Regeneron, and Sanofi, among others. Dr. Sidbury reported ties with Regeneron, UCB, Pfizer, Leo Pharma, and Lilly, among others. Dr. Rosmarin reported ties with AbbVie, Incyte, Lilly, Pfizer, Regeneron, and Sanofi, among others. Dr. Siegfried reported ties with Regeneron, Sanofi Genzyme, AbbVie, Incyte, Leo, and Pfizer, among others. Dr. De Benedetto reported ties with Incyte, Pfizer, AbbVie, and Sanofi Advent, among others. Dr. Gooderham reported ties with AbbVie, Eli Lilly, Incyte, Leo Pharma, Pfizer, Regeneron, and Sanofi Genzyme, among others. Dr. Eichenfield disclosed ties with AbbVie, Eli Lilly, Incyte, Leo Pharma, Pfizer, Regeneron, and Sanofi, among others.
WASHINGTON –
The question was top of mind for experts who shared their advice during a “Tips and Tricks” session at the Revolutionizing Atopic Dermatitis meeting. Dupilumab dosing and dupilumab-associated facial redness and ocular disease, self-image issues, topical regimen adherence, and the quantification of disease were among the other topics raised by the experts.
Here are some of their practice pearls.
Treatment decisions, safety concerns
Deciding on a treatment is “kind of confusing ... particularly in the last year ... and it will only get more complicated,” said Raj J. Chovatiya, MD, PhD, assistant professor of dermatology at Northwestern University, Chicago. “We’re all about some version of shared decision-making, but if all else is equal, sometimes it pays to explicitly ask the patient, what do you want to do?”
Questions about how long a systemic treatment should be tried, both initially and in the long run, are common. “I think that oftentimes we all get antsy about making changes when we’re not getting to the endpoint we want to. And at least in my real-world experience, late responders are a real thing. Sometimes 3-4 months ... isn’t enough,” he said.
Trial extension data show that patients who were nonresponders for various endpoints at 16 weeks are “captured continuously as you go further and further out,” Dr. Chovatiya said. Regarding the long term, “realistically, there’s no perfect time to call it quits.”
Addressing fears about Janus kinase inhibitors can be challenging, he said. “When you’ve identified the right patient and labs are done ... have them take the medication in front of you and hang out,” he advised. “It may sound ridiculous, but for the extremely anxious person it can be a big stress reducer for everyone involved.”
Regarding treatment fears more generally, “asking patients ‘what is the biggest risk of not treating your disease?’ sometimes gets people thinking,” Dr. Chovatiya said.
For parents of children with AD, said Robert Sidbury, MD, MPH, risks of not treating can become apparent once treatments are started and benefits are realized. “It’s so easy to focus on the risks of any treatment because they’re right there in black and white, and the risks of not treating are not always as apparent, even though – or maybe because – they live with them every day.”
When treatment is underway, “they see [how] everyone sleeps better, how school performance gets better, how concentration gets better,” said Dr. Sidbury, professor in the department of pediatrics at the University of Washington. Seattle, and chief of dermatology at Seattle Children’s Hospital.
“Always contextualize,” he advised. “As dermatologists, we’re savvy with navigating boxed warnings.”
David Rosmarin, MD, chair of dermatology, at Indiana University, Indianapolis, and formerly vice chair for research and education at Tufts Medical Center, Boston, said he addresses questions about the length of systemic treatment by advising patients: “Why don’t we start taking [the medication] for 3 months and then we’ll take it from there.”
In some pediatric cases, Dr. Rosmarin said, having the child express “what their AD means to them – how it affects them,” and then acknowledging and validating what the child says, is helpful to parents who are concerned about systemic treatments.
Dupilumab in the real world
Some patients on dupilumab do not have a complete response with dosing every 2 weeks and may benefit from more frequent dosing, said Dr. Rosmarin.
“We know from the SOLO-1 and SOLO-2 studies that dupilumab weekly dosing was evaluated. It was only the every-other-week dosing that was approved, and we can see why – in terms of the changes in EASI [Eczema Area and Severity Index] score they’re close to overlapping,” he said.
In real life, however, “some patients benefit from different dosing. It’s important to realize that. I think we all have some patients who may dose more frequently and some who may dose less frequently,” Dr. Rosmarin said.
For a patient who “gets absolutely no response from dupilumab after 3-4 months, I’d switch them to something else. But for those who are partial responders, particularly those who tell me they’re getting itchy before their next dose, they’re the ones who benefit most from doubling the dose to dupilumab weekly,” he said.
For patients who experience dupilumab-associated head and neck dermatitis, itraconazole may help, Dr. Rosmarin added. “We’re using 200 mg daily for 2 weeks and weekly thereafter, and it helps some of our patients.” The average self-reported improvement was 52% for patients with dupilumab-associated facial redness treated with itraconazole in a retrospective medical record review that he and his colleagues published in 2022.
Dr. Rosmarin pointed to a multicenter prospective cohort study also published in 2022 showing that baseline/pretreatment levels of Malassezia-specific IgE were associated with the development of dupilumab-associated head and neck dermatitis. The median levels of Malassezia-specific IgE were 32 kUL–1 versus 2.3 kUL–1 in patients who experienced dupilumab-associated facial redness, compared with those who did not.
He said that, while there “may be multiple reasons” for dupilumab-associated head and neck dermatitis and that “plenty of patients” who don’t have Malassezia-specific IgE develop head and neck dermatitis, “this could be one cause.”
Itraconazole has been shown in his practice to be superior to fluconazole, likely because it has greater anti-inflammatory effects and provides better coverage of Malassezia because it is more lipophilic, said Dr. Rosmarin, who does not test for Malassezia-specific IgE before trying itraconazole.
For dupilumab-associated ocular surface disease, Elaine C. Siegfried, MD, offered her first-line suggestions: warm compresses (such as a microwaved bean bag), bland ocular lubricant (such as preservative-free artificial tears), oral hydration, and if needed and accessible, the prescription ophthalmic solution lifitegrast.
“It’s become an issue – what the dermatologist can do first line,” said Dr. Siegfried, professor of pediatrics and dermatology at Saint Louis University and director of the division of pediatric dermatology at Cardinal Glennon Children’s Hospital, St. Louis.
“If these don’t work, then I’ll identify an ophthalmologist who’s knowledgeable about Dupixent-related ocular surface disease,” she said. Selection is “important because they’re not all knowledgeable ... corneal specialists typically have the most knowledge.”
Topical adherence with diffuse xerosis and mild-moderate AD
For patients with diffuse xerosis and mild-moderate AD, especially those who are older and having difficulty with topical regimens, Anna De Benedetto, MD, said she tries to enhance adherence by simplifying the regimen. She asks patients to buy a pound jar of base cream (ceramide base) – “whatever emollient they like” – and mixes into it a high-potency steroid solution. They’re instructed to apply the combined cream once daily for 1-2 weeks, and then three times a week alternating with a nonmedicated cream.
“This way they’re using one [cream] to target the immune system and the skin barrier,” said Dr. De Benedetto, associate professor of dermatology and director of the dermatology clinical trial unit at the University of Rochester (N.Y.) Medical Center.
‘Wet wrap’ pajamas; self-image for children, teens
Dermatologist Melinda Gooderham, MSc, MD, assistant professor at Queen’s University, Kingston, Ont., and medical director at the SKiN Centre for Dermatology, said that, for widespread and troublesome AD, she advises patients or parents to wet a thin cotton pajama top and bottom and spin it in the dryer “so it’s almost dry but still moist.” Dry, looser pajamas or a light track suit can then be worn over the damp pajamas. “I usually tell [patients] to buy one size up,” she said.
Body dysmorphia is common with skin disease, and its incidence is six times higher in people with eczema than those without the disease, said Dr. Siegfried. “I’ve found that, for patients subjected to AD for a long time,” this is still an issue, “even when you clear their skin.”
For children, teens and their families, the nonprofit organization Made a Masterpiece can be valuable, Dr. Siegfried said. It offers resources from parents, children, psychologists, dermatologists, and others to help manage the emotional, social and spiritual aspects of living with a skin condition.
To use or not to use BSA; environmental counseling
“I think [assessing] body surface area [BSA] is very important in pediatrics and for adolescents [especially in those with moderate to severe disease] because it quantifies the disease for the family,” said Lawrence F. Eichenfield, MD, professor of dermatology and pediatrics and vice chair of the department of dermatology at the University of California, San Diego.
“Families live with the disease, but quantification really matters” for understanding the extent and impact of the disease and for motivating families to treat, said Dr. Eichenfield.
(When the disease is markedly diminished in follow-up, knowing the BSA then “helps families to register the improvement and gives positive reinforcement,” Dr. Eichenfeld said after the meeting.)
Young patients can participate, he noted at the meeting. “When I do telemedicine visits, kids can tell me how many hands of eczema they have.”
Dr. Eichenfield also said that he now routinely counsels on the environmental impacts on eczema. For example, “I explain to people that we’re probably going to have a bad wildfire season in California, and it’s the kind of environmental perturbation that may impact some eczema patients,” he said, noting the 2021 study documenting an association of wildfire air pollution from the 2018 California Camp fire with an increase in dermatology clinic visits for AD and itch in San Francisco.
“It helps to keep an eye out for that, and also to be aware of some of the environmental changes,” he said.
Dr. Chovatiya reported ties with AbbVie, Eli Lilly, Incyte, Leo Pharma, Pfizer, Regeneron, and Sanofi, among others. Dr. Sidbury reported ties with Regeneron, UCB, Pfizer, Leo Pharma, and Lilly, among others. Dr. Rosmarin reported ties with AbbVie, Incyte, Lilly, Pfizer, Regeneron, and Sanofi, among others. Dr. Siegfried reported ties with Regeneron, Sanofi Genzyme, AbbVie, Incyte, Leo, and Pfizer, among others. Dr. De Benedetto reported ties with Incyte, Pfizer, AbbVie, and Sanofi Advent, among others. Dr. Gooderham reported ties with AbbVie, Eli Lilly, Incyte, Leo Pharma, Pfizer, Regeneron, and Sanofi Genzyme, among others. Dr. Eichenfield disclosed ties with AbbVie, Eli Lilly, Incyte, Leo Pharma, Pfizer, Regeneron, and Sanofi, among others.
AT RAD 2023
Abrocitinib remains effective at 96 weeks, in older as well as younger adults
WASHINGTON – A substantial proportion of , Andrew F. Alexis, MD, MPH, reported in a late-breaker abstract session at the annual Revolutionizing Atopic Dermatitis conference.
The analysis stratified patients by age – 18-50 and over 50 years – and found that the sustained improvement with the JAK-1 selective inhibitor as monotherapy was seen regardless of age. “In practice, patients who are older tend to have had AD for a longer period of time and tend to be more difficult to treat so it’s reassuring to see that even in the over-50 age group, they show substantial responses, even with more stringent endpoints,” said Dr. Alexis, professor of clinical dermatology at Weill Cornell Medical College, New York.
At week 96, for instance, the proportion of patients who achieved at least a 75% improvement from baseline on the Eczema Area and Severity Index (EASI-75) was 73% with the 100-mg dose and 85% with the 200-mg dose in the younger age group, and 86% and 89%, respectively, in the older age group.
An EASI-90 response – one of the more stringent outcomes – was achieved by 45% and 58% in the 18-50 group and 58% and 73% in the over 50 group (for 100-mg and 200-mg doses, respectively), Dr. Alexis reported.
The interim analysis also showed dose-dependent efficacy overall up to 96 weeks in the younger age group but only up to 48 weeks in the older age group. Response to some outcome measures in patients over age 50 years was “less clearly dose dependent after week 48” than earlier, Dr. Alexis said.
The ongoing JADE EXTEND trial enrolled patients who had participated in the phase 3 JADE clinical trials. This analysis covered 1,309 patients who were enrolled by a September 2021 cutoff. The patient population leaned young: Eighty percent (1,046) were aged 18-50, and 20% (263) were over 50.
Patients who were randomly assigned to abrocitinib 200 mg or 100 mg in the parent trials continued to receive the same dose in JADE EXTEND with blinding maintained. Those who received placebo in the qualifying trial were randomly assigned to abrocitinib 200 mg or 100 mg. And patients from JADE DARE continued with their dosing of 200 mg. Grouping by age for the analysis was made based on the age recorded at the screening visit of the qualifying trial.
IGA, PP-NRS, and DLQI results
At week 96, the proportion of patients 18-50 years of age who achieved the Investigator’s Global Assessment (IGA) score of 0 or 1 (clear or almost clear) with at least a 2-grade improvement from baseline was 44% in the 100-mg group and 55% in the 200-mg group. Among patients over 50, these proportions were 51% and 58%, respectively.
The proportion of patients who achieved at least a 4-point improvement from baseline in the Peak Pruritus Numerical Rating Scale (PP-NRS) score was 54% and 66% (on 100 mg and 200 mg, respectively) among those aged 18-50, and 79% and 80%, respectively, among those over 50.
Looking at more stringent outcomes, 26% and 38% in the 18-50 group on 100 mg and 200 mg, respectively, achieved a PP-NRS of 0/1, as did 54% and 44% in the over-50 group.
Lastly, a score of less than 2 on the Dermatology Life Quality Index (DLQI 0/1) was achieved by 32% and 41% of patients aged 18-50 and by 51% and 48% of patients over 50, for the 100-mg and 200-mg doses, respectively.
The decline in dose-dependent efficacy in the older age group after 48 weeks may be due to the smaller sample of older patients and/or the fact that a higher proportion of older patients had moderate baseline disease per their IGA score, versus severe disease, compared with the younger patients, Dr. Alexis said. “We see a skewing toward a bit more severe [disease] in the younger age group compared to the older,” he noted.
Abrocitinib (Cibinqo) is approved for the treatment of moderate to severe AD in adolescents aged 12 and up and adults whose disease is not adequately controlled with other systemic treatments or those for whom the use of these drugs is not advised. It is available in a 50-mg dose for dose adjustments in special populations, but this dose was not studied in the clinical trials, Dr. Alexis noted. The interim analysis did not include safety data.
In a separate presentation in which he reviewed long-term data on AD medications, Raj Chovatiya, MD, PhD, assistant professor of dermatology at Northwestern University, Chicago, said that most patients who meet defined endpoints at week 12 of treatment with abrocitinib maintain that response over time. “By and large, there’s a steep initial rise that flattens over the long run, which is what you want to see. People getting that response are generally staying there over the course of treatment,” he said, referring to the JADE EXTEND data up to week 48.
It’s important to also appreciate, however, that the proportion of patients meeting efficacy outcomes in the trials of abrocitinib has grown well beyond 12 weeks, Dr. Chovatiya said.
Pointing to data presented at a 2021 RAD meeting depicting the proportion of 12-week nonresponders achieving a response at weeks 24 and 48 on IGA 0/1, EASI-75, and PP-NRS, Dr. Chovatiya said the level of response grew at both time points. “You’re capturing a chunk of people well beyond the primary endpoint if you keep them on therapy continuously, suggesting that ... we may need to reframe how we’re thinking about oral JAK inhibitors,” he said. “Not only are they rapidly acting, but they are medications that can provide good control and changes in the long run.”
Dr. Alexis and Dr. Chovatiya disclosed ties with Pfizer, which funded the study.
WASHINGTON – A substantial proportion of , Andrew F. Alexis, MD, MPH, reported in a late-breaker abstract session at the annual Revolutionizing Atopic Dermatitis conference.
The analysis stratified patients by age – 18-50 and over 50 years – and found that the sustained improvement with the JAK-1 selective inhibitor as monotherapy was seen regardless of age. “In practice, patients who are older tend to have had AD for a longer period of time and tend to be more difficult to treat so it’s reassuring to see that even in the over-50 age group, they show substantial responses, even with more stringent endpoints,” said Dr. Alexis, professor of clinical dermatology at Weill Cornell Medical College, New York.
At week 96, for instance, the proportion of patients who achieved at least a 75% improvement from baseline on the Eczema Area and Severity Index (EASI-75) was 73% with the 100-mg dose and 85% with the 200-mg dose in the younger age group, and 86% and 89%, respectively, in the older age group.
An EASI-90 response – one of the more stringent outcomes – was achieved by 45% and 58% in the 18-50 group and 58% and 73% in the over 50 group (for 100-mg and 200-mg doses, respectively), Dr. Alexis reported.
The interim analysis also showed dose-dependent efficacy overall up to 96 weeks in the younger age group but only up to 48 weeks in the older age group. Response to some outcome measures in patients over age 50 years was “less clearly dose dependent after week 48” than earlier, Dr. Alexis said.
The ongoing JADE EXTEND trial enrolled patients who had participated in the phase 3 JADE clinical trials. This analysis covered 1,309 patients who were enrolled by a September 2021 cutoff. The patient population leaned young: Eighty percent (1,046) were aged 18-50, and 20% (263) were over 50.
Patients who were randomly assigned to abrocitinib 200 mg or 100 mg in the parent trials continued to receive the same dose in JADE EXTEND with blinding maintained. Those who received placebo in the qualifying trial were randomly assigned to abrocitinib 200 mg or 100 mg. And patients from JADE DARE continued with their dosing of 200 mg. Grouping by age for the analysis was made based on the age recorded at the screening visit of the qualifying trial.
IGA, PP-NRS, and DLQI results
At week 96, the proportion of patients 18-50 years of age who achieved the Investigator’s Global Assessment (IGA) score of 0 or 1 (clear or almost clear) with at least a 2-grade improvement from baseline was 44% in the 100-mg group and 55% in the 200-mg group. Among patients over 50, these proportions were 51% and 58%, respectively.
The proportion of patients who achieved at least a 4-point improvement from baseline in the Peak Pruritus Numerical Rating Scale (PP-NRS) score was 54% and 66% (on 100 mg and 200 mg, respectively) among those aged 18-50, and 79% and 80%, respectively, among those over 50.
Looking at more stringent outcomes, 26% and 38% in the 18-50 group on 100 mg and 200 mg, respectively, achieved a PP-NRS of 0/1, as did 54% and 44% in the over-50 group.
Lastly, a score of less than 2 on the Dermatology Life Quality Index (DLQI 0/1) was achieved by 32% and 41% of patients aged 18-50 and by 51% and 48% of patients over 50, for the 100-mg and 200-mg doses, respectively.
The decline in dose-dependent efficacy in the older age group after 48 weeks may be due to the smaller sample of older patients and/or the fact that a higher proportion of older patients had moderate baseline disease per their IGA score, versus severe disease, compared with the younger patients, Dr. Alexis said. “We see a skewing toward a bit more severe [disease] in the younger age group compared to the older,” he noted.
Abrocitinib (Cibinqo) is approved for the treatment of moderate to severe AD in adolescents aged 12 and up and adults whose disease is not adequately controlled with other systemic treatments or those for whom the use of these drugs is not advised. It is available in a 50-mg dose for dose adjustments in special populations, but this dose was not studied in the clinical trials, Dr. Alexis noted. The interim analysis did not include safety data.
In a separate presentation in which he reviewed long-term data on AD medications, Raj Chovatiya, MD, PhD, assistant professor of dermatology at Northwestern University, Chicago, said that most patients who meet defined endpoints at week 12 of treatment with abrocitinib maintain that response over time. “By and large, there’s a steep initial rise that flattens over the long run, which is what you want to see. People getting that response are generally staying there over the course of treatment,” he said, referring to the JADE EXTEND data up to week 48.
It’s important to also appreciate, however, that the proportion of patients meeting efficacy outcomes in the trials of abrocitinib has grown well beyond 12 weeks, Dr. Chovatiya said.
Pointing to data presented at a 2021 RAD meeting depicting the proportion of 12-week nonresponders achieving a response at weeks 24 and 48 on IGA 0/1, EASI-75, and PP-NRS, Dr. Chovatiya said the level of response grew at both time points. “You’re capturing a chunk of people well beyond the primary endpoint if you keep them on therapy continuously, suggesting that ... we may need to reframe how we’re thinking about oral JAK inhibitors,” he said. “Not only are they rapidly acting, but they are medications that can provide good control and changes in the long run.”
Dr. Alexis and Dr. Chovatiya disclosed ties with Pfizer, which funded the study.
WASHINGTON – A substantial proportion of , Andrew F. Alexis, MD, MPH, reported in a late-breaker abstract session at the annual Revolutionizing Atopic Dermatitis conference.
The analysis stratified patients by age – 18-50 and over 50 years – and found that the sustained improvement with the JAK-1 selective inhibitor as monotherapy was seen regardless of age. “In practice, patients who are older tend to have had AD for a longer period of time and tend to be more difficult to treat so it’s reassuring to see that even in the over-50 age group, they show substantial responses, even with more stringent endpoints,” said Dr. Alexis, professor of clinical dermatology at Weill Cornell Medical College, New York.
At week 96, for instance, the proportion of patients who achieved at least a 75% improvement from baseline on the Eczema Area and Severity Index (EASI-75) was 73% with the 100-mg dose and 85% with the 200-mg dose in the younger age group, and 86% and 89%, respectively, in the older age group.
An EASI-90 response – one of the more stringent outcomes – was achieved by 45% and 58% in the 18-50 group and 58% and 73% in the over 50 group (for 100-mg and 200-mg doses, respectively), Dr. Alexis reported.
The interim analysis also showed dose-dependent efficacy overall up to 96 weeks in the younger age group but only up to 48 weeks in the older age group. Response to some outcome measures in patients over age 50 years was “less clearly dose dependent after week 48” than earlier, Dr. Alexis said.
The ongoing JADE EXTEND trial enrolled patients who had participated in the phase 3 JADE clinical trials. This analysis covered 1,309 patients who were enrolled by a September 2021 cutoff. The patient population leaned young: Eighty percent (1,046) were aged 18-50, and 20% (263) were over 50.
Patients who were randomly assigned to abrocitinib 200 mg or 100 mg in the parent trials continued to receive the same dose in JADE EXTEND with blinding maintained. Those who received placebo in the qualifying trial were randomly assigned to abrocitinib 200 mg or 100 mg. And patients from JADE DARE continued with their dosing of 200 mg. Grouping by age for the analysis was made based on the age recorded at the screening visit of the qualifying trial.
IGA, PP-NRS, and DLQI results
At week 96, the proportion of patients 18-50 years of age who achieved the Investigator’s Global Assessment (IGA) score of 0 or 1 (clear or almost clear) with at least a 2-grade improvement from baseline was 44% in the 100-mg group and 55% in the 200-mg group. Among patients over 50, these proportions were 51% and 58%, respectively.
The proportion of patients who achieved at least a 4-point improvement from baseline in the Peak Pruritus Numerical Rating Scale (PP-NRS) score was 54% and 66% (on 100 mg and 200 mg, respectively) among those aged 18-50, and 79% and 80%, respectively, among those over 50.
Looking at more stringent outcomes, 26% and 38% in the 18-50 group on 100 mg and 200 mg, respectively, achieved a PP-NRS of 0/1, as did 54% and 44% in the over-50 group.
Lastly, a score of less than 2 on the Dermatology Life Quality Index (DLQI 0/1) was achieved by 32% and 41% of patients aged 18-50 and by 51% and 48% of patients over 50, for the 100-mg and 200-mg doses, respectively.
The decline in dose-dependent efficacy in the older age group after 48 weeks may be due to the smaller sample of older patients and/or the fact that a higher proportion of older patients had moderate baseline disease per their IGA score, versus severe disease, compared with the younger patients, Dr. Alexis said. “We see a skewing toward a bit more severe [disease] in the younger age group compared to the older,” he noted.
Abrocitinib (Cibinqo) is approved for the treatment of moderate to severe AD in adolescents aged 12 and up and adults whose disease is not adequately controlled with other systemic treatments or those for whom the use of these drugs is not advised. It is available in a 50-mg dose for dose adjustments in special populations, but this dose was not studied in the clinical trials, Dr. Alexis noted. The interim analysis did not include safety data.
In a separate presentation in which he reviewed long-term data on AD medications, Raj Chovatiya, MD, PhD, assistant professor of dermatology at Northwestern University, Chicago, said that most patients who meet defined endpoints at week 12 of treatment with abrocitinib maintain that response over time. “By and large, there’s a steep initial rise that flattens over the long run, which is what you want to see. People getting that response are generally staying there over the course of treatment,” he said, referring to the JADE EXTEND data up to week 48.
It’s important to also appreciate, however, that the proportion of patients meeting efficacy outcomes in the trials of abrocitinib has grown well beyond 12 weeks, Dr. Chovatiya said.
Pointing to data presented at a 2021 RAD meeting depicting the proportion of 12-week nonresponders achieving a response at weeks 24 and 48 on IGA 0/1, EASI-75, and PP-NRS, Dr. Chovatiya said the level of response grew at both time points. “You’re capturing a chunk of people well beyond the primary endpoint if you keep them on therapy continuously, suggesting that ... we may need to reframe how we’re thinking about oral JAK inhibitors,” he said. “Not only are they rapidly acting, but they are medications that can provide good control and changes in the long run.”
Dr. Alexis and Dr. Chovatiya disclosed ties with Pfizer, which funded the study.
AT RAD 2023
Dupilumab outcomes stable at end of open label atopic dermatitis study
WASHINGTON – The and no new emergent side effects, Lisa Beck, MD, reported during a late-breaking session at the annual Revolutionizing Atopic Dermatitis conference.
Other recent research on the biologic has shown that it improves lesional skin barrier function and rapidly reduces the abundance of Staphylococcus aureus on lesional skin, Dr. Beck, professor of dermatology at the University of Rochester (N.Y.), said during another session at the meeting on long-term control of AD. Dr. Beck directs a laboratory at the University of Rochester Medical Center that focuses on understanding AD and is involved in the National Institute of Allergy and Infectious Diseases (NIAID)-funded Atopic Dermatitis Research Network (ADRN).
The LIBERTY AD open-label extension (OLE) study was a phase 3 trial of 2,677 adults with moderate to severe AD who had participated in previous dupilumab clinical trials and were treated with 300 mg dupilumab weekly or every other week. Concomitant treatments were permitted, including topical corticosteroids and topical calcineurin inhibitors. (The proportion of patients dosed on an every-other-week or weekly dosing schedule was not available.)
Of 334 patients (12.5%) who remained in the trial at week 260, or 5 years, 88.9% achieved at least a 75% improvement in lesion extent and severity (Eczema Area and Severity Index [EASI]-75), and 76.2% achieved an EASI-90. The proportion achieving at least a 4-point reduction in the Peak Pruritus Numerical Rating Scale (NRS) or a score of 0 was 66.5%. At 5 years, improvements “seem very stable,” with “no loss in efficacy,” Dr. Beck said.
The majority of patients who withdrew from the open-label extension trial did so because the study was terminated at their site or because of the drug’s approval and commercialization – not for a medical reason, Dr. Beck said. Over the course of the extension trial, 4% of those enrolled withdrew because of adverse events and about 2% withdrew because of lack of efficacy.
Safety of dupilumab
The extension trial lacked a control arm, so Dr. Beck and her colleagues compared safety results to those in the final data set for patients in the LIBERTY AD CHRONOS study who received dupilumab 300 mg weekly with concomitant corticosteroids. The CHRONOS study was a 1-year randomized, double-blinded placebo-controlled phase 3 trial.
The exposure-adjusted incidence rate of severe treatment-emergent adverse events (TEAE) was lower at the close of the extension trial (5 patients/100 patient years [PY]) than at the end of the CHRONOS study (5.9 patients/100 PY). The incidence of serious adverse events related to treatment was 0.6 patients/100 PY in the final open label extension study data set, compared with 0.7 patients/100 PY in the CHRONOS final data set.
Adverse event rates “are really, if anything, slightly less in the OLE study versus the CHRONOS study, which was 1 year of treatment,” Dr. Beck said. And “no new adverse events have emerged.”
During a question and answer period, Dr. Beck pointed out that existing and future “real world” registries of patients on dupilumab and other new therapies will better inform dermatologists of adverse events than clinical trials have done.
Ocular surface disease
In a separate presentation on the safety of biologics, Andrew Blauvelt, MD, MBA, of the Oregon Medical Research Center, Portland, said that in routine care, ocular surface disease is the most predominant side effect associated with dupilumab. “We don’t know the mechanism of action. But it’s not infectious, it’s not pink eye, and importantly, it’s not allergic conjunctivitis,” he said, noting that the spectrum of disease ranges from dry eye and eye itching to “frank conjunctivitis” and keratitis.
Most cases are mild to moderate and can often be managed with lubricating eye drops and periodic use of corticosteroid eye drops. Co-management with an ophthalmologist is often advisable, he said.
Dupilumab-associated erythema/eczema of the face was “not seen much” in clinical trials but is also being reported in the literature, largely by European researchers, Dr. Blauvelt said. “We hear a lot about red face, but I don’t think it’s much of an issue,” he said. “Most of the time, in my experience, it will [reflect] breakthrough residual AD, and I like to treat it with non-steroidal topicals.”
Occasionally, the withdrawal of steroids or allergic contact dermatitis are at play, Dr. Blauvelt said. “If you see red face in a person on dupilumab, use your clinical prowess, do a differential diagnosis, and treat accordingly.”
Effect on S. aureus
The vast majority of adults with moderate to severe AD have skin colonization with S. aureus, Dr. Beck said during the session on long-term control of AD. The presence of S. aureus in skin cultures correlates strongly with AD severity, type 2 immunity polarization, skin barrier disruption, and allergen sensitization, she said.
“So if we could do something to get rid of the staph and keep it away, one might imagine that would help” control the AD disease process, she said.
An ADRN study evaluated S. aureus in the skin of 71 patients who were randomized to receive dupilumab or placebo and found a “profound” effect of the biologic. “We were truly shocked by how quickly we saw a reduction in Staph aureus ... in lesional skin as early as 3 days” into treatment with dupilumab, she said of the unpublished findings. “And there is a pretty nice association with improvement in disease severity.”
Dr. Beck reported consultancy/advisory board work with Regeneron, Sanofi/Genzyme, among other disclosures. Dr. Blauvelt reported consultancy/advisory board work for Regeneron and Sanofi Genzyme and has received speakers bureau/honoraria for non-CME work for Regeneron and Sanofi, among other disclosures.
WASHINGTON – The and no new emergent side effects, Lisa Beck, MD, reported during a late-breaking session at the annual Revolutionizing Atopic Dermatitis conference.
Other recent research on the biologic has shown that it improves lesional skin barrier function and rapidly reduces the abundance of Staphylococcus aureus on lesional skin, Dr. Beck, professor of dermatology at the University of Rochester (N.Y.), said during another session at the meeting on long-term control of AD. Dr. Beck directs a laboratory at the University of Rochester Medical Center that focuses on understanding AD and is involved in the National Institute of Allergy and Infectious Diseases (NIAID)-funded Atopic Dermatitis Research Network (ADRN).
The LIBERTY AD open-label extension (OLE) study was a phase 3 trial of 2,677 adults with moderate to severe AD who had participated in previous dupilumab clinical trials and were treated with 300 mg dupilumab weekly or every other week. Concomitant treatments were permitted, including topical corticosteroids and topical calcineurin inhibitors. (The proportion of patients dosed on an every-other-week or weekly dosing schedule was not available.)
Of 334 patients (12.5%) who remained in the trial at week 260, or 5 years, 88.9% achieved at least a 75% improvement in lesion extent and severity (Eczema Area and Severity Index [EASI]-75), and 76.2% achieved an EASI-90. The proportion achieving at least a 4-point reduction in the Peak Pruritus Numerical Rating Scale (NRS) or a score of 0 was 66.5%. At 5 years, improvements “seem very stable,” with “no loss in efficacy,” Dr. Beck said.
The majority of patients who withdrew from the open-label extension trial did so because the study was terminated at their site or because of the drug’s approval and commercialization – not for a medical reason, Dr. Beck said. Over the course of the extension trial, 4% of those enrolled withdrew because of adverse events and about 2% withdrew because of lack of efficacy.
Safety of dupilumab
The extension trial lacked a control arm, so Dr. Beck and her colleagues compared safety results to those in the final data set for patients in the LIBERTY AD CHRONOS study who received dupilumab 300 mg weekly with concomitant corticosteroids. The CHRONOS study was a 1-year randomized, double-blinded placebo-controlled phase 3 trial.
The exposure-adjusted incidence rate of severe treatment-emergent adverse events (TEAE) was lower at the close of the extension trial (5 patients/100 patient years [PY]) than at the end of the CHRONOS study (5.9 patients/100 PY). The incidence of serious adverse events related to treatment was 0.6 patients/100 PY in the final open label extension study data set, compared with 0.7 patients/100 PY in the CHRONOS final data set.
Adverse event rates “are really, if anything, slightly less in the OLE study versus the CHRONOS study, which was 1 year of treatment,” Dr. Beck said. And “no new adverse events have emerged.”
During a question and answer period, Dr. Beck pointed out that existing and future “real world” registries of patients on dupilumab and other new therapies will better inform dermatologists of adverse events than clinical trials have done.
Ocular surface disease
In a separate presentation on the safety of biologics, Andrew Blauvelt, MD, MBA, of the Oregon Medical Research Center, Portland, said that in routine care, ocular surface disease is the most predominant side effect associated with dupilumab. “We don’t know the mechanism of action. But it’s not infectious, it’s not pink eye, and importantly, it’s not allergic conjunctivitis,” he said, noting that the spectrum of disease ranges from dry eye and eye itching to “frank conjunctivitis” and keratitis.
Most cases are mild to moderate and can often be managed with lubricating eye drops and periodic use of corticosteroid eye drops. Co-management with an ophthalmologist is often advisable, he said.
Dupilumab-associated erythema/eczema of the face was “not seen much” in clinical trials but is also being reported in the literature, largely by European researchers, Dr. Blauvelt said. “We hear a lot about red face, but I don’t think it’s much of an issue,” he said. “Most of the time, in my experience, it will [reflect] breakthrough residual AD, and I like to treat it with non-steroidal topicals.”
Occasionally, the withdrawal of steroids or allergic contact dermatitis are at play, Dr. Blauvelt said. “If you see red face in a person on dupilumab, use your clinical prowess, do a differential diagnosis, and treat accordingly.”
Effect on S. aureus
The vast majority of adults with moderate to severe AD have skin colonization with S. aureus, Dr. Beck said during the session on long-term control of AD. The presence of S. aureus in skin cultures correlates strongly with AD severity, type 2 immunity polarization, skin barrier disruption, and allergen sensitization, she said.
“So if we could do something to get rid of the staph and keep it away, one might imagine that would help” control the AD disease process, she said.
An ADRN study evaluated S. aureus in the skin of 71 patients who were randomized to receive dupilumab or placebo and found a “profound” effect of the biologic. “We were truly shocked by how quickly we saw a reduction in Staph aureus ... in lesional skin as early as 3 days” into treatment with dupilumab, she said of the unpublished findings. “And there is a pretty nice association with improvement in disease severity.”
Dr. Beck reported consultancy/advisory board work with Regeneron, Sanofi/Genzyme, among other disclosures. Dr. Blauvelt reported consultancy/advisory board work for Regeneron and Sanofi Genzyme and has received speakers bureau/honoraria for non-CME work for Regeneron and Sanofi, among other disclosures.
WASHINGTON – The and no new emergent side effects, Lisa Beck, MD, reported during a late-breaking session at the annual Revolutionizing Atopic Dermatitis conference.
Other recent research on the biologic has shown that it improves lesional skin barrier function and rapidly reduces the abundance of Staphylococcus aureus on lesional skin, Dr. Beck, professor of dermatology at the University of Rochester (N.Y.), said during another session at the meeting on long-term control of AD. Dr. Beck directs a laboratory at the University of Rochester Medical Center that focuses on understanding AD and is involved in the National Institute of Allergy and Infectious Diseases (NIAID)-funded Atopic Dermatitis Research Network (ADRN).
The LIBERTY AD open-label extension (OLE) study was a phase 3 trial of 2,677 adults with moderate to severe AD who had participated in previous dupilumab clinical trials and were treated with 300 mg dupilumab weekly or every other week. Concomitant treatments were permitted, including topical corticosteroids and topical calcineurin inhibitors. (The proportion of patients dosed on an every-other-week or weekly dosing schedule was not available.)
Of 334 patients (12.5%) who remained in the trial at week 260, or 5 years, 88.9% achieved at least a 75% improvement in lesion extent and severity (Eczema Area and Severity Index [EASI]-75), and 76.2% achieved an EASI-90. The proportion achieving at least a 4-point reduction in the Peak Pruritus Numerical Rating Scale (NRS) or a score of 0 was 66.5%. At 5 years, improvements “seem very stable,” with “no loss in efficacy,” Dr. Beck said.
The majority of patients who withdrew from the open-label extension trial did so because the study was terminated at their site or because of the drug’s approval and commercialization – not for a medical reason, Dr. Beck said. Over the course of the extension trial, 4% of those enrolled withdrew because of adverse events and about 2% withdrew because of lack of efficacy.
Safety of dupilumab
The extension trial lacked a control arm, so Dr. Beck and her colleagues compared safety results to those in the final data set for patients in the LIBERTY AD CHRONOS study who received dupilumab 300 mg weekly with concomitant corticosteroids. The CHRONOS study was a 1-year randomized, double-blinded placebo-controlled phase 3 trial.
The exposure-adjusted incidence rate of severe treatment-emergent adverse events (TEAE) was lower at the close of the extension trial (5 patients/100 patient years [PY]) than at the end of the CHRONOS study (5.9 patients/100 PY). The incidence of serious adverse events related to treatment was 0.6 patients/100 PY in the final open label extension study data set, compared with 0.7 patients/100 PY in the CHRONOS final data set.
Adverse event rates “are really, if anything, slightly less in the OLE study versus the CHRONOS study, which was 1 year of treatment,” Dr. Beck said. And “no new adverse events have emerged.”
During a question and answer period, Dr. Beck pointed out that existing and future “real world” registries of patients on dupilumab and other new therapies will better inform dermatologists of adverse events than clinical trials have done.
Ocular surface disease
In a separate presentation on the safety of biologics, Andrew Blauvelt, MD, MBA, of the Oregon Medical Research Center, Portland, said that in routine care, ocular surface disease is the most predominant side effect associated with dupilumab. “We don’t know the mechanism of action. But it’s not infectious, it’s not pink eye, and importantly, it’s not allergic conjunctivitis,” he said, noting that the spectrum of disease ranges from dry eye and eye itching to “frank conjunctivitis” and keratitis.
Most cases are mild to moderate and can often be managed with lubricating eye drops and periodic use of corticosteroid eye drops. Co-management with an ophthalmologist is often advisable, he said.
Dupilumab-associated erythema/eczema of the face was “not seen much” in clinical trials but is also being reported in the literature, largely by European researchers, Dr. Blauvelt said. “We hear a lot about red face, but I don’t think it’s much of an issue,” he said. “Most of the time, in my experience, it will [reflect] breakthrough residual AD, and I like to treat it with non-steroidal topicals.”
Occasionally, the withdrawal of steroids or allergic contact dermatitis are at play, Dr. Blauvelt said. “If you see red face in a person on dupilumab, use your clinical prowess, do a differential diagnosis, and treat accordingly.”
Effect on S. aureus
The vast majority of adults with moderate to severe AD have skin colonization with S. aureus, Dr. Beck said during the session on long-term control of AD. The presence of S. aureus in skin cultures correlates strongly with AD severity, type 2 immunity polarization, skin barrier disruption, and allergen sensitization, she said.
“So if we could do something to get rid of the staph and keep it away, one might imagine that would help” control the AD disease process, she said.
An ADRN study evaluated S. aureus in the skin of 71 patients who were randomized to receive dupilumab or placebo and found a “profound” effect of the biologic. “We were truly shocked by how quickly we saw a reduction in Staph aureus ... in lesional skin as early as 3 days” into treatment with dupilumab, she said of the unpublished findings. “And there is a pretty nice association with improvement in disease severity.”
Dr. Beck reported consultancy/advisory board work with Regeneron, Sanofi/Genzyme, among other disclosures. Dr. Blauvelt reported consultancy/advisory board work for Regeneron and Sanofi Genzyme and has received speakers bureau/honoraria for non-CME work for Regeneron and Sanofi, among other disclosures.
AT RAD 2023
JAK-inhibitor safety in adolescents with AD: Long-term analyses reported
WASHINGTON – and over 1,000 patient-years of exposure, Lawrence F. Eichenfield, MD, reported at the annual Revolutionizing Atopic Dermatitis conference.
In March 2023, the oral Janus kinase 1 (JAK1) inhibitor was approved by the Food and Drug Administration for treating adolescents aged 12-17 with refractory moderate to severe AD – an expanded indication from the approval in adults in 2022.
The new analysis evaluated data from patients who participated in the phase 3 JADE clinical trials – MONO-1, MONO-2, TEEN, and REGIMEN – and were subsequently enrolled in the ongoing phase 3 extension trial JADE EXTEND. Compared with a previous post hoc analysis in which adolescent patients had approximately 1 year of exposure, this updated analysis includes a sizable portion of patients with more than 96 weeks of exposure.
“We’re starting to get good numbers of [adolescents] who’ve had about 2 years of exposure,” said Dr. Eichenfield, professor of dermatology and pediatrics and vice chair of the department of dermatology at the University of California, San Diego, during a late-breaking research session.
With a data cut for this analysis of September 2021, “we haven’t seen additive long-term [adverse] effects” with longer exposures, he said. In addition, “there were no unique safety concerns related to adolescents compared to the findings observed [in an] integrated safety analysis using the same data cut in which most patients were adults.”
(The analysis in adults covered 3,802 patients with over 5,000 patient-years of exposure, and was presented at the annual American Academy of Dermatology meeting in March 2023.)
Also presented in the late-breaking abstract session at RAD 2023 was a long-term safety study of upadacitinib (Rinvoq), the other JAK1 inhibitor approved for adolescents with AD – approved by the FDA for both adolescents and adults with moderate to severe AD in 2022. The new analysis captures exposure of up to 4 years and shows no “worsening or accumulation of events,” compared with 1-year data, reported Christopher G. Bunick, MD, PhD, of the department of dermatology and the program in translational biomedicine at Yale University, New Haven, Conn.
Abrocitinib in adolescents
For the safety analysis of abrocitinib (Cibinqo), data were pooled into two cohorts: A consistent-dose cohort of 490 adolescents who received the same dose (200 mg or 100 mg) during the entire duration of the qualifying JADE trials, and a variable-dose cohort of 145 adolescents who received different doses (200 mg or 100 mg) during the JADE REGIMEN qualifying trial.
Duration of exposure was 96 weeks or more in 37%-38% of the consistent-dose cohort and 68% of the variable-dose cohort.
In the consistent-dose cohort, adverse events occurred in 243 (84%) and 153 (76%) of patients receiving 200-mg doses and 100-mg doses, respectively. Incidence rates for severe adverse events were 5.87 per 100 patient-years at both doses, and rates for adverse events leading to study discontinuation were 6.96/100 patient-years at 200 mg and 5.13/100 patient-years at 100 mg.
“No meaningful dose-response relationship was observed for serious adverse events, or adverse events leading to discontinuation, or adverse events of special interest,” said Dr. Eichenfield, also chief of pediatric and adolescent dermatology at Rady Children’s Hospital, San Diego.
The IRs of adverse events of special interest were 1.84/100 patient-years and 1.28/100 patient-years for serious infection; 2.11/100 patient-years, and 1.62/100 patient-years for all herpes zoster infections; and 0.69/100 patient-years and 0.32/100 patient-years for opportunistic herpes zoster infections in the 200-mg and 100-mg arms, respectively.
“Other than herpes zoster, there were no opportunistic infections observed and no tuberculosis cases,” he said. “There was one nonfatal venous thromboembolism in an adolescent who had a very strong family history of [pulmonary embolism], one retinal detachment [with a concurrent diagnosis of cataracts and of left eyebrow folliculitis], and no events of nonmelanoma skin cancer or other malignancies, major adverse cardiovascular events, or deaths.” The thromboembolism case was reported in the previous post hoc analysis.
In the variable-dose cohort, data were similar, Dr. Eichenfield said. The IRs for severe adverse events, adverse events leading to study withdrawal, and adverse events of special interest were consistent with those in the other cohort. And similarly, there were no reports of tuberculosis or other opportunistic infections (excluding herpes zoster), and no reports of nonmelanoma skin cancer (NMSC) or other malignancies, major adverse cardiovascular events (MACE), or death. In this cohort, there were no venous thromboembolism (VTE) reports.
Upadacitinib in adolescents, adults
The new analysis looked at up to 4 years of upadacitinib treatment in almost 2,700 adolescents and adults– and over 6,200 patient-years – using integrated data from three ongoing pivotal phase 3 studies: Measure Up 1, Measure Up 2, and AD Up. (Of these patients, 539 were adolescents, Dr. Bunick said after the meeting.)
In the Measure Up studies, patients were randomized 1:1:1 to receive a 15-mg dose, a 30-mg dose, or placebo once daily. In AD Up, patients in each arm received concomitant topical corticosteroids. At week 16, patients receiving the drug continued their assigned treatment during the ongoing blinded extension period, and those receiving placebo were rerandomized to upadacitinib 15 mg or 30 mg.
The exposure-adjusted event rates for any adverse event leading to discontinuation were 4.1/100 patient-years and 4.7/100 patient-years in patients receiving 15 mg and 30 mg, respectively, and the rates of any serious adverse event were 6.5/100 patient-years and 7.5/100 patient-years, Dr. Bunick reported. Three deaths occurred in the 30-mg group; all deaths were related to COVID infection and occurred in adults with cardiovascular risk factors.
Incidence rates of adverse events of special interest were similar to those in a previous 1-year analysis. The rate of serious infections per 100 patient years, for instance, was 2.3 and 2.8 in the 15-mg and 30-mg groups, respectively, compared with 2.2 and 2.8 in the 1-year analysis.
The rate of opportunistic infections, including eczema herpeticum (and excluding TB and herpes zoster), saw a slight bump in the new analysis to 2.4/100 patient-years with the 30-mg dose. Other event rates, across both dosages and durations, were less than 0.1/100 patient-years for active TB; 0.3-0.4/100 patient-years for NMSC, and 0.1/100 patient-years or below for other malignancies, MACE, and VTE. Herpes zoster had the highest event rate in both the 1- and 4-year analyses of between 3.1/100 patient-years and 5.8/100 patient-years, Dr. Bunick reported.
The adverse event rates for adolescents and adults “show consistency and are very low,” Dr. Bunick said. At 4 years, no new safety risks were identified.
‘The more data ... the better’
Data on the safety of new medications in children and adolescents is always important, and with systemic JAK inhibitors in particular, “the more data we can accumulate in [younger] patients with AD ... the better,” said Robert Sidbury, MD, MPH, professor in the department of pediatrics at the University of Washington, Seattle, and chief of the division of dermatology at Seattle Children’s Hospital, who was asked to comment on the two studies.
Dermatologists have taken comfort in the fact that the “daunting” boxed warning on JAK inhibitors “was generated in a very different population than we generally propose to treat, certainly when talking about children and adolescents,” said Dr. Sidbury, who was not involved in either of the new safety analyses.
The JAK inhibitor boxed warning “reflects a study of tofacitinib – a different JAK inhibitor with arguably more risk of adverse effects – in adults over the age of 50 with rheumatoid arthritis and multiple risk factors for comorbidities included in the boxed warning,” he said.
“This allows dermatologists to reasonably conclude that the boxed warning – while critical to discuss and consider in every patient – is likely less concerning than might otherwise by implied.”
With more patient experience, “the more our assessment of risk, and of the ‘legitimacy’ of the boxed warning in our patient population, becomes evidence-based as opposed to extrapolation,” Dr. Sidbury said.
The two studies reported, he said, “detail an experience that is not adverse effect free –I have yet to find that medication – but is a reasonable profile considering the robust efficacy results they accompany.”
The abrocitinib safety analysis was sponsored by Pfizer. Regarding the study of upadacitinib, AbbVie contributed to the design of the safety analysis and participated in data collection. No honoria or payments were made to the authors, according to the study abstract. Dr. Eichenfield is a consultant/advisory board member for Pfizer and other companies, and has served on the speakers bureau/received honoria for Pfizer and other companies. Dr. Bunick is a consultant for AbbVie and other companies, and has served as an speaker/received honoraria or served as an investigator for several companies. Dr. Sidbury disclosed being a consultant/advisory board member for Lilly and Leo and serving on the speakers bureau/honoraria for Beiersdorf. All reported receiving grant/research support from various companies.
WASHINGTON – and over 1,000 patient-years of exposure, Lawrence F. Eichenfield, MD, reported at the annual Revolutionizing Atopic Dermatitis conference.
In March 2023, the oral Janus kinase 1 (JAK1) inhibitor was approved by the Food and Drug Administration for treating adolescents aged 12-17 with refractory moderate to severe AD – an expanded indication from the approval in adults in 2022.
The new analysis evaluated data from patients who participated in the phase 3 JADE clinical trials – MONO-1, MONO-2, TEEN, and REGIMEN – and were subsequently enrolled in the ongoing phase 3 extension trial JADE EXTEND. Compared with a previous post hoc analysis in which adolescent patients had approximately 1 year of exposure, this updated analysis includes a sizable portion of patients with more than 96 weeks of exposure.
“We’re starting to get good numbers of [adolescents] who’ve had about 2 years of exposure,” said Dr. Eichenfield, professor of dermatology and pediatrics and vice chair of the department of dermatology at the University of California, San Diego, during a late-breaking research session.
With a data cut for this analysis of September 2021, “we haven’t seen additive long-term [adverse] effects” with longer exposures, he said. In addition, “there were no unique safety concerns related to adolescents compared to the findings observed [in an] integrated safety analysis using the same data cut in which most patients were adults.”
(The analysis in adults covered 3,802 patients with over 5,000 patient-years of exposure, and was presented at the annual American Academy of Dermatology meeting in March 2023.)
Also presented in the late-breaking abstract session at RAD 2023 was a long-term safety study of upadacitinib (Rinvoq), the other JAK1 inhibitor approved for adolescents with AD – approved by the FDA for both adolescents and adults with moderate to severe AD in 2022. The new analysis captures exposure of up to 4 years and shows no “worsening or accumulation of events,” compared with 1-year data, reported Christopher G. Bunick, MD, PhD, of the department of dermatology and the program in translational biomedicine at Yale University, New Haven, Conn.
Abrocitinib in adolescents
For the safety analysis of abrocitinib (Cibinqo), data were pooled into two cohorts: A consistent-dose cohort of 490 adolescents who received the same dose (200 mg or 100 mg) during the entire duration of the qualifying JADE trials, and a variable-dose cohort of 145 adolescents who received different doses (200 mg or 100 mg) during the JADE REGIMEN qualifying trial.
Duration of exposure was 96 weeks or more in 37%-38% of the consistent-dose cohort and 68% of the variable-dose cohort.
In the consistent-dose cohort, adverse events occurred in 243 (84%) and 153 (76%) of patients receiving 200-mg doses and 100-mg doses, respectively. Incidence rates for severe adverse events were 5.87 per 100 patient-years at both doses, and rates for adverse events leading to study discontinuation were 6.96/100 patient-years at 200 mg and 5.13/100 patient-years at 100 mg.
“No meaningful dose-response relationship was observed for serious adverse events, or adverse events leading to discontinuation, or adverse events of special interest,” said Dr. Eichenfield, also chief of pediatric and adolescent dermatology at Rady Children’s Hospital, San Diego.
The IRs of adverse events of special interest were 1.84/100 patient-years and 1.28/100 patient-years for serious infection; 2.11/100 patient-years, and 1.62/100 patient-years for all herpes zoster infections; and 0.69/100 patient-years and 0.32/100 patient-years for opportunistic herpes zoster infections in the 200-mg and 100-mg arms, respectively.
“Other than herpes zoster, there were no opportunistic infections observed and no tuberculosis cases,” he said. “There was one nonfatal venous thromboembolism in an adolescent who had a very strong family history of [pulmonary embolism], one retinal detachment [with a concurrent diagnosis of cataracts and of left eyebrow folliculitis], and no events of nonmelanoma skin cancer or other malignancies, major adverse cardiovascular events, or deaths.” The thromboembolism case was reported in the previous post hoc analysis.
In the variable-dose cohort, data were similar, Dr. Eichenfield said. The IRs for severe adverse events, adverse events leading to study withdrawal, and adverse events of special interest were consistent with those in the other cohort. And similarly, there were no reports of tuberculosis or other opportunistic infections (excluding herpes zoster), and no reports of nonmelanoma skin cancer (NMSC) or other malignancies, major adverse cardiovascular events (MACE), or death. In this cohort, there were no venous thromboembolism (VTE) reports.
Upadacitinib in adolescents, adults
The new analysis looked at up to 4 years of upadacitinib treatment in almost 2,700 adolescents and adults– and over 6,200 patient-years – using integrated data from three ongoing pivotal phase 3 studies: Measure Up 1, Measure Up 2, and AD Up. (Of these patients, 539 were adolescents, Dr. Bunick said after the meeting.)
In the Measure Up studies, patients were randomized 1:1:1 to receive a 15-mg dose, a 30-mg dose, or placebo once daily. In AD Up, patients in each arm received concomitant topical corticosteroids. At week 16, patients receiving the drug continued their assigned treatment during the ongoing blinded extension period, and those receiving placebo were rerandomized to upadacitinib 15 mg or 30 mg.
The exposure-adjusted event rates for any adverse event leading to discontinuation were 4.1/100 patient-years and 4.7/100 patient-years in patients receiving 15 mg and 30 mg, respectively, and the rates of any serious adverse event were 6.5/100 patient-years and 7.5/100 patient-years, Dr. Bunick reported. Three deaths occurred in the 30-mg group; all deaths were related to COVID infection and occurred in adults with cardiovascular risk factors.
Incidence rates of adverse events of special interest were similar to those in a previous 1-year analysis. The rate of serious infections per 100 patient years, for instance, was 2.3 and 2.8 in the 15-mg and 30-mg groups, respectively, compared with 2.2 and 2.8 in the 1-year analysis.
The rate of opportunistic infections, including eczema herpeticum (and excluding TB and herpes zoster), saw a slight bump in the new analysis to 2.4/100 patient-years with the 30-mg dose. Other event rates, across both dosages and durations, were less than 0.1/100 patient-years for active TB; 0.3-0.4/100 patient-years for NMSC, and 0.1/100 patient-years or below for other malignancies, MACE, and VTE. Herpes zoster had the highest event rate in both the 1- and 4-year analyses of between 3.1/100 patient-years and 5.8/100 patient-years, Dr. Bunick reported.
The adverse event rates for adolescents and adults “show consistency and are very low,” Dr. Bunick said. At 4 years, no new safety risks were identified.
‘The more data ... the better’
Data on the safety of new medications in children and adolescents is always important, and with systemic JAK inhibitors in particular, “the more data we can accumulate in [younger] patients with AD ... the better,” said Robert Sidbury, MD, MPH, professor in the department of pediatrics at the University of Washington, Seattle, and chief of the division of dermatology at Seattle Children’s Hospital, who was asked to comment on the two studies.
Dermatologists have taken comfort in the fact that the “daunting” boxed warning on JAK inhibitors “was generated in a very different population than we generally propose to treat, certainly when talking about children and adolescents,” said Dr. Sidbury, who was not involved in either of the new safety analyses.
The JAK inhibitor boxed warning “reflects a study of tofacitinib – a different JAK inhibitor with arguably more risk of adverse effects – in adults over the age of 50 with rheumatoid arthritis and multiple risk factors for comorbidities included in the boxed warning,” he said.
“This allows dermatologists to reasonably conclude that the boxed warning – while critical to discuss and consider in every patient – is likely less concerning than might otherwise by implied.”
With more patient experience, “the more our assessment of risk, and of the ‘legitimacy’ of the boxed warning in our patient population, becomes evidence-based as opposed to extrapolation,” Dr. Sidbury said.
The two studies reported, he said, “detail an experience that is not adverse effect free –I have yet to find that medication – but is a reasonable profile considering the robust efficacy results they accompany.”
The abrocitinib safety analysis was sponsored by Pfizer. Regarding the study of upadacitinib, AbbVie contributed to the design of the safety analysis and participated in data collection. No honoria or payments were made to the authors, according to the study abstract. Dr. Eichenfield is a consultant/advisory board member for Pfizer and other companies, and has served on the speakers bureau/received honoria for Pfizer and other companies. Dr. Bunick is a consultant for AbbVie and other companies, and has served as an speaker/received honoraria or served as an investigator for several companies. Dr. Sidbury disclosed being a consultant/advisory board member for Lilly and Leo and serving on the speakers bureau/honoraria for Beiersdorf. All reported receiving grant/research support from various companies.
WASHINGTON – and over 1,000 patient-years of exposure, Lawrence F. Eichenfield, MD, reported at the annual Revolutionizing Atopic Dermatitis conference.
In March 2023, the oral Janus kinase 1 (JAK1) inhibitor was approved by the Food and Drug Administration for treating adolescents aged 12-17 with refractory moderate to severe AD – an expanded indication from the approval in adults in 2022.
The new analysis evaluated data from patients who participated in the phase 3 JADE clinical trials – MONO-1, MONO-2, TEEN, and REGIMEN – and were subsequently enrolled in the ongoing phase 3 extension trial JADE EXTEND. Compared with a previous post hoc analysis in which adolescent patients had approximately 1 year of exposure, this updated analysis includes a sizable portion of patients with more than 96 weeks of exposure.
“We’re starting to get good numbers of [adolescents] who’ve had about 2 years of exposure,” said Dr. Eichenfield, professor of dermatology and pediatrics and vice chair of the department of dermatology at the University of California, San Diego, during a late-breaking research session.
With a data cut for this analysis of September 2021, “we haven’t seen additive long-term [adverse] effects” with longer exposures, he said. In addition, “there were no unique safety concerns related to adolescents compared to the findings observed [in an] integrated safety analysis using the same data cut in which most patients were adults.”
(The analysis in adults covered 3,802 patients with over 5,000 patient-years of exposure, and was presented at the annual American Academy of Dermatology meeting in March 2023.)
Also presented in the late-breaking abstract session at RAD 2023 was a long-term safety study of upadacitinib (Rinvoq), the other JAK1 inhibitor approved for adolescents with AD – approved by the FDA for both adolescents and adults with moderate to severe AD in 2022. The new analysis captures exposure of up to 4 years and shows no “worsening or accumulation of events,” compared with 1-year data, reported Christopher G. Bunick, MD, PhD, of the department of dermatology and the program in translational biomedicine at Yale University, New Haven, Conn.
Abrocitinib in adolescents
For the safety analysis of abrocitinib (Cibinqo), data were pooled into two cohorts: A consistent-dose cohort of 490 adolescents who received the same dose (200 mg or 100 mg) during the entire duration of the qualifying JADE trials, and a variable-dose cohort of 145 adolescents who received different doses (200 mg or 100 mg) during the JADE REGIMEN qualifying trial.
Duration of exposure was 96 weeks or more in 37%-38% of the consistent-dose cohort and 68% of the variable-dose cohort.
In the consistent-dose cohort, adverse events occurred in 243 (84%) and 153 (76%) of patients receiving 200-mg doses and 100-mg doses, respectively. Incidence rates for severe adverse events were 5.87 per 100 patient-years at both doses, and rates for adverse events leading to study discontinuation were 6.96/100 patient-years at 200 mg and 5.13/100 patient-years at 100 mg.
“No meaningful dose-response relationship was observed for serious adverse events, or adverse events leading to discontinuation, or adverse events of special interest,” said Dr. Eichenfield, also chief of pediatric and adolescent dermatology at Rady Children’s Hospital, San Diego.
The IRs of adverse events of special interest were 1.84/100 patient-years and 1.28/100 patient-years for serious infection; 2.11/100 patient-years, and 1.62/100 patient-years for all herpes zoster infections; and 0.69/100 patient-years and 0.32/100 patient-years for opportunistic herpes zoster infections in the 200-mg and 100-mg arms, respectively.
“Other than herpes zoster, there were no opportunistic infections observed and no tuberculosis cases,” he said. “There was one nonfatal venous thromboembolism in an adolescent who had a very strong family history of [pulmonary embolism], one retinal detachment [with a concurrent diagnosis of cataracts and of left eyebrow folliculitis], and no events of nonmelanoma skin cancer or other malignancies, major adverse cardiovascular events, or deaths.” The thromboembolism case was reported in the previous post hoc analysis.
In the variable-dose cohort, data were similar, Dr. Eichenfield said. The IRs for severe adverse events, adverse events leading to study withdrawal, and adverse events of special interest were consistent with those in the other cohort. And similarly, there were no reports of tuberculosis or other opportunistic infections (excluding herpes zoster), and no reports of nonmelanoma skin cancer (NMSC) or other malignancies, major adverse cardiovascular events (MACE), or death. In this cohort, there were no venous thromboembolism (VTE) reports.
Upadacitinib in adolescents, adults
The new analysis looked at up to 4 years of upadacitinib treatment in almost 2,700 adolescents and adults– and over 6,200 patient-years – using integrated data from three ongoing pivotal phase 3 studies: Measure Up 1, Measure Up 2, and AD Up. (Of these patients, 539 were adolescents, Dr. Bunick said after the meeting.)
In the Measure Up studies, patients were randomized 1:1:1 to receive a 15-mg dose, a 30-mg dose, or placebo once daily. In AD Up, patients in each arm received concomitant topical corticosteroids. At week 16, patients receiving the drug continued their assigned treatment during the ongoing blinded extension period, and those receiving placebo were rerandomized to upadacitinib 15 mg or 30 mg.
The exposure-adjusted event rates for any adverse event leading to discontinuation were 4.1/100 patient-years and 4.7/100 patient-years in patients receiving 15 mg and 30 mg, respectively, and the rates of any serious adverse event were 6.5/100 patient-years and 7.5/100 patient-years, Dr. Bunick reported. Three deaths occurred in the 30-mg group; all deaths were related to COVID infection and occurred in adults with cardiovascular risk factors.
Incidence rates of adverse events of special interest were similar to those in a previous 1-year analysis. The rate of serious infections per 100 patient years, for instance, was 2.3 and 2.8 in the 15-mg and 30-mg groups, respectively, compared with 2.2 and 2.8 in the 1-year analysis.
The rate of opportunistic infections, including eczema herpeticum (and excluding TB and herpes zoster), saw a slight bump in the new analysis to 2.4/100 patient-years with the 30-mg dose. Other event rates, across both dosages and durations, were less than 0.1/100 patient-years for active TB; 0.3-0.4/100 patient-years for NMSC, and 0.1/100 patient-years or below for other malignancies, MACE, and VTE. Herpes zoster had the highest event rate in both the 1- and 4-year analyses of between 3.1/100 patient-years and 5.8/100 patient-years, Dr. Bunick reported.
The adverse event rates for adolescents and adults “show consistency and are very low,” Dr. Bunick said. At 4 years, no new safety risks were identified.
‘The more data ... the better’
Data on the safety of new medications in children and adolescents is always important, and with systemic JAK inhibitors in particular, “the more data we can accumulate in [younger] patients with AD ... the better,” said Robert Sidbury, MD, MPH, professor in the department of pediatrics at the University of Washington, Seattle, and chief of the division of dermatology at Seattle Children’s Hospital, who was asked to comment on the two studies.
Dermatologists have taken comfort in the fact that the “daunting” boxed warning on JAK inhibitors “was generated in a very different population than we generally propose to treat, certainly when talking about children and adolescents,” said Dr. Sidbury, who was not involved in either of the new safety analyses.
The JAK inhibitor boxed warning “reflects a study of tofacitinib – a different JAK inhibitor with arguably more risk of adverse effects – in adults over the age of 50 with rheumatoid arthritis and multiple risk factors for comorbidities included in the boxed warning,” he said.
“This allows dermatologists to reasonably conclude that the boxed warning – while critical to discuss and consider in every patient – is likely less concerning than might otherwise by implied.”
With more patient experience, “the more our assessment of risk, and of the ‘legitimacy’ of the boxed warning in our patient population, becomes evidence-based as opposed to extrapolation,” Dr. Sidbury said.
The two studies reported, he said, “detail an experience that is not adverse effect free –I have yet to find that medication – but is a reasonable profile considering the robust efficacy results they accompany.”
The abrocitinib safety analysis was sponsored by Pfizer. Regarding the study of upadacitinib, AbbVie contributed to the design of the safety analysis and participated in data collection. No honoria or payments were made to the authors, according to the study abstract. Dr. Eichenfield is a consultant/advisory board member for Pfizer and other companies, and has served on the speakers bureau/received honoria for Pfizer and other companies. Dr. Bunick is a consultant for AbbVie and other companies, and has served as an speaker/received honoraria or served as an investigator for several companies. Dr. Sidbury disclosed being a consultant/advisory board member for Lilly and Leo and serving on the speakers bureau/honoraria for Beiersdorf. All reported receiving grant/research support from various companies.
AT RAD 2023
AD in infancy: Diagnostic advice and treatment tips
WASHINGTON – mean it is often “woefully undertreated,” Robert Sidbury, MD, MPH, said at the annual Revolutionizing Atopic Dermatitis conference.
Identifying and mitigating triggers – such as irritation, contact allergy, and infection – is a cornerstone of treatment in infants, but tailored therapy with topical corticosteroids, topical calcineurin inhibitors (TCIs), and topical phosphodiesterase 4 (PDE4) inhibitors also have roles to play, said Dr. Sidbury, chief of dermatology at Seattle Children’s Hospital and professor in the department of pediatrics at the University of Washington, Seattle.
Views on the use of dupilumab as a systemic agent for severe infantile AD, meanwhile, have shifted significantly in the past year with the Food and Drug Administration approval of the biologic for children aged 6 months to 5 years and with extended experience with the biologic in all ages, including children, Lawrence F. Eichenfield, MD, professor of dermatology and pediatrics at the University of California, San Diego, said at the meeting.
The pediatric dermatologists spoke during a session devoted to AD in infants, during which the diagnosis of AD and the role – and risks – of food allergy testing were also discussed. Diagnosis, said Elaine C. Siegfried, MD, who also spoke during the session, requires careful consideration of mimicking conditions and a broader list of differential diagnoses in those infants with poor growth or frequent infections.
Here are some of the experts’ pearls for practice.
Diagnosing AD in infants
Among infants who are growing well and otherwise healthy, the infantile eczema phenotype encompasses AD, seborrheic dermatitis, contact dermatitis, psoriasis – and overlap of more than one of these conditions. “Overlap is common,” said Dr. Siegfried, professor of pediatrics and dermatology at Saint Louis University, and director of the division of pediatric dermatology at Cardinal Glennon Children’s Hospital.
(Initial topical treatment for all these conditions is similar, but optimal treatment may differ for young children with moderate to severe disease that requires systemic treatment, she said in an interview after the meeting.)
Sparing of the diaper area that reflects skin barrier integrity is a classic feature of AD in infants and can be a useful diagnostic sign. In addition, “hypopigmentation is more characteristic of psoriasis” than AD, whereas AD tends to be hyperpigmented, which is most obvious in skin-of-color patients, Dr. Siegfried said.
Disease-specific pigment changes may be related to microbial colonization – such as Malassezia-associated hypopigmentation – or cell turnover, which is faster in psoriasis and slower in AD – with corresponding differences in pigment retention, and may be more obvious in children than adults, she said.
A less common scenario is dermatitis in infants who are not growing well. For these patients, she noted, the differential diagnosis includes metabolic or immune deficiency dermatitis as well as a variety of genodermatoses.
Generalized redness and scaling present on the first day of life is suggestive of non-atopic dermatitis. “If you’re born with red scaly skin, that’s very different than if you develop red skin in the first month or two of life,” Dr. Siegfried said.
When there is diaper area involvement with AD, contact dermatitis, impetigo, and Candida may be complicating factors. And in infants with other morbidities – especially those who are not growing well – diaper area involvement suggests a broader differential diagnosis. “I implore you, if you see children, make sure you weigh and measure them at every appointment,” she said.
Dr. Siegfried has seen infants with Netherton syndrome, and those with cystic fibrosis with zinc deficiency, for instance, presenting with “an eczematous-like picture,” diaper-area involvement, and other morbidities.
For infants with AD, she maintains a high index of suspicion for secondary infections such as molluscum, herpes simplex virus (HSV) with or without streptococci, scabies, tinea, and group A streptococci. “Secondary infections ... may be incognito,” she said. “Look for subtle signs. Even molluscum can be very subtle.”
Secondary allergic contact dermatitis is also common although it’s “technically difficult to confirm the diagnosis,” she said. Patch testing in infants is technically challenging, sensitivity is low, and monosensitization is uncommon. “So I do initial empiric topical allergen avoidance,” she said, keeping in mind ubiquitous and avoidable topical allergens such as Kathon, cocamidopropyl betaine, propylene glycol, disperse blue, and adhesives.
Treating AD in infancy
Irritation “is probably one of the biggest triggers” of AD in infants, and the often “pristine” diaper area compared with inflamed eczema elsewhere can demonstrate the importance of moisturization for healthy skin in atopic infants, Dr. Sidbury said.
Among treatments that “punch above their weight” for AD in infants is an ointment-based barrier applied around the mouth, chin, and chest – where the wet/dry impact of drooling is maximal – before and after meals, he said.
Another is hydrocortisone 2.5% mixed 1:1 with mupirocin for those infants who have secondary infections and “that exudative, weepy-looking appearance on the face,” he said. The topical antibiotic in the combination cream “lessens the potency of the steroid and oftentimes by synergy, makes it more effective” by simultaneously treating inflammation, he said. He cautions against products containing neomycin, which can be an allergen.
A combination antibiotic-steroid-emollient cream (the Aron Regimen) can also “sometimes punch above its weight,” Dr. Sidbury said.
Infections typically involve Staphylococcus aureus, but in up to 16% of cases Streptococcus is involved. And notably, lurking underneath the honey-colored crusting of S. aureus infections may be the grouped vesicles that characterize eczema herpeticum, Dr. Sidbury said.
“Counsel [parents] preemptively to treat cold sores immediately [in order to] decrease HSV shedding and minimize risk to their baby,” Dr. Sidbury said.
For treating AD-associated inflammation in skin not affected by secondary infections, over-the-counter 1% hydrocortisone cream is often sufficient, and “for very young babies and preemies in particular, I generally don’t use anything stronger because their skin barrier isn’t fully complete yet, so they absorb more than an older child does,” he said, referring to ages 2 months corrected as a marker for considering a stronger formulation if needed.
Many parents are “very concerned” about topical corticosteroid (TCS) use and pediatricians are also “often concerned,” Dr. Sidbury said. Addressing this concern, he tries to provide context and promote adherence by pointing out that infants have an easily visible vein at the temple area where the skin is naturally thin. If parents were to see this appearance for the first time in other areas while using topical steroids, he tells them, it may be the first sign of skin thinning, but “it’s entirely reversible at that stage.”
He also stressed the cost of not treating. It’s unknown whether “treating aggressively early on prevents any future development or manifestation of eczema, or future comorbidities, but we don’t know that it doesn’t,” Dr. Sidbury said. “And we certainly know how miserable that baby with eczema can be in the short term. So we need to use these medicines.”
Dr. Sidbury utilizes tacrolimus 0.03% ointment, a topical calcineurin inhibitor (TCI), only if he is worried about overuse of steroids, and uses a regimen that alternates the TCI (used in infants off-label because it is approved for ages 2 years and older) with TCS in periods of similar duration (for example, treatment with TCS for 1 week and TCI for 1 week, or rotations of 2 weeks each or 3 days each). “And these rotations may be dynamic depending on severity of the flare at any given time,” he said after the meeting.
Preapproval data from the pivotal trials of tacrolimus are reassuring and can be shared with parents. “Two-year-olds had 90% of BSA [body surface area] treated for 12 weeks” with no signs of systemic risks, Dr. Sidbury said at the meeting.
Crisaborole, a topical phosphodiesterase 4 (PDE4) inhibitor approved for AD down to age 3 months, does not, like tacrolimus, have a boxed warning about a possible risk for cancer, and may also be alternated with TCSs. It will cause stinging in some children, but TCSs and TCIs can also sting in some children, he said, noting that samples can be helpful to predict what will or won’t sting each infant.
Systemic treatment in infants
The Liberty AD PRESCHOOL phase 3 trial that supported the FDA’s approval of dupilumab down to 6 months of age, published in 2022 in The Lancet, covered ages 6 months to 5 years but included only six children under the age of 2, “leaving us with a very limited dataset in this age group,” Dr. Eichenfield said at the meeting.
Other data and analyses that have provided reassurance, such as a laboratory safety analysis published online in 2022 showing no meaningful changes in laboratory safety parameters in children as young as 6 months, and pediatric data (not including infants) presented at a RAD meeting in 2022 showing that dupilumab, an interleukin-4 receptor alpha antagonist, may have positive effects on bone mineral density.
Data from the Liberty AD PRESCHOOL open-label extension study presented at the American Academy of Dermatology meeting in 2023, meanwhile, show that “the adverse event profile is not looking much different than what we see in older children,” Dr. Eichenfield said. “There are low rates of severe adverse events and a very low rate of discontinuations.”
At Rady Children’s Hospital, where Dr. Eichenfield is chief of pediatric and adolescent dermatology, dupilumab has become a first-line systemic agent for severe infantile AD, supplanting prior traditional but little used systemic agents such as oral corticosteroids, cyclosporine, methotrexate, azathioprine, or mycophenolate, he said after the meeting.
The decision to use systemics in the first 2 years of life is “a comprehensive one,” requiring knowledge of the child’s history, disease course, and assessment of response to prior therapies, comorbidities and severity, he said.
Food allergy in infants with AD
Food allergy is common in children with moderate to severe AD, but true food-triggered AD, with AD being the only symptom of food allergy, is rare, said Anne Marie Singh, MD, associate professor in the division of allergy and immunology and rheumatology at the University of Wisconsin, Madison, who focuses on pediatrics.
Over the years, studies of double-blind placebo-controlled food challenge tests in children with AD have tended to conflate immediate IgE hypersensitivity (and skin symptoms like urticaria) with AD, said Dr. Singh, who directs the university’s Food Allergy Research and Education Center of Excellence. In a recently published study she led involving 374 children with AD referred to allergy and/or dermatology subspecialty clinics at the University of Wisconsin, Madison, 55% had a food allergy but only 2% had food-triggered AD “where eczema is the only symptom and removal of the food cleared up the eczema and its return brought it back,” Dr. Singh said at the meeting. Another 4% had combined IgE-mediated food allergy and food-triggered AD. Almost half of the children with food-triggered AD were under 1 year of age, and egg was the most common trigger, she noted.
Food should be implicated largely by history, Dr. Singh emphasized.
Food allergy testing in the context of AD can be done but is challenging, with the clinical relevance of skin prick testing and food-specific immunoglobulin E (sIgE) difficult to predict. Predictive values of sIgE levels are established for immediate IgE mediated food allergy, but “cut-offs” for food-triggered AD are not established, she explained, noting that “cut-offs are likely higher for our children with AD.”
Elimination diets, moreover, pose significant risks of future oral tolerance and risks of nutritional deficiencies and poor growth, Dr. Singh said. New and immediate reactions to foods that are reintroduced after an elimination diet are common, and research has shown that 20% or more of such reactions involve anaphylaxis. “If an elimination diet is undertaken, you need emergency action plans, injectable epinephrine, and nutrition counseling,” she said.
A recent systematic review and meta-analysis conditionally recommended against elimination diets for the treatment of AD, Dr. Singh noted.
Asked by Dr. Sidbury whether there “is a sweet spot where you can eliminate [foods] without going all the way,” Dr. Singh said she will sometimes do a “diagnostic elimination trial” with food elimination for 2-4 weeks only – a time period after which “I’ll feel really comfortable reintroducing the food.”
Dr. Singh urged dermatologists to “know your allergist” because “patients respond best with a consistent message.”
Dr. Sidbury reported ties with Regeneron, UCB, Pfizer, Leo Pharma, Lilly, and Beiersdorf. Dr. Siegfried reported ties with Pfizer, Regeneron, Sanofi Genzyme, Pfizer, UCB, Novan and Leo Pharma. Dr. Singh reported ties with Incyte and Siolta Therapeutics. Dr. Eichenfield reported ties with Pfizer, Regeneron, Sanofi Genzyme, Incyte, and Pfizer.
WASHINGTON – mean it is often “woefully undertreated,” Robert Sidbury, MD, MPH, said at the annual Revolutionizing Atopic Dermatitis conference.
Identifying and mitigating triggers – such as irritation, contact allergy, and infection – is a cornerstone of treatment in infants, but tailored therapy with topical corticosteroids, topical calcineurin inhibitors (TCIs), and topical phosphodiesterase 4 (PDE4) inhibitors also have roles to play, said Dr. Sidbury, chief of dermatology at Seattle Children’s Hospital and professor in the department of pediatrics at the University of Washington, Seattle.
Views on the use of dupilumab as a systemic agent for severe infantile AD, meanwhile, have shifted significantly in the past year with the Food and Drug Administration approval of the biologic for children aged 6 months to 5 years and with extended experience with the biologic in all ages, including children, Lawrence F. Eichenfield, MD, professor of dermatology and pediatrics at the University of California, San Diego, said at the meeting.
The pediatric dermatologists spoke during a session devoted to AD in infants, during which the diagnosis of AD and the role – and risks – of food allergy testing were also discussed. Diagnosis, said Elaine C. Siegfried, MD, who also spoke during the session, requires careful consideration of mimicking conditions and a broader list of differential diagnoses in those infants with poor growth or frequent infections.
Here are some of the experts’ pearls for practice.
Diagnosing AD in infants
Among infants who are growing well and otherwise healthy, the infantile eczema phenotype encompasses AD, seborrheic dermatitis, contact dermatitis, psoriasis – and overlap of more than one of these conditions. “Overlap is common,” said Dr. Siegfried, professor of pediatrics and dermatology at Saint Louis University, and director of the division of pediatric dermatology at Cardinal Glennon Children’s Hospital.
(Initial topical treatment for all these conditions is similar, but optimal treatment may differ for young children with moderate to severe disease that requires systemic treatment, she said in an interview after the meeting.)
Sparing of the diaper area that reflects skin barrier integrity is a classic feature of AD in infants and can be a useful diagnostic sign. In addition, “hypopigmentation is more characteristic of psoriasis” than AD, whereas AD tends to be hyperpigmented, which is most obvious in skin-of-color patients, Dr. Siegfried said.
Disease-specific pigment changes may be related to microbial colonization – such as Malassezia-associated hypopigmentation – or cell turnover, which is faster in psoriasis and slower in AD – with corresponding differences in pigment retention, and may be more obvious in children than adults, she said.
A less common scenario is dermatitis in infants who are not growing well. For these patients, she noted, the differential diagnosis includes metabolic or immune deficiency dermatitis as well as a variety of genodermatoses.
Generalized redness and scaling present on the first day of life is suggestive of non-atopic dermatitis. “If you’re born with red scaly skin, that’s very different than if you develop red skin in the first month or two of life,” Dr. Siegfried said.
When there is diaper area involvement with AD, contact dermatitis, impetigo, and Candida may be complicating factors. And in infants with other morbidities – especially those who are not growing well – diaper area involvement suggests a broader differential diagnosis. “I implore you, if you see children, make sure you weigh and measure them at every appointment,” she said.
Dr. Siegfried has seen infants with Netherton syndrome, and those with cystic fibrosis with zinc deficiency, for instance, presenting with “an eczematous-like picture,” diaper-area involvement, and other morbidities.
For infants with AD, she maintains a high index of suspicion for secondary infections such as molluscum, herpes simplex virus (HSV) with or without streptococci, scabies, tinea, and group A streptococci. “Secondary infections ... may be incognito,” she said. “Look for subtle signs. Even molluscum can be very subtle.”
Secondary allergic contact dermatitis is also common although it’s “technically difficult to confirm the diagnosis,” she said. Patch testing in infants is technically challenging, sensitivity is low, and monosensitization is uncommon. “So I do initial empiric topical allergen avoidance,” she said, keeping in mind ubiquitous and avoidable topical allergens such as Kathon, cocamidopropyl betaine, propylene glycol, disperse blue, and adhesives.
Treating AD in infancy
Irritation “is probably one of the biggest triggers” of AD in infants, and the often “pristine” diaper area compared with inflamed eczema elsewhere can demonstrate the importance of moisturization for healthy skin in atopic infants, Dr. Sidbury said.
Among treatments that “punch above their weight” for AD in infants is an ointment-based barrier applied around the mouth, chin, and chest – where the wet/dry impact of drooling is maximal – before and after meals, he said.
Another is hydrocortisone 2.5% mixed 1:1 with mupirocin for those infants who have secondary infections and “that exudative, weepy-looking appearance on the face,” he said. The topical antibiotic in the combination cream “lessens the potency of the steroid and oftentimes by synergy, makes it more effective” by simultaneously treating inflammation, he said. He cautions against products containing neomycin, which can be an allergen.
A combination antibiotic-steroid-emollient cream (the Aron Regimen) can also “sometimes punch above its weight,” Dr. Sidbury said.
Infections typically involve Staphylococcus aureus, but in up to 16% of cases Streptococcus is involved. And notably, lurking underneath the honey-colored crusting of S. aureus infections may be the grouped vesicles that characterize eczema herpeticum, Dr. Sidbury said.
“Counsel [parents] preemptively to treat cold sores immediately [in order to] decrease HSV shedding and minimize risk to their baby,” Dr. Sidbury said.
For treating AD-associated inflammation in skin not affected by secondary infections, over-the-counter 1% hydrocortisone cream is often sufficient, and “for very young babies and preemies in particular, I generally don’t use anything stronger because their skin barrier isn’t fully complete yet, so they absorb more than an older child does,” he said, referring to ages 2 months corrected as a marker for considering a stronger formulation if needed.
Many parents are “very concerned” about topical corticosteroid (TCS) use and pediatricians are also “often concerned,” Dr. Sidbury said. Addressing this concern, he tries to provide context and promote adherence by pointing out that infants have an easily visible vein at the temple area where the skin is naturally thin. If parents were to see this appearance for the first time in other areas while using topical steroids, he tells them, it may be the first sign of skin thinning, but “it’s entirely reversible at that stage.”
He also stressed the cost of not treating. It’s unknown whether “treating aggressively early on prevents any future development or manifestation of eczema, or future comorbidities, but we don’t know that it doesn’t,” Dr. Sidbury said. “And we certainly know how miserable that baby with eczema can be in the short term. So we need to use these medicines.”
Dr. Sidbury utilizes tacrolimus 0.03% ointment, a topical calcineurin inhibitor (TCI), only if he is worried about overuse of steroids, and uses a regimen that alternates the TCI (used in infants off-label because it is approved for ages 2 years and older) with TCS in periods of similar duration (for example, treatment with TCS for 1 week and TCI for 1 week, or rotations of 2 weeks each or 3 days each). “And these rotations may be dynamic depending on severity of the flare at any given time,” he said after the meeting.
Preapproval data from the pivotal trials of tacrolimus are reassuring and can be shared with parents. “Two-year-olds had 90% of BSA [body surface area] treated for 12 weeks” with no signs of systemic risks, Dr. Sidbury said at the meeting.
Crisaborole, a topical phosphodiesterase 4 (PDE4) inhibitor approved for AD down to age 3 months, does not, like tacrolimus, have a boxed warning about a possible risk for cancer, and may also be alternated with TCSs. It will cause stinging in some children, but TCSs and TCIs can also sting in some children, he said, noting that samples can be helpful to predict what will or won’t sting each infant.
Systemic treatment in infants
The Liberty AD PRESCHOOL phase 3 trial that supported the FDA’s approval of dupilumab down to 6 months of age, published in 2022 in The Lancet, covered ages 6 months to 5 years but included only six children under the age of 2, “leaving us with a very limited dataset in this age group,” Dr. Eichenfield said at the meeting.
Other data and analyses that have provided reassurance, such as a laboratory safety analysis published online in 2022 showing no meaningful changes in laboratory safety parameters in children as young as 6 months, and pediatric data (not including infants) presented at a RAD meeting in 2022 showing that dupilumab, an interleukin-4 receptor alpha antagonist, may have positive effects on bone mineral density.
Data from the Liberty AD PRESCHOOL open-label extension study presented at the American Academy of Dermatology meeting in 2023, meanwhile, show that “the adverse event profile is not looking much different than what we see in older children,” Dr. Eichenfield said. “There are low rates of severe adverse events and a very low rate of discontinuations.”
At Rady Children’s Hospital, where Dr. Eichenfield is chief of pediatric and adolescent dermatology, dupilumab has become a first-line systemic agent for severe infantile AD, supplanting prior traditional but little used systemic agents such as oral corticosteroids, cyclosporine, methotrexate, azathioprine, or mycophenolate, he said after the meeting.
The decision to use systemics in the first 2 years of life is “a comprehensive one,” requiring knowledge of the child’s history, disease course, and assessment of response to prior therapies, comorbidities and severity, he said.
Food allergy in infants with AD
Food allergy is common in children with moderate to severe AD, but true food-triggered AD, with AD being the only symptom of food allergy, is rare, said Anne Marie Singh, MD, associate professor in the division of allergy and immunology and rheumatology at the University of Wisconsin, Madison, who focuses on pediatrics.
Over the years, studies of double-blind placebo-controlled food challenge tests in children with AD have tended to conflate immediate IgE hypersensitivity (and skin symptoms like urticaria) with AD, said Dr. Singh, who directs the university’s Food Allergy Research and Education Center of Excellence. In a recently published study she led involving 374 children with AD referred to allergy and/or dermatology subspecialty clinics at the University of Wisconsin, Madison, 55% had a food allergy but only 2% had food-triggered AD “where eczema is the only symptom and removal of the food cleared up the eczema and its return brought it back,” Dr. Singh said at the meeting. Another 4% had combined IgE-mediated food allergy and food-triggered AD. Almost half of the children with food-triggered AD were under 1 year of age, and egg was the most common trigger, she noted.
Food should be implicated largely by history, Dr. Singh emphasized.
Food allergy testing in the context of AD can be done but is challenging, with the clinical relevance of skin prick testing and food-specific immunoglobulin E (sIgE) difficult to predict. Predictive values of sIgE levels are established for immediate IgE mediated food allergy, but “cut-offs” for food-triggered AD are not established, she explained, noting that “cut-offs are likely higher for our children with AD.”
Elimination diets, moreover, pose significant risks of future oral tolerance and risks of nutritional deficiencies and poor growth, Dr. Singh said. New and immediate reactions to foods that are reintroduced after an elimination diet are common, and research has shown that 20% or more of such reactions involve anaphylaxis. “If an elimination diet is undertaken, you need emergency action plans, injectable epinephrine, and nutrition counseling,” she said.
A recent systematic review and meta-analysis conditionally recommended against elimination diets for the treatment of AD, Dr. Singh noted.
Asked by Dr. Sidbury whether there “is a sweet spot where you can eliminate [foods] without going all the way,” Dr. Singh said she will sometimes do a “diagnostic elimination trial” with food elimination for 2-4 weeks only – a time period after which “I’ll feel really comfortable reintroducing the food.”
Dr. Singh urged dermatologists to “know your allergist” because “patients respond best with a consistent message.”
Dr. Sidbury reported ties with Regeneron, UCB, Pfizer, Leo Pharma, Lilly, and Beiersdorf. Dr. Siegfried reported ties with Pfizer, Regeneron, Sanofi Genzyme, Pfizer, UCB, Novan and Leo Pharma. Dr. Singh reported ties with Incyte and Siolta Therapeutics. Dr. Eichenfield reported ties with Pfizer, Regeneron, Sanofi Genzyme, Incyte, and Pfizer.
WASHINGTON – mean it is often “woefully undertreated,” Robert Sidbury, MD, MPH, said at the annual Revolutionizing Atopic Dermatitis conference.
Identifying and mitigating triggers – such as irritation, contact allergy, and infection – is a cornerstone of treatment in infants, but tailored therapy with topical corticosteroids, topical calcineurin inhibitors (TCIs), and topical phosphodiesterase 4 (PDE4) inhibitors also have roles to play, said Dr. Sidbury, chief of dermatology at Seattle Children’s Hospital and professor in the department of pediatrics at the University of Washington, Seattle.
Views on the use of dupilumab as a systemic agent for severe infantile AD, meanwhile, have shifted significantly in the past year with the Food and Drug Administration approval of the biologic for children aged 6 months to 5 years and with extended experience with the biologic in all ages, including children, Lawrence F. Eichenfield, MD, professor of dermatology and pediatrics at the University of California, San Diego, said at the meeting.
The pediatric dermatologists spoke during a session devoted to AD in infants, during which the diagnosis of AD and the role – and risks – of food allergy testing were also discussed. Diagnosis, said Elaine C. Siegfried, MD, who also spoke during the session, requires careful consideration of mimicking conditions and a broader list of differential diagnoses in those infants with poor growth or frequent infections.
Here are some of the experts’ pearls for practice.
Diagnosing AD in infants
Among infants who are growing well and otherwise healthy, the infantile eczema phenotype encompasses AD, seborrheic dermatitis, contact dermatitis, psoriasis – and overlap of more than one of these conditions. “Overlap is common,” said Dr. Siegfried, professor of pediatrics and dermatology at Saint Louis University, and director of the division of pediatric dermatology at Cardinal Glennon Children’s Hospital.
(Initial topical treatment for all these conditions is similar, but optimal treatment may differ for young children with moderate to severe disease that requires systemic treatment, she said in an interview after the meeting.)
Sparing of the diaper area that reflects skin barrier integrity is a classic feature of AD in infants and can be a useful diagnostic sign. In addition, “hypopigmentation is more characteristic of psoriasis” than AD, whereas AD tends to be hyperpigmented, which is most obvious in skin-of-color patients, Dr. Siegfried said.
Disease-specific pigment changes may be related to microbial colonization – such as Malassezia-associated hypopigmentation – or cell turnover, which is faster in psoriasis and slower in AD – with corresponding differences in pigment retention, and may be more obvious in children than adults, she said.
A less common scenario is dermatitis in infants who are not growing well. For these patients, she noted, the differential diagnosis includes metabolic or immune deficiency dermatitis as well as a variety of genodermatoses.
Generalized redness and scaling present on the first day of life is suggestive of non-atopic dermatitis. “If you’re born with red scaly skin, that’s very different than if you develop red skin in the first month or two of life,” Dr. Siegfried said.
When there is diaper area involvement with AD, contact dermatitis, impetigo, and Candida may be complicating factors. And in infants with other morbidities – especially those who are not growing well – diaper area involvement suggests a broader differential diagnosis. “I implore you, if you see children, make sure you weigh and measure them at every appointment,” she said.
Dr. Siegfried has seen infants with Netherton syndrome, and those with cystic fibrosis with zinc deficiency, for instance, presenting with “an eczematous-like picture,” diaper-area involvement, and other morbidities.
For infants with AD, she maintains a high index of suspicion for secondary infections such as molluscum, herpes simplex virus (HSV) with or without streptococci, scabies, tinea, and group A streptococci. “Secondary infections ... may be incognito,” she said. “Look for subtle signs. Even molluscum can be very subtle.”
Secondary allergic contact dermatitis is also common although it’s “technically difficult to confirm the diagnosis,” she said. Patch testing in infants is technically challenging, sensitivity is low, and monosensitization is uncommon. “So I do initial empiric topical allergen avoidance,” she said, keeping in mind ubiquitous and avoidable topical allergens such as Kathon, cocamidopropyl betaine, propylene glycol, disperse blue, and adhesives.
Treating AD in infancy
Irritation “is probably one of the biggest triggers” of AD in infants, and the often “pristine” diaper area compared with inflamed eczema elsewhere can demonstrate the importance of moisturization for healthy skin in atopic infants, Dr. Sidbury said.
Among treatments that “punch above their weight” for AD in infants is an ointment-based barrier applied around the mouth, chin, and chest – where the wet/dry impact of drooling is maximal – before and after meals, he said.
Another is hydrocortisone 2.5% mixed 1:1 with mupirocin for those infants who have secondary infections and “that exudative, weepy-looking appearance on the face,” he said. The topical antibiotic in the combination cream “lessens the potency of the steroid and oftentimes by synergy, makes it more effective” by simultaneously treating inflammation, he said. He cautions against products containing neomycin, which can be an allergen.
A combination antibiotic-steroid-emollient cream (the Aron Regimen) can also “sometimes punch above its weight,” Dr. Sidbury said.
Infections typically involve Staphylococcus aureus, but in up to 16% of cases Streptococcus is involved. And notably, lurking underneath the honey-colored crusting of S. aureus infections may be the grouped vesicles that characterize eczema herpeticum, Dr. Sidbury said.
“Counsel [parents] preemptively to treat cold sores immediately [in order to] decrease HSV shedding and minimize risk to their baby,” Dr. Sidbury said.
For treating AD-associated inflammation in skin not affected by secondary infections, over-the-counter 1% hydrocortisone cream is often sufficient, and “for very young babies and preemies in particular, I generally don’t use anything stronger because their skin barrier isn’t fully complete yet, so they absorb more than an older child does,” he said, referring to ages 2 months corrected as a marker for considering a stronger formulation if needed.
Many parents are “very concerned” about topical corticosteroid (TCS) use and pediatricians are also “often concerned,” Dr. Sidbury said. Addressing this concern, he tries to provide context and promote adherence by pointing out that infants have an easily visible vein at the temple area where the skin is naturally thin. If parents were to see this appearance for the first time in other areas while using topical steroids, he tells them, it may be the first sign of skin thinning, but “it’s entirely reversible at that stage.”
He also stressed the cost of not treating. It’s unknown whether “treating aggressively early on prevents any future development or manifestation of eczema, or future comorbidities, but we don’t know that it doesn’t,” Dr. Sidbury said. “And we certainly know how miserable that baby with eczema can be in the short term. So we need to use these medicines.”
Dr. Sidbury utilizes tacrolimus 0.03% ointment, a topical calcineurin inhibitor (TCI), only if he is worried about overuse of steroids, and uses a regimen that alternates the TCI (used in infants off-label because it is approved for ages 2 years and older) with TCS in periods of similar duration (for example, treatment with TCS for 1 week and TCI for 1 week, or rotations of 2 weeks each or 3 days each). “And these rotations may be dynamic depending on severity of the flare at any given time,” he said after the meeting.
Preapproval data from the pivotal trials of tacrolimus are reassuring and can be shared with parents. “Two-year-olds had 90% of BSA [body surface area] treated for 12 weeks” with no signs of systemic risks, Dr. Sidbury said at the meeting.
Crisaborole, a topical phosphodiesterase 4 (PDE4) inhibitor approved for AD down to age 3 months, does not, like tacrolimus, have a boxed warning about a possible risk for cancer, and may also be alternated with TCSs. It will cause stinging in some children, but TCSs and TCIs can also sting in some children, he said, noting that samples can be helpful to predict what will or won’t sting each infant.
Systemic treatment in infants
The Liberty AD PRESCHOOL phase 3 trial that supported the FDA’s approval of dupilumab down to 6 months of age, published in 2022 in The Lancet, covered ages 6 months to 5 years but included only six children under the age of 2, “leaving us with a very limited dataset in this age group,” Dr. Eichenfield said at the meeting.
Other data and analyses that have provided reassurance, such as a laboratory safety analysis published online in 2022 showing no meaningful changes in laboratory safety parameters in children as young as 6 months, and pediatric data (not including infants) presented at a RAD meeting in 2022 showing that dupilumab, an interleukin-4 receptor alpha antagonist, may have positive effects on bone mineral density.
Data from the Liberty AD PRESCHOOL open-label extension study presented at the American Academy of Dermatology meeting in 2023, meanwhile, show that “the adverse event profile is not looking much different than what we see in older children,” Dr. Eichenfield said. “There are low rates of severe adverse events and a very low rate of discontinuations.”
At Rady Children’s Hospital, where Dr. Eichenfield is chief of pediatric and adolescent dermatology, dupilumab has become a first-line systemic agent for severe infantile AD, supplanting prior traditional but little used systemic agents such as oral corticosteroids, cyclosporine, methotrexate, azathioprine, or mycophenolate, he said after the meeting.
The decision to use systemics in the first 2 years of life is “a comprehensive one,” requiring knowledge of the child’s history, disease course, and assessment of response to prior therapies, comorbidities and severity, he said.
Food allergy in infants with AD
Food allergy is common in children with moderate to severe AD, but true food-triggered AD, with AD being the only symptom of food allergy, is rare, said Anne Marie Singh, MD, associate professor in the division of allergy and immunology and rheumatology at the University of Wisconsin, Madison, who focuses on pediatrics.
Over the years, studies of double-blind placebo-controlled food challenge tests in children with AD have tended to conflate immediate IgE hypersensitivity (and skin symptoms like urticaria) with AD, said Dr. Singh, who directs the university’s Food Allergy Research and Education Center of Excellence. In a recently published study she led involving 374 children with AD referred to allergy and/or dermatology subspecialty clinics at the University of Wisconsin, Madison, 55% had a food allergy but only 2% had food-triggered AD “where eczema is the only symptom and removal of the food cleared up the eczema and its return brought it back,” Dr. Singh said at the meeting. Another 4% had combined IgE-mediated food allergy and food-triggered AD. Almost half of the children with food-triggered AD were under 1 year of age, and egg was the most common trigger, she noted.
Food should be implicated largely by history, Dr. Singh emphasized.
Food allergy testing in the context of AD can be done but is challenging, with the clinical relevance of skin prick testing and food-specific immunoglobulin E (sIgE) difficult to predict. Predictive values of sIgE levels are established for immediate IgE mediated food allergy, but “cut-offs” for food-triggered AD are not established, she explained, noting that “cut-offs are likely higher for our children with AD.”
Elimination diets, moreover, pose significant risks of future oral tolerance and risks of nutritional deficiencies and poor growth, Dr. Singh said. New and immediate reactions to foods that are reintroduced after an elimination diet are common, and research has shown that 20% or more of such reactions involve anaphylaxis. “If an elimination diet is undertaken, you need emergency action plans, injectable epinephrine, and nutrition counseling,” she said.
A recent systematic review and meta-analysis conditionally recommended against elimination diets for the treatment of AD, Dr. Singh noted.
Asked by Dr. Sidbury whether there “is a sweet spot where you can eliminate [foods] without going all the way,” Dr. Singh said she will sometimes do a “diagnostic elimination trial” with food elimination for 2-4 weeks only – a time period after which “I’ll feel really comfortable reintroducing the food.”
Dr. Singh urged dermatologists to “know your allergist” because “patients respond best with a consistent message.”
Dr. Sidbury reported ties with Regeneron, UCB, Pfizer, Leo Pharma, Lilly, and Beiersdorf. Dr. Siegfried reported ties with Pfizer, Regeneron, Sanofi Genzyme, Pfizer, UCB, Novan and Leo Pharma. Dr. Singh reported ties with Incyte and Siolta Therapeutics. Dr. Eichenfield reported ties with Pfizer, Regeneron, Sanofi Genzyme, Incyte, and Pfizer.
AT RAD 2023
Facial, hand, and foot dermatitis: Lebrikizumab and dupilumab show efficacy in new studies
in a secondary analysis of randomized, double-blind, placebo-controlled phase 3 trials of the drug, Jenny E. Murase, MD, reported at the annual Revolutionizing Atopic Dermatitis conference.
At week 16 in the ADvocate 1, ADvocate 2, and ADhere trials, with and without concomitant topical corticosteroid (TCS) use, at least 58% of treated patients experienced improvement in facial dermatitis, and 62% or more experienced improvement in hand dermatitis – statistically significant differences over placebo.
“Lebrikizumab was efficacious in clearing and improving facial and hand dermatitis, burdensome and difficult-to-treat areas, in most patients with moderate to severe AD,” said Dr. Murase, of the department of dermatology at the University of California, San Francisco, and director of medical dermatology consultative services and patch testing for the Palo Alto (Calf.) Foundation Medical Group.
In another late-breaking abstract presented at the RAD conference, the injectable biologic dupilumab – now in its 6th year on the market – was reported by Jonathan I. Silverberg, MD, PhD, MPH, to “rapidly and significantly” improve the signs, symptoms, and quality of life in some adults and adolescents with moderate to severe hand and foot AD in a recently completed phase 3 trial of dupilumab.
Lebrikizumab results for facial, hand dermatitis
The ADvocate 1 and ADvocate 2 trials evaluated lebrikizumab monotherapy and randomized patients to receive 250 mg subcutaneously every 2 weeks (after a 500-mg loading dose at baseline and week 2) or placebo. (Patients who received any corticosteroid as a rescue medication were considered nonresponders.) The ADhere trial compared low to mid–potency TCS plus lebrikizumab, using the same dosing of lebrikizumab as in the ADvocate studies, versus TCS plus placebo.
In all three trials, with a total of more than 1,000 participants, clinicians assessed for the presence or absence of facial or hand dermatitis at baseline. At week 16, they then assessed the change from baseline based on a 4-point scale of cleared, improved, no change, and worsened. “Improvement” was defined as cleared or improved.
Both facial and hand dermatitis were identified in a majority of patients at baseline. For instance, in ADvocate 1, facial dermatitis was identified in 71.4% of patients in the lebrikizumab group and 80.9% of those in the placebo group. Hand dermatitis was identified in 72% and 73% of the treatment and placebo groups, respectively.
Across the trials, at 16 weeks, 58%-69% of adult and adolescent patients receiving lebrikizumab had improvement in facial dermatitis, compared with 22%-46% on placebo. For hand dermatitis, 62%-73% experienced improvement, compared with 19%-43% on placebo, respectively. Proportions of improved patients in both the lebrikizumab and placebo groups were highest in the ADhere trial, Dr. Murase reported.
In the ADvocate trials, 16 weeks marked the end of the induction phase and the start of a 36-week maintenance period. The ADhere trial was a 16-week study. Overall results from ADhere were published in January in JAMA Dermatology, and results from the 16-week induction period of the ADvocate trials were published in March in the New England Journal of Medicine.
Lebrikizumab received fast-track designation for AD by the Food and Drug Administration in 2019. Regulatory decisions in the United States and the European Union are expected later this year, according to a press release from Eli Lilly, the drug’s developer.
Asked to comment on the study results, Zelma Chiesa Fuxench, MD, MSCE, assistant professor of dermatology at the University of Pennsylvania, Philadelphia, called the post-hoc results promising. “While newer, more targeted treatments for AD offer the possibility of overall improvement and long-term disease control, we do not have sufficient data to help guide us when it comes to selecting treatment based on which area of the body is affected,” she explained. Most published findings have used “overall scores and not scores stratified by body region.”
The new findings, “help expand our current understanding of how the drug works for different areas of the body,” which can help inform treatment discussions with patients, she added.
AD can be especially challenging to treat when it involves “what are considered to be more sensitive areas such as the face or hands,” said Dr. Chiesa Fuxench. Challenges may include poor tolerance to topical medications, concerns for safety with long-term use, and the need for constant reapplication.
“Those of us who treat a large number of AD patients suspect that the impact and/or burden of AD may be different depending on what areas of the body are affected,” but more data are needed, she added. Limitations of the study, she noted, include “that the study may not have been adequately powered and that the sample size was small.”
Dupilumab result for hand, foot dermatitis
The phase 3 LIBERTY-AD-HAFT trial randomized 133 patients with moderate to severe atopic hand and/or foot dermatitis to a 16-week course of dupilumab (Dupixent) monotherapy, 300 mg every 2 weeks in adults and 200 or 300 mg every 2 weeks in adolescents, or placebo. Patients were then followed during a 12-week safety follow-up period.
Significantly more patients in the dupilumab group achieved the primary endpoint of a hand and foot Investigator Global Assessment (IGA) score of 0/1 at 16 weeks: 40.3% vs. 16.7% in the placebo group (P = .003). Statistical significance was reached at week 8, reported Dr. Silverberg, professor of dermatology and director of clinical research at George Washington University, Washington. Dupilumab, a human monoclonal IgG4 antibody that inhibits IL-4 and IL-13 signaling, is FDA approved for treating moderate to severe AD in patients age 6 months and older, among other indications.
In addition, the proportion of patients achieving a 4-point or greater improvement in the weekly average of daily hand and foot Peak Pruritus Numerical Rating Scale (PPNRS), the key secondary endpoint, was about fourfold greater with dupilumab: 52.2%, compared with 13.6% on placebo (P < .0001). This reduction in itch reached statistical significance by week 1. Dupilumab-treated patients also experienced significant improvement in other lesion measures and in Quality of Life in Hand Eczema Questionnaire scores, Dr. Silverberg noted.
The patients had a mean age in their 30s and a mean duration of atopic hand and/or foot dermatitis of 15-16 years. For more than one-quarter of patients, morphology was hyperkeratotic, which “has to be one of the toughest subsets to affect positive change in,” he said.
About 40% of patients had lesions on the hands only, and more than half had lesions on both hands and feet. “This is pretty realistic – we generally don’t see much isolated foot dermatitis in the AD population,” Dr. Silverberg said.
About 70%-75% had concomitant AD outside of the hands and feet, mostly of moderate severity. Patients with positive patch tests or whose hand and foot eczema was believed to be driven by irritants were excluded from the trial, as were patients who had used TCS or other topical treatments within 2 weeks of the baseline visit.
Rescue medication use was low (3% with dupilumab vs. 21% with placebo), and adverse events were “pretty consistent with everything we’ve seen with dupilumab,” said Dr. Silverberg.
Commenting on this study, Dr. Chiesa Fuxench said she was “excited to see [the findings], as hand and foot AD can often be quite challenging to treat in clinic.” The improvements in overall disease scores, itch, and quality of life scores – with fairly good tolerance – are “reassuring and what we would expect based on our current experience with dupilumab,” she said.
The lebrikizumab study was funded by Dermira, a wholly owned subsidiary of Eli Lilly. The dupilumab study was sponsored by Sanofi and Regeneron Pharmaceuticals. Some of the data were also reported by lead investigator Eric Simpson, MD, of Oregon Health and Science University at the annual meeting of the American Academy of Dermatology in March 2023.
Dr. Murase reported consulting/advising for Eli Lilly, Leo Pharma, UCB, Sanofi-Genzyme, and non-CME speaking/honoraria for UCB and Regeneron. Dr. Silverberg reported consulting fees and fees for non-CME services from Sanofi Genzyme, Regeneron, Pfizer, and other companies. Dr. Chiesa Fuxench, who was a speaker at the RAD meeting but was not involved in the studies, disclosed receiving honoraria for CME work in AD sponsored by education grants from Regeneron/Sanofi, and grant/research support from Lilly, Regeneron, and Sanofi, among other disclosures.
in a secondary analysis of randomized, double-blind, placebo-controlled phase 3 trials of the drug, Jenny E. Murase, MD, reported at the annual Revolutionizing Atopic Dermatitis conference.
At week 16 in the ADvocate 1, ADvocate 2, and ADhere trials, with and without concomitant topical corticosteroid (TCS) use, at least 58% of treated patients experienced improvement in facial dermatitis, and 62% or more experienced improvement in hand dermatitis – statistically significant differences over placebo.
“Lebrikizumab was efficacious in clearing and improving facial and hand dermatitis, burdensome and difficult-to-treat areas, in most patients with moderate to severe AD,” said Dr. Murase, of the department of dermatology at the University of California, San Francisco, and director of medical dermatology consultative services and patch testing for the Palo Alto (Calf.) Foundation Medical Group.
In another late-breaking abstract presented at the RAD conference, the injectable biologic dupilumab – now in its 6th year on the market – was reported by Jonathan I. Silverberg, MD, PhD, MPH, to “rapidly and significantly” improve the signs, symptoms, and quality of life in some adults and adolescents with moderate to severe hand and foot AD in a recently completed phase 3 trial of dupilumab.
Lebrikizumab results for facial, hand dermatitis
The ADvocate 1 and ADvocate 2 trials evaluated lebrikizumab monotherapy and randomized patients to receive 250 mg subcutaneously every 2 weeks (after a 500-mg loading dose at baseline and week 2) or placebo. (Patients who received any corticosteroid as a rescue medication were considered nonresponders.) The ADhere trial compared low to mid–potency TCS plus lebrikizumab, using the same dosing of lebrikizumab as in the ADvocate studies, versus TCS plus placebo.
In all three trials, with a total of more than 1,000 participants, clinicians assessed for the presence or absence of facial or hand dermatitis at baseline. At week 16, they then assessed the change from baseline based on a 4-point scale of cleared, improved, no change, and worsened. “Improvement” was defined as cleared or improved.
Both facial and hand dermatitis were identified in a majority of patients at baseline. For instance, in ADvocate 1, facial dermatitis was identified in 71.4% of patients in the lebrikizumab group and 80.9% of those in the placebo group. Hand dermatitis was identified in 72% and 73% of the treatment and placebo groups, respectively.
Across the trials, at 16 weeks, 58%-69% of adult and adolescent patients receiving lebrikizumab had improvement in facial dermatitis, compared with 22%-46% on placebo. For hand dermatitis, 62%-73% experienced improvement, compared with 19%-43% on placebo, respectively. Proportions of improved patients in both the lebrikizumab and placebo groups were highest in the ADhere trial, Dr. Murase reported.
In the ADvocate trials, 16 weeks marked the end of the induction phase and the start of a 36-week maintenance period. The ADhere trial was a 16-week study. Overall results from ADhere were published in January in JAMA Dermatology, and results from the 16-week induction period of the ADvocate trials were published in March in the New England Journal of Medicine.
Lebrikizumab received fast-track designation for AD by the Food and Drug Administration in 2019. Regulatory decisions in the United States and the European Union are expected later this year, according to a press release from Eli Lilly, the drug’s developer.
Asked to comment on the study results, Zelma Chiesa Fuxench, MD, MSCE, assistant professor of dermatology at the University of Pennsylvania, Philadelphia, called the post-hoc results promising. “While newer, more targeted treatments for AD offer the possibility of overall improvement and long-term disease control, we do not have sufficient data to help guide us when it comes to selecting treatment based on which area of the body is affected,” she explained. Most published findings have used “overall scores and not scores stratified by body region.”
The new findings, “help expand our current understanding of how the drug works for different areas of the body,” which can help inform treatment discussions with patients, she added.
AD can be especially challenging to treat when it involves “what are considered to be more sensitive areas such as the face or hands,” said Dr. Chiesa Fuxench. Challenges may include poor tolerance to topical medications, concerns for safety with long-term use, and the need for constant reapplication.
“Those of us who treat a large number of AD patients suspect that the impact and/or burden of AD may be different depending on what areas of the body are affected,” but more data are needed, she added. Limitations of the study, she noted, include “that the study may not have been adequately powered and that the sample size was small.”
Dupilumab result for hand, foot dermatitis
The phase 3 LIBERTY-AD-HAFT trial randomized 133 patients with moderate to severe atopic hand and/or foot dermatitis to a 16-week course of dupilumab (Dupixent) monotherapy, 300 mg every 2 weeks in adults and 200 or 300 mg every 2 weeks in adolescents, or placebo. Patients were then followed during a 12-week safety follow-up period.
Significantly more patients in the dupilumab group achieved the primary endpoint of a hand and foot Investigator Global Assessment (IGA) score of 0/1 at 16 weeks: 40.3% vs. 16.7% in the placebo group (P = .003). Statistical significance was reached at week 8, reported Dr. Silverberg, professor of dermatology and director of clinical research at George Washington University, Washington. Dupilumab, a human monoclonal IgG4 antibody that inhibits IL-4 and IL-13 signaling, is FDA approved for treating moderate to severe AD in patients age 6 months and older, among other indications.
In addition, the proportion of patients achieving a 4-point or greater improvement in the weekly average of daily hand and foot Peak Pruritus Numerical Rating Scale (PPNRS), the key secondary endpoint, was about fourfold greater with dupilumab: 52.2%, compared with 13.6% on placebo (P < .0001). This reduction in itch reached statistical significance by week 1. Dupilumab-treated patients also experienced significant improvement in other lesion measures and in Quality of Life in Hand Eczema Questionnaire scores, Dr. Silverberg noted.
The patients had a mean age in their 30s and a mean duration of atopic hand and/or foot dermatitis of 15-16 years. For more than one-quarter of patients, morphology was hyperkeratotic, which “has to be one of the toughest subsets to affect positive change in,” he said.
About 40% of patients had lesions on the hands only, and more than half had lesions on both hands and feet. “This is pretty realistic – we generally don’t see much isolated foot dermatitis in the AD population,” Dr. Silverberg said.
About 70%-75% had concomitant AD outside of the hands and feet, mostly of moderate severity. Patients with positive patch tests or whose hand and foot eczema was believed to be driven by irritants were excluded from the trial, as were patients who had used TCS or other topical treatments within 2 weeks of the baseline visit.
Rescue medication use was low (3% with dupilumab vs. 21% with placebo), and adverse events were “pretty consistent with everything we’ve seen with dupilumab,” said Dr. Silverberg.
Commenting on this study, Dr. Chiesa Fuxench said she was “excited to see [the findings], as hand and foot AD can often be quite challenging to treat in clinic.” The improvements in overall disease scores, itch, and quality of life scores – with fairly good tolerance – are “reassuring and what we would expect based on our current experience with dupilumab,” she said.
The lebrikizumab study was funded by Dermira, a wholly owned subsidiary of Eli Lilly. The dupilumab study was sponsored by Sanofi and Regeneron Pharmaceuticals. Some of the data were also reported by lead investigator Eric Simpson, MD, of Oregon Health and Science University at the annual meeting of the American Academy of Dermatology in March 2023.
Dr. Murase reported consulting/advising for Eli Lilly, Leo Pharma, UCB, Sanofi-Genzyme, and non-CME speaking/honoraria for UCB and Regeneron. Dr. Silverberg reported consulting fees and fees for non-CME services from Sanofi Genzyme, Regeneron, Pfizer, and other companies. Dr. Chiesa Fuxench, who was a speaker at the RAD meeting but was not involved in the studies, disclosed receiving honoraria for CME work in AD sponsored by education grants from Regeneron/Sanofi, and grant/research support from Lilly, Regeneron, and Sanofi, among other disclosures.
in a secondary analysis of randomized, double-blind, placebo-controlled phase 3 trials of the drug, Jenny E. Murase, MD, reported at the annual Revolutionizing Atopic Dermatitis conference.
At week 16 in the ADvocate 1, ADvocate 2, and ADhere trials, with and without concomitant topical corticosteroid (TCS) use, at least 58% of treated patients experienced improvement in facial dermatitis, and 62% or more experienced improvement in hand dermatitis – statistically significant differences over placebo.
“Lebrikizumab was efficacious in clearing and improving facial and hand dermatitis, burdensome and difficult-to-treat areas, in most patients with moderate to severe AD,” said Dr. Murase, of the department of dermatology at the University of California, San Francisco, and director of medical dermatology consultative services and patch testing for the Palo Alto (Calf.) Foundation Medical Group.
In another late-breaking abstract presented at the RAD conference, the injectable biologic dupilumab – now in its 6th year on the market – was reported by Jonathan I. Silverberg, MD, PhD, MPH, to “rapidly and significantly” improve the signs, symptoms, and quality of life in some adults and adolescents with moderate to severe hand and foot AD in a recently completed phase 3 trial of dupilumab.
Lebrikizumab results for facial, hand dermatitis
The ADvocate 1 and ADvocate 2 trials evaluated lebrikizumab monotherapy and randomized patients to receive 250 mg subcutaneously every 2 weeks (after a 500-mg loading dose at baseline and week 2) or placebo. (Patients who received any corticosteroid as a rescue medication were considered nonresponders.) The ADhere trial compared low to mid–potency TCS plus lebrikizumab, using the same dosing of lebrikizumab as in the ADvocate studies, versus TCS plus placebo.
In all three trials, with a total of more than 1,000 participants, clinicians assessed for the presence or absence of facial or hand dermatitis at baseline. At week 16, they then assessed the change from baseline based on a 4-point scale of cleared, improved, no change, and worsened. “Improvement” was defined as cleared or improved.
Both facial and hand dermatitis were identified in a majority of patients at baseline. For instance, in ADvocate 1, facial dermatitis was identified in 71.4% of patients in the lebrikizumab group and 80.9% of those in the placebo group. Hand dermatitis was identified in 72% and 73% of the treatment and placebo groups, respectively.
Across the trials, at 16 weeks, 58%-69% of adult and adolescent patients receiving lebrikizumab had improvement in facial dermatitis, compared with 22%-46% on placebo. For hand dermatitis, 62%-73% experienced improvement, compared with 19%-43% on placebo, respectively. Proportions of improved patients in both the lebrikizumab and placebo groups were highest in the ADhere trial, Dr. Murase reported.
In the ADvocate trials, 16 weeks marked the end of the induction phase and the start of a 36-week maintenance period. The ADhere trial was a 16-week study. Overall results from ADhere were published in January in JAMA Dermatology, and results from the 16-week induction period of the ADvocate trials were published in March in the New England Journal of Medicine.
Lebrikizumab received fast-track designation for AD by the Food and Drug Administration in 2019. Regulatory decisions in the United States and the European Union are expected later this year, according to a press release from Eli Lilly, the drug’s developer.
Asked to comment on the study results, Zelma Chiesa Fuxench, MD, MSCE, assistant professor of dermatology at the University of Pennsylvania, Philadelphia, called the post-hoc results promising. “While newer, more targeted treatments for AD offer the possibility of overall improvement and long-term disease control, we do not have sufficient data to help guide us when it comes to selecting treatment based on which area of the body is affected,” she explained. Most published findings have used “overall scores and not scores stratified by body region.”
The new findings, “help expand our current understanding of how the drug works for different areas of the body,” which can help inform treatment discussions with patients, she added.
AD can be especially challenging to treat when it involves “what are considered to be more sensitive areas such as the face or hands,” said Dr. Chiesa Fuxench. Challenges may include poor tolerance to topical medications, concerns for safety with long-term use, and the need for constant reapplication.
“Those of us who treat a large number of AD patients suspect that the impact and/or burden of AD may be different depending on what areas of the body are affected,” but more data are needed, she added. Limitations of the study, she noted, include “that the study may not have been adequately powered and that the sample size was small.”
Dupilumab result for hand, foot dermatitis
The phase 3 LIBERTY-AD-HAFT trial randomized 133 patients with moderate to severe atopic hand and/or foot dermatitis to a 16-week course of dupilumab (Dupixent) monotherapy, 300 mg every 2 weeks in adults and 200 or 300 mg every 2 weeks in adolescents, or placebo. Patients were then followed during a 12-week safety follow-up period.
Significantly more patients in the dupilumab group achieved the primary endpoint of a hand and foot Investigator Global Assessment (IGA) score of 0/1 at 16 weeks: 40.3% vs. 16.7% in the placebo group (P = .003). Statistical significance was reached at week 8, reported Dr. Silverberg, professor of dermatology and director of clinical research at George Washington University, Washington. Dupilumab, a human monoclonal IgG4 antibody that inhibits IL-4 and IL-13 signaling, is FDA approved for treating moderate to severe AD in patients age 6 months and older, among other indications.
In addition, the proportion of patients achieving a 4-point or greater improvement in the weekly average of daily hand and foot Peak Pruritus Numerical Rating Scale (PPNRS), the key secondary endpoint, was about fourfold greater with dupilumab: 52.2%, compared with 13.6% on placebo (P < .0001). This reduction in itch reached statistical significance by week 1. Dupilumab-treated patients also experienced significant improvement in other lesion measures and in Quality of Life in Hand Eczema Questionnaire scores, Dr. Silverberg noted.
The patients had a mean age in their 30s and a mean duration of atopic hand and/or foot dermatitis of 15-16 years. For more than one-quarter of patients, morphology was hyperkeratotic, which “has to be one of the toughest subsets to affect positive change in,” he said.
About 40% of patients had lesions on the hands only, and more than half had lesions on both hands and feet. “This is pretty realistic – we generally don’t see much isolated foot dermatitis in the AD population,” Dr. Silverberg said.
About 70%-75% had concomitant AD outside of the hands and feet, mostly of moderate severity. Patients with positive patch tests or whose hand and foot eczema was believed to be driven by irritants were excluded from the trial, as were patients who had used TCS or other topical treatments within 2 weeks of the baseline visit.
Rescue medication use was low (3% with dupilumab vs. 21% with placebo), and adverse events were “pretty consistent with everything we’ve seen with dupilumab,” said Dr. Silverberg.
Commenting on this study, Dr. Chiesa Fuxench said she was “excited to see [the findings], as hand and foot AD can often be quite challenging to treat in clinic.” The improvements in overall disease scores, itch, and quality of life scores – with fairly good tolerance – are “reassuring and what we would expect based on our current experience with dupilumab,” she said.
The lebrikizumab study was funded by Dermira, a wholly owned subsidiary of Eli Lilly. The dupilumab study was sponsored by Sanofi and Regeneron Pharmaceuticals. Some of the data were also reported by lead investigator Eric Simpson, MD, of Oregon Health and Science University at the annual meeting of the American Academy of Dermatology in March 2023.
Dr. Murase reported consulting/advising for Eli Lilly, Leo Pharma, UCB, Sanofi-Genzyme, and non-CME speaking/honoraria for UCB and Regeneron. Dr. Silverberg reported consulting fees and fees for non-CME services from Sanofi Genzyme, Regeneron, Pfizer, and other companies. Dr. Chiesa Fuxench, who was a speaker at the RAD meeting but was not involved in the studies, disclosed receiving honoraria for CME work in AD sponsored by education grants from Regeneron/Sanofi, and grant/research support from Lilly, Regeneron, and Sanofi, among other disclosures.
AT RAD 2023