Federal Practitioner

Despite new options in non–hormone-based treatments, hormone therapy remains the most effective treatment for vasomotor symptoms (VMS) and should be considered for healthy menopausal women without contraindications within 10 years of their final menstrual periods.

This recommendation emerged from an updated position statement from the North American Menopause Society in its first review of the scientific literature since 2015. The statement specifically targets nonhormonal management of symptoms such as hot flashes and night sweats, which occur in as many as 80% of menopausal women but are undertreated. The statement appears in the June issue of the Journal of The North American Menopause Society.

“Women with contraindications or objections to hormone treatment should be informed by professionals of evidence-based effective nonhormone treatment options,” stated a NAMS advisory panel led by Chrisandra L. Shufelt, MD, MS, professor and chair of the division of general internal medicine and associate director of the Women’s Health Research Center at the Mayo Clinic in Jacksonville, Fla. The statement is one of multiple NAMS updates performed at regular intervals, said Dr. Shufelt, also past president of NAMS, in an interview. “But the research has changed, and we wanted to make clinicians aware of new medications. One of our interesting findings was more evidence that off-label use of the nonhormonal overactive bladder drug oxybutynin can lower the rate of hot flashes.”

Dr. Shufelt noted that many of the current update’s findings align with previous research, and stressed that the therapeutic recommendations apply specifically to VMS. “Not all menopause-related symptoms are vasomotor, however,” she said. “While a lot of the lifestyle options such as cooling techniques and exercise are not recommended for controlling hot flashes, diet and exercise changes can be beneficial for other health reasons.”

Although it’s the most effective option for VMS, hormone therapy is not suitable for women with contraindications such as a previous blood clot, an estrogen-dependent cancer, a family history of such cancers, or a personal preference against hormone use, Dr. Shufelt added, so nonhormonal alternatives are important to prevent women from wasting time and money on ineffective remedies. “Women need to know what works and what doesn’t,” she said.
 

Recommended nonhormonal therapies

Based on a rigorous review of the scientific evidence to date, NAMS found the following therapies to be effective: cognitive-behavioral therapy; clinical hypnosis; SSRIs and serotonin-norepinephrine reuptake inhibitors – which yield mild to moderate improvements; gabapentin – which lessens the frequency and severity of hot flashes; fezolinetant (Veozah), a novel first-in-class neurokinin B antagonist that was Food and Drug Administration–approved in May for VSM; and oxybutynin, an antimuscarinic, anticholinergic drug, that reduces moderate to severe VMS, although long-term use in older adults may be linked to cognitive decline, weight loss, and stellate ganglion block.

Therapies that were ineffective, associated with adverse effects (AEs), or lacking adequate evidence of efficacy and thus not recommended for VMS included: paced respiration; supplemental and herbal remedies such as black cohosh, milk thistle, and evening primrose; cooling techniques; trigger avoidance; exercise and yoga; mindfulness-based intervention and relaxation; suvorexant, a dual orexin-receptor antagonist used for insomnia; soy foods, extracts, and the soy metabolite equol; cannabinoids; acupuncture; calibration of neural oscillations; chiropractics; clonidine, an alpha-2 adrenergic agonist that is associated with significant AEs with no recent evidence of benefit over placebo; dietary modification; and pregabalin – which is associated with significant AEs and has controlled-substance prescribing restrictions.

Ultimately, clinicians should individualize menopause care to each patient. For example, “if a patient says that avoiding caffeine in the morning stops her from having hot flashes in the afternoon, that’s fine,” Dr. Shufelt said.
 

HT still most effective

“This statement is excellent, comprehensive, and evidence-based,” commented Jill M. Rabin MD, vice chair of education and development, obstetrics and gynecology, at Northshore University Hospital/LIJ Medical Center in Manhasset, N.Y., and professor of obstetrics and gynecology at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Health in Hempstead, N.Y.

Dr. Rabin, coauthor of Mind Over Bladder was not involved in compiling the statement.

She agreed that hormone therapy is the most effective option for VMS and regularly prescribes it for suitable candidates in different forms depending on the type and severity of menopausal symptoms. As for nonhormonal options, Dr. Rabin added in an interview, some of those not recommended in the current NAMS statement could yet prove to be effective as more data accumulate. Suvorexant may be one to watch, for instance, but currently there are not enough data on its effectiveness.

“It’s really important to keep up on this nonhormonal research,” Dr. Rabin said. “As the population ages, more and more women will be in the peri- and postmenopausal periods and some have medical reasons for not taking hormone therapy.” It’s important to recommend nonhormonal therapies of proven benefit according to current high-level evidence, she said, “but also to keep your ear to the ground about those still under investigation.”

As for the lifestyle and alternative remedies of unproven benefit, Dr. Rabin added, there’s little harm in trying them. “As far as I know, no one’s ever died of relaxation and paced breathing.” In addition, a patient’s interaction with and sense of control over her own physiology provided by these techniques may be beneficial in themselves.

Dr. Shufelt reported grant support from the National Institutes of Health. Numerous authors reported consulting fees from and other financial ties to private-sector companies. Dr. Rabin had no relevant competing interests to disclose with regard to her comments.

Despite new options in non–hormone-based treatments, hormone therapy remains the most effective treatment for vasomotor symptoms (VMS) and should be considered for healthy menopausal women without contraindications within 10 years of their final menstrual periods.

This recommendation emerged from an updated position statement from the North American Menopause Society in its first review of the scientific literature since 2015. The statement specifically targets nonhormonal management of symptoms such as hot flashes and night sweats, which occur in as many as 80% of menopausal women but are undertreated. The statement appears in the June issue of the Journal of The North American Menopause Society.

“Women with contraindications or objections to hormone treatment should be informed by professionals of evidence-based effective nonhormone treatment options,” stated a NAMS advisory panel led by Chrisandra L. Shufelt, MD, MS, professor and chair of the division of general internal medicine and associate director of the Women’s Health Research Center at the Mayo Clinic in Jacksonville, Fla. The statement is one of multiple NAMS updates performed at regular intervals, said Dr. Shufelt, also past president of NAMS, in an interview. “But the research has changed, and we wanted to make clinicians aware of new medications. One of our interesting findings was more evidence that off-label use of the nonhormonal overactive bladder drug oxybutynin can lower the rate of hot flashes.”

Dr. Shufelt noted that many of the current update’s findings align with previous research, and stressed that the therapeutic recommendations apply specifically to VMS. “Not all menopause-related symptoms are vasomotor, however,” she said. “While a lot of the lifestyle options such as cooling techniques and exercise are not recommended for controlling hot flashes, diet and exercise changes can be beneficial for other health reasons.”

Although it’s the most effective option for VMS, hormone therapy is not suitable for women with contraindications such as a previous blood clot, an estrogen-dependent cancer, a family history of such cancers, or a personal preference against hormone use, Dr. Shufelt added, so nonhormonal alternatives are important to prevent women from wasting time and money on ineffective remedies. “Women need to know what works and what doesn’t,” she said.
 

Recommended nonhormonal therapies

Based on a rigorous review of the scientific evidence to date, NAMS found the following therapies to be effective: cognitive-behavioral therapy; clinical hypnosis; SSRIs and serotonin-norepinephrine reuptake inhibitors – which yield mild to moderate improvements; gabapentin – which lessens the frequency and severity of hot flashes; fezolinetant (Veozah), a novel first-in-class neurokinin B antagonist that was Food and Drug Administration–approved in May for VSM; and oxybutynin, an antimuscarinic, anticholinergic drug, that reduces moderate to severe VMS, although long-term use in older adults may be linked to cognitive decline, weight loss, and stellate ganglion block.

Therapies that were ineffective, associated with adverse effects (AEs), or lacking adequate evidence of efficacy and thus not recommended for VMS included: paced respiration; supplemental and herbal remedies such as black cohosh, milk thistle, and evening primrose; cooling techniques; trigger avoidance; exercise and yoga; mindfulness-based intervention and relaxation; suvorexant, a dual orexin-receptor antagonist used for insomnia; soy foods, extracts, and the soy metabolite equol; cannabinoids; acupuncture; calibration of neural oscillations; chiropractics; clonidine, an alpha-2 adrenergic agonist that is associated with significant AEs with no recent evidence of benefit over placebo; dietary modification; and pregabalin – which is associated with significant AEs and has controlled-substance prescribing restrictions.

Ultimately, clinicians should individualize menopause care to each patient. For example, “if a patient says that avoiding caffeine in the morning stops her from having hot flashes in the afternoon, that’s fine,” Dr. Shufelt said.
 

HT still most effective

“This statement is excellent, comprehensive, and evidence-based,” commented Jill M. Rabin MD, vice chair of education and development, obstetrics and gynecology, at Northshore University Hospital/LIJ Medical Center in Manhasset, N.Y., and professor of obstetrics and gynecology at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Health in Hempstead, N.Y.

Dr. Rabin, coauthor of Mind Over Bladder was not involved in compiling the statement.

She agreed that hormone therapy is the most effective option for VMS and regularly prescribes it for suitable candidates in different forms depending on the type and severity of menopausal symptoms. As for nonhormonal options, Dr. Rabin added in an interview, some of those not recommended in the current NAMS statement could yet prove to be effective as more data accumulate. Suvorexant may be one to watch, for instance, but currently there are not enough data on its effectiveness.

“It’s really important to keep up on this nonhormonal research,” Dr. Rabin said. “As the population ages, more and more women will be in the peri- and postmenopausal periods and some have medical reasons for not taking hormone therapy.” It’s important to recommend nonhormonal therapies of proven benefit according to current high-level evidence, she said, “but also to keep your ear to the ground about those still under investigation.”

As for the lifestyle and alternative remedies of unproven benefit, Dr. Rabin added, there’s little harm in trying them. “As far as I know, no one’s ever died of relaxation and paced breathing.” In addition, a patient’s interaction with and sense of control over her own physiology provided by these techniques may be beneficial in themselves.

Dr. Shufelt reported grant support from the National Institutes of Health. Numerous authors reported consulting fees from and other financial ties to private-sector companies. Dr. Rabin had no relevant competing interests to disclose with regard to her comments.

Despite new options in non–hormone-based treatments, hormone therapy remains the most effective treatment for vasomotor symptoms (VMS) and should be considered for healthy menopausal women without contraindications within 10 years of their final menstrual periods.

This recommendation emerged from an updated position statement from the North American Menopause Society in its first review of the scientific literature since 2015. The statement specifically targets nonhormonal management of symptoms such as hot flashes and night sweats, which occur in as many as 80% of menopausal women but are undertreated. The statement appears in the June issue of the Journal of The North American Menopause Society.

“Women with contraindications or objections to hormone treatment should be informed by professionals of evidence-based effective nonhormone treatment options,” stated a NAMS advisory panel led by Chrisandra L. Shufelt, MD, MS, professor and chair of the division of general internal medicine and associate director of the Women’s Health Research Center at the Mayo Clinic in Jacksonville, Fla. The statement is one of multiple NAMS updates performed at regular intervals, said Dr. Shufelt, also past president of NAMS, in an interview. “But the research has changed, and we wanted to make clinicians aware of new medications. One of our interesting findings was more evidence that off-label use of the nonhormonal overactive bladder drug oxybutynin can lower the rate of hot flashes.”

Dr. Shufelt noted that many of the current update’s findings align with previous research, and stressed that the therapeutic recommendations apply specifically to VMS. “Not all menopause-related symptoms are vasomotor, however,” she said. “While a lot of the lifestyle options such as cooling techniques and exercise are not recommended for controlling hot flashes, diet and exercise changes can be beneficial for other health reasons.”

Although it’s the most effective option for VMS, hormone therapy is not suitable for women with contraindications such as a previous blood clot, an estrogen-dependent cancer, a family history of such cancers, or a personal preference against hormone use, Dr. Shufelt added, so nonhormonal alternatives are important to prevent women from wasting time and money on ineffective remedies. “Women need to know what works and what doesn’t,” she said.
 

Recommended nonhormonal therapies

Based on a rigorous review of the scientific evidence to date, NAMS found the following therapies to be effective: cognitive-behavioral therapy; clinical hypnosis; SSRIs and serotonin-norepinephrine reuptake inhibitors – which yield mild to moderate improvements; gabapentin – which lessens the frequency and severity of hot flashes; fezolinetant (Veozah), a novel first-in-class neurokinin B antagonist that was Food and Drug Administration–approved in May for VSM; and oxybutynin, an antimuscarinic, anticholinergic drug, that reduces moderate to severe VMS, although long-term use in older adults may be linked to cognitive decline, weight loss, and stellate ganglion block.

Therapies that were ineffective, associated with adverse effects (AEs), or lacking adequate evidence of efficacy and thus not recommended for VMS included: paced respiration; supplemental and herbal remedies such as black cohosh, milk thistle, and evening primrose; cooling techniques; trigger avoidance; exercise and yoga; mindfulness-based intervention and relaxation; suvorexant, a dual orexin-receptor antagonist used for insomnia; soy foods, extracts, and the soy metabolite equol; cannabinoids; acupuncture; calibration of neural oscillations; chiropractics; clonidine, an alpha-2 adrenergic agonist that is associated with significant AEs with no recent evidence of benefit over placebo; dietary modification; and pregabalin – which is associated with significant AEs and has controlled-substance prescribing restrictions.

Ultimately, clinicians should individualize menopause care to each patient. For example, “if a patient says that avoiding caffeine in the morning stops her from having hot flashes in the afternoon, that’s fine,” Dr. Shufelt said.
 

HT still most effective

“This statement is excellent, comprehensive, and evidence-based,” commented Jill M. Rabin MD, vice chair of education and development, obstetrics and gynecology, at Northshore University Hospital/LIJ Medical Center in Manhasset, N.Y., and professor of obstetrics and gynecology at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Health in Hempstead, N.Y.

Dr. Rabin, coauthor of Mind Over Bladder was not involved in compiling the statement.

She agreed that hormone therapy is the most effective option for VMS and regularly prescribes it for suitable candidates in different forms depending on the type and severity of menopausal symptoms. As for nonhormonal options, Dr. Rabin added in an interview, some of those not recommended in the current NAMS statement could yet prove to be effective as more data accumulate. Suvorexant may be one to watch, for instance, but currently there are not enough data on its effectiveness.

“It’s really important to keep up on this nonhormonal research,” Dr. Rabin said. “As the population ages, more and more women will be in the peri- and postmenopausal periods and some have medical reasons for not taking hormone therapy.” It’s important to recommend nonhormonal therapies of proven benefit according to current high-level evidence, she said, “but also to keep your ear to the ground about those still under investigation.”

As for the lifestyle and alternative remedies of unproven benefit, Dr. Rabin added, there’s little harm in trying them. “As far as I know, no one’s ever died of relaxation and paced breathing.” In addition, a patient’s interaction with and sense of control over her own physiology provided by these techniques may be beneficial in themselves.

Dr. Shufelt reported grant support from the National Institutes of Health. Numerous authors reported consulting fees from and other financial ties to private-sector companies. Dr. Rabin had no relevant competing interests to disclose with regard to her comments.

Researchers using a modeling study of rabies in the United States have quantified the risk of death and exposure and estimated a threshold to help health care providers decide when postexposure prophylaxis (PEP) is appropriate.

© astridb05/Fotolia.com

The model, reported in JAMA Network Open, could help clinicians, particularly those in primary care settings, to more rationally prescribe PEP to people concerned about a potential exposure to the rabies virus (RABV). In the United States, rabies PEP often is given without a comprehensive assessment that considers regional factors as well as species, nature of an attack, and the health and vaccination status of the animal.

Providers err on the side of caution, as rabies infection has a fatality rate near 100%. When exposures are low-risk, however, patients can rack up substantial out-of-pocket expenses or experience unnecessary adverse effects from the series of shots. Those can include injection site reactions, hypersensitivity reactions, and neurological complications.

The authors write that an estimated 55,000 people per year in the United States were treated for potential exposure to RABV in 2017 and 2018, at an estimated cost of more than $3,800 per person treated.
 

Researchers calculate risk threshold

The researchers, led by Kelly Charniga, PhD, MPH, an infectious disease epidemiologist with the U.S. Centers for Disease Control and Prevention in Atlanta, calculated positivity rates using more than 900,000 animal samples tested for RABV between 2011 and 2020. Other parameters were estimated from surveillance data and the literature and probabilities were estimated using Bayes’ rule.

A convenience sample of state public health officials in all states (excluding Hawaii) plus Washington and Puerto Rico was used to help determine a risk threshold for recommending PEP. Respondents were asked whether they would recommend PEP given 24 standardized exposure scenarios while accounting for local rabies epidemiology.

Their model establishes a risk threshold of 0.0004 for PEP administration, which represents the probability that an animal would test positive for RABV given that a person was exposed, and the probability that a person would die from rabies after exposure to a suspect rabid animal and no PEP. PEP should not be recommended with any value lower than that cutoff.

Alfred DeMaria, DPH, a consultant to the Massachusetts Department of Public Health in Boston, who was not involved with the study, said the work will be particularly helpful for primary care physicians, giving them confidence to not recommend PEP when infection is statistically highly unlikely and thereby to reduce unnecessary and costly measures.

“Concern about rabies is often based on a very unlikely scenario,” Dr. DeMaria said. He gave the example of people coming into primary care worried that they might have been exposed after comforting their dog who had been bitten in a fight with a wild animal.

“Has that ever happened in the history of the human species? Not that we know of,” he said.

Many people also think dogs and other domestic animals are a likely source of rabies, which is not the case in the United States, Dr. DeMaria said.

“In most cases, it is exposure to a raccoon, a skunk, or a bat,” he said. “Most calls are for potential bat exposure, especially in the summer when young bats are flying around and are not very savvy about avoiding humans.”

The authors note the difference between the animals likely to bite and the species that carry RABV: “The most common mammals involved in bite events in the U.S. are dogs, cats, and small rodents. These species, when healthy and provoked into biting, represent some of the lowest risk exposures evaluated in this model.”

The canine rabies variant virus was eliminated in the United States in 2004.

The study authors note that their model should not be used in other countries because “most rabies deaths globally are caused by domestic dogs.”

Health department consultation can reduce inappropriate treatment

Dr. DeMaria said the paper may also convince physicians to consult with their health department for a final recommendation.

The authors note that a 2020 study in Cook County, Ill., found patients who received PEP were about 90% less likely to receive inappropriate treatment if their clinician had consulted with a health department.

“Anything that puts the risk in a context, like this paper does, is helpful,” he said.

Most physicians in the United States will never see a patient with rabies, the authors write, but animal bites are common – resulting in hundreds of thousands of primary care and emergency department visits each year when physicians must decide whether to administer PEP.

The study authors and Dr. DeMaria report no relevant financial relationships.

Researchers using a modeling study of rabies in the United States have quantified the risk of death and exposure and estimated a threshold to help health care providers decide when postexposure prophylaxis (PEP) is appropriate.

© astridb05/Fotolia.com

The model, reported in JAMA Network Open, could help clinicians, particularly those in primary care settings, to more rationally prescribe PEP to people concerned about a potential exposure to the rabies virus (RABV). In the United States, rabies PEP often is given without a comprehensive assessment that considers regional factors as well as species, nature of an attack, and the health and vaccination status of the animal.

Providers err on the side of caution, as rabies infection has a fatality rate near 100%. When exposures are low-risk, however, patients can rack up substantial out-of-pocket expenses or experience unnecessary adverse effects from the series of shots. Those can include injection site reactions, hypersensitivity reactions, and neurological complications.

The authors write that an estimated 55,000 people per year in the United States were treated for potential exposure to RABV in 2017 and 2018, at an estimated cost of more than $3,800 per person treated.
 

Researchers calculate risk threshold

The researchers, led by Kelly Charniga, PhD, MPH, an infectious disease epidemiologist with the U.S. Centers for Disease Control and Prevention in Atlanta, calculated positivity rates using more than 900,000 animal samples tested for RABV between 2011 and 2020. Other parameters were estimated from surveillance data and the literature and probabilities were estimated using Bayes’ rule.

A convenience sample of state public health officials in all states (excluding Hawaii) plus Washington and Puerto Rico was used to help determine a risk threshold for recommending PEP. Respondents were asked whether they would recommend PEP given 24 standardized exposure scenarios while accounting for local rabies epidemiology.

Their model establishes a risk threshold of 0.0004 for PEP administration, which represents the probability that an animal would test positive for RABV given that a person was exposed, and the probability that a person would die from rabies after exposure to a suspect rabid animal and no PEP. PEP should not be recommended with any value lower than that cutoff.

Alfred DeMaria, DPH, a consultant to the Massachusetts Department of Public Health in Boston, who was not involved with the study, said the work will be particularly helpful for primary care physicians, giving them confidence to not recommend PEP when infection is statistically highly unlikely and thereby to reduce unnecessary and costly measures.

“Concern about rabies is often based on a very unlikely scenario,” Dr. DeMaria said. He gave the example of people coming into primary care worried that they might have been exposed after comforting their dog who had been bitten in a fight with a wild animal.

“Has that ever happened in the history of the human species? Not that we know of,” he said.

Many people also think dogs and other domestic animals are a likely source of rabies, which is not the case in the United States, Dr. DeMaria said.

“In most cases, it is exposure to a raccoon, a skunk, or a bat,” he said. “Most calls are for potential bat exposure, especially in the summer when young bats are flying around and are not very savvy about avoiding humans.”

The authors note the difference between the animals likely to bite and the species that carry RABV: “The most common mammals involved in bite events in the U.S. are dogs, cats, and small rodents. These species, when healthy and provoked into biting, represent some of the lowest risk exposures evaluated in this model.”

The canine rabies variant virus was eliminated in the United States in 2004.

The study authors note that their model should not be used in other countries because “most rabies deaths globally are caused by domestic dogs.”

Health department consultation can reduce inappropriate treatment

Dr. DeMaria said the paper may also convince physicians to consult with their health department for a final recommendation.

The authors note that a 2020 study in Cook County, Ill., found patients who received PEP were about 90% less likely to receive inappropriate treatment if their clinician had consulted with a health department.

“Anything that puts the risk in a context, like this paper does, is helpful,” he said.

Most physicians in the United States will never see a patient with rabies, the authors write, but animal bites are common – resulting in hundreds of thousands of primary care and emergency department visits each year when physicians must decide whether to administer PEP.

The study authors and Dr. DeMaria report no relevant financial relationships.

Researchers using a modeling study of rabies in the United States have quantified the risk of death and exposure and estimated a threshold to help health care providers decide when postexposure prophylaxis (PEP) is appropriate.

© astridb05/Fotolia.com

The model, reported in JAMA Network Open, could help clinicians, particularly those in primary care settings, to more rationally prescribe PEP to people concerned about a potential exposure to the rabies virus (RABV). In the United States, rabies PEP often is given without a comprehensive assessment that considers regional factors as well as species, nature of an attack, and the health and vaccination status of the animal.

Providers err on the side of caution, as rabies infection has a fatality rate near 100%. When exposures are low-risk, however, patients can rack up substantial out-of-pocket expenses or experience unnecessary adverse effects from the series of shots. Those can include injection site reactions, hypersensitivity reactions, and neurological complications.

The authors write that an estimated 55,000 people per year in the United States were treated for potential exposure to RABV in 2017 and 2018, at an estimated cost of more than $3,800 per person treated.
 

Researchers calculate risk threshold

The researchers, led by Kelly Charniga, PhD, MPH, an infectious disease epidemiologist with the U.S. Centers for Disease Control and Prevention in Atlanta, calculated positivity rates using more than 900,000 animal samples tested for RABV between 2011 and 2020. Other parameters were estimated from surveillance data and the literature and probabilities were estimated using Bayes’ rule.

A convenience sample of state public health officials in all states (excluding Hawaii) plus Washington and Puerto Rico was used to help determine a risk threshold for recommending PEP. Respondents were asked whether they would recommend PEP given 24 standardized exposure scenarios while accounting for local rabies epidemiology.

Their model establishes a risk threshold of 0.0004 for PEP administration, which represents the probability that an animal would test positive for RABV given that a person was exposed, and the probability that a person would die from rabies after exposure to a suspect rabid animal and no PEP. PEP should not be recommended with any value lower than that cutoff.

Alfred DeMaria, DPH, a consultant to the Massachusetts Department of Public Health in Boston, who was not involved with the study, said the work will be particularly helpful for primary care physicians, giving them confidence to not recommend PEP when infection is statistically highly unlikely and thereby to reduce unnecessary and costly measures.

“Concern about rabies is often based on a very unlikely scenario,” Dr. DeMaria said. He gave the example of people coming into primary care worried that they might have been exposed after comforting their dog who had been bitten in a fight with a wild animal.

“Has that ever happened in the history of the human species? Not that we know of,” he said.

Many people also think dogs and other domestic animals are a likely source of rabies, which is not the case in the United States, Dr. DeMaria said.

“In most cases, it is exposure to a raccoon, a skunk, or a bat,” he said. “Most calls are for potential bat exposure, especially in the summer when young bats are flying around and are not very savvy about avoiding humans.”

The authors note the difference between the animals likely to bite and the species that carry RABV: “The most common mammals involved in bite events in the U.S. are dogs, cats, and small rodents. These species, when healthy and provoked into biting, represent some of the lowest risk exposures evaluated in this model.”

The canine rabies variant virus was eliminated in the United States in 2004.

The study authors note that their model should not be used in other countries because “most rabies deaths globally are caused by domestic dogs.”

Health department consultation can reduce inappropriate treatment

Dr. DeMaria said the paper may also convince physicians to consult with their health department for a final recommendation.

The authors note that a 2020 study in Cook County, Ill., found patients who received PEP were about 90% less likely to receive inappropriate treatment if their clinician had consulted with a health department.

“Anything that puts the risk in a context, like this paper does, is helpful,” he said.

Most physicians in the United States will never see a patient with rabies, the authors write, but animal bites are common – resulting in hundreds of thousands of primary care and emergency department visits each year when physicians must decide whether to administer PEP.

The study authors and Dr. DeMaria report no relevant financial relationships.

MUNICH, GERMANY – Giving intensive statin therapy to patients with acute mild ischemic stroke or with high-risk for transient ischemic attack (TIA) immediately after onset significantly reduces the risk for a poor functional outcome compared with delaying treatment, without compromising safety, results of the INSPIRES trial show.

The research, presented at the annual European Stroke Organisation Conference, also showed that intensive antiplatelet therapy reduced the risk for recurrent stroke albeit at an increased in bleeding risk versus standard treatment.

The study involved more than 6,000 patients with acute mild ischemic stroke or TIA and intracranial or extracranial atherosclerosis (ICAS/ECAS), who were randomly assigned in a 2 x 2 factorial design to compare intensive versus standard antiplatelet therapy and intensive statin therapy within 24 hours versus waiting up to 72 hours after onset.

Intensive antiplatelet therapy with clopidogrel plus aspirin reduced the risk for recurrent stroke within 90 days by 21% versus standard single-agent therapy, although it also doubled the risk for moderate to severe bleeding.

Starting intensive statin therapy with atorvastatin within 24 hours of onset had no impact on recurrent stroke risk but did reduce the risk for a poor functional outcome versus waiting up to 72 hours by 16%.

Moreover, it was “safe, with no increased risk of bleeding, hepatotoxicity, or muscle toxicity,” said study presenter Yilong Wang, MD, department of neurology, Beijing Tiantan Hospital, National Clinical Research Center.

There was, however, a suggestion of an interaction between intensive antiplatelet therapy and immediate intensive statin therapy, he noted, with a trend toward increased bleeding vs delaying the start of statin therapy.

Approached for comment, session cochair Carlos Molina, MD, director of the stroke unit and brain hemodynamics in Hospital Universitari Vall d’Hebron, Barcelona, said that the study is “important because when we look at studies of minor stroke and TIA, they are just focused on long-term outcomes in terms of recurrent stroke.”

He said in an interview that “putting statins in the equation and looking at their impact on long-term outcomes, the study demonstrates that statins are associated ... in particular with reductions in disabling stoke, and that’s good.”
 

Recurrence and progression

Dr. Wang began by highlighting that acute mild stroke and high-risk TIA are common and underestimated, with a relatively high risk for recurrence and progression, often caused by ICAS/ECAS.

Numerous guidelines recommend intensive antiplatelet therapy in the first 24 hours after the event, but Wang pointed out that there is little evidence to support this, and a meta-analysis suggested the window for effective treatment may be up to 72 hours.

In addition, intense statin therapy appears to be beneficial for the secondary prevention of atherosclerotic stroke in the nonacute phase, although there is no evidence for any neuroprotective effects in the acute phase nor for the optimal timing of starting the drugs.

Dr. Wang also noted that there is the potential for an interaction between intensive antiplatelet and statin therapy that could increase the risk for bleeding.

To investigate further, the researchers conducted a multicenter study involving patients aged 35-80 years with acute ischemic stroke or TIA.

The former was defined as an acute single infarction with 50% or greater stenosis of a major intracranial or extracranial artery that “probably account for the infarction and symptoms,” or multiple infarctions of large artery origin, including nonstenotic vulnerable plaques.

Patients were required to have a National Institutes of Health Stroke Scale score of 4-5 24 hours or less from acute stoke onset or 0-5 between 24 and 72 hours of onset.

TIA was defined as 50% or more stenosis of major intracranial or extracranial arteries that probably account for the symptoms, and an ABCD2 score for stroke risk of 4 or more within 24-72 hours of onset.

Patients were excluded if they had received dual antiplatelet therapy with aspirin and clopidogrel or high-intensity statin therapy within 14 days of random assignment or had intravenous thrombolysis or endovascular therapy after acute stroke or TIA onset.

Those included in the trial were randomly assigned in a 2 x 2 factorial design to receive:

• Intensive or dual antiplatelet therapy with clopidogrel and aspirin plus immediate high-intensity statin therapy with atorvastatin
• Intensive antiplatelet therapy plus delayed high-intensity statin therapy
• Standard antiplatelet therapy with aspirin alone plus immediate high-intensity statin therapy
• Standard antiplatelet therapy plus delayed high-intensity statin therapy

In all, 6,100 patients were enrolled from 222 hospitals in 99 cities across 25 provinces in China. The mean age was 65 years, and 34.6%-37.0% were women. TIA was recorded in 12.2%-14.1% of patients; 19.5%-19.7% had a single acute infarction, and 66.4%-68.1% had acute multiple infarctions.

The time to randomization was 24 hours or less after event onset in 12.5%-13.2% of cases versus 24-48 hours in 41.2%-42.5% and 48 hours or more in 44.9%-45.7% of patients.

The primary efficacy outcome, defined as stroke at 90 days, was significantly less common with intensive versus standard antiplatelet therapy, at a cumulative probability of 9.2% versus 7.3% (hazard ratio, 0.79; 95% confidence interval, 0.66-0.94; P = .007).

Clopidogrel plus aspirin was also associated with a significant reduction in a composite vascular event of stroke, myocardial infarction, or vascular death versus aspirin alone, at 7.5% versus 9.3% (HR, 0.80; 95% CI, 0.67-0.95, P = .01), as well as a reduction in rates of ischemic stroke (P = .002), and TIA (P = .02).

The primary safety outcome, defined as moderate to severe bleeding on the GUSTO criteria, was increased with intensive antiplatelet therapy, at 0.9% versus 0.4% for aspirin alone (HR, 2.08; 95% CI, 1.07-4.03; P = .02).

Turning to statin use, Dr. Wang showed that there was no significant difference in rates of stroke at 90 days between delayed and immediate intensive therapy, at a cumulative probability of 8.4% versus 8.1% (HR, 0.95; P = .58).

There was also no difference in rates of moderate to severe bleeding, at 0.8% with immediate versus 0.6% for delayed intensive statin therapy (HR, 1.36; 95% CI, 0.73-2.54; P = .34).

Dr. Wang reported that there were no significant differences in key secondary efficacy and safety outcomes.

Analysis of the distribution of modified Rankin Scale scores at 90 days, however, indicated that there was a significant reduction in the risk for poor functional outcome, defined as a score of 2-6, with immediate versus delayed statin therapy (odds ratio, 0.84; 95% CI, 0.72-0.99; P = .04).

Finally, it was found that combining dual antiplatelet therapy with immediate intensive statin therapy was associated with an increase in moderate to severe bleeding versus delayed statin therapy, affecting 1.1% versus 0.7% of patients. The association nonetheless did not reach statistical significance (HR, 1.70; 95% CI, 0.78-3.71; P = .18).

The study was funded by the National Natural Science Foundation of China, the National Key R&D Program of China, the Beijing Outstanding Young Scientist Program, the Beijing Youth Scholar Program, and the Beijing Talent Project. The drug was provided by Sanofi and Jialin Pharmaceutical. No relevant financial relationships were declared.

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

MUNICH, GERMANY – Giving intensive statin therapy to patients with acute mild ischemic stroke or with high-risk for transient ischemic attack (TIA) immediately after onset significantly reduces the risk for a poor functional outcome compared with delaying treatment, without compromising safety, results of the INSPIRES trial show.

The research, presented at the annual European Stroke Organisation Conference, also showed that intensive antiplatelet therapy reduced the risk for recurrent stroke albeit at an increased in bleeding risk versus standard treatment.

The study involved more than 6,000 patients with acute mild ischemic stroke or TIA and intracranial or extracranial atherosclerosis (ICAS/ECAS), who were randomly assigned in a 2 x 2 factorial design to compare intensive versus standard antiplatelet therapy and intensive statin therapy within 24 hours versus waiting up to 72 hours after onset.

Intensive antiplatelet therapy with clopidogrel plus aspirin reduced the risk for recurrent stroke within 90 days by 21% versus standard single-agent therapy, although it also doubled the risk for moderate to severe bleeding.

Starting intensive statin therapy with atorvastatin within 24 hours of onset had no impact on recurrent stroke risk but did reduce the risk for a poor functional outcome versus waiting up to 72 hours by 16%.

Moreover, it was “safe, with no increased risk of bleeding, hepatotoxicity, or muscle toxicity,” said study presenter Yilong Wang, MD, department of neurology, Beijing Tiantan Hospital, National Clinical Research Center.

There was, however, a suggestion of an interaction between intensive antiplatelet therapy and immediate intensive statin therapy, he noted, with a trend toward increased bleeding vs delaying the start of statin therapy.

Approached for comment, session cochair Carlos Molina, MD, director of the stroke unit and brain hemodynamics in Hospital Universitari Vall d’Hebron, Barcelona, said that the study is “important because when we look at studies of minor stroke and TIA, they are just focused on long-term outcomes in terms of recurrent stroke.”

He said in an interview that “putting statins in the equation and looking at their impact on long-term outcomes, the study demonstrates that statins are associated ... in particular with reductions in disabling stoke, and that’s good.”
 

Recurrence and progression

Dr. Wang began by highlighting that acute mild stroke and high-risk TIA are common and underestimated, with a relatively high risk for recurrence and progression, often caused by ICAS/ECAS.

Numerous guidelines recommend intensive antiplatelet therapy in the first 24 hours after the event, but Wang pointed out that there is little evidence to support this, and a meta-analysis suggested the window for effective treatment may be up to 72 hours.

In addition, intense statin therapy appears to be beneficial for the secondary prevention of atherosclerotic stroke in the nonacute phase, although there is no evidence for any neuroprotective effects in the acute phase nor for the optimal timing of starting the drugs.

Dr. Wang also noted that there is the potential for an interaction between intensive antiplatelet and statin therapy that could increase the risk for bleeding.

To investigate further, the researchers conducted a multicenter study involving patients aged 35-80 years with acute ischemic stroke or TIA.

The former was defined as an acute single infarction with 50% or greater stenosis of a major intracranial or extracranial artery that “probably account for the infarction and symptoms,” or multiple infarctions of large artery origin, including nonstenotic vulnerable plaques.

Patients were required to have a National Institutes of Health Stroke Scale score of 4-5 24 hours or less from acute stoke onset or 0-5 between 24 and 72 hours of onset.

TIA was defined as 50% or more stenosis of major intracranial or extracranial arteries that probably account for the symptoms, and an ABCD2 score for stroke risk of 4 or more within 24-72 hours of onset.

Patients were excluded if they had received dual antiplatelet therapy with aspirin and clopidogrel or high-intensity statin therapy within 14 days of random assignment or had intravenous thrombolysis or endovascular therapy after acute stroke or TIA onset.

Those included in the trial were randomly assigned in a 2 x 2 factorial design to receive:

• Intensive or dual antiplatelet therapy with clopidogrel and aspirin plus immediate high-intensity statin therapy with atorvastatin
• Intensive antiplatelet therapy plus delayed high-intensity statin therapy
• Standard antiplatelet therapy with aspirin alone plus immediate high-intensity statin therapy
• Standard antiplatelet therapy plus delayed high-intensity statin therapy

In all, 6,100 patients were enrolled from 222 hospitals in 99 cities across 25 provinces in China. The mean age was 65 years, and 34.6%-37.0% were women. TIA was recorded in 12.2%-14.1% of patients; 19.5%-19.7% had a single acute infarction, and 66.4%-68.1% had acute multiple infarctions.

The time to randomization was 24 hours or less after event onset in 12.5%-13.2% of cases versus 24-48 hours in 41.2%-42.5% and 48 hours or more in 44.9%-45.7% of patients.

The primary efficacy outcome, defined as stroke at 90 days, was significantly less common with intensive versus standard antiplatelet therapy, at a cumulative probability of 9.2% versus 7.3% (hazard ratio, 0.79; 95% confidence interval, 0.66-0.94; P = .007).

Clopidogrel plus aspirin was also associated with a significant reduction in a composite vascular event of stroke, myocardial infarction, or vascular death versus aspirin alone, at 7.5% versus 9.3% (HR, 0.80; 95% CI, 0.67-0.95, P = .01), as well as a reduction in rates of ischemic stroke (P = .002), and TIA (P = .02).

The primary safety outcome, defined as moderate to severe bleeding on the GUSTO criteria, was increased with intensive antiplatelet therapy, at 0.9% versus 0.4% for aspirin alone (HR, 2.08; 95% CI, 1.07-4.03; P = .02).

Turning to statin use, Dr. Wang showed that there was no significant difference in rates of stroke at 90 days between delayed and immediate intensive therapy, at a cumulative probability of 8.4% versus 8.1% (HR, 0.95; P = .58).

There was also no difference in rates of moderate to severe bleeding, at 0.8% with immediate versus 0.6% for delayed intensive statin therapy (HR, 1.36; 95% CI, 0.73-2.54; P = .34).

Dr. Wang reported that there were no significant differences in key secondary efficacy and safety outcomes.

Analysis of the distribution of modified Rankin Scale scores at 90 days, however, indicated that there was a significant reduction in the risk for poor functional outcome, defined as a score of 2-6, with immediate versus delayed statin therapy (odds ratio, 0.84; 95% CI, 0.72-0.99; P = .04).

Finally, it was found that combining dual antiplatelet therapy with immediate intensive statin therapy was associated with an increase in moderate to severe bleeding versus delayed statin therapy, affecting 1.1% versus 0.7% of patients. The association nonetheless did not reach statistical significance (HR, 1.70; 95% CI, 0.78-3.71; P = .18).

The study was funded by the National Natural Science Foundation of China, the National Key R&D Program of China, the Beijing Outstanding Young Scientist Program, the Beijing Youth Scholar Program, and the Beijing Talent Project. The drug was provided by Sanofi and Jialin Pharmaceutical. No relevant financial relationships were declared.

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

MUNICH, GERMANY – Giving intensive statin therapy to patients with acute mild ischemic stroke or with high-risk for transient ischemic attack (TIA) immediately after onset significantly reduces the risk for a poor functional outcome compared with delaying treatment, without compromising safety, results of the INSPIRES trial show.

The research, presented at the annual European Stroke Organisation Conference, also showed that intensive antiplatelet therapy reduced the risk for recurrent stroke albeit at an increased in bleeding risk versus standard treatment.

The study involved more than 6,000 patients with acute mild ischemic stroke or TIA and intracranial or extracranial atherosclerosis (ICAS/ECAS), who were randomly assigned in a 2 x 2 factorial design to compare intensive versus standard antiplatelet therapy and intensive statin therapy within 24 hours versus waiting up to 72 hours after onset.

Intensive antiplatelet therapy with clopidogrel plus aspirin reduced the risk for recurrent stroke within 90 days by 21% versus standard single-agent therapy, although it also doubled the risk for moderate to severe bleeding.

Starting intensive statin therapy with atorvastatin within 24 hours of onset had no impact on recurrent stroke risk but did reduce the risk for a poor functional outcome versus waiting up to 72 hours by 16%.

Moreover, it was “safe, with no increased risk of bleeding, hepatotoxicity, or muscle toxicity,” said study presenter Yilong Wang, MD, department of neurology, Beijing Tiantan Hospital, National Clinical Research Center.

There was, however, a suggestion of an interaction between intensive antiplatelet therapy and immediate intensive statin therapy, he noted, with a trend toward increased bleeding vs delaying the start of statin therapy.

Approached for comment, session cochair Carlos Molina, MD, director of the stroke unit and brain hemodynamics in Hospital Universitari Vall d’Hebron, Barcelona, said that the study is “important because when we look at studies of minor stroke and TIA, they are just focused on long-term outcomes in terms of recurrent stroke.”

He said in an interview that “putting statins in the equation and looking at their impact on long-term outcomes, the study demonstrates that statins are associated ... in particular with reductions in disabling stoke, and that’s good.”
 

Recurrence and progression

Dr. Wang began by highlighting that acute mild stroke and high-risk TIA are common and underestimated, with a relatively high risk for recurrence and progression, often caused by ICAS/ECAS.

Numerous guidelines recommend intensive antiplatelet therapy in the first 24 hours after the event, but Wang pointed out that there is little evidence to support this, and a meta-analysis suggested the window for effective treatment may be up to 72 hours.

In addition, intense statin therapy appears to be beneficial for the secondary prevention of atherosclerotic stroke in the nonacute phase, although there is no evidence for any neuroprotective effects in the acute phase nor for the optimal timing of starting the drugs.

Dr. Wang also noted that there is the potential for an interaction between intensive antiplatelet and statin therapy that could increase the risk for bleeding.

To investigate further, the researchers conducted a multicenter study involving patients aged 35-80 years with acute ischemic stroke or TIA.

The former was defined as an acute single infarction with 50% or greater stenosis of a major intracranial or extracranial artery that “probably account for the infarction and symptoms,” or multiple infarctions of large artery origin, including nonstenotic vulnerable plaques.

Patients were required to have a National Institutes of Health Stroke Scale score of 4-5 24 hours or less from acute stoke onset or 0-5 between 24 and 72 hours of onset.

TIA was defined as 50% or more stenosis of major intracranial or extracranial arteries that probably account for the symptoms, and an ABCD2 score for stroke risk of 4 or more within 24-72 hours of onset.

Patients were excluded if they had received dual antiplatelet therapy with aspirin and clopidogrel or high-intensity statin therapy within 14 days of random assignment or had intravenous thrombolysis or endovascular therapy after acute stroke or TIA onset.

Those included in the trial were randomly assigned in a 2 x 2 factorial design to receive:

• Intensive or dual antiplatelet therapy with clopidogrel and aspirin plus immediate high-intensity statin therapy with atorvastatin
• Intensive antiplatelet therapy plus delayed high-intensity statin therapy
• Standard antiplatelet therapy with aspirin alone plus immediate high-intensity statin therapy
• Standard antiplatelet therapy plus delayed high-intensity statin therapy

In all, 6,100 patients were enrolled from 222 hospitals in 99 cities across 25 provinces in China. The mean age was 65 years, and 34.6%-37.0% were women. TIA was recorded in 12.2%-14.1% of patients; 19.5%-19.7% had a single acute infarction, and 66.4%-68.1% had acute multiple infarctions.

The time to randomization was 24 hours or less after event onset in 12.5%-13.2% of cases versus 24-48 hours in 41.2%-42.5% and 48 hours or more in 44.9%-45.7% of patients.

The primary efficacy outcome, defined as stroke at 90 days, was significantly less common with intensive versus standard antiplatelet therapy, at a cumulative probability of 9.2% versus 7.3% (hazard ratio, 0.79; 95% confidence interval, 0.66-0.94; P = .007).

Clopidogrel plus aspirin was also associated with a significant reduction in a composite vascular event of stroke, myocardial infarction, or vascular death versus aspirin alone, at 7.5% versus 9.3% (HR, 0.80; 95% CI, 0.67-0.95, P = .01), as well as a reduction in rates of ischemic stroke (P = .002), and TIA (P = .02).

The primary safety outcome, defined as moderate to severe bleeding on the GUSTO criteria, was increased with intensive antiplatelet therapy, at 0.9% versus 0.4% for aspirin alone (HR, 2.08; 95% CI, 1.07-4.03; P = .02).

Turning to statin use, Dr. Wang showed that there was no significant difference in rates of stroke at 90 days between delayed and immediate intensive therapy, at a cumulative probability of 8.4% versus 8.1% (HR, 0.95; P = .58).

There was also no difference in rates of moderate to severe bleeding, at 0.8% with immediate versus 0.6% for delayed intensive statin therapy (HR, 1.36; 95% CI, 0.73-2.54; P = .34).

Dr. Wang reported that there were no significant differences in key secondary efficacy and safety outcomes.

Analysis of the distribution of modified Rankin Scale scores at 90 days, however, indicated that there was a significant reduction in the risk for poor functional outcome, defined as a score of 2-6, with immediate versus delayed statin therapy (odds ratio, 0.84; 95% CI, 0.72-0.99; P = .04).

Finally, it was found that combining dual antiplatelet therapy with immediate intensive statin therapy was associated with an increase in moderate to severe bleeding versus delayed statin therapy, affecting 1.1% versus 0.7% of patients. The association nonetheless did not reach statistical significance (HR, 1.70; 95% CI, 0.78-3.71; P = .18).

The study was funded by the National Natural Science Foundation of China, the National Key R&D Program of China, the Beijing Outstanding Young Scientist Program, the Beijing Youth Scholar Program, and the Beijing Talent Project. The drug was provided by Sanofi and Jialin Pharmaceutical. No relevant financial relationships were declared.

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

In this column, I will describe the results of a recently published study from my group.¹ We sought to profile Streptococcus pneumoniae (pneumococcus), Haemophilus influenzae (Hflu) and Moraxella catarrhalis (Mcat) in the nasopharynx among 13-valent pneumococcal conjugate vaccine (PCV13)-immunized children, with a focus on the first 6 months of life. The rationale was to provide heretofore unreported contemporary data in a highly PCV13-immunized, community-based child population in the United States. A secondary objective was to assess nasopharyngeal bacterial density because higher density associates with greater likelihood of progression to infection. Thirdly, the serotype distribution and antibiotic susceptibility of pneumococci among children seen in primary care settings in the United States had not been evaluated for strains circulating among infants less than 6 months old and they may differ from strains recovered from older children. Therefore, comparisons were made within the same cohort of children to later child age time points.

Risk factors identified

The study was prospective and collected from a cohort of 101 children in Rochester, N.Y., during 2018-2020. Nasopharyngeal swabs were taken for study at age 1, 2 and 3 weeks, then 1, 2, 4, 6, 9, 12, 15, 18 and 24 months. All children had received PCV13 vaccine according to the Centers for Disease Control and Prevention recommended schedule.

We found two significant risk factors in the first 6 months of life for detection of nasopharyngeal colonization of pneumococcus, Hflu, and Mcat. They were daycare attendance and one or more siblings aged 1-5 years at home.

Colonization by one or more of the three bacteria was detected in only 5% of infants before age 2 months. None of the five children attended daycare but all five had young siblings at home. Pneumococcal colonization was detected in 12%, Hflu in 3%, and Mcat in 21% of nasopharyngeal swabs collected during the first 6 months of life. Nasopharyngeal colonization with the bacteria increased rapidly between age 4 and 6 months of life, coincident with infants going to daycare and other social interaction opportunities. Bacterial density of pneumococcus, Hflu, and Mcat during the first 6 months of life was significantly lower in the nasopharynx compared with bacterial density when samples were collected during child age 7-24 months.

The prevalent pneumococcal serotypes in children up to 6 months old were 23B (17%), 22F (13%), 15B/C (11%), 16F (9%), and 21 (7%), 19F (7%), which differed from those isolated from children age 7-24 months, where serotypes 35B (15%), 21 (10%), 15B (9%), and 23B (7%), 23A (7%) were most commonly observed. Antibiotic resistance among isolates did not significantly differ in comparisons between infants younger than 6 months versus 7- to 24-month-olds.
 

What is the clinical significance?

Colonization of the nasopharynx is a necessary first step in infection pathogenesis (Figure).

Michael Pichichero, MD

In a prior study of a different cohort of 358 prospectively-enrolled children, we sought associations between physician-attended illness visits and bacterial colonization in the first 5 years of life.² We showed that early age of first colonization with pneumococcus, Hflu, and Mcat was associated with respiratory infection proneness and asthma among the children.

Multiple demographic and risk factors may contribute to early life and high-density colonization that in turn may increase risk of infections. High densities and early life pneumococcal colonization in low/middle-income countries might impact PCV responses by induction of immunity tolerance. While it is appealing to study new vaccines in low/middle-income populations with high infection incidence, there are reasons that infection incidence is higher compared with high-income countries like the United States, among them may be early life nasopharyngeal colonization and density of colonization.

Prevalent pneumococcal serotype appear to differ with age. The most common serotypes in the first 6 months of life for the children were 23B> 22F> 16F and 21=19F, but in children 7-24 months, serotypes 35B> 21>15B>23A=23B were most commonly observed. This difference might be due to the impact of antibiotics.³ Pneumococci expressing serotypes 22F and 16F were oxacillin susceptible and antibiotic exposure in the first 6 months of life is very uncommon in our study cohorts. In contrast, all pneumococci expressing 35B capsule were oxacillin resistant and in our cohorts antibiotic exposures are common among 7- to 24-month-olds.

In conclusion, we determined that children in the first 6 months of life seen in pediatric primary care settings in Rochester, N.Y., have very low prevalence and low-density colonization of pneumococcus, Hflu, and Mcat compared with 7- to 24-month olds. Our results may explain the significantly lower rates of infections caused by pneumococci, Hflu, and Mcat in infants younger than 6 months old compared with low/middle-income countries.
 

Dr. Pichichero is a specialist in pediatric infectious diseases, Center for Infectious Diseases and Immunology, and director of the Research Institute at Rochester (N.Y.) General Hospital. He has no conflicts of interest to disclose.

References

1. Kaur R and Pichichero M. Colonization, density, and antibiotic resistance of Streptococcus pneumoniae, Haemophilus Influenzae, and Moraxella catarrhalis among PCV13 vaccinated infants in the first six months of life in Rochester, New York. J Pediatric Infect Dis Soc. 2023 Apr 18;12(3):135-42.

2. Chapman T et al. Nasopharyngeal colonization with pathobionts is associated with susceptibility to respiratory illnesses in young children. PLoS One. 2020 Dec 11;15(12):e0243942. doi: 10.1371/journal.pone.0243942.

3. Chapman TJ et al. Antibiotic use and vaccine antibody levels. Pediatrics 2022 May 1;149(5):e2021052061. doi: 10.1542/peds.2021-052061.

In this column, I will describe the results of a recently published study from my group.¹ We sought to profile Streptococcus pneumoniae (pneumococcus), Haemophilus influenzae (Hflu) and Moraxella catarrhalis (Mcat) in the nasopharynx among 13-valent pneumococcal conjugate vaccine (PCV13)-immunized children, with a focus on the first 6 months of life. The rationale was to provide heretofore unreported contemporary data in a highly PCV13-immunized, community-based child population in the United States. A secondary objective was to assess nasopharyngeal bacterial density because higher density associates with greater likelihood of progression to infection. Thirdly, the serotype distribution and antibiotic susceptibility of pneumococci among children seen in primary care settings in the United States had not been evaluated for strains circulating among infants less than 6 months old and they may differ from strains recovered from older children. Therefore, comparisons were made within the same cohort of children to later child age time points.

Risk factors identified

The study was prospective and collected from a cohort of 101 children in Rochester, N.Y., during 2018-2020. Nasopharyngeal swabs were taken for study at age 1, 2 and 3 weeks, then 1, 2, 4, 6, 9, 12, 15, 18 and 24 months. All children had received PCV13 vaccine according to the Centers for Disease Control and Prevention recommended schedule.

We found two significant risk factors in the first 6 months of life for detection of nasopharyngeal colonization of pneumococcus, Hflu, and Mcat. They were daycare attendance and one or more siblings aged 1-5 years at home.

Colonization by one or more of the three bacteria was detected in only 5% of infants before age 2 months. None of the five children attended daycare but all five had young siblings at home. Pneumococcal colonization was detected in 12%, Hflu in 3%, and Mcat in 21% of nasopharyngeal swabs collected during the first 6 months of life. Nasopharyngeal colonization with the bacteria increased rapidly between age 4 and 6 months of life, coincident with infants going to daycare and other social interaction opportunities. Bacterial density of pneumococcus, Hflu, and Mcat during the first 6 months of life was significantly lower in the nasopharynx compared with bacterial density when samples were collected during child age 7-24 months.

The prevalent pneumococcal serotypes in children up to 6 months old were 23B (17%), 22F (13%), 15B/C (11%), 16F (9%), and 21 (7%), 19F (7%), which differed from those isolated from children age 7-24 months, where serotypes 35B (15%), 21 (10%), 15B (9%), and 23B (7%), 23A (7%) were most commonly observed. Antibiotic resistance among isolates did not significantly differ in comparisons between infants younger than 6 months versus 7- to 24-month-olds.
 

What is the clinical significance?

Colonization of the nasopharynx is a necessary first step in infection pathogenesis (Figure).

Michael Pichichero, MD

In a prior study of a different cohort of 358 prospectively-enrolled children, we sought associations between physician-attended illness visits and bacterial colonization in the first 5 years of life.² We showed that early age of first colonization with pneumococcus, Hflu, and Mcat was associated with respiratory infection proneness and asthma among the children.

Multiple demographic and risk factors may contribute to early life and high-density colonization that in turn may increase risk of infections. High densities and early life pneumococcal colonization in low/middle-income countries might impact PCV responses by induction of immunity tolerance. While it is appealing to study new vaccines in low/middle-income populations with high infection incidence, there are reasons that infection incidence is higher compared with high-income countries like the United States, among them may be early life nasopharyngeal colonization and density of colonization.

Prevalent pneumococcal serotype appear to differ with age. The most common serotypes in the first 6 months of life for the children were 23B> 22F> 16F and 21=19F, but in children 7-24 months, serotypes 35B> 21>15B>23A=23B were most commonly observed. This difference might be due to the impact of antibiotics.³ Pneumococci expressing serotypes 22F and 16F were oxacillin susceptible and antibiotic exposure in the first 6 months of life is very uncommon in our study cohorts. In contrast, all pneumococci expressing 35B capsule were oxacillin resistant and in our cohorts antibiotic exposures are common among 7- to 24-month-olds.

In conclusion, we determined that children in the first 6 months of life seen in pediatric primary care settings in Rochester, N.Y., have very low prevalence and low-density colonization of pneumococcus, Hflu, and Mcat compared with 7- to 24-month olds. Our results may explain the significantly lower rates of infections caused by pneumococci, Hflu, and Mcat in infants younger than 6 months old compared with low/middle-income countries.
 

Dr. Pichichero is a specialist in pediatric infectious diseases, Center for Infectious Diseases and Immunology, and director of the Research Institute at Rochester (N.Y.) General Hospital. He has no conflicts of interest to disclose.

References

1. Kaur R and Pichichero M. Colonization, density, and antibiotic resistance of Streptococcus pneumoniae, Haemophilus Influenzae, and Moraxella catarrhalis among PCV13 vaccinated infants in the first six months of life in Rochester, New York. J Pediatric Infect Dis Soc. 2023 Apr 18;12(3):135-42.

2. Chapman T et al. Nasopharyngeal colonization with pathobionts is associated with susceptibility to respiratory illnesses in young children. PLoS One. 2020 Dec 11;15(12):e0243942. doi: 10.1371/journal.pone.0243942.

3. Chapman TJ et al. Antibiotic use and vaccine antibody levels. Pediatrics 2022 May 1;149(5):e2021052061. doi: 10.1542/peds.2021-052061.

In this column, I will describe the results of a recently published study from my group.¹ We sought to profile Streptococcus pneumoniae (pneumococcus), Haemophilus influenzae (Hflu) and Moraxella catarrhalis (Mcat) in the nasopharynx among 13-valent pneumococcal conjugate vaccine (PCV13)-immunized children, with a focus on the first 6 months of life. The rationale was to provide heretofore unreported contemporary data in a highly PCV13-immunized, community-based child population in the United States. A secondary objective was to assess nasopharyngeal bacterial density because higher density associates with greater likelihood of progression to infection. Thirdly, the serotype distribution and antibiotic susceptibility of pneumococci among children seen in primary care settings in the United States had not been evaluated for strains circulating among infants less than 6 months old and they may differ from strains recovered from older children. Therefore, comparisons were made within the same cohort of children to later child age time points.

Risk factors identified

The study was prospective and collected from a cohort of 101 children in Rochester, N.Y., during 2018-2020. Nasopharyngeal swabs were taken for study at age 1, 2 and 3 weeks, then 1, 2, 4, 6, 9, 12, 15, 18 and 24 months. All children had received PCV13 vaccine according to the Centers for Disease Control and Prevention recommended schedule.

We found two significant risk factors in the first 6 months of life for detection of nasopharyngeal colonization of pneumococcus, Hflu, and Mcat. They were daycare attendance and one or more siblings aged 1-5 years at home.

Colonization by one or more of the three bacteria was detected in only 5% of infants before age 2 months. None of the five children attended daycare but all five had young siblings at home. Pneumococcal colonization was detected in 12%, Hflu in 3%, and Mcat in 21% of nasopharyngeal swabs collected during the first 6 months of life. Nasopharyngeal colonization with the bacteria increased rapidly between age 4 and 6 months of life, coincident with infants going to daycare and other social interaction opportunities. Bacterial density of pneumococcus, Hflu, and Mcat during the first 6 months of life was significantly lower in the nasopharynx compared with bacterial density when samples were collected during child age 7-24 months.

The prevalent pneumococcal serotypes in children up to 6 months old were 23B (17%), 22F (13%), 15B/C (11%), 16F (9%), and 21 (7%), 19F (7%), which differed from those isolated from children age 7-24 months, where serotypes 35B (15%), 21 (10%), 15B (9%), and 23B (7%), 23A (7%) were most commonly observed. Antibiotic resistance among isolates did not significantly differ in comparisons between infants younger than 6 months versus 7- to 24-month-olds.
 

What is the clinical significance?

Colonization of the nasopharynx is a necessary first step in infection pathogenesis (Figure).

Michael Pichichero, MD

In a prior study of a different cohort of 358 prospectively-enrolled children, we sought associations between physician-attended illness visits and bacterial colonization in the first 5 years of life.² We showed that early age of first colonization with pneumococcus, Hflu, and Mcat was associated with respiratory infection proneness and asthma among the children.

Multiple demographic and risk factors may contribute to early life and high-density colonization that in turn may increase risk of infections. High densities and early life pneumococcal colonization in low/middle-income countries might impact PCV responses by induction of immunity tolerance. While it is appealing to study new vaccines in low/middle-income populations with high infection incidence, there are reasons that infection incidence is higher compared with high-income countries like the United States, among them may be early life nasopharyngeal colonization and density of colonization.

Prevalent pneumococcal serotype appear to differ with age. The most common serotypes in the first 6 months of life for the children were 23B> 22F> 16F and 21=19F, but in children 7-24 months, serotypes 35B> 21>15B>23A=23B were most commonly observed. This difference might be due to the impact of antibiotics.³ Pneumococci expressing serotypes 22F and 16F were oxacillin susceptible and antibiotic exposure in the first 6 months of life is very uncommon in our study cohorts. In contrast, all pneumococci expressing 35B capsule were oxacillin resistant and in our cohorts antibiotic exposures are common among 7- to 24-month-olds.

In conclusion, we determined that children in the first 6 months of life seen in pediatric primary care settings in Rochester, N.Y., have very low prevalence and low-density colonization of pneumococcus, Hflu, and Mcat compared with 7- to 24-month olds. Our results may explain the significantly lower rates of infections caused by pneumococci, Hflu, and Mcat in infants younger than 6 months old compared with low/middle-income countries.
 

Dr. Pichichero is a specialist in pediatric infectious diseases, Center for Infectious Diseases and Immunology, and director of the Research Institute at Rochester (N.Y.) General Hospital. He has no conflicts of interest to disclose.

References

1. Kaur R and Pichichero M. Colonization, density, and antibiotic resistance of Streptococcus pneumoniae, Haemophilus Influenzae, and Moraxella catarrhalis among PCV13 vaccinated infants in the first six months of life in Rochester, New York. J Pediatric Infect Dis Soc. 2023 Apr 18;12(3):135-42.

2. Chapman T et al. Nasopharyngeal colonization with pathobionts is associated with susceptibility to respiratory illnesses in young children. PLoS One. 2020 Dec 11;15(12):e0243942. doi: 10.1371/journal.pone.0243942.

3. Chapman TJ et al. Antibiotic use and vaccine antibody levels. Pediatrics 2022 May 1;149(5):e2021052061. doi: 10.1542/peds.2021-052061.

Delivering microdose incision-site injections of clindamycin significantly reduced the rate of surgical site infections (SSIs) in skin cancer surgery.

However, prophylaxis with flucloxacillin did not significantly lower SSI rates, compared with not using incision site antibiotics.

The rate of postoperative SSIs was 2.1% in the clindamycin arm, vs. 5.7% in the control arm and 5.3% in the flucloxacillin arm.

“Based on these results, we recommend the routine adoption of incisional microdosed clindamycin for patients undergoing skin cancer surgery,” Maple Goh, MBChB, of the Auckland Regional Plastic and Reconstructive Surgery Unit, Auckland, New Zealand, and the coauthors conclude. “This strategy appears suitable for widespread implementation because of the magnitude of the effect observed and the absence of adverse events.”

The study was published online in JAMA Surgery.

Skin cancer surgery carries a high risk of SSIs, which represent costly yet largely preventable complications of surgery. Despite the risk, there’s a lack of evidence from randomized clinical trials of the role of antibiotic prophylaxis in reducing SSI rates among patients undergoing skin cancer surgery. Previous studies have investigated incisional antibiotic prophylaxis to reduce SSIs with Mohs micrographic surgery, but these surgeries represent a relatively small proportion of overall skin cancer surgeries.

To understand whether this benefit extends to more general skin cancer surgeries, investigators recruited patients from a high-volume skin cancer center in New Zealand who were treated from February to July 2019. In the double-blind, prospective PICASSo trial, patients were randomly assigned to receive an incision site injection of buffered local anesthetic alone (control group), buffered local anesthetic with microdoses of flucloxacillin (500 mcg/mL), or buffered local anesthetic with microdoses of clindamycin (500 mcg/mL). The most common surgery type was excision and direct closure (approximately 80% in all arms), and the mean volume injected per length of direct closure was 1.5 mL/cm.

The primary endpoint was the rate of postoperative SSIs, defined as a postoperative wound infection score of 5 or more. The SSI rate was calculated as the number of lesions with SSIs per total number of lesions in the group.

Overall, 681 patients with 1,133 total lesions were included in the study. Compared with the control arm, the rate of postoperative SSIs was nearly threefold lower among patients who received clindamycin, –2.1% (9 of 422) vs. 5.7% (22 of 388) in the control arm (P = .01 for clindamycin vs. control).

However, flucloxacillin did not demonstrate the same effectiveness. The flucloxacillin arm and the control arm demonstrated similar postoperative SSI rates – 5.3% (17 of 323) vs. 5.7%.

The results were similar after adjusting for baseline differences and lesion ulceration.

The researchers also found that the proportion of lesions that required postoperative systemic antibiotics was four times higher among the control arm, in comparison with the clindamycin arm (8% vs. 2.1%; P < .001). It was two times higher than in the flucloxacillin arm (8% vs. 4%; P = .03).

Treatment with microdoses of incisional flucloxacillin and clindamycin was safe and well tolerated.

The researchers speculated that clindamycin’s greater effectiveness may come down to its slightly broader coverage of commonly cultured bacteria in skin and soft tissue infections, including community-associated methicillin-resistant Staphylococcus aureus. Clindamycin is known to have more efficacy against anaerobic bacteria that may be lurking in chronically ulcerated skin lesions and is associated with less local tissue inflammation, compared with flucloxacillin.

Overall, “clindamycin was significantly more effective at preventing SSI than flucloxacillin in our study,” the authors conclude. They note that the use of clindamycin as a first-line prophylaxis agent against SSIs for patients undergoing skin cancer surgery is a practical option.

“These results establish evidence-based guidelines for antibiotic prophylaxis in one of the most common surgical interventions performed worldwide, where they have been previously absent,” the researchers say.

The authors of an editorial published with the study underscore other advantages of incisional microdosing with antibiotics.

“One advantage of cutaneous antibiotic administration is improved drug delivery to poorly perfused tissue, which would have limited reach by the systemic circulation,” wrote Amanda R. Sergesketter, MD, of Duke University, Durham, N.C., and Scott T. Hollenbeck, MD, of the University of Virginia, Charlottesville.

“While not evaluated in this study, local antibiotic delivery may be especially relevant to larger and more complex wounds,” the editorialists say. They note that the next step for future studies should be to evaluate prophylaxis in more complex situations.

“Such studies should be considered enthusiastically, given the clearly favorable impact on surgical site infections demonstrated in the PICASSo trial,” Dr. Sergesketter and Dr. Hollenbeck said.

The study was supported by a grant from the New Zealand Health Research Council. Dr. Hollenbeck reported educational grants to Duke University from Allergan, Acelity, Synovis, Integra, Smith & Nephew, Stryker, Cook, KLs Martin, Bard, VOptix, Scanlan, True Digital Surgery, Nautilus, Mitaka, Checkpoint Surgical, and Omniguide, and he is a founder and equity holder for InSoma Bio, a premarket company focused on tissue regeneration.

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

Delivering microdose incision-site injections of clindamycin significantly reduced the rate of surgical site infections (SSIs) in skin cancer surgery.

However, prophylaxis with flucloxacillin did not significantly lower SSI rates, compared with not using incision site antibiotics.

The rate of postoperative SSIs was 2.1% in the clindamycin arm, vs. 5.7% in the control arm and 5.3% in the flucloxacillin arm.

“Based on these results, we recommend the routine adoption of incisional microdosed clindamycin for patients undergoing skin cancer surgery,” Maple Goh, MBChB, of the Auckland Regional Plastic and Reconstructive Surgery Unit, Auckland, New Zealand, and the coauthors conclude. “This strategy appears suitable for widespread implementation because of the magnitude of the effect observed and the absence of adverse events.”

The study was published online in JAMA Surgery.

Skin cancer surgery carries a high risk of SSIs, which represent costly yet largely preventable complications of surgery. Despite the risk, there’s a lack of evidence from randomized clinical trials of the role of antibiotic prophylaxis in reducing SSI rates among patients undergoing skin cancer surgery. Previous studies have investigated incisional antibiotic prophylaxis to reduce SSIs with Mohs micrographic surgery, but these surgeries represent a relatively small proportion of overall skin cancer surgeries.

To understand whether this benefit extends to more general skin cancer surgeries, investigators recruited patients from a high-volume skin cancer center in New Zealand who were treated from February to July 2019. In the double-blind, prospective PICASSo trial, patients were randomly assigned to receive an incision site injection of buffered local anesthetic alone (control group), buffered local anesthetic with microdoses of flucloxacillin (500 mcg/mL), or buffered local anesthetic with microdoses of clindamycin (500 mcg/mL). The most common surgery type was excision and direct closure (approximately 80% in all arms), and the mean volume injected per length of direct closure was 1.5 mL/cm.

The primary endpoint was the rate of postoperative SSIs, defined as a postoperative wound infection score of 5 or more. The SSI rate was calculated as the number of lesions with SSIs per total number of lesions in the group.

Overall, 681 patients with 1,133 total lesions were included in the study. Compared with the control arm, the rate of postoperative SSIs was nearly threefold lower among patients who received clindamycin, –2.1% (9 of 422) vs. 5.7% (22 of 388) in the control arm (P = .01 for clindamycin vs. control).

However, flucloxacillin did not demonstrate the same effectiveness. The flucloxacillin arm and the control arm demonstrated similar postoperative SSI rates – 5.3% (17 of 323) vs. 5.7%.

The results were similar after adjusting for baseline differences and lesion ulceration.

The researchers also found that the proportion of lesions that required postoperative systemic antibiotics was four times higher among the control arm, in comparison with the clindamycin arm (8% vs. 2.1%; P < .001). It was two times higher than in the flucloxacillin arm (8% vs. 4%; P = .03).

Treatment with microdoses of incisional flucloxacillin and clindamycin was safe and well tolerated.

The researchers speculated that clindamycin’s greater effectiveness may come down to its slightly broader coverage of commonly cultured bacteria in skin and soft tissue infections, including community-associated methicillin-resistant Staphylococcus aureus. Clindamycin is known to have more efficacy against anaerobic bacteria that may be lurking in chronically ulcerated skin lesions and is associated with less local tissue inflammation, compared with flucloxacillin.

Overall, “clindamycin was significantly more effective at preventing SSI than flucloxacillin in our study,” the authors conclude. They note that the use of clindamycin as a first-line prophylaxis agent against SSIs for patients undergoing skin cancer surgery is a practical option.

“These results establish evidence-based guidelines for antibiotic prophylaxis in one of the most common surgical interventions performed worldwide, where they have been previously absent,” the researchers say.

The authors of an editorial published with the study underscore other advantages of incisional microdosing with antibiotics.

“One advantage of cutaneous antibiotic administration is improved drug delivery to poorly perfused tissue, which would have limited reach by the systemic circulation,” wrote Amanda R. Sergesketter, MD, of Duke University, Durham, N.C., and Scott T. Hollenbeck, MD, of the University of Virginia, Charlottesville.

“While not evaluated in this study, local antibiotic delivery may be especially relevant to larger and more complex wounds,” the editorialists say. They note that the next step for future studies should be to evaluate prophylaxis in more complex situations.

“Such studies should be considered enthusiastically, given the clearly favorable impact on surgical site infections demonstrated in the PICASSo trial,” Dr. Sergesketter and Dr. Hollenbeck said.

The study was supported by a grant from the New Zealand Health Research Council. Dr. Hollenbeck reported educational grants to Duke University from Allergan, Acelity, Synovis, Integra, Smith & Nephew, Stryker, Cook, KLs Martin, Bard, VOptix, Scanlan, True Digital Surgery, Nautilus, Mitaka, Checkpoint Surgical, and Omniguide, and he is a founder and equity holder for InSoma Bio, a premarket company focused on tissue regeneration.

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

Delivering microdose incision-site injections of clindamycin significantly reduced the rate of surgical site infections (SSIs) in skin cancer surgery.

However, prophylaxis with flucloxacillin did not significantly lower SSI rates, compared with not using incision site antibiotics.

The rate of postoperative SSIs was 2.1% in the clindamycin arm, vs. 5.7% in the control arm and 5.3% in the flucloxacillin arm.

“Based on these results, we recommend the routine adoption of incisional microdosed clindamycin for patients undergoing skin cancer surgery,” Maple Goh, MBChB, of the Auckland Regional Plastic and Reconstructive Surgery Unit, Auckland, New Zealand, and the coauthors conclude. “This strategy appears suitable for widespread implementation because of the magnitude of the effect observed and the absence of adverse events.”

The study was published online in JAMA Surgery.

Skin cancer surgery carries a high risk of SSIs, which represent costly yet largely preventable complications of surgery. Despite the risk, there’s a lack of evidence from randomized clinical trials of the role of antibiotic prophylaxis in reducing SSI rates among patients undergoing skin cancer surgery. Previous studies have investigated incisional antibiotic prophylaxis to reduce SSIs with Mohs micrographic surgery, but these surgeries represent a relatively small proportion of overall skin cancer surgeries.

To understand whether this benefit extends to more general skin cancer surgeries, investigators recruited patients from a high-volume skin cancer center in New Zealand who were treated from February to July 2019. In the double-blind, prospective PICASSo trial, patients were randomly assigned to receive an incision site injection of buffered local anesthetic alone (control group), buffered local anesthetic with microdoses of flucloxacillin (500 mcg/mL), or buffered local anesthetic with microdoses of clindamycin (500 mcg/mL). The most common surgery type was excision and direct closure (approximately 80% in all arms), and the mean volume injected per length of direct closure was 1.5 mL/cm.

The primary endpoint was the rate of postoperative SSIs, defined as a postoperative wound infection score of 5 or more. The SSI rate was calculated as the number of lesions with SSIs per total number of lesions in the group.

Overall, 681 patients with 1,133 total lesions were included in the study. Compared with the control arm, the rate of postoperative SSIs was nearly threefold lower among patients who received clindamycin, –2.1% (9 of 422) vs. 5.7% (22 of 388) in the control arm (P = .01 for clindamycin vs. control).

However, flucloxacillin did not demonstrate the same effectiveness. The flucloxacillin arm and the control arm demonstrated similar postoperative SSI rates – 5.3% (17 of 323) vs. 5.7%.

The results were similar after adjusting for baseline differences and lesion ulceration.

The researchers also found that the proportion of lesions that required postoperative systemic antibiotics was four times higher among the control arm, in comparison with the clindamycin arm (8% vs. 2.1%; P < .001). It was two times higher than in the flucloxacillin arm (8% vs. 4%; P = .03).

Treatment with microdoses of incisional flucloxacillin and clindamycin was safe and well tolerated.

The researchers speculated that clindamycin’s greater effectiveness may come down to its slightly broader coverage of commonly cultured bacteria in skin and soft tissue infections, including community-associated methicillin-resistant Staphylococcus aureus. Clindamycin is known to have more efficacy against anaerobic bacteria that may be lurking in chronically ulcerated skin lesions and is associated with less local tissue inflammation, compared with flucloxacillin.

Overall, “clindamycin was significantly more effective at preventing SSI than flucloxacillin in our study,” the authors conclude. They note that the use of clindamycin as a first-line prophylaxis agent against SSIs for patients undergoing skin cancer surgery is a practical option.

“These results establish evidence-based guidelines for antibiotic prophylaxis in one of the most common surgical interventions performed worldwide, where they have been previously absent,” the researchers say.

The authors of an editorial published with the study underscore other advantages of incisional microdosing with antibiotics.

“One advantage of cutaneous antibiotic administration is improved drug delivery to poorly perfused tissue, which would have limited reach by the systemic circulation,” wrote Amanda R. Sergesketter, MD, of Duke University, Durham, N.C., and Scott T. Hollenbeck, MD, of the University of Virginia, Charlottesville.

“While not evaluated in this study, local antibiotic delivery may be especially relevant to larger and more complex wounds,” the editorialists say. They note that the next step for future studies should be to evaluate prophylaxis in more complex situations.

“Such studies should be considered enthusiastically, given the clearly favorable impact on surgical site infections demonstrated in the PICASSo trial,” Dr. Sergesketter and Dr. Hollenbeck said.

The study was supported by a grant from the New Zealand Health Research Council. Dr. Hollenbeck reported educational grants to Duke University from Allergan, Acelity, Synovis, Integra, Smith & Nephew, Stryker, Cook, KLs Martin, Bard, VOptix, Scanlan, True Digital Surgery, Nautilus, Mitaka, Checkpoint Surgical, and Omniguide, and he is a founder and equity holder for InSoma Bio, a premarket company focused on tissue regeneration.

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

WASHINGTON – What does shared decision-making about atopic dermatitis (AD) treatment mean at a time of increasing treatment options and patient concerns about drug safety and the potentially lifelong need for systemic treatment?

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.

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.

Bruce Jancin/Frontline Medical News

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.

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 – What does shared decision-making about atopic dermatitis (AD) treatment mean at a time of increasing treatment options and patient concerns about drug safety and the potentially lifelong need for systemic treatment?

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.

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.

Bruce Jancin/Frontline Medical News

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.

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 – What does shared decision-making about atopic dermatitis (AD) treatment mean at a time of increasing treatment options and patient concerns about drug safety and the potentially lifelong need for systemic treatment?

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.

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.

Bruce Jancin/Frontline Medical News

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.

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.

Given the presentation and the unique location of the lesions he was diagnosed with follicular keratosis of the chin (FKC).

This is a rare and poorly understood condition that can be present in older children and young teenagers. In the cases reported by Kanzaki et al.¹ were two boys who presented with the condition; it was thought to be associated with rubbing of the chin with their hands when watching TV or reading. The author described improvement with habit change. This condition is usually described in boys, and some cases presented in brothers,² suggesting a genetic predisposition. Some reports lack a history of rubbing or trauma to the area.

Histopathologic evaluation of the lesions demonstrates dilated hair follicles containing keratotic basophilic material without any signs of inflammation.

The lesions can be confused with keratosis pilaris (KP). Keratosis pilaris can be described in association with atopic dermatitis and ichthyosis, which were not present in our patient. The lesions usually present on the sides of the cheeks and lateral region of the arms and legs. Compared with follicular keratosis, KP lesions usually present with associated perifollicular erythema. Our patient did not present with lesions on the cheeks or the sides of the arms or legs. Milia can present on the chin of children, usually if there is history of rubbing or trauma, or on a scar. Milia are micro keratin cysts, usually seen in areas of the face. Lichen spinulous is described as rough small follicular papules that present in oval or circular patches that can grow up to 5 cm and spread rapidly. They usually present on the extensor surfaces of the extremities, neck, abdomen, and knees. These lesions are thought to be secondary to infections, have been associated with atopy, and have been seen in patients with atopic dermatitis. There is a probable genetic predisposition. The lesions are usually treated with gentle soaps and moisturizer containing keratolytics like urea or salicylic acid, and in some cases topical retinoids can also be tried. Follicular mucinosis can also present similarly to keratosis follicularis. The lesions present as scaly plaques or as grouped skin color papules on the face, scalp, or the neck that can also be associated with hair loss. Sometimes a biopsy needs to be done to be able to distinguish it from follicular keratosis. There is an increase of mucin around hair follicles and sebaceous glands with associated inflammation and degeneration of the follicular structures. In patients with primary follicular mucinosis the lesions can resolve spontaneously in a couple of years. Lesions can be treated with topical corticosteroids, oral antibiotics like macrolides or tetracyclines, dapsone, and phototherapy.

KFC can be treated with vitamin D analogues. It is usually unresponsive to corticosteroids, keratolytic lotions, and retinoids. Our patient was prescribed calcipotriene.

Dr. Matiz is a pediatric dermatologist at Southern California Permanente Medical Group, San Diego

References

1. Kanzaki T et al. J Am Acad Dermatol. 1992;26(1):134-5.

2. Buechner AA et al. JAMA Dermatol. 2018 Jan 1;154(1):111-2.

Given the presentation and the unique location of the lesions he was diagnosed with follicular keratosis of the chin (FKC).

This is a rare and poorly understood condition that can be present in older children and young teenagers. In the cases reported by Kanzaki et al.¹ were two boys who presented with the condition; it was thought to be associated with rubbing of the chin with their hands when watching TV or reading. The author described improvement with habit change. This condition is usually described in boys, and some cases presented in brothers,² suggesting a genetic predisposition. Some reports lack a history of rubbing or trauma to the area.

Histopathologic evaluation of the lesions demonstrates dilated hair follicles containing keratotic basophilic material without any signs of inflammation.

The lesions can be confused with keratosis pilaris (KP). Keratosis pilaris can be described in association with atopic dermatitis and ichthyosis, which were not present in our patient. The lesions usually present on the sides of the cheeks and lateral region of the arms and legs. Compared with follicular keratosis, KP lesions usually present with associated perifollicular erythema. Our patient did not present with lesions on the cheeks or the sides of the arms or legs. Milia can present on the chin of children, usually if there is history of rubbing or trauma, or on a scar. Milia are micro keratin cysts, usually seen in areas of the face. Lichen spinulous is described as rough small follicular papules that present in oval or circular patches that can grow up to 5 cm and spread rapidly. They usually present on the extensor surfaces of the extremities, neck, abdomen, and knees. These lesions are thought to be secondary to infections, have been associated with atopy, and have been seen in patients with atopic dermatitis. There is a probable genetic predisposition. The lesions are usually treated with gentle soaps and moisturizer containing keratolytics like urea or salicylic acid, and in some cases topical retinoids can also be tried. Follicular mucinosis can also present similarly to keratosis follicularis. The lesions present as scaly plaques or as grouped skin color papules on the face, scalp, or the neck that can also be associated with hair loss. Sometimes a biopsy needs to be done to be able to distinguish it from follicular keratosis. There is an increase of mucin around hair follicles and sebaceous glands with associated inflammation and degeneration of the follicular structures. In patients with primary follicular mucinosis the lesions can resolve spontaneously in a couple of years. Lesions can be treated with topical corticosteroids, oral antibiotics like macrolides or tetracyclines, dapsone, and phototherapy.

KFC can be treated with vitamin D analogues. It is usually unresponsive to corticosteroids, keratolytic lotions, and retinoids. Our patient was prescribed calcipotriene.

Dr. Matiz is a pediatric dermatologist at Southern California Permanente Medical Group, San Diego

References

1. Kanzaki T et al. J Am Acad Dermatol. 1992;26(1):134-5.

2. Buechner AA et al. JAMA Dermatol. 2018 Jan 1;154(1):111-2.

Given the presentation and the unique location of the lesions he was diagnosed with follicular keratosis of the chin (FKC).

This is a rare and poorly understood condition that can be present in older children and young teenagers. In the cases reported by Kanzaki et al.¹ were two boys who presented with the condition; it was thought to be associated with rubbing of the chin with their hands when watching TV or reading. The author described improvement with habit change. This condition is usually described in boys, and some cases presented in brothers,² suggesting a genetic predisposition. Some reports lack a history of rubbing or trauma to the area.

Histopathologic evaluation of the lesions demonstrates dilated hair follicles containing keratotic basophilic material without any signs of inflammation.

The lesions can be confused with keratosis pilaris (KP). Keratosis pilaris can be described in association with atopic dermatitis and ichthyosis, which were not present in our patient. The lesions usually present on the sides of the cheeks and lateral region of the arms and legs. Compared with follicular keratosis, KP lesions usually present with associated perifollicular erythema. Our patient did not present with lesions on the cheeks or the sides of the arms or legs. Milia can present on the chin of children, usually if there is history of rubbing or trauma, or on a scar. Milia are micro keratin cysts, usually seen in areas of the face. Lichen spinulous is described as rough small follicular papules that present in oval or circular patches that can grow up to 5 cm and spread rapidly. They usually present on the extensor surfaces of the extremities, neck, abdomen, and knees. These lesions are thought to be secondary to infections, have been associated with atopy, and have been seen in patients with atopic dermatitis. There is a probable genetic predisposition. The lesions are usually treated with gentle soaps and moisturizer containing keratolytics like urea or salicylic acid, and in some cases topical retinoids can also be tried. Follicular mucinosis can also present similarly to keratosis follicularis. The lesions present as scaly plaques or as grouped skin color papules on the face, scalp, or the neck that can also be associated with hair loss. Sometimes a biopsy needs to be done to be able to distinguish it from follicular keratosis. There is an increase of mucin around hair follicles and sebaceous glands with associated inflammation and degeneration of the follicular structures. In patients with primary follicular mucinosis the lesions can resolve spontaneously in a couple of years. Lesions can be treated with topical corticosteroids, oral antibiotics like macrolides or tetracyclines, dapsone, and phototherapy.

KFC can be treated with vitamin D analogues. It is usually unresponsive to corticosteroids, keratolytic lotions, and retinoids. Our patient was prescribed calcipotriene.

Dr. Matiz is a pediatric dermatologist at Southern California Permanente Medical Group, San Diego

References

1. Kanzaki T et al. J Am Acad Dermatol. 1992;26(1):134-5.

2. Buechner AA et al. JAMA Dermatol. 2018 Jan 1;154(1):111-2.

MILAN – Dazodalibep, an intravenously administered inhibitor of CD40 ligand, shows promise in reducing disease activity and alleviating key subjective symptoms of Sjögren’s syndrome, compared with placebo. These preliminary findings are from the initial phase of the ALISS trial, a phase 2 randomized, double-blind, placebo-controlled, crossover clinical trial presented at the annul European Congress of Rheumatology.

Over the course of the 169-day trial, both the disease activity score and the patient-reported symptom score dropped significantly for patients who were treated with dazodalibep, also known as VIB4920 or HZN4920, compared with those treated with placebo, meeting both primary endpoints. This benefit was particularly evident for patients who had limited systemic organ involvement but substantial symptom burden.

Dazodalibep is a fusion protein that functions as an inhibitor by blocking the interaction between T cells and CD40-expressing B cells. This inhibition effectively suppresses costimulatory signaling between immune cells. Unlike previous CD40-targeting biologics, dazodalibep does not belong to the antibody class. According to Horizon Thereapeutics, this distinction is expected to help mitigate safety concerns, particularly those related to blood clot formation that were encountered with antibody-based biologics such as ruplizumab, according to Horizon, which acquired the trial’s sponsor, Viela Bio.
 

Patients with moderate to high systemic disease activity

The trial investigated dazodalibep in two patient populations. Wan-Fai Ng, MBBCh, PhD, professor of rheumatology at Newcastle University and honorary consultant rheumatologist at Newcastle upon Tyne Hospitals NHS Foundation Trust, England, presented results from the first group, which comprised 74 adult patients with Sjögren’s syndrome with moderate to high systemic disease activity. Disease activity was defined as a score of ≥ 5 on the EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI).

A post hoc responder analysis demonstrated that dazodalibep outperformed placebo in patients who achieved a 5- or 6-point improvement on the ESSDAI. Response rates for these patients was 61.1% and 60.0%, respectively, compared with 35.1% and 34.3% for patients who received placebo. Patients who received dazodalibep experienced a reduction of –6.3 ± 0.6 points in ESSDAI score, whereas the placebo group experienced a reduction of –4.1 ± 0.6 points, a difference of –2.2 (P = .0167). However, there was no significant change in any symptom-related score in this population.
 

Patients with unacceptable symptom burden but limited systemic involvement

Also at EULAR 2023, Chiara Baldini, MD, of the University of Pisa, Italy, reported the results from the second group of 109 adult patients with Sjögren’s syndrome who had notable symptom burden but limited systemic organ involvement. “These patients represent a significant portion of individuals with reduced quality of life who are largely excluded from other clinical trials,” Dr. Baldini said in an interview. The study population was defined by having a EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI) ≥ 5 and, in contrast to the previous group, an ESSDAI score < 5.

In this case, treatment with dazodalibep correlated with a substantial reduction in symptom burden, compared with placebo. Among the patients who received dazodalibep, 66.7% achieved ≥ 1 point or ≥ 15% reduction in symptoms, as measured by ESSPRI, compared with 32.7% in the placebo group. The ESSPRI score decreased by –1.80 ± 0.23 points in the dazodalibep group, while it decreased by –0.53 ± 0.23 points in the placebo group, a difference of −1.27 ± 0.33 points favoring dazodalibep (P = .0002). The reduction in symptoms in the dazodalibep group was evident from the first data point on day 29 and was statistically significant for each of the three symptom components included in the ESSPRI score: dryness, pain, and fatigue.

Additionally, a significant improvement was observed in one of the secondary endpoints, namely, a reduction in the Functional Assessment of Chronic Illness Therapy-Fatigue score. The dazodalibep group exhibited a considerably greater reduction (+8.1 ± 1.4, compared with baseline) than did the placebo group (+2.8 ± 1.4; P = .0095).
 

Dazodalibep safety

“Dazodalibep therapy was generally safe and well tolerated,” Dr. Baldini said in her presentation. Adverse events that were reported for both investigations were generally mild and occurred with similar frequency between the treatment groups. The most commonly reported adverse events, each occurring in more than 5% of patients who received dazodalibep, were COVID-19, diarrhea, anemia, dizziness, ligament sprain, upper respiratory tract infection, and nasopharyngitis. The incidence of COVID-19 and nasopharyngitis was comparable between the treatment and placebo arms.

However, in the patient group with moderate to high systemic disease activity, one patient who was treated with dazodalibep experienced two serious adverse events: a grade 3 SARS-CoV-2 infection, and subsequent death from an unknown cause, which occurred 46 days after the last administration of dazodalibep (12 days after COVID-19 diagnosis). Additionally, there was one case of herpes zoster in a patient treated with dazodalibep. In the group with limited systemic organ involvement, three serious adverse events were reported in the dazodalibep group (pneumonia influenza, postacute COVID-19 syndrome [long COVID], and gammopathy); one serious adverse event (neutropenia) was reported in the placebo group. One patient in the dazodalibep group discontinued participation in the study because of an adverse event, compared with two in the placebo group. Investigators determined that, thus far, all serious adverse events in both populations have been unrelated to the medication.

Throughout the trial, eligible participants in both populations were randomly assigned in a 1:1 ratio to receive either intravenous dazodalibep 1,500 mg or placebo every 2 weeks for three doses, followed by every 4 weeks for an additional four doses, up to day 169. The majority of participants in all populations and treatment arms were women (> 90%). Key inclusion criteria were being aged 18 years or older, meeting the 2016 American College of Rheumatology–EULAR classification criteria for Sjögren’s syndrome, and testing positive for anti-SSA and/or rheumatoid factors. Exclusion criteria were having a medical history of thrombosis or anticoagulant use, as well as prior treatment with B cell–depleting therapies. The proportions of patients who received glucocorticoids, antimalarials, or disease-modifying antirheumatic drugs were consistent between both arms of each population.

“Larger clinical trials are necessary to validate the clinical effectiveness and safety of dazodalibep therapy in this specific subgroup of patients,” Dr. Baldini concluded. Currently, dazodalibep is being studied for the treatment of rheumatoid arthritis and renal transplant rejection, and Horizon Therapeutics has plans to explore its use in focal segmental glomerulosclerosis.

Dr. Ng has served as a consultant to Novartis, GlaxoSmithKline, AbbVie, Bristol-Myers Squibb, Sanofi, MedImmune, Resolves Therapeutics, Janssen, and UCB. Dr. Baldini has served as a consultant to GlaxoSmithKline and Sanofi.

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

MILAN – Dazodalibep, an intravenously administered inhibitor of CD40 ligand, shows promise in reducing disease activity and alleviating key subjective symptoms of Sjögren’s syndrome, compared with placebo. These preliminary findings are from the initial phase of the ALISS trial, a phase 2 randomized, double-blind, placebo-controlled, crossover clinical trial presented at the annul European Congress of Rheumatology.

Over the course of the 169-day trial, both the disease activity score and the patient-reported symptom score dropped significantly for patients who were treated with dazodalibep, also known as VIB4920 or HZN4920, compared with those treated with placebo, meeting both primary endpoints. This benefit was particularly evident for patients who had limited systemic organ involvement but substantial symptom burden.

Dazodalibep is a fusion protein that functions as an inhibitor by blocking the interaction between T cells and CD40-expressing B cells. This inhibition effectively suppresses costimulatory signaling between immune cells. Unlike previous CD40-targeting biologics, dazodalibep does not belong to the antibody class. According to Horizon Thereapeutics, this distinction is expected to help mitigate safety concerns, particularly those related to blood clot formation that were encountered with antibody-based biologics such as ruplizumab, according to Horizon, which acquired the trial’s sponsor, Viela Bio.
 

Patients with moderate to high systemic disease activity

The trial investigated dazodalibep in two patient populations. Wan-Fai Ng, MBBCh, PhD, professor of rheumatology at Newcastle University and honorary consultant rheumatologist at Newcastle upon Tyne Hospitals NHS Foundation Trust, England, presented results from the first group, which comprised 74 adult patients with Sjögren’s syndrome with moderate to high systemic disease activity. Disease activity was defined as a score of ≥ 5 on the EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI).

A post hoc responder analysis demonstrated that dazodalibep outperformed placebo in patients who achieved a 5- or 6-point improvement on the ESSDAI. Response rates for these patients was 61.1% and 60.0%, respectively, compared with 35.1% and 34.3% for patients who received placebo. Patients who received dazodalibep experienced a reduction of –6.3 ± 0.6 points in ESSDAI score, whereas the placebo group experienced a reduction of –4.1 ± 0.6 points, a difference of –2.2 (P = .0167). However, there was no significant change in any symptom-related score in this population.
 

Patients with unacceptable symptom burden but limited systemic involvement

Also at EULAR 2023, Chiara Baldini, MD, of the University of Pisa, Italy, reported the results from the second group of 109 adult patients with Sjögren’s syndrome who had notable symptom burden but limited systemic organ involvement. “These patients represent a significant portion of individuals with reduced quality of life who are largely excluded from other clinical trials,” Dr. Baldini said in an interview. The study population was defined by having a EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI) ≥ 5 and, in contrast to the previous group, an ESSDAI score < 5.

In this case, treatment with dazodalibep correlated with a substantial reduction in symptom burden, compared with placebo. Among the patients who received dazodalibep, 66.7% achieved ≥ 1 point or ≥ 15% reduction in symptoms, as measured by ESSPRI, compared with 32.7% in the placebo group. The ESSPRI score decreased by –1.80 ± 0.23 points in the dazodalibep group, while it decreased by –0.53 ± 0.23 points in the placebo group, a difference of −1.27 ± 0.33 points favoring dazodalibep (P = .0002). The reduction in symptoms in the dazodalibep group was evident from the first data point on day 29 and was statistically significant for each of the three symptom components included in the ESSPRI score: dryness, pain, and fatigue.

Additionally, a significant improvement was observed in one of the secondary endpoints, namely, a reduction in the Functional Assessment of Chronic Illness Therapy-Fatigue score. The dazodalibep group exhibited a considerably greater reduction (+8.1 ± 1.4, compared with baseline) than did the placebo group (+2.8 ± 1.4; P = .0095).
 

Dazodalibep safety

“Dazodalibep therapy was generally safe and well tolerated,” Dr. Baldini said in her presentation. Adverse events that were reported for both investigations were generally mild and occurred with similar frequency between the treatment groups. The most commonly reported adverse events, each occurring in more than 5% of patients who received dazodalibep, were COVID-19, diarrhea, anemia, dizziness, ligament sprain, upper respiratory tract infection, and nasopharyngitis. The incidence of COVID-19 and nasopharyngitis was comparable between the treatment and placebo arms.

However, in the patient group with moderate to high systemic disease activity, one patient who was treated with dazodalibep experienced two serious adverse events: a grade 3 SARS-CoV-2 infection, and subsequent death from an unknown cause, which occurred 46 days after the last administration of dazodalibep (12 days after COVID-19 diagnosis). Additionally, there was one case of herpes zoster in a patient treated with dazodalibep. In the group with limited systemic organ involvement, three serious adverse events were reported in the dazodalibep group (pneumonia influenza, postacute COVID-19 syndrome [long COVID], and gammopathy); one serious adverse event (neutropenia) was reported in the placebo group. One patient in the dazodalibep group discontinued participation in the study because of an adverse event, compared with two in the placebo group. Investigators determined that, thus far, all serious adverse events in both populations have been unrelated to the medication.

Throughout the trial, eligible participants in both populations were randomly assigned in a 1:1 ratio to receive either intravenous dazodalibep 1,500 mg or placebo every 2 weeks for three doses, followed by every 4 weeks for an additional four doses, up to day 169. The majority of participants in all populations and treatment arms were women (> 90%). Key inclusion criteria were being aged 18 years or older, meeting the 2016 American College of Rheumatology–EULAR classification criteria for Sjögren’s syndrome, and testing positive for anti-SSA and/or rheumatoid factors. Exclusion criteria were having a medical history of thrombosis or anticoagulant use, as well as prior treatment with B cell–depleting therapies. The proportions of patients who received glucocorticoids, antimalarials, or disease-modifying antirheumatic drugs were consistent between both arms of each population.

“Larger clinical trials are necessary to validate the clinical effectiveness and safety of dazodalibep therapy in this specific subgroup of patients,” Dr. Baldini concluded. Currently, dazodalibep is being studied for the treatment of rheumatoid arthritis and renal transplant rejection, and Horizon Therapeutics has plans to explore its use in focal segmental glomerulosclerosis.

Dr. Ng has served as a consultant to Novartis, GlaxoSmithKline, AbbVie, Bristol-Myers Squibb, Sanofi, MedImmune, Resolves Therapeutics, Janssen, and UCB. Dr. Baldini has served as a consultant to GlaxoSmithKline and Sanofi.

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

MILAN – Dazodalibep, an intravenously administered inhibitor of CD40 ligand, shows promise in reducing disease activity and alleviating key subjective symptoms of Sjögren’s syndrome, compared with placebo. These preliminary findings are from the initial phase of the ALISS trial, a phase 2 randomized, double-blind, placebo-controlled, crossover clinical trial presented at the annul European Congress of Rheumatology.

Over the course of the 169-day trial, both the disease activity score and the patient-reported symptom score dropped significantly for patients who were treated with dazodalibep, also known as VIB4920 or HZN4920, compared with those treated with placebo, meeting both primary endpoints. This benefit was particularly evident for patients who had limited systemic organ involvement but substantial symptom burden.

Dazodalibep is a fusion protein that functions as an inhibitor by blocking the interaction between T cells and CD40-expressing B cells. This inhibition effectively suppresses costimulatory signaling between immune cells. Unlike previous CD40-targeting biologics, dazodalibep does not belong to the antibody class. According to Horizon Thereapeutics, this distinction is expected to help mitigate safety concerns, particularly those related to blood clot formation that were encountered with antibody-based biologics such as ruplizumab, according to Horizon, which acquired the trial’s sponsor, Viela Bio.
 

Patients with moderate to high systemic disease activity

The trial investigated dazodalibep in two patient populations. Wan-Fai Ng, MBBCh, PhD, professor of rheumatology at Newcastle University and honorary consultant rheumatologist at Newcastle upon Tyne Hospitals NHS Foundation Trust, England, presented results from the first group, which comprised 74 adult patients with Sjögren’s syndrome with moderate to high systemic disease activity. Disease activity was defined as a score of ≥ 5 on the EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI).

A post hoc responder analysis demonstrated that dazodalibep outperformed placebo in patients who achieved a 5- or 6-point improvement on the ESSDAI. Response rates for these patients was 61.1% and 60.0%, respectively, compared with 35.1% and 34.3% for patients who received placebo. Patients who received dazodalibep experienced a reduction of –6.3 ± 0.6 points in ESSDAI score, whereas the placebo group experienced a reduction of –4.1 ± 0.6 points, a difference of –2.2 (P = .0167). However, there was no significant change in any symptom-related score in this population.
 

Patients with unacceptable symptom burden but limited systemic involvement

Also at EULAR 2023, Chiara Baldini, MD, of the University of Pisa, Italy, reported the results from the second group of 109 adult patients with Sjögren’s syndrome who had notable symptom burden but limited systemic organ involvement. “These patients represent a significant portion of individuals with reduced quality of life who are largely excluded from other clinical trials,” Dr. Baldini said in an interview. The study population was defined by having a EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI) ≥ 5 and, in contrast to the previous group, an ESSDAI score < 5.

In this case, treatment with dazodalibep correlated with a substantial reduction in symptom burden, compared with placebo. Among the patients who received dazodalibep, 66.7% achieved ≥ 1 point or ≥ 15% reduction in symptoms, as measured by ESSPRI, compared with 32.7% in the placebo group. The ESSPRI score decreased by –1.80 ± 0.23 points in the dazodalibep group, while it decreased by –0.53 ± 0.23 points in the placebo group, a difference of −1.27 ± 0.33 points favoring dazodalibep (P = .0002). The reduction in symptoms in the dazodalibep group was evident from the first data point on day 29 and was statistically significant for each of the three symptom components included in the ESSPRI score: dryness, pain, and fatigue.

Additionally, a significant improvement was observed in one of the secondary endpoints, namely, a reduction in the Functional Assessment of Chronic Illness Therapy-Fatigue score. The dazodalibep group exhibited a considerably greater reduction (+8.1 ± 1.4, compared with baseline) than did the placebo group (+2.8 ± 1.4; P = .0095).
 

Dazodalibep safety

“Dazodalibep therapy was generally safe and well tolerated,” Dr. Baldini said in her presentation. Adverse events that were reported for both investigations were generally mild and occurred with similar frequency between the treatment groups. The most commonly reported adverse events, each occurring in more than 5% of patients who received dazodalibep, were COVID-19, diarrhea, anemia, dizziness, ligament sprain, upper respiratory tract infection, and nasopharyngitis. The incidence of COVID-19 and nasopharyngitis was comparable between the treatment and placebo arms.

However, in the patient group with moderate to high systemic disease activity, one patient who was treated with dazodalibep experienced two serious adverse events: a grade 3 SARS-CoV-2 infection, and subsequent death from an unknown cause, which occurred 46 days after the last administration of dazodalibep (12 days after COVID-19 diagnosis). Additionally, there was one case of herpes zoster in a patient treated with dazodalibep. In the group with limited systemic organ involvement, three serious adverse events were reported in the dazodalibep group (pneumonia influenza, postacute COVID-19 syndrome [long COVID], and gammopathy); one serious adverse event (neutropenia) was reported in the placebo group. One patient in the dazodalibep group discontinued participation in the study because of an adverse event, compared with two in the placebo group. Investigators determined that, thus far, all serious adverse events in both populations have been unrelated to the medication.

Throughout the trial, eligible participants in both populations were randomly assigned in a 1:1 ratio to receive either intravenous dazodalibep 1,500 mg or placebo every 2 weeks for three doses, followed by every 4 weeks for an additional four doses, up to day 169. The majority of participants in all populations and treatment arms were women (> 90%). Key inclusion criteria were being aged 18 years or older, meeting the 2016 American College of Rheumatology–EULAR classification criteria for Sjögren’s syndrome, and testing positive for anti-SSA and/or rheumatoid factors. Exclusion criteria were having a medical history of thrombosis or anticoagulant use, as well as prior treatment with B cell–depleting therapies. The proportions of patients who received glucocorticoids, antimalarials, or disease-modifying antirheumatic drugs were consistent between both arms of each population.

“Larger clinical trials are necessary to validate the clinical effectiveness and safety of dazodalibep therapy in this specific subgroup of patients,” Dr. Baldini concluded. Currently, dazodalibep is being studied for the treatment of rheumatoid arthritis and renal transplant rejection, and Horizon Therapeutics has plans to explore its use in focal segmental glomerulosclerosis.

Dr. Ng has served as a consultant to Novartis, GlaxoSmithKline, AbbVie, Bristol-Myers Squibb, Sanofi, MedImmune, Resolves Therapeutics, Janssen, and UCB. Dr. Baldini has served as a consultant to GlaxoSmithKline and Sanofi.

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

The introduction of tumor necrosis factor (TNF) inhibitors in the late 1990s revolutionized treatment of rheumatic diseases, such as rheumatoid arthritis (RA) and psoriatic arthritis (PsA), providing patients with another treatment option when conventional therapies were ineffective. However, when these diseases don’t respond to anti-TNF therapy, it is still difficult to determine the next best course of action.

“One of the big challenges we have in treatment of psoriatic arthritis, and I would say rheumatoid arthritis was well, is how to handle patients who have failed their first biologic therapy,” Christopher T. Ritchlin, MD, MPH, professor of allergy, immunology, and rheumatology at the University of Rochester (N.Y.), told this news organization. “In the case of both RA and PsA, that’s quite frequently an anti-TNF agent.”

For an estimated 30% to 40% of patients, TNF inhibitor therapy is discontinued because of nonresponse or intolerance. Clinicians can switch to another biologic or targeted synthetic disease-modifying antirheumatic drug (DMARD) or add another conventional DMARD, such as methotrexate. Now, several case studies as well as promising findings from phase 2 clinical trials suggest that combining two biologics could be an alternative strategy to improve patient response to treatment. However, concerns about safety and higher costs remain.
 

Targeting multiple mechanisms of action

Rheumatic conditions affect multiple areas of the body and involve different signaling pathways, said Dr. Ritchlin, who heads the Clinical Immunology Research Unit at the University of Rochester. PsA, for example, affects the skin, peripheral joints, the axial skeleton, and the entheses.

“The question is, Are these various manifestations – of which multiple [ones] are often seen in one patient – likely to respond to one therapy that targets one single pathway?” he said.

Combination therapies have been effective in treating leukemia and lymphoma as well as infection with HIV, Melek Yalçin Mutlu, MD, and colleagues from Friedrich Alexander University Erlangen-Nuremberg and the University Clinic Erlangen (Germany), wrote in a review about combining biologic DMARDs in the treatment of RA and PsA. The review was published in Joint Bone Spine.

“Cumulative evidence on the success of combination therapies in various diseases supports an akin approach in rheumatology, and simultaneous or sequential blockade of multiple mechanisms that generate or propagate arthritis could theoretically enhance efficacy,” the authors wrote. “On the other hand, intervening on multiple targets in the immune system brings about a risk of adverse events, among which infection is a major concern.”
 

Failed clinical trials

Clinical trials of combination biologic therapies for rheumatic disease have been tried before, but these combinations did not show superior efficacy, and they increased patients’ risk for infection. One study published in 2004 compared monotherapy with the TNF inhibitor etanercept (Enbrel) to the combination of etanercept and anakinra (Kineret), an interleukin-1 (IL-1) antagonist, in 244 patients with active RA despite methotrexate therapy. Researchers found no statistically significant difference in achieving 20% improvement in modified American College of Rheumatology response criteria (ACR20), ACR50, or ACR70 between the groups that received etanercept and anakinra and those that received etanercept alone. There were nine serious infections among patients given etanercept and anakinra, including one death due to pneumonia. There were no serious infections in the etanercept monotherapy group.

In another RA trial, 121 patients were given etanercept 25 mg twice weekly and were randomly assigned to also receive a placebo or low-dose abatacept (Orencia), a T-cell co-stimulation inhibitor. There was no significant difference in disease improvement between the two groups, although the rate of serious adverse events was nearly six times higher in the etanercept-abatacept group (16.5% vs. 2.8%).

These studies had a “chilling effect on the whole field for some years,” Brian G. Feagan, MD, the senior scientific director of the gastrointestinal contract research firm Alimentiv in London, Ontario, told this news organization. People were reluctant to try new biologic combinations, owing to the fear that these safety issues would plague subsequent trials.

University of Western Ontario, London

Promising combinations

But a recent phase 2 trial, led by Dr. Feagan, suggests that certain combinations can be effective. In the Janssen-sponsored VEGA trial, researchers found that a combination of guselkumab (Tremfya), an IL-23 inhibitor, and golimumab (Simponi), an anti-TNF agent, was more effective than either drug used as monotherapy for initial induction treatment for moderate to severe ulcerative colitis. Importantly, there was no difference in adverse events between any of the groups. This same combination therapy is now being tried for patients with active PsA in Janssen’s AFFINITY trial, for which Dr. Ritchlin is one of the lead investigators.

Other trials have also delivered promising results. One study enrolled 51 adults with active RA who were all receiving stable doses of both a TNF inhibitor – either etanercept or adalimumab (Humira) – and methotrexate. Patients were randomly assigned to receive one course of rituximab (Rituxan) or placebo. The researchers found that the safety profile of this TNF inhibitor/methotrexate/rituximab combination was “consistent” with the safety profiles of previous studies of methotrexate/rituximab dual combinations with no TNF inhibitor; there were no new safety signals. At 24 weeks, 30% of the group that received rituximab reached ACR20, compared with 17% of the group that was given placebo. Twelve percent of the rituximab group achieved ACR50, compared with 6% of the group that received placebo.

“B-cell depletion is fundamentally different from cytokine inhibition and even from co-stimulation blockade, making an additive effect more likely,” Dr. Mutlu and colleagues wrote in their review. Reports have also suggested possible benefits of combining a TNF inhibitor and an IL-17 inhibitor in the treatment of RA and PsA, as well as the combination of a TNF inhibitor and an IL-23 antagonist for PsA.

While these combinations require controlled clinical trials, “there’s some smoke signals out there that this might be an effective strategy for some patients,” Dr. Ritchlin said.

In addition to the AFFINITY trial, two clinical trials are underway in France. The first, CRI-RA, is evaluating the combination of baricitinib (Olumiant), a Janus kinase (JAK) inhibitor, and adalimumab. Although baricitinib is not a biologic, as a targeted synthetic DMARD, the therapy is more potent than conventional DMARDs, and the same potential safety concerns apply. However, use of a combination of tofacitinib (Xeljanz) and different biologics for RA patients has been reported; no serious side effects were reported over 11 months of therapy. The randomized, placebo-controlled trial began in July 2021 and will enroll 178 patients. The estimated study completion date is July 2025.

“Of note, baricitinib does not directly block signaling downstream of TNF, even if an indirect effect on TNF production is likely to occur,” the CRI-RA entry on clinicaltrials.gov reads. “Targeting multiple inflammatory cytokines in combination may lead to more effective treatment and enhanced clinical responses in patients with RA compared to the current second-line strategies.”

The second trial, SEQUENS-RA, is evaluating the use of TNF inhibitors followed by abatacept for patients with RA who test positive for anticitrullinated protein autoantibodies (ACPAs). In the past, the combination of a TNF inhibitor and abatacept did not lead to promising results, but in this trial, the drugs will be administered sequentially.

“Although abatacept has shown a very good tolerance profile that might be superior to other bDMARDs [biologic DMARDs], rheumatologists might be reluctant to use it as a first line bDMARD as there is a belief of a slower efficacy compared to other bDMARDs or JAK inhibitors,” according to the clinical trial’s description. “Investigators have hypothesized that first rapidly controlling the inflammation phase, using TNF inhibitors, followed by abatacept to induce an immunological remission, would optimize response and tolerance of ACPA-positive patients with RA.”

The randomized trial of 220 participants began in November 2022. The estimated completion date for the study is November 2025.
 

Finding the right patients

Though these studies have had some promising results, the difference in efficacy between biologic monotherapy and dual therapy has been mostly moderate, Dr. Mutlu and coauthors wrote. Identifying disease subtypes for which there might be a higher likelihood of response to dual biologic treatment, especially multidrug-resistant types, could improve efficacies in future trials, they argued. “The good effects of bDMARD combinations in resistant patients in fact point into this direction, though they were observed in uncontrolled studies,” the authors noted.

Insurance coverage remains a “huge challenge” for these dual therapies because of the higher expense, noted Dr. Ritchlin. Better targeting therapies could help convince these companies to pay for these therapies.

“I would say that if we were able to demonstrate a phenotype of a patient that would respond to biologics and not monotherapies, [then] many companies would be amenable to this kind of approach,” he said.

Dr. Ritchlin reports financial relationships with AbbVie, Bristol-Myers Squibb, Janssen, Pfizer, Eli Lilly, Novartis, and UCB. Dr. Feagan reports financial relationships with AbbVie, Amgen, Janssen, Pfizer, Takeda, and several other pharmaceutical companies.

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

The introduction of tumor necrosis factor (TNF) inhibitors in the late 1990s revolutionized treatment of rheumatic diseases, such as rheumatoid arthritis (RA) and psoriatic arthritis (PsA), providing patients with another treatment option when conventional therapies were ineffective. However, when these diseases don’t respond to anti-TNF therapy, it is still difficult to determine the next best course of action.

“One of the big challenges we have in treatment of psoriatic arthritis, and I would say rheumatoid arthritis was well, is how to handle patients who have failed their first biologic therapy,” Christopher T. Ritchlin, MD, MPH, professor of allergy, immunology, and rheumatology at the University of Rochester (N.Y.), told this news organization. “In the case of both RA and PsA, that’s quite frequently an anti-TNF agent.”

For an estimated 30% to 40% of patients, TNF inhibitor therapy is discontinued because of nonresponse or intolerance. Clinicians can switch to another biologic or targeted synthetic disease-modifying antirheumatic drug (DMARD) or add another conventional DMARD, such as methotrexate. Now, several case studies as well as promising findings from phase 2 clinical trials suggest that combining two biologics could be an alternative strategy to improve patient response to treatment. However, concerns about safety and higher costs remain.
 

Targeting multiple mechanisms of action

Rheumatic conditions affect multiple areas of the body and involve different signaling pathways, said Dr. Ritchlin, who heads the Clinical Immunology Research Unit at the University of Rochester. PsA, for example, affects the skin, peripheral joints, the axial skeleton, and the entheses.

“The question is, Are these various manifestations – of which multiple [ones] are often seen in one patient – likely to respond to one therapy that targets one single pathway?” he said.

Combination therapies have been effective in treating leukemia and lymphoma as well as infection with HIV, Melek Yalçin Mutlu, MD, and colleagues from Friedrich Alexander University Erlangen-Nuremberg and the University Clinic Erlangen (Germany), wrote in a review about combining biologic DMARDs in the treatment of RA and PsA. The review was published in Joint Bone Spine.

“Cumulative evidence on the success of combination therapies in various diseases supports an akin approach in rheumatology, and simultaneous or sequential blockade of multiple mechanisms that generate or propagate arthritis could theoretically enhance efficacy,” the authors wrote. “On the other hand, intervening on multiple targets in the immune system brings about a risk of adverse events, among which infection is a major concern.”