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Risk to infant may warrant drug treatment for postpartum depression
If moderate to severe postpartum depression poses a risk to child development, that argues in favor of pharmacologic therapy, according to a detailed risk-benefit assessment presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.
“It is important to consider that there are potential risks of antidepressant drugs, but there are also potential risks from not providing effective treatment,” reported Neha Hudepohl, MD, at the virtual meeting, presented by MedscapeLive.
On a website maintained by the Centers for Disease Control and Prevention, the question of whether antidepressants pose a risk to breast-feeding children is answered with a “maybe.” Although many of these drugs can be detected in breast milk, according to the CDC, “most have little or no effect on milk supply or on infant well-being.”
This is enough uncertainty that antidepressants are not first-line intervention when postpartum depression is mild, said Dr. Hudepohl, director of women’s mental health at Prisma Health Upstate, Greenville, S.C. However, she noted that the American College of Obstetricians and Gynecologists is among the organizations that recommend drug treatment if symptoms are moderate to severe.
“Depression in the mother affects interactions in feeding practices, sleep routines and patterns, and safety practices,” said Dr. Hudepohl, citing published studies supporting each of these consequences.
For the child, there is some degree of uncertainty about risk from untreated maternal depression as well as from breast mild exposure to antidepressants. Conclusive statements are not offered by ACOG and others.
“Some but not all studies have shown an impact of either antenatal or postnatal depression on speech recognition in infancy of native versus nonnative languages, IQ, and cognitive development, and reduction in left frontal brain electrical activity associated with impaired positive emotions,” Dr. Hudepohl reported.
Sifting through published data, Dr. Hudepohl cited studies associating persistent postpartum depression with a more than fourfold risk of behavioral problems at the age of 3.5 years, lower grades in mathematics at age 16, and a higher prevalence of depression at age 18. Among children who had depressed mothers in infancy, there have also been studies showing a higher reactivity to stressors and higher baseline cortisol levels.
“The good news is that Dr. Hudepohl said. In fact, she cited evidence of a correlation between improvement in maternal symptoms and a reduction in the complications in children, such as behavioral problems.
Postpartum depression, which can develop anytime in the first 12 months after childbirth, is not uncommon, occurring in approximately 15% of women, according to Dr. Hudepohl. Risk factors include personal or family history of depression, anxiety or depression during pregnancy, and a prior history of postpartum depression.
Postpartum depression increases the risk of maternal suicide by about 70-fold, Dr. Hudepohl reported. She noted that the peaks in suicide attempts in the 1st and 12th month after delivery. Adverse infant outcomes are not a predictor of increase risk of attempts, but fetal or infant death are.
According to one study, about 40% of mothers with postpartum depression have intrusive thoughts that involve harming their child. About 15% fear being alone with their infant. Behaviors such as decreased playfulness, less talking, or other interactions with the child, and inconsistent response to the child are all likely to contribute to impaired maternal-child bonding, Dr. Hudepohl reported.
For women who discontinued antidepressants for pregnancy but have now developed significant postpartum depression, Dr. Hudepohl recommended using “what has worked in the past.” She considered monotherapy preferable if possible, but severe symptoms warrant more aggressive intervention. Dr. Hudepohl pointed out that the risks of antidepressants taken by the breast-feeding mother to the infant remain unclear despite multiple studies attempting to establish and quantify risk.
“Antidepressants are the most researched medication in pregnancy,” she said.
Conversely, the risks of untreated symptoms to the mother are significant, and the potential risks to the infant and family – if variable – are not insignificant.
Overall, “nonpharmacologic treatment is preferred first line for mild symptoms,” Dr. Hudepohl, but she and others consider a risk-benefit ratio growing increasingly in favor of drug therapy when this approach is the best option for bringing moderate to severe symptoms under control.
Whether depression arises during pregnancy or in the postpartum period, “psychotherapy is generally considered first-line treatment,” agreed Nancy Byatt, DO, MS, MBA, professor of psychiatry and of obstetrics and gynecology at the University of Massachusetts, Worcester.
Dr. Byatt, who has published frequently on this topic, further agreed that risks to the mother and the child increase with uncontrolled depression in the postpartum period. With symptoms of greater intensity, the uncertain risks of medication are outweighed by substantial potential benefits.
“When a pregnant or postpartum individual has moderate to severe illness, treatment with medication is typically recommended, because the benefits are thought to outweigh the risks,” she said, echoing a consensus opinion among experts and organized medicine.
MedscapeLive and this news organization are owned by the same parent company. Dr. Hudepohl and Dr. Byatt reported no potential financial conflicts of interest.
If moderate to severe postpartum depression poses a risk to child development, that argues in favor of pharmacologic therapy, according to a detailed risk-benefit assessment presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.
“It is important to consider that there are potential risks of antidepressant drugs, but there are also potential risks from not providing effective treatment,” reported Neha Hudepohl, MD, at the virtual meeting, presented by MedscapeLive.
On a website maintained by the Centers for Disease Control and Prevention, the question of whether antidepressants pose a risk to breast-feeding children is answered with a “maybe.” Although many of these drugs can be detected in breast milk, according to the CDC, “most have little or no effect on milk supply or on infant well-being.”
This is enough uncertainty that antidepressants are not first-line intervention when postpartum depression is mild, said Dr. Hudepohl, director of women’s mental health at Prisma Health Upstate, Greenville, S.C. However, she noted that the American College of Obstetricians and Gynecologists is among the organizations that recommend drug treatment if symptoms are moderate to severe.
“Depression in the mother affects interactions in feeding practices, sleep routines and patterns, and safety practices,” said Dr. Hudepohl, citing published studies supporting each of these consequences.
For the child, there is some degree of uncertainty about risk from untreated maternal depression as well as from breast mild exposure to antidepressants. Conclusive statements are not offered by ACOG and others.
“Some but not all studies have shown an impact of either antenatal or postnatal depression on speech recognition in infancy of native versus nonnative languages, IQ, and cognitive development, and reduction in left frontal brain electrical activity associated with impaired positive emotions,” Dr. Hudepohl reported.
Sifting through published data, Dr. Hudepohl cited studies associating persistent postpartum depression with a more than fourfold risk of behavioral problems at the age of 3.5 years, lower grades in mathematics at age 16, and a higher prevalence of depression at age 18. Among children who had depressed mothers in infancy, there have also been studies showing a higher reactivity to stressors and higher baseline cortisol levels.
“The good news is that Dr. Hudepohl said. In fact, she cited evidence of a correlation between improvement in maternal symptoms and a reduction in the complications in children, such as behavioral problems.
Postpartum depression, which can develop anytime in the first 12 months after childbirth, is not uncommon, occurring in approximately 15% of women, according to Dr. Hudepohl. Risk factors include personal or family history of depression, anxiety or depression during pregnancy, and a prior history of postpartum depression.
Postpartum depression increases the risk of maternal suicide by about 70-fold, Dr. Hudepohl reported. She noted that the peaks in suicide attempts in the 1st and 12th month after delivery. Adverse infant outcomes are not a predictor of increase risk of attempts, but fetal or infant death are.
According to one study, about 40% of mothers with postpartum depression have intrusive thoughts that involve harming their child. About 15% fear being alone with their infant. Behaviors such as decreased playfulness, less talking, or other interactions with the child, and inconsistent response to the child are all likely to contribute to impaired maternal-child bonding, Dr. Hudepohl reported.
For women who discontinued antidepressants for pregnancy but have now developed significant postpartum depression, Dr. Hudepohl recommended using “what has worked in the past.” She considered monotherapy preferable if possible, but severe symptoms warrant more aggressive intervention. Dr. Hudepohl pointed out that the risks of antidepressants taken by the breast-feeding mother to the infant remain unclear despite multiple studies attempting to establish and quantify risk.
“Antidepressants are the most researched medication in pregnancy,” she said.
Conversely, the risks of untreated symptoms to the mother are significant, and the potential risks to the infant and family – if variable – are not insignificant.
Overall, “nonpharmacologic treatment is preferred first line for mild symptoms,” Dr. Hudepohl, but she and others consider a risk-benefit ratio growing increasingly in favor of drug therapy when this approach is the best option for bringing moderate to severe symptoms under control.
Whether depression arises during pregnancy or in the postpartum period, “psychotherapy is generally considered first-line treatment,” agreed Nancy Byatt, DO, MS, MBA, professor of psychiatry and of obstetrics and gynecology at the University of Massachusetts, Worcester.
Dr. Byatt, who has published frequently on this topic, further agreed that risks to the mother and the child increase with uncontrolled depression in the postpartum period. With symptoms of greater intensity, the uncertain risks of medication are outweighed by substantial potential benefits.
“When a pregnant or postpartum individual has moderate to severe illness, treatment with medication is typically recommended, because the benefits are thought to outweigh the risks,” she said, echoing a consensus opinion among experts and organized medicine.
MedscapeLive and this news organization are owned by the same parent company. Dr. Hudepohl and Dr. Byatt reported no potential financial conflicts of interest.
If moderate to severe postpartum depression poses a risk to child development, that argues in favor of pharmacologic therapy, according to a detailed risk-benefit assessment presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.
“It is important to consider that there are potential risks of antidepressant drugs, but there are also potential risks from not providing effective treatment,” reported Neha Hudepohl, MD, at the virtual meeting, presented by MedscapeLive.
On a website maintained by the Centers for Disease Control and Prevention, the question of whether antidepressants pose a risk to breast-feeding children is answered with a “maybe.” Although many of these drugs can be detected in breast milk, according to the CDC, “most have little or no effect on milk supply or on infant well-being.”
This is enough uncertainty that antidepressants are not first-line intervention when postpartum depression is mild, said Dr. Hudepohl, director of women’s mental health at Prisma Health Upstate, Greenville, S.C. However, she noted that the American College of Obstetricians and Gynecologists is among the organizations that recommend drug treatment if symptoms are moderate to severe.
“Depression in the mother affects interactions in feeding practices, sleep routines and patterns, and safety practices,” said Dr. Hudepohl, citing published studies supporting each of these consequences.
For the child, there is some degree of uncertainty about risk from untreated maternal depression as well as from breast mild exposure to antidepressants. Conclusive statements are not offered by ACOG and others.
“Some but not all studies have shown an impact of either antenatal or postnatal depression on speech recognition in infancy of native versus nonnative languages, IQ, and cognitive development, and reduction in left frontal brain electrical activity associated with impaired positive emotions,” Dr. Hudepohl reported.
Sifting through published data, Dr. Hudepohl cited studies associating persistent postpartum depression with a more than fourfold risk of behavioral problems at the age of 3.5 years, lower grades in mathematics at age 16, and a higher prevalence of depression at age 18. Among children who had depressed mothers in infancy, there have also been studies showing a higher reactivity to stressors and higher baseline cortisol levels.
“The good news is that Dr. Hudepohl said. In fact, she cited evidence of a correlation between improvement in maternal symptoms and a reduction in the complications in children, such as behavioral problems.
Postpartum depression, which can develop anytime in the first 12 months after childbirth, is not uncommon, occurring in approximately 15% of women, according to Dr. Hudepohl. Risk factors include personal or family history of depression, anxiety or depression during pregnancy, and a prior history of postpartum depression.
Postpartum depression increases the risk of maternal suicide by about 70-fold, Dr. Hudepohl reported. She noted that the peaks in suicide attempts in the 1st and 12th month after delivery. Adverse infant outcomes are not a predictor of increase risk of attempts, but fetal or infant death are.
According to one study, about 40% of mothers with postpartum depression have intrusive thoughts that involve harming their child. About 15% fear being alone with their infant. Behaviors such as decreased playfulness, less talking, or other interactions with the child, and inconsistent response to the child are all likely to contribute to impaired maternal-child bonding, Dr. Hudepohl reported.
For women who discontinued antidepressants for pregnancy but have now developed significant postpartum depression, Dr. Hudepohl recommended using “what has worked in the past.” She considered monotherapy preferable if possible, but severe symptoms warrant more aggressive intervention. Dr. Hudepohl pointed out that the risks of antidepressants taken by the breast-feeding mother to the infant remain unclear despite multiple studies attempting to establish and quantify risk.
“Antidepressants are the most researched medication in pregnancy,” she said.
Conversely, the risks of untreated symptoms to the mother are significant, and the potential risks to the infant and family – if variable – are not insignificant.
Overall, “nonpharmacologic treatment is preferred first line for mild symptoms,” Dr. Hudepohl, but she and others consider a risk-benefit ratio growing increasingly in favor of drug therapy when this approach is the best option for bringing moderate to severe symptoms under control.
Whether depression arises during pregnancy or in the postpartum period, “psychotherapy is generally considered first-line treatment,” agreed Nancy Byatt, DO, MS, MBA, professor of psychiatry and of obstetrics and gynecology at the University of Massachusetts, Worcester.
Dr. Byatt, who has published frequently on this topic, further agreed that risks to the mother and the child increase with uncontrolled depression in the postpartum period. With symptoms of greater intensity, the uncertain risks of medication are outweighed by substantial potential benefits.
“When a pregnant or postpartum individual has moderate to severe illness, treatment with medication is typically recommended, because the benefits are thought to outweigh the risks,” she said, echoing a consensus opinion among experts and organized medicine.
MedscapeLive and this news organization are owned by the same parent company. Dr. Hudepohl and Dr. Byatt reported no potential financial conflicts of interest.
FROM CP/AACP PSYCHIATRY UPDATE
Long-acting injectable antipsychotics deserve first-line consideration
Long-acting injectable (LAI) antipsychotic therapies continue to be largely reserved for patients who already have adherence issues. But most patients, including first-episode patients, should be considering drugs with this mode of delivery for their broad array of advantages, according to an overview presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.
“Due to the perception that long-acting injectables are for coercive applications, patients are not hearing about the many reasons this option might be preferable,” reported Diana Perkins, MD, MPH, professor, department of psychiatry, University of North Carolina, Chapel Hill.
According to Dr. Perkins, patients starting treatment for first-episode schizophrenia are particularly unlikely to even hear about injectable therapies even though “these might be the best candidates.”
The advantage of LAI in first-episode patients is that it takes adherence off the table as a risk for treatment failure. Ultimately, many patients educated about LAI in the context of other options, prefer LAI, according to Dr. Perkins, and she provided data to support these assertions.
Of several published articles reporting that patients fail to discuss LAI with patients, one was published last year (J Clin Psychopharmacol. 2020 Jul/Aug;40:346-9). For evidence that patients prefer LAI over pills for antipsychotic treatment, Dr. Perkins cited a study with data from more than 1,400 patients (Patient Prefer Adherence. 2020;14:1093-102).
In this latter analysis, 77% of patients preferred LAI over pills, Dr. Perkins reported at the virtual meeting, presented by MedscapeLive. Moreover, 50% of patients preferred every-3-month injections over monthly injections. For those who preferred LAI, the reasons included the convenience of avoiding daily therapy but also the empowerment derived from feeling healthier from not having to depend on a daily schedule of treatment.
LAI has benefits independent of adherence
“Some patients prefer injectables because the daily pills remind them of their illness even when they are feeling well,” Dr. Perkins said.
By eliminating pills and pill bottles, injections also provide a certain degree of confidentiality, said Dr. Perkins. She said that LAI, which avoids the peaks and troughs inherent in pill taking, provides more consistent drug levels even to the degree that doses can sometimes be lowered and adverse events reduced.
Yet, of all the reasons that patients might want to consider LAI, the most compelling is a lower risk of failure from inadequate adherence to daily pills. The evidence that patients do not take daily pills for chronic diseases, whether schizophrenia or any other illness that requires maintenance regimens for persistent disease control, is extensive and overwhelming, according to Dr. Perkins, who cited multiple studies.
For schizophrenia, with a relapsing and remitting pattern of symptoms, poor adherence is a particular risk. When symptoms abate, the cue and motivation for adherence dissipates.
“Most patients with schizophrenia already have some ambivalence about taking their medication.
When patients forget their daily pills or when the they decide to skip doses when they feel well, they do not necessarily tell their physicians.
Poor adherence often goes unrecognized
“Clinicians are not very good at estimating adherence in their patients,” Dr. Perkins said. While she listed several strategies to help patients adhere to daily pills, she also said that LAI should not be discounted as a means to circumvent this problem altogether.
Importantly, suboptimal adherence by itself places the patient at a high risk for relapse. In one study of partial adherence, delayed doses were associated with increased risk of hospitalization overall, but each increment in further delay led to still more risk (Psychiatr Serv. 2004;55:886-91).
Imperfect adherence to daily pills is very common. In one study evaluating 34,000 veterans with schizophrenia, the proportion with consistently good adherence over the 12 months of study was not quite 40% (J Clin Psychiatry. 2006 Oct;67[10]:1542-50). While most of the remaining were intermittently adherent, more than 15% of the populations was consistently poorly adherent.
Simple regimens and adherence closely linked
In general, the simpler the regimen, the greater the adherence, according to Dr. Perkins. For oral therapies, one pill per day is associated with greater adherence than is more than one. LAI, which is even simpler, is consistently associated with a large relative advantage. In one comparative study, 77% were adherent to LAI versus about 30% (P < .001) over a period of 12 months (Ment Health Clin. 2018 Mar 26;8[2]:56-62).
In a large recently published meta-analysis, LAI was associated with objective advantages over oral therapy (Lancet Psychiatry. 2021 May 1;8:[5]387-404). This included a statistically significant lower risk of hospitalizations or relapses for LAI over oral therapy whether the two modes of delivery were compared in randomized controls studies (RR 0.88; P = .033) or cohort studies (RR 0.92; P = .0044).
Overall, clinicians should discard several false assumptions about LAI, including the fact they are not appropriate in first-episode disease and that patients will not elect to take LAI if informed of the choices, according to Dr. Perkins. Rather than just listing LAI among options, Dr. Perkins suggested that clinicians should specifically explain the many advantages.
“When people say I do not like shots, this is not necessarily a no,” she said. If patients understand the potential for a reduced risk of relapse without having to take a daily pill, injections might be preferable whether or not they like shots in particular.
This is not an isolated view among experienced physicians. John M. Kane, MD, chairman of psychiatry, Zucker Hillside Hospital, Northwell Health, Glen Oaks, N.Y., also sees LAI as method of drug delivery that should be considered widely in schizophrenia.
“I am in complete agreement with Dr. Perkins that long-acting injectable formulations of antipsychotic medications should be presented routinely to patients and families as an option for illness management and relapse prevention,” said Dr. Kane, who was a coauthor of the meta-analysis published in Lancet Psychiatry.
“This would include patients early in the course of illness who currently have an unnecessarily high risk of relapse and hospitalization,” he added.
MedscapeLive and this news organization are owned by the same parent company. Dr. Perkins has a financial relationship with Alkermes. Dr. Kane has financial relationships with Abbott, AstraZeneca, Bristol-Myers Squibb, Janssen, Lilly, Otsuka, Pfizer, and Wyeth.
Long-acting injectable (LAI) antipsychotic therapies continue to be largely reserved for patients who already have adherence issues. But most patients, including first-episode patients, should be considering drugs with this mode of delivery for their broad array of advantages, according to an overview presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.
“Due to the perception that long-acting injectables are for coercive applications, patients are not hearing about the many reasons this option might be preferable,” reported Diana Perkins, MD, MPH, professor, department of psychiatry, University of North Carolina, Chapel Hill.
According to Dr. Perkins, patients starting treatment for first-episode schizophrenia are particularly unlikely to even hear about injectable therapies even though “these might be the best candidates.”
The advantage of LAI in first-episode patients is that it takes adherence off the table as a risk for treatment failure. Ultimately, many patients educated about LAI in the context of other options, prefer LAI, according to Dr. Perkins, and she provided data to support these assertions.
Of several published articles reporting that patients fail to discuss LAI with patients, one was published last year (J Clin Psychopharmacol. 2020 Jul/Aug;40:346-9). For evidence that patients prefer LAI over pills for antipsychotic treatment, Dr. Perkins cited a study with data from more than 1,400 patients (Patient Prefer Adherence. 2020;14:1093-102).
In this latter analysis, 77% of patients preferred LAI over pills, Dr. Perkins reported at the virtual meeting, presented by MedscapeLive. Moreover, 50% of patients preferred every-3-month injections over monthly injections. For those who preferred LAI, the reasons included the convenience of avoiding daily therapy but also the empowerment derived from feeling healthier from not having to depend on a daily schedule of treatment.
LAI has benefits independent of adherence
“Some patients prefer injectables because the daily pills remind them of their illness even when they are feeling well,” Dr. Perkins said.
By eliminating pills and pill bottles, injections also provide a certain degree of confidentiality, said Dr. Perkins. She said that LAI, which avoids the peaks and troughs inherent in pill taking, provides more consistent drug levels even to the degree that doses can sometimes be lowered and adverse events reduced.
Yet, of all the reasons that patients might want to consider LAI, the most compelling is a lower risk of failure from inadequate adherence to daily pills. The evidence that patients do not take daily pills for chronic diseases, whether schizophrenia or any other illness that requires maintenance regimens for persistent disease control, is extensive and overwhelming, according to Dr. Perkins, who cited multiple studies.
For schizophrenia, with a relapsing and remitting pattern of symptoms, poor adherence is a particular risk. When symptoms abate, the cue and motivation for adherence dissipates.
“Most patients with schizophrenia already have some ambivalence about taking their medication.
When patients forget their daily pills or when the they decide to skip doses when they feel well, they do not necessarily tell their physicians.
Poor adherence often goes unrecognized
“Clinicians are not very good at estimating adherence in their patients,” Dr. Perkins said. While she listed several strategies to help patients adhere to daily pills, she also said that LAI should not be discounted as a means to circumvent this problem altogether.
Importantly, suboptimal adherence by itself places the patient at a high risk for relapse. In one study of partial adherence, delayed doses were associated with increased risk of hospitalization overall, but each increment in further delay led to still more risk (Psychiatr Serv. 2004;55:886-91).
Imperfect adherence to daily pills is very common. In one study evaluating 34,000 veterans with schizophrenia, the proportion with consistently good adherence over the 12 months of study was not quite 40% (J Clin Psychiatry. 2006 Oct;67[10]:1542-50). While most of the remaining were intermittently adherent, more than 15% of the populations was consistently poorly adherent.
Simple regimens and adherence closely linked
In general, the simpler the regimen, the greater the adherence, according to Dr. Perkins. For oral therapies, one pill per day is associated with greater adherence than is more than one. LAI, which is even simpler, is consistently associated with a large relative advantage. In one comparative study, 77% were adherent to LAI versus about 30% (P < .001) over a period of 12 months (Ment Health Clin. 2018 Mar 26;8[2]:56-62).
In a large recently published meta-analysis, LAI was associated with objective advantages over oral therapy (Lancet Psychiatry. 2021 May 1;8:[5]387-404). This included a statistically significant lower risk of hospitalizations or relapses for LAI over oral therapy whether the two modes of delivery were compared in randomized controls studies (RR 0.88; P = .033) or cohort studies (RR 0.92; P = .0044).
Overall, clinicians should discard several false assumptions about LAI, including the fact they are not appropriate in first-episode disease and that patients will not elect to take LAI if informed of the choices, according to Dr. Perkins. Rather than just listing LAI among options, Dr. Perkins suggested that clinicians should specifically explain the many advantages.
“When people say I do not like shots, this is not necessarily a no,” she said. If patients understand the potential for a reduced risk of relapse without having to take a daily pill, injections might be preferable whether or not they like shots in particular.
This is not an isolated view among experienced physicians. John M. Kane, MD, chairman of psychiatry, Zucker Hillside Hospital, Northwell Health, Glen Oaks, N.Y., also sees LAI as method of drug delivery that should be considered widely in schizophrenia.
“I am in complete agreement with Dr. Perkins that long-acting injectable formulations of antipsychotic medications should be presented routinely to patients and families as an option for illness management and relapse prevention,” said Dr. Kane, who was a coauthor of the meta-analysis published in Lancet Psychiatry.
“This would include patients early in the course of illness who currently have an unnecessarily high risk of relapse and hospitalization,” he added.
MedscapeLive and this news organization are owned by the same parent company. Dr. Perkins has a financial relationship with Alkermes. Dr. Kane has financial relationships with Abbott, AstraZeneca, Bristol-Myers Squibb, Janssen, Lilly, Otsuka, Pfizer, and Wyeth.
Long-acting injectable (LAI) antipsychotic therapies continue to be largely reserved for patients who already have adherence issues. But most patients, including first-episode patients, should be considering drugs with this mode of delivery for their broad array of advantages, according to an overview presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.
“Due to the perception that long-acting injectables are for coercive applications, patients are not hearing about the many reasons this option might be preferable,” reported Diana Perkins, MD, MPH, professor, department of psychiatry, University of North Carolina, Chapel Hill.
According to Dr. Perkins, patients starting treatment for first-episode schizophrenia are particularly unlikely to even hear about injectable therapies even though “these might be the best candidates.”
The advantage of LAI in first-episode patients is that it takes adherence off the table as a risk for treatment failure. Ultimately, many patients educated about LAI in the context of other options, prefer LAI, according to Dr. Perkins, and she provided data to support these assertions.
Of several published articles reporting that patients fail to discuss LAI with patients, one was published last year (J Clin Psychopharmacol. 2020 Jul/Aug;40:346-9). For evidence that patients prefer LAI over pills for antipsychotic treatment, Dr. Perkins cited a study with data from more than 1,400 patients (Patient Prefer Adherence. 2020;14:1093-102).
In this latter analysis, 77% of patients preferred LAI over pills, Dr. Perkins reported at the virtual meeting, presented by MedscapeLive. Moreover, 50% of patients preferred every-3-month injections over monthly injections. For those who preferred LAI, the reasons included the convenience of avoiding daily therapy but also the empowerment derived from feeling healthier from not having to depend on a daily schedule of treatment.
LAI has benefits independent of adherence
“Some patients prefer injectables because the daily pills remind them of their illness even when they are feeling well,” Dr. Perkins said.
By eliminating pills and pill bottles, injections also provide a certain degree of confidentiality, said Dr. Perkins. She said that LAI, which avoids the peaks and troughs inherent in pill taking, provides more consistent drug levels even to the degree that doses can sometimes be lowered and adverse events reduced.
Yet, of all the reasons that patients might want to consider LAI, the most compelling is a lower risk of failure from inadequate adherence to daily pills. The evidence that patients do not take daily pills for chronic diseases, whether schizophrenia or any other illness that requires maintenance regimens for persistent disease control, is extensive and overwhelming, according to Dr. Perkins, who cited multiple studies.
For schizophrenia, with a relapsing and remitting pattern of symptoms, poor adherence is a particular risk. When symptoms abate, the cue and motivation for adherence dissipates.
“Most patients with schizophrenia already have some ambivalence about taking their medication.
When patients forget their daily pills or when the they decide to skip doses when they feel well, they do not necessarily tell their physicians.
Poor adherence often goes unrecognized
“Clinicians are not very good at estimating adherence in their patients,” Dr. Perkins said. While she listed several strategies to help patients adhere to daily pills, she also said that LAI should not be discounted as a means to circumvent this problem altogether.
Importantly, suboptimal adherence by itself places the patient at a high risk for relapse. In one study of partial adherence, delayed doses were associated with increased risk of hospitalization overall, but each increment in further delay led to still more risk (Psychiatr Serv. 2004;55:886-91).
Imperfect adherence to daily pills is very common. In one study evaluating 34,000 veterans with schizophrenia, the proportion with consistently good adherence over the 12 months of study was not quite 40% (J Clin Psychiatry. 2006 Oct;67[10]:1542-50). While most of the remaining were intermittently adherent, more than 15% of the populations was consistently poorly adherent.
Simple regimens and adherence closely linked
In general, the simpler the regimen, the greater the adherence, according to Dr. Perkins. For oral therapies, one pill per day is associated with greater adherence than is more than one. LAI, which is even simpler, is consistently associated with a large relative advantage. In one comparative study, 77% were adherent to LAI versus about 30% (P < .001) over a period of 12 months (Ment Health Clin. 2018 Mar 26;8[2]:56-62).
In a large recently published meta-analysis, LAI was associated with objective advantages over oral therapy (Lancet Psychiatry. 2021 May 1;8:[5]387-404). This included a statistically significant lower risk of hospitalizations or relapses for LAI over oral therapy whether the two modes of delivery were compared in randomized controls studies (RR 0.88; P = .033) or cohort studies (RR 0.92; P = .0044).
Overall, clinicians should discard several false assumptions about LAI, including the fact they are not appropriate in first-episode disease and that patients will not elect to take LAI if informed of the choices, according to Dr. Perkins. Rather than just listing LAI among options, Dr. Perkins suggested that clinicians should specifically explain the many advantages.
“When people say I do not like shots, this is not necessarily a no,” she said. If patients understand the potential for a reduced risk of relapse without having to take a daily pill, injections might be preferable whether or not they like shots in particular.
This is not an isolated view among experienced physicians. John M. Kane, MD, chairman of psychiatry, Zucker Hillside Hospital, Northwell Health, Glen Oaks, N.Y., also sees LAI as method of drug delivery that should be considered widely in schizophrenia.
“I am in complete agreement with Dr. Perkins that long-acting injectable formulations of antipsychotic medications should be presented routinely to patients and families as an option for illness management and relapse prevention,” said Dr. Kane, who was a coauthor of the meta-analysis published in Lancet Psychiatry.
“This would include patients early in the course of illness who currently have an unnecessarily high risk of relapse and hospitalization,” he added.
MedscapeLive and this news organization are owned by the same parent company. Dr. Perkins has a financial relationship with Alkermes. Dr. Kane has financial relationships with Abbott, AstraZeneca, Bristol-Myers Squibb, Janssen, Lilly, Otsuka, Pfizer, and Wyeth.
FROM CP/AACP PSYCHIATRY UPDATE
Telemedicine is poised to drive new models of care
Telemedicine has been proposed as a solution for an array of health care access problems over decades of gradual growth. The vast ramping up of , according to an update at the annual health policy and advocacy conference sponsored by the American College of Chest Physicians.
“The cat is out of the bag,” said Jaspal Singh, MD, professor of medicine, Atrium Health, Charlotte, N.C. Due to changes in access and reimbursement to telemedicine driven by the pandemic, he said, “we now have permission to explore new models of care.”
Prior to February 2020, telemedicine was crawling forward at a leisurely pace, according to Dr. Singh. After March 2020, it broke into a run due to enormous demand and was met by a rapid response from the U.S. Congress. The first of four legislative bills that directly or indirectly supported telemedicine was passed on March 6, 2020.
The Centers for Medicare and Medicaid Services responded in kind, making modifications in a number of rules that removed obstacles to telehealth. One modification on April 6, 2020, for example, removed the requirement for a preexisting relationship between the clinician and patient, Dr. Singh said. The CMS also subsequently modified reimbursement policies in order to make telemedicine more tenable for physicians.
Given the risk of contagion from face-to-face encounters, telemedicine in the early days of the pandemic was not just attractive but the only practical and safe approach to medical care in many circumstances. Physicians and patients were anxious for health care that did not require in-office visits even though many critical issues for telemedicine, including its relative effectiveness, had not yet been fully evaluated.
Much has been learned regarding the feasibility and acceptability of telemedicine during the pandemic, but Dr. Singh noted that quality of care relative to in-person visits remains weakly supported for most indications. Indeed, he outlined sizable list of incompletely resolved issues, including optimal payment models, management of privacy concerns, and how to balance advantages to disadvantages.
For patients and physicians, the strengths of telemedicine include greater convenience made possible by the elimination of travel and waiting rooms. For the health care system, it can include less infrastructure and overhead. For many physicians, telemedicine might be perceived as more efficient.
On the other hand, some patients might feel that a clinical encounter is incomplete without a physical examination even when the physician does not feel the physical examination is needed, according to Dr. Singh. He cited a survey suggesting nearly half of patients expressed concern about a lack of connection to health care providers following a virtual visit.
In the same 2020 National Poll on Healthy Aging 2020 survey conducted by the University of Michigan 67% of respondents reported that the quality of care was not as good as that provided by in-patient visits, and 24% expressed concern about privacy. However, at the time the poll was taken in May 2020, experience with telemedicine among many of the respondents may have been limited. As telemedicine is integrated into routine care, perceptions might change as experience increases.
A distinction between telemedicine in routine care and telemedicine as a strategy to respond to a pandemic is important, Dr. Singh indicated. Dr. Singh was the lead author for a position paper on telemedicine for the diagnosis and treatment of sleep disorders from the American Academy of Sleep Medicine 5 years ago, but he acknowledged that models of care might differ when responding to abnormal surges in health care demand.
The surge in demand for COVID-19–related care engendered numerous innovative solutions. As examples, Dr. Singh recounted how a virtual hospital was created at his own institution. In a published study, 1,477 patients diagnosed with COVID-19 over a 6-week period remained at home and received care in a virtual observation unit (VCU) or a virtual acute care unit (VACU) . Only a small percentage required eventual hospital admission. In the VACU, patients were able to receive advanced care including IV fluids and some form of respiratory support .
It is unclear how the COVID-19 pandemic will change telemedicine. Now, with declining cases of the infection, telemedicine is back to a walk after the sprint required during the height of the pandemic, according to Dr. Singh. However, Dr. Singh thinks many physicians and patients will have a different perception of telemedicine after the widespread exposure to this type of care.
In terms of the relative role of in-patient and virtual visits across indications, “we do not know how this will play out, but we will probably end up toggling between the two,” Dr. Singh said.
This is an area that is being followed closely by the CHEST Health Policy and Advocacy Committee, according to Kathleen Sarmiento, MD, director, VISN 21 Sleep Clinical Resource Hub for the San Francisco VA Health Care System. A member of that committee and moderator of the session in which Dr. Singh spoke,
Dr. Sarmiento called the effort to bring permanent coverage of telehealth services “the shared responsibility of every medical society engaged in advocacy.”
However, she cautioned that there might be intended and unintended consequences from telehealth that require analysis to develop policies that are in the best interests of effective care. She said, the “ACCP, along with its sister societies, does have a role in supporting the evaluation of the impact of these changes on both patients and providers in the fields of pulmonary medicine, critical care, and sleep medicine.”
Dr. Singh reports a financial relationship with AstraZeneca. Dr. Sarmiento reports no relevant financial relationship with AstraZeneca.
Telemedicine has been proposed as a solution for an array of health care access problems over decades of gradual growth. The vast ramping up of , according to an update at the annual health policy and advocacy conference sponsored by the American College of Chest Physicians.
“The cat is out of the bag,” said Jaspal Singh, MD, professor of medicine, Atrium Health, Charlotte, N.C. Due to changes in access and reimbursement to telemedicine driven by the pandemic, he said, “we now have permission to explore new models of care.”
Prior to February 2020, telemedicine was crawling forward at a leisurely pace, according to Dr. Singh. After March 2020, it broke into a run due to enormous demand and was met by a rapid response from the U.S. Congress. The first of four legislative bills that directly or indirectly supported telemedicine was passed on March 6, 2020.
The Centers for Medicare and Medicaid Services responded in kind, making modifications in a number of rules that removed obstacles to telehealth. One modification on April 6, 2020, for example, removed the requirement for a preexisting relationship between the clinician and patient, Dr. Singh said. The CMS also subsequently modified reimbursement policies in order to make telemedicine more tenable for physicians.
Given the risk of contagion from face-to-face encounters, telemedicine in the early days of the pandemic was not just attractive but the only practical and safe approach to medical care in many circumstances. Physicians and patients were anxious for health care that did not require in-office visits even though many critical issues for telemedicine, including its relative effectiveness, had not yet been fully evaluated.
Much has been learned regarding the feasibility and acceptability of telemedicine during the pandemic, but Dr. Singh noted that quality of care relative to in-person visits remains weakly supported for most indications. Indeed, he outlined sizable list of incompletely resolved issues, including optimal payment models, management of privacy concerns, and how to balance advantages to disadvantages.
For patients and physicians, the strengths of telemedicine include greater convenience made possible by the elimination of travel and waiting rooms. For the health care system, it can include less infrastructure and overhead. For many physicians, telemedicine might be perceived as more efficient.
On the other hand, some patients might feel that a clinical encounter is incomplete without a physical examination even when the physician does not feel the physical examination is needed, according to Dr. Singh. He cited a survey suggesting nearly half of patients expressed concern about a lack of connection to health care providers following a virtual visit.
In the same 2020 National Poll on Healthy Aging 2020 survey conducted by the University of Michigan 67% of respondents reported that the quality of care was not as good as that provided by in-patient visits, and 24% expressed concern about privacy. However, at the time the poll was taken in May 2020, experience with telemedicine among many of the respondents may have been limited. As telemedicine is integrated into routine care, perceptions might change as experience increases.
A distinction between telemedicine in routine care and telemedicine as a strategy to respond to a pandemic is important, Dr. Singh indicated. Dr. Singh was the lead author for a position paper on telemedicine for the diagnosis and treatment of sleep disorders from the American Academy of Sleep Medicine 5 years ago, but he acknowledged that models of care might differ when responding to abnormal surges in health care demand.
The surge in demand for COVID-19–related care engendered numerous innovative solutions. As examples, Dr. Singh recounted how a virtual hospital was created at his own institution. In a published study, 1,477 patients diagnosed with COVID-19 over a 6-week period remained at home and received care in a virtual observation unit (VCU) or a virtual acute care unit (VACU) . Only a small percentage required eventual hospital admission. In the VACU, patients were able to receive advanced care including IV fluids and some form of respiratory support .
It is unclear how the COVID-19 pandemic will change telemedicine. Now, with declining cases of the infection, telemedicine is back to a walk after the sprint required during the height of the pandemic, according to Dr. Singh. However, Dr. Singh thinks many physicians and patients will have a different perception of telemedicine after the widespread exposure to this type of care.
In terms of the relative role of in-patient and virtual visits across indications, “we do not know how this will play out, but we will probably end up toggling between the two,” Dr. Singh said.
This is an area that is being followed closely by the CHEST Health Policy and Advocacy Committee, according to Kathleen Sarmiento, MD, director, VISN 21 Sleep Clinical Resource Hub for the San Francisco VA Health Care System. A member of that committee and moderator of the session in which Dr. Singh spoke,
Dr. Sarmiento called the effort to bring permanent coverage of telehealth services “the shared responsibility of every medical society engaged in advocacy.”
However, she cautioned that there might be intended and unintended consequences from telehealth that require analysis to develop policies that are in the best interests of effective care. She said, the “ACCP, along with its sister societies, does have a role in supporting the evaluation of the impact of these changes on both patients and providers in the fields of pulmonary medicine, critical care, and sleep medicine.”
Dr. Singh reports a financial relationship with AstraZeneca. Dr. Sarmiento reports no relevant financial relationship with AstraZeneca.
Telemedicine has been proposed as a solution for an array of health care access problems over decades of gradual growth. The vast ramping up of , according to an update at the annual health policy and advocacy conference sponsored by the American College of Chest Physicians.
“The cat is out of the bag,” said Jaspal Singh, MD, professor of medicine, Atrium Health, Charlotte, N.C. Due to changes in access and reimbursement to telemedicine driven by the pandemic, he said, “we now have permission to explore new models of care.”
Prior to February 2020, telemedicine was crawling forward at a leisurely pace, according to Dr. Singh. After March 2020, it broke into a run due to enormous demand and was met by a rapid response from the U.S. Congress. The first of four legislative bills that directly or indirectly supported telemedicine was passed on March 6, 2020.
The Centers for Medicare and Medicaid Services responded in kind, making modifications in a number of rules that removed obstacles to telehealth. One modification on April 6, 2020, for example, removed the requirement for a preexisting relationship between the clinician and patient, Dr. Singh said. The CMS also subsequently modified reimbursement policies in order to make telemedicine more tenable for physicians.
Given the risk of contagion from face-to-face encounters, telemedicine in the early days of the pandemic was not just attractive but the only practical and safe approach to medical care in many circumstances. Physicians and patients were anxious for health care that did not require in-office visits even though many critical issues for telemedicine, including its relative effectiveness, had not yet been fully evaluated.
Much has been learned regarding the feasibility and acceptability of telemedicine during the pandemic, but Dr. Singh noted that quality of care relative to in-person visits remains weakly supported for most indications. Indeed, he outlined sizable list of incompletely resolved issues, including optimal payment models, management of privacy concerns, and how to balance advantages to disadvantages.
For patients and physicians, the strengths of telemedicine include greater convenience made possible by the elimination of travel and waiting rooms. For the health care system, it can include less infrastructure and overhead. For many physicians, telemedicine might be perceived as more efficient.
On the other hand, some patients might feel that a clinical encounter is incomplete without a physical examination even when the physician does not feel the physical examination is needed, according to Dr. Singh. He cited a survey suggesting nearly half of patients expressed concern about a lack of connection to health care providers following a virtual visit.
In the same 2020 National Poll on Healthy Aging 2020 survey conducted by the University of Michigan 67% of respondents reported that the quality of care was not as good as that provided by in-patient visits, and 24% expressed concern about privacy. However, at the time the poll was taken in May 2020, experience with telemedicine among many of the respondents may have been limited. As telemedicine is integrated into routine care, perceptions might change as experience increases.
A distinction between telemedicine in routine care and telemedicine as a strategy to respond to a pandemic is important, Dr. Singh indicated. Dr. Singh was the lead author for a position paper on telemedicine for the diagnosis and treatment of sleep disorders from the American Academy of Sleep Medicine 5 years ago, but he acknowledged that models of care might differ when responding to abnormal surges in health care demand.
The surge in demand for COVID-19–related care engendered numerous innovative solutions. As examples, Dr. Singh recounted how a virtual hospital was created at his own institution. In a published study, 1,477 patients diagnosed with COVID-19 over a 6-week period remained at home and received care in a virtual observation unit (VCU) or a virtual acute care unit (VACU) . Only a small percentage required eventual hospital admission. In the VACU, patients were able to receive advanced care including IV fluids and some form of respiratory support .
It is unclear how the COVID-19 pandemic will change telemedicine. Now, with declining cases of the infection, telemedicine is back to a walk after the sprint required during the height of the pandemic, according to Dr. Singh. However, Dr. Singh thinks many physicians and patients will have a different perception of telemedicine after the widespread exposure to this type of care.
In terms of the relative role of in-patient and virtual visits across indications, “we do not know how this will play out, but we will probably end up toggling between the two,” Dr. Singh said.
This is an area that is being followed closely by the CHEST Health Policy and Advocacy Committee, according to Kathleen Sarmiento, MD, director, VISN 21 Sleep Clinical Resource Hub for the San Francisco VA Health Care System. A member of that committee and moderator of the session in which Dr. Singh spoke,
Dr. Sarmiento called the effort to bring permanent coverage of telehealth services “the shared responsibility of every medical society engaged in advocacy.”
However, she cautioned that there might be intended and unintended consequences from telehealth that require analysis to develop policies that are in the best interests of effective care. She said, the “ACCP, along with its sister societies, does have a role in supporting the evaluation of the impact of these changes on both patients and providers in the fields of pulmonary medicine, critical care, and sleep medicine.”
Dr. Singh reports a financial relationship with AstraZeneca. Dr. Sarmiento reports no relevant financial relationship with AstraZeneca.
FROM A HEALTH POLICY AND ADVOCACY CONFERENCE
Emerging drugs for schizophrenia targeting negative symptoms
Late-stage trials of new antipsychotic drugs are showing promise in the control of negative symptoms, according to an overview presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.
The progress in these trials deserves attention, because control of negative symptoms is “a major unmet need in schizophrenia,” according to Henry A. Nasrallah, MD, director of the schizophrenia program at the University of Cincinnati.
The novel mechanisms of the agents in development are credited with the promise. Not least, several antipsychotic agents with activity against both positive and negative symptoms “are completely devoid of dopamine receptor blockade,” Dr. Nasrallah said at the virtual meeting, presented by MedscapeLive!
The xanomeline portion of the investigational treatment xanomeline-trospium is one example. Xanomeline is a muscarinic receptor agonist with no activity on dopamine D2 receptors. The role of trospium, a muscarinic receptor antagonist, is to reduce peripheral cholinergic side effects.
Xanomeline-trospium: Negative vs. positive symptoms
In a recently published placebo-controlled, double-blind, phase 2 trial, the reductions relative to placebo after 5 weeks on the negative subscale of the Positive and Negative Syndrome Scale (PANSS) tool (–3.9 vs. –1.3; P < .001) was about as robust as that achieved on the positive subscale (–5.6 vs. –3.2; P < .001).
These subscales were secondary endpoints. Relative to placebo, xanomeline-trospium was also effective on the primary endpoint of the PANSS total score (–17.9 vs. –5.9; P < .001).
The presence of trospium did not eliminate cholinergic side effects, which included constipation, dry mouth, and nausea, but the therapy strengthens the evidence that newer agents with novel mechanisms of action, including those without dopamine blockade, can achieve meaningful clinical effects.
SEP-363856, another example of an experimental agent without direct dopamine blockade, was also recently tested in placebo-controlled, double-blind study.
“This is the first agonist of the TAAR1 [trace amine-associated receptor 1] and 5-HT1A [serotonin 5–hydroxytryptamine type 1A receptor] to reach clinical trials,” said Dr. Nasrallah, calling this an interesting agent for its range of clinical activity, which appears to include antianxiety effects.
SEP-363856: Negative vs. positive symptoms
It also appears to include activity against negative symptoms. While the primary endpoint of total PANSS score favored SEP-363856 over placebo at the end of 4 weeks (–17.2 points vs. –9.7; P = .001), the reductions in the subscales for negative (–3.1 vs. –1.6) and positive (–5.5 vs. 3.9) symptoms were also substantial even if statistical differences were not calculated.
The rates of side effects on SEP-3638656 were low, according to Dr. Nasrallah. The most common complaints, such as somnolence, agitation, and nausea, were observed in fewer than 10% of patients.
Roluperidone, another agent with no direct dopamine blockade, has reached phase 3 trials. The activity of this agent is attributed to antagonist activity on the serotonin 5-HT2A and sigma2 receptors. In a multinational, phase 2b study cited by Dr. Nasrallah, both of two study doses of roluperidone were superior to placebo for the negative symptom dimensions of expressive deficit and experiential deficit. Patients enrolled in the trial were required to have baseline PANSS negative symptom subscale scores of 20 points or greater.
Pimavanserin, an inverse agonist of 5-HT2A receptors, is already approved for the treatment of psychosis in Parkinson’s disease, but it is now attracting interest for its potential efficacy against negative symptoms in schizophrenia, according to Dr. Nasrallah, who cited a poster presented last November at the Psych Congress 2020.
The poster provided results of ADVANCE, a double-blind, placebo-controlled, phase 2 study that associated pimavanserin with significant improvement across several types of negative symptoms, Dr. Nasrallah said. The drug was well tolerated with a side-effect profile “similar to placebo.”
Traditional antipsychotic therapies are generally associated with limited effect against negative symptoms, but it has never been proven that the interaction of treatments on the dopaminergic system is the reason. Indeed, in his list of therapies being pursued for potential benefit against negative symptoms, Dr. Nasrallah cited a clinical study with cariprazine, an agent with multiple effects on dopamine and serotonin signaling.
“Cariprazine is a partial agonist at D2, D3, and 5-HT1A receptors and an antagonist at 5-HT2c and 5-HT7 receptors, but it has the highest affinity to the D3 receptor,” Dr. Nasrallah reported.
Cariprazine is already approved for schizophrenia, acute mania, and bipolar depression, but the authors of a recent review claim evidence of activity against negative symptoms. Furthermore, they speculate that this activity might be mediated by agonism of the D3 receptor.
Despite the evidence that these agents might control negative symptoms, the relative roles will be defined by clinical experience, not just clinical trials, Dr. Nasrallah said. However, he did indicate that there appears to be meaningful progress in this area.
Potential progress in this area is important, because “negative symptoms are a largely unaddressed treatment target in people with schizophrenia,” reported Christoph U. Correll, MD, professor of psychiatry, Hofstra University, Hempstead, N.Y. These symptoms deserve attention for their “important potential to improve interpersonal, educational, and work function.”
Dr. Correll agreed that the newer drugs with mechanisms other than postsynaptic dopamine blockade could be a very important advance in the treatment of schizophrenia.
“Promising new medications with potential efficacy for negative symptoms, either based on their pharmacological profile and/or emerging data, include cariprazine, lumateperone, ulotaront [SEP-363856], and xanomeline plus trospium,” he said. Efficacy for negative symptoms, if proven, will address an “elusive goal.”
MedscapeLive! and this news organization are owned by the same parent company. Dr. Nasrallah reported financial relationships with Acadia Pharmaceuticals, Alkermes, Avanir, Intra-Cellular Therapies, Indivior, Janssen, Neurocrine, and Teva. Dr. Correll listed financial relationships with more than 25 pharmaceutical companies, including several developing medications with potential activity against negative symptoms.
Late-stage trials of new antipsychotic drugs are showing promise in the control of negative symptoms, according to an overview presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.
The progress in these trials deserves attention, because control of negative symptoms is “a major unmet need in schizophrenia,” according to Henry A. Nasrallah, MD, director of the schizophrenia program at the University of Cincinnati.
The novel mechanisms of the agents in development are credited with the promise. Not least, several antipsychotic agents with activity against both positive and negative symptoms “are completely devoid of dopamine receptor blockade,” Dr. Nasrallah said at the virtual meeting, presented by MedscapeLive!
The xanomeline portion of the investigational treatment xanomeline-trospium is one example. Xanomeline is a muscarinic receptor agonist with no activity on dopamine D2 receptors. The role of trospium, a muscarinic receptor antagonist, is to reduce peripheral cholinergic side effects.
Xanomeline-trospium: Negative vs. positive symptoms
In a recently published placebo-controlled, double-blind, phase 2 trial, the reductions relative to placebo after 5 weeks on the negative subscale of the Positive and Negative Syndrome Scale (PANSS) tool (–3.9 vs. –1.3; P < .001) was about as robust as that achieved on the positive subscale (–5.6 vs. –3.2; P < .001).
These subscales were secondary endpoints. Relative to placebo, xanomeline-trospium was also effective on the primary endpoint of the PANSS total score (–17.9 vs. –5.9; P < .001).
The presence of trospium did not eliminate cholinergic side effects, which included constipation, dry mouth, and nausea, but the therapy strengthens the evidence that newer agents with novel mechanisms of action, including those without dopamine blockade, can achieve meaningful clinical effects.
SEP-363856, another example of an experimental agent without direct dopamine blockade, was also recently tested in placebo-controlled, double-blind study.
“This is the first agonist of the TAAR1 [trace amine-associated receptor 1] and 5-HT1A [serotonin 5–hydroxytryptamine type 1A receptor] to reach clinical trials,” said Dr. Nasrallah, calling this an interesting agent for its range of clinical activity, which appears to include antianxiety effects.
SEP-363856: Negative vs. positive symptoms
It also appears to include activity against negative symptoms. While the primary endpoint of total PANSS score favored SEP-363856 over placebo at the end of 4 weeks (–17.2 points vs. –9.7; P = .001), the reductions in the subscales for negative (–3.1 vs. –1.6) and positive (–5.5 vs. 3.9) symptoms were also substantial even if statistical differences were not calculated.
The rates of side effects on SEP-3638656 were low, according to Dr. Nasrallah. The most common complaints, such as somnolence, agitation, and nausea, were observed in fewer than 10% of patients.
Roluperidone, another agent with no direct dopamine blockade, has reached phase 3 trials. The activity of this agent is attributed to antagonist activity on the serotonin 5-HT2A and sigma2 receptors. In a multinational, phase 2b study cited by Dr. Nasrallah, both of two study doses of roluperidone were superior to placebo for the negative symptom dimensions of expressive deficit and experiential deficit. Patients enrolled in the trial were required to have baseline PANSS negative symptom subscale scores of 20 points or greater.
Pimavanserin, an inverse agonist of 5-HT2A receptors, is already approved for the treatment of psychosis in Parkinson’s disease, but it is now attracting interest for its potential efficacy against negative symptoms in schizophrenia, according to Dr. Nasrallah, who cited a poster presented last November at the Psych Congress 2020.
The poster provided results of ADVANCE, a double-blind, placebo-controlled, phase 2 study that associated pimavanserin with significant improvement across several types of negative symptoms, Dr. Nasrallah said. The drug was well tolerated with a side-effect profile “similar to placebo.”
Traditional antipsychotic therapies are generally associated with limited effect against negative symptoms, but it has never been proven that the interaction of treatments on the dopaminergic system is the reason. Indeed, in his list of therapies being pursued for potential benefit against negative symptoms, Dr. Nasrallah cited a clinical study with cariprazine, an agent with multiple effects on dopamine and serotonin signaling.
“Cariprazine is a partial agonist at D2, D3, and 5-HT1A receptors and an antagonist at 5-HT2c and 5-HT7 receptors, but it has the highest affinity to the D3 receptor,” Dr. Nasrallah reported.
Cariprazine is already approved for schizophrenia, acute mania, and bipolar depression, but the authors of a recent review claim evidence of activity against negative symptoms. Furthermore, they speculate that this activity might be mediated by agonism of the D3 receptor.
Despite the evidence that these agents might control negative symptoms, the relative roles will be defined by clinical experience, not just clinical trials, Dr. Nasrallah said. However, he did indicate that there appears to be meaningful progress in this area.
Potential progress in this area is important, because “negative symptoms are a largely unaddressed treatment target in people with schizophrenia,” reported Christoph U. Correll, MD, professor of psychiatry, Hofstra University, Hempstead, N.Y. These symptoms deserve attention for their “important potential to improve interpersonal, educational, and work function.”
Dr. Correll agreed that the newer drugs with mechanisms other than postsynaptic dopamine blockade could be a very important advance in the treatment of schizophrenia.
“Promising new medications with potential efficacy for negative symptoms, either based on their pharmacological profile and/or emerging data, include cariprazine, lumateperone, ulotaront [SEP-363856], and xanomeline plus trospium,” he said. Efficacy for negative symptoms, if proven, will address an “elusive goal.”
MedscapeLive! and this news organization are owned by the same parent company. Dr. Nasrallah reported financial relationships with Acadia Pharmaceuticals, Alkermes, Avanir, Intra-Cellular Therapies, Indivior, Janssen, Neurocrine, and Teva. Dr. Correll listed financial relationships with more than 25 pharmaceutical companies, including several developing medications with potential activity against negative symptoms.
Late-stage trials of new antipsychotic drugs are showing promise in the control of negative symptoms, according to an overview presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.
The progress in these trials deserves attention, because control of negative symptoms is “a major unmet need in schizophrenia,” according to Henry A. Nasrallah, MD, director of the schizophrenia program at the University of Cincinnati.
The novel mechanisms of the agents in development are credited with the promise. Not least, several antipsychotic agents with activity against both positive and negative symptoms “are completely devoid of dopamine receptor blockade,” Dr. Nasrallah said at the virtual meeting, presented by MedscapeLive!
The xanomeline portion of the investigational treatment xanomeline-trospium is one example. Xanomeline is a muscarinic receptor agonist with no activity on dopamine D2 receptors. The role of trospium, a muscarinic receptor antagonist, is to reduce peripheral cholinergic side effects.
Xanomeline-trospium: Negative vs. positive symptoms
In a recently published placebo-controlled, double-blind, phase 2 trial, the reductions relative to placebo after 5 weeks on the negative subscale of the Positive and Negative Syndrome Scale (PANSS) tool (–3.9 vs. –1.3; P < .001) was about as robust as that achieved on the positive subscale (–5.6 vs. –3.2; P < .001).
These subscales were secondary endpoints. Relative to placebo, xanomeline-trospium was also effective on the primary endpoint of the PANSS total score (–17.9 vs. –5.9; P < .001).
The presence of trospium did not eliminate cholinergic side effects, which included constipation, dry mouth, and nausea, but the therapy strengthens the evidence that newer agents with novel mechanisms of action, including those without dopamine blockade, can achieve meaningful clinical effects.
SEP-363856, another example of an experimental agent without direct dopamine blockade, was also recently tested in placebo-controlled, double-blind study.
“This is the first agonist of the TAAR1 [trace amine-associated receptor 1] and 5-HT1A [serotonin 5–hydroxytryptamine type 1A receptor] to reach clinical trials,” said Dr. Nasrallah, calling this an interesting agent for its range of clinical activity, which appears to include antianxiety effects.
SEP-363856: Negative vs. positive symptoms
It also appears to include activity against negative symptoms. While the primary endpoint of total PANSS score favored SEP-363856 over placebo at the end of 4 weeks (–17.2 points vs. –9.7; P = .001), the reductions in the subscales for negative (–3.1 vs. –1.6) and positive (–5.5 vs. 3.9) symptoms were also substantial even if statistical differences were not calculated.
The rates of side effects on SEP-3638656 were low, according to Dr. Nasrallah. The most common complaints, such as somnolence, agitation, and nausea, were observed in fewer than 10% of patients.
Roluperidone, another agent with no direct dopamine blockade, has reached phase 3 trials. The activity of this agent is attributed to antagonist activity on the serotonin 5-HT2A and sigma2 receptors. In a multinational, phase 2b study cited by Dr. Nasrallah, both of two study doses of roluperidone were superior to placebo for the negative symptom dimensions of expressive deficit and experiential deficit. Patients enrolled in the trial were required to have baseline PANSS negative symptom subscale scores of 20 points or greater.
Pimavanserin, an inverse agonist of 5-HT2A receptors, is already approved for the treatment of psychosis in Parkinson’s disease, but it is now attracting interest for its potential efficacy against negative symptoms in schizophrenia, according to Dr. Nasrallah, who cited a poster presented last November at the Psych Congress 2020.
The poster provided results of ADVANCE, a double-blind, placebo-controlled, phase 2 study that associated pimavanserin with significant improvement across several types of negative symptoms, Dr. Nasrallah said. The drug was well tolerated with a side-effect profile “similar to placebo.”
Traditional antipsychotic therapies are generally associated with limited effect against negative symptoms, but it has never been proven that the interaction of treatments on the dopaminergic system is the reason. Indeed, in his list of therapies being pursued for potential benefit against negative symptoms, Dr. Nasrallah cited a clinical study with cariprazine, an agent with multiple effects on dopamine and serotonin signaling.
“Cariprazine is a partial agonist at D2, D3, and 5-HT1A receptors and an antagonist at 5-HT2c and 5-HT7 receptors, but it has the highest affinity to the D3 receptor,” Dr. Nasrallah reported.
Cariprazine is already approved for schizophrenia, acute mania, and bipolar depression, but the authors of a recent review claim evidence of activity against negative symptoms. Furthermore, they speculate that this activity might be mediated by agonism of the D3 receptor.
Despite the evidence that these agents might control negative symptoms, the relative roles will be defined by clinical experience, not just clinical trials, Dr. Nasrallah said. However, he did indicate that there appears to be meaningful progress in this area.
Potential progress in this area is important, because “negative symptoms are a largely unaddressed treatment target in people with schizophrenia,” reported Christoph U. Correll, MD, professor of psychiatry, Hofstra University, Hempstead, N.Y. These symptoms deserve attention for their “important potential to improve interpersonal, educational, and work function.”
Dr. Correll agreed that the newer drugs with mechanisms other than postsynaptic dopamine blockade could be a very important advance in the treatment of schizophrenia.
“Promising new medications with potential efficacy for negative symptoms, either based on their pharmacological profile and/or emerging data, include cariprazine, lumateperone, ulotaront [SEP-363856], and xanomeline plus trospium,” he said. Efficacy for negative symptoms, if proven, will address an “elusive goal.”
MedscapeLive! and this news organization are owned by the same parent company. Dr. Nasrallah reported financial relationships with Acadia Pharmaceuticals, Alkermes, Avanir, Intra-Cellular Therapies, Indivior, Janssen, Neurocrine, and Teva. Dr. Correll listed financial relationships with more than 25 pharmaceutical companies, including several developing medications with potential activity against negative symptoms.
FROM CP/AACP PSYCHIATRY UPDATE
Western and proinflammatory diets are important drivers of gout risk
Diets high in red meats, saturated fats, and sugars, relative to diets dominated by fruits, vegetables, and legumes, are associated with an increased risk of gout independent of an underlying genetic risk, according to independent sets of data presented at the annual European Congress of Rheumatology.
Only one of the two retrospective analyses evaluated diet in the context of a genetic risk score, but “no evidence of an additional or multiplicative interaction” was seen when genetic risk was evaluated on top of the risk already known to be associated with a Western diet, reported Chio Yokose, MD, a researcher and clinician in the division of rheumatology, allergy, and immunology at Massachusetts General Hospital, Boston.
A parallel study presented at the EULAR Congress looked at the impact of a proinflammatory diet. Although genetic predisposition was not considered in this analysis, this diet, too, was associated with increased risk of gout independent of a long list of other variables. Each of the studies supports the potential for diet to be a target for risk reduction.
“Adhering to a diet with low inflammatory potential may mediate systemic and metabolic inflammation,” reported Natalie McCormick, PhD, a research fellow at Massachusetts General Hospital. She said the association of an inflammatory diet with gout is analogous to previous studies linking this type of diet to type 2 diabetes mellitus and cardiovascular disease because the inflammatory response is a pathogenic factor.
The two retrospective studies evaluated different but overlapping sets of data. Dr. Yokose and Dr. McCormick collaborated on both studies.
In the study of Western diet, which was restricted to women, the focus was on both diet and genes. Using food frequency questionnaires completed by 18,512 women participating in the Nurses’ Health Study (NHS), subjects were placed in quintiles for relative exposure to Western diets and for an interventional diet called DASH (Dietary Approaches to Stop Hypertension) that is high in fruits and vegetables.
A genetic risk score (GRS) was developed for participants using 114 serum urate single-nucleotide polymorphisms from a genomewide association study.
For the Western diet, there was a stepwise increased risk of gout per quintile associated with greater exposure. For the DASH diet, the same phenomenon was seen in reverse so that risk of gout was incrementally lower per quintile defining greater adherence.
When considered as a variable, GRS altered these basic relationships only for the DASH diet. After adjusting for multiple factors, such as age, menopause, use of hormone therapy, and hypertension, there was no significant interaction observed for genetic predisposition in relation to the Western diet.
For the DASH diet, there was an even greater reduction in the relative risk of gout among those with a high GRS if they were in the quintile defining greatest adherence to the DASH diet. Although this association fell just short of reaching statistical significance (P = .056), Dr. Yokose indicated that it was a strong trend.
Gout similarly associated with proinflammatory diet
The proinflammatory diet shares many food items with the Western diet, including refined carbohydrates, sweetened beverages, red meat, and fried foods. The study that evaluated its impact used dietary history collected from in 164,090 women in the NHS and 40,598 men in the Health Professionals Follow-up Study. In both, participants completed dietary questionnaires every 4 years. Patients were assigned an Empirical Dietary Index of Inflammatory Potential (EDIP) score on the basis of these questionnaires.
When the 2,874 incident gout cases were evaluated by EDIP quintile, those in the highest had a 50% greater risk of gout than did those in the lowest when adjusted for multiple potential confounders. When stratified by intake of alcohol, the impact of being in the highest quintile of inflammatory diet was even greater, producing a 2.37-fold increased risk of gout.
Impact of weight on risk for gout
The impact of proinflammatory diet was detectable even after adjusting for adiposity, a gout risk factor reconfirmed in a third study presented at EULAR by this same team of investigators. In that study, presented by Dr. Yokose, a GRS above the mean was associated with a further increased likelihood of gout among those with elevated body mass index. However, obesity remained a risk factor for gout even among those with a low GRS.
The data from this study indicate “maintaining healthy weight is an important gout prevention strategy, regardless of underlying genetic risk,” Dr. Yokose reported.
All three studies reinforce diet as a modifiable risk factor for gout. According to both Dr. Yokose and Dr. McCormick, healthy diets should be considered as a gout prevention strategy.
Annelies Boonen, MD, PhD, professor of internal medicine (rheumatology) at the University of Maastricht (the Netherlands), did not challenge these conclusions. However, she cautioned that it is “very difficult to evaluate food questionnaires.” She further noted that retrospective analyses complicate efforts to control for the many potential confounders.
Ultimately, healthy diets can be recommended for many reasons, particularly in individuals with other risk factors for gout. For this reason, Dr. Boonen indicated that it will be difficult to prove definitively that gout can be prevented by avoiding Western diets and other diets high in proinflammatory foods. However, definitive proof of this benefit might not be essential for the purpose of a general recommendation to eat healthy foods.
Dr. Yokose and Dr. McCormick reported no potential conflicts of interest.
Diets high in red meats, saturated fats, and sugars, relative to diets dominated by fruits, vegetables, and legumes, are associated with an increased risk of gout independent of an underlying genetic risk, according to independent sets of data presented at the annual European Congress of Rheumatology.
Only one of the two retrospective analyses evaluated diet in the context of a genetic risk score, but “no evidence of an additional or multiplicative interaction” was seen when genetic risk was evaluated on top of the risk already known to be associated with a Western diet, reported Chio Yokose, MD, a researcher and clinician in the division of rheumatology, allergy, and immunology at Massachusetts General Hospital, Boston.
A parallel study presented at the EULAR Congress looked at the impact of a proinflammatory diet. Although genetic predisposition was not considered in this analysis, this diet, too, was associated with increased risk of gout independent of a long list of other variables. Each of the studies supports the potential for diet to be a target for risk reduction.
“Adhering to a diet with low inflammatory potential may mediate systemic and metabolic inflammation,” reported Natalie McCormick, PhD, a research fellow at Massachusetts General Hospital. She said the association of an inflammatory diet with gout is analogous to previous studies linking this type of diet to type 2 diabetes mellitus and cardiovascular disease because the inflammatory response is a pathogenic factor.
The two retrospective studies evaluated different but overlapping sets of data. Dr. Yokose and Dr. McCormick collaborated on both studies.
In the study of Western diet, which was restricted to women, the focus was on both diet and genes. Using food frequency questionnaires completed by 18,512 women participating in the Nurses’ Health Study (NHS), subjects were placed in quintiles for relative exposure to Western diets and for an interventional diet called DASH (Dietary Approaches to Stop Hypertension) that is high in fruits and vegetables.
A genetic risk score (GRS) was developed for participants using 114 serum urate single-nucleotide polymorphisms from a genomewide association study.
For the Western diet, there was a stepwise increased risk of gout per quintile associated with greater exposure. For the DASH diet, the same phenomenon was seen in reverse so that risk of gout was incrementally lower per quintile defining greater adherence.
When considered as a variable, GRS altered these basic relationships only for the DASH diet. After adjusting for multiple factors, such as age, menopause, use of hormone therapy, and hypertension, there was no significant interaction observed for genetic predisposition in relation to the Western diet.
For the DASH diet, there was an even greater reduction in the relative risk of gout among those with a high GRS if they were in the quintile defining greatest adherence to the DASH diet. Although this association fell just short of reaching statistical significance (P = .056), Dr. Yokose indicated that it was a strong trend.
Gout similarly associated with proinflammatory diet
The proinflammatory diet shares many food items with the Western diet, including refined carbohydrates, sweetened beverages, red meat, and fried foods. The study that evaluated its impact used dietary history collected from in 164,090 women in the NHS and 40,598 men in the Health Professionals Follow-up Study. In both, participants completed dietary questionnaires every 4 years. Patients were assigned an Empirical Dietary Index of Inflammatory Potential (EDIP) score on the basis of these questionnaires.
When the 2,874 incident gout cases were evaluated by EDIP quintile, those in the highest had a 50% greater risk of gout than did those in the lowest when adjusted for multiple potential confounders. When stratified by intake of alcohol, the impact of being in the highest quintile of inflammatory diet was even greater, producing a 2.37-fold increased risk of gout.
Impact of weight on risk for gout
The impact of proinflammatory diet was detectable even after adjusting for adiposity, a gout risk factor reconfirmed in a third study presented at EULAR by this same team of investigators. In that study, presented by Dr. Yokose, a GRS above the mean was associated with a further increased likelihood of gout among those with elevated body mass index. However, obesity remained a risk factor for gout even among those with a low GRS.
The data from this study indicate “maintaining healthy weight is an important gout prevention strategy, regardless of underlying genetic risk,” Dr. Yokose reported.
All three studies reinforce diet as a modifiable risk factor for gout. According to both Dr. Yokose and Dr. McCormick, healthy diets should be considered as a gout prevention strategy.
Annelies Boonen, MD, PhD, professor of internal medicine (rheumatology) at the University of Maastricht (the Netherlands), did not challenge these conclusions. However, she cautioned that it is “very difficult to evaluate food questionnaires.” She further noted that retrospective analyses complicate efforts to control for the many potential confounders.
Ultimately, healthy diets can be recommended for many reasons, particularly in individuals with other risk factors for gout. For this reason, Dr. Boonen indicated that it will be difficult to prove definitively that gout can be prevented by avoiding Western diets and other diets high in proinflammatory foods. However, definitive proof of this benefit might not be essential for the purpose of a general recommendation to eat healthy foods.
Dr. Yokose and Dr. McCormick reported no potential conflicts of interest.
Diets high in red meats, saturated fats, and sugars, relative to diets dominated by fruits, vegetables, and legumes, are associated with an increased risk of gout independent of an underlying genetic risk, according to independent sets of data presented at the annual European Congress of Rheumatology.
Only one of the two retrospective analyses evaluated diet in the context of a genetic risk score, but “no evidence of an additional or multiplicative interaction” was seen when genetic risk was evaluated on top of the risk already known to be associated with a Western diet, reported Chio Yokose, MD, a researcher and clinician in the division of rheumatology, allergy, and immunology at Massachusetts General Hospital, Boston.
A parallel study presented at the EULAR Congress looked at the impact of a proinflammatory diet. Although genetic predisposition was not considered in this analysis, this diet, too, was associated with increased risk of gout independent of a long list of other variables. Each of the studies supports the potential for diet to be a target for risk reduction.
“Adhering to a diet with low inflammatory potential may mediate systemic and metabolic inflammation,” reported Natalie McCormick, PhD, a research fellow at Massachusetts General Hospital. She said the association of an inflammatory diet with gout is analogous to previous studies linking this type of diet to type 2 diabetes mellitus and cardiovascular disease because the inflammatory response is a pathogenic factor.
The two retrospective studies evaluated different but overlapping sets of data. Dr. Yokose and Dr. McCormick collaborated on both studies.
In the study of Western diet, which was restricted to women, the focus was on both diet and genes. Using food frequency questionnaires completed by 18,512 women participating in the Nurses’ Health Study (NHS), subjects were placed in quintiles for relative exposure to Western diets and for an interventional diet called DASH (Dietary Approaches to Stop Hypertension) that is high in fruits and vegetables.
A genetic risk score (GRS) was developed for participants using 114 serum urate single-nucleotide polymorphisms from a genomewide association study.
For the Western diet, there was a stepwise increased risk of gout per quintile associated with greater exposure. For the DASH diet, the same phenomenon was seen in reverse so that risk of gout was incrementally lower per quintile defining greater adherence.
When considered as a variable, GRS altered these basic relationships only for the DASH diet. After adjusting for multiple factors, such as age, menopause, use of hormone therapy, and hypertension, there was no significant interaction observed for genetic predisposition in relation to the Western diet.
For the DASH diet, there was an even greater reduction in the relative risk of gout among those with a high GRS if they were in the quintile defining greatest adherence to the DASH diet. Although this association fell just short of reaching statistical significance (P = .056), Dr. Yokose indicated that it was a strong trend.
Gout similarly associated with proinflammatory diet
The proinflammatory diet shares many food items with the Western diet, including refined carbohydrates, sweetened beverages, red meat, and fried foods. The study that evaluated its impact used dietary history collected from in 164,090 women in the NHS and 40,598 men in the Health Professionals Follow-up Study. In both, participants completed dietary questionnaires every 4 years. Patients were assigned an Empirical Dietary Index of Inflammatory Potential (EDIP) score on the basis of these questionnaires.
When the 2,874 incident gout cases were evaluated by EDIP quintile, those in the highest had a 50% greater risk of gout than did those in the lowest when adjusted for multiple potential confounders. When stratified by intake of alcohol, the impact of being in the highest quintile of inflammatory diet was even greater, producing a 2.37-fold increased risk of gout.
Impact of weight on risk for gout
The impact of proinflammatory diet was detectable even after adjusting for adiposity, a gout risk factor reconfirmed in a third study presented at EULAR by this same team of investigators. In that study, presented by Dr. Yokose, a GRS above the mean was associated with a further increased likelihood of gout among those with elevated body mass index. However, obesity remained a risk factor for gout even among those with a low GRS.
The data from this study indicate “maintaining healthy weight is an important gout prevention strategy, regardless of underlying genetic risk,” Dr. Yokose reported.
All three studies reinforce diet as a modifiable risk factor for gout. According to both Dr. Yokose and Dr. McCormick, healthy diets should be considered as a gout prevention strategy.
Annelies Boonen, MD, PhD, professor of internal medicine (rheumatology) at the University of Maastricht (the Netherlands), did not challenge these conclusions. However, she cautioned that it is “very difficult to evaluate food questionnaires.” She further noted that retrospective analyses complicate efforts to control for the many potential confounders.
Ultimately, healthy diets can be recommended for many reasons, particularly in individuals with other risk factors for gout. For this reason, Dr. Boonen indicated that it will be difficult to prove definitively that gout can be prevented by avoiding Western diets and other diets high in proinflammatory foods. However, definitive proof of this benefit might not be essential for the purpose of a general recommendation to eat healthy foods.
Dr. Yokose and Dr. McCormick reported no potential conflicts of interest.
FROM THE EULAR 2021 CONGRESS
Secukinumab provides clinical benefit in phase 3 juvenile arthritis trial
Favorable safety sustained at 104 weeks
Secukinumab (Cosentyx), an interleukin-17A inhibitor, is effective and reasonably well tolerated for treatment of enthesitis-related arthritis (ERA) and juvenile psoriatic arthritis (JPsA) in children and adolescents, according to a phase 3 trial presented at a late breaking abstracts session of the annual European Congress of Rheumatology.
On the primary outcome of time to flare, the curves for secukinumab and placebo separated almost immediately, with fewer than half the number of flares occurring in the experimental arm over the course of the study, according to Nicolino Ruperto, MD, senior research scientist at IRCCS Istituto Giannina Gaslini in Genoa, Italy.
The trial, called JUNIPERA, was conducted over 2 years and included an open-label treatment period (TP1) and then a randomized, placebo-controlled comparison (TP2). In TP1, 86 children were initiated on open-label secukinumab administered subcutaneously on weeks 1, 2, 3, 4, 8, and 12. The dose was 75 mg for children less than 50 kg and 150 kg for those heavier.
Average patient age was 13.1 years
Of these 86 children, 52 had ERA and 34 had JPsA. Disease duration of at least 6 months was required for entry. Patients up to the age of 18 years were permitted to enroll. The average age was 13.1 years. Most patients, two-thirds of whom were male, had received an immunomodulator prior to study entry.
At the end of TP1, 69.9% of patients had achieved 70% improvement in the Juvenile Idiopathic Arthritis American College of Rheumatology joint score (JIA ACR70). The 90.4% of patients who achieved JIA ACR30 were invited to enroll in TP2. A total of 75 patients did so.
At the end of TP2, response rates strongly favored secukinumab over placebo for JIA ACR30 (89.2% vs. 64.9%; P = .014) and JIA ACR70 (67.7% vs. 43.2%; P = .042). Higher but not statistically significant differences in response rates were seen for secukinumab over placebo for JIA ACR50 (78.4% vs. 62.2%; P = .152), JIA ACR90 (51.4% vs. 40.5%; P = .431) and JIA ACR100 (43.2% vs. 37.8%; P = .755).
During TP2, there were 10 flares in the group randomized to secukinumab versus 21 flares in the placebo group, translating by hazard ratio (HR) into a 72% risk reduction (HR, 0.28; P < .001).
Side effects similar to those in adults
The types and rates of serious adverse events were similar to those reported previously in adult patients, according to Dr. Ruperto. Although the rate of serious adverse events (14.6% vs. 10.6%) was only moderately higher in the experimental arm, more patients randomized to secukinumab than placebo discontinued therapy (13.2% vs. 6.3%) before the end of follow-up.
The side effects that occurred more commonly on secukinumab included gastrointestinal complaints, such as diarrhea (22.9% vs. 15.8%). Other adverse events occurring in more than 10% of patients included headache and nasopharyngitis, but most side effects were mild and resolved.
Although the proportion of patients with flare increased over time in both groups, Dr. Ruperto reported that protection against flares and relative improvement in clinical markers of disease activity relative to placebo “were sustained out to 2 years of follow-up.”
The submission of these data to regulatory agencies is anticipated. If secukinumab is given an indication for these forms of arthritis, it will join an indication for plaque psoriasis in children that was granted just a few days before these data were presented. The psoriasis indication is the only current use approved for children in the United States.
More biologics needed for JPsA
Additional biologics will be helpful for children with arthritis who are poorly controlled on available treatments, according to Natasha M. Ruth, MD, director of the division of pediatric rheumatology at the Medical University of South Carolina, Charleston. Dr. Ruth was senior author of a case study published 2 years ago in which secukinumab was used to control psoriatic arthritis and nail manifestations of psoriasis.
“It was a girl who had already failed to improve adequately to TNF inhibitors,” reported Dr. Ruth, who had said the child and her parent were very concerned about the nail appearance.
“The nail involvement completely resolved, so it was a very good result in a difficult situation,” Dr. Ruth explained. She said that the decision to try secukinumab was made collaboratively in a clinic in which dermatologists and rheumatologists at her institution work together on difficult cases.
“There is a need for more biologics with different mechanisms of action,” Dr. Ruth said. Based on her experience, secukinumab could be an important addition to treatment options.
Dr. Ruperto reported having financial relationships with more than 20 pharmaceutical companies, including Novartis, which provided financial support for this trial. Many coauthors had financial relationships with multiple companies, including Novartis, and some were employees of the company. Dr. Ruth reported having no potential conflicts of interest.
Favorable safety sustained at 104 weeks
Favorable safety sustained at 104 weeks
Secukinumab (Cosentyx), an interleukin-17A inhibitor, is effective and reasonably well tolerated for treatment of enthesitis-related arthritis (ERA) and juvenile psoriatic arthritis (JPsA) in children and adolescents, according to a phase 3 trial presented at a late breaking abstracts session of the annual European Congress of Rheumatology.
On the primary outcome of time to flare, the curves for secukinumab and placebo separated almost immediately, with fewer than half the number of flares occurring in the experimental arm over the course of the study, according to Nicolino Ruperto, MD, senior research scientist at IRCCS Istituto Giannina Gaslini in Genoa, Italy.
The trial, called JUNIPERA, was conducted over 2 years and included an open-label treatment period (TP1) and then a randomized, placebo-controlled comparison (TP2). In TP1, 86 children were initiated on open-label secukinumab administered subcutaneously on weeks 1, 2, 3, 4, 8, and 12. The dose was 75 mg for children less than 50 kg and 150 kg for those heavier.
Average patient age was 13.1 years
Of these 86 children, 52 had ERA and 34 had JPsA. Disease duration of at least 6 months was required for entry. Patients up to the age of 18 years were permitted to enroll. The average age was 13.1 years. Most patients, two-thirds of whom were male, had received an immunomodulator prior to study entry.
At the end of TP1, 69.9% of patients had achieved 70% improvement in the Juvenile Idiopathic Arthritis American College of Rheumatology joint score (JIA ACR70). The 90.4% of patients who achieved JIA ACR30 were invited to enroll in TP2. A total of 75 patients did so.
At the end of TP2, response rates strongly favored secukinumab over placebo for JIA ACR30 (89.2% vs. 64.9%; P = .014) and JIA ACR70 (67.7% vs. 43.2%; P = .042). Higher but not statistically significant differences in response rates were seen for secukinumab over placebo for JIA ACR50 (78.4% vs. 62.2%; P = .152), JIA ACR90 (51.4% vs. 40.5%; P = .431) and JIA ACR100 (43.2% vs. 37.8%; P = .755).
During TP2, there were 10 flares in the group randomized to secukinumab versus 21 flares in the placebo group, translating by hazard ratio (HR) into a 72% risk reduction (HR, 0.28; P < .001).
Side effects similar to those in adults
The types and rates of serious adverse events were similar to those reported previously in adult patients, according to Dr. Ruperto. Although the rate of serious adverse events (14.6% vs. 10.6%) was only moderately higher in the experimental arm, more patients randomized to secukinumab than placebo discontinued therapy (13.2% vs. 6.3%) before the end of follow-up.
The side effects that occurred more commonly on secukinumab included gastrointestinal complaints, such as diarrhea (22.9% vs. 15.8%). Other adverse events occurring in more than 10% of patients included headache and nasopharyngitis, but most side effects were mild and resolved.
Although the proportion of patients with flare increased over time in both groups, Dr. Ruperto reported that protection against flares and relative improvement in clinical markers of disease activity relative to placebo “were sustained out to 2 years of follow-up.”
The submission of these data to regulatory agencies is anticipated. If secukinumab is given an indication for these forms of arthritis, it will join an indication for plaque psoriasis in children that was granted just a few days before these data were presented. The psoriasis indication is the only current use approved for children in the United States.
More biologics needed for JPsA
Additional biologics will be helpful for children with arthritis who are poorly controlled on available treatments, according to Natasha M. Ruth, MD, director of the division of pediatric rheumatology at the Medical University of South Carolina, Charleston. Dr. Ruth was senior author of a case study published 2 years ago in which secukinumab was used to control psoriatic arthritis and nail manifestations of psoriasis.
“It was a girl who had already failed to improve adequately to TNF inhibitors,” reported Dr. Ruth, who had said the child and her parent were very concerned about the nail appearance.
“The nail involvement completely resolved, so it was a very good result in a difficult situation,” Dr. Ruth explained. She said that the decision to try secukinumab was made collaboratively in a clinic in which dermatologists and rheumatologists at her institution work together on difficult cases.
“There is a need for more biologics with different mechanisms of action,” Dr. Ruth said. Based on her experience, secukinumab could be an important addition to treatment options.
Dr. Ruperto reported having financial relationships with more than 20 pharmaceutical companies, including Novartis, which provided financial support for this trial. Many coauthors had financial relationships with multiple companies, including Novartis, and some were employees of the company. Dr. Ruth reported having no potential conflicts of interest.
Secukinumab (Cosentyx), an interleukin-17A inhibitor, is effective and reasonably well tolerated for treatment of enthesitis-related arthritis (ERA) and juvenile psoriatic arthritis (JPsA) in children and adolescents, according to a phase 3 trial presented at a late breaking abstracts session of the annual European Congress of Rheumatology.
On the primary outcome of time to flare, the curves for secukinumab and placebo separated almost immediately, with fewer than half the number of flares occurring in the experimental arm over the course of the study, according to Nicolino Ruperto, MD, senior research scientist at IRCCS Istituto Giannina Gaslini in Genoa, Italy.
The trial, called JUNIPERA, was conducted over 2 years and included an open-label treatment period (TP1) and then a randomized, placebo-controlled comparison (TP2). In TP1, 86 children were initiated on open-label secukinumab administered subcutaneously on weeks 1, 2, 3, 4, 8, and 12. The dose was 75 mg for children less than 50 kg and 150 kg for those heavier.
Average patient age was 13.1 years
Of these 86 children, 52 had ERA and 34 had JPsA. Disease duration of at least 6 months was required for entry. Patients up to the age of 18 years were permitted to enroll. The average age was 13.1 years. Most patients, two-thirds of whom were male, had received an immunomodulator prior to study entry.
At the end of TP1, 69.9% of patients had achieved 70% improvement in the Juvenile Idiopathic Arthritis American College of Rheumatology joint score (JIA ACR70). The 90.4% of patients who achieved JIA ACR30 were invited to enroll in TP2. A total of 75 patients did so.
At the end of TP2, response rates strongly favored secukinumab over placebo for JIA ACR30 (89.2% vs. 64.9%; P = .014) and JIA ACR70 (67.7% vs. 43.2%; P = .042). Higher but not statistically significant differences in response rates were seen for secukinumab over placebo for JIA ACR50 (78.4% vs. 62.2%; P = .152), JIA ACR90 (51.4% vs. 40.5%; P = .431) and JIA ACR100 (43.2% vs. 37.8%; P = .755).
During TP2, there were 10 flares in the group randomized to secukinumab versus 21 flares in the placebo group, translating by hazard ratio (HR) into a 72% risk reduction (HR, 0.28; P < .001).
Side effects similar to those in adults
The types and rates of serious adverse events were similar to those reported previously in adult patients, according to Dr. Ruperto. Although the rate of serious adverse events (14.6% vs. 10.6%) was only moderately higher in the experimental arm, more patients randomized to secukinumab than placebo discontinued therapy (13.2% vs. 6.3%) before the end of follow-up.
The side effects that occurred more commonly on secukinumab included gastrointestinal complaints, such as diarrhea (22.9% vs. 15.8%). Other adverse events occurring in more than 10% of patients included headache and nasopharyngitis, but most side effects were mild and resolved.
Although the proportion of patients with flare increased over time in both groups, Dr. Ruperto reported that protection against flares and relative improvement in clinical markers of disease activity relative to placebo “were sustained out to 2 years of follow-up.”
The submission of these data to regulatory agencies is anticipated. If secukinumab is given an indication for these forms of arthritis, it will join an indication for plaque psoriasis in children that was granted just a few days before these data were presented. The psoriasis indication is the only current use approved for children in the United States.
More biologics needed for JPsA
Additional biologics will be helpful for children with arthritis who are poorly controlled on available treatments, according to Natasha M. Ruth, MD, director of the division of pediatric rheumatology at the Medical University of South Carolina, Charleston. Dr. Ruth was senior author of a case study published 2 years ago in which secukinumab was used to control psoriatic arthritis and nail manifestations of psoriasis.
“It was a girl who had already failed to improve adequately to TNF inhibitors,” reported Dr. Ruth, who had said the child and her parent were very concerned about the nail appearance.
“The nail involvement completely resolved, so it was a very good result in a difficult situation,” Dr. Ruth explained. She said that the decision to try secukinumab was made collaboratively in a clinic in which dermatologists and rheumatologists at her institution work together on difficult cases.
“There is a need for more biologics with different mechanisms of action,” Dr. Ruth said. Based on her experience, secukinumab could be an important addition to treatment options.
Dr. Ruperto reported having financial relationships with more than 20 pharmaceutical companies, including Novartis, which provided financial support for this trial. Many coauthors had financial relationships with multiple companies, including Novartis, and some were employees of the company. Dr. Ruth reported having no potential conflicts of interest.
FROM THE EULAR 2021 CONGRESS
Medicare rules for CPAP: Nonadherence begets more nonadherence for low-income patients
The relationship between adherence and benefit for those prescribed continuous positive airway pressure (CPAP) devices is clear. However, a Medicare-reimbursement rule that demands adherence blind to circumstances appears to be denying access to many low-income patients, according to an analysis delivered at the annual health policy and advocacy conference sponsored by the American College of Chest Physicians.
Over the past several years, adherence to CPAP has improved substantially following a series of studies that demonstrated the device must be used at least 4 hours per night to achieve improved outcomes. Medicare defines adherence as using the device more than 4 hours per night for 70% of nights (21 nights) during a consecutive 30-day period any time in the first 3 months of initial usage.
However, the studies that show improved adherence show a lag among those in the lowest income quartile, according to Sairam Parthasarathy, MD, director of the Center for Sleep and Circadian Sciences at the University of Arizona, Tucson.
When patients are followed for a year after being prescribed CPAP, the lag for the low-income patients is not seen immediately. Rather, adherence studies show a steady climb in adherence in all income groups initially, but ”right at 90 days there is a marked change,” said Dr. Parthasarathy.
This change happens to coincide with Medicare policy that denies reimbursement for CPAP after 90 days if patients are not using CPAP at least 4 hours per night, which is the threshold associated with benefit.
The correlation between this policy and income disparity is “observational” rather than proven, but Dr. Parthasarathy is confident it is valid. He believes it is a prime example of a health inequity driven by poorly conceived policy.
“The 90-day rule needs to go,” he said, calling the choice of threshold “man-made.” He added: “This is the only disease condition for which a therapy is withheld if it is not used according to some magical threshold. I cannot think of a more draconian policy.”
In an effort to illustrate the problem, he likened this policy to withholding insulin in a diabetes patient judged nonadherent because of a persistently elevated Hb1Ac.
At 90 days, adherence rates remain at a relatively early point in their upwards trajectory in all income groups. One year later, adherence rates are more than twice as high in the highest income relative to the lowest quartile and approaching twofold greater in quartiles 2 and 3.
“It takes time to get used to these devices,” Dr. Parthasarathy explained. Given studies demonstrating that “more is better” with CPAP, whether measured by sleep scales or quality of life, Dr. Parthasarathy advocates strategies to improve adherence, but he questioned an approach that penalizes low-income patients for a definition of nonadherence at an arbitrary point in time. He suggested it is just one example of health policies that ultimately penalize individuals with lower incomes.
“There are millions of dollars spent every year on understanding the genetics of disease, but the biggest influence on how long you live is the ZIP code of where you live,” said Dr. Parthasarathy, referring to ZIP codes as a surrogate for socioeconomic status.
This is not to imply, however, that genetics are irrelevant, Dr. Parthasarathy said. He pointed to data linking genetic traits that determine melanin levels and circadian rhythms. He noted one genotype associated with later bedtimes that is more commonly found in African-Americans and Hispanics. This has relevance to a variety of sleep disorders and other health conditions, but it might serve as a fundamental disadvantage for children with this genotype, Dr. Parthasarathy maintained. He cited a study conducted at his center that found Hispanic children sleep on average 30 minutes less than White children (Sleep Med 2016;18:61-6). The reason was simple. Hispanic children went to bed 30 minutes later but rose at the same time.
The later bedtimes and reduced sleep could potentially be one obstacle among many, such as the need for lower-income patients to hold several jobs, that prevent these patients from becoming accustomed to CPAP at the same speed as wealthier patients, according to Dr. Parthasarathy.
The current Medicare policy that withholds CPAP on the basis of a single definition of nonadherence appears to lead directly to an inequity in treatment of sleep apnea, he maintained. Dr. Parthasarathy, who was a coauthor of a recently published paper on addressing disparities in sleep health (Chest 2021;159:1232-40), described this issue as part of a larger problem of the failure to deliver health care that is sensitive to the cultural and racial differences underlying these inequities.
Kathleen Sarmiento, MD, FCCP, director, VISN 21 Sleep Clinical Resource Hub for the San Francisco VA Health Care System, agreed. “This type of issue is exactly what our committee would like to address,” said Dr. Sarmiento, a member of the CHEST Health Policy and Advocacy Committee and the moderator of the session in which Dr. Parthasarathy presented his data.
The association between the 90-day Medicare rule for CPAP reimbursement and reduced access to this therapy among patients of lower economic status is compelling, she indicated. Within the goal of advocacy for health policies that will reduce inequities, Dr. Sarmiento explained that the committee is attempting to identify and reverse the source of these types of disparity.
“Specific rules or regulations are actionable targets to effect broader change in health care access and health care delivery,” said Dr. Sarmiento, alluding to the mission of the Health Policy and Advocacy Committee.
Dr. Parthasarathy and Dr. Sarmiento report no relevant conflicts of interest.
The relationship between adherence and benefit for those prescribed continuous positive airway pressure (CPAP) devices is clear. However, a Medicare-reimbursement rule that demands adherence blind to circumstances appears to be denying access to many low-income patients, according to an analysis delivered at the annual health policy and advocacy conference sponsored by the American College of Chest Physicians.
Over the past several years, adherence to CPAP has improved substantially following a series of studies that demonstrated the device must be used at least 4 hours per night to achieve improved outcomes. Medicare defines adherence as using the device more than 4 hours per night for 70% of nights (21 nights) during a consecutive 30-day period any time in the first 3 months of initial usage.
However, the studies that show improved adherence show a lag among those in the lowest income quartile, according to Sairam Parthasarathy, MD, director of the Center for Sleep and Circadian Sciences at the University of Arizona, Tucson.
When patients are followed for a year after being prescribed CPAP, the lag for the low-income patients is not seen immediately. Rather, adherence studies show a steady climb in adherence in all income groups initially, but ”right at 90 days there is a marked change,” said Dr. Parthasarathy.
This change happens to coincide with Medicare policy that denies reimbursement for CPAP after 90 days if patients are not using CPAP at least 4 hours per night, which is the threshold associated with benefit.
The correlation between this policy and income disparity is “observational” rather than proven, but Dr. Parthasarathy is confident it is valid. He believes it is a prime example of a health inequity driven by poorly conceived policy.
“The 90-day rule needs to go,” he said, calling the choice of threshold “man-made.” He added: “This is the only disease condition for which a therapy is withheld if it is not used according to some magical threshold. I cannot think of a more draconian policy.”
In an effort to illustrate the problem, he likened this policy to withholding insulin in a diabetes patient judged nonadherent because of a persistently elevated Hb1Ac.
At 90 days, adherence rates remain at a relatively early point in their upwards trajectory in all income groups. One year later, adherence rates are more than twice as high in the highest income relative to the lowest quartile and approaching twofold greater in quartiles 2 and 3.
“It takes time to get used to these devices,” Dr. Parthasarathy explained. Given studies demonstrating that “more is better” with CPAP, whether measured by sleep scales or quality of life, Dr. Parthasarathy advocates strategies to improve adherence, but he questioned an approach that penalizes low-income patients for a definition of nonadherence at an arbitrary point in time. He suggested it is just one example of health policies that ultimately penalize individuals with lower incomes.
“There are millions of dollars spent every year on understanding the genetics of disease, but the biggest influence on how long you live is the ZIP code of where you live,” said Dr. Parthasarathy, referring to ZIP codes as a surrogate for socioeconomic status.
This is not to imply, however, that genetics are irrelevant, Dr. Parthasarathy said. He pointed to data linking genetic traits that determine melanin levels and circadian rhythms. He noted one genotype associated with later bedtimes that is more commonly found in African-Americans and Hispanics. This has relevance to a variety of sleep disorders and other health conditions, but it might serve as a fundamental disadvantage for children with this genotype, Dr. Parthasarathy maintained. He cited a study conducted at his center that found Hispanic children sleep on average 30 minutes less than White children (Sleep Med 2016;18:61-6). The reason was simple. Hispanic children went to bed 30 minutes later but rose at the same time.
The later bedtimes and reduced sleep could potentially be one obstacle among many, such as the need for lower-income patients to hold several jobs, that prevent these patients from becoming accustomed to CPAP at the same speed as wealthier patients, according to Dr. Parthasarathy.
The current Medicare policy that withholds CPAP on the basis of a single definition of nonadherence appears to lead directly to an inequity in treatment of sleep apnea, he maintained. Dr. Parthasarathy, who was a coauthor of a recently published paper on addressing disparities in sleep health (Chest 2021;159:1232-40), described this issue as part of a larger problem of the failure to deliver health care that is sensitive to the cultural and racial differences underlying these inequities.
Kathleen Sarmiento, MD, FCCP, director, VISN 21 Sleep Clinical Resource Hub for the San Francisco VA Health Care System, agreed. “This type of issue is exactly what our committee would like to address,” said Dr. Sarmiento, a member of the CHEST Health Policy and Advocacy Committee and the moderator of the session in which Dr. Parthasarathy presented his data.
The association between the 90-day Medicare rule for CPAP reimbursement and reduced access to this therapy among patients of lower economic status is compelling, she indicated. Within the goal of advocacy for health policies that will reduce inequities, Dr. Sarmiento explained that the committee is attempting to identify and reverse the source of these types of disparity.
“Specific rules or regulations are actionable targets to effect broader change in health care access and health care delivery,” said Dr. Sarmiento, alluding to the mission of the Health Policy and Advocacy Committee.
Dr. Parthasarathy and Dr. Sarmiento report no relevant conflicts of interest.
The relationship between adherence and benefit for those prescribed continuous positive airway pressure (CPAP) devices is clear. However, a Medicare-reimbursement rule that demands adherence blind to circumstances appears to be denying access to many low-income patients, according to an analysis delivered at the annual health policy and advocacy conference sponsored by the American College of Chest Physicians.
Over the past several years, adherence to CPAP has improved substantially following a series of studies that demonstrated the device must be used at least 4 hours per night to achieve improved outcomes. Medicare defines adherence as using the device more than 4 hours per night for 70% of nights (21 nights) during a consecutive 30-day period any time in the first 3 months of initial usage.
However, the studies that show improved adherence show a lag among those in the lowest income quartile, according to Sairam Parthasarathy, MD, director of the Center for Sleep and Circadian Sciences at the University of Arizona, Tucson.
When patients are followed for a year after being prescribed CPAP, the lag for the low-income patients is not seen immediately. Rather, adherence studies show a steady climb in adherence in all income groups initially, but ”right at 90 days there is a marked change,” said Dr. Parthasarathy.
This change happens to coincide with Medicare policy that denies reimbursement for CPAP after 90 days if patients are not using CPAP at least 4 hours per night, which is the threshold associated with benefit.
The correlation between this policy and income disparity is “observational” rather than proven, but Dr. Parthasarathy is confident it is valid. He believes it is a prime example of a health inequity driven by poorly conceived policy.
“The 90-day rule needs to go,” he said, calling the choice of threshold “man-made.” He added: “This is the only disease condition for which a therapy is withheld if it is not used according to some magical threshold. I cannot think of a more draconian policy.”
In an effort to illustrate the problem, he likened this policy to withholding insulin in a diabetes patient judged nonadherent because of a persistently elevated Hb1Ac.
At 90 days, adherence rates remain at a relatively early point in their upwards trajectory in all income groups. One year later, adherence rates are more than twice as high in the highest income relative to the lowest quartile and approaching twofold greater in quartiles 2 and 3.
“It takes time to get used to these devices,” Dr. Parthasarathy explained. Given studies demonstrating that “more is better” with CPAP, whether measured by sleep scales or quality of life, Dr. Parthasarathy advocates strategies to improve adherence, but he questioned an approach that penalizes low-income patients for a definition of nonadherence at an arbitrary point in time. He suggested it is just one example of health policies that ultimately penalize individuals with lower incomes.
“There are millions of dollars spent every year on understanding the genetics of disease, but the biggest influence on how long you live is the ZIP code of where you live,” said Dr. Parthasarathy, referring to ZIP codes as a surrogate for socioeconomic status.
This is not to imply, however, that genetics are irrelevant, Dr. Parthasarathy said. He pointed to data linking genetic traits that determine melanin levels and circadian rhythms. He noted one genotype associated with later bedtimes that is more commonly found in African-Americans and Hispanics. This has relevance to a variety of sleep disorders and other health conditions, but it might serve as a fundamental disadvantage for children with this genotype, Dr. Parthasarathy maintained. He cited a study conducted at his center that found Hispanic children sleep on average 30 minutes less than White children (Sleep Med 2016;18:61-6). The reason was simple. Hispanic children went to bed 30 minutes later but rose at the same time.
The later bedtimes and reduced sleep could potentially be one obstacle among many, such as the need for lower-income patients to hold several jobs, that prevent these patients from becoming accustomed to CPAP at the same speed as wealthier patients, according to Dr. Parthasarathy.
The current Medicare policy that withholds CPAP on the basis of a single definition of nonadherence appears to lead directly to an inequity in treatment of sleep apnea, he maintained. Dr. Parthasarathy, who was a coauthor of a recently published paper on addressing disparities in sleep health (Chest 2021;159:1232-40), described this issue as part of a larger problem of the failure to deliver health care that is sensitive to the cultural and racial differences underlying these inequities.
Kathleen Sarmiento, MD, FCCP, director, VISN 21 Sleep Clinical Resource Hub for the San Francisco VA Health Care System, agreed. “This type of issue is exactly what our committee would like to address,” said Dr. Sarmiento, a member of the CHEST Health Policy and Advocacy Committee and the moderator of the session in which Dr. Parthasarathy presented his data.
The association between the 90-day Medicare rule for CPAP reimbursement and reduced access to this therapy among patients of lower economic status is compelling, she indicated. Within the goal of advocacy for health policies that will reduce inequities, Dr. Sarmiento explained that the committee is attempting to identify and reverse the source of these types of disparity.
“Specific rules or regulations are actionable targets to effect broader change in health care access and health care delivery,” said Dr. Sarmiento, alluding to the mission of the Health Policy and Advocacy Committee.
Dr. Parthasarathy and Dr. Sarmiento report no relevant conflicts of interest.
FROM A HEALTH POLICY AND ADVOCACY CONFERENCE
Under new administration, best time to lobby for health care may be now
The ambitious infrastructure bill now being debated in the US Congress might be one of the best immediate opportunities to lobby for legislative or policy changes in delivery of health care during the current Biden administration, according to an analysis delivered at the annual health policy and advocacy conference sponsored by the American College of Chest Physicians.
The infrastructure bill is likely to be pushed forward in the filibuster-proof reconciliation process, which means “that some things might get passed that otherwise would not,” explained Keith S. Studdard, Vice President, Jeffrey J. Kimbell & Associates, Washington, DC.
With few exceptions, the key players in the health care team of President Joe Biden’s new administration are in place, according to Mr. Studdard, who is a lobbyist and health care expert. By moving quickly to fill key positions, the new administration “got off to a good start” for a health care agenda that Mr. Studdard believes will be a focus of the Biden presidency. There is some degree of urgency.
“The amount of time [the Biden administration has] to get their agenda through is fairly limited,” Mr. Studdard reported. The problems include a slim majority of fellow Democrats in the House of Representatives (222 vs 213), no majority of Democrats over Republicans in the Senate (50 vs 50), and mid-term elections that are already looming.
“Midterms historically favor the opposition party,” Mr. Studdard said. He expects party lines to harden as the midterms approach, dissipating the already limited appetite for bipartisan cooperation.
The midterms provide the basis for trying to affect change in advance of legislative gridlock, but the recently announced $2 trillion infrastructure bill is an even more compelling impetus. Infrastructure in this case is not limited to the construction of bridges and roads. Rather, this bill “is a massive package that will almost certainly touch on health care policy,” according to Mr. Studdard.
As the infrastructure bill winds its way through the legislative process, Mr. Studdard expects there will be efforts to include language that favors expansion of services and funding for health care. This includes those related to the Affordable Care Act (ACA) and the temporary modifications permitted under the CARES Act, which was passed during the early months of the COVID-19 pandemic.
For those who think that waivers and exceptions introduced in the CARES Act, such as the expansion of telehealth, should be made permanent, “this will be your main shot on goal,” Mr. Studdard said.
The debates around the ambitious infrastructure bill are “all that we will be hearing about from the legislative standpoint for the next few months,” Mr. Studdard said. He expects major lobbying efforts in regard to this legislation from a vast array of interest groups, not just those with a stake in health care.
If the bill passes, it will likely to be greatly helped by a vote under the reconciliation process. Created in 1974 to allow expedited consideration of spending legislation, the reconciliation process allows bills to be enacted with a simple majority, which is 51 votes in the Senate and 218 votes in the House. Filibustering is not permitted.
This means that the infrastructure bill, like the CARES Act, which was also passed through the reconciliation process, can be made into law even if all 50 Republican senators vote against it. As she has already done three times since taking office—most recently for COVID19 relief bill in early March—Vice President Kamala Harris can break a 50-50 tie with her vote for the administration’s agenda.
Legislation is one of two paths for altering funding and rules regarding health care in the United States. Policy is the other. For reaching decision makers with influence on policy, Mr. Studdard provided a long list of agencies, political appointees, and elected representatives that could be targeted. Many, such as the director of the Centers for Medicare & Medicaid Services (CMS), are well known, but others might be overlooked without a detailed list of the players.
As one example, he pointed to the Center for Medicare and Medicaid Innovation (CMMI), which is a relatively new organization within CMS. Led by Liz Fowler, a former Senate aide involved in writing the ACA, the CMMI has broad authority over several aspects of health policy, such as value-based care.
“The CCMI is something you should put on your radar. It moves with more flexibility than the HHS [Department of Health and Human Services],” Mr. Studdard said.
Mr. Studdard’s detailed overview of the intricacies of how to affect change in health policy and the likely trajectory under the Biden Administration included frequent comments about the traits, background, and goals of the specific decision makers he identified. The implication is that personal relations matter. Mr. Studdard indicated that knowing who to contact is just the first step.
For the Health Policy and Advocacy Committee, this information is critical. In his outline of the numerous paths for influencing health care policy, Mr. Studdard’s comments lead directly to strategies to lobbying goals for CHEST.
“CHEST and its Health Policy and Advocacy Committee are keeping a focus on health care policy to improve access and to improve care for our patients and reduce the burden on our providers,” according to the Chair of the Committee, Neil Freedman, MD, FCCP. Dr, Freedman is the Division Head Pulmonary, Critical Care, Allergy, and Immunology, Northshore University HeatlhSystem, Evanston, Illinois.
“We would hope that, in addition to the proposed infrastructure bill subsidizing some additional costs for the ACA and COBRA [Consolidated Omnibus Budget Reconciliation Act] and enhancing Medicaid eligibility, the bill would also provide some additional funding for the provider relief fund,” he said.
Mr. Studdard or his lobbying firm represent 62 clients with interests in health care policy.
The ambitious infrastructure bill now being debated in the US Congress might be one of the best immediate opportunities to lobby for legislative or policy changes in delivery of health care during the current Biden administration, according to an analysis delivered at the annual health policy and advocacy conference sponsored by the American College of Chest Physicians.
The infrastructure bill is likely to be pushed forward in the filibuster-proof reconciliation process, which means “that some things might get passed that otherwise would not,” explained Keith S. Studdard, Vice President, Jeffrey J. Kimbell & Associates, Washington, DC.
With few exceptions, the key players in the health care team of President Joe Biden’s new administration are in place, according to Mr. Studdard, who is a lobbyist and health care expert. By moving quickly to fill key positions, the new administration “got off to a good start” for a health care agenda that Mr. Studdard believes will be a focus of the Biden presidency. There is some degree of urgency.
“The amount of time [the Biden administration has] to get their agenda through is fairly limited,” Mr. Studdard reported. The problems include a slim majority of fellow Democrats in the House of Representatives (222 vs 213), no majority of Democrats over Republicans in the Senate (50 vs 50), and mid-term elections that are already looming.
“Midterms historically favor the opposition party,” Mr. Studdard said. He expects party lines to harden as the midterms approach, dissipating the already limited appetite for bipartisan cooperation.
The midterms provide the basis for trying to affect change in advance of legislative gridlock, but the recently announced $2 trillion infrastructure bill is an even more compelling impetus. Infrastructure in this case is not limited to the construction of bridges and roads. Rather, this bill “is a massive package that will almost certainly touch on health care policy,” according to Mr. Studdard.
As the infrastructure bill winds its way through the legislative process, Mr. Studdard expects there will be efforts to include language that favors expansion of services and funding for health care. This includes those related to the Affordable Care Act (ACA) and the temporary modifications permitted under the CARES Act, which was passed during the early months of the COVID-19 pandemic.
For those who think that waivers and exceptions introduced in the CARES Act, such as the expansion of telehealth, should be made permanent, “this will be your main shot on goal,” Mr. Studdard said.
The debates around the ambitious infrastructure bill are “all that we will be hearing about from the legislative standpoint for the next few months,” Mr. Studdard said. He expects major lobbying efforts in regard to this legislation from a vast array of interest groups, not just those with a stake in health care.
If the bill passes, it will likely to be greatly helped by a vote under the reconciliation process. Created in 1974 to allow expedited consideration of spending legislation, the reconciliation process allows bills to be enacted with a simple majority, which is 51 votes in the Senate and 218 votes in the House. Filibustering is not permitted.
This means that the infrastructure bill, like the CARES Act, which was also passed through the reconciliation process, can be made into law even if all 50 Republican senators vote against it. As she has already done three times since taking office—most recently for COVID19 relief bill in early March—Vice President Kamala Harris can break a 50-50 tie with her vote for the administration’s agenda.
Legislation is one of two paths for altering funding and rules regarding health care in the United States. Policy is the other. For reaching decision makers with influence on policy, Mr. Studdard provided a long list of agencies, political appointees, and elected representatives that could be targeted. Many, such as the director of the Centers for Medicare & Medicaid Services (CMS), are well known, but others might be overlooked without a detailed list of the players.
As one example, he pointed to the Center for Medicare and Medicaid Innovation (CMMI), which is a relatively new organization within CMS. Led by Liz Fowler, a former Senate aide involved in writing the ACA, the CMMI has broad authority over several aspects of health policy, such as value-based care.
“The CCMI is something you should put on your radar. It moves with more flexibility than the HHS [Department of Health and Human Services],” Mr. Studdard said.
Mr. Studdard’s detailed overview of the intricacies of how to affect change in health policy and the likely trajectory under the Biden Administration included frequent comments about the traits, background, and goals of the specific decision makers he identified. The implication is that personal relations matter. Mr. Studdard indicated that knowing who to contact is just the first step.
For the Health Policy and Advocacy Committee, this information is critical. In his outline of the numerous paths for influencing health care policy, Mr. Studdard’s comments lead directly to strategies to lobbying goals for CHEST.
“CHEST and its Health Policy and Advocacy Committee are keeping a focus on health care policy to improve access and to improve care for our patients and reduce the burden on our providers,” according to the Chair of the Committee, Neil Freedman, MD, FCCP. Dr, Freedman is the Division Head Pulmonary, Critical Care, Allergy, and Immunology, Northshore University HeatlhSystem, Evanston, Illinois.
“We would hope that, in addition to the proposed infrastructure bill subsidizing some additional costs for the ACA and COBRA [Consolidated Omnibus Budget Reconciliation Act] and enhancing Medicaid eligibility, the bill would also provide some additional funding for the provider relief fund,” he said.
Mr. Studdard or his lobbying firm represent 62 clients with interests in health care policy.
The ambitious infrastructure bill now being debated in the US Congress might be one of the best immediate opportunities to lobby for legislative or policy changes in delivery of health care during the current Biden administration, according to an analysis delivered at the annual health policy and advocacy conference sponsored by the American College of Chest Physicians.
The infrastructure bill is likely to be pushed forward in the filibuster-proof reconciliation process, which means “that some things might get passed that otherwise would not,” explained Keith S. Studdard, Vice President, Jeffrey J. Kimbell & Associates, Washington, DC.
With few exceptions, the key players in the health care team of President Joe Biden’s new administration are in place, according to Mr. Studdard, who is a lobbyist and health care expert. By moving quickly to fill key positions, the new administration “got off to a good start” for a health care agenda that Mr. Studdard believes will be a focus of the Biden presidency. There is some degree of urgency.
“The amount of time [the Biden administration has] to get their agenda through is fairly limited,” Mr. Studdard reported. The problems include a slim majority of fellow Democrats in the House of Representatives (222 vs 213), no majority of Democrats over Republicans in the Senate (50 vs 50), and mid-term elections that are already looming.
“Midterms historically favor the opposition party,” Mr. Studdard said. He expects party lines to harden as the midterms approach, dissipating the already limited appetite for bipartisan cooperation.
The midterms provide the basis for trying to affect change in advance of legislative gridlock, but the recently announced $2 trillion infrastructure bill is an even more compelling impetus. Infrastructure in this case is not limited to the construction of bridges and roads. Rather, this bill “is a massive package that will almost certainly touch on health care policy,” according to Mr. Studdard.
As the infrastructure bill winds its way through the legislative process, Mr. Studdard expects there will be efforts to include language that favors expansion of services and funding for health care. This includes those related to the Affordable Care Act (ACA) and the temporary modifications permitted under the CARES Act, which was passed during the early months of the COVID-19 pandemic.
For those who think that waivers and exceptions introduced in the CARES Act, such as the expansion of telehealth, should be made permanent, “this will be your main shot on goal,” Mr. Studdard said.
The debates around the ambitious infrastructure bill are “all that we will be hearing about from the legislative standpoint for the next few months,” Mr. Studdard said. He expects major lobbying efforts in regard to this legislation from a vast array of interest groups, not just those with a stake in health care.
If the bill passes, it will likely to be greatly helped by a vote under the reconciliation process. Created in 1974 to allow expedited consideration of spending legislation, the reconciliation process allows bills to be enacted with a simple majority, which is 51 votes in the Senate and 218 votes in the House. Filibustering is not permitted.
This means that the infrastructure bill, like the CARES Act, which was also passed through the reconciliation process, can be made into law even if all 50 Republican senators vote against it. As she has already done three times since taking office—most recently for COVID19 relief bill in early March—Vice President Kamala Harris can break a 50-50 tie with her vote for the administration’s agenda.
Legislation is one of two paths for altering funding and rules regarding health care in the United States. Policy is the other. For reaching decision makers with influence on policy, Mr. Studdard provided a long list of agencies, political appointees, and elected representatives that could be targeted. Many, such as the director of the Centers for Medicare & Medicaid Services (CMS), are well known, but others might be overlooked without a detailed list of the players.
As one example, he pointed to the Center for Medicare and Medicaid Innovation (CMMI), which is a relatively new organization within CMS. Led by Liz Fowler, a former Senate aide involved in writing the ACA, the CMMI has broad authority over several aspects of health policy, such as value-based care.
“The CCMI is something you should put on your radar. It moves with more flexibility than the HHS [Department of Health and Human Services],” Mr. Studdard said.
Mr. Studdard’s detailed overview of the intricacies of how to affect change in health policy and the likely trajectory under the Biden Administration included frequent comments about the traits, background, and goals of the specific decision makers he identified. The implication is that personal relations matter. Mr. Studdard indicated that knowing who to contact is just the first step.
For the Health Policy and Advocacy Committee, this information is critical. In his outline of the numerous paths for influencing health care policy, Mr. Studdard’s comments lead directly to strategies to lobbying goals for CHEST.
“CHEST and its Health Policy and Advocacy Committee are keeping a focus on health care policy to improve access and to improve care for our patients and reduce the burden on our providers,” according to the Chair of the Committee, Neil Freedman, MD, FCCP. Dr, Freedman is the Division Head Pulmonary, Critical Care, Allergy, and Immunology, Northshore University HeatlhSystem, Evanston, Illinois.
“We would hope that, in addition to the proposed infrastructure bill subsidizing some additional costs for the ACA and COBRA [Consolidated Omnibus Budget Reconciliation Act] and enhancing Medicaid eligibility, the bill would also provide some additional funding for the provider relief fund,” he said.
Mr. Studdard or his lobbying firm represent 62 clients with interests in health care policy.
REPORTING FROM THE CHEST HEALTH POLICY AND ADVOCACY CONFERENCE
Novel study links air pollution to increased risk of rheumatoid arthritis flares
Pollution appears to trigger inflammation
In patients with rheumatoid arthritis, exposure to air pollution is associated with both elevated levels of C-reactive protein (CRP) and increased risk of arthritis flares, according to a novel longitudinal study presented at the annual European Congress of Rheumatology.
The data revealed “a striking association between air pollution and increased CRP levels and risk of an arthritis flare,” reported first author Giovanni Adami, MD, DSc, of the rheumatology unit at the University of Verona (Italy).
The excess risk of elevated CRP and flares began “at very low levels of exposure, even those below commonly used thresholds for risk to human health,” he added.
Study details
Researchers collected data on 888 patients with RA from numerous patient visits in the context of more than 13,000 air pollution records. The CRP levels and RA flares were evaluated in the context of air pollution monitoring that is performed on a daily basis at several sites in the city of Verona where the study was conducted. Verona is an industrial city in northern Italy that has high but variable levels of air pollution based on factory activity and weather conditions.
Patients with RA who provided clinical data for this study were matched by their proximity to specific air pollution monitoring sites. By linking CRP levels and disease activity to air pollution levels over multiple follow-up visits, the design allowed the RA study participants “to serve as their own controls,” Dr. Adami explained.
At each patient visit during the study, CRP levels were measured and disease activity assessed. Patients were considered to have elevated CRP when levels were 5 mg/L or higher. The presence of an RA flare was defined by a 1.2-point increase or more in 28-joint Disease Activity Score using CRP (DAS28-CRP).
Both the CRP level and the presence or absence of a flare were evaluated in relationship to the patient’s specific local air pollution levels in the prior 60 days.
Increased levels of CRP, a surrogate for inflammatory activity, and increased disease activity, were both associated with elevated exposure to air pollutants prior to an office visit. These associations remained statistically significant when evaluated by specific air pollutants such as carbon monoxide (CO), nitrogen oxides (NO2, NO), small particulate matter (PM10; particles ≤ 10 mcm), and ozone (O3).
The relationship between increased exposure to air pollution contaminants and elevated CRP was supported by a dose effect. In the case of PM10, for example, the odds ratio of having elevated CRP was increased by only about 25% (OR, 1.25) when mean levels were 30 mcg/m3 or lower in the period prior to the office visit. This rose incrementally for higher mean levels of PM10, reaching 70% (OR, 1.70) for levels > 50 mcg/m3.
The researchers detected statistically significant differences in mean and area-under-the curve (AUC) values of most air pollutants in the 60 days prior to office visits when patients had a flare versus when disease activity was low. For example, the difference in mean and AUC levels in the period prior to a flare relative to a period with low disease activity was significant for CO (P = .001 for both) and NO and NO2 (P = .003 for both), and O3 (P = .002 and P = .001, respectively). For PM10, P values were .011 and .005, respectively.
“Remarkably, we found that the cumulative exposure to NO2 in the 60 days preceding a flare was approximately 500 mcg/m3 higher than the low disease activity visit, an exposure that equates to approximately 200 passively smoked cigarettes,” Dr. Adami reported.
Trying to confirm causality of association
Dr. Adami’s study is not the first study to link air pollution to risk of RA. Several have suggested that air pollution is a risk factor for developing joint disease, but a recently published study conducted in Kuwait associated greater disease activity with NO2 and another air pollutant, sulfur dioxide (SO2), although not CO, PM10, or O3.
A coauthor of that study, which evaluated pollution in regard to disease activity on DAS score, Adeeba Al-Herz, MD, a rheumatology consultant at Al-Amiri Hospital, Kuwait City, said in an interview, “We proved the correlation between them but not the causality.”
However, she believes that this is an important area of inquiry.
“We are working now on another paper in which we studied a causal relationship between the two, meaning that we are evaluating whether SO2 and NO2 trigger RA activity,” Dr. Al-Herz said. That study is now complete, and the manuscript is being written.
The magnitude of the association in these two studies suggest that there might be a clinical message if causality can be confirmed, according to Dr. Adami. Although there are many reasons to seek to reduce and avoid air pollution, these data suggest risk of a proinflammatory state might be one of them.
Dr. Adami believes that the evidence of an adverse effect on patients with RA is strong.
“In order to reduce the burden of RA, public and environmental health policy makers should aim to diminish gaseous and particulate matter emissions to a larger extent than currently recommended,” he said.
In an interview after his presentation, Dr. Adami suggested that the risk of an inflammatory response and increases in arthritis flares from air pollution is not surprising. Previous studies have linked cigarette smoking to both.
“The mechanisms underlying the development of inflammation are very similar. Indeed, the toxic components contained in cigarette smoking are largely shared with diesel exhaust and fossil fuel combustion,” he said.
Although causality between air pollution and arthritis flares cannot be confirmed in these data, a basis for suspecting a causal relationship is supported by “plenty of in vitro and animal studies,” according to Dr. Adami.
On the basis of these studies, several mechanisms have been postulated.
“As an example, exposure to air pollution can promote the activation of the bronchus-associated lymphoid tissue (BALT), which can trigger the activation of the transcription factor nuclear factor-kappaB,” he said. This, in turn, can “lead to the secretion of proinflammatory cytokines, such as tumor necrosis factor–alpha and interleukin-1.”
Another theory is that posttranslational modification of proteins in the lung, a process called citrullination, “can lead to production of autoantibodies known to have a pathogenic role in RA,” he added.
Proving a causal relationship, however, is difficult.
“We certainly cannot conduct a randomized clinical trial on that and voluntarily expose some patients to pollution. Thus, we need to rely on observational data,” Dr. Adami said.
Of strategies being considered to generate evidence of a causal relationship between pollution and the exacerbation of RA, “we certainly will try to study those patients that move from a highly polluted area to a greener zone and vice versa,” he said. This will allow us “to explore what happens when the exposure to pollution changes dramatically in a short period of time.”
In the meantime, “given what is known to date, I would certainly advise my RA patients to avoid exposure to air pollution,” Dr. Adami said. He acknowledged there is no proof that this will help patients to reduce the risk of flares, but there are already many good reasons to minimize exposure to air pollution.
Dr. Adami and Dr. Al-Herz report no potential conflicts of interest.
Pollution appears to trigger inflammation
Pollution appears to trigger inflammation
In patients with rheumatoid arthritis, exposure to air pollution is associated with both elevated levels of C-reactive protein (CRP) and increased risk of arthritis flares, according to a novel longitudinal study presented at the annual European Congress of Rheumatology.
The data revealed “a striking association between air pollution and increased CRP levels and risk of an arthritis flare,” reported first author Giovanni Adami, MD, DSc, of the rheumatology unit at the University of Verona (Italy).
The excess risk of elevated CRP and flares began “at very low levels of exposure, even those below commonly used thresholds for risk to human health,” he added.
Study details
Researchers collected data on 888 patients with RA from numerous patient visits in the context of more than 13,000 air pollution records. The CRP levels and RA flares were evaluated in the context of air pollution monitoring that is performed on a daily basis at several sites in the city of Verona where the study was conducted. Verona is an industrial city in northern Italy that has high but variable levels of air pollution based on factory activity and weather conditions.
Patients with RA who provided clinical data for this study were matched by their proximity to specific air pollution monitoring sites. By linking CRP levels and disease activity to air pollution levels over multiple follow-up visits, the design allowed the RA study participants “to serve as their own controls,” Dr. Adami explained.
At each patient visit during the study, CRP levels were measured and disease activity assessed. Patients were considered to have elevated CRP when levels were 5 mg/L or higher. The presence of an RA flare was defined by a 1.2-point increase or more in 28-joint Disease Activity Score using CRP (DAS28-CRP).
Both the CRP level and the presence or absence of a flare were evaluated in relationship to the patient’s specific local air pollution levels in the prior 60 days.
Increased levels of CRP, a surrogate for inflammatory activity, and increased disease activity, were both associated with elevated exposure to air pollutants prior to an office visit. These associations remained statistically significant when evaluated by specific air pollutants such as carbon monoxide (CO), nitrogen oxides (NO2, NO), small particulate matter (PM10; particles ≤ 10 mcm), and ozone (O3).
The relationship between increased exposure to air pollution contaminants and elevated CRP was supported by a dose effect. In the case of PM10, for example, the odds ratio of having elevated CRP was increased by only about 25% (OR, 1.25) when mean levels were 30 mcg/m3 or lower in the period prior to the office visit. This rose incrementally for higher mean levels of PM10, reaching 70% (OR, 1.70) for levels > 50 mcg/m3.
The researchers detected statistically significant differences in mean and area-under-the curve (AUC) values of most air pollutants in the 60 days prior to office visits when patients had a flare versus when disease activity was low. For example, the difference in mean and AUC levels in the period prior to a flare relative to a period with low disease activity was significant for CO (P = .001 for both) and NO and NO2 (P = .003 for both), and O3 (P = .002 and P = .001, respectively). For PM10, P values were .011 and .005, respectively.
“Remarkably, we found that the cumulative exposure to NO2 in the 60 days preceding a flare was approximately 500 mcg/m3 higher than the low disease activity visit, an exposure that equates to approximately 200 passively smoked cigarettes,” Dr. Adami reported.
Trying to confirm causality of association
Dr. Adami’s study is not the first study to link air pollution to risk of RA. Several have suggested that air pollution is a risk factor for developing joint disease, but a recently published study conducted in Kuwait associated greater disease activity with NO2 and another air pollutant, sulfur dioxide (SO2), although not CO, PM10, or O3.
A coauthor of that study, which evaluated pollution in regard to disease activity on DAS score, Adeeba Al-Herz, MD, a rheumatology consultant at Al-Amiri Hospital, Kuwait City, said in an interview, “We proved the correlation between them but not the causality.”
However, she believes that this is an important area of inquiry.
“We are working now on another paper in which we studied a causal relationship between the two, meaning that we are evaluating whether SO2 and NO2 trigger RA activity,” Dr. Al-Herz said. That study is now complete, and the manuscript is being written.
The magnitude of the association in these two studies suggest that there might be a clinical message if causality can be confirmed, according to Dr. Adami. Although there are many reasons to seek to reduce and avoid air pollution, these data suggest risk of a proinflammatory state might be one of them.
Dr. Adami believes that the evidence of an adverse effect on patients with RA is strong.
“In order to reduce the burden of RA, public and environmental health policy makers should aim to diminish gaseous and particulate matter emissions to a larger extent than currently recommended,” he said.
In an interview after his presentation, Dr. Adami suggested that the risk of an inflammatory response and increases in arthritis flares from air pollution is not surprising. Previous studies have linked cigarette smoking to both.
“The mechanisms underlying the development of inflammation are very similar. Indeed, the toxic components contained in cigarette smoking are largely shared with diesel exhaust and fossil fuel combustion,” he said.
Although causality between air pollution and arthritis flares cannot be confirmed in these data, a basis for suspecting a causal relationship is supported by “plenty of in vitro and animal studies,” according to Dr. Adami.
On the basis of these studies, several mechanisms have been postulated.
“As an example, exposure to air pollution can promote the activation of the bronchus-associated lymphoid tissue (BALT), which can trigger the activation of the transcription factor nuclear factor-kappaB,” he said. This, in turn, can “lead to the secretion of proinflammatory cytokines, such as tumor necrosis factor–alpha and interleukin-1.”
Another theory is that posttranslational modification of proteins in the lung, a process called citrullination, “can lead to production of autoantibodies known to have a pathogenic role in RA,” he added.
Proving a causal relationship, however, is difficult.
“We certainly cannot conduct a randomized clinical trial on that and voluntarily expose some patients to pollution. Thus, we need to rely on observational data,” Dr. Adami said.
Of strategies being considered to generate evidence of a causal relationship between pollution and the exacerbation of RA, “we certainly will try to study those patients that move from a highly polluted area to a greener zone and vice versa,” he said. This will allow us “to explore what happens when the exposure to pollution changes dramatically in a short period of time.”
In the meantime, “given what is known to date, I would certainly advise my RA patients to avoid exposure to air pollution,” Dr. Adami said. He acknowledged there is no proof that this will help patients to reduce the risk of flares, but there are already many good reasons to minimize exposure to air pollution.
Dr. Adami and Dr. Al-Herz report no potential conflicts of interest.
In patients with rheumatoid arthritis, exposure to air pollution is associated with both elevated levels of C-reactive protein (CRP) and increased risk of arthritis flares, according to a novel longitudinal study presented at the annual European Congress of Rheumatology.
The data revealed “a striking association between air pollution and increased CRP levels and risk of an arthritis flare,” reported first author Giovanni Adami, MD, DSc, of the rheumatology unit at the University of Verona (Italy).
The excess risk of elevated CRP and flares began “at very low levels of exposure, even those below commonly used thresholds for risk to human health,” he added.
Study details
Researchers collected data on 888 patients with RA from numerous patient visits in the context of more than 13,000 air pollution records. The CRP levels and RA flares were evaluated in the context of air pollution monitoring that is performed on a daily basis at several sites in the city of Verona where the study was conducted. Verona is an industrial city in northern Italy that has high but variable levels of air pollution based on factory activity and weather conditions.
Patients with RA who provided clinical data for this study were matched by their proximity to specific air pollution monitoring sites. By linking CRP levels and disease activity to air pollution levels over multiple follow-up visits, the design allowed the RA study participants “to serve as their own controls,” Dr. Adami explained.
At each patient visit during the study, CRP levels were measured and disease activity assessed. Patients were considered to have elevated CRP when levels were 5 mg/L or higher. The presence of an RA flare was defined by a 1.2-point increase or more in 28-joint Disease Activity Score using CRP (DAS28-CRP).
Both the CRP level and the presence or absence of a flare were evaluated in relationship to the patient’s specific local air pollution levels in the prior 60 days.
Increased levels of CRP, a surrogate for inflammatory activity, and increased disease activity, were both associated with elevated exposure to air pollutants prior to an office visit. These associations remained statistically significant when evaluated by specific air pollutants such as carbon monoxide (CO), nitrogen oxides (NO2, NO), small particulate matter (PM10; particles ≤ 10 mcm), and ozone (O3).
The relationship between increased exposure to air pollution contaminants and elevated CRP was supported by a dose effect. In the case of PM10, for example, the odds ratio of having elevated CRP was increased by only about 25% (OR, 1.25) when mean levels were 30 mcg/m3 or lower in the period prior to the office visit. This rose incrementally for higher mean levels of PM10, reaching 70% (OR, 1.70) for levels > 50 mcg/m3.
The researchers detected statistically significant differences in mean and area-under-the curve (AUC) values of most air pollutants in the 60 days prior to office visits when patients had a flare versus when disease activity was low. For example, the difference in mean and AUC levels in the period prior to a flare relative to a period with low disease activity was significant for CO (P = .001 for both) and NO and NO2 (P = .003 for both), and O3 (P = .002 and P = .001, respectively). For PM10, P values were .011 and .005, respectively.
“Remarkably, we found that the cumulative exposure to NO2 in the 60 days preceding a flare was approximately 500 mcg/m3 higher than the low disease activity visit, an exposure that equates to approximately 200 passively smoked cigarettes,” Dr. Adami reported.
Trying to confirm causality of association
Dr. Adami’s study is not the first study to link air pollution to risk of RA. Several have suggested that air pollution is a risk factor for developing joint disease, but a recently published study conducted in Kuwait associated greater disease activity with NO2 and another air pollutant, sulfur dioxide (SO2), although not CO, PM10, or O3.
A coauthor of that study, which evaluated pollution in regard to disease activity on DAS score, Adeeba Al-Herz, MD, a rheumatology consultant at Al-Amiri Hospital, Kuwait City, said in an interview, “We proved the correlation between them but not the causality.”
However, she believes that this is an important area of inquiry.
“We are working now on another paper in which we studied a causal relationship between the two, meaning that we are evaluating whether SO2 and NO2 trigger RA activity,” Dr. Al-Herz said. That study is now complete, and the manuscript is being written.
The magnitude of the association in these two studies suggest that there might be a clinical message if causality can be confirmed, according to Dr. Adami. Although there are many reasons to seek to reduce and avoid air pollution, these data suggest risk of a proinflammatory state might be one of them.
Dr. Adami believes that the evidence of an adverse effect on patients with RA is strong.
“In order to reduce the burden of RA, public and environmental health policy makers should aim to diminish gaseous and particulate matter emissions to a larger extent than currently recommended,” he said.
In an interview after his presentation, Dr. Adami suggested that the risk of an inflammatory response and increases in arthritis flares from air pollution is not surprising. Previous studies have linked cigarette smoking to both.
“The mechanisms underlying the development of inflammation are very similar. Indeed, the toxic components contained in cigarette smoking are largely shared with diesel exhaust and fossil fuel combustion,” he said.
Although causality between air pollution and arthritis flares cannot be confirmed in these data, a basis for suspecting a causal relationship is supported by “plenty of in vitro and animal studies,” according to Dr. Adami.
On the basis of these studies, several mechanisms have been postulated.
“As an example, exposure to air pollution can promote the activation of the bronchus-associated lymphoid tissue (BALT), which can trigger the activation of the transcription factor nuclear factor-kappaB,” he said. This, in turn, can “lead to the secretion of proinflammatory cytokines, such as tumor necrosis factor–alpha and interleukin-1.”
Another theory is that posttranslational modification of proteins in the lung, a process called citrullination, “can lead to production of autoantibodies known to have a pathogenic role in RA,” he added.
Proving a causal relationship, however, is difficult.
“We certainly cannot conduct a randomized clinical trial on that and voluntarily expose some patients to pollution. Thus, we need to rely on observational data,” Dr. Adami said.
Of strategies being considered to generate evidence of a causal relationship between pollution and the exacerbation of RA, “we certainly will try to study those patients that move from a highly polluted area to a greener zone and vice versa,” he said. This will allow us “to explore what happens when the exposure to pollution changes dramatically in a short period of time.”
In the meantime, “given what is known to date, I would certainly advise my RA patients to avoid exposure to air pollution,” Dr. Adami said. He acknowledged there is no proof that this will help patients to reduce the risk of flares, but there are already many good reasons to minimize exposure to air pollution.
Dr. Adami and Dr. Al-Herz report no potential conflicts of interest.
FROM THE EULAR 2021 CONGRESS
Gene variant confirmed as strong predictor of lung disease in RA
Carriers have more than twofold greater risk
Patients with rheumatoid arthritis who carry a specific allele of the gene MUC5B have about double the risk of developing interstitial lung disease when compared with noncarriers, according to a large Finnish biobank study presented at the annual European Congress of Rheumatology.
“The risk difference [or carriers relative to noncarriers] started at about age 65, with a bigger difference [for] men than women,” reported Antti Palomäki, MD, PhD, of the center for rheumatology and clinical immunology at Turku (Finland) University.
The gain-of-function MUC5B variant, which encodes mucin 5B, was first linked to RA-associated interstitial lung disease (ILD) more than 3 years ago. At that time, it was already a known genetic risk factor for idiopathic pulmonary fibrosis in the general population. The new data confirm the association in a longitudinal analysis of a large biobank and suggest the association might have clinical utility.
“This is not ready for clinical practice at the moment. We do not yet know whether we can change therapy to reduce risk,” Dr. Palomäki said, adding “in the future we can look.”
One question that might be asked in clinical studies using MUC5B as a tool to assess and modify risk of ILD in patients with RA is whether one therapy is better than another in avoiding or delaying development of lung fibrosis. Dr. Palomäki noted that biologics, for example, might be a more favorable choice in patients with RA who are at high risk of developing ILD.
The association of the MUC5B variant with increased ILD incidence in patients with RA was drawn from a data set known as FinnGen, a biobank collection of epidemiologic cohorts and hospital samples with genotypes of about 10% of the Finnish population. Follow-up extends to 46 years in some of these individuals.
When 248,4000 individuals in this data set were evaluated, 5,534 had a diagnosis of RA. Of these, 178 (3.2%) developed ILD. About 20% of both those with and without RA were MUC5B variant carriers, meaning the remainder were not.
Sex and age factor into lifetime risk
In patients with RA, the lifetime rate of ILD among MUC5B variant carriers was 16.8% versus only 6.1% among noncarriers. This finding translated into a hazard ratio for ILD of 2.27 (95% confidence interval, 1.75–2.96) for variant carriers versus noncarriers.
The lifetime rate of ILD in patients with RA was greater in men versus women regardless of carrier status (18.5% vs. 8.5%). For women, the lifetime rate was lower for carriers, although the difference relative to female noncarriers was greater (14.5% vs. 4.7%).
ILD, whether in the general population or in patients with RA, is a disease of advancing age. When Dr. Palomäki showed a graph, the rise in ILD incidence did not start in any population, whether those with or without RA and regardless of carrier status, until about age 55. In those without RA and in noncarriers of the variant, ILD incidence remained low and began a discernible climb at around age 70.
In those who did not have RA but were positive for the variant, the rates rose more than twice as fast, particularly after age 70. In people who had RA but not the variant, the rate of ILD was greater than in patients who carried the variant without RA, starting the climb earlier and rising more steeply with age. In those with RA and the variant, the climb in ILD incidence rose rapidly after age 65 years even though the incidence remained fairly similar between all of these groups at age 60.
Putting the findings into context
The need to develop ways to prevent ILD in RA is urgent. ILD is one of the most common extraarticular manifestations of RA, developing in up to 60% of patients with RA in older age groups when evaluated with imaging, according to Dr. Palomäki. Although it develops into a clinically significant complication in only about 10% of these patients, ILD still is a significant cause of illness and death in elderly patients with RA.
In the 2018 study that first linked the MUC5B variant to RA-ILD, the investigators also found that the variant was associated with an increased likelihood of developing the usual interstitial pneumonia type of ILD on imaging. David Schwartz, MD, professor of medicine, pulmonary sciences, and critical care and chair of the department of medicine at the University of Colorado at Denver, Aurora, was a senior author of that study. He said these findings build on the 2018 study.
“While the gain-of-function MUC5B promoter variant is important in predicting who will develop RA-ILD, these findings also suggest that MUC5B may be involved in the etiology of RA-ILD, at least for those with the MUC5B variant,” he said.
“The study also raises the possibility that there are several subtypes of RA-ILD, and the subtype that is driven by MUC5B may respond differently to RA biologics or therapeutic agents to treat ILD,” he added.
In the discussion following the presentation by Dr. Palomäki, others agreed, with that statement including Dr. Palomäki. He expressed interest in clinical studies comparing different classes of RA therapies for their relative impact on the risk of developing ILD.Dr. Palomäki reported financial relationships with AbbVie, Merck, Pfizer, and Sanofi. Dr. Schwartz is the founder of Eleven P15, which is developing methods for early diagnosis and treatment of pulmonary fibrosis.
Carriers have more than twofold greater risk
Carriers have more than twofold greater risk
Patients with rheumatoid arthritis who carry a specific allele of the gene MUC5B have about double the risk of developing interstitial lung disease when compared with noncarriers, according to a large Finnish biobank study presented at the annual European Congress of Rheumatology.
“The risk difference [or carriers relative to noncarriers] started at about age 65, with a bigger difference [for] men than women,” reported Antti Palomäki, MD, PhD, of the center for rheumatology and clinical immunology at Turku (Finland) University.
The gain-of-function MUC5B variant, which encodes mucin 5B, was first linked to RA-associated interstitial lung disease (ILD) more than 3 years ago. At that time, it was already a known genetic risk factor for idiopathic pulmonary fibrosis in the general population. The new data confirm the association in a longitudinal analysis of a large biobank and suggest the association might have clinical utility.
“This is not ready for clinical practice at the moment. We do not yet know whether we can change therapy to reduce risk,” Dr. Palomäki said, adding “in the future we can look.”
One question that might be asked in clinical studies using MUC5B as a tool to assess and modify risk of ILD in patients with RA is whether one therapy is better than another in avoiding or delaying development of lung fibrosis. Dr. Palomäki noted that biologics, for example, might be a more favorable choice in patients with RA who are at high risk of developing ILD.
The association of the MUC5B variant with increased ILD incidence in patients with RA was drawn from a data set known as FinnGen, a biobank collection of epidemiologic cohorts and hospital samples with genotypes of about 10% of the Finnish population. Follow-up extends to 46 years in some of these individuals.
When 248,4000 individuals in this data set were evaluated, 5,534 had a diagnosis of RA. Of these, 178 (3.2%) developed ILD. About 20% of both those with and without RA were MUC5B variant carriers, meaning the remainder were not.
Sex and age factor into lifetime risk
In patients with RA, the lifetime rate of ILD among MUC5B variant carriers was 16.8% versus only 6.1% among noncarriers. This finding translated into a hazard ratio for ILD of 2.27 (95% confidence interval, 1.75–2.96) for variant carriers versus noncarriers.
The lifetime rate of ILD in patients with RA was greater in men versus women regardless of carrier status (18.5% vs. 8.5%). For women, the lifetime rate was lower for carriers, although the difference relative to female noncarriers was greater (14.5% vs. 4.7%).
ILD, whether in the general population or in patients with RA, is a disease of advancing age. When Dr. Palomäki showed a graph, the rise in ILD incidence did not start in any population, whether those with or without RA and regardless of carrier status, until about age 55. In those without RA and in noncarriers of the variant, ILD incidence remained low and began a discernible climb at around age 70.
In those who did not have RA but were positive for the variant, the rates rose more than twice as fast, particularly after age 70. In people who had RA but not the variant, the rate of ILD was greater than in patients who carried the variant without RA, starting the climb earlier and rising more steeply with age. In those with RA and the variant, the climb in ILD incidence rose rapidly after age 65 years even though the incidence remained fairly similar between all of these groups at age 60.
Putting the findings into context
The need to develop ways to prevent ILD in RA is urgent. ILD is one of the most common extraarticular manifestations of RA, developing in up to 60% of patients with RA in older age groups when evaluated with imaging, according to Dr. Palomäki. Although it develops into a clinically significant complication in only about 10% of these patients, ILD still is a significant cause of illness and death in elderly patients with RA.
In the 2018 study that first linked the MUC5B variant to RA-ILD, the investigators also found that the variant was associated with an increased likelihood of developing the usual interstitial pneumonia type of ILD on imaging. David Schwartz, MD, professor of medicine, pulmonary sciences, and critical care and chair of the department of medicine at the University of Colorado at Denver, Aurora, was a senior author of that study. He said these findings build on the 2018 study.
“While the gain-of-function MUC5B promoter variant is important in predicting who will develop RA-ILD, these findings also suggest that MUC5B may be involved in the etiology of RA-ILD, at least for those with the MUC5B variant,” he said.
“The study also raises the possibility that there are several subtypes of RA-ILD, and the subtype that is driven by MUC5B may respond differently to RA biologics or therapeutic agents to treat ILD,” he added.
In the discussion following the presentation by Dr. Palomäki, others agreed, with that statement including Dr. Palomäki. He expressed interest in clinical studies comparing different classes of RA therapies for their relative impact on the risk of developing ILD.Dr. Palomäki reported financial relationships with AbbVie, Merck, Pfizer, and Sanofi. Dr. Schwartz is the founder of Eleven P15, which is developing methods for early diagnosis and treatment of pulmonary fibrosis.
Patients with rheumatoid arthritis who carry a specific allele of the gene MUC5B have about double the risk of developing interstitial lung disease when compared with noncarriers, according to a large Finnish biobank study presented at the annual European Congress of Rheumatology.
“The risk difference [or carriers relative to noncarriers] started at about age 65, with a bigger difference [for] men than women,” reported Antti Palomäki, MD, PhD, of the center for rheumatology and clinical immunology at Turku (Finland) University.
The gain-of-function MUC5B variant, which encodes mucin 5B, was first linked to RA-associated interstitial lung disease (ILD) more than 3 years ago. At that time, it was already a known genetic risk factor for idiopathic pulmonary fibrosis in the general population. The new data confirm the association in a longitudinal analysis of a large biobank and suggest the association might have clinical utility.
“This is not ready for clinical practice at the moment. We do not yet know whether we can change therapy to reduce risk,” Dr. Palomäki said, adding “in the future we can look.”
One question that might be asked in clinical studies using MUC5B as a tool to assess and modify risk of ILD in patients with RA is whether one therapy is better than another in avoiding or delaying development of lung fibrosis. Dr. Palomäki noted that biologics, for example, might be a more favorable choice in patients with RA who are at high risk of developing ILD.
The association of the MUC5B variant with increased ILD incidence in patients with RA was drawn from a data set known as FinnGen, a biobank collection of epidemiologic cohorts and hospital samples with genotypes of about 10% of the Finnish population. Follow-up extends to 46 years in some of these individuals.
When 248,4000 individuals in this data set were evaluated, 5,534 had a diagnosis of RA. Of these, 178 (3.2%) developed ILD. About 20% of both those with and without RA were MUC5B variant carriers, meaning the remainder were not.
Sex and age factor into lifetime risk
In patients with RA, the lifetime rate of ILD among MUC5B variant carriers was 16.8% versus only 6.1% among noncarriers. This finding translated into a hazard ratio for ILD of 2.27 (95% confidence interval, 1.75–2.96) for variant carriers versus noncarriers.
The lifetime rate of ILD in patients with RA was greater in men versus women regardless of carrier status (18.5% vs. 8.5%). For women, the lifetime rate was lower for carriers, although the difference relative to female noncarriers was greater (14.5% vs. 4.7%).
ILD, whether in the general population or in patients with RA, is a disease of advancing age. When Dr. Palomäki showed a graph, the rise in ILD incidence did not start in any population, whether those with or without RA and regardless of carrier status, until about age 55. In those without RA and in noncarriers of the variant, ILD incidence remained low and began a discernible climb at around age 70.
In those who did not have RA but were positive for the variant, the rates rose more than twice as fast, particularly after age 70. In people who had RA but not the variant, the rate of ILD was greater than in patients who carried the variant without RA, starting the climb earlier and rising more steeply with age. In those with RA and the variant, the climb in ILD incidence rose rapidly after age 65 years even though the incidence remained fairly similar between all of these groups at age 60.
Putting the findings into context
The need to develop ways to prevent ILD in RA is urgent. ILD is one of the most common extraarticular manifestations of RA, developing in up to 60% of patients with RA in older age groups when evaluated with imaging, according to Dr. Palomäki. Although it develops into a clinically significant complication in only about 10% of these patients, ILD still is a significant cause of illness and death in elderly patients with RA.
In the 2018 study that first linked the MUC5B variant to RA-ILD, the investigators also found that the variant was associated with an increased likelihood of developing the usual interstitial pneumonia type of ILD on imaging. David Schwartz, MD, professor of medicine, pulmonary sciences, and critical care and chair of the department of medicine at the University of Colorado at Denver, Aurora, was a senior author of that study. He said these findings build on the 2018 study.
“While the gain-of-function MUC5B promoter variant is important in predicting who will develop RA-ILD, these findings also suggest that MUC5B may be involved in the etiology of RA-ILD, at least for those with the MUC5B variant,” he said.
“The study also raises the possibility that there are several subtypes of RA-ILD, and the subtype that is driven by MUC5B may respond differently to RA biologics or therapeutic agents to treat ILD,” he added.
In the discussion following the presentation by Dr. Palomäki, others agreed, with that statement including Dr. Palomäki. He expressed interest in clinical studies comparing different classes of RA therapies for their relative impact on the risk of developing ILD.Dr. Palomäki reported financial relationships with AbbVie, Merck, Pfizer, and Sanofi. Dr. Schwartz is the founder of Eleven P15, which is developing methods for early diagnosis and treatment of pulmonary fibrosis.
FROM THE EULAR 2021 CONGRESS