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Nadolol bests propranolol for infantile hemangioma treatment out to 52 weeks
of 71 patients showed.
“In clinical practice, we notice that nadolol works very well in terms of controlling the size and the appearance of the hemangioma,” lead study author Elena Pope, MD, MSc, said during the annual meeting of the Society for Pediatric Dermatology. Hence, she and her colleagues were interested in comparing their clinical experience with the standard treatment with propranolol, and designed a prospective, randomized, controlled, double-blinded study, with the aim of proving that “nadolol is noninferior to propranolol, with a margin of noninferiority of 10%.”
Between 2016 and 2020, Dr. Pope and colleagues at two academic Canadian pediatric dermatology centers enrolled 71 infants aged 1-6 months with significant hemangioma that had either the potential for functional impairment or cosmetic deformity, defined as a lesion greater than 1.5 cm on the face or greater than 3 cm on another body part. Treatment consisted of oral propranolol or nadolol in escalating doses up to 2 mg/kg per day. “The blinding portion of the study was for 24 weeks with a follow-up up to 52 weeks,” said Dr. Pope, professor of pediatrics at the University of Toronto and section head of pediatric dermatology at The Hospital for Sick Children, also in Toronto. “After the unblinding at 24 weeks, patients were allowed to switch their intervention if they were not happy with the results.”
Of the 71 patients, 35 received nadolol and 36 received propranolol. The two groups were similar in terms of clinical and demographic characteristics. Their mean age at enrollment was 3.15 months, 80% were female, 61% were White, 20% were Asian, and the rest were from other ethnic backgrounds.
At 24 weeks, the researchers found that the mean size involution was 97.94% in the nadolol group and 89.14% in the propranolol group (P = .005), while the mean color fading on the visual analogue scale (VAS) was 94.47% in the nadolol group and 80.54% in the propranolol group (P < .001). At 52 weeks, the mean size involution was 99.63% in the nadolol group and 93.63% in the propranolol group (P = .001), while the mean VAS color fading was 97.34% in the nadolol group and 87.23% in the propranolol group (P = .001).
According to Dr. Pope, Kaplan-Meir analysis showed that patients in the propranolol group responded slower to treatment (P = .019), while safety data was similar between the two groups. For example, between weeks 25 and 52, 84.2% of patients in the nadolol group experienced an adverse event, compared with 74.2% of patients in the propranolol group (P = .466). The most common respiratory adverse event was upper respiratory tract infection, which affected 87.5% of patients in the nadolol group, compared with 100% of patients in the propranolol group (P = 0.341).
The most common gastrointestinal adverse event was diarrhea, which affected 66.7% of patients in both groups. One patient in the propranolol group was admitted to the hospital with pneumonia and fully recovered. The incident was not suspected to be related to the medication.
“We believe that this data backs up our clinical experience and it may offer an alternative treatment in other centers where patients experience propranolol unresponsiveness, side effects, or intolerance, or where a fast response is needed,” Dr. Pope said. As for the potential cost implications, “nadolol is cheaper than the Hemangiol but comparable with the compounded formulation of propranolol.”
Concern over the safety of nadolol was raised in a case report published in Pediatrics in 2020. Authors from Alberta reported the case of a 10-week-old girl who was started on nadolol for infantile hemangioma, died 7 weeks later, and was found to have an elevated postmortem cardiac blood nadolol level of 0.94 mg/L. “The infant had no bowel movements for 10 days before her death, which we hypothesize contributed to nadolol toxicity,” the authors wrote.
In a reply to the authors in the same issue of Pediatrics, Dr. Pope, Cathryn Sibbald, MD, and Erin Chung, PhD, pointed out that postmortem redistribution of medications “is complex and measured postmortem cardiac blood concentrations may be significantly higher than the true blood nadolol concentration at the time of death due to significant diffusion from the peripheral tissues.”
They added that the report did not address “other potential errors such as in compounding, dispensing, and administration of the solution,” they wrote, adding: “Finally, we are aware of a Canadian case of death in an infant receiving propranolol, although the cause of death in that case was unable to be determined (ISMP Canada 2016 Safety Bulletin).We agree with the authors that careful consideration of the risks and benefits of beta-blocker therapy should be employed, parents need to be informed when to discontinue therapy and that further research into the pharmacokinetics and pharmacogenetics of beta-blockers are warranted.”
Following publication of the case report in Pediatrics, Dr. Pope said that the only change she made in her practice was to ask families to temporarily discontinue nadolol if their child had constipation for more than 5 days.
The study was supported by a grant from Physician Services, Inc. Dr. Pope reported having no financial disclosures.
of 71 patients showed.
“In clinical practice, we notice that nadolol works very well in terms of controlling the size and the appearance of the hemangioma,” lead study author Elena Pope, MD, MSc, said during the annual meeting of the Society for Pediatric Dermatology. Hence, she and her colleagues were interested in comparing their clinical experience with the standard treatment with propranolol, and designed a prospective, randomized, controlled, double-blinded study, with the aim of proving that “nadolol is noninferior to propranolol, with a margin of noninferiority of 10%.”
Between 2016 and 2020, Dr. Pope and colleagues at two academic Canadian pediatric dermatology centers enrolled 71 infants aged 1-6 months with significant hemangioma that had either the potential for functional impairment or cosmetic deformity, defined as a lesion greater than 1.5 cm on the face or greater than 3 cm on another body part. Treatment consisted of oral propranolol or nadolol in escalating doses up to 2 mg/kg per day. “The blinding portion of the study was for 24 weeks with a follow-up up to 52 weeks,” said Dr. Pope, professor of pediatrics at the University of Toronto and section head of pediatric dermatology at The Hospital for Sick Children, also in Toronto. “After the unblinding at 24 weeks, patients were allowed to switch their intervention if they were not happy with the results.”
Of the 71 patients, 35 received nadolol and 36 received propranolol. The two groups were similar in terms of clinical and demographic characteristics. Their mean age at enrollment was 3.15 months, 80% were female, 61% were White, 20% were Asian, and the rest were from other ethnic backgrounds.
At 24 weeks, the researchers found that the mean size involution was 97.94% in the nadolol group and 89.14% in the propranolol group (P = .005), while the mean color fading on the visual analogue scale (VAS) was 94.47% in the nadolol group and 80.54% in the propranolol group (P < .001). At 52 weeks, the mean size involution was 99.63% in the nadolol group and 93.63% in the propranolol group (P = .001), while the mean VAS color fading was 97.34% in the nadolol group and 87.23% in the propranolol group (P = .001).
According to Dr. Pope, Kaplan-Meir analysis showed that patients in the propranolol group responded slower to treatment (P = .019), while safety data was similar between the two groups. For example, between weeks 25 and 52, 84.2% of patients in the nadolol group experienced an adverse event, compared with 74.2% of patients in the propranolol group (P = .466). The most common respiratory adverse event was upper respiratory tract infection, which affected 87.5% of patients in the nadolol group, compared with 100% of patients in the propranolol group (P = 0.341).
The most common gastrointestinal adverse event was diarrhea, which affected 66.7% of patients in both groups. One patient in the propranolol group was admitted to the hospital with pneumonia and fully recovered. The incident was not suspected to be related to the medication.
“We believe that this data backs up our clinical experience and it may offer an alternative treatment in other centers where patients experience propranolol unresponsiveness, side effects, or intolerance, or where a fast response is needed,” Dr. Pope said. As for the potential cost implications, “nadolol is cheaper than the Hemangiol but comparable with the compounded formulation of propranolol.”
Concern over the safety of nadolol was raised in a case report published in Pediatrics in 2020. Authors from Alberta reported the case of a 10-week-old girl who was started on nadolol for infantile hemangioma, died 7 weeks later, and was found to have an elevated postmortem cardiac blood nadolol level of 0.94 mg/L. “The infant had no bowel movements for 10 days before her death, which we hypothesize contributed to nadolol toxicity,” the authors wrote.
In a reply to the authors in the same issue of Pediatrics, Dr. Pope, Cathryn Sibbald, MD, and Erin Chung, PhD, pointed out that postmortem redistribution of medications “is complex and measured postmortem cardiac blood concentrations may be significantly higher than the true blood nadolol concentration at the time of death due to significant diffusion from the peripheral tissues.”
They added that the report did not address “other potential errors such as in compounding, dispensing, and administration of the solution,” they wrote, adding: “Finally, we are aware of a Canadian case of death in an infant receiving propranolol, although the cause of death in that case was unable to be determined (ISMP Canada 2016 Safety Bulletin).We agree with the authors that careful consideration of the risks and benefits of beta-blocker therapy should be employed, parents need to be informed when to discontinue therapy and that further research into the pharmacokinetics and pharmacogenetics of beta-blockers are warranted.”
Following publication of the case report in Pediatrics, Dr. Pope said that the only change she made in her practice was to ask families to temporarily discontinue nadolol if their child had constipation for more than 5 days.
The study was supported by a grant from Physician Services, Inc. Dr. Pope reported having no financial disclosures.
of 71 patients showed.
“In clinical practice, we notice that nadolol works very well in terms of controlling the size and the appearance of the hemangioma,” lead study author Elena Pope, MD, MSc, said during the annual meeting of the Society for Pediatric Dermatology. Hence, she and her colleagues were interested in comparing their clinical experience with the standard treatment with propranolol, and designed a prospective, randomized, controlled, double-blinded study, with the aim of proving that “nadolol is noninferior to propranolol, with a margin of noninferiority of 10%.”
Between 2016 and 2020, Dr. Pope and colleagues at two academic Canadian pediatric dermatology centers enrolled 71 infants aged 1-6 months with significant hemangioma that had either the potential for functional impairment or cosmetic deformity, defined as a lesion greater than 1.5 cm on the face or greater than 3 cm on another body part. Treatment consisted of oral propranolol or nadolol in escalating doses up to 2 mg/kg per day. “The blinding portion of the study was for 24 weeks with a follow-up up to 52 weeks,” said Dr. Pope, professor of pediatrics at the University of Toronto and section head of pediatric dermatology at The Hospital for Sick Children, also in Toronto. “After the unblinding at 24 weeks, patients were allowed to switch their intervention if they were not happy with the results.”
Of the 71 patients, 35 received nadolol and 36 received propranolol. The two groups were similar in terms of clinical and demographic characteristics. Their mean age at enrollment was 3.15 months, 80% were female, 61% were White, 20% were Asian, and the rest were from other ethnic backgrounds.
At 24 weeks, the researchers found that the mean size involution was 97.94% in the nadolol group and 89.14% in the propranolol group (P = .005), while the mean color fading on the visual analogue scale (VAS) was 94.47% in the nadolol group and 80.54% in the propranolol group (P < .001). At 52 weeks, the mean size involution was 99.63% in the nadolol group and 93.63% in the propranolol group (P = .001), while the mean VAS color fading was 97.34% in the nadolol group and 87.23% in the propranolol group (P = .001).
According to Dr. Pope, Kaplan-Meir analysis showed that patients in the propranolol group responded slower to treatment (P = .019), while safety data was similar between the two groups. For example, between weeks 25 and 52, 84.2% of patients in the nadolol group experienced an adverse event, compared with 74.2% of patients in the propranolol group (P = .466). The most common respiratory adverse event was upper respiratory tract infection, which affected 87.5% of patients in the nadolol group, compared with 100% of patients in the propranolol group (P = 0.341).
The most common gastrointestinal adverse event was diarrhea, which affected 66.7% of patients in both groups. One patient in the propranolol group was admitted to the hospital with pneumonia and fully recovered. The incident was not suspected to be related to the medication.
“We believe that this data backs up our clinical experience and it may offer an alternative treatment in other centers where patients experience propranolol unresponsiveness, side effects, or intolerance, or where a fast response is needed,” Dr. Pope said. As for the potential cost implications, “nadolol is cheaper than the Hemangiol but comparable with the compounded formulation of propranolol.”
Concern over the safety of nadolol was raised in a case report published in Pediatrics in 2020. Authors from Alberta reported the case of a 10-week-old girl who was started on nadolol for infantile hemangioma, died 7 weeks later, and was found to have an elevated postmortem cardiac blood nadolol level of 0.94 mg/L. “The infant had no bowel movements for 10 days before her death, which we hypothesize contributed to nadolol toxicity,” the authors wrote.
In a reply to the authors in the same issue of Pediatrics, Dr. Pope, Cathryn Sibbald, MD, and Erin Chung, PhD, pointed out that postmortem redistribution of medications “is complex and measured postmortem cardiac blood concentrations may be significantly higher than the true blood nadolol concentration at the time of death due to significant diffusion from the peripheral tissues.”
They added that the report did not address “other potential errors such as in compounding, dispensing, and administration of the solution,” they wrote, adding: “Finally, we are aware of a Canadian case of death in an infant receiving propranolol, although the cause of death in that case was unable to be determined (ISMP Canada 2016 Safety Bulletin).We agree with the authors that careful consideration of the risks and benefits of beta-blocker therapy should be employed, parents need to be informed when to discontinue therapy and that further research into the pharmacokinetics and pharmacogenetics of beta-blockers are warranted.”
Following publication of the case report in Pediatrics, Dr. Pope said that the only change she made in her practice was to ask families to temporarily discontinue nadolol if their child had constipation for more than 5 days.
The study was supported by a grant from Physician Services, Inc. Dr. Pope reported having no financial disclosures.
FROM SPD 2021
OSA in women: Different symptoms, risks and consequences
The reported prevalence and severity of obstructive sleep apnea in women is lower, compared with men, but the consequences of the disease are “at least the same, if not worse,” with women appearing to have greater susceptibility to adverse OSA-related cardiovascular consequences – particularly as it pertains to endothelial dysfunction, Reena Mehra, MD, MS, said at the virtual annual meeting of the Associated Professional Sleep Societies.
Women more so than men have endothelial dysfunction associated with OSA, “suggesting there is an enhanced sensitivity of the female vascular endothelium to intermittent hypoxia,” said Dr. Mehra, director of sleep disorders research at the Cleveland Clinic and professor of medicine at Case Western Reserve University, also in Cleveland.
Sex-specific differences in the anatomic and physiological characteristics of the upper airway, in fat distribution and in respiratory stability as they relate to OSA have been documented for some time – and today, these and other differences relating to the diagnosis, treatment, and consequences of sleep apnea continue to be studied and elucidated, said Dr. Mehra, Anita Rajagopal, MD, and Chitra Lal, MD, in a session on OSA in women. Each spoke about the breath and implications of these differences, and of increasing recognition of the significance of OSA in women.
Likely underdiagnosis
Epidemiologic studies have suggested a three- to fivefold higher prevalence of OSA in men than in women in the general population. But it has also been estimated that 17%-25% of women have sleep apnea, and the prevalence reported in various studies has generally increased with time, said Dr. Rajagopal, department medical director for sleep medicine at Community Physician Network in Indianapolis, and medical director of the Community Health Network Sleep/Wake Disorders Center, also in Indianapolis.
One population-based study in Sweden, reported in 2013, found OSA (defined as an apnea-hypopnea index [AHI] ≥5) in 50% of women aged 20-70, she noted.
It’s quite possible women are being misdiagnosed or underdiagnosed because of their reporting of different symptoms, Dr. Rajagopal said. The Epworth Sleepiness Scale, commonly used to screen for OSA, has not been validated for use in women and has not been strongly associated with daytime sleepiness in women in population-based studies, she said, noting that women who report similar levels of daytime sleepiness to men are less likely to have an ESS score greater than 10.
“We shouldn’t rule out obstructive sleep apnea in women with a low ESS,” Dr. Rajagopal said in an interview after the meeting. Attentiveness to the symptoms more often reported by women – generalized daytime fatigue/lack of energy, insomnia, morning headaches, mood disturbances, and nightmares – is important, as is performance of overnight polysomnography when a home sleep study is negative and there is clinical suspicion of OSA.Respiratory disturbances in women are frequently associated with arousals – which induce less ventilatory instability in women than in men – rather than oxygen desaturations, leading to underestimation of OSA on home sleep testing. Insomnia associated with OSA in women may also increase the likelihood of a false negative result, Dr. Rajagopal said at the meeting.
“It’s really important [in sleep testing] to consider your AHI values in women,” she said. “The AHI value may not provide a true indication of the degree of sleep fragmentation being experienced by patients.” That OSA symptoms manifest in women with lower AHIs has been elucidated in research showing, for instance, that those with an AHI of 2-5 per hour have a similar level of symptoms to men with an AHI of at least 15 per hour, she said.
Women tend to have a clustering of apnea during REM sleep, and it’s possible that “the long-term effects of REM disruption contribute to greater symptomatology at lower AHI values in women compared to men,” Dr. Rajagopal said.
Also at play are when it comes to testing and diagnosis are several other key sex differences, she said. For one, the upper airways in women are less collapsible and more stable during sleep (most evident during non-REM sleep), and respiratory events during sleep are less frequently associated with complete upper airway collapse.
Women also have shorter apneic episodes, but “the longest apneas are associated with a more severe oxygen desaturation,” she said. Moreover, they have more episodes of upper airway resistance during sleep, which in and of itself “has been shown to produce clinical symptoms such as daytime fatigue and clinical depression.”
In her presentation, Dr. Mehra similarly commented on a likely underdiagnosis of OSA in women. In addition to differing symptoms, including palpitations, “women are less likely to have arousals, and have a lesser degree of nocturnal hypoxia compared to men ... perhaps leading to even more of an underdiagnosis.”
Unique consequences
Differences in upper airway physiology and other sex-specific differences impacting OSA susceptibility are at least partly attributable to sex hormones, said Dr. Mehra and Dr. Lal, associate professor of medicine at the Medical University of South Carolina, Charleston.
A significant increase in prevalence is seen after menopause, and research has shown that each additional year in menopause is associated with a greater AHI – a “dose-response effect,” Dr. Lal said. An inverse association between hormone replacement therapy and OSA severity has been seen in epidemiological studies including the Sleep Heart Health Study, Dr. Mehra said. But in prospective studies, Dr. Lal noted, hormone replacement therapy has not been shown to decrease AHI.
Experimental and clinical studies suggest that the vascular endothelium is influenced by sex hormones, Dr. Mehra said. Estrogen is known to improve endothelial function by inducing increased nitric oxide bioavailability – important in the setting of hypoxemia, which leads to reduced bioavailability of nitric oxide. “Alterations of sex-specific hormones in OSA may represent a key factor in increasing vulnerability to vascular dysfunction,” Dr. Mehra added.
The Sleep Heart Health Study also documented sex-specific differences, showing a graded increase of troponin with increasing OSA severity category as well as an increase in left ventricular mass thickness, and a 30% increased risk of heart failure or death in women with moderate/severe OSA, compared with women without OSA or with mild OSA, Dr. Mehra said. These findings were not observed in men.
The dominance of REM-related OSA in women raises risk because sleep disturbances during REM sleep are associated with adverse cardiometabolic outcomes including prevalent and incident hypertension, Dr. Mehra noted. “REM-related OSA may also adversely impact glucose metabolism,” she said, “even in the absence of non-REM obstructive sleep apnea.”
Regarding OSA treatment and responsivity, Dr. Mehra said that preliminary, post hoc data from a randomized, controlled trial of the impact of continuous positive airway pressure (CPAP) therapy on cardiovascular biomarkers showed a sex-specific effect. “There were differences in men versus women in terms of responsiveness with regards to biomarkers of inflammation and oxidative stress ... with reductions from CPAP observed in women but not in men,” said Dr. Mehra, a co-investigator of the study.
The data suggests, she said that “these biomarkers may be more responsive to treatment and a reversal of sleep apnea pathophysiology in women.”
Women also appear to respond better than men to upper airway nerve stimulation (UAS), she said, referring to an international registry study showing a 3.6-fold higher odds of responsiveness to the therapy relative to men. Women in the study were 60% less likely to be approved by insurance for UAS, however, making it “a public policy issue, said Dr. Mehra, a coinvestigator.
Dr. Rajagopal, Dr. Mehra, and Dr. Lal all reported that they had no potential conflicts of interest.
The reported prevalence and severity of obstructive sleep apnea in women is lower, compared with men, but the consequences of the disease are “at least the same, if not worse,” with women appearing to have greater susceptibility to adverse OSA-related cardiovascular consequences – particularly as it pertains to endothelial dysfunction, Reena Mehra, MD, MS, said at the virtual annual meeting of the Associated Professional Sleep Societies.
Women more so than men have endothelial dysfunction associated with OSA, “suggesting there is an enhanced sensitivity of the female vascular endothelium to intermittent hypoxia,” said Dr. Mehra, director of sleep disorders research at the Cleveland Clinic and professor of medicine at Case Western Reserve University, also in Cleveland.
Sex-specific differences in the anatomic and physiological characteristics of the upper airway, in fat distribution and in respiratory stability as they relate to OSA have been documented for some time – and today, these and other differences relating to the diagnosis, treatment, and consequences of sleep apnea continue to be studied and elucidated, said Dr. Mehra, Anita Rajagopal, MD, and Chitra Lal, MD, in a session on OSA in women. Each spoke about the breath and implications of these differences, and of increasing recognition of the significance of OSA in women.
Likely underdiagnosis
Epidemiologic studies have suggested a three- to fivefold higher prevalence of OSA in men than in women in the general population. But it has also been estimated that 17%-25% of women have sleep apnea, and the prevalence reported in various studies has generally increased with time, said Dr. Rajagopal, department medical director for sleep medicine at Community Physician Network in Indianapolis, and medical director of the Community Health Network Sleep/Wake Disorders Center, also in Indianapolis.
One population-based study in Sweden, reported in 2013, found OSA (defined as an apnea-hypopnea index [AHI] ≥5) in 50% of women aged 20-70, she noted.
It’s quite possible women are being misdiagnosed or underdiagnosed because of their reporting of different symptoms, Dr. Rajagopal said. The Epworth Sleepiness Scale, commonly used to screen for OSA, has not been validated for use in women and has not been strongly associated with daytime sleepiness in women in population-based studies, she said, noting that women who report similar levels of daytime sleepiness to men are less likely to have an ESS score greater than 10.
“We shouldn’t rule out obstructive sleep apnea in women with a low ESS,” Dr. Rajagopal said in an interview after the meeting. Attentiveness to the symptoms more often reported by women – generalized daytime fatigue/lack of energy, insomnia, morning headaches, mood disturbances, and nightmares – is important, as is performance of overnight polysomnography when a home sleep study is negative and there is clinical suspicion of OSA.Respiratory disturbances in women are frequently associated with arousals – which induce less ventilatory instability in women than in men – rather than oxygen desaturations, leading to underestimation of OSA on home sleep testing. Insomnia associated with OSA in women may also increase the likelihood of a false negative result, Dr. Rajagopal said at the meeting.
“It’s really important [in sleep testing] to consider your AHI values in women,” she said. “The AHI value may not provide a true indication of the degree of sleep fragmentation being experienced by patients.” That OSA symptoms manifest in women with lower AHIs has been elucidated in research showing, for instance, that those with an AHI of 2-5 per hour have a similar level of symptoms to men with an AHI of at least 15 per hour, she said.
Women tend to have a clustering of apnea during REM sleep, and it’s possible that “the long-term effects of REM disruption contribute to greater symptomatology at lower AHI values in women compared to men,” Dr. Rajagopal said.
Also at play are when it comes to testing and diagnosis are several other key sex differences, she said. For one, the upper airways in women are less collapsible and more stable during sleep (most evident during non-REM sleep), and respiratory events during sleep are less frequently associated with complete upper airway collapse.
Women also have shorter apneic episodes, but “the longest apneas are associated with a more severe oxygen desaturation,” she said. Moreover, they have more episodes of upper airway resistance during sleep, which in and of itself “has been shown to produce clinical symptoms such as daytime fatigue and clinical depression.”
In her presentation, Dr. Mehra similarly commented on a likely underdiagnosis of OSA in women. In addition to differing symptoms, including palpitations, “women are less likely to have arousals, and have a lesser degree of nocturnal hypoxia compared to men ... perhaps leading to even more of an underdiagnosis.”
Unique consequences
Differences in upper airway physiology and other sex-specific differences impacting OSA susceptibility are at least partly attributable to sex hormones, said Dr. Mehra and Dr. Lal, associate professor of medicine at the Medical University of South Carolina, Charleston.
A significant increase in prevalence is seen after menopause, and research has shown that each additional year in menopause is associated with a greater AHI – a “dose-response effect,” Dr. Lal said. An inverse association between hormone replacement therapy and OSA severity has been seen in epidemiological studies including the Sleep Heart Health Study, Dr. Mehra said. But in prospective studies, Dr. Lal noted, hormone replacement therapy has not been shown to decrease AHI.
Experimental and clinical studies suggest that the vascular endothelium is influenced by sex hormones, Dr. Mehra said. Estrogen is known to improve endothelial function by inducing increased nitric oxide bioavailability – important in the setting of hypoxemia, which leads to reduced bioavailability of nitric oxide. “Alterations of sex-specific hormones in OSA may represent a key factor in increasing vulnerability to vascular dysfunction,” Dr. Mehra added.
The Sleep Heart Health Study also documented sex-specific differences, showing a graded increase of troponin with increasing OSA severity category as well as an increase in left ventricular mass thickness, and a 30% increased risk of heart failure or death in women with moderate/severe OSA, compared with women without OSA or with mild OSA, Dr. Mehra said. These findings were not observed in men.
The dominance of REM-related OSA in women raises risk because sleep disturbances during REM sleep are associated with adverse cardiometabolic outcomes including prevalent and incident hypertension, Dr. Mehra noted. “REM-related OSA may also adversely impact glucose metabolism,” she said, “even in the absence of non-REM obstructive sleep apnea.”
Regarding OSA treatment and responsivity, Dr. Mehra said that preliminary, post hoc data from a randomized, controlled trial of the impact of continuous positive airway pressure (CPAP) therapy on cardiovascular biomarkers showed a sex-specific effect. “There were differences in men versus women in terms of responsiveness with regards to biomarkers of inflammation and oxidative stress ... with reductions from CPAP observed in women but not in men,” said Dr. Mehra, a co-investigator of the study.
The data suggests, she said that “these biomarkers may be more responsive to treatment and a reversal of sleep apnea pathophysiology in women.”
Women also appear to respond better than men to upper airway nerve stimulation (UAS), she said, referring to an international registry study showing a 3.6-fold higher odds of responsiveness to the therapy relative to men. Women in the study were 60% less likely to be approved by insurance for UAS, however, making it “a public policy issue, said Dr. Mehra, a coinvestigator.
Dr. Rajagopal, Dr. Mehra, and Dr. Lal all reported that they had no potential conflicts of interest.
The reported prevalence and severity of obstructive sleep apnea in women is lower, compared with men, but the consequences of the disease are “at least the same, if not worse,” with women appearing to have greater susceptibility to adverse OSA-related cardiovascular consequences – particularly as it pertains to endothelial dysfunction, Reena Mehra, MD, MS, said at the virtual annual meeting of the Associated Professional Sleep Societies.
Women more so than men have endothelial dysfunction associated with OSA, “suggesting there is an enhanced sensitivity of the female vascular endothelium to intermittent hypoxia,” said Dr. Mehra, director of sleep disorders research at the Cleveland Clinic and professor of medicine at Case Western Reserve University, also in Cleveland.
Sex-specific differences in the anatomic and physiological characteristics of the upper airway, in fat distribution and in respiratory stability as they relate to OSA have been documented for some time – and today, these and other differences relating to the diagnosis, treatment, and consequences of sleep apnea continue to be studied and elucidated, said Dr. Mehra, Anita Rajagopal, MD, and Chitra Lal, MD, in a session on OSA in women. Each spoke about the breath and implications of these differences, and of increasing recognition of the significance of OSA in women.
Likely underdiagnosis
Epidemiologic studies have suggested a three- to fivefold higher prevalence of OSA in men than in women in the general population. But it has also been estimated that 17%-25% of women have sleep apnea, and the prevalence reported in various studies has generally increased with time, said Dr. Rajagopal, department medical director for sleep medicine at Community Physician Network in Indianapolis, and medical director of the Community Health Network Sleep/Wake Disorders Center, also in Indianapolis.
One population-based study in Sweden, reported in 2013, found OSA (defined as an apnea-hypopnea index [AHI] ≥5) in 50% of women aged 20-70, she noted.
It’s quite possible women are being misdiagnosed or underdiagnosed because of their reporting of different symptoms, Dr. Rajagopal said. The Epworth Sleepiness Scale, commonly used to screen for OSA, has not been validated for use in women and has not been strongly associated with daytime sleepiness in women in population-based studies, she said, noting that women who report similar levels of daytime sleepiness to men are less likely to have an ESS score greater than 10.
“We shouldn’t rule out obstructive sleep apnea in women with a low ESS,” Dr. Rajagopal said in an interview after the meeting. Attentiveness to the symptoms more often reported by women – generalized daytime fatigue/lack of energy, insomnia, morning headaches, mood disturbances, and nightmares – is important, as is performance of overnight polysomnography when a home sleep study is negative and there is clinical suspicion of OSA.Respiratory disturbances in women are frequently associated with arousals – which induce less ventilatory instability in women than in men – rather than oxygen desaturations, leading to underestimation of OSA on home sleep testing. Insomnia associated with OSA in women may also increase the likelihood of a false negative result, Dr. Rajagopal said at the meeting.
“It’s really important [in sleep testing] to consider your AHI values in women,” she said. “The AHI value may not provide a true indication of the degree of sleep fragmentation being experienced by patients.” That OSA symptoms manifest in women with lower AHIs has been elucidated in research showing, for instance, that those with an AHI of 2-5 per hour have a similar level of symptoms to men with an AHI of at least 15 per hour, she said.
Women tend to have a clustering of apnea during REM sleep, and it’s possible that “the long-term effects of REM disruption contribute to greater symptomatology at lower AHI values in women compared to men,” Dr. Rajagopal said.
Also at play are when it comes to testing and diagnosis are several other key sex differences, she said. For one, the upper airways in women are less collapsible and more stable during sleep (most evident during non-REM sleep), and respiratory events during sleep are less frequently associated with complete upper airway collapse.
Women also have shorter apneic episodes, but “the longest apneas are associated with a more severe oxygen desaturation,” she said. Moreover, they have more episodes of upper airway resistance during sleep, which in and of itself “has been shown to produce clinical symptoms such as daytime fatigue and clinical depression.”
In her presentation, Dr. Mehra similarly commented on a likely underdiagnosis of OSA in women. In addition to differing symptoms, including palpitations, “women are less likely to have arousals, and have a lesser degree of nocturnal hypoxia compared to men ... perhaps leading to even more of an underdiagnosis.”
Unique consequences
Differences in upper airway physiology and other sex-specific differences impacting OSA susceptibility are at least partly attributable to sex hormones, said Dr. Mehra and Dr. Lal, associate professor of medicine at the Medical University of South Carolina, Charleston.
A significant increase in prevalence is seen after menopause, and research has shown that each additional year in menopause is associated with a greater AHI – a “dose-response effect,” Dr. Lal said. An inverse association between hormone replacement therapy and OSA severity has been seen in epidemiological studies including the Sleep Heart Health Study, Dr. Mehra said. But in prospective studies, Dr. Lal noted, hormone replacement therapy has not been shown to decrease AHI.
Experimental and clinical studies suggest that the vascular endothelium is influenced by sex hormones, Dr. Mehra said. Estrogen is known to improve endothelial function by inducing increased nitric oxide bioavailability – important in the setting of hypoxemia, which leads to reduced bioavailability of nitric oxide. “Alterations of sex-specific hormones in OSA may represent a key factor in increasing vulnerability to vascular dysfunction,” Dr. Mehra added.
The Sleep Heart Health Study also documented sex-specific differences, showing a graded increase of troponin with increasing OSA severity category as well as an increase in left ventricular mass thickness, and a 30% increased risk of heart failure or death in women with moderate/severe OSA, compared with women without OSA or with mild OSA, Dr. Mehra said. These findings were not observed in men.
The dominance of REM-related OSA in women raises risk because sleep disturbances during REM sleep are associated with adverse cardiometabolic outcomes including prevalent and incident hypertension, Dr. Mehra noted. “REM-related OSA may also adversely impact glucose metabolism,” she said, “even in the absence of non-REM obstructive sleep apnea.”
Regarding OSA treatment and responsivity, Dr. Mehra said that preliminary, post hoc data from a randomized, controlled trial of the impact of continuous positive airway pressure (CPAP) therapy on cardiovascular biomarkers showed a sex-specific effect. “There were differences in men versus women in terms of responsiveness with regards to biomarkers of inflammation and oxidative stress ... with reductions from CPAP observed in women but not in men,” said Dr. Mehra, a co-investigator of the study.
The data suggests, she said that “these biomarkers may be more responsive to treatment and a reversal of sleep apnea pathophysiology in women.”
Women also appear to respond better than men to upper airway nerve stimulation (UAS), she said, referring to an international registry study showing a 3.6-fold higher odds of responsiveness to the therapy relative to men. Women in the study were 60% less likely to be approved by insurance for UAS, however, making it “a public policy issue, said Dr. Mehra, a coinvestigator.
Dr. Rajagopal, Dr. Mehra, and Dr. Lal all reported that they had no potential conflicts of interest.
FROM SLEEP 2021
Study eyes impact of isotretinoin on triglycerides, other lab measures
.
“Isotretinoin is a very effective treatment for severe acne,” Varsha Parthasarathy said at the annual meeting of the Society for Pediatric Dermatology. “However, initiating this medication requires a complex process of laboratory testing,” which includes human chorionic gonadotropin pregnancy testing, because isotretinoin is a teratogen, as well as lipid labs and liver function tests, she noted. “Importantly, triglycerides are measured due to an association in adults between isotretinoin and hypertriglyceridemia-associated pancreatitis. However, these findings in children are limited to case reports, as are findings of retinoid-induced hepatotoxicity.”
To identify the role of isotretinoin on changes in lipids, aspartate aminotransferase (AST), and alanine aminotransferase (ALT), and to determine the impact on treatment course, Ms. Parthasarathy, a 4-year medical student at George Washington University, Washington, and colleagues retrospectively reviewed the charts of 130 patients aged 12-21 years who were cared for at Children’s National Hospital between January 2012 and October 2020. Nearly two-thirds (65%) were male, their average age was 16 years, and the mean time to obtain follow-up labs after starting isotretinoin was 3.25 months.
Between baseline and follow-up, the researchers observed increases in total cholesterol, triglycerides, and LDL (P less than .001 for all associations) and a decrease in HDL (P = .001), but there were no significant changes in AST or ALT levels. These findings were consistent with prior studies in adults examining the utility of these laboratory tests, most notably a 2016 study by Timothy J. Hansen, MD, and colleagues.
Among the 13 patients with elevated triglycerides at baseline, 9 (69%) were overweight or obese. Of the 20 patients with elevated triglycerides at follow-up, 11 patients (55%) were obese. At follow-up, 11 patients had levels of 200-500 mg/dL (grade I elevation), and 2 patients had levels of 501-1,000 mg/dL (grade II elevation). Isotretinoin was stopped in the latter two patients, who also had obesity as a risk factor for their hypertriglyceridemia.
“None of these patients had clinical sequelae from their hypertriglyceridemia, such as pancreatitis at baseline or follow-up,” Ms. Parthasarathy said. “However, since pancreatitis would be expected to be exceedingly rare, the sample size may be limited in identifying this adverse effect.”
She noted that while isotretinoin might cause a significant increase in lipid levels, the mean levels remained within normal limits at both baseline and follow-up. “Of the patients with elevated triglycerides at baseline and follow-up, obesity may have been a potential risk factor,” she said. “This could suggest a possible strategy for reduced testing in nonobese isotretinoin patients, which can be further explored in larger study populations.”
In addition, “there was a lack of significant change in AST and ALT in this study and adult studies, as well as minimal evidence for pediatric retinoid-induced hepatotoxicity, which raises the question of the necessity of baseline and follow-up comprehensive metabolic panel testing,” Ms. Parthasarathy added. “Clinicians must weigh the laboratory values with the costs of laboratory testing, including opportunity costs such as time, monetary costs, and the discomfort of testing for pediatric patients.”
The study’s senior author was A. Yasmine Kirkorian, MD, chief of dermatology at Children’s National Hospital, Washington. The researchers reported having no relevant financial disclosures.
.
“Isotretinoin is a very effective treatment for severe acne,” Varsha Parthasarathy said at the annual meeting of the Society for Pediatric Dermatology. “However, initiating this medication requires a complex process of laboratory testing,” which includes human chorionic gonadotropin pregnancy testing, because isotretinoin is a teratogen, as well as lipid labs and liver function tests, she noted. “Importantly, triglycerides are measured due to an association in adults between isotretinoin and hypertriglyceridemia-associated pancreatitis. However, these findings in children are limited to case reports, as are findings of retinoid-induced hepatotoxicity.”
To identify the role of isotretinoin on changes in lipids, aspartate aminotransferase (AST), and alanine aminotransferase (ALT), and to determine the impact on treatment course, Ms. Parthasarathy, a 4-year medical student at George Washington University, Washington, and colleagues retrospectively reviewed the charts of 130 patients aged 12-21 years who were cared for at Children’s National Hospital between January 2012 and October 2020. Nearly two-thirds (65%) were male, their average age was 16 years, and the mean time to obtain follow-up labs after starting isotretinoin was 3.25 months.
Between baseline and follow-up, the researchers observed increases in total cholesterol, triglycerides, and LDL (P less than .001 for all associations) and a decrease in HDL (P = .001), but there were no significant changes in AST or ALT levels. These findings were consistent with prior studies in adults examining the utility of these laboratory tests, most notably a 2016 study by Timothy J. Hansen, MD, and colleagues.
Among the 13 patients with elevated triglycerides at baseline, 9 (69%) were overweight or obese. Of the 20 patients with elevated triglycerides at follow-up, 11 patients (55%) were obese. At follow-up, 11 patients had levels of 200-500 mg/dL (grade I elevation), and 2 patients had levels of 501-1,000 mg/dL (grade II elevation). Isotretinoin was stopped in the latter two patients, who also had obesity as a risk factor for their hypertriglyceridemia.
“None of these patients had clinical sequelae from their hypertriglyceridemia, such as pancreatitis at baseline or follow-up,” Ms. Parthasarathy said. “However, since pancreatitis would be expected to be exceedingly rare, the sample size may be limited in identifying this adverse effect.”
She noted that while isotretinoin might cause a significant increase in lipid levels, the mean levels remained within normal limits at both baseline and follow-up. “Of the patients with elevated triglycerides at baseline and follow-up, obesity may have been a potential risk factor,” she said. “This could suggest a possible strategy for reduced testing in nonobese isotretinoin patients, which can be further explored in larger study populations.”
In addition, “there was a lack of significant change in AST and ALT in this study and adult studies, as well as minimal evidence for pediatric retinoid-induced hepatotoxicity, which raises the question of the necessity of baseline and follow-up comprehensive metabolic panel testing,” Ms. Parthasarathy added. “Clinicians must weigh the laboratory values with the costs of laboratory testing, including opportunity costs such as time, monetary costs, and the discomfort of testing for pediatric patients.”
The study’s senior author was A. Yasmine Kirkorian, MD, chief of dermatology at Children’s National Hospital, Washington. The researchers reported having no relevant financial disclosures.
.
“Isotretinoin is a very effective treatment for severe acne,” Varsha Parthasarathy said at the annual meeting of the Society for Pediatric Dermatology. “However, initiating this medication requires a complex process of laboratory testing,” which includes human chorionic gonadotropin pregnancy testing, because isotretinoin is a teratogen, as well as lipid labs and liver function tests, she noted. “Importantly, triglycerides are measured due to an association in adults between isotretinoin and hypertriglyceridemia-associated pancreatitis. However, these findings in children are limited to case reports, as are findings of retinoid-induced hepatotoxicity.”
To identify the role of isotretinoin on changes in lipids, aspartate aminotransferase (AST), and alanine aminotransferase (ALT), and to determine the impact on treatment course, Ms. Parthasarathy, a 4-year medical student at George Washington University, Washington, and colleagues retrospectively reviewed the charts of 130 patients aged 12-21 years who were cared for at Children’s National Hospital between January 2012 and October 2020. Nearly two-thirds (65%) were male, their average age was 16 years, and the mean time to obtain follow-up labs after starting isotretinoin was 3.25 months.
Between baseline and follow-up, the researchers observed increases in total cholesterol, triglycerides, and LDL (P less than .001 for all associations) and a decrease in HDL (P = .001), but there were no significant changes in AST or ALT levels. These findings were consistent with prior studies in adults examining the utility of these laboratory tests, most notably a 2016 study by Timothy J. Hansen, MD, and colleagues.
Among the 13 patients with elevated triglycerides at baseline, 9 (69%) were overweight or obese. Of the 20 patients with elevated triglycerides at follow-up, 11 patients (55%) were obese. At follow-up, 11 patients had levels of 200-500 mg/dL (grade I elevation), and 2 patients had levels of 501-1,000 mg/dL (grade II elevation). Isotretinoin was stopped in the latter two patients, who also had obesity as a risk factor for their hypertriglyceridemia.
“None of these patients had clinical sequelae from their hypertriglyceridemia, such as pancreatitis at baseline or follow-up,” Ms. Parthasarathy said. “However, since pancreatitis would be expected to be exceedingly rare, the sample size may be limited in identifying this adverse effect.”
She noted that while isotretinoin might cause a significant increase in lipid levels, the mean levels remained within normal limits at both baseline and follow-up. “Of the patients with elevated triglycerides at baseline and follow-up, obesity may have been a potential risk factor,” she said. “This could suggest a possible strategy for reduced testing in nonobese isotretinoin patients, which can be further explored in larger study populations.”
In addition, “there was a lack of significant change in AST and ALT in this study and adult studies, as well as minimal evidence for pediatric retinoid-induced hepatotoxicity, which raises the question of the necessity of baseline and follow-up comprehensive metabolic panel testing,” Ms. Parthasarathy added. “Clinicians must weigh the laboratory values with the costs of laboratory testing, including opportunity costs such as time, monetary costs, and the discomfort of testing for pediatric patients.”
The study’s senior author was A. Yasmine Kirkorian, MD, chief of dermatology at Children’s National Hospital, Washington. The researchers reported having no relevant financial disclosures.
FROM SPD 2021
Isotretinoin benefits similar in overweight, obese adolescents, and those in normal weight range
a retrospective cohort study found.
“Oral isotretinoin is among the most effective treatments for acne and is indicated for the treatment of severe acne or when first-line regimens have failed,” Maggie Tallmadge said at the annual meeting of the Society for Pediatric Dermatology. In adolescents with acne, isotretinoin is prescribed at a dose of 0.5-1 mg/kg per day “with the goal of reaching a cumulative dose of 120-150 mg/kg and clinical clearance with durable remission,” she said. “Most providers do not prescribe a daily dose over 80 mg due to perceived increased risk of side effects, including xerosis, cheilitis, liver dysfunction, and acne flare. However, many adolescents weigh over 80 kg and are therefore effectively underdosed, prolonging treatment time and possibly increasing the risk of side effects due to prolonged therapy.”
To evaluate differences in treatment courses among normal-weight, overweight, and obese adolescents, and the efficacy and safety of treatment, Ms. Tallmadge, a third-year medical student at the Medical College of Wisconsin, Milwaukee, and colleagues completed a retrospective chart review of 550 dermatology patients at Children’s Wisconsin, also in Milwaukee, who completed at least 2 months of isotretinoin treatment for acne when they were between the ages of 10 and 24, from November 2012 to January 2020. They collected data on age, weight, height, daily dose, cumulative dose, time to acne clearance, side effects, and acne recurrence after treatment, and classified patients as normal weight, overweight, or obese based on their body mass index for age percentile.
Of the 550 patients, 367 (67%) were normal weight, 101 (18%) were overweight, and 82 (15%) were obese. The median age of those in the normal-weight and overweight groups was 16, and was 15 in the obese group.
There was were significant differences in the median cumulative dose in each weight group: 143.7 mg/kg for normal-weight patients, 138.2 mg/kg for overweight patients, and 140.6 mg/kg for obese patients (P < .001).
“Despite achieving different cumulative doses, there was no difference in acne clearance, relapse, and most side effects among the three [body mass index] cohorts,” Ms. Tallmadge said. “Thus, it appears that current treatment strategies may be appropriate for overweight and obese adolescents.”
The proportion of patients with acne clearance did not differ significantly among the three groups of patients: 62% who were in the normal weight range, 60% who were overweight, and 59% who were obese had clearance of facial acne with treatment (P = .84).
Of patients whose treatment course was completed by the time of data collection, the proportion with acne recurrences was similar between the three groups: 25% of normal-weight patients, 27% of overweight patients, and 35% of obese patients (P > .05). Of patients whose treatment course was completed by the time of data collection, there was no significant differences in acne recurrence: 25% of normal-weight patients, 27% of overweight patients, and 35% of obese patients.
However, the proportion of patients reporting headaches differed significantly between the groups: 29% of normal-weight patients, compared with 40% of both overweight and obese patients (P = .035). The researchers also observed a significant positive correlation between increased BMI and increased triglyceride and ALT levels during treatment (P < .001 for both associations), yet no elevations required clinical action.
Funding for the study was provided by the MCW Medical Student Summer Research Program and the American Acne & Rosacea Society.
a retrospective cohort study found.
“Oral isotretinoin is among the most effective treatments for acne and is indicated for the treatment of severe acne or when first-line regimens have failed,” Maggie Tallmadge said at the annual meeting of the Society for Pediatric Dermatology. In adolescents with acne, isotretinoin is prescribed at a dose of 0.5-1 mg/kg per day “with the goal of reaching a cumulative dose of 120-150 mg/kg and clinical clearance with durable remission,” she said. “Most providers do not prescribe a daily dose over 80 mg due to perceived increased risk of side effects, including xerosis, cheilitis, liver dysfunction, and acne flare. However, many adolescents weigh over 80 kg and are therefore effectively underdosed, prolonging treatment time and possibly increasing the risk of side effects due to prolonged therapy.”
To evaluate differences in treatment courses among normal-weight, overweight, and obese adolescents, and the efficacy and safety of treatment, Ms. Tallmadge, a third-year medical student at the Medical College of Wisconsin, Milwaukee, and colleagues completed a retrospective chart review of 550 dermatology patients at Children’s Wisconsin, also in Milwaukee, who completed at least 2 months of isotretinoin treatment for acne when they were between the ages of 10 and 24, from November 2012 to January 2020. They collected data on age, weight, height, daily dose, cumulative dose, time to acne clearance, side effects, and acne recurrence after treatment, and classified patients as normal weight, overweight, or obese based on their body mass index for age percentile.
Of the 550 patients, 367 (67%) were normal weight, 101 (18%) were overweight, and 82 (15%) were obese. The median age of those in the normal-weight and overweight groups was 16, and was 15 in the obese group.
There was were significant differences in the median cumulative dose in each weight group: 143.7 mg/kg for normal-weight patients, 138.2 mg/kg for overweight patients, and 140.6 mg/kg for obese patients (P < .001).
“Despite achieving different cumulative doses, there was no difference in acne clearance, relapse, and most side effects among the three [body mass index] cohorts,” Ms. Tallmadge said. “Thus, it appears that current treatment strategies may be appropriate for overweight and obese adolescents.”
The proportion of patients with acne clearance did not differ significantly among the three groups of patients: 62% who were in the normal weight range, 60% who were overweight, and 59% who were obese had clearance of facial acne with treatment (P = .84).
Of patients whose treatment course was completed by the time of data collection, the proportion with acne recurrences was similar between the three groups: 25% of normal-weight patients, 27% of overweight patients, and 35% of obese patients (P > .05). Of patients whose treatment course was completed by the time of data collection, there was no significant differences in acne recurrence: 25% of normal-weight patients, 27% of overweight patients, and 35% of obese patients.
However, the proportion of patients reporting headaches differed significantly between the groups: 29% of normal-weight patients, compared with 40% of both overweight and obese patients (P = .035). The researchers also observed a significant positive correlation between increased BMI and increased triglyceride and ALT levels during treatment (P < .001 for both associations), yet no elevations required clinical action.
Funding for the study was provided by the MCW Medical Student Summer Research Program and the American Acne & Rosacea Society.
a retrospective cohort study found.
“Oral isotretinoin is among the most effective treatments for acne and is indicated for the treatment of severe acne or when first-line regimens have failed,” Maggie Tallmadge said at the annual meeting of the Society for Pediatric Dermatology. In adolescents with acne, isotretinoin is prescribed at a dose of 0.5-1 mg/kg per day “with the goal of reaching a cumulative dose of 120-150 mg/kg and clinical clearance with durable remission,” she said. “Most providers do not prescribe a daily dose over 80 mg due to perceived increased risk of side effects, including xerosis, cheilitis, liver dysfunction, and acne flare. However, many adolescents weigh over 80 kg and are therefore effectively underdosed, prolonging treatment time and possibly increasing the risk of side effects due to prolonged therapy.”
To evaluate differences in treatment courses among normal-weight, overweight, and obese adolescents, and the efficacy and safety of treatment, Ms. Tallmadge, a third-year medical student at the Medical College of Wisconsin, Milwaukee, and colleagues completed a retrospective chart review of 550 dermatology patients at Children’s Wisconsin, also in Milwaukee, who completed at least 2 months of isotretinoin treatment for acne when they were between the ages of 10 and 24, from November 2012 to January 2020. They collected data on age, weight, height, daily dose, cumulative dose, time to acne clearance, side effects, and acne recurrence after treatment, and classified patients as normal weight, overweight, or obese based on their body mass index for age percentile.
Of the 550 patients, 367 (67%) were normal weight, 101 (18%) were overweight, and 82 (15%) were obese. The median age of those in the normal-weight and overweight groups was 16, and was 15 in the obese group.
There was were significant differences in the median cumulative dose in each weight group: 143.7 mg/kg for normal-weight patients, 138.2 mg/kg for overweight patients, and 140.6 mg/kg for obese patients (P < .001).
“Despite achieving different cumulative doses, there was no difference in acne clearance, relapse, and most side effects among the three [body mass index] cohorts,” Ms. Tallmadge said. “Thus, it appears that current treatment strategies may be appropriate for overweight and obese adolescents.”
The proportion of patients with acne clearance did not differ significantly among the three groups of patients: 62% who were in the normal weight range, 60% who were overweight, and 59% who were obese had clearance of facial acne with treatment (P = .84).
Of patients whose treatment course was completed by the time of data collection, the proportion with acne recurrences was similar between the three groups: 25% of normal-weight patients, 27% of overweight patients, and 35% of obese patients (P > .05). Of patients whose treatment course was completed by the time of data collection, there was no significant differences in acne recurrence: 25% of normal-weight patients, 27% of overweight patients, and 35% of obese patients.
However, the proportion of patients reporting headaches differed significantly between the groups: 29% of normal-weight patients, compared with 40% of both overweight and obese patients (P = .035). The researchers also observed a significant positive correlation between increased BMI and increased triglyceride and ALT levels during treatment (P < .001 for both associations), yet no elevations required clinical action.
Funding for the study was provided by the MCW Medical Student Summer Research Program and the American Acne & Rosacea Society.
FROM SPD 2021
Antibiotic linked to rise in early onset colon cancer?
Exposure to antibiotics appears to be associated with the development of colon cancer, particularly in younger people, and could be contributing to the increase in early-onset colorectal cancer (CRC) that is being documented, say U.K. researchers.
The team conducted a nested case-control study using data from primary care in Scotland, which involved almost 8,000 cases of CRC and over 30,000 healthy controls.
The analysis suggests that a history of antibiotic use among individuals younger than 50 appeared to increase the risk of developing colon cancer (but not rectal) by 49%.
“To our knowledge, this is the first study to link antibiotic use with the growing risk of early onset colon cancer, a disease which has been increasing at a rate of at least 3% per year over the last two decades,” said study presenter Sarah Perrott, a medical student at the University of Aberdeen, Scotland.
“Junk food, sugary drinks, obesity, and alcohol are likely to have played a part in that rise, but our data stress the importance of avoiding unnecessary antibiotics, especially in children and young adults,” Ms. Perrott said in a statement.
“We now want to find out if there is a link between antibiotic use and changes in the microbiome which can make the colon more susceptible to cancer, especially in younger people,” added senior author Leslie Samuel, MD, consultant oncologist at Aberdeen Royal Infirmary.
“It’s a complex situation, as we know that the microbiome can quickly revert to its previous state, even when the bowel has been cleared out for a diagnostic procedure,” Dr. Samuel continued.
The research was presented on July 2 at the European Society for Medical Oncology Congress 2021.
Commenting for ESMO, Alberto Sobrero, MD, PhD, Medical Oncology Unit, Ospedale San Martino, Genoa, Italy, said that younger patients with colon cancer typically have a worse prognosis than older people because they are generally diagnosed later.
“Physicians are less likely to investigate a patient with abdominal discomfort for colon cancer if they are in their 30s than if they are in their 70s, and younger patients are not eligible for bowel cancer screening,” he explained.
However, Dr. Sobrero believes it is “too early to say if excessive use of antibiotics could be a causative factor, and we need to understand more about the possible role of the microbiome in bowel cancer before we consider the impact of antibiotics on the intestinal flora.”
The results, nevertheless, “remind us that antibiotics should not be given unless they are really needed, and we cannot exclude the possibility that unnecessary use of antibiotics may be exposing people to an increased risk of cancer,” he concluded.
Similar comments were made by Thomas Seufferlein, MD, department of internal medicine, Ulm University, Germany, who discussed the findings.
He agreed with the authors “that careful use of antibiotics is sensible and paramount” but added that more studies are needed on this suggestion of a link between antibiotic use and the observed increase in early CRC.
Study details
Previous studies have demonstrated that, in older adults, significant alterations in the structure and diversity of the gut microbiome induced by antibiotic therapy influence the development of colorectal cancer.
However, Ms. Perrott said that the impact of antibiotic use on early onset colorectal cancer has not been investigated.
The researchers therefore conducted a nested case-control study of primary care records to identify colorectal cancer cases diagnosed in Scotland between 1999 and 2011.
Patients were divided into those diagnosed before 50 years of age and those diagnosed at 50 years and older and matched with up to five healthy controls.
The study included 7,903 CRC cases, of which 5,281 were colon cancer and 2,622 rectal cancer, alongside 30,418 controls.
Among the CRC patients, 445 (5.6%) were under 50 years of age at diagnosis.
The team also analyzed antibiotic use history. Prescriptions for oral antibiotics, stratified by drug class and by anaerobic/nonanaerobic effect, were extracted, and the total antibiotic exposure period was calculated and categorized as 0, 1-15, 16-60, and >60 days.
Overall, 45% of the patients were prescribed antibiotics. Any antibiotic use was associated with a significantly increased risk of colon cancer, but this was most pronounced in patients aged less than 50 years at diagnosis.
Specifically, any antibiotic use was associated with an adjusted odds ratio of colon cancer of 1.49 (P = .018) in patients aged less than 50 years versus 1.09 (P = .029) in those aged 50 years and over.
In younger patients, the largest association between antibiotic use and colon cancer was seen in patients with a total antibiotic exposure of 1-15 days (at an adjusted odds ratio of 1.55), falling to 1.46 with 16-60 days of exposure, and no association for >60 days exposure.
No such relationship was seen in patients with colon cancer aged 50 years and over at diagnosis.
There was also no significant relationship between any antibiotic use and the occurrence of rectal cancer, at an adjusted odds ratio of 1.17 (P = .493) in those aged under 50 years at diagnosis and 1.07 (P = .698) in older patients.
The study was supported by Cancer Research UK. Ms. Perrott, Dr. Sobrero, and Dr. Samuels declared having no conflicts of interest. Dr. Seufferlien has reported relationships with Amgen, Bayer, Merck, Sanofi, Celgene, Shire, Roche, Falk Foundation, AstraZeneca, Lilly, Merck-Serono, Servier, Pierre Fabre, Cantargia, and Boehringer Ingelheim.
A version of this article first appeared on Medscape.com.
Exposure to antibiotics appears to be associated with the development of colon cancer, particularly in younger people, and could be contributing to the increase in early-onset colorectal cancer (CRC) that is being documented, say U.K. researchers.
The team conducted a nested case-control study using data from primary care in Scotland, which involved almost 8,000 cases of CRC and over 30,000 healthy controls.
The analysis suggests that a history of antibiotic use among individuals younger than 50 appeared to increase the risk of developing colon cancer (but not rectal) by 49%.
“To our knowledge, this is the first study to link antibiotic use with the growing risk of early onset colon cancer, a disease which has been increasing at a rate of at least 3% per year over the last two decades,” said study presenter Sarah Perrott, a medical student at the University of Aberdeen, Scotland.
“Junk food, sugary drinks, obesity, and alcohol are likely to have played a part in that rise, but our data stress the importance of avoiding unnecessary antibiotics, especially in children and young adults,” Ms. Perrott said in a statement.
“We now want to find out if there is a link between antibiotic use and changes in the microbiome which can make the colon more susceptible to cancer, especially in younger people,” added senior author Leslie Samuel, MD, consultant oncologist at Aberdeen Royal Infirmary.
“It’s a complex situation, as we know that the microbiome can quickly revert to its previous state, even when the bowel has been cleared out for a diagnostic procedure,” Dr. Samuel continued.
The research was presented on July 2 at the European Society for Medical Oncology Congress 2021.
Commenting for ESMO, Alberto Sobrero, MD, PhD, Medical Oncology Unit, Ospedale San Martino, Genoa, Italy, said that younger patients with colon cancer typically have a worse prognosis than older people because they are generally diagnosed later.
“Physicians are less likely to investigate a patient with abdominal discomfort for colon cancer if they are in their 30s than if they are in their 70s, and younger patients are not eligible for bowel cancer screening,” he explained.
However, Dr. Sobrero believes it is “too early to say if excessive use of antibiotics could be a causative factor, and we need to understand more about the possible role of the microbiome in bowel cancer before we consider the impact of antibiotics on the intestinal flora.”
The results, nevertheless, “remind us that antibiotics should not be given unless they are really needed, and we cannot exclude the possibility that unnecessary use of antibiotics may be exposing people to an increased risk of cancer,” he concluded.
Similar comments were made by Thomas Seufferlein, MD, department of internal medicine, Ulm University, Germany, who discussed the findings.
He agreed with the authors “that careful use of antibiotics is sensible and paramount” but added that more studies are needed on this suggestion of a link between antibiotic use and the observed increase in early CRC.
Study details
Previous studies have demonstrated that, in older adults, significant alterations in the structure and diversity of the gut microbiome induced by antibiotic therapy influence the development of colorectal cancer.
However, Ms. Perrott said that the impact of antibiotic use on early onset colorectal cancer has not been investigated.
The researchers therefore conducted a nested case-control study of primary care records to identify colorectal cancer cases diagnosed in Scotland between 1999 and 2011.
Patients were divided into those diagnosed before 50 years of age and those diagnosed at 50 years and older and matched with up to five healthy controls.
The study included 7,903 CRC cases, of which 5,281 were colon cancer and 2,622 rectal cancer, alongside 30,418 controls.
Among the CRC patients, 445 (5.6%) were under 50 years of age at diagnosis.
The team also analyzed antibiotic use history. Prescriptions for oral antibiotics, stratified by drug class and by anaerobic/nonanaerobic effect, were extracted, and the total antibiotic exposure period was calculated and categorized as 0, 1-15, 16-60, and >60 days.
Overall, 45% of the patients were prescribed antibiotics. Any antibiotic use was associated with a significantly increased risk of colon cancer, but this was most pronounced in patients aged less than 50 years at diagnosis.
Specifically, any antibiotic use was associated with an adjusted odds ratio of colon cancer of 1.49 (P = .018) in patients aged less than 50 years versus 1.09 (P = .029) in those aged 50 years and over.
In younger patients, the largest association between antibiotic use and colon cancer was seen in patients with a total antibiotic exposure of 1-15 days (at an adjusted odds ratio of 1.55), falling to 1.46 with 16-60 days of exposure, and no association for >60 days exposure.
No such relationship was seen in patients with colon cancer aged 50 years and over at diagnosis.
There was also no significant relationship between any antibiotic use and the occurrence of rectal cancer, at an adjusted odds ratio of 1.17 (P = .493) in those aged under 50 years at diagnosis and 1.07 (P = .698) in older patients.
The study was supported by Cancer Research UK. Ms. Perrott, Dr. Sobrero, and Dr. Samuels declared having no conflicts of interest. Dr. Seufferlien has reported relationships with Amgen, Bayer, Merck, Sanofi, Celgene, Shire, Roche, Falk Foundation, AstraZeneca, Lilly, Merck-Serono, Servier, Pierre Fabre, Cantargia, and Boehringer Ingelheim.
A version of this article first appeared on Medscape.com.
Exposure to antibiotics appears to be associated with the development of colon cancer, particularly in younger people, and could be contributing to the increase in early-onset colorectal cancer (CRC) that is being documented, say U.K. researchers.
The team conducted a nested case-control study using data from primary care in Scotland, which involved almost 8,000 cases of CRC and over 30,000 healthy controls.
The analysis suggests that a history of antibiotic use among individuals younger than 50 appeared to increase the risk of developing colon cancer (but not rectal) by 49%.
“To our knowledge, this is the first study to link antibiotic use with the growing risk of early onset colon cancer, a disease which has been increasing at a rate of at least 3% per year over the last two decades,” said study presenter Sarah Perrott, a medical student at the University of Aberdeen, Scotland.
“Junk food, sugary drinks, obesity, and alcohol are likely to have played a part in that rise, but our data stress the importance of avoiding unnecessary antibiotics, especially in children and young adults,” Ms. Perrott said in a statement.
“We now want to find out if there is a link between antibiotic use and changes in the microbiome which can make the colon more susceptible to cancer, especially in younger people,” added senior author Leslie Samuel, MD, consultant oncologist at Aberdeen Royal Infirmary.
“It’s a complex situation, as we know that the microbiome can quickly revert to its previous state, even when the bowel has been cleared out for a diagnostic procedure,” Dr. Samuel continued.
The research was presented on July 2 at the European Society for Medical Oncology Congress 2021.
Commenting for ESMO, Alberto Sobrero, MD, PhD, Medical Oncology Unit, Ospedale San Martino, Genoa, Italy, said that younger patients with colon cancer typically have a worse prognosis than older people because they are generally diagnosed later.
“Physicians are less likely to investigate a patient with abdominal discomfort for colon cancer if they are in their 30s than if they are in their 70s, and younger patients are not eligible for bowel cancer screening,” he explained.
However, Dr. Sobrero believes it is “too early to say if excessive use of antibiotics could be a causative factor, and we need to understand more about the possible role of the microbiome in bowel cancer before we consider the impact of antibiotics on the intestinal flora.”
The results, nevertheless, “remind us that antibiotics should not be given unless they are really needed, and we cannot exclude the possibility that unnecessary use of antibiotics may be exposing people to an increased risk of cancer,” he concluded.
Similar comments were made by Thomas Seufferlein, MD, department of internal medicine, Ulm University, Germany, who discussed the findings.
He agreed with the authors “that careful use of antibiotics is sensible and paramount” but added that more studies are needed on this suggestion of a link between antibiotic use and the observed increase in early CRC.
Study details
Previous studies have demonstrated that, in older adults, significant alterations in the structure and diversity of the gut microbiome induced by antibiotic therapy influence the development of colorectal cancer.
However, Ms. Perrott said that the impact of antibiotic use on early onset colorectal cancer has not been investigated.
The researchers therefore conducted a nested case-control study of primary care records to identify colorectal cancer cases diagnosed in Scotland between 1999 and 2011.
Patients were divided into those diagnosed before 50 years of age and those diagnosed at 50 years and older and matched with up to five healthy controls.
The study included 7,903 CRC cases, of which 5,281 were colon cancer and 2,622 rectal cancer, alongside 30,418 controls.
Among the CRC patients, 445 (5.6%) were under 50 years of age at diagnosis.
The team also analyzed antibiotic use history. Prescriptions for oral antibiotics, stratified by drug class and by anaerobic/nonanaerobic effect, were extracted, and the total antibiotic exposure period was calculated and categorized as 0, 1-15, 16-60, and >60 days.
Overall, 45% of the patients were prescribed antibiotics. Any antibiotic use was associated with a significantly increased risk of colon cancer, but this was most pronounced in patients aged less than 50 years at diagnosis.
Specifically, any antibiotic use was associated with an adjusted odds ratio of colon cancer of 1.49 (P = .018) in patients aged less than 50 years versus 1.09 (P = .029) in those aged 50 years and over.
In younger patients, the largest association between antibiotic use and colon cancer was seen in patients with a total antibiotic exposure of 1-15 days (at an adjusted odds ratio of 1.55), falling to 1.46 with 16-60 days of exposure, and no association for >60 days exposure.
No such relationship was seen in patients with colon cancer aged 50 years and over at diagnosis.
There was also no significant relationship between any antibiotic use and the occurrence of rectal cancer, at an adjusted odds ratio of 1.17 (P = .493) in those aged under 50 years at diagnosis and 1.07 (P = .698) in older patients.
The study was supported by Cancer Research UK. Ms. Perrott, Dr. Sobrero, and Dr. Samuels declared having no conflicts of interest. Dr. Seufferlien has reported relationships with Amgen, Bayer, Merck, Sanofi, Celgene, Shire, Roche, Falk Foundation, AstraZeneca, Lilly, Merck-Serono, Servier, Pierre Fabre, Cantargia, and Boehringer Ingelheim.
A version of this article first appeared on Medscape.com.
Study spanning 2 decades offers insights into pediatric psoriasis trends
, while predictors of moderate to severe disease include morphology, non-White race, and culture-confirmed infection.
Those are among the key findings from a retrospective analysis of pediatric psoriasis patients who were seen at the University of California, San Francisco, over a 24-year period.
“Overall, our data support prior findings of age- and sex-based differences in location and morphology and presents new information demonstrating associations with severity,” presenting study author Carmel Aghdasi said during the annual meeting of the Society for Pediatric Dermatology. “We provide evidence of the increased use of systemic and biologic therapies over time, an important step in ensuring pediatric patients are adequately treated.”
To characterize the demographics, clinical features, comorbidities, and treatments, and to determine predictors of severity and changes in treatment patterns over 2 decades in a large cohort of pediatric psoriasis patients, Ms. Aghdasi, a 4th-year medical student at the University of California, San Francisco, and colleagues retrospectively evaluated the records of 754 pediatric patients up to 18 years of age who were seen at UCSF for psoriasis from 1997 to 2021. They collected demographic, clinical, familial, comorbidity, and treatment data and divided the cohort into two groups by date of last visit.
Group 1 consisted of 332 patients whose last visit was between 2001 and 2011, while the second group included 422 patients whose last visit was between 2012 and 2021. The researchers also divided the cohort into three age groups: infants (0-2 years of age), children (3-12 years of age), and adolescents (13-18 years of age).
Slightly more than half of the patients (55%) were female and 67% presented between ages 3 and 12. (Seventy-four patients were in the youngest category, 0-2 years, when they presented.) The average age of disease onset was 7 years, the average age at presentation to pediatric dermatology was 8.8 years, and 37% of the total cohort were overweight or obese. The top four comorbidities were being overweight or obese (37%), followed by atopic dermatitis (19%), psychiatric disease (7%), and arthritis (4%).
Plaque was the most common morphology (56%), while the most common sites of involvement were the head and neck (69%), extremities (61%), and trunk (44%). About half of the cohort (51%) had mild disease, 15% had culture-confirmed infections (9% had Streptococcal infections), and 66% of patients reported itch as a symptom.
The researchers observed that inverse psoriasis was significantly more common in infants and decreased with age. Anogenital involvement was more common in males and in those aged 0-2, while head and neck involvement was more common in females. Nail involvement was more common in childhood.
Topical therapy was the most common treatment overall and by far the most common among those in the 0-2 age category. “Overall, phototherapy was used in childhood and adolescents but almost never in infancy,” Ms. Aghdasi said. “Looking at changes in systemic treatment over time, conventional systemic use increased in infants and children and decreased in adolescents. Biologic use increased in all ages, most notably in children aged 3-12 years old.”
Multivariate regression analyses revealed that the following independent variables predicted moderate to severe psoriasis: adolescent age (adjusted odds ratio, 1.9; P = .03), guttate morphology (aOR, 2.2; P = .006), plaque and guttate morphology (aOR, 7.6; P less than .001), pustular or erythrodermic morphology (aOR, 5; P = .003), culture-confirmed infection (aOR, 2; P = .007), Black race (aOR, 3.3; P = .007), Asian race (aOR, 1.8; P = .04, and Hispanic race (aOR, 1.9; P = .03).
“Further analysis is needed to elucidate the influence of race on severity and of the clinical utility of infection as a marker of severity,” Ms. Aghdasi said. “Interestingly, we did not find that obesity was a marker of severity in our cohort.”
In an interview, senior study author Kelly M. Cordoro, MD, professor of dermatology and pediatrics at UCSF, noted that this finding conflicts with prior studies showing an association between obesity and severe psoriasis in children.
“Though methodologies and patient populations differ among studies, what is striking,” she said, is the percentage of overweight/obese patients (37%; defined as a body mass index ≥ 85th percentile) “in our 2-decade single institution dataset.” This “is nearly identical” to the percentage of patients with excess adiposity – 37.9% (also defined as BMI ≥ 85th percentile) – in an international cross-sectional study, which also identified an association between obesity (BMI ≥ 95th percentile) and psoriasis severity in children, she noted.
“What is clear is the strong association between obesity and childhood psoriasis, as multiple studies, including ours, confirm obesity as a major comorbidity of pediatric psoriasis,” Dr. Cordoro said. “Both conditions must be adequately managed to reduce the risk of adverse health outcomes for obese patients with psoriasis.”
The other study coauthors were Dana Feigenbaum, MD, and Alana Ju, MD. The work was supported by the UCSF Yearlong Inquiry Program. The researchers reported having no relevant financial disclosures.
, while predictors of moderate to severe disease include morphology, non-White race, and culture-confirmed infection.
Those are among the key findings from a retrospective analysis of pediatric psoriasis patients who were seen at the University of California, San Francisco, over a 24-year period.
“Overall, our data support prior findings of age- and sex-based differences in location and morphology and presents new information demonstrating associations with severity,” presenting study author Carmel Aghdasi said during the annual meeting of the Society for Pediatric Dermatology. “We provide evidence of the increased use of systemic and biologic therapies over time, an important step in ensuring pediatric patients are adequately treated.”
To characterize the demographics, clinical features, comorbidities, and treatments, and to determine predictors of severity and changes in treatment patterns over 2 decades in a large cohort of pediatric psoriasis patients, Ms. Aghdasi, a 4th-year medical student at the University of California, San Francisco, and colleagues retrospectively evaluated the records of 754 pediatric patients up to 18 years of age who were seen at UCSF for psoriasis from 1997 to 2021. They collected demographic, clinical, familial, comorbidity, and treatment data and divided the cohort into two groups by date of last visit.
Group 1 consisted of 332 patients whose last visit was between 2001 and 2011, while the second group included 422 patients whose last visit was between 2012 and 2021. The researchers also divided the cohort into three age groups: infants (0-2 years of age), children (3-12 years of age), and adolescents (13-18 years of age).
Slightly more than half of the patients (55%) were female and 67% presented between ages 3 and 12. (Seventy-four patients were in the youngest category, 0-2 years, when they presented.) The average age of disease onset was 7 years, the average age at presentation to pediatric dermatology was 8.8 years, and 37% of the total cohort were overweight or obese. The top four comorbidities were being overweight or obese (37%), followed by atopic dermatitis (19%), psychiatric disease (7%), and arthritis (4%).
Plaque was the most common morphology (56%), while the most common sites of involvement were the head and neck (69%), extremities (61%), and trunk (44%). About half of the cohort (51%) had mild disease, 15% had culture-confirmed infections (9% had Streptococcal infections), and 66% of patients reported itch as a symptom.
The researchers observed that inverse psoriasis was significantly more common in infants and decreased with age. Anogenital involvement was more common in males and in those aged 0-2, while head and neck involvement was more common in females. Nail involvement was more common in childhood.
Topical therapy was the most common treatment overall and by far the most common among those in the 0-2 age category. “Overall, phototherapy was used in childhood and adolescents but almost never in infancy,” Ms. Aghdasi said. “Looking at changes in systemic treatment over time, conventional systemic use increased in infants and children and decreased in adolescents. Biologic use increased in all ages, most notably in children aged 3-12 years old.”
Multivariate regression analyses revealed that the following independent variables predicted moderate to severe psoriasis: adolescent age (adjusted odds ratio, 1.9; P = .03), guttate morphology (aOR, 2.2; P = .006), plaque and guttate morphology (aOR, 7.6; P less than .001), pustular or erythrodermic morphology (aOR, 5; P = .003), culture-confirmed infection (aOR, 2; P = .007), Black race (aOR, 3.3; P = .007), Asian race (aOR, 1.8; P = .04, and Hispanic race (aOR, 1.9; P = .03).
“Further analysis is needed to elucidate the influence of race on severity and of the clinical utility of infection as a marker of severity,” Ms. Aghdasi said. “Interestingly, we did not find that obesity was a marker of severity in our cohort.”
In an interview, senior study author Kelly M. Cordoro, MD, professor of dermatology and pediatrics at UCSF, noted that this finding conflicts with prior studies showing an association between obesity and severe psoriasis in children.
“Though methodologies and patient populations differ among studies, what is striking,” she said, is the percentage of overweight/obese patients (37%; defined as a body mass index ≥ 85th percentile) “in our 2-decade single institution dataset.” This “is nearly identical” to the percentage of patients with excess adiposity – 37.9% (also defined as BMI ≥ 85th percentile) – in an international cross-sectional study, which also identified an association between obesity (BMI ≥ 95th percentile) and psoriasis severity in children, she noted.
“What is clear is the strong association between obesity and childhood psoriasis, as multiple studies, including ours, confirm obesity as a major comorbidity of pediatric psoriasis,” Dr. Cordoro said. “Both conditions must be adequately managed to reduce the risk of adverse health outcomes for obese patients with psoriasis.”
The other study coauthors were Dana Feigenbaum, MD, and Alana Ju, MD. The work was supported by the UCSF Yearlong Inquiry Program. The researchers reported having no relevant financial disclosures.
, while predictors of moderate to severe disease include morphology, non-White race, and culture-confirmed infection.
Those are among the key findings from a retrospective analysis of pediatric psoriasis patients who were seen at the University of California, San Francisco, over a 24-year period.
“Overall, our data support prior findings of age- and sex-based differences in location and morphology and presents new information demonstrating associations with severity,” presenting study author Carmel Aghdasi said during the annual meeting of the Society for Pediatric Dermatology. “We provide evidence of the increased use of systemic and biologic therapies over time, an important step in ensuring pediatric patients are adequately treated.”
To characterize the demographics, clinical features, comorbidities, and treatments, and to determine predictors of severity and changes in treatment patterns over 2 decades in a large cohort of pediatric psoriasis patients, Ms. Aghdasi, a 4th-year medical student at the University of California, San Francisco, and colleagues retrospectively evaluated the records of 754 pediatric patients up to 18 years of age who were seen at UCSF for psoriasis from 1997 to 2021. They collected demographic, clinical, familial, comorbidity, and treatment data and divided the cohort into two groups by date of last visit.
Group 1 consisted of 332 patients whose last visit was between 2001 and 2011, while the second group included 422 patients whose last visit was between 2012 and 2021. The researchers also divided the cohort into three age groups: infants (0-2 years of age), children (3-12 years of age), and adolescents (13-18 years of age).
Slightly more than half of the patients (55%) were female and 67% presented between ages 3 and 12. (Seventy-four patients were in the youngest category, 0-2 years, when they presented.) The average age of disease onset was 7 years, the average age at presentation to pediatric dermatology was 8.8 years, and 37% of the total cohort were overweight or obese. The top four comorbidities were being overweight or obese (37%), followed by atopic dermatitis (19%), psychiatric disease (7%), and arthritis (4%).
Plaque was the most common morphology (56%), while the most common sites of involvement were the head and neck (69%), extremities (61%), and trunk (44%). About half of the cohort (51%) had mild disease, 15% had culture-confirmed infections (9% had Streptococcal infections), and 66% of patients reported itch as a symptom.
The researchers observed that inverse psoriasis was significantly more common in infants and decreased with age. Anogenital involvement was more common in males and in those aged 0-2, while head and neck involvement was more common in females. Nail involvement was more common in childhood.
Topical therapy was the most common treatment overall and by far the most common among those in the 0-2 age category. “Overall, phototherapy was used in childhood and adolescents but almost never in infancy,” Ms. Aghdasi said. “Looking at changes in systemic treatment over time, conventional systemic use increased in infants and children and decreased in adolescents. Biologic use increased in all ages, most notably in children aged 3-12 years old.”
Multivariate regression analyses revealed that the following independent variables predicted moderate to severe psoriasis: adolescent age (adjusted odds ratio, 1.9; P = .03), guttate morphology (aOR, 2.2; P = .006), plaque and guttate morphology (aOR, 7.6; P less than .001), pustular or erythrodermic morphology (aOR, 5; P = .003), culture-confirmed infection (aOR, 2; P = .007), Black race (aOR, 3.3; P = .007), Asian race (aOR, 1.8; P = .04, and Hispanic race (aOR, 1.9; P = .03).
“Further analysis is needed to elucidate the influence of race on severity and of the clinical utility of infection as a marker of severity,” Ms. Aghdasi said. “Interestingly, we did not find that obesity was a marker of severity in our cohort.”
In an interview, senior study author Kelly M. Cordoro, MD, professor of dermatology and pediatrics at UCSF, noted that this finding conflicts with prior studies showing an association between obesity and severe psoriasis in children.
“Though methodologies and patient populations differ among studies, what is striking,” she said, is the percentage of overweight/obese patients (37%; defined as a body mass index ≥ 85th percentile) “in our 2-decade single institution dataset.” This “is nearly identical” to the percentage of patients with excess adiposity – 37.9% (also defined as BMI ≥ 85th percentile) – in an international cross-sectional study, which also identified an association between obesity (BMI ≥ 95th percentile) and psoriasis severity in children, she noted.
“What is clear is the strong association between obesity and childhood psoriasis, as multiple studies, including ours, confirm obesity as a major comorbidity of pediatric psoriasis,” Dr. Cordoro said. “Both conditions must be adequately managed to reduce the risk of adverse health outcomes for obese patients with psoriasis.”
The other study coauthors were Dana Feigenbaum, MD, and Alana Ju, MD. The work was supported by the UCSF Yearlong Inquiry Program. The researchers reported having no relevant financial disclosures.
FROM SPD 2021
Sleep-disordered breathing in neuromuscular disease: Early noninvasive ventilation needed
Sleep-disordered breathing is common in patients with neuromuscular disease and is increasingly addressed with noninvasive ventilation, but its patterns go beyond obstructive sleep apnea (OSA) and include hypoventilation, hypoxemia, central sleep apnea, pseudocentrals, periodic breathing, and Cheyne-Stokes respiration, Gaurav Singh, MD, MPH said at the virtual annual meeting of the Associated Professional Sleep Societies.
The prevalence of sleep-related disordered breathing surpasses 40% in patients diagnosed with neuromuscular disease, but “sleep disordered breathing [in these patients] does not equal obstructive sleep apnea,” said Dr. Singh, staff physician at the Veteran Affairs Palo Alto (Calif.) Health Care System in the section of pulmonary, critical care and sleep medicine, and an affiliated clinical assistant professor at Stanford (Calif.) University.
“The most common sleep-related breathing disorder in neuromuscular disease is probably hypopnea and hypoventilation with the sawtooth pattern of dips in oxygen saturation that occur during REM sleep,” he said. As neuromuscular diseases progress, hypoventilation may occur during non-REM sleep as well.
Evaluation is usually performed with polysomnography and pulmonary function testing, he said, but supplementary testing including serum bicarbonate levels, arterial blood gases, and echocardiography to assess for left ventricular ejection fraction and cardiomyopathy may be useful as well.
While a sleep study is not required per Centers for Medicare & Medicaid coverage criteria for the use of respiratory assist devices in patients with neuromuscular disease, polysomnography is valuable for identifying early nocturnal respiratory impairment before the appearance of symptoms and daytime abnormalities in gas exchange, and is better than home testing for distinguishing different types of events (including pseudocentrals). It also is helpful for determining the appropriate pressures needed for ventilatory support and for assessing the need for a backup rate, Dr. Singh said.
Commonly used types of noninvasive ventilation include bilevel positive airway pressure on the spontaneous/timed or pressure control modes, with or without volume-assured pressure support, he said.
Expiratory positive airway pressure (EPAP) is usually set low initially to help decrease the work of breathing and improve triggering, then titrated up to ensure that upper airway obstructive events are treated. Pressure support (the difference between the inspiratory positive airway pressure and EPAP) is set to achieve target tidal volume and to rest the respiratory muscles. And inspiratory time is set “on the longer end” to achieve maximal target volume and ensure appropriate gas exchange, Dr. Singh said.
Data from randomized controlled trials evaluating the effectiveness of NIV are limited, he said. A study published 15 years ago showed a survival benefit and improvement in quality of life measures in patients with amyotrophic lateral sclerosis (ALS) with normal or moderately impaired bulbar function but not in those with severe bulbar weakness.
Regarding the timing of initiating NIV, a retrospective study published several years ago looked at almost 200 ALS patients and evaluated differences in survival amongst those started earlier with NIV (forced vital capacity ≥80%) and those started later (FVC <80%). At 36 months from diagnosis, mortality was 35% for the early group and 53% for the later group. “Improved survival was driven by benefit in patients with non–bulbar-onset ALS, compared with bulbar-onset disease,” Dr. Singh said.
“This study and several other similar studies seem to indicate that the earlier NIV [noninvasive ventilation] is started in patients with neuromuscular disease, the better in terms of improving survival and other relevant measures such as quality of life,” he said.
Asked about Dr. Singh’s presentation, Michelle Cao, DO, clinical associate professor at Stanford University, said that NIV is an “invaluable tool in the treatment of conditions leading to chronic respiratory failure,” such as neuromuscular disease, and that it’s important to incorporate NIV training for future pulmonary, critical care and sleep physicians. Dr. Cao directs the adult NIV program for the neuromuscular medical program at Stanford Health Care.
Saiprakash B. Venkateshiah, MD, of Emory University, Atlanta, also said in introducing Dr. Singh at the meeting that earlier diagnosis and appropriate NIV therapy “may improve quality of life and possibly even lower survival in certain disorders.”
In addition, he noted that sleep disturbances “may be the earliest sign of muscle weakness in [patients with neuromuscular disease], sometimes being detected before their underlying neuromuscular disease is diagnosed.”
Dr. Singh, Dr. Cao, and Dr. Venkateshiah each reported that they had no potential conflicts of interest.
Sleep-disordered breathing is common in patients with neuromuscular disease and is increasingly addressed with noninvasive ventilation, but its patterns go beyond obstructive sleep apnea (OSA) and include hypoventilation, hypoxemia, central sleep apnea, pseudocentrals, periodic breathing, and Cheyne-Stokes respiration, Gaurav Singh, MD, MPH said at the virtual annual meeting of the Associated Professional Sleep Societies.
The prevalence of sleep-related disordered breathing surpasses 40% in patients diagnosed with neuromuscular disease, but “sleep disordered breathing [in these patients] does not equal obstructive sleep apnea,” said Dr. Singh, staff physician at the Veteran Affairs Palo Alto (Calif.) Health Care System in the section of pulmonary, critical care and sleep medicine, and an affiliated clinical assistant professor at Stanford (Calif.) University.
“The most common sleep-related breathing disorder in neuromuscular disease is probably hypopnea and hypoventilation with the sawtooth pattern of dips in oxygen saturation that occur during REM sleep,” he said. As neuromuscular diseases progress, hypoventilation may occur during non-REM sleep as well.
Evaluation is usually performed with polysomnography and pulmonary function testing, he said, but supplementary testing including serum bicarbonate levels, arterial blood gases, and echocardiography to assess for left ventricular ejection fraction and cardiomyopathy may be useful as well.
While a sleep study is not required per Centers for Medicare & Medicaid coverage criteria for the use of respiratory assist devices in patients with neuromuscular disease, polysomnography is valuable for identifying early nocturnal respiratory impairment before the appearance of symptoms and daytime abnormalities in gas exchange, and is better than home testing for distinguishing different types of events (including pseudocentrals). It also is helpful for determining the appropriate pressures needed for ventilatory support and for assessing the need for a backup rate, Dr. Singh said.
Commonly used types of noninvasive ventilation include bilevel positive airway pressure on the spontaneous/timed or pressure control modes, with or without volume-assured pressure support, he said.
Expiratory positive airway pressure (EPAP) is usually set low initially to help decrease the work of breathing and improve triggering, then titrated up to ensure that upper airway obstructive events are treated. Pressure support (the difference between the inspiratory positive airway pressure and EPAP) is set to achieve target tidal volume and to rest the respiratory muscles. And inspiratory time is set “on the longer end” to achieve maximal target volume and ensure appropriate gas exchange, Dr. Singh said.
Data from randomized controlled trials evaluating the effectiveness of NIV are limited, he said. A study published 15 years ago showed a survival benefit and improvement in quality of life measures in patients with amyotrophic lateral sclerosis (ALS) with normal or moderately impaired bulbar function but not in those with severe bulbar weakness.
Regarding the timing of initiating NIV, a retrospective study published several years ago looked at almost 200 ALS patients and evaluated differences in survival amongst those started earlier with NIV (forced vital capacity ≥80%) and those started later (FVC <80%). At 36 months from diagnosis, mortality was 35% for the early group and 53% for the later group. “Improved survival was driven by benefit in patients with non–bulbar-onset ALS, compared with bulbar-onset disease,” Dr. Singh said.
“This study and several other similar studies seem to indicate that the earlier NIV [noninvasive ventilation] is started in patients with neuromuscular disease, the better in terms of improving survival and other relevant measures such as quality of life,” he said.
Asked about Dr. Singh’s presentation, Michelle Cao, DO, clinical associate professor at Stanford University, said that NIV is an “invaluable tool in the treatment of conditions leading to chronic respiratory failure,” such as neuromuscular disease, and that it’s important to incorporate NIV training for future pulmonary, critical care and sleep physicians. Dr. Cao directs the adult NIV program for the neuromuscular medical program at Stanford Health Care.
Saiprakash B. Venkateshiah, MD, of Emory University, Atlanta, also said in introducing Dr. Singh at the meeting that earlier diagnosis and appropriate NIV therapy “may improve quality of life and possibly even lower survival in certain disorders.”
In addition, he noted that sleep disturbances “may be the earliest sign of muscle weakness in [patients with neuromuscular disease], sometimes being detected before their underlying neuromuscular disease is diagnosed.”
Dr. Singh, Dr. Cao, and Dr. Venkateshiah each reported that they had no potential conflicts of interest.
Sleep-disordered breathing is common in patients with neuromuscular disease and is increasingly addressed with noninvasive ventilation, but its patterns go beyond obstructive sleep apnea (OSA) and include hypoventilation, hypoxemia, central sleep apnea, pseudocentrals, periodic breathing, and Cheyne-Stokes respiration, Gaurav Singh, MD, MPH said at the virtual annual meeting of the Associated Professional Sleep Societies.
The prevalence of sleep-related disordered breathing surpasses 40% in patients diagnosed with neuromuscular disease, but “sleep disordered breathing [in these patients] does not equal obstructive sleep apnea,” said Dr. Singh, staff physician at the Veteran Affairs Palo Alto (Calif.) Health Care System in the section of pulmonary, critical care and sleep medicine, and an affiliated clinical assistant professor at Stanford (Calif.) University.
“The most common sleep-related breathing disorder in neuromuscular disease is probably hypopnea and hypoventilation with the sawtooth pattern of dips in oxygen saturation that occur during REM sleep,” he said. As neuromuscular diseases progress, hypoventilation may occur during non-REM sleep as well.
Evaluation is usually performed with polysomnography and pulmonary function testing, he said, but supplementary testing including serum bicarbonate levels, arterial blood gases, and echocardiography to assess for left ventricular ejection fraction and cardiomyopathy may be useful as well.
While a sleep study is not required per Centers for Medicare & Medicaid coverage criteria for the use of respiratory assist devices in patients with neuromuscular disease, polysomnography is valuable for identifying early nocturnal respiratory impairment before the appearance of symptoms and daytime abnormalities in gas exchange, and is better than home testing for distinguishing different types of events (including pseudocentrals). It also is helpful for determining the appropriate pressures needed for ventilatory support and for assessing the need for a backup rate, Dr. Singh said.
Commonly used types of noninvasive ventilation include bilevel positive airway pressure on the spontaneous/timed or pressure control modes, with or without volume-assured pressure support, he said.
Expiratory positive airway pressure (EPAP) is usually set low initially to help decrease the work of breathing and improve triggering, then titrated up to ensure that upper airway obstructive events are treated. Pressure support (the difference between the inspiratory positive airway pressure and EPAP) is set to achieve target tidal volume and to rest the respiratory muscles. And inspiratory time is set “on the longer end” to achieve maximal target volume and ensure appropriate gas exchange, Dr. Singh said.
Data from randomized controlled trials evaluating the effectiveness of NIV are limited, he said. A study published 15 years ago showed a survival benefit and improvement in quality of life measures in patients with amyotrophic lateral sclerosis (ALS) with normal or moderately impaired bulbar function but not in those with severe bulbar weakness.
Regarding the timing of initiating NIV, a retrospective study published several years ago looked at almost 200 ALS patients and evaluated differences in survival amongst those started earlier with NIV (forced vital capacity ≥80%) and those started later (FVC <80%). At 36 months from diagnosis, mortality was 35% for the early group and 53% for the later group. “Improved survival was driven by benefit in patients with non–bulbar-onset ALS, compared with bulbar-onset disease,” Dr. Singh said.
“This study and several other similar studies seem to indicate that the earlier NIV [noninvasive ventilation] is started in patients with neuromuscular disease, the better in terms of improving survival and other relevant measures such as quality of life,” he said.
Asked about Dr. Singh’s presentation, Michelle Cao, DO, clinical associate professor at Stanford University, said that NIV is an “invaluable tool in the treatment of conditions leading to chronic respiratory failure,” such as neuromuscular disease, and that it’s important to incorporate NIV training for future pulmonary, critical care and sleep physicians. Dr. Cao directs the adult NIV program for the neuromuscular medical program at Stanford Health Care.
Saiprakash B. Venkateshiah, MD, of Emory University, Atlanta, also said in introducing Dr. Singh at the meeting that earlier diagnosis and appropriate NIV therapy “may improve quality of life and possibly even lower survival in certain disorders.”
In addition, he noted that sleep disturbances “may be the earliest sign of muscle weakness in [patients with neuromuscular disease], sometimes being detected before their underlying neuromuscular disease is diagnosed.”
Dr. Singh, Dr. Cao, and Dr. Venkateshiah each reported that they had no potential conflicts of interest.
FROM SLEEP 2021
Heart failure med undertreatment because of older age common, flouts evidence
, suggests a large cohort study.
About 80% of patients aged 80 years or older were prescribed renin-angiotensin-system inhibitors (RASi) in a multivariate-adjusted analysis of more than 27,000 patients in the Swedish Heart Failure Registry (SwedeHF). In contrast, such drugs – which included angiotensin receptor-neprilysin inhibitors (ARNi), angiotensin receptor blockers, and ACE inhibitors – were prescribed to 95% of patients younger than 70 years.
Similarly, fewer of the oldest patients were offered meds from the two other drug classes core to HF management at the time: Beta blockers and mineralocorticoid receptor antagonists (MRA).
And among those in the 80-and-older age group who were prescribed RASi or beta blockers, their uptitration more often fell short of even half the target dosage, compared with the youngest patients in the analysis.
Physicians may hold back on full guideline-directed medical therapy in their very elderly patients with HFrEF for many reasons, including a perceived likelihood of drug intolerance due to frailty or multiple comorbidities, including renal dysfunction, Davide Stolfo, MD, Karolinska Institutet, Stockholm, and University of Trieste, Italy, told this news organization.
But the current analysis was adjusted for about 80 variables “that in our interpretation may be main reasons for not introducing drugs and using them in the older patients,” he said. They included care setting (that is, inpatient or outpatient), HF severity by several measures, a range of comorbidities, renal dysfunction, and history of serious illness such as cancer.
Even then, age emerged as a significant, independent predictor of medical therapy underuse in the oldest patients. Some physicians apparently see advanced age, by itself, as an “intrinsic reason” not to abide by HFrEF medical therapy recommendations, said Dr. Stolfo, who presented the analysis at HFA 2021, the annual meeting of the Heart Failure Association of the European Society of Cardiology (ESC-HFA), conducted both virtually and live in Florence, Italy.
Most major HF-drug trials have excluded or admitted few patients aged 80 years or older, but “the guidelines recommend treatment regardless of age, and in the trials there has been no influence from age on the effectiveness of drugs,” Dr. Stolfo observed.
Moreover, in a prior SwedeHF analysis with propensity matching, patients with HFrEF aged 80 or older showed steeper reductions in risk for death or HF hospitalization from treatment with RASi than those in younger age groups.
One of the few randomized trials to focus on the very elderly, called SENIORS, enrolled patients aged 70 years and older – the average age was 76 – and saw a significantly reduced risk of death or cardiovascular hospitalization for those assigned to the beta blocker nebivolol. The benefits in the trial, which was conducted 15 years ago, were independent of left ventricular function.
So in the oldest patients, “we could question the need to achieve full dose of an evidence-based drug, but we shouldn’t question the use of these drugs.”
The findings are consistent with a need to individualize medical therapy in senior patients with HFrEF, especially those of more advanced age, some of whom may be robust enough to be managed similarly to younger patients while others who may be less suitable for full guideline-directed medical therapy, Dr. Stolfo said.
Even for those who are more frail or have major comorbidities, drug therapy of HFrEF continues to be important for symptom control even if competing causes of death make it harder to prolong survival, Dr. Stolfo said.
“We should provide to all patients the best strategy they can tolerate,” he said. “If we cannot greatly impact on the long-term survival for these patients, treatment can be aimed to improve the quality of life and keep the patient out of the hospital.”
The analysis was supported by Boehringer Ingelheim. Dr. Stolfo disclosed personal fees from Novartis, Merck, GlaxoSmithKline, and Acceleron.
A version of this article first appeared on Medscape.com.
, suggests a large cohort study.
About 80% of patients aged 80 years or older were prescribed renin-angiotensin-system inhibitors (RASi) in a multivariate-adjusted analysis of more than 27,000 patients in the Swedish Heart Failure Registry (SwedeHF). In contrast, such drugs – which included angiotensin receptor-neprilysin inhibitors (ARNi), angiotensin receptor blockers, and ACE inhibitors – were prescribed to 95% of patients younger than 70 years.
Similarly, fewer of the oldest patients were offered meds from the two other drug classes core to HF management at the time: Beta blockers and mineralocorticoid receptor antagonists (MRA).
And among those in the 80-and-older age group who were prescribed RASi or beta blockers, their uptitration more often fell short of even half the target dosage, compared with the youngest patients in the analysis.
Physicians may hold back on full guideline-directed medical therapy in their very elderly patients with HFrEF for many reasons, including a perceived likelihood of drug intolerance due to frailty or multiple comorbidities, including renal dysfunction, Davide Stolfo, MD, Karolinska Institutet, Stockholm, and University of Trieste, Italy, told this news organization.
But the current analysis was adjusted for about 80 variables “that in our interpretation may be main reasons for not introducing drugs and using them in the older patients,” he said. They included care setting (that is, inpatient or outpatient), HF severity by several measures, a range of comorbidities, renal dysfunction, and history of serious illness such as cancer.
Even then, age emerged as a significant, independent predictor of medical therapy underuse in the oldest patients. Some physicians apparently see advanced age, by itself, as an “intrinsic reason” not to abide by HFrEF medical therapy recommendations, said Dr. Stolfo, who presented the analysis at HFA 2021, the annual meeting of the Heart Failure Association of the European Society of Cardiology (ESC-HFA), conducted both virtually and live in Florence, Italy.
Most major HF-drug trials have excluded or admitted few patients aged 80 years or older, but “the guidelines recommend treatment regardless of age, and in the trials there has been no influence from age on the effectiveness of drugs,” Dr. Stolfo observed.
Moreover, in a prior SwedeHF analysis with propensity matching, patients with HFrEF aged 80 or older showed steeper reductions in risk for death or HF hospitalization from treatment with RASi than those in younger age groups.
One of the few randomized trials to focus on the very elderly, called SENIORS, enrolled patients aged 70 years and older – the average age was 76 – and saw a significantly reduced risk of death or cardiovascular hospitalization for those assigned to the beta blocker nebivolol. The benefits in the trial, which was conducted 15 years ago, were independent of left ventricular function.
So in the oldest patients, “we could question the need to achieve full dose of an evidence-based drug, but we shouldn’t question the use of these drugs.”
The findings are consistent with a need to individualize medical therapy in senior patients with HFrEF, especially those of more advanced age, some of whom may be robust enough to be managed similarly to younger patients while others who may be less suitable for full guideline-directed medical therapy, Dr. Stolfo said.
Even for those who are more frail or have major comorbidities, drug therapy of HFrEF continues to be important for symptom control even if competing causes of death make it harder to prolong survival, Dr. Stolfo said.
“We should provide to all patients the best strategy they can tolerate,” he said. “If we cannot greatly impact on the long-term survival for these patients, treatment can be aimed to improve the quality of life and keep the patient out of the hospital.”
The analysis was supported by Boehringer Ingelheim. Dr. Stolfo disclosed personal fees from Novartis, Merck, GlaxoSmithKline, and Acceleron.
A version of this article first appeared on Medscape.com.
, suggests a large cohort study.
About 80% of patients aged 80 years or older were prescribed renin-angiotensin-system inhibitors (RASi) in a multivariate-adjusted analysis of more than 27,000 patients in the Swedish Heart Failure Registry (SwedeHF). In contrast, such drugs – which included angiotensin receptor-neprilysin inhibitors (ARNi), angiotensin receptor blockers, and ACE inhibitors – were prescribed to 95% of patients younger than 70 years.
Similarly, fewer of the oldest patients were offered meds from the two other drug classes core to HF management at the time: Beta blockers and mineralocorticoid receptor antagonists (MRA).
And among those in the 80-and-older age group who were prescribed RASi or beta blockers, their uptitration more often fell short of even half the target dosage, compared with the youngest patients in the analysis.
Physicians may hold back on full guideline-directed medical therapy in their very elderly patients with HFrEF for many reasons, including a perceived likelihood of drug intolerance due to frailty or multiple comorbidities, including renal dysfunction, Davide Stolfo, MD, Karolinska Institutet, Stockholm, and University of Trieste, Italy, told this news organization.
But the current analysis was adjusted for about 80 variables “that in our interpretation may be main reasons for not introducing drugs and using them in the older patients,” he said. They included care setting (that is, inpatient or outpatient), HF severity by several measures, a range of comorbidities, renal dysfunction, and history of serious illness such as cancer.
Even then, age emerged as a significant, independent predictor of medical therapy underuse in the oldest patients. Some physicians apparently see advanced age, by itself, as an “intrinsic reason” not to abide by HFrEF medical therapy recommendations, said Dr. Stolfo, who presented the analysis at HFA 2021, the annual meeting of the Heart Failure Association of the European Society of Cardiology (ESC-HFA), conducted both virtually and live in Florence, Italy.
Most major HF-drug trials have excluded or admitted few patients aged 80 years or older, but “the guidelines recommend treatment regardless of age, and in the trials there has been no influence from age on the effectiveness of drugs,” Dr. Stolfo observed.
Moreover, in a prior SwedeHF analysis with propensity matching, patients with HFrEF aged 80 or older showed steeper reductions in risk for death or HF hospitalization from treatment with RASi than those in younger age groups.
One of the few randomized trials to focus on the very elderly, called SENIORS, enrolled patients aged 70 years and older – the average age was 76 – and saw a significantly reduced risk of death or cardiovascular hospitalization for those assigned to the beta blocker nebivolol. The benefits in the trial, which was conducted 15 years ago, were independent of left ventricular function.
So in the oldest patients, “we could question the need to achieve full dose of an evidence-based drug, but we shouldn’t question the use of these drugs.”
The findings are consistent with a need to individualize medical therapy in senior patients with HFrEF, especially those of more advanced age, some of whom may be robust enough to be managed similarly to younger patients while others who may be less suitable for full guideline-directed medical therapy, Dr. Stolfo said.
Even for those who are more frail or have major comorbidities, drug therapy of HFrEF continues to be important for symptom control even if competing causes of death make it harder to prolong survival, Dr. Stolfo said.
“We should provide to all patients the best strategy they can tolerate,” he said. “If we cannot greatly impact on the long-term survival for these patients, treatment can be aimed to improve the quality of life and keep the patient out of the hospital.”
The analysis was supported by Boehringer Ingelheim. Dr. Stolfo disclosed personal fees from Novartis, Merck, GlaxoSmithKline, and Acceleron.
A version of this article first appeared on Medscape.com.
Fibrosis severity in ALD predicts survival
Moderate fibrosis in patients with alcoholic liver disease is not a benign condition, say investigators who studied the natural history of ALD according to biopsy-proven fibrosis stage.
In a study of 422 patients who were followed for a median of 43 months, 5.8% of patients with no or minimal fibrosis had a liver decompensation event. This compares with 21% (hazard ratio, 3.8; 95% confidence interval, 1.9-7.5; P < .01) of patients with significant fibrosis and 45% (HR, 9.6; 95% CI, 5.2-18.0; P < .01) of patients with advanced fibrosis, said Ditlev Nytoft Rasmussen, PhD, in an oral presentation at the meeting sponsored by the European Association for the Study of the Liver.
“The most obvious implication of this study is that the stage of fibrosis is a very strong predictor for the prognosis in early asymptomatic alcohol-related liver disease,” he said.
The findings suggest that gastroenterologists do not need to follow patients with no or only minor fibrosis, but patients with significant (F2) fibrosis, or greater, should be closely followed, said Dr. Rasmussen, who is with the FLASH Center for Liver Research at Odense (Denmark) University.
A gastroenterologist who was not involved in the study commented on the excess mortality the investigators saw.
“The really striking finding here to me is the excess mortality in the significant fibrosis group. They are not healthy, and some of that excess mortality does appear to be liver related, but some of it may not be liver related,“ said Esperance A. Schaefer, MD, MPH, of Massachusetts General Hospital in Boston.
“I think it will be important to be vigilant about the causes of death that are not liver related in patients with significant and advanced fibrosis, and the healthy group,” she said in an interview.
Ewan H. Forrest, MD, from the University of Glasgow, who was not involved in the study, said: “These are a challenging group of patients to identify with early disease. You quite rightly raise the question of how we should follow-up with these patients.”
Managing asymptomatic patients
Although noninvasive tests can identify ALD in the early fibrotic stage, it’s unclear how patients with early asymptomatic disease should be managed, Dr. Rasmussen said.
This uncertainty prompted FLASH investigators to study patients with ALD to determine how fibrosis affected outcomes such as decompensation, hospitalization, and death.
They looked at a prospective cohort of patients diagnosed with ALD by biopsy and transient elastography (FibroScan) from 2013 to 2018. Follow-up data for the patients were collected retrospectively from electronic health records or charts.
The patients, who all had alcohol overuse and no history of decompensation or other etiologies at baseline, were classified into three groups: 225 liver-healthy patients with minimal to no fibrosis (F1 or transient elastography <6 kPa kPa); 104 patients with significant fibrosis (F2); and, 93 patients with advanced fibrosis (F3 or F4).
The median patient age was 57 years, and 75% of the patients were men. The patients were followed for 1,149 patient-years.
Findings and outcomes
During follow-up, 53 patients died, and 51 had a decompensation event: overt hepatoencephalopathy, ascites, variceal bleeding, hepatorenal syndrome, or jaundice. Of the 51 patients, 27 died.
There was a protocol change during the study, with the new protocol stating that patients with transient elastography below 6 kPa could not undergo biopsy. Based on the 106 patients who had both a FibroScan and biopsy, of whom 20% had F2 fibrosis, the investigators calculated that 14 patients who did not undergo biopsy may have been incorrectly classified as having healthy livers, Dr. Rasmussen said.
Patients with healthy livers had a significantly better decompensation-free survival rates, with only 5.8% of those with healthy livers having a decompensation event out to 4.5 years, compared with 21% of patients with significant fibrosis or advanced fibrosis.
Within the first year of follow-up, 98% of patients with healthy livers were alive and free of decompensations, compared with 94% with significant fibrosis and 84% with advanced fibrosis. The respective rates at 3 years were 95%, 82%, and 55%.
The percentage of hospital admissions that were liver related was 5% in the healthy-liver group, 24% in the significant group, and 47% in the advanced group.
Ongoing alcohol use during follow-up was also a significant predictor of worse decompensation-free survival (HR, 1.6; P = .04), with two in three decompensation events occurring in patients with alcohol overuse. The effect of alcohol was less strong than fibrosis stage, however, Dr. Rasmussen noted.
Dr. Schaefer said that “we see individuals who with heavy alcohol use progress much more rapidly than you’d anticipate with the rule of thumb that you see in other diseases of one fibrosis stage every 5-7 years.”
Among the strengths of this study included the use of biopsy and the inclusion of all stages of fibrosis. The investigators acknowledged as potential limitations the retrospective collection of follow-up data, reliance on medical charts to estimate alcohol consumption, and the single-center design.
The study was supported by grants from the European Union’s Horizon 2020 research and innovation program and the Novo Nordisk Foundation Challenge program. Dr. Rasmussen, Dr. Schaefer, and Dr. Forrest reported no conflicts of interest to disclose.
Moderate fibrosis in patients with alcoholic liver disease is not a benign condition, say investigators who studied the natural history of ALD according to biopsy-proven fibrosis stage.
In a study of 422 patients who were followed for a median of 43 months, 5.8% of patients with no or minimal fibrosis had a liver decompensation event. This compares with 21% (hazard ratio, 3.8; 95% confidence interval, 1.9-7.5; P < .01) of patients with significant fibrosis and 45% (HR, 9.6; 95% CI, 5.2-18.0; P < .01) of patients with advanced fibrosis, said Ditlev Nytoft Rasmussen, PhD, in an oral presentation at the meeting sponsored by the European Association for the Study of the Liver.
“The most obvious implication of this study is that the stage of fibrosis is a very strong predictor for the prognosis in early asymptomatic alcohol-related liver disease,” he said.
The findings suggest that gastroenterologists do not need to follow patients with no or only minor fibrosis, but patients with significant (F2) fibrosis, or greater, should be closely followed, said Dr. Rasmussen, who is with the FLASH Center for Liver Research at Odense (Denmark) University.
A gastroenterologist who was not involved in the study commented on the excess mortality the investigators saw.
“The really striking finding here to me is the excess mortality in the significant fibrosis group. They are not healthy, and some of that excess mortality does appear to be liver related, but some of it may not be liver related,“ said Esperance A. Schaefer, MD, MPH, of Massachusetts General Hospital in Boston.
“I think it will be important to be vigilant about the causes of death that are not liver related in patients with significant and advanced fibrosis, and the healthy group,” she said in an interview.
Ewan H. Forrest, MD, from the University of Glasgow, who was not involved in the study, said: “These are a challenging group of patients to identify with early disease. You quite rightly raise the question of how we should follow-up with these patients.”
Managing asymptomatic patients
Although noninvasive tests can identify ALD in the early fibrotic stage, it’s unclear how patients with early asymptomatic disease should be managed, Dr. Rasmussen said.
This uncertainty prompted FLASH investigators to study patients with ALD to determine how fibrosis affected outcomes such as decompensation, hospitalization, and death.
They looked at a prospective cohort of patients diagnosed with ALD by biopsy and transient elastography (FibroScan) from 2013 to 2018. Follow-up data for the patients were collected retrospectively from electronic health records or charts.
The patients, who all had alcohol overuse and no history of decompensation or other etiologies at baseline, were classified into three groups: 225 liver-healthy patients with minimal to no fibrosis (F1 or transient elastography <6 kPa kPa); 104 patients with significant fibrosis (F2); and, 93 patients with advanced fibrosis (F3 or F4).
The median patient age was 57 years, and 75% of the patients were men. The patients were followed for 1,149 patient-years.
Findings and outcomes
During follow-up, 53 patients died, and 51 had a decompensation event: overt hepatoencephalopathy, ascites, variceal bleeding, hepatorenal syndrome, or jaundice. Of the 51 patients, 27 died.
There was a protocol change during the study, with the new protocol stating that patients with transient elastography below 6 kPa could not undergo biopsy. Based on the 106 patients who had both a FibroScan and biopsy, of whom 20% had F2 fibrosis, the investigators calculated that 14 patients who did not undergo biopsy may have been incorrectly classified as having healthy livers, Dr. Rasmussen said.
Patients with healthy livers had a significantly better decompensation-free survival rates, with only 5.8% of those with healthy livers having a decompensation event out to 4.5 years, compared with 21% of patients with significant fibrosis or advanced fibrosis.
Within the first year of follow-up, 98% of patients with healthy livers were alive and free of decompensations, compared with 94% with significant fibrosis and 84% with advanced fibrosis. The respective rates at 3 years were 95%, 82%, and 55%.
The percentage of hospital admissions that were liver related was 5% in the healthy-liver group, 24% in the significant group, and 47% in the advanced group.
Ongoing alcohol use during follow-up was also a significant predictor of worse decompensation-free survival (HR, 1.6; P = .04), with two in three decompensation events occurring in patients with alcohol overuse. The effect of alcohol was less strong than fibrosis stage, however, Dr. Rasmussen noted.
Dr. Schaefer said that “we see individuals who with heavy alcohol use progress much more rapidly than you’d anticipate with the rule of thumb that you see in other diseases of one fibrosis stage every 5-7 years.”
Among the strengths of this study included the use of biopsy and the inclusion of all stages of fibrosis. The investigators acknowledged as potential limitations the retrospective collection of follow-up data, reliance on medical charts to estimate alcohol consumption, and the single-center design.
The study was supported by grants from the European Union’s Horizon 2020 research and innovation program and the Novo Nordisk Foundation Challenge program. Dr. Rasmussen, Dr. Schaefer, and Dr. Forrest reported no conflicts of interest to disclose.
Moderate fibrosis in patients with alcoholic liver disease is not a benign condition, say investigators who studied the natural history of ALD according to biopsy-proven fibrosis stage.
In a study of 422 patients who were followed for a median of 43 months, 5.8% of patients with no or minimal fibrosis had a liver decompensation event. This compares with 21% (hazard ratio, 3.8; 95% confidence interval, 1.9-7.5; P < .01) of patients with significant fibrosis and 45% (HR, 9.6; 95% CI, 5.2-18.0; P < .01) of patients with advanced fibrosis, said Ditlev Nytoft Rasmussen, PhD, in an oral presentation at the meeting sponsored by the European Association for the Study of the Liver.
“The most obvious implication of this study is that the stage of fibrosis is a very strong predictor for the prognosis in early asymptomatic alcohol-related liver disease,” he said.
The findings suggest that gastroenterologists do not need to follow patients with no or only minor fibrosis, but patients with significant (F2) fibrosis, or greater, should be closely followed, said Dr. Rasmussen, who is with the FLASH Center for Liver Research at Odense (Denmark) University.
A gastroenterologist who was not involved in the study commented on the excess mortality the investigators saw.
“The really striking finding here to me is the excess mortality in the significant fibrosis group. They are not healthy, and some of that excess mortality does appear to be liver related, but some of it may not be liver related,“ said Esperance A. Schaefer, MD, MPH, of Massachusetts General Hospital in Boston.
“I think it will be important to be vigilant about the causes of death that are not liver related in patients with significant and advanced fibrosis, and the healthy group,” she said in an interview.
Ewan H. Forrest, MD, from the University of Glasgow, who was not involved in the study, said: “These are a challenging group of patients to identify with early disease. You quite rightly raise the question of how we should follow-up with these patients.”
Managing asymptomatic patients
Although noninvasive tests can identify ALD in the early fibrotic stage, it’s unclear how patients with early asymptomatic disease should be managed, Dr. Rasmussen said.
This uncertainty prompted FLASH investigators to study patients with ALD to determine how fibrosis affected outcomes such as decompensation, hospitalization, and death.
They looked at a prospective cohort of patients diagnosed with ALD by biopsy and transient elastography (FibroScan) from 2013 to 2018. Follow-up data for the patients were collected retrospectively from electronic health records or charts.
The patients, who all had alcohol overuse and no history of decompensation or other etiologies at baseline, were classified into three groups: 225 liver-healthy patients with minimal to no fibrosis (F1 or transient elastography <6 kPa kPa); 104 patients with significant fibrosis (F2); and, 93 patients with advanced fibrosis (F3 or F4).
The median patient age was 57 years, and 75% of the patients were men. The patients were followed for 1,149 patient-years.
Findings and outcomes
During follow-up, 53 patients died, and 51 had a decompensation event: overt hepatoencephalopathy, ascites, variceal bleeding, hepatorenal syndrome, or jaundice. Of the 51 patients, 27 died.
There was a protocol change during the study, with the new protocol stating that patients with transient elastography below 6 kPa could not undergo biopsy. Based on the 106 patients who had both a FibroScan and biopsy, of whom 20% had F2 fibrosis, the investigators calculated that 14 patients who did not undergo biopsy may have been incorrectly classified as having healthy livers, Dr. Rasmussen said.
Patients with healthy livers had a significantly better decompensation-free survival rates, with only 5.8% of those with healthy livers having a decompensation event out to 4.5 years, compared with 21% of patients with significant fibrosis or advanced fibrosis.
Within the first year of follow-up, 98% of patients with healthy livers were alive and free of decompensations, compared with 94% with significant fibrosis and 84% with advanced fibrosis. The respective rates at 3 years were 95%, 82%, and 55%.
The percentage of hospital admissions that were liver related was 5% in the healthy-liver group, 24% in the significant group, and 47% in the advanced group.
Ongoing alcohol use during follow-up was also a significant predictor of worse decompensation-free survival (HR, 1.6; P = .04), with two in three decompensation events occurring in patients with alcohol overuse. The effect of alcohol was less strong than fibrosis stage, however, Dr. Rasmussen noted.
Dr. Schaefer said that “we see individuals who with heavy alcohol use progress much more rapidly than you’d anticipate with the rule of thumb that you see in other diseases of one fibrosis stage every 5-7 years.”
Among the strengths of this study included the use of biopsy and the inclusion of all stages of fibrosis. The investigators acknowledged as potential limitations the retrospective collection of follow-up data, reliance on medical charts to estimate alcohol consumption, and the single-center design.
The study was supported by grants from the European Union’s Horizon 2020 research and innovation program and the Novo Nordisk Foundation Challenge program. Dr. Rasmussen, Dr. Schaefer, and Dr. Forrest reported no conflicts of interest to disclose.
FROM ILC 2021
Protein expression may predict HBV DNA suppression
Stopping nucleoside analog therapy in patients with hepatitis B viral (HBV) infections results in sustained viral suppression in only a minority of patients, but a new study suggests there are immune signatures that may serve as predictive biomarkers to help clinicians determine how to improve immune responses in these patients, according to investigators.
In a study of 359 patients enrolled in clinical trials of antiviral therapy for HBV infections, there were 29 immune-related proteins that were found in significantly higher levels among patients who continued to have viral suppression 24 weeks after the end of treatment, compared with patients who did not maintain viral suppression, reported Henry L.Y. Chan, MD, from the Chinese University of Hong Kong.
“In this study, plasma proteomics shows that sustained HBV suppression following treatment discontinuation is associated with higher levels of innate and adaptive immune responses during treatment, but whether these signatures vary by specific treatment regimens remains to be determined,” he said in an oral session at the meeting sponsored by the European Association for the Study of the Liver.
The clustering of proteins differed between patients treated with nucleoside analogs and those who received pegylated interferon (PEG-IFN), Dr. Chan noted.
Is it safe?
Although current international guidelines say that clinicians may consider stopping nucleoside analogs in certain patient populations with the goal of promoting sustained off-treatment responses, pooled data from four large phase 3 studies showed that only 10% of patients had sustained HBV DNA suppression, and only 32% had persistent low-level viremia, Dr. Chan said, citing a presentation from ILC in 2019.
Dr. Chan and colleagues sought to identify immune biomarkers that at the end of treatment predict HBV off-treatment response. This is important because existing treatments do not kill the virus which – even if suppressed – can lead to hepatocellular carcinoma.
The researchers examined plasma samples from patients with chronic hepatitis B who were enrolled in two studies: a registrational study comparing tenofovir disoproxil fumarate with adefovir followed by tenofovir maintenance (GS-US-174-0102) and one comparing TDF plus PEG-IFN with either drug alone (GS-US-174-0149).
They identified a total of 359 patients who had at least two treatment-free follow-up visits, were positive for the hepatitis B S antigen (HBsAg) at the end of the treatment, including patients who had antigen loss on treatment but subsequently seroverted, and had available plasma samples collected before the end of treatment.
The study outcomes were sustained viral suppression 24 weeks after the end of treatment, defined as HBV DNA less than 29 IU/mL, and a low replicative state defined as HBV DNA below 2,000 IU/mL with ALT levels at or below the upper limit of normal.
The median patient age was 39 years. In all, 67% of the population was male, and 70% were Asian.
Immune-related proteins
The investigators performed proteomic analyses looking for expression levels in serum or plasma proteins at the end of treatment.
A total of 25 patients had HBV DNA suppression at posttreatment week 24, 111 patients had a low replicative states, and 4 had HBsAg loss.
The patients with HBV DNA suppression had significantly higher expression of 29 immune-related proteins, the majority of which were related to the host immune response.
The proteins included myeloid cell markers, leukocyte-trafficking chemokines, natural killer cell markers, and extracellular matrix and/or extracellular matrix–associated proteins.
Among patients with HBV suppression, there was evidence of enrichment for extracellular remodeling pathways, as well as pathways involved in innate immune response to viral infections and immune regulation.
Among patients with low viral replication, there was a trend toward higher CD8a expression levels at the 24-week follow-up, but there were no proteins with significantly elevated expression levels.
“Assessment of unique protein signatures associated with HBsAg loss following treatment discontinuation is ongoing,” Dr. Chan said.
Timing of expression patterns
During the question-and-answer session following his presentation, comoderator Pablo Sarobe, MD, from the Clinica Universidad de Navarra (Spain), said: “I’ve seen that you have compared the different proteins which are detected in your cell samples 24 weeks after stopping treatment. Do you think that these differences are already relevant just at the end of treatment, or that these proteins are being expressed [during] the 24 weeks between the end of treatment and your determination?”
“We only have one time-point sample, so it’s hard to say,” Dr. Chan replied, but he speculated that the delay would not have a direct impact on protein expression, “so probably this expression should last after treatment has stopped. But we only have only posttreatment 24-week data, and we believe that some of the outcome measures may change with longer follow-up. After 1 year some patients in suppression may relapse.”
Asked by an audience member whether the investigators had performed a subanalysis of patients treated with nucleoside analogs, Dr. Chan noted that such an analysis was under consideration, although the patient numbers were relatively small. He did add, however, that protein expression patterns differed among patients treated with nucleoside analogs and PEG-IFN.
The study was funded by Gilead Sciences. Dr. Chan disclosed sponsored lecture activities and consulting for Gilead and others. Dr. Sarobe reported no conflicts of interest.
Stopping nucleoside analog therapy in patients with hepatitis B viral (HBV) infections results in sustained viral suppression in only a minority of patients, but a new study suggests there are immune signatures that may serve as predictive biomarkers to help clinicians determine how to improve immune responses in these patients, according to investigators.
In a study of 359 patients enrolled in clinical trials of antiviral therapy for HBV infections, there were 29 immune-related proteins that were found in significantly higher levels among patients who continued to have viral suppression 24 weeks after the end of treatment, compared with patients who did not maintain viral suppression, reported Henry L.Y. Chan, MD, from the Chinese University of Hong Kong.
“In this study, plasma proteomics shows that sustained HBV suppression following treatment discontinuation is associated with higher levels of innate and adaptive immune responses during treatment, but whether these signatures vary by specific treatment regimens remains to be determined,” he said in an oral session at the meeting sponsored by the European Association for the Study of the Liver.
The clustering of proteins differed between patients treated with nucleoside analogs and those who received pegylated interferon (PEG-IFN), Dr. Chan noted.
Is it safe?
Although current international guidelines say that clinicians may consider stopping nucleoside analogs in certain patient populations with the goal of promoting sustained off-treatment responses, pooled data from four large phase 3 studies showed that only 10% of patients had sustained HBV DNA suppression, and only 32% had persistent low-level viremia, Dr. Chan said, citing a presentation from ILC in 2019.
Dr. Chan and colleagues sought to identify immune biomarkers that at the end of treatment predict HBV off-treatment response. This is important because existing treatments do not kill the virus which – even if suppressed – can lead to hepatocellular carcinoma.
The researchers examined plasma samples from patients with chronic hepatitis B who were enrolled in two studies: a registrational study comparing tenofovir disoproxil fumarate with adefovir followed by tenofovir maintenance (GS-US-174-0102) and one comparing TDF plus PEG-IFN with either drug alone (GS-US-174-0149).
They identified a total of 359 patients who had at least two treatment-free follow-up visits, were positive for the hepatitis B S antigen (HBsAg) at the end of the treatment, including patients who had antigen loss on treatment but subsequently seroverted, and had available plasma samples collected before the end of treatment.
The study outcomes were sustained viral suppression 24 weeks after the end of treatment, defined as HBV DNA less than 29 IU/mL, and a low replicative state defined as HBV DNA below 2,000 IU/mL with ALT levels at or below the upper limit of normal.
The median patient age was 39 years. In all, 67% of the population was male, and 70% were Asian.
Immune-related proteins
The investigators performed proteomic analyses looking for expression levels in serum or plasma proteins at the end of treatment.
A total of 25 patients had HBV DNA suppression at posttreatment week 24, 111 patients had a low replicative states, and 4 had HBsAg loss.
The patients with HBV DNA suppression had significantly higher expression of 29 immune-related proteins, the majority of which were related to the host immune response.
The proteins included myeloid cell markers, leukocyte-trafficking chemokines, natural killer cell markers, and extracellular matrix and/or extracellular matrix–associated proteins.
Among patients with HBV suppression, there was evidence of enrichment for extracellular remodeling pathways, as well as pathways involved in innate immune response to viral infections and immune regulation.
Among patients with low viral replication, there was a trend toward higher CD8a expression levels at the 24-week follow-up, but there were no proteins with significantly elevated expression levels.
“Assessment of unique protein signatures associated with HBsAg loss following treatment discontinuation is ongoing,” Dr. Chan said.
Timing of expression patterns
During the question-and-answer session following his presentation, comoderator Pablo Sarobe, MD, from the Clinica Universidad de Navarra (Spain), said: “I’ve seen that you have compared the different proteins which are detected in your cell samples 24 weeks after stopping treatment. Do you think that these differences are already relevant just at the end of treatment, or that these proteins are being expressed [during] the 24 weeks between the end of treatment and your determination?”
“We only have one time-point sample, so it’s hard to say,” Dr. Chan replied, but he speculated that the delay would not have a direct impact on protein expression, “so probably this expression should last after treatment has stopped. But we only have only posttreatment 24-week data, and we believe that some of the outcome measures may change with longer follow-up. After 1 year some patients in suppression may relapse.”
Asked by an audience member whether the investigators had performed a subanalysis of patients treated with nucleoside analogs, Dr. Chan noted that such an analysis was under consideration, although the patient numbers were relatively small. He did add, however, that protein expression patterns differed among patients treated with nucleoside analogs and PEG-IFN.
The study was funded by Gilead Sciences. Dr. Chan disclosed sponsored lecture activities and consulting for Gilead and others. Dr. Sarobe reported no conflicts of interest.
Stopping nucleoside analog therapy in patients with hepatitis B viral (HBV) infections results in sustained viral suppression in only a minority of patients, but a new study suggests there are immune signatures that may serve as predictive biomarkers to help clinicians determine how to improve immune responses in these patients, according to investigators.
In a study of 359 patients enrolled in clinical trials of antiviral therapy for HBV infections, there were 29 immune-related proteins that were found in significantly higher levels among patients who continued to have viral suppression 24 weeks after the end of treatment, compared with patients who did not maintain viral suppression, reported Henry L.Y. Chan, MD, from the Chinese University of Hong Kong.
“In this study, plasma proteomics shows that sustained HBV suppression following treatment discontinuation is associated with higher levels of innate and adaptive immune responses during treatment, but whether these signatures vary by specific treatment regimens remains to be determined,” he said in an oral session at the meeting sponsored by the European Association for the Study of the Liver.
The clustering of proteins differed between patients treated with nucleoside analogs and those who received pegylated interferon (PEG-IFN), Dr. Chan noted.
Is it safe?
Although current international guidelines say that clinicians may consider stopping nucleoside analogs in certain patient populations with the goal of promoting sustained off-treatment responses, pooled data from four large phase 3 studies showed that only 10% of patients had sustained HBV DNA suppression, and only 32% had persistent low-level viremia, Dr. Chan said, citing a presentation from ILC in 2019.
Dr. Chan and colleagues sought to identify immune biomarkers that at the end of treatment predict HBV off-treatment response. This is important because existing treatments do not kill the virus which – even if suppressed – can lead to hepatocellular carcinoma.
The researchers examined plasma samples from patients with chronic hepatitis B who were enrolled in two studies: a registrational study comparing tenofovir disoproxil fumarate with adefovir followed by tenofovir maintenance (GS-US-174-0102) and one comparing TDF plus PEG-IFN with either drug alone (GS-US-174-0149).
They identified a total of 359 patients who had at least two treatment-free follow-up visits, were positive for the hepatitis B S antigen (HBsAg) at the end of the treatment, including patients who had antigen loss on treatment but subsequently seroverted, and had available plasma samples collected before the end of treatment.
The study outcomes were sustained viral suppression 24 weeks after the end of treatment, defined as HBV DNA less than 29 IU/mL, and a low replicative state defined as HBV DNA below 2,000 IU/mL with ALT levels at or below the upper limit of normal.
The median patient age was 39 years. In all, 67% of the population was male, and 70% were Asian.
Immune-related proteins
The investigators performed proteomic analyses looking for expression levels in serum or plasma proteins at the end of treatment.
A total of 25 patients had HBV DNA suppression at posttreatment week 24, 111 patients had a low replicative states, and 4 had HBsAg loss.
The patients with HBV DNA suppression had significantly higher expression of 29 immune-related proteins, the majority of which were related to the host immune response.
The proteins included myeloid cell markers, leukocyte-trafficking chemokines, natural killer cell markers, and extracellular matrix and/or extracellular matrix–associated proteins.
Among patients with HBV suppression, there was evidence of enrichment for extracellular remodeling pathways, as well as pathways involved in innate immune response to viral infections and immune regulation.
Among patients with low viral replication, there was a trend toward higher CD8a expression levels at the 24-week follow-up, but there were no proteins with significantly elevated expression levels.
“Assessment of unique protein signatures associated with HBsAg loss following treatment discontinuation is ongoing,” Dr. Chan said.
Timing of expression patterns
During the question-and-answer session following his presentation, comoderator Pablo Sarobe, MD, from the Clinica Universidad de Navarra (Spain), said: “I’ve seen that you have compared the different proteins which are detected in your cell samples 24 weeks after stopping treatment. Do you think that these differences are already relevant just at the end of treatment, or that these proteins are being expressed [during] the 24 weeks between the end of treatment and your determination?”
“We only have one time-point sample, so it’s hard to say,” Dr. Chan replied, but he speculated that the delay would not have a direct impact on protein expression, “so probably this expression should last after treatment has stopped. But we only have only posttreatment 24-week data, and we believe that some of the outcome measures may change with longer follow-up. After 1 year some patients in suppression may relapse.”
Asked by an audience member whether the investigators had performed a subanalysis of patients treated with nucleoside analogs, Dr. Chan noted that such an analysis was under consideration, although the patient numbers were relatively small. He did add, however, that protein expression patterns differed among patients treated with nucleoside analogs and PEG-IFN.
The study was funded by Gilead Sciences. Dr. Chan disclosed sponsored lecture activities and consulting for Gilead and others. Dr. Sarobe reported no conflicts of interest.
FROM ILC 2021