Oral agents are taking on an ever-greater role in the management of gynecologic cancers. However, women being treated for these cancers have less than ideal adherence to such medications, a new study has found – with just over half reporting taking them exactly as prescribed.

Ingram Publishing/Thinkstock

The findings reported in Obstetrics & Gynecology are consistent with reports from other populations taking oral anticancer agents, in which adherence is generally lower than with intravenous therapies.

For their research, Catherine Watson, MD, and colleagues at Duke University, Durham, N.C., recruited 100 women at their institution taking a variety of oral anticancer agents for uterine or ovarian cancer for 30 days or more (median time, 6 months). The women answered a questionnaire that measured adherence as well as health literacy, quality of life, and distress. The researchers also collected information on the subjects’ race, age, insurance type, medication burden, and medication costs.

Fourteen of the women in the study additionally underwent qualitative interviews about their experiences with oral anticancer drugs. The researchers also queried physicians and nurse practitioners about their thoughts on adherence.

Dr. Watson and colleagues reported that 54% of women self-reported perfect adherence to their medication in the previous week, while 21% had missed or skipped one dose, and 25% reported skipping or missing more than one dose.

The researchers saw no significant differences between the adherent and nonadherent groups corresponding with race, age, or other demographic or clinical characteristics, but they noted that their study was not powered to detect such associations. The small sample size and self-reported data were among this study’s limitations, Dr. Watson and colleagues acknowledged.

Interviews with patients revealed some surprising reasons for the less-than-optimal adherence, with 43% of women reporting feeling anxiety about the burden of administering medication at home. While patients acknowledged the convenience of oral regimens, some also expressed a wish for more physician contact and support. Some women who were nonadherent said they perceived the efficacy of oral agents to be less than intravenous therapies.

Physicians and nurse practitioners interviewed by the researchers “tended to assume that their patients were adherent to oral anticancer therapy because of the therapy’s importance, and many did not routinely ask their patients about adherence,” Dr. Watson and colleagues wrote.

Emma Rossi, MD, a gynecologic oncologist at the University of North Carolina at Chapel Hill, commented in an interview that the study highlighted “the importance of not generalizing our perception of patients. As providers we have to spend the time asking patients where they’re at and how they’re thinking about taking an oral medication, with special attention to their fears, their expectations, and their concerns. We should be touching base with them not just before starting drugs, but during the course of treatment.”

Dr. Rossi stressed that compliance in real-life settings is likely to be different from that seen in clinical trials of oral anticancer drugs. “It’s important to recognize that real-world efficacy of treatments may be different from trial efficacy. We see these differences a lot in medicine where studies show a large magnitude of effect that doesn’t play out in real life practice – because of factors like this.”

Some 57% of the women in the study were taking their medications as maintenance, while the rest were taking the medications as active treatment. This too might have an effect on adherence, she said, with the active-treatment group potentially more motivated to maintain perfect adherence.

“You see in the interviews that doctors assume patients would be compliant because of the seriousness of the disease,” Dr. Rossi said. “But some patients said they perceived oral drugs as less strong or effective. If a patient is cancer free on a scan and doesn’t have measurable disease, prescribing an oral medication may be sending the subliminal message that it’s not as important.”

Physicians “may need to take the extra steps to individualize our counseling of patients – especially with therapies that they’re responsible for administering,” Dr. Rossi continued. “As this study shows, every patient sees treatment through her own individual lens. We really need to meet them where they’re at to make them comfortable with their treatment and optimize compliance.”

Dr. Watson and colleagues’ study was supported by their institution. One coauthor reported financial ties with drug manufacturers in the form of grant and clinical trial support and honoraria. Another coauthor is the member of various boards and steering committees, which are uncompensated. Dr. Rossi reported no financial conflicts of interest.

SOURCE: Watson C et al. Obstet Gynecol. 2020. doi: 10.1097/AOG.0000000000004170.

Oral agents are taking on an ever-greater role in the management of gynecologic cancers. However, women being treated for these cancers have less than ideal adherence to such medications, a new study has found – with just over half reporting taking them exactly as prescribed.

Ingram Publishing/Thinkstock

The findings reported in Obstetrics & Gynecology are consistent with reports from other populations taking oral anticancer agents, in which adherence is generally lower than with intravenous therapies.

For their research, Catherine Watson, MD, and colleagues at Duke University, Durham, N.C., recruited 100 women at their institution taking a variety of oral anticancer agents for uterine or ovarian cancer for 30 days or more (median time, 6 months). The women answered a questionnaire that measured adherence as well as health literacy, quality of life, and distress. The researchers also collected information on the subjects’ race, age, insurance type, medication burden, and medication costs.

Fourteen of the women in the study additionally underwent qualitative interviews about their experiences with oral anticancer drugs. The researchers also queried physicians and nurse practitioners about their thoughts on adherence.

Dr. Watson and colleagues reported that 54% of women self-reported perfect adherence to their medication in the previous week, while 21% had missed or skipped one dose, and 25% reported skipping or missing more than one dose.

The researchers saw no significant differences between the adherent and nonadherent groups corresponding with race, age, or other demographic or clinical characteristics, but they noted that their study was not powered to detect such associations. The small sample size and self-reported data were among this study’s limitations, Dr. Watson and colleagues acknowledged.

Interviews with patients revealed some surprising reasons for the less-than-optimal adherence, with 43% of women reporting feeling anxiety about the burden of administering medication at home. While patients acknowledged the convenience of oral regimens, some also expressed a wish for more physician contact and support. Some women who were nonadherent said they perceived the efficacy of oral agents to be less than intravenous therapies.

Physicians and nurse practitioners interviewed by the researchers “tended to assume that their patients were adherent to oral anticancer therapy because of the therapy’s importance, and many did not routinely ask their patients about adherence,” Dr. Watson and colleagues wrote.

Emma Rossi, MD, a gynecologic oncologist at the University of North Carolina at Chapel Hill, commented in an interview that the study highlighted “the importance of not generalizing our perception of patients. As providers we have to spend the time asking patients where they’re at and how they’re thinking about taking an oral medication, with special attention to their fears, their expectations, and their concerns. We should be touching base with them not just before starting drugs, but during the course of treatment.”

Dr. Rossi stressed that compliance in real-life settings is likely to be different from that seen in clinical trials of oral anticancer drugs. “It’s important to recognize that real-world efficacy of treatments may be different from trial efficacy. We see these differences a lot in medicine where studies show a large magnitude of effect that doesn’t play out in real life practice – because of factors like this.”

Some 57% of the women in the study were taking their medications as maintenance, while the rest were taking the medications as active treatment. This too might have an effect on adherence, she said, with the active-treatment group potentially more motivated to maintain perfect adherence.

“You see in the interviews that doctors assume patients would be compliant because of the seriousness of the disease,” Dr. Rossi said. “But some patients said they perceived oral drugs as less strong or effective. If a patient is cancer free on a scan and doesn’t have measurable disease, prescribing an oral medication may be sending the subliminal message that it’s not as important.”

Physicians “may need to take the extra steps to individualize our counseling of patients – especially with therapies that they’re responsible for administering,” Dr. Rossi continued. “As this study shows, every patient sees treatment through her own individual lens. We really need to meet them where they’re at to make them comfortable with their treatment and optimize compliance.”

Dr. Watson and colleagues’ study was supported by their institution. One coauthor reported financial ties with drug manufacturers in the form of grant and clinical trial support and honoraria. Another coauthor is the member of various boards and steering committees, which are uncompensated. Dr. Rossi reported no financial conflicts of interest.

SOURCE: Watson C et al. Obstet Gynecol. 2020. doi: 10.1097/AOG.0000000000004170.

Oral agents are taking on an ever-greater role in the management of gynecologic cancers. However, women being treated for these cancers have less than ideal adherence to such medications, a new study has found – with just over half reporting taking them exactly as prescribed.

Ingram Publishing/Thinkstock

The findings reported in Obstetrics & Gynecology are consistent with reports from other populations taking oral anticancer agents, in which adherence is generally lower than with intravenous therapies.

For their research, Catherine Watson, MD, and colleagues at Duke University, Durham, N.C., recruited 100 women at their institution taking a variety of oral anticancer agents for uterine or ovarian cancer for 30 days or more (median time, 6 months). The women answered a questionnaire that measured adherence as well as health literacy, quality of life, and distress. The researchers also collected information on the subjects’ race, age, insurance type, medication burden, and medication costs.

Fourteen of the women in the study additionally underwent qualitative interviews about their experiences with oral anticancer drugs. The researchers also queried physicians and nurse practitioners about their thoughts on adherence.

Dr. Watson and colleagues reported that 54% of women self-reported perfect adherence to their medication in the previous week, while 21% had missed or skipped one dose, and 25% reported skipping or missing more than one dose.

The researchers saw no significant differences between the adherent and nonadherent groups corresponding with race, age, or other demographic or clinical characteristics, but they noted that their study was not powered to detect such associations. The small sample size and self-reported data were among this study’s limitations, Dr. Watson and colleagues acknowledged.

Interviews with patients revealed some surprising reasons for the less-than-optimal adherence, with 43% of women reporting feeling anxiety about the burden of administering medication at home. While patients acknowledged the convenience of oral regimens, some also expressed a wish for more physician contact and support. Some women who were nonadherent said they perceived the efficacy of oral agents to be less than intravenous therapies.

Physicians and nurse practitioners interviewed by the researchers “tended to assume that their patients were adherent to oral anticancer therapy because of the therapy’s importance, and many did not routinely ask their patients about adherence,” Dr. Watson and colleagues wrote.

Emma Rossi, MD, a gynecologic oncologist at the University of North Carolina at Chapel Hill, commented in an interview that the study highlighted “the importance of not generalizing our perception of patients. As providers we have to spend the time asking patients where they’re at and how they’re thinking about taking an oral medication, with special attention to their fears, their expectations, and their concerns. We should be touching base with them not just before starting drugs, but during the course of treatment.”

Dr. Rossi stressed that compliance in real-life settings is likely to be different from that seen in clinical trials of oral anticancer drugs. “It’s important to recognize that real-world efficacy of treatments may be different from trial efficacy. We see these differences a lot in medicine where studies show a large magnitude of effect that doesn’t play out in real life practice – because of factors like this.”

Some 57% of the women in the study were taking their medications as maintenance, while the rest were taking the medications as active treatment. This too might have an effect on adherence, she said, with the active-treatment group potentially more motivated to maintain perfect adherence.

“You see in the interviews that doctors assume patients would be compliant because of the seriousness of the disease,” Dr. Rossi said. “But some patients said they perceived oral drugs as less strong or effective. If a patient is cancer free on a scan and doesn’t have measurable disease, prescribing an oral medication may be sending the subliminal message that it’s not as important.”

Physicians “may need to take the extra steps to individualize our counseling of patients – especially with therapies that they’re responsible for administering,” Dr. Rossi continued. “As this study shows, every patient sees treatment through her own individual lens. We really need to meet them where they’re at to make them comfortable with their treatment and optimize compliance.”

Dr. Watson and colleagues’ study was supported by their institution. One coauthor reported financial ties with drug manufacturers in the form of grant and clinical trial support and honoraria. Another coauthor is the member of various boards and steering committees, which are uncompensated. Dr. Rossi reported no financial conflicts of interest.

SOURCE: Watson C et al. Obstet Gynecol. 2020. doi: 10.1097/AOG.0000000000004170.

Among patients with polycystic ovary syndrome (PCOS), those with obstructive sleep apnea (OSA) are more likely to have moderate to severe depression or anxiety, a study suggests.

This finding could have implications for screening and treatment, Diana Xiaojie Zhou, MD, said at the American Society for Reproductive Medicine’s 2020 annual meeting, held virtually this year.

“Routine OSA screening in women with PCOS should be considered in the setting of existing depression and anxiety,” said Dr. Zhou, a reproductive endocrinology and infertility fellow at the University of California, San Francisco. “Referral for OSA diagnosis and treatment in those who screen positive may have added psychological benefits in this population, as has been seen in the general population.”

Patients with PCOS experience a range of comorbidities, including higher rates of psychological disorders and OSA, she said.

OSA has been associated with depression and anxiety in the general population, and research indicates that treatment, such as with continuous positive airway pressure (CPAP), may have psychological benefits, such as reduced depression symptoms.

PCOS guidelines recommend screening for OSA to identify and alleviate symptoms such as fatigue that may to contribute to mood disorders. “However, there is a lack of studies assessing the relationship between OSA and depression and anxiety specifically in women with PCOS,” Dr. Zhou said.
 

A cross-sectional study

To evaluate whether OSA is associated with depression and anxiety in women with PCOS, Dr. Zhou and colleagues conducted a cross-sectional study of all women seen at a multidisciplinary PCOS clinic at university between June 2017 and June 2020.

Participants had a diagnosis of PCOS clinically confirmed by the Rotterdam criteria. Researchers determined OSA risk using the Berlin questionnaire, which is divided into three domains. A positive score in two or more domains indicates a high risk of OSA.

The investigators used the Patient Health Questionnaire-9 (PHQ-9) to assess depression symptoms, and they used the Generalized Anxiety Disorder-7 (GAD-7) to assess anxiety symptoms.

Researchers used two-sided t-test, chi-square test, and Fisher’s exact test to evaluate for differences in patient characteristics. They performed multivariate logistic regression analyses to determine the odds of moderate to severe symptoms of depression (that is, a PHQ-9 score of 10 or greater) and anxiety (a GAD-7 score of 10 or greater) among patients with a high risk of OSA, compared with patients with a low risk of OSA. They adjusted for age, body mass index, free testosterone level, and insulin resistance using the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR).

The researchers examined data from 201 patients: 125 with a low risk of OSA and 76 with a high risk of OSA. The average age of the patients was 28 years.

On average, patients in the high-risk OSA group had a greater body mass index (37.9 vs. 26.5), a higher level of free testosterone (6.5 ng/dL vs. 4.5 ng/dL), and a higher HOMA-IR score (7 vs. 3.1), relative to those with a low risk of OSA. In addition, a greater percentage of patients with a high risk of OSA experienced oligomenorrhea (84.9% vs. 70.5%).

The average PHQ-9 score was significantly higher in the high-risk OSA group (12 vs. 8.3), as was the average GAD-7 score (8.9 vs. 6.1).

In univariate analyses, having a high risk of OSA increased the likelihood of moderate or severe depression or anxiety approximately threefold.

In multivariate analyses, a high risk of OSA remained significantly associated with moderate or severe depression or anxiety, with an odds ratio of about 2.5. “Of note, BMI was a statistically significant predictor in the univariate analyses, but not so in the multivariate analyses,” Dr. Zhou said.

Although the investigators assessed OSA, depression, and anxiety using validated questionnaires, a study with clinically confirmed diagnoses of those conditions would strengthen these findings, she said.
 

Various possible links

Investigators have proposed various links between PCOS, OSA, and depression and anxiety, Dr. Zhou noted. Features of PCOS such as insulin resistance, obesity, and hyperandrogenemia increase the risk of OSA. “The sleep loss and fragmentation and hypoxia that define OSA then serve to increase sympathetic tone and oxidative stress, which then potentially can lead to an increase in depression and anxiety,” Dr. Zhou said.

The results suggests that treating OSA “may have added psychological benefits for women with PCOS and highlights the broad health implications of this condition,” Marla Lujan, PhD, chair of the ASRM’s androgen excess special interest group, said in a society news release.

“The cause of PCOS is still not well understood, but we do know that 1 in 10 women in their childbearing years suffer from PCOS,” said Dr. Lujan, of Cornell University, Ithaca, N.Y. “In addition to infertility, PCOS is also associated with type 2 diabetes and cardiovascular complications such as hypertension and abnormal blood lipids.”

In a discussion following Dr. Zhou’s presentation, Alice D. Domar, PhD, said the study was eye opening.

Dr. Domar, director of integrative care at Boston IVF and associate professor of obstetrics, gynecology, and reproductive biology at Harvard Medical School, Boston, said that she does not typically discuss sleep apnea with patients. “For those of us who routinely work with PCOS patients, we are always looking for more information.”

Although PCOS guidelines mention screening for OSA, Dr. Zhou expects that few generalists who see PCOS patients or even subspecialists actually do.

Nevertheless, the potential for intervention is fascinating, she said. And if treating OSA also reduced a patient’s need for psychiatric medications, there could be added benefit in PCOS due to the metabolic side effects that accompany some of the drugs.

Dr. Zhou and Dr. Lujan had no relevant disclosures. Dr. Domar is a co-owner of FertiCalm, FertiStrong, and Aliz Health Apps, and a speaker for Ferring, EMD Serono, Merck, and Abbott.

[email protected]

SOURCE: Zhou DX et al. ASRM 2020. Abstract O-146.

Among patients with polycystic ovary syndrome (PCOS), those with obstructive sleep apnea (OSA) are more likely to have moderate to severe depression or anxiety, a study suggests.

This finding could have implications for screening and treatment, Diana Xiaojie Zhou, MD, said at the American Society for Reproductive Medicine’s 2020 annual meeting, held virtually this year.

“Routine OSA screening in women with PCOS should be considered in the setting of existing depression and anxiety,” said Dr. Zhou, a reproductive endocrinology and infertility fellow at the University of California, San Francisco. “Referral for OSA diagnosis and treatment in those who screen positive may have added psychological benefits in this population, as has been seen in the general population.”

Patients with PCOS experience a range of comorbidities, including higher rates of psychological disorders and OSA, she said.

OSA has been associated with depression and anxiety in the general population, and research indicates that treatment, such as with continuous positive airway pressure (CPAP), may have psychological benefits, such as reduced depression symptoms.

PCOS guidelines recommend screening for OSA to identify and alleviate symptoms such as fatigue that may to contribute to mood disorders. “However, there is a lack of studies assessing the relationship between OSA and depression and anxiety specifically in women with PCOS,” Dr. Zhou said.
 

A cross-sectional study

To evaluate whether OSA is associated with depression and anxiety in women with PCOS, Dr. Zhou and colleagues conducted a cross-sectional study of all women seen at a multidisciplinary PCOS clinic at university between June 2017 and June 2020.

Participants had a diagnosis of PCOS clinically confirmed by the Rotterdam criteria. Researchers determined OSA risk using the Berlin questionnaire, which is divided into three domains. A positive score in two or more domains indicates a high risk of OSA.

The investigators used the Patient Health Questionnaire-9 (PHQ-9) to assess depression symptoms, and they used the Generalized Anxiety Disorder-7 (GAD-7) to assess anxiety symptoms.

Researchers used two-sided t-test, chi-square test, and Fisher’s exact test to evaluate for differences in patient characteristics. They performed multivariate logistic regression analyses to determine the odds of moderate to severe symptoms of depression (that is, a PHQ-9 score of 10 or greater) and anxiety (a GAD-7 score of 10 or greater) among patients with a high risk of OSA, compared with patients with a low risk of OSA. They adjusted for age, body mass index, free testosterone level, and insulin resistance using the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR).

The researchers examined data from 201 patients: 125 with a low risk of OSA and 76 with a high risk of OSA. The average age of the patients was 28 years.

On average, patients in the high-risk OSA group had a greater body mass index (37.9 vs. 26.5), a higher level of free testosterone (6.5 ng/dL vs. 4.5 ng/dL), and a higher HOMA-IR score (7 vs. 3.1), relative to those with a low risk of OSA. In addition, a greater percentage of patients with a high risk of OSA experienced oligomenorrhea (84.9% vs. 70.5%).

The average PHQ-9 score was significantly higher in the high-risk OSA group (12 vs. 8.3), as was the average GAD-7 score (8.9 vs. 6.1).

In univariate analyses, having a high risk of OSA increased the likelihood of moderate or severe depression or anxiety approximately threefold.

In multivariate analyses, a high risk of OSA remained significantly associated with moderate or severe depression or anxiety, with an odds ratio of about 2.5. “Of note, BMI was a statistically significant predictor in the univariate analyses, but not so in the multivariate analyses,” Dr. Zhou said.

Although the investigators assessed OSA, depression, and anxiety using validated questionnaires, a study with clinically confirmed diagnoses of those conditions would strengthen these findings, she said.
 

Various possible links

Investigators have proposed various links between PCOS, OSA, and depression and anxiety, Dr. Zhou noted. Features of PCOS such as insulin resistance, obesity, and hyperandrogenemia increase the risk of OSA. “The sleep loss and fragmentation and hypoxia that define OSA then serve to increase sympathetic tone and oxidative stress, which then potentially can lead to an increase in depression and anxiety,” Dr. Zhou said.

The results suggests that treating OSA “may have added psychological benefits for women with PCOS and highlights the broad health implications of this condition,” Marla Lujan, PhD, chair of the ASRM’s androgen excess special interest group, said in a society news release.

“The cause of PCOS is still not well understood, but we do know that 1 in 10 women in their childbearing years suffer from PCOS,” said Dr. Lujan, of Cornell University, Ithaca, N.Y. “In addition to infertility, PCOS is also associated with type 2 diabetes and cardiovascular complications such as hypertension and abnormal blood lipids.”

In a discussion following Dr. Zhou’s presentation, Alice D. Domar, PhD, said the study was eye opening.

Dr. Domar, director of integrative care at Boston IVF and associate professor of obstetrics, gynecology, and reproductive biology at Harvard Medical School, Boston, said that she does not typically discuss sleep apnea with patients. “For those of us who routinely work with PCOS patients, we are always looking for more information.”

Although PCOS guidelines mention screening for OSA, Dr. Zhou expects that few generalists who see PCOS patients or even subspecialists actually do.

Nevertheless, the potential for intervention is fascinating, she said. And if treating OSA also reduced a patient’s need for psychiatric medications, there could be added benefit in PCOS due to the metabolic side effects that accompany some of the drugs.

Dr. Zhou and Dr. Lujan had no relevant disclosures. Dr. Domar is a co-owner of FertiCalm, FertiStrong, and Aliz Health Apps, and a speaker for Ferring, EMD Serono, Merck, and Abbott.

[email protected]

SOURCE: Zhou DX et al. ASRM 2020. Abstract O-146.

Among patients with polycystic ovary syndrome (PCOS), those with obstructive sleep apnea (OSA) are more likely to have moderate to severe depression or anxiety, a study suggests.

This finding could have implications for screening and treatment, Diana Xiaojie Zhou, MD, said at the American Society for Reproductive Medicine’s 2020 annual meeting, held virtually this year.

“Routine OSA screening in women with PCOS should be considered in the setting of existing depression and anxiety,” said Dr. Zhou, a reproductive endocrinology and infertility fellow at the University of California, San Francisco. “Referral for OSA diagnosis and treatment in those who screen positive may have added psychological benefits in this population, as has been seen in the general population.”

Patients with PCOS experience a range of comorbidities, including higher rates of psychological disorders and OSA, she said.

OSA has been associated with depression and anxiety in the general population, and research indicates that treatment, such as with continuous positive airway pressure (CPAP), may have psychological benefits, such as reduced depression symptoms.

PCOS guidelines recommend screening for OSA to identify and alleviate symptoms such as fatigue that may to contribute to mood disorders. “However, there is a lack of studies assessing the relationship between OSA and depression and anxiety specifically in women with PCOS,” Dr. Zhou said.
 

A cross-sectional study

To evaluate whether OSA is associated with depression and anxiety in women with PCOS, Dr. Zhou and colleagues conducted a cross-sectional study of all women seen at a multidisciplinary PCOS clinic at university between June 2017 and June 2020.

Participants had a diagnosis of PCOS clinically confirmed by the Rotterdam criteria. Researchers determined OSA risk using the Berlin questionnaire, which is divided into three domains. A positive score in two or more domains indicates a high risk of OSA.

The investigators used the Patient Health Questionnaire-9 (PHQ-9) to assess depression symptoms, and they used the Generalized Anxiety Disorder-7 (GAD-7) to assess anxiety symptoms.

Researchers used two-sided t-test, chi-square test, and Fisher’s exact test to evaluate for differences in patient characteristics. They performed multivariate logistic regression analyses to determine the odds of moderate to severe symptoms of depression (that is, a PHQ-9 score of 10 or greater) and anxiety (a GAD-7 score of 10 or greater) among patients with a high risk of OSA, compared with patients with a low risk of OSA. They adjusted for age, body mass index, free testosterone level, and insulin resistance using the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR).

The researchers examined data from 201 patients: 125 with a low risk of OSA and 76 with a high risk of OSA. The average age of the patients was 28 years.

On average, patients in the high-risk OSA group had a greater body mass index (37.9 vs. 26.5), a higher level of free testosterone (6.5 ng/dL vs. 4.5 ng/dL), and a higher HOMA-IR score (7 vs. 3.1), relative to those with a low risk of OSA. In addition, a greater percentage of patients with a high risk of OSA experienced oligomenorrhea (84.9% vs. 70.5%).

The average PHQ-9 score was significantly higher in the high-risk OSA group (12 vs. 8.3), as was the average GAD-7 score (8.9 vs. 6.1).

In univariate analyses, having a high risk of OSA increased the likelihood of moderate or severe depression or anxiety approximately threefold.

In multivariate analyses, a high risk of OSA remained significantly associated with moderate or severe depression or anxiety, with an odds ratio of about 2.5. “Of note, BMI was a statistically significant predictor in the univariate analyses, but not so in the multivariate analyses,” Dr. Zhou said.

Although the investigators assessed OSA, depression, and anxiety using validated questionnaires, a study with clinically confirmed diagnoses of those conditions would strengthen these findings, she said.
 

Various possible links

Investigators have proposed various links between PCOS, OSA, and depression and anxiety, Dr. Zhou noted. Features of PCOS such as insulin resistance, obesity, and hyperandrogenemia increase the risk of OSA. “The sleep loss and fragmentation and hypoxia that define OSA then serve to increase sympathetic tone and oxidative stress, which then potentially can lead to an increase in depression and anxiety,” Dr. Zhou said.

The results suggests that treating OSA “may have added psychological benefits for women with PCOS and highlights the broad health implications of this condition,” Marla Lujan, PhD, chair of the ASRM’s androgen excess special interest group, said in a society news release.

“The cause of PCOS is still not well understood, but we do know that 1 in 10 women in their childbearing years suffer from PCOS,” said Dr. Lujan, of Cornell University, Ithaca, N.Y. “In addition to infertility, PCOS is also associated with type 2 diabetes and cardiovascular complications such as hypertension and abnormal blood lipids.”

In a discussion following Dr. Zhou’s presentation, Alice D. Domar, PhD, said the study was eye opening.

Dr. Domar, director of integrative care at Boston IVF and associate professor of obstetrics, gynecology, and reproductive biology at Harvard Medical School, Boston, said that she does not typically discuss sleep apnea with patients. “For those of us who routinely work with PCOS patients, we are always looking for more information.”

Although PCOS guidelines mention screening for OSA, Dr. Zhou expects that few generalists who see PCOS patients or even subspecialists actually do.

Nevertheless, the potential for intervention is fascinating, she said. And if treating OSA also reduced a patient’s need for psychiatric medications, there could be added benefit in PCOS due to the metabolic side effects that accompany some of the drugs.

Dr. Zhou and Dr. Lujan had no relevant disclosures. Dr. Domar is a co-owner of FertiCalm, FertiStrong, and Aliz Health Apps, and a speaker for Ferring, EMD Serono, Merck, and Abbott.

[email protected]

SOURCE: Zhou DX et al. ASRM 2020. Abstract O-146.

What is the next step in treatment after a person with rheumatoid arthritis fails to adequately respond to methotrexate – a Janus kinase (JAK) inhibitor or a biologic? That was the focus of a lively debate at the virtual annual meeting of the American College of Rheumatology.

Vibeke Strand, MD, argued that JAK inhibitors offer the distinct advantage of a faster clinical response than biologics, meaning that decisions to change therapy based on nonresponse or adverse effects can be made earlier in a treatment plan.

Michael Weinblatt, MD, countered that the faster-response advantage is offset by potential adverse events associated with the JAK inhibitors, including increased risk of herpes zoster infection, venous thromboembolism (VTE), and arterial thromboembolism (ATE). He suggested switching patients to a biologic instead.

In addition, the debate was held just days before the ACR released a proposed guideline for the management of RA. This update to the 2015 guidance is the first to prioritize the order of RA treatments, emphasizing that clinicians should maximize methotrexate therapy before switching RA patients to a JAK inhibitor or a biologic. Release of the full guidelines is pending, and it remains unclear if the ACR provides any guidance regarding the “jakinib” versus biologic decision.

Interestingly, the debate did not hinge on any differences in efficacy. Both speakers pointed to similar efficacy between anti–tumor necrosis factor (TNF) agents and JAK inhibitors, and despite working on different pathways, among the individual JAK inhibitors as well.
 

Is timing of the essence?

Knowing whether a person with RA responds to a JAK inhibitor more quickly than to a biologic is a major advantage, said Dr. Strand, of the division of immunology and rheumatology at Stanford (Calif.) University. “The argument that I am making is that patients are more responsive if treated earlier in the disease process and they are less treatment-experienced.”

Dr. Strand said the advantages extend to remission as well. “When patients are aware of early improvements, their adherence is increased. Remission is more likely because it occurs earlier.”

“I will certainly grant it to Vibeke that jakinibs work much faster,” said Dr. Weinblatt, chair of rheumatology at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School in Boston. However, he added, “my bias is that you give patients an anti-TNF therapy first, and if they are not responding by 12 weeks, you move on to another class of drugs, perhaps even the jakinibs.”

Herpes zoster risk

Dr. Strand and Dr. Weinblatt addressed potential adverse events associated with both classes of agents. For the JAK inhibitors, concerns include herpes zoster infections, increased VTE and ATE incidence, and largely unknown risks during pregnancy and lactation. For the anti-TNF agents, safety concerns include reactivation of tuberculosis, fungal infections, demyelinating syndrome, and skin cancer.

With the shortest half-life of any therapeutic class in rheumatology, adverse events with JAK inhibitors often can resolve quickly, Dr. Strand said.

The increased risk of herpes zoster is important, she added, “but we have a recombinant vaccination that works. It’s quite effective.”

Dr. Weinblatt pointed out that all the JAK inhibitors carry this increase herpes zoster risk, which is related to their mechanism of action. There is a catch with the vaccine, however, he added. The vaccine is approved for treatment of patients 50 years and older. For younger people with RA starting a JAK inhibitor, the cost is out-of-pocket.
 

Evaluating risk of emboli

The incidence of VTE is about two times higher among people with RA, compared with the general population, Dr. Strand said, with research suggesting the majority of risk resides among people with a previous event. However, she added, an emerging profile of thromboembolic events associated with JAK inhibitors is “considered a class effect by the FDA.”

One exception in the JAK inhibitor class could be tofacitinib (Xeljanz), which might carry less risk because “most of the data with tofacitinib are quite good,” Dr. Weinblatt said. One study presented at ACR 2018, for example, showed a similar VTE rate between tofacitinib and TNF inhibitors.

Nevertheless, the FDA issued a boxed warning in July 2019 about elevated risks of blood clots and death at a higher dose of tofacitinib. The concerns stem from an open-label, endpoint-driven study mandated by the FDA to explore major adverse cardiac events. “There was a clinically important and statistically significant occurrence of pulmonary embolism and VTE, and an increase in mortality in the 10-mg dose group as opposed to the anti-TNF therapies,” Dr. Weinblatt said. As a result, the FDA requested patients on the 10-mg twice-daily dose be transitioned to the 5-mg twice-daily dose.

The package labeling for the JAK inhibitors baricitinib (Olumiant) and upadacitinib (Rinvoq) feature warnings about increased risk for thromboembolic events. Furthermore, the labeling for filgotinib, a JAK inhibitor in development that received a complete response letter from the FDA in August 2020, is expected to carry the same warning.An unanswered question remains on why this class of agents potentially increases risk of thromboembolism. “We’re all uncomfortable because there is no known mechanism of JAK inhibition that should lead to this,” he added. Another unresolved issue is whether or not patients prescribed a JAK inhibitor should also be prescribed an anticoagulant.
 

Anti-TNF adverse events

Infections, primarily reactivation of tuberculosis and an increased risk for fungal disease, are concerns with the anti-TNF agents. However, the risk is not restricted to this class. “Greater risk of infection is seen with all our immune-modulating therapies,” Dr. Weinblatt said.

Rare adverse events include demyelinating syndromes, hematologic toxicity, and a worsening of heart failure in some cases.

“Despite a concern about malignancy, the only defined cancer reported over 22 years of use was skin cancer,” he said. “It took more than a decade of ongoing registry data for skin cancer to be identified. It was not noted in randomized, placebo-controlled trials.”
 

Potential pregnancy concerns

When it comes to risk during reproduction, “there is a clear difference,” Dr. Weinblatt said. “We know anti-TNF therapy can be used safely in pregnant women. We know they can conceive on them and maintain them during pregnancy. They can also breastfeed on them.”

“Frankly, I’m not so ‘gung ho’ on TNF inhibitor safety in pregnancy and lactation with exception of certolizumab, which doesn’t result in high levels of antibody in the placenta or the mother’s milk,” Dr. Strand said.

The 2020 ACR Guideline for the Management of Reproductive Health in Rheumatic and Musculoskeletal Diseases states that all anti-TNF therapies can be used during pregnancy and lactation, Dr. Weinblatt said. “Although I agree certolizumab has the best safety profile, all of them can be used.”

“The same is not true with the jakinibs,” he added, pointing to warnings that women of reproductive age should use contraception while on JAK inhibitors and for 4 weeks after stopping treatment.

However, Dr. Strand defended the pregnancy risk with JAK inhibitors. She cited two publications, including a 2016 study where researchers evaluated the safety of tofacitinib during pregnancy in women with rheumatoid arthritis and psoriasis. “There was only one possible deformity, a pulmonary stenosis,” Dr. Strand said. “Essentially, the majority of patients delivered healthy babies. There was very little difference from what we know occurs in RA otherwise.”

A 2018 study assessed pregnancy outcomes with tofacitinib among people with ulcerative colitis, “again showing the majority of patients had normal deliveries.”

“There just aren’t enough data,” Dr. Weinblatt said. “Perhaps in 5 years, we will reach same conclusion with the jakinibs.”
 

Differences in cost?

“We have not benefited yet from the biosimilar costs. But in Europe, the cost of an adalimumab or etanercept biosimilar is about $5,000, versus about $50,000 to $60,000 in the U.S. for the JAK inhibitors,” Dr. Weinblatt said. “So there are major cost savings with biosimilars.”

“I can’t understand cost at all for our drugs,” he continued. “They’re not rational, and the price increases are clearly not rational. Potentially, a small molecule is going to be a lot easier to produce than a biologic, so you could argue that generic jakinibs ought to be less. But in the United States we have a distorted pricing model.”

“Until that changes, I don’t think we can predict [future costs]. One could predict that generics and biosimilars will be less than the orginators,” Dr. Weinblatt said.

“It is really criminal we don’t have biosimilars for most of our TNFs, but that is the way it is,” Dr. Strand said.
 

Summary statements

“The JAK-inhibitor class is an exciting development for rheumatology and a broad variety of autoimmune diseases,” Dr. Strand said.

“In rheumatoid arthritis, they should be used early,” she added. “Based on phase 3 trials, responses are better in progressively earlier disease with less treatment-experienced patients.”

She pointed out that many patients like the convenience of the oral JAK inhibitors.

Dr. Weinblatt stated the 22 years of clinical experience with the anti-TNF class versus about 8 years with jakinibs favors the biologics. “Virtually every approved drug has been tested versus methotrexate, in early studies, long-term studies, and most importantly, in reduction and withdrawal studies, which are not available with the JAK inhibitors.”

Anti-TNFs have impressive effects on clinical disease activity, functional outcomes, and radiographic progression, Dr. Weinblatt said. They work in early and longstanding disease among patients who are disease-modifying antirheumatic drug naive and after multiple DMARD failures, he added.
 

Adding up the vote

The question was: Should JAK inhibitors be used before TNF inhibitors? The results showed 69%-31% in favor of anti-TNF agents.

“So the majority are more comfortable using TNFs,” said debate moderator Elizabeth Wahl, MD, of the department of rheumatology at VA Puget Sound Healthcare System and the University of Washington in Seattle. Regarding a switch to JAK inhibitors, she interpreted the poll numbers to mean, “we are not there yet, it takes years and years of safety data.”

Both Dr. Strand and Dr. Weinblatt disclosed numerous financial relationships with pharmaceutical companies that market RA drugs.

What is the next step in treatment after a person with rheumatoid arthritis fails to adequately respond to methotrexate – a Janus kinase (JAK) inhibitor or a biologic? That was the focus of a lively debate at the virtual annual meeting of the American College of Rheumatology.

Vibeke Strand, MD, argued that JAK inhibitors offer the distinct advantage of a faster clinical response than biologics, meaning that decisions to change therapy based on nonresponse or adverse effects can be made earlier in a treatment plan.

Michael Weinblatt, MD, countered that the faster-response advantage is offset by potential adverse events associated with the JAK inhibitors, including increased risk of herpes zoster infection, venous thromboembolism (VTE), and arterial thromboembolism (ATE). He suggested switching patients to a biologic instead.

In addition, the debate was held just days before the ACR released a proposed guideline for the management of RA. This update to the 2015 guidance is the first to prioritize the order of RA treatments, emphasizing that clinicians should maximize methotrexate therapy before switching RA patients to a JAK inhibitor or a biologic. Release of the full guidelines is pending, and it remains unclear if the ACR provides any guidance regarding the “jakinib” versus biologic decision.

Interestingly, the debate did not hinge on any differences in efficacy. Both speakers pointed to similar efficacy between anti–tumor necrosis factor (TNF) agents and JAK inhibitors, and despite working on different pathways, among the individual JAK inhibitors as well.
 

Is timing of the essence?

Knowing whether a person with RA responds to a JAK inhibitor more quickly than to a biologic is a major advantage, said Dr. Strand, of the division of immunology and rheumatology at Stanford (Calif.) University. “The argument that I am making is that patients are more responsive if treated earlier in the disease process and they are less treatment-experienced.”

Dr. Strand said the advantages extend to remission as well. “When patients are aware of early improvements, their adherence is increased. Remission is more likely because it occurs earlier.”

“I will certainly grant it to Vibeke that jakinibs work much faster,” said Dr. Weinblatt, chair of rheumatology at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School in Boston. However, he added, “my bias is that you give patients an anti-TNF therapy first, and if they are not responding by 12 weeks, you move on to another class of drugs, perhaps even the jakinibs.”

Herpes zoster risk

Dr. Strand and Dr. Weinblatt addressed potential adverse events associated with both classes of agents. For the JAK inhibitors, concerns include herpes zoster infections, increased VTE and ATE incidence, and largely unknown risks during pregnancy and lactation. For the anti-TNF agents, safety concerns include reactivation of tuberculosis, fungal infections, demyelinating syndrome, and skin cancer.

With the shortest half-life of any therapeutic class in rheumatology, adverse events with JAK inhibitors often can resolve quickly, Dr. Strand said.

The increased risk of herpes zoster is important, she added, “but we have a recombinant vaccination that works. It’s quite effective.”

Dr. Weinblatt pointed out that all the JAK inhibitors carry this increase herpes zoster risk, which is related to their mechanism of action. There is a catch with the vaccine, however, he added. The vaccine is approved for treatment of patients 50 years and older. For younger people with RA starting a JAK inhibitor, the cost is out-of-pocket.
 

Evaluating risk of emboli

The incidence of VTE is about two times higher among people with RA, compared with the general population, Dr. Strand said, with research suggesting the majority of risk resides among people with a previous event. However, she added, an emerging profile of thromboembolic events associated with JAK inhibitors is “considered a class effect by the FDA.”

One exception in the JAK inhibitor class could be tofacitinib (Xeljanz), which might carry less risk because “most of the data with tofacitinib are quite good,” Dr. Weinblatt said. One study presented at ACR 2018, for example, showed a similar VTE rate between tofacitinib and TNF inhibitors.

Nevertheless, the FDA issued a boxed warning in July 2019 about elevated risks of blood clots and death at a higher dose of tofacitinib. The concerns stem from an open-label, endpoint-driven study mandated by the FDA to explore major adverse cardiac events. “There was a clinically important and statistically significant occurrence of pulmonary embolism and VTE, and an increase in mortality in the 10-mg dose group as opposed to the anti-TNF therapies,” Dr. Weinblatt said. As a result, the FDA requested patients on the 10-mg twice-daily dose be transitioned to the 5-mg twice-daily dose.

The package labeling for the JAK inhibitors baricitinib (Olumiant) and upadacitinib (Rinvoq) feature warnings about increased risk for thromboembolic events. Furthermore, the labeling for filgotinib, a JAK inhibitor in development that received a complete response letter from the FDA in August 2020, is expected to carry the same warning.An unanswered question remains on why this class of agents potentially increases risk of thromboembolism. “We’re all uncomfortable because there is no known mechanism of JAK inhibition that should lead to this,” he added. Another unresolved issue is whether or not patients prescribed a JAK inhibitor should also be prescribed an anticoagulant.
 

Anti-TNF adverse events

Infections, primarily reactivation of tuberculosis and an increased risk for fungal disease, are concerns with the anti-TNF agents. However, the risk is not restricted to this class. “Greater risk of infection is seen with all our immune-modulating therapies,” Dr. Weinblatt said.

Rare adverse events include demyelinating syndromes, hematologic toxicity, and a worsening of heart failure in some cases.

“Despite a concern about malignancy, the only defined cancer reported over 22 years of use was skin cancer,” he said. “It took more than a decade of ongoing registry data for skin cancer to be identified. It was not noted in randomized, placebo-controlled trials.”
 

Potential pregnancy concerns

When it comes to risk during reproduction, “there is a clear difference,” Dr. Weinblatt said. “We know anti-TNF therapy can be used safely in pregnant women. We know they can conceive on them and maintain them during pregnancy. They can also breastfeed on them.”

“Frankly, I’m not so ‘gung ho’ on TNF inhibitor safety in pregnancy and lactation with exception of certolizumab, which doesn’t result in high levels of antibody in the placenta or the mother’s milk,” Dr. Strand said.

The 2020 ACR Guideline for the Management of Reproductive Health in Rheumatic and Musculoskeletal Diseases states that all anti-TNF therapies can be used during pregnancy and lactation, Dr. Weinblatt said. “Although I agree certolizumab has the best safety profile, all of them can be used.”

“The same is not true with the jakinibs,” he added, pointing to warnings that women of reproductive age should use contraception while on JAK inhibitors and for 4 weeks after stopping treatment.

However, Dr. Strand defended the pregnancy risk with JAK inhibitors. She cited two publications, including a 2016 study where researchers evaluated the safety of tofacitinib during pregnancy in women with rheumatoid arthritis and psoriasis. “There was only one possible deformity, a pulmonary stenosis,” Dr. Strand said. “Essentially, the majority of patients delivered healthy babies. There was very little difference from what we know occurs in RA otherwise.”

A 2018 study assessed pregnancy outcomes with tofacitinib among people with ulcerative colitis, “again showing the majority of patients had normal deliveries.”

“There just aren’t enough data,” Dr. Weinblatt said. “Perhaps in 5 years, we will reach same conclusion with the jakinibs.”
 

Differences in cost?

“We have not benefited yet from the biosimilar costs. But in Europe, the cost of an adalimumab or etanercept biosimilar is about $5,000, versus about $50,000 to $60,000 in the U.S. for the JAK inhibitors,” Dr. Weinblatt said. “So there are major cost savings with biosimilars.”

“I can’t understand cost at all for our drugs,” he continued. “They’re not rational, and the price increases are clearly not rational. Potentially, a small molecule is going to be a lot easier to produce than a biologic, so you could argue that generic jakinibs ought to be less. But in the United States we have a distorted pricing model.”

“Until that changes, I don’t think we can predict [future costs]. One could predict that generics and biosimilars will be less than the orginators,” Dr. Weinblatt said.

“It is really criminal we don’t have biosimilars for most of our TNFs, but that is the way it is,” Dr. Strand said.
 

Summary statements

“The JAK-inhibitor class is an exciting development for rheumatology and a broad variety of autoimmune diseases,” Dr. Strand said.

“In rheumatoid arthritis, they should be used early,” she added. “Based on phase 3 trials, responses are better in progressively earlier disease with less treatment-experienced patients.”

She pointed out that many patients like the convenience of the oral JAK inhibitors.

Dr. Weinblatt stated the 22 years of clinical experience with the anti-TNF class versus about 8 years with jakinibs favors the biologics. “Virtually every approved drug has been tested versus methotrexate, in early studies, long-term studies, and most importantly, in reduction and withdrawal studies, which are not available with the JAK inhibitors.”

Anti-TNFs have impressive effects on clinical disease activity, functional outcomes, and radiographic progression, Dr. Weinblatt said. They work in early and longstanding disease among patients who are disease-modifying antirheumatic drug naive and after multiple DMARD failures, he added.
 

Adding up the vote

The question was: Should JAK inhibitors be used before TNF inhibitors? The results showed 69%-31% in favor of anti-TNF agents.

“So the majority are more comfortable using TNFs,” said debate moderator Elizabeth Wahl, MD, of the department of rheumatology at VA Puget Sound Healthcare System and the University of Washington in Seattle. Regarding a switch to JAK inhibitors, she interpreted the poll numbers to mean, “we are not there yet, it takes years and years of safety data.”

Both Dr. Strand and Dr. Weinblatt disclosed numerous financial relationships with pharmaceutical companies that market RA drugs.

What is the next step in treatment after a person with rheumatoid arthritis fails to adequately respond to methotrexate – a Janus kinase (JAK) inhibitor or a biologic? That was the focus of a lively debate at the virtual annual meeting of the American College of Rheumatology.

Vibeke Strand, MD, argued that JAK inhibitors offer the distinct advantage of a faster clinical response than biologics, meaning that decisions to change therapy based on nonresponse or adverse effects can be made earlier in a treatment plan.

Michael Weinblatt, MD, countered that the faster-response advantage is offset by potential adverse events associated with the JAK inhibitors, including increased risk of herpes zoster infection, venous thromboembolism (VTE), and arterial thromboembolism (ATE). He suggested switching patients to a biologic instead.

In addition, the debate was held just days before the ACR released a proposed guideline for the management of RA. This update to the 2015 guidance is the first to prioritize the order of RA treatments, emphasizing that clinicians should maximize methotrexate therapy before switching RA patients to a JAK inhibitor or a biologic. Release of the full guidelines is pending, and it remains unclear if the ACR provides any guidance regarding the “jakinib” versus biologic decision.

Interestingly, the debate did not hinge on any differences in efficacy. Both speakers pointed to similar efficacy between anti–tumor necrosis factor (TNF) agents and JAK inhibitors, and despite working on different pathways, among the individual JAK inhibitors as well.
 

Is timing of the essence?

Knowing whether a person with RA responds to a JAK inhibitor more quickly than to a biologic is a major advantage, said Dr. Strand, of the division of immunology and rheumatology at Stanford (Calif.) University. “The argument that I am making is that patients are more responsive if treated earlier in the disease process and they are less treatment-experienced.”

Dr. Strand said the advantages extend to remission as well. “When patients are aware of early improvements, their adherence is increased. Remission is more likely because it occurs earlier.”

“I will certainly grant it to Vibeke that jakinibs work much faster,” said Dr. Weinblatt, chair of rheumatology at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School in Boston. However, he added, “my bias is that you give patients an anti-TNF therapy first, and if they are not responding by 12 weeks, you move on to another class of drugs, perhaps even the jakinibs.”

Herpes zoster risk

Dr. Strand and Dr. Weinblatt addressed potential adverse events associated with both classes of agents. For the JAK inhibitors, concerns include herpes zoster infections, increased VTE and ATE incidence, and largely unknown risks during pregnancy and lactation. For the anti-TNF agents, safety concerns include reactivation of tuberculosis, fungal infections, demyelinating syndrome, and skin cancer.

With the shortest half-life of any therapeutic class in rheumatology, adverse events with JAK inhibitors often can resolve quickly, Dr. Strand said.

The increased risk of herpes zoster is important, she added, “but we have a recombinant vaccination that works. It’s quite effective.”

Dr. Weinblatt pointed out that all the JAK inhibitors carry this increase herpes zoster risk, which is related to their mechanism of action. There is a catch with the vaccine, however, he added. The vaccine is approved for treatment of patients 50 years and older. For younger people with RA starting a JAK inhibitor, the cost is out-of-pocket.
 

Evaluating risk of emboli

The incidence of VTE is about two times higher among people with RA, compared with the general population, Dr. Strand said, with research suggesting the majority of risk resides among people with a previous event. However, she added, an emerging profile of thromboembolic events associated with JAK inhibitors is “considered a class effect by the FDA.”

One exception in the JAK inhibitor class could be tofacitinib (Xeljanz), which might carry less risk because “most of the data with tofacitinib are quite good,” Dr. Weinblatt said. One study presented at ACR 2018, for example, showed a similar VTE rate between tofacitinib and TNF inhibitors.

Nevertheless, the FDA issued a boxed warning in July 2019 about elevated risks of blood clots and death at a higher dose of tofacitinib. The concerns stem from an open-label, endpoint-driven study mandated by the FDA to explore major adverse cardiac events. “There was a clinically important and statistically significant occurrence of pulmonary embolism and VTE, and an increase in mortality in the 10-mg dose group as opposed to the anti-TNF therapies,” Dr. Weinblatt said. As a result, the FDA requested patients on the 10-mg twice-daily dose be transitioned to the 5-mg twice-daily dose.

The package labeling for the JAK inhibitors baricitinib (Olumiant) and upadacitinib (Rinvoq) feature warnings about increased risk for thromboembolic events. Furthermore, the labeling for filgotinib, a JAK inhibitor in development that received a complete response letter from the FDA in August 2020, is expected to carry the same warning.An unanswered question remains on why this class of agents potentially increases risk of thromboembolism. “We’re all uncomfortable because there is no known mechanism of JAK inhibition that should lead to this,” he added. Another unresolved issue is whether or not patients prescribed a JAK inhibitor should also be prescribed an anticoagulant.
 

Anti-TNF adverse events

Infections, primarily reactivation of tuberculosis and an increased risk for fungal disease, are concerns with the anti-TNF agents. However, the risk is not restricted to this class. “Greater risk of infection is seen with all our immune-modulating therapies,” Dr. Weinblatt said.

Rare adverse events include demyelinating syndromes, hematologic toxicity, and a worsening of heart failure in some cases.

“Despite a concern about malignancy, the only defined cancer reported over 22 years of use was skin cancer,” he said. “It took more than a decade of ongoing registry data for skin cancer to be identified. It was not noted in randomized, placebo-controlled trials.”
 

Potential pregnancy concerns

When it comes to risk during reproduction, “there is a clear difference,” Dr. Weinblatt said. “We know anti-TNF therapy can be used safely in pregnant women. We know they can conceive on them and maintain them during pregnancy. They can also breastfeed on them.”

“Frankly, I’m not so ‘gung ho’ on TNF inhibitor safety in pregnancy and lactation with exception of certolizumab, which doesn’t result in high levels of antibody in the placenta or the mother’s milk,” Dr. Strand said.

The 2020 ACR Guideline for the Management of Reproductive Health in Rheumatic and Musculoskeletal Diseases states that all anti-TNF therapies can be used during pregnancy and lactation, Dr. Weinblatt said. “Although I agree certolizumab has the best safety profile, all of them can be used.”

“The same is not true with the jakinibs,” he added, pointing to warnings that women of reproductive age should use contraception while on JAK inhibitors and for 4 weeks after stopping treatment.

However, Dr. Strand defended the pregnancy risk with JAK inhibitors. She cited two publications, including a 2016 study where researchers evaluated the safety of tofacitinib during pregnancy in women with rheumatoid arthritis and psoriasis. “There was only one possible deformity, a pulmonary stenosis,” Dr. Strand said. “Essentially, the majority of patients delivered healthy babies. There was very little difference from what we know occurs in RA otherwise.”

A 2018 study assessed pregnancy outcomes with tofacitinib among people with ulcerative colitis, “again showing the majority of patients had normal deliveries.”

“There just aren’t enough data,” Dr. Weinblatt said. “Perhaps in 5 years, we will reach same conclusion with the jakinibs.”
 

Differences in cost?

“We have not benefited yet from the biosimilar costs. But in Europe, the cost of an adalimumab or etanercept biosimilar is about $5,000, versus about $50,000 to $60,000 in the U.S. for the JAK inhibitors,” Dr. Weinblatt said. “So there are major cost savings with biosimilars.”

“I can’t understand cost at all for our drugs,” he continued. “They’re not rational, and the price increases are clearly not rational. Potentially, a small molecule is going to be a lot easier to produce than a biologic, so you could argue that generic jakinibs ought to be less. But in the United States we have a distorted pricing model.”

“Until that changes, I don’t think we can predict [future costs]. One could predict that generics and biosimilars will be less than the orginators,” Dr. Weinblatt said.

“It is really criminal we don’t have biosimilars for most of our TNFs, but that is the way it is,” Dr. Strand said.
 

Summary statements

“The JAK-inhibitor class is an exciting development for rheumatology and a broad variety of autoimmune diseases,” Dr. Strand said.

“In rheumatoid arthritis, they should be used early,” she added. “Based on phase 3 trials, responses are better in progressively earlier disease with less treatment-experienced patients.”

She pointed out that many patients like the convenience of the oral JAK inhibitors.

Dr. Weinblatt stated the 22 years of clinical experience with the anti-TNF class versus about 8 years with jakinibs favors the biologics. “Virtually every approved drug has been tested versus methotrexate, in early studies, long-term studies, and most importantly, in reduction and withdrawal studies, which are not available with the JAK inhibitors.”

Anti-TNFs have impressive effects on clinical disease activity, functional outcomes, and radiographic progression, Dr. Weinblatt said. They work in early and longstanding disease among patients who are disease-modifying antirheumatic drug naive and after multiple DMARD failures, he added.
 

Adding up the vote

The question was: Should JAK inhibitors be used before TNF inhibitors? The results showed 69%-31% in favor of anti-TNF agents.

“So the majority are more comfortable using TNFs,” said debate moderator Elizabeth Wahl, MD, of the department of rheumatology at VA Puget Sound Healthcare System and the University of Washington in Seattle. Regarding a switch to JAK inhibitors, she interpreted the poll numbers to mean, “we are not there yet, it takes years and years of safety data.”

Both Dr. Strand and Dr. Weinblatt disclosed numerous financial relationships with pharmaceutical companies that market RA drugs.

Restricting percutaneous interventions (PCI) to only those stenotic lesions that are ischemic by fractional flow reserve (FFR) thresholds is associated with better 5-year outcomes whether or not PCI is deployed, according to a cohort study presented at the American Heart Association scientific sessions.

For those that met the FFR threshold for ischemia, defined as up to 0.80, PCI reduced the risk of a major adverse cardiac event (MACE) at 5 years by 23% (hazard ratio, 0.77) relative to no PCI. Conversely, those not indicated for PCI because of a higher FFR had a 37% higher risk of MACE (HR, 1.37) at 5 years if treated with PCI relative to those who were not.

“The story of overuse of PCI is important,” reported the senior author Dennis Ko, MD, a scientist affiliated with the Schulich Heart Research Program, Sunnybrook Research Institute, University of Toronto, Canada. “We as interventionalists often think that putting in a stent is not harmful, and that turned out not to be the case.”

The FFR threshold for intervening with PCI is evidence based. Several trials, including one published in 2014, have associated PCI with better outcomes relative to medical therapy when FFR is 0.80 or lower. Other evidence suggests no advantage and possible harm for PCI performed if FFR is higher. Multiple guidelines, including those from the AHA, recommend against PCI if FFR is more than 0.80.

“As FRR is gaining in popularity, we were interested in whether physicians follow the thresholds in routine clinical practice and what happens to patient outcomes [if they are or are not followed],” Dr. Ko explained.

In this retrospective study by Dr. Ko’s trainee, Maneesh Sud, MD, and simultaneously published in JAMA, the answer was that there is deviation, and deviation leads to bad outcomes.

The 9,106 coronary artery disease patients included in the study underwent single-vessel FFR assessment within a 5-year period in Canada. The two cohorts evaluated were those with a lesional FFR of 0.80 or less, defined as ischemic, and those with a lesion with higher FFR, defined as nonischemic. The primary MACE outcome comprised death, myocardial infarction, unstable angina, or urgent coronary revascularization.

Of the 2,693 patients who met the FFR threshold of ischemia, 75.3% received PCI, and 24.7% were treated with medical therapy only. Of the 6,413 patients with nonischemic FFR, 87.4% were treated with medical therapy and 12.6% received PCI.

In those with ischemic FFR, event curves for MACE separated rapidly. At 30 days, the risk of MACE was 53% lower (HR, 0.47) in those receiving PCI. By 1 year, the advantage was less (HR, 0.76), but it was steady thereafter and remained about the same at 5 years (HR, 0.77; 95% confidence interval, 0.63-0.94). Relative advantages for each component of MACE went in the same direction. At 5 years, PCI exerted its greatest numerical advantage for the outcome or urgent coronary revascularization (HR, 0.71) and its least numerical advantage for MI (HR, 0.92), but none of these differences reached statistical significance.

In those with nonischemic coronary lesions on FFR, PCI was associated with more than twice the risk for MACE at 30 days (HR, 2.11), but the increase in risk relative to medical management fell at 1 year (HR 1.67) and 5 years (HR, 1.37). All of the individual components of MACE were numerically increased at all time points except for death, which was numerically lower at 30 days (HR, 0.41) and 5 years (HR, 0.94), even though these differences were not significant.

It could not be ascertained from these data why PCI was not performed when there was an indication or why it was performed when there was not. The investigators speculated that some clinicians may decide against PCI for ischemic lesions in the absence of symptoms or when concerned about comorbidities. They might offer PCI in nonischemic lesions because of symptoms, positive tests other than FFR, or FFR values near the threshold.

“I think the main message of our paper is that adherence of the FFR threshold as established by clinical trials is important,” Dr. Ko said in an interview. This not only means performing PCI when it is indicated, but refraining from PCI when it is not.

Basically, this study confirms that the guideline thresholds are valid, according to Jared M. O’Leary, MD, who is experienced with FFR and is Medical Director for Quality at the Vanderbilt Heart and Vascular Institute, Nashville, Tenn.

“It confirms the utility of FFR in the real world,” he said, adding that the results are “totally consistent with our practice.” He called FFR “an important tool in the cardiac cath lab” not only for determining when revascularization will benefit the patient but the opposite.

“The flip side is also true: Stenting should be avoided if a negative FFR is obtained,” he said, calling this technique “particularly useful for lesions that appear borderline by visual estimation alone.”
 

SOURCE: Sud M et al. AHA 2020. JAMA. 2020 Nov 13. doi: 10.1001/jama.2020.22708.

Restricting percutaneous interventions (PCI) to only those stenotic lesions that are ischemic by fractional flow reserve (FFR) thresholds is associated with better 5-year outcomes whether or not PCI is deployed, according to a cohort study presented at the American Heart Association scientific sessions.

For those that met the FFR threshold for ischemia, defined as up to 0.80, PCI reduced the risk of a major adverse cardiac event (MACE) at 5 years by 23% (hazard ratio, 0.77) relative to no PCI. Conversely, those not indicated for PCI because of a higher FFR had a 37% higher risk of MACE (HR, 1.37) at 5 years if treated with PCI relative to those who were not.

“The story of overuse of PCI is important,” reported the senior author Dennis Ko, MD, a scientist affiliated with the Schulich Heart Research Program, Sunnybrook Research Institute, University of Toronto, Canada. “We as interventionalists often think that putting in a stent is not harmful, and that turned out not to be the case.”

The FFR threshold for intervening with PCI is evidence based. Several trials, including one published in 2014, have associated PCI with better outcomes relative to medical therapy when FFR is 0.80 or lower. Other evidence suggests no advantage and possible harm for PCI performed if FFR is higher. Multiple guidelines, including those from the AHA, recommend against PCI if FFR is more than 0.80.

“As FRR is gaining in popularity, we were interested in whether physicians follow the thresholds in routine clinical practice and what happens to patient outcomes [if they are or are not followed],” Dr. Ko explained.

In this retrospective study by Dr. Ko’s trainee, Maneesh Sud, MD, and simultaneously published in JAMA, the answer was that there is deviation, and deviation leads to bad outcomes.

The 9,106 coronary artery disease patients included in the study underwent single-vessel FFR assessment within a 5-year period in Canada. The two cohorts evaluated were those with a lesional FFR of 0.80 or less, defined as ischemic, and those with a lesion with higher FFR, defined as nonischemic. The primary MACE outcome comprised death, myocardial infarction, unstable angina, or urgent coronary revascularization.

Of the 2,693 patients who met the FFR threshold of ischemia, 75.3% received PCI, and 24.7% were treated with medical therapy only. Of the 6,413 patients with nonischemic FFR, 87.4% were treated with medical therapy and 12.6% received PCI.

In those with ischemic FFR, event curves for MACE separated rapidly. At 30 days, the risk of MACE was 53% lower (HR, 0.47) in those receiving PCI. By 1 year, the advantage was less (HR, 0.76), but it was steady thereafter and remained about the same at 5 years (HR, 0.77; 95% confidence interval, 0.63-0.94). Relative advantages for each component of MACE went in the same direction. At 5 years, PCI exerted its greatest numerical advantage for the outcome or urgent coronary revascularization (HR, 0.71) and its least numerical advantage for MI (HR, 0.92), but none of these differences reached statistical significance.

In those with nonischemic coronary lesions on FFR, PCI was associated with more than twice the risk for MACE at 30 days (HR, 2.11), but the increase in risk relative to medical management fell at 1 year (HR 1.67) and 5 years (HR, 1.37). All of the individual components of MACE were numerically increased at all time points except for death, which was numerically lower at 30 days (HR, 0.41) and 5 years (HR, 0.94), even though these differences were not significant.

It could not be ascertained from these data why PCI was not performed when there was an indication or why it was performed when there was not. The investigators speculated that some clinicians may decide against PCI for ischemic lesions in the absence of symptoms or when concerned about comorbidities. They might offer PCI in nonischemic lesions because of symptoms, positive tests other than FFR, or FFR values near the threshold.

“I think the main message of our paper is that adherence of the FFR threshold as established by clinical trials is important,” Dr. Ko said in an interview. This not only means performing PCI when it is indicated, but refraining from PCI when it is not.

Basically, this study confirms that the guideline thresholds are valid, according to Jared M. O’Leary, MD, who is experienced with FFR and is Medical Director for Quality at the Vanderbilt Heart and Vascular Institute, Nashville, Tenn.

“It confirms the utility of FFR in the real world,” he said, adding that the results are “totally consistent with our practice.” He called FFR “an important tool in the cardiac cath lab” not only for determining when revascularization will benefit the patient but the opposite.

“The flip side is also true: Stenting should be avoided if a negative FFR is obtained,” he said, calling this technique “particularly useful for lesions that appear borderline by visual estimation alone.”
 

SOURCE: Sud M et al. AHA 2020. JAMA. 2020 Nov 13. doi: 10.1001/jama.2020.22708.

Restricting percutaneous interventions (PCI) to only those stenotic lesions that are ischemic by fractional flow reserve (FFR) thresholds is associated with better 5-year outcomes whether or not PCI is deployed, according to a cohort study presented at the American Heart Association scientific sessions.

For those that met the FFR threshold for ischemia, defined as up to 0.80, PCI reduced the risk of a major adverse cardiac event (MACE) at 5 years by 23% (hazard ratio, 0.77) relative to no PCI. Conversely, those not indicated for PCI because of a higher FFR had a 37% higher risk of MACE (HR, 1.37) at 5 years if treated with PCI relative to those who were not.

“The story of overuse of PCI is important,” reported the senior author Dennis Ko, MD, a scientist affiliated with the Schulich Heart Research Program, Sunnybrook Research Institute, University of Toronto, Canada. “We as interventionalists often think that putting in a stent is not harmful, and that turned out not to be the case.”

The FFR threshold for intervening with PCI is evidence based. Several trials, including one published in 2014, have associated PCI with better outcomes relative to medical therapy when FFR is 0.80 or lower. Other evidence suggests no advantage and possible harm for PCI performed if FFR is higher. Multiple guidelines, including those from the AHA, recommend against PCI if FFR is more than 0.80.

“As FRR is gaining in popularity, we were interested in whether physicians follow the thresholds in routine clinical practice and what happens to patient outcomes [if they are or are not followed],” Dr. Ko explained.

In this retrospective study by Dr. Ko’s trainee, Maneesh Sud, MD, and simultaneously published in JAMA, the answer was that there is deviation, and deviation leads to bad outcomes.

The 9,106 coronary artery disease patients included in the study underwent single-vessel FFR assessment within a 5-year period in Canada. The two cohorts evaluated were those with a lesional FFR of 0.80 or less, defined as ischemic, and those with a lesion with higher FFR, defined as nonischemic. The primary MACE outcome comprised death, myocardial infarction, unstable angina, or urgent coronary revascularization.

Of the 2,693 patients who met the FFR threshold of ischemia, 75.3% received PCI, and 24.7% were treated with medical therapy only. Of the 6,413 patients with nonischemic FFR, 87.4% were treated with medical therapy and 12.6% received PCI.

In those with ischemic FFR, event curves for MACE separated rapidly. At 30 days, the risk of MACE was 53% lower (HR, 0.47) in those receiving PCI. By 1 year, the advantage was less (HR, 0.76), but it was steady thereafter and remained about the same at 5 years (HR, 0.77; 95% confidence interval, 0.63-0.94). Relative advantages for each component of MACE went in the same direction. At 5 years, PCI exerted its greatest numerical advantage for the outcome or urgent coronary revascularization (HR, 0.71) and its least numerical advantage for MI (HR, 0.92), but none of these differences reached statistical significance.

In those with nonischemic coronary lesions on FFR, PCI was associated with more than twice the risk for MACE at 30 days (HR, 2.11), but the increase in risk relative to medical management fell at 1 year (HR 1.67) and 5 years (HR, 1.37). All of the individual components of MACE were numerically increased at all time points except for death, which was numerically lower at 30 days (HR, 0.41) and 5 years (HR, 0.94), even though these differences were not significant.

It could not be ascertained from these data why PCI was not performed when there was an indication or why it was performed when there was not. The investigators speculated that some clinicians may decide against PCI for ischemic lesions in the absence of symptoms or when concerned about comorbidities. They might offer PCI in nonischemic lesions because of symptoms, positive tests other than FFR, or FFR values near the threshold.

“I think the main message of our paper is that adherence of the FFR threshold as established by clinical trials is important,” Dr. Ko said in an interview. This not only means performing PCI when it is indicated, but refraining from PCI when it is not.

Basically, this study confirms that the guideline thresholds are valid, according to Jared M. O’Leary, MD, who is experienced with FFR and is Medical Director for Quality at the Vanderbilt Heart and Vascular Institute, Nashville, Tenn.

“It confirms the utility of FFR in the real world,” he said, adding that the results are “totally consistent with our practice.” He called FFR “an important tool in the cardiac cath lab” not only for determining when revascularization will benefit the patient but the opposite.

“The flip side is also true: Stenting should be avoided if a negative FFR is obtained,” he said, calling this technique “particularly useful for lesions that appear borderline by visual estimation alone.”
 

SOURCE: Sud M et al. AHA 2020. JAMA. 2020 Nov 13. doi: 10.1001/jama.2020.22708.

Researchers are testing whether a probiotic called Lactobacillus rhamnosus GG can prevent COVID-19 in household contacts of COVID patients.

On the Nov. 12 episode of the Blood & Cancer podcast, Anthony D. Sung, MD, of Duke University, Durham, N.C., joined host David H. Henry, MD, of Penn Medicine in Philadelphia, to discuss the trial of LGG as well as other research. The following transcript of that discussion has been edited for length and clarity.
 

David Henry, MD: Here we are in COVID. We’re recording this the first week in November. Sadly, cases are spiking in the country. And I understand you’ve got some information that you might share about how manipulating ... the microbiome that we all exist with inside our gut might somehow play into doing better or worse with COVID.

Anthony Sung, MD: Absolutely. So, as associate director of the Duke Microbiome Center, I was approached by one of my colleagues, Paul Wischmeyer, who is a professor of anesthesiology and critical care medicine at Duke. Paul had previously done some very nice murine studies with the probiotic Lactobacillus rhamnosus GG, or LGG.

He showed, in a murine model of pseudomonas pneumonia, that giving LGG to mice would help modulate their microbiome and, in turn, their immune system, leading to decreased inflammation, decreased TNF-alpha, IL [interleukin]-2, and IL-6, [and] increased Treg cells [Clin Nutr. 2017;36[6]:1549-57]. This also helped prevent lung injury, and it actually significantly improved survival in mice receiving LGG [Shock. 2013;40[6]:496-503].

In addition, there has been a randomized clinical trial of LGG showing that its administration would help prevent ventilator-associated pneumonia, or VAP [Am J Respir Crit Care Med. 2010 Oct 15;182[8]:1058-64].

And a few years ago, there was another RCT [randomized, controlled trial], published in Nature, showing that another Lactobacillus product significantly decreased the combined endpoint of sepsis and mortality, primarily by reducing lower respiratory tract infection [Nature. 2017 Aug 24;548[7668]:407-12].
 

Dr. Henry: And how is that working? What is the bacillus doing to help us?

Dr. Sung: We think it’s through modulating the immune system. As mentioned in Paul’s studies, we saw significantly decreased amounts of TNF-alpha, IL-2, and IL-6, which are the same cytokines that have been implicated in COVID-19 and associated with increased lung injury in patients during this pandemic.

And we believe that by giving individuals this probiotic, LGG, we may help modulate the immune system, decrease lung injury and symptoms, and maybe even prevent COVID-19.

So with support from the Duke Microbiome Center, as well as private donations and philanthropy, we are conducting a randomized clinical trial of LGG to prevent COVID-19 in household contacts who’ve been exposed to the disease. In other words, if someone in the house gets COVID-19, we want to try to prophylax everybody else living in that house and prevent them from coming down with the same infection.
 

Dr. Henry: And this is an oral administration?

Dr. Sung: Correct. This is an oral pill, two pills once a day.

Dr. Henry: And it’s an ongoing study, of course, in COVID right now?

Dr. Sung: Correct. So we have an IND [investigational new drug application] from the FDA [Food and Drug Administration], and we are actively recruiting subjects both at Duke University, but also due to the unique study design, we can enroll patients anywhere across the country. Because of the importance of social distancing, everything is done remotely.

So a household contact can hear about us, either through your podcast or one of our Facebook ads or through other media. They can reach out to our study website, which is https://sites.duke.edu/protectehc, or reach out to us at our study email, [email protected].

And we can go ahead and screen them for eligibility in our trial. And if they are eligible and they consent to participate, we will mail them a package basically overnight, FedEx, containing either LGG or placebo, as well as kits so that they can self-collect their stool and nasal swabs so we can test it for SARS-CoV-2 by PCR [polymerase chain reaction] and look at the microbiome.

Dr. Sung and Dr. Henry have no relevant disclosures. Funding for the trial is provided by the Duke Microbiome Center and philanthropic giving. The LGG and placebo used in the trial are provided by DSM.

Researchers are testing whether a probiotic called Lactobacillus rhamnosus GG can prevent COVID-19 in household contacts of COVID patients.

On the Nov. 12 episode of the Blood & Cancer podcast, Anthony D. Sung, MD, of Duke University, Durham, N.C., joined host David H. Henry, MD, of Penn Medicine in Philadelphia, to discuss the trial of LGG as well as other research. The following transcript of that discussion has been edited for length and clarity.
 

David Henry, MD: Here we are in COVID. We’re recording this the first week in November. Sadly, cases are spiking in the country. And I understand you’ve got some information that you might share about how manipulating ... the microbiome that we all exist with inside our gut might somehow play into doing better or worse with COVID.

Anthony Sung, MD: Absolutely. So, as associate director of the Duke Microbiome Center, I was approached by one of my colleagues, Paul Wischmeyer, who is a professor of anesthesiology and critical care medicine at Duke. Paul had previously done some very nice murine studies with the probiotic Lactobacillus rhamnosus GG, or LGG.

He showed, in a murine model of pseudomonas pneumonia, that giving LGG to mice would help modulate their microbiome and, in turn, their immune system, leading to decreased inflammation, decreased TNF-alpha, IL [interleukin]-2, and IL-6, [and] increased Treg cells [Clin Nutr. 2017;36[6]:1549-57]. This also helped prevent lung injury, and it actually significantly improved survival in mice receiving LGG [Shock. 2013;40[6]:496-503].

In addition, there has been a randomized clinical trial of LGG showing that its administration would help prevent ventilator-associated pneumonia, or VAP [Am J Respir Crit Care Med. 2010 Oct 15;182[8]:1058-64].

And a few years ago, there was another RCT [randomized, controlled trial], published in Nature, showing that another Lactobacillus product significantly decreased the combined endpoint of sepsis and mortality, primarily by reducing lower respiratory tract infection [Nature. 2017 Aug 24;548[7668]:407-12].
 

Dr. Henry: And how is that working? What is the bacillus doing to help us?

Dr. Sung: We think it’s through modulating the immune system. As mentioned in Paul’s studies, we saw significantly decreased amounts of TNF-alpha, IL-2, and IL-6, which are the same cytokines that have been implicated in COVID-19 and associated with increased lung injury in patients during this pandemic.

And we believe that by giving individuals this probiotic, LGG, we may help modulate the immune system, decrease lung injury and symptoms, and maybe even prevent COVID-19.

So with support from the Duke Microbiome Center, as well as private donations and philanthropy, we are conducting a randomized clinical trial of LGG to prevent COVID-19 in household contacts who’ve been exposed to the disease. In other words, if someone in the house gets COVID-19, we want to try to prophylax everybody else living in that house and prevent them from coming down with the same infection.
 

Dr. Henry: And this is an oral administration?

Dr. Sung: Correct. This is an oral pill, two pills once a day.

Dr. Henry: And it’s an ongoing study, of course, in COVID right now?

Dr. Sung: Correct. So we have an IND [investigational new drug application] from the FDA [Food and Drug Administration], and we are actively recruiting subjects both at Duke University, but also due to the unique study design, we can enroll patients anywhere across the country. Because of the importance of social distancing, everything is done remotely.

So a household contact can hear about us, either through your podcast or one of our Facebook ads or through other media. They can reach out to our study website, which is https://sites.duke.edu/protectehc, or reach out to us at our study email, [email protected].

And we can go ahead and screen them for eligibility in our trial. And if they are eligible and they consent to participate, we will mail them a package basically overnight, FedEx, containing either LGG or placebo, as well as kits so that they can self-collect their stool and nasal swabs so we can test it for SARS-CoV-2 by PCR [polymerase chain reaction] and look at the microbiome.

Dr. Sung and Dr. Henry have no relevant disclosures. Funding for the trial is provided by the Duke Microbiome Center and philanthropic giving. The LGG and placebo used in the trial are provided by DSM.

Researchers are testing whether a probiotic called Lactobacillus rhamnosus GG can prevent COVID-19 in household contacts of COVID patients.

On the Nov. 12 episode of the Blood & Cancer podcast, Anthony D. Sung, MD, of Duke University, Durham, N.C., joined host David H. Henry, MD, of Penn Medicine in Philadelphia, to discuss the trial of LGG as well as other research. The following transcript of that discussion has been edited for length and clarity.
 

David Henry, MD: Here we are in COVID. We’re recording this the first week in November. Sadly, cases are spiking in the country. And I understand you’ve got some information that you might share about how manipulating ... the microbiome that we all exist with inside our gut might somehow play into doing better or worse with COVID.

Anthony Sung, MD: Absolutely. So, as associate director of the Duke Microbiome Center, I was approached by one of my colleagues, Paul Wischmeyer, who is a professor of anesthesiology and critical care medicine at Duke. Paul had previously done some very nice murine studies with the probiotic Lactobacillus rhamnosus GG, or LGG.

He showed, in a murine model of pseudomonas pneumonia, that giving LGG to mice would help modulate their microbiome and, in turn, their immune system, leading to decreased inflammation, decreased TNF-alpha, IL [interleukin]-2, and IL-6, [and] increased Treg cells [Clin Nutr. 2017;36[6]:1549-57]. This also helped prevent lung injury, and it actually significantly improved survival in mice receiving LGG [Shock. 2013;40[6]:496-503].

In addition, there has been a randomized clinical trial of LGG showing that its administration would help prevent ventilator-associated pneumonia, or VAP [Am J Respir Crit Care Med. 2010 Oct 15;182[8]:1058-64].

And a few years ago, there was another RCT [randomized, controlled trial], published in Nature, showing that another Lactobacillus product significantly decreased the combined endpoint of sepsis and mortality, primarily by reducing lower respiratory tract infection [Nature. 2017 Aug 24;548[7668]:407-12].
 

Dr. Henry: And how is that working? What is the bacillus doing to help us?

Dr. Sung: We think it’s through modulating the immune system. As mentioned in Paul’s studies, we saw significantly decreased amounts of TNF-alpha, IL-2, and IL-6, which are the same cytokines that have been implicated in COVID-19 and associated with increased lung injury in patients during this pandemic.

And we believe that by giving individuals this probiotic, LGG, we may help modulate the immune system, decrease lung injury and symptoms, and maybe even prevent COVID-19.

So with support from the Duke Microbiome Center, as well as private donations and philanthropy, we are conducting a randomized clinical trial of LGG to prevent COVID-19 in household contacts who’ve been exposed to the disease. In other words, if someone in the house gets COVID-19, we want to try to prophylax everybody else living in that house and prevent them from coming down with the same infection.
 

Dr. Henry: And this is an oral administration?

Dr. Sung: Correct. This is an oral pill, two pills once a day.

Dr. Henry: And it’s an ongoing study, of course, in COVID right now?

Dr. Sung: Correct. So we have an IND [investigational new drug application] from the FDA [Food and Drug Administration], and we are actively recruiting subjects both at Duke University, but also due to the unique study design, we can enroll patients anywhere across the country. Because of the importance of social distancing, everything is done remotely.

So a household contact can hear about us, either through your podcast or one of our Facebook ads or through other media. They can reach out to our study website, which is https://sites.duke.edu/protectehc, or reach out to us at our study email, [email protected].

And we can go ahead and screen them for eligibility in our trial. And if they are eligible and they consent to participate, we will mail them a package basically overnight, FedEx, containing either LGG or placebo, as well as kits so that they can self-collect their stool and nasal swabs so we can test it for SARS-CoV-2 by PCR [polymerase chain reaction] and look at the microbiome.

Dr. Sung and Dr. Henry have no relevant disclosures. Funding for the trial is provided by the Duke Microbiome Center and philanthropic giving. The LGG and placebo used in the trial are provided by DSM.

Can receiving all posttransplant care at home improve outcomes for patients undergoing hematopoietic stem cell transplant (HSCT)? Researchers are conducting phase 2 trials to find out.

Anthony D. Sung, MD, of Duke University, Durham, N.C., described this research to David H. Henry, MD, of Penn Medicine in Philadelphia, host of the Blood & Cancer podcast.

On the Nov. 12 episode of Blood & Cancer, Dr. Sung outlined the process of receiving post-HSCT care at home and discussed Duke’s clinical trials assessing the impact of home care on costs, quality of life, the microbiome, graft-versus-host disease (GVHD), and other outcomes. The following transcript of that discussion has been edited for length and clarity.
 

David Henry, MD: Welcome to this podcast. We’re delighted to have you listening today because we’re going to be speaking with Dr. Anthony Sung from Duke University, where he is assistant professor of medicine in the division of hematologic malignancies and cellular therapies.

So let’s get right into it. I’m a generalist at Pennsylvania Hospital in Philadelphia, where we do auto [autologous] transplants at the main university hospital, autos and allos [allogeneic], and these patients are in [hospital] anywhere from a little bit to a long time. And I’ve often thought to try and do some of this as outpatient. But I think you have a project, which I’m going to ask you to describe, where you try and do most [treatment] outpatient. So tell me what this project is all about, and we’ll skip through how it works.
 

Anthony Sung, MD: Absolutely. So this is focused on both autologous as well as allogeneic stem cell transplant patients at Duke and a few other centers around the country. Duke University has actually had a long history of an outpatient transplant program. This program is based in a day hospital, which is basically like a high-functioning clinic that’s open 7 days a week. Patients can come into the hospital and receive blood transfusions, IV infusions, and any other therapies that they would need as part of their stem cell transplant treatment in the outpatient setting, returning to their home or to a furnished apartment, temporary lodging, while they’re receiving their care.

What we have done, however, is to take this a step further and deliver care within the patient’s own home. In a sense, we’re returning to an older form of medicine where doctors would make house calls. Within our home-transplant program, instead of the patients having to be in the hospital or instead of having to come back and forth to the outpatient hospital every day, which places additional stresses and strains upon them, our providers will make house calls to the patient’s homes, will draw their labs right there, do a history and physical exam, assess and attend to any of the needs that they have.

Then in the afternoon, the providers will return, have the labs run in the hospital, as they would normally do, a CBC, CMP [comprehensive metabolic panel], and so forth. And then a nurse would return to the patient’s home if needed to deliver any interventions, such as blood transfusions, intravenous fluids, or electrolytes, right there in the comfort of the patient’s own home.
 

Dr. Henry: So let’s then take it through what happens. Say I am a patient with myeloma. I’ve had various therapies, and it’s time for me to get an autotransplant, let’s say. And so I need to do a couple of things. I need to get my stem cells collected. I need to then get my high-dose [conditioning] therapy, and then follows the stem cell therapy reinfusion. So can you take me through each step? Where is that done?

Dr. Sung: Absolutely. So the collection will occur in the outpatient setting, typically after mobilization with G-CSF [granulocyte colony–stimulating factor] and/or plerixafor. That will occur in our outpatient clinic with one of our leukapheresis machines. And the patient will then return to that same outpatient clinic, which is the same building, the same facility as the hospital, to receive melphalan conditioning. And then, following conditioning, about 24 hours after, day 0, that’s the day of their stem cell transplant infusion, which we do in the hospital setting just because of the potential for reactions associated with that.

But everything after that, from day 1 onwards, we try to keep them at home. And as I said, they will stay in their home. One of our nurse practitioners or physician assistants will visit them in the morning, do the assessment and draw the labs. And nurses will return in the afternoon to deliver any supportive care that they need.
 

Dr. Henry: So let’s define “home.” So I’m a Philadelphia resident and I say to you, Dr. Sung, I want to go home. You say, well, Philadelphia is too far. What is close enough and not too far, when you say home?

Dr. Sung: Absolutely. So when we originally conceived the program, we focused on patients who lived within an hour of our transplant center. And in part, that was because, as you know, unfortunately, things can sometimes go wrong during transplant. One of the most concerning ones is infections. And if a patient were to develop a neutropenic fever, we would want them to be seen as urgently as possible within an hour. And that’s where our limitation comes from.

So for our patients who live more than an hour away, those are the ones that we will have relocate to temporary lodging near our transplant center. And we’ve worked with several facilities in the area that have clean, furnished units that are available for rent. Many insurances also include lodging benefits for patients during stem cell transplant, recognizing this need. And historically, those [patients] were not considered part of our transplant patient cohorts.

I have not mentioned, but we initially did this in a phase 1 study, and we’re now studying it in a series of randomized, phase 2 studies that I can go into detail later on. And because they were not necessarily in their home, but a temporary lodging environment, those patients who relocated to Durham were not eligible for a home transplant study.

However, in the setting of the COVID-19 pandemic, we’ve actually pivoted our program in many ways. Specifically, if you think about a patient who’s coming into contact with the medical system, they come to the hospital, they meet someone at the door who is screening them for COVID-19. They see someone who checks them in at the front desk. A medical assistant takes them in the back. Someone calls their labs and phlebotomy. They may encounter other patients and environmental services, other individuals in the setting. You’re talking about dozens of different encounters. Who knows how many surfaces that potentially someone with COVID-19 has coughed on or contaminated?

And in contrast, you have house calls, which even if they are located in the temporary lodging, that’s just one or two individuals going into their living environment. They’re not encountering any different surfaces. And so, in the setting of COVID-19, we felt that this platform had the potential to help protect all our transplant patients who are among the most vulnerable patients, the most immunocompromised patients, and so we expanded our program to include those individuals as well.
 

Dr. Henry: So ... what are the actual outcomes of your patients in terms of how they’re doing, engrafting, and getting cured of their malignancy?

Dr. Sung: So as I mentioned, we first did this in a phase 1 safety and feasibility pilot study of both autologous and allo-transplant patients. This was presented at the annual meeting of the American Society of Hematology [Blood. 2017;130:745]. And we’re actually about ready to submit our manuscript on this.

And we found no difference in outcomes between patients who received care in the home transplant setting versus those who received conventional care either in the day hospital or hospital environment. The process appeared safe. Patients did just as well, if not better. Certainly, anecdotally, patients would talk about feeling so much more comfortable and happier being cared for in that home environment.

And we are now in the process of formally studying these outcomes in two NIH [National Institutes of Health]-funded clinical trials, one focused on allogeneic transplant patients [NCT02218151] and the other focused on autologous transplant patients [NCT01725022].
 

Dr. Henry: So of course, I’m waiting for this next question, which is cost. The services are the same, but you have people traveling, people who are highly skilled caregivers. Have you looked at cost differences from hospital versus home?

Dr. Sung: Absolutely. So you do have increased upfront costs because you have travel time for advanced practice providers and nurses. Not only that, but when a nurse is helping to give a patient a blood transfusion in the home environment, they’re 1:1 with that patient as opposed to the day hospital where a nurse could help with transfusions simultaneously for multiple patients. At the same time, by keeping patients out of the hospital, you have drastic, significant cost savings in that way.

In addition, I should mention, part of why we’re conducting these randomized, phase 2 clinical trials is we believe home care actually has the potential to decrease complications. One area of my research is on the impact of the microbiome, the bacteria in the gut, on transplant outcomes. And we’ve done a number of studies, many in collaboration with Memorial Sloan Kettering, showing that disruption of the microbiota, the bacteria in the gut, is associated with increased infections, graft-versus-host disease, and treatment-related mortality if we’re able to keep patients in their home setting.

However, I actually should go back a step. It’s well known that, if you take an individual from their home setting and put them in a foreign environment such as the hospital, that new environment, that new diet, hospital food as opposed to home food, and so forth, can dramatically shift the microbiome. Our hypothesis is that, by keeping patients in the home environment, their familiar environment will be able to help preserve their microbiome, thus decreasing infections, graft-versus-host disease, and other complications. That’s actually the goal of our studies: to see if we can preserve the microbiome and decrease complications.
 

Dr. Henry: So how will you evaluate that? Are you doing fecal studies, patient culture studies? How are you testing that?

Dr. Sung: So we have a very broad biobank program where we collect stool on our transplantations, pretransplant, day 0, weekly for the first month. And then, in the case of our allogeneic transplant patients, day 60, 90, 180, and 365.

And we do that both in our home transplant patients as well as their matched controls on the phase 2 studies. And we also collect it on a lot of our other transplant patients as part of our biobanking programs and our observational studies to try to understand what’s going on during transplant and how to help improve transplant outcomes.
 

Dr. Henry: Do you have any results of that? You’re probably showing a difference.

Dr. Sung: We think so, on some preliminary results, but those were based on small numbers of patients. And we’re really hoping that these randomized clinical trials with the larger numbers of patients enrolled will help show that difference.

But getting back to your earlier question about cost, a case of graft-versus-host disease, grade 2 or higher, can add about $100,000 to the cost of care. So if you prevent one case of bad gut or liver graft-versus-host disease, those are your cost savings right there.

The randomized, phase 2 trial for allogeneic transplant patients, the primary endpoint is graft-versus-host disease. So we’re looking at the microbiome and those associations and the prevention of GVHD. For the randomized clinical trial in autologous transplant patients – with autologous stem cells, you’re not going to get GVHD – but we do hope to improve quality of life and long-term outcomes in those patients as well.
 

Dr. Henry: Wonderful. Well, Tony, I really want to thank you so much for talking with us today.

Dr. Sung: Thank you very much for this opportunity. And again, I also want to just thank everyone who’s been involved in these studies, the advanced practice providers and nurses who are caring for our patients at home, the study staff who have been involved. Particularly, I’d like to highlight the role of both Nelson Chao, who’s our division chief and my mentor who piloted and first developed home transplant, and Kristin Nichols, our research nurse who has really led the drive forward.

Dr. Sung and Dr. Henry have no relevant disclosures. The trials are funded by grants from the National Institutes of Health.

Can receiving all posttransplant care at home improve outcomes for patients undergoing hematopoietic stem cell transplant (HSCT)? Researchers are conducting phase 2 trials to find out.

Anthony D. Sung, MD, of Duke University, Durham, N.C., described this research to David H. Henry, MD, of Penn Medicine in Philadelphia, host of the Blood & Cancer podcast.

On the Nov. 12 episode of Blood & Cancer, Dr. Sung outlined the process of receiving post-HSCT care at home and discussed Duke’s clinical trials assessing the impact of home care on costs, quality of life, the microbiome, graft-versus-host disease (GVHD), and other outcomes. The following transcript of that discussion has been edited for length and clarity.
 

David Henry, MD: Welcome to this podcast. We’re delighted to have you listening today because we’re going to be speaking with Dr. Anthony Sung from Duke University, where he is assistant professor of medicine in the division of hematologic malignancies and cellular therapies.

So let’s get right into it. I’m a generalist at Pennsylvania Hospital in Philadelphia, where we do auto [autologous] transplants at the main university hospital, autos and allos [allogeneic], and these patients are in [hospital] anywhere from a little bit to a long time. And I’ve often thought to try and do some of this as outpatient. But I think you have a project, which I’m going to ask you to describe, where you try and do most [treatment] outpatient. So tell me what this project is all about, and we’ll skip through how it works.
 

Anthony Sung, MD: Absolutely. So this is focused on both autologous as well as allogeneic stem cell transplant patients at Duke and a few other centers around the country. Duke University has actually had a long history of an outpatient transplant program. This program is based in a day hospital, which is basically like a high-functioning clinic that’s open 7 days a week. Patients can come into the hospital and receive blood transfusions, IV infusions, and any other therapies that they would need as part of their stem cell transplant treatment in the outpatient setting, returning to their home or to a furnished apartment, temporary lodging, while they’re receiving their care.

What we have done, however, is to take this a step further and deliver care within the patient’s own home. In a sense, we’re returning to an older form of medicine where doctors would make house calls. Within our home-transplant program, instead of the patients having to be in the hospital or instead of having to come back and forth to the outpatient hospital every day, which places additional stresses and strains upon them, our providers will make house calls to the patient’s homes, will draw their labs right there, do a history and physical exam, assess and attend to any of the needs that they have.

Then in the afternoon, the providers will return, have the labs run in the hospital, as they would normally do, a CBC, CMP [comprehensive metabolic panel], and so forth. And then a nurse would return to the patient’s home if needed to deliver any interventions, such as blood transfusions, intravenous fluids, or electrolytes, right there in the comfort of the patient’s own home.
 

Dr. Henry: So let’s then take it through what happens. Say I am a patient with myeloma. I’ve had various therapies, and it’s time for me to get an autotransplant, let’s say. And so I need to do a couple of things. I need to get my stem cells collected. I need to then get my high-dose [conditioning] therapy, and then follows the stem cell therapy reinfusion. So can you take me through each step? Where is that done?

Dr. Sung: Absolutely. So the collection will occur in the outpatient setting, typically after mobilization with G-CSF [granulocyte colony–stimulating factor] and/or plerixafor. That will occur in our outpatient clinic with one of our leukapheresis machines. And the patient will then return to that same outpatient clinic, which is the same building, the same facility as the hospital, to receive melphalan conditioning. And then, following conditioning, about 24 hours after, day 0, that’s the day of their stem cell transplant infusion, which we do in the hospital setting just because of the potential for reactions associated with that.

But everything after that, from day 1 onwards, we try to keep them at home. And as I said, they will stay in their home. One of our nurse practitioners or physician assistants will visit them in the morning, do the assessment and draw the labs. And nurses will return in the afternoon to deliver any supportive care that they need.
 

Dr. Henry: So let’s define “home.” So I’m a Philadelphia resident and I say to you, Dr. Sung, I want to go home. You say, well, Philadelphia is too far. What is close enough and not too far, when you say home?

Dr. Sung: Absolutely. So when we originally conceived the program, we focused on patients who lived within an hour of our transplant center. And in part, that was because, as you know, unfortunately, things can sometimes go wrong during transplant. One of the most concerning ones is infections. And if a patient were to develop a neutropenic fever, we would want them to be seen as urgently as possible within an hour. And that’s where our limitation comes from.

So for our patients who live more than an hour away, those are the ones that we will have relocate to temporary lodging near our transplant center. And we’ve worked with several facilities in the area that have clean, furnished units that are available for rent. Many insurances also include lodging benefits for patients during stem cell transplant, recognizing this need. And historically, those [patients] were not considered part of our transplant patient cohorts.

I have not mentioned, but we initially did this in a phase 1 study, and we’re now studying it in a series of randomized, phase 2 studies that I can go into detail later on. And because they were not necessarily in their home, but a temporary lodging environment, those patients who relocated to Durham were not eligible for a home transplant study.

However, in the setting of the COVID-19 pandemic, we’ve actually pivoted our program in many ways. Specifically, if you think about a patient who’s coming into contact with the medical system, they come to the hospital, they meet someone at the door who is screening them for COVID-19. They see someone who checks them in at the front desk. A medical assistant takes them in the back. Someone calls their labs and phlebotomy. They may encounter other patients and environmental services, other individuals in the setting. You’re talking about dozens of different encounters. Who knows how many surfaces that potentially someone with COVID-19 has coughed on or contaminated?

And in contrast, you have house calls, which even if they are located in the temporary lodging, that’s just one or two individuals going into their living environment. They’re not encountering any different surfaces. And so, in the setting of COVID-19, we felt that this platform had the potential to help protect all our transplant patients who are among the most vulnerable patients, the most immunocompromised patients, and so we expanded our program to include those individuals as well.
 

Dr. Henry: So ... what are the actual outcomes of your patients in terms of how they’re doing, engrafting, and getting cured of their malignancy?

Dr. Sung: So as I mentioned, we first did this in a phase 1 safety and feasibility pilot study of both autologous and allo-transplant patients. This was presented at the annual meeting of the American Society of Hematology [Blood. 2017;130:745]. And we’re actually about ready to submit our manuscript on this.

And we found no difference in outcomes between patients who received care in the home transplant setting versus those who received conventional care either in the day hospital or hospital environment. The process appeared safe. Patients did just as well, if not better. Certainly, anecdotally, patients would talk about feeling so much more comfortable and happier being cared for in that home environment.

And we are now in the process of formally studying these outcomes in two NIH [National Institutes of Health]-funded clinical trials, one focused on allogeneic transplant patients [NCT02218151] and the other focused on autologous transplant patients [NCT01725022].
 

Dr. Henry: So of course, I’m waiting for this next question, which is cost. The services are the same, but you have people traveling, people who are highly skilled caregivers. Have you looked at cost differences from hospital versus home?

Dr. Sung: Absolutely. So you do have increased upfront costs because you have travel time for advanced practice providers and nurses. Not only that, but when a nurse is helping to give a patient a blood transfusion in the home environment, they’re 1:1 with that patient as opposed to the day hospital where a nurse could help with transfusions simultaneously for multiple patients. At the same time, by keeping patients out of the hospital, you have drastic, significant cost savings in that way.

In addition, I should mention, part of why we’re conducting these randomized, phase 2 clinical trials is we believe home care actually has the potential to decrease complications. One area of my research is on the impact of the microbiome, the bacteria in the gut, on transplant outcomes. And we’ve done a number of studies, many in collaboration with Memorial Sloan Kettering, showing that disruption of the microbiota, the bacteria in the gut, is associated with increased infections, graft-versus-host disease, and treatment-related mortality if we’re able to keep patients in their home setting.

However, I actually should go back a step. It’s well known that, if you take an individual from their home setting and put them in a foreign environment such as the hospital, that new environment, that new diet, hospital food as opposed to home food, and so forth, can dramatically shift the microbiome. Our hypothesis is that, by keeping patients in the home environment, their familiar environment will be able to help preserve their microbiome, thus decreasing infections, graft-versus-host disease, and other complications. That’s actually the goal of our studies: to see if we can preserve the microbiome and decrease complications.
 

Dr. Henry: So how will you evaluate that? Are you doing fecal studies, patient culture studies? How are you testing that?

Dr. Sung: So we have a very broad biobank program where we collect stool on our transplantations, pretransplant, day 0, weekly for the first month. And then, in the case of our allogeneic transplant patients, day 60, 90, 180, and 365.

And we do that both in our home transplant patients as well as their matched controls on the phase 2 studies. And we also collect it on a lot of our other transplant patients as part of our biobanking programs and our observational studies to try to understand what’s going on during transplant and how to help improve transplant outcomes.
 

Dr. Henry: Do you have any results of that? You’re probably showing a difference.

Dr. Sung: We think so, on some preliminary results, but those were based on small numbers of patients. And we’re really hoping that these randomized clinical trials with the larger numbers of patients enrolled will help show that difference.

But getting back to your earlier question about cost, a case of graft-versus-host disease, grade 2 or higher, can add about $100,000 to the cost of care. So if you prevent one case of bad gut or liver graft-versus-host disease, those are your cost savings right there.

The randomized, phase 2 trial for allogeneic transplant patients, the primary endpoint is graft-versus-host disease. So we’re looking at the microbiome and those associations and the prevention of GVHD. For the randomized clinical trial in autologous transplant patients – with autologous stem cells, you’re not going to get GVHD – but we do hope to improve quality of life and long-term outcomes in those patients as well.
 

Dr. Henry: Wonderful. Well, Tony, I really want to thank you so much for talking with us today.

Dr. Sung: Thank you very much for this opportunity. And again, I also want to just thank everyone who’s been involved in these studies, the advanced practice providers and nurses who are caring for our patients at home, the study staff who have been involved. Particularly, I’d like to highlight the role of both Nelson Chao, who’s our division chief and my mentor who piloted and first developed home transplant, and Kristin Nichols, our research nurse who has really led the drive forward.

Dr. Sung and Dr. Henry have no relevant disclosures. The trials are funded by grants from the National Institutes of Health.

Can receiving all posttransplant care at home improve outcomes for patients undergoing hematopoietic stem cell transplant (HSCT)? Researchers are conducting phase 2 trials to find out.

Anthony D. Sung, MD, of Duke University, Durham, N.C., described this research to David H. Henry, MD, of Penn Medicine in Philadelphia, host of the Blood & Cancer podcast.

On the Nov. 12 episode of Blood & Cancer, Dr. Sung outlined the process of receiving post-HSCT care at home and discussed Duke’s clinical trials assessing the impact of home care on costs, quality of life, the microbiome, graft-versus-host disease (GVHD), and other outcomes. The following transcript of that discussion has been edited for length and clarity.
 

David Henry, MD: Welcome to this podcast. We’re delighted to have you listening today because we’re going to be speaking with Dr. Anthony Sung from Duke University, where he is assistant professor of medicine in the division of hematologic malignancies and cellular therapies.

So let’s get right into it. I’m a generalist at Pennsylvania Hospital in Philadelphia, where we do auto [autologous] transplants at the main university hospital, autos and allos [allogeneic], and these patients are in [hospital] anywhere from a little bit to a long time. And I’ve often thought to try and do some of this as outpatient. But I think you have a project, which I’m going to ask you to describe, where you try and do most [treatment] outpatient. So tell me what this project is all about, and we’ll skip through how it works.
 

Anthony Sung, MD: Absolutely. So this is focused on both autologous as well as allogeneic stem cell transplant patients at Duke and a few other centers around the country. Duke University has actually had a long history of an outpatient transplant program. This program is based in a day hospital, which is basically like a high-functioning clinic that’s open 7 days a week. Patients can come into the hospital and receive blood transfusions, IV infusions, and any other therapies that they would need as part of their stem cell transplant treatment in the outpatient setting, returning to their home or to a furnished apartment, temporary lodging, while they’re receiving their care.

What we have done, however, is to take this a step further and deliver care within the patient’s own home. In a sense, we’re returning to an older form of medicine where doctors would make house calls. Within our home-transplant program, instead of the patients having to be in the hospital or instead of having to come back and forth to the outpatient hospital every day, which places additional stresses and strains upon them, our providers will make house calls to the patient’s homes, will draw their labs right there, do a history and physical exam, assess and attend to any of the needs that they have.

Then in the afternoon, the providers will return, have the labs run in the hospital, as they would normally do, a CBC, CMP [comprehensive metabolic panel], and so forth. And then a nurse would return to the patient’s home if needed to deliver any interventions, such as blood transfusions, intravenous fluids, or electrolytes, right there in the comfort of the patient’s own home.
 

Dr. Henry: So let’s then take it through what happens. Say I am a patient with myeloma. I’ve had various therapies, and it’s time for me to get an autotransplant, let’s say. And so I need to do a couple of things. I need to get my stem cells collected. I need to then get my high-dose [conditioning] therapy, and then follows the stem cell therapy reinfusion. So can you take me through each step? Where is that done?

Dr. Sung: Absolutely. So the collection will occur in the outpatient setting, typically after mobilization with G-CSF [granulocyte colony–stimulating factor] and/or plerixafor. That will occur in our outpatient clinic with one of our leukapheresis machines. And the patient will then return to that same outpatient clinic, which is the same building, the same facility as the hospital, to receive melphalan conditioning. And then, following conditioning, about 24 hours after, day 0, that’s the day of their stem cell transplant infusion, which we do in the hospital setting just because of the potential for reactions associated with that.

But everything after that, from day 1 onwards, we try to keep them at home. And as I said, they will stay in their home. One of our nurse practitioners or physician assistants will visit them in the morning, do the assessment and draw the labs. And nurses will return in the afternoon to deliver any supportive care that they need.
 

Dr. Henry: So let’s define “home.” So I’m a Philadelphia resident and I say to you, Dr. Sung, I want to go home. You say, well, Philadelphia is too far. What is close enough and not too far, when you say home?

Dr. Sung: Absolutely. So when we originally conceived the program, we focused on patients who lived within an hour of our transplant center. And in part, that was because, as you know, unfortunately, things can sometimes go wrong during transplant. One of the most concerning ones is infections. And if a patient were to develop a neutropenic fever, we would want them to be seen as urgently as possible within an hour. And that’s where our limitation comes from.

So for our patients who live more than an hour away, those are the ones that we will have relocate to temporary lodging near our transplant center. And we’ve worked with several facilities in the area that have clean, furnished units that are available for rent. Many insurances also include lodging benefits for patients during stem cell transplant, recognizing this need. And historically, those [patients] were not considered part of our transplant patient cohorts.

I have not mentioned, but we initially did this in a phase 1 study, and we’re now studying it in a series of randomized, phase 2 studies that I can go into detail later on. And because they were not necessarily in their home, but a temporary lodging environment, those patients who relocated to Durham were not eligible for a home transplant study.

However, in the setting of the COVID-19 pandemic, we’ve actually pivoted our program in many ways. Specifically, if you think about a patient who’s coming into contact with the medical system, they come to the hospital, they meet someone at the door who is screening them for COVID-19. They see someone who checks them in at the front desk. A medical assistant takes them in the back. Someone calls their labs and phlebotomy. They may encounter other patients and environmental services, other individuals in the setting. You’re talking about dozens of different encounters. Who knows how many surfaces that potentially someone with COVID-19 has coughed on or contaminated?

And in contrast, you have house calls, which even if they are located in the temporary lodging, that’s just one or two individuals going into their living environment. They’re not encountering any different surfaces. And so, in the setting of COVID-19, we felt that this platform had the potential to help protect all our transplant patients who are among the most vulnerable patients, the most immunocompromised patients, and so we expanded our program to include those individuals as well.
 

Dr. Henry: So ... what are the actual outcomes of your patients in terms of how they’re doing, engrafting, and getting cured of their malignancy?

Dr. Sung: So as I mentioned, we first did this in a phase 1 safety and feasibility pilot study of both autologous and allo-transplant patients. This was presented at the annual meeting of the American Society of Hematology [Blood. 2017;130:745]. And we’re actually about ready to submit our manuscript on this.

And we found no difference in outcomes between patients who received care in the home transplant setting versus those who received conventional care either in the day hospital or hospital environment. The process appeared safe. Patients did just as well, if not better. Certainly, anecdotally, patients would talk about feeling so much more comfortable and happier being cared for in that home environment.

And we are now in the process of formally studying these outcomes in two NIH [National Institutes of Health]-funded clinical trials, one focused on allogeneic transplant patients [NCT02218151] and the other focused on autologous transplant patients [NCT01725022].
 

Dr. Henry: So of course, I’m waiting for this next question, which is cost. The services are the same, but you have people traveling, people who are highly skilled caregivers. Have you looked at cost differences from hospital versus home?

Dr. Sung: Absolutely. So you do have increased upfront costs because you have travel time for advanced practice providers and nurses. Not only that, but when a nurse is helping to give a patient a blood transfusion in the home environment, they’re 1:1 with that patient as opposed to the day hospital where a nurse could help with transfusions simultaneously for multiple patients. At the same time, by keeping patients out of the hospital, you have drastic, significant cost savings in that way.

In addition, I should mention, part of why we’re conducting these randomized, phase 2 clinical trials is we believe home care actually has the potential to decrease complications. One area of my research is on the impact of the microbiome, the bacteria in the gut, on transplant outcomes. And we’ve done a number of studies, many in collaboration with Memorial Sloan Kettering, showing that disruption of the microbiota, the bacteria in the gut, is associated with increased infections, graft-versus-host disease, and treatment-related mortality if we’re able to keep patients in their home setting.

However, I actually should go back a step. It’s well known that, if you take an individual from their home setting and put them in a foreign environment such as the hospital, that new environment, that new diet, hospital food as opposed to home food, and so forth, can dramatically shift the microbiome. Our hypothesis is that, by keeping patients in the home environment, their familiar environment will be able to help preserve their microbiome, thus decreasing infections, graft-versus-host disease, and other complications. That’s actually the goal of our studies: to see if we can preserve the microbiome and decrease complications.
 

Dr. Henry: So how will you evaluate that? Are you doing fecal studies, patient culture studies? How are you testing that?

Dr. Sung: So we have a very broad biobank program where we collect stool on our transplantations, pretransplant, day 0, weekly for the first month. And then, in the case of our allogeneic transplant patients, day 60, 90, 180, and 365.

And we do that both in our home transplant patients as well as their matched controls on the phase 2 studies. And we also collect it on a lot of our other transplant patients as part of our biobanking programs and our observational studies to try to understand what’s going on during transplant and how to help improve transplant outcomes.
 

Dr. Henry: Do you have any results of that? You’re probably showing a difference.

Dr. Sung: We think so, on some preliminary results, but those were based on small numbers of patients. And we’re really hoping that these randomized clinical trials with the larger numbers of patients enrolled will help show that difference.

But getting back to your earlier question about cost, a case of graft-versus-host disease, grade 2 or higher, can add about $100,000 to the cost of care. So if you prevent one case of bad gut or liver graft-versus-host disease, those are your cost savings right there.

The randomized, phase 2 trial for allogeneic transplant patients, the primary endpoint is graft-versus-host disease. So we’re looking at the microbiome and those associations and the prevention of GVHD. For the randomized clinical trial in autologous transplant patients – with autologous stem cells, you’re not going to get GVHD – but we do hope to improve quality of life and long-term outcomes in those patients as well.
 

Dr. Henry: Wonderful. Well, Tony, I really want to thank you so much for talking with us today.

Dr. Sung: Thank you very much for this opportunity. And again, I also want to just thank everyone who’s been involved in these studies, the advanced practice providers and nurses who are caring for our patients at home, the study staff who have been involved. Particularly, I’d like to highlight the role of both Nelson Chao, who’s our division chief and my mentor who piloted and first developed home transplant, and Kristin Nichols, our research nurse who has really led the drive forward.

Dr. Sung and Dr. Henry have no relevant disclosures. The trials are funded by grants from the National Institutes of Health.

When Maryam M. Asgari, MD, reviewed results from a large population-based study published in 2017, which found that a large proportion of cutaneous squamous cell carcinomas were being detected on the lower extremities of women, it caused her to reflect on her own clinical practice as a Mohs surgeon.

The best available research suggests that patients at the highest risk of KC include men and women between the ages of 60 and 89. Dr. Asgari said that she informs her patients that people in their 80s have about a 20-fold risk of BCC or SCC compared with people in their 30s. “I raise this because a lot of time the people who come in for skin cancer screenings are the ‘worried well,’ ” she said. “They can be at risk, but they’re not our highest risk subgroup. They come in proactively wanting to have those full skin screens done, but where we really need to be focusing is in people in their 60s to 80s.”

Risk factors can be shared or unique to each tumor type. Extrinsic factors include chronic UV exposure, ionizing radiation, and tanning bed use. “Acute UV exposures that give you a blistering sunburn puts you at risk for BCC, whereas chronic sun exposures puts you at risk for SCC,” she said. “Tanning bed use can increase the risk for both types, as can ionizing radiation, although it ups the risk for BCCs much more than it does for SCCs.” Intrinsic risk factors for both tumor types include fair skin, blue/green eyes, blond/red hair, male gender, having pigment gene variants, and being immunosuppressed.

By race/ethnicity, the highest risk for KC in the United States falls to non-Hispanic Whites (a rate of 150-360 per 100,000 individuals), while the rate among blacks is 3 per 100,000 individuals. “In darker skin phenotypes, sun exposure tends to be less of a risk factor,” Dr. Asgari said. “They can rise on sun-protected areas and are frequently associated with chronic inflammation, chronic wounds, or scarring.”

In a soon-to-be published study, Dr. Asgari and colleagues sought to examine the association between genetic ancestry and SCC risk. The found that people with northwestern European ancestry faced the highest risk of SCC, especially those with Irish/Scottish ancestry. Among people of Hispanic/Latino descent, the highest risk of SCC came in those who had the most European ancestry.

Global Academy for Medical Education and this news organization are owned by the same parent company.

Dr. Asgari disclosed that she receives royalties from UpToDate.

[email protected]

When Maryam M. Asgari, MD, reviewed results from a large population-based study published in 2017, which found that a large proportion of cutaneous squamous cell carcinomas were being detected on the lower extremities of women, it caused her to reflect on her own clinical practice as a Mohs surgeon.

The best available research suggests that patients at the highest risk of KC include men and women between the ages of 60 and 89. Dr. Asgari said that she informs her patients that people in their 80s have about a 20-fold risk of BCC or SCC compared with people in their 30s. “I raise this because a lot of time the people who come in for skin cancer screenings are the ‘worried well,’ ” she said. “They can be at risk, but they’re not our highest risk subgroup. They come in proactively wanting to have those full skin screens done, but where we really need to be focusing is in people in their 60s to 80s.”

Risk factors can be shared or unique to each tumor type. Extrinsic factors include chronic UV exposure, ionizing radiation, and tanning bed use. “Acute UV exposures that give you a blistering sunburn puts you at risk for BCC, whereas chronic sun exposures puts you at risk for SCC,” she said. “Tanning bed use can increase the risk for both types, as can ionizing radiation, although it ups the risk for BCCs much more than it does for SCCs.” Intrinsic risk factors for both tumor types include fair skin, blue/green eyes, blond/red hair, male gender, having pigment gene variants, and being immunosuppressed.

By race/ethnicity, the highest risk for KC in the United States falls to non-Hispanic Whites (a rate of 150-360 per 100,000 individuals), while the rate among blacks is 3 per 100,000 individuals. “In darker skin phenotypes, sun exposure tends to be less of a risk factor,” Dr. Asgari said. “They can rise on sun-protected areas and are frequently associated with chronic inflammation, chronic wounds, or scarring.”

In a soon-to-be published study, Dr. Asgari and colleagues sought to examine the association between genetic ancestry and SCC risk. The found that people with northwestern European ancestry faced the highest risk of SCC, especially those with Irish/Scottish ancestry. Among people of Hispanic/Latino descent, the highest risk of SCC came in those who had the most European ancestry.

Global Academy for Medical Education and this news organization are owned by the same parent company.

Dr. Asgari disclosed that she receives royalties from UpToDate.

[email protected]

When Maryam M. Asgari, MD, reviewed results from a large population-based study published in 2017, which found that a large proportion of cutaneous squamous cell carcinomas were being detected on the lower extremities of women, it caused her to reflect on her own clinical practice as a Mohs surgeon.

The best available research suggests that patients at the highest risk of KC include men and women between the ages of 60 and 89. Dr. Asgari said that she informs her patients that people in their 80s have about a 20-fold risk of BCC or SCC compared with people in their 30s. “I raise this because a lot of time the people who come in for skin cancer screenings are the ‘worried well,’ ” she said. “They can be at risk, but they’re not our highest risk subgroup. They come in proactively wanting to have those full skin screens done, but where we really need to be focusing is in people in their 60s to 80s.”

Risk factors can be shared or unique to each tumor type. Extrinsic factors include chronic UV exposure, ionizing radiation, and tanning bed use. “Acute UV exposures that give you a blistering sunburn puts you at risk for BCC, whereas chronic sun exposures puts you at risk for SCC,” she said. “Tanning bed use can increase the risk for both types, as can ionizing radiation, although it ups the risk for BCCs much more than it does for SCCs.” Intrinsic risk factors for both tumor types include fair skin, blue/green eyes, blond/red hair, male gender, having pigment gene variants, and being immunosuppressed.

By race/ethnicity, the highest risk for KC in the United States falls to non-Hispanic Whites (a rate of 150-360 per 100,000 individuals), while the rate among blacks is 3 per 100,000 individuals. “In darker skin phenotypes, sun exposure tends to be less of a risk factor,” Dr. Asgari said. “They can rise on sun-protected areas and are frequently associated with chronic inflammation, chronic wounds, or scarring.”

In a soon-to-be published study, Dr. Asgari and colleagues sought to examine the association between genetic ancestry and SCC risk. The found that people with northwestern European ancestry faced the highest risk of SCC, especially those with Irish/Scottish ancestry. Among people of Hispanic/Latino descent, the highest risk of SCC came in those who had the most European ancestry.

Global Academy for Medical Education and this news organization are owned by the same parent company.

Dr. Asgari disclosed that she receives royalties from UpToDate.

[email protected]

ANSWER

The correct answer is granuloma annulare (GA; choice “a”).

DISCUSSION

One of the most difficult concepts to grasp in dermatologic diagnosis is that almost all lesions and conditions—even the most common—have a broad range of morphologic presentations. These will often differ from the textbook photos. In this digital age, a simple Internet search will provide many results showing a diverse morphologic spectrum for many diseases, conditions, and lesions.

GA is a good example of how the presentation can vary. It has raised rolled margins and delled (gently concave) centers. The brownish red color is typical, but this patient showed a deeper red than most cases of GA. Occasionally, the red color is even deeper, with large patches of darkened skin and no palpable component.

Unfortunately, the misdiagnosis of fungal infection in this patient is typical. But dermatophytosis (otherwise known as “ringworm”)—the most common fungal skin infection—involves the epidermis. This means the patient would have scaly skin, probably with a well-defined margin—factors missing in this case. In addition, this patient reported no contact with sources of infection: animals, children, or immunosuppressive agents.

Ultimately, the most basic information that this patient's past providers neglected was a differential diagnosis. By establishing a differential, there was a clear decision to biopsy, which not only revealed the correct diagnosis but effectively ruled out the other options.

In defense of the patient’s other providers, I must admit that as a young primary care provider, I made this same mistake for exactly the same reasons.

TREATMENT

Most cases of GA are mild and self-limited, requiring no treatment. This is fortunate because no effective treatment exists. Topical steroids and cryotherapy will lighten the lesion, but GA nearly always resolves on its own.

ANSWER

The correct answer is granuloma annulare (GA; choice “a”).

DISCUSSION

One of the most difficult concepts to grasp in dermatologic diagnosis is that almost all lesions and conditions—even the most common—have a broad range of morphologic presentations. These will often differ from the textbook photos. In this digital age, a simple Internet search will provide many results showing a diverse morphologic spectrum for many diseases, conditions, and lesions.

GA is a good example of how the presentation can vary. It has raised rolled margins and delled (gently concave) centers. The brownish red color is typical, but this patient showed a deeper red than most cases of GA. Occasionally, the red color is even deeper, with large patches of darkened skin and no palpable component.

Unfortunately, the misdiagnosis of fungal infection in this patient is typical. But dermatophytosis (otherwise known as “ringworm”)—the most common fungal skin infection—involves the epidermis. This means the patient would have scaly skin, probably with a well-defined margin—factors missing in this case. In addition, this patient reported no contact with sources of infection: animals, children, or immunosuppressive agents.

Ultimately, the most basic information that this patient's past providers neglected was a differential diagnosis. By establishing a differential, there was a clear decision to biopsy, which not only revealed the correct diagnosis but effectively ruled out the other options.

In defense of the patient’s other providers, I must admit that as a young primary care provider, I made this same mistake for exactly the same reasons.

TREATMENT

Most cases of GA are mild and self-limited, requiring no treatment. This is fortunate because no effective treatment exists. Topical steroids and cryotherapy will lighten the lesion, but GA nearly always resolves on its own.

ANSWER

The correct answer is granuloma annulare (GA; choice “a”).

DISCUSSION

One of the most difficult concepts to grasp in dermatologic diagnosis is that almost all lesions and conditions—even the most common—have a broad range of morphologic presentations. These will often differ from the textbook photos. In this digital age, a simple Internet search will provide many results showing a diverse morphologic spectrum for many diseases, conditions, and lesions.

GA is a good example of how the presentation can vary. It has raised rolled margins and delled (gently concave) centers. The brownish red color is typical, but this patient showed a deeper red than most cases of GA. Occasionally, the red color is even deeper, with large patches of darkened skin and no palpable component.

Unfortunately, the misdiagnosis of fungal infection in this patient is typical. But dermatophytosis (otherwise known as “ringworm”)—the most common fungal skin infection—involves the epidermis. This means the patient would have scaly skin, probably with a well-defined margin—factors missing in this case. In addition, this patient reported no contact with sources of infection: animals, children, or immunosuppressive agents.

Ultimately, the most basic information that this patient's past providers neglected was a differential diagnosis. By establishing a differential, there was a clear decision to biopsy, which not only revealed the correct diagnosis but effectively ruled out the other options.

In defense of the patient’s other providers, I must admit that as a young primary care provider, I made this same mistake for exactly the same reasons.

TREATMENT

Most cases of GA are mild and self-limited, requiring no treatment. This is fortunate because no effective treatment exists. Topical steroids and cryotherapy will lighten the lesion, but GA nearly always resolves on its own.

After initial promising interim results on Nov. 9, Pfizer and BioNTech today announced that their mRNA vaccine, in development to prevent COVID-19, is 95% effective.

Final analysis of the randomized, phase 3 study of more than 43,000 people yielded 170 confirmed cases of COVID-19 – with 162 positive cases in the placebo group versus 8 in the BNT162b2 vaccine group.

Researchers reported 10 severe cases of COVID-19 in the trial, 9 of which occurred in the placebo group.

The study was ethnically diverse, and results were consistent across gender and age groups, with a 94% efficacy reported among participants aged older than 65 years.

Pfizer plans to file for an emergency-use authorization with the Food and Drug Administration “within days,” having now met all the FDA data endpoints, according to a news release from the two companies.

The vaccine was well tolerated with no serious safety concerns, the company stated. Two grade 3 adverse events were reported – fatigue in 3.8% of participants and headache in 2%.

The 95% efficacy places the Pfizer vaccine in the same neighborhood as the interim results of the Moderna vaccine, reported at 94.5%. Both products are two-dose mRNA vaccines.

As of Nov. 13, of 43,661 total participants in the Pfizer vaccine phase 3 trial, 41,135 received a second dose. The final results are based on two outcomes measured 7 days after the second dose: vaccine efficacy in people without prior SARS-CoV-2 infection as well as a secondary outcome in people both with and without prior SARS-CoV-2 infection.

The 95% vaccine efficacy was statistically significant, compared with placebo (P < .0001).
 

‘Historic 8-month journey’

The BNT162b2 vaccine candidate is a joint effort between Pfizer and BioNTech. “The study results mark an important step in this historic 8-month journey to bring forward a vaccine capable of helping to end this devastating pandemic,” Albert Bourla, DVM, PhD, Pfizer chairman and CEO, said in a statement. “With hundreds of thousands of people around the globe infected every day, we urgently need to get a safe and effective vaccine to the world.”

Ugur Sahin, MD, PhD, cofounder and CEO of BioNTech, added, “we are grateful that the first global trial to reach the final efficacy analysis mark indicates that a high rate of protection against COVID-19 can be achieved very fast after the first 30-mcg dose, underscoring the power of BNT162 in providing early protection.”

The two companies expect to produce up to 50 million vaccine doses in 2020 for global distribution. Projections for 2021 include up to 1.3 billion doses.

The companies also designed temperature-controlled thermal shipping containers with dry ice to maintain the required, approximate –70° C (–94° F) conditions. Clinicians can use the containers as temporary storage units for up to 15 days by replacing the dry ice.

This article first appeared on Medscape.com.

After initial promising interim results on Nov. 9, Pfizer and BioNTech today announced that their mRNA vaccine, in development to prevent COVID-19, is 95% effective.

Final analysis of the randomized, phase 3 study of more than 43,000 people yielded 170 confirmed cases of COVID-19 – with 162 positive cases in the placebo group versus 8 in the BNT162b2 vaccine group.

Researchers reported 10 severe cases of COVID-19 in the trial, 9 of which occurred in the placebo group.

The study was ethnically diverse, and results were consistent across gender and age groups, with a 94% efficacy reported among participants aged older than 65 years.

Pfizer plans to file for an emergency-use authorization with the Food and Drug Administration “within days,” having now met all the FDA data endpoints, according to a news release from the two companies.

The vaccine was well tolerated with no serious safety concerns, the company stated. Two grade 3 adverse events were reported – fatigue in 3.8% of participants and headache in 2%.

The 95% efficacy places the Pfizer vaccine in the same neighborhood as the interim results of the Moderna vaccine, reported at 94.5%. Both products are two-dose mRNA vaccines.

As of Nov. 13, of 43,661 total participants in the Pfizer vaccine phase 3 trial, 41,135 received a second dose. The final results are based on two outcomes measured 7 days after the second dose: vaccine efficacy in people without prior SARS-CoV-2 infection as well as a secondary outcome in people both with and without prior SARS-CoV-2 infection.

The 95% vaccine efficacy was statistically significant, compared with placebo (P < .0001).
 

‘Historic 8-month journey’

The BNT162b2 vaccine candidate is a joint effort between Pfizer and BioNTech. “The study results mark an important step in this historic 8-month journey to bring forward a vaccine capable of helping to end this devastating pandemic,” Albert Bourla, DVM, PhD, Pfizer chairman and CEO, said in a statement. “With hundreds of thousands of people around the globe infected every day, we urgently need to get a safe and effective vaccine to the world.”

Ugur Sahin, MD, PhD, cofounder and CEO of BioNTech, added, “we are grateful that the first global trial to reach the final efficacy analysis mark indicates that a high rate of protection against COVID-19 can be achieved very fast after the first 30-mcg dose, underscoring the power of BNT162 in providing early protection.”

The two companies expect to produce up to 50 million vaccine doses in 2020 for global distribution. Projections for 2021 include up to 1.3 billion doses.

The companies also designed temperature-controlled thermal shipping containers with dry ice to maintain the required, approximate –70° C (–94° F) conditions. Clinicians can use the containers as temporary storage units for up to 15 days by replacing the dry ice.

This article first appeared on Medscape.com.

After initial promising interim results on Nov. 9, Pfizer and BioNTech today announced that their mRNA vaccine, in development to prevent COVID-19, is 95% effective.

Final analysis of the randomized, phase 3 study of more than 43,000 people yielded 170 confirmed cases of COVID-19 – with 162 positive cases in the placebo group versus 8 in the BNT162b2 vaccine group.

Researchers reported 10 severe cases of COVID-19 in the trial, 9 of which occurred in the placebo group.

The study was ethnically diverse, and results were consistent across gender and age groups, with a 94% efficacy reported among participants aged older than 65 years.

Pfizer plans to file for an emergency-use authorization with the Food and Drug Administration “within days,” having now met all the FDA data endpoints, according to a news release from the two companies.

The vaccine was well tolerated with no serious safety concerns, the company stated. Two grade 3 adverse events were reported – fatigue in 3.8% of participants and headache in 2%.

The 95% efficacy places the Pfizer vaccine in the same neighborhood as the interim results of the Moderna vaccine, reported at 94.5%. Both products are two-dose mRNA vaccines.

As of Nov. 13, of 43,661 total participants in the Pfizer vaccine phase 3 trial, 41,135 received a second dose. The final results are based on two outcomes measured 7 days after the second dose: vaccine efficacy in people without prior SARS-CoV-2 infection as well as a secondary outcome in people both with and without prior SARS-CoV-2 infection.

The 95% vaccine efficacy was statistically significant, compared with placebo (P < .0001).
 

‘Historic 8-month journey’

The BNT162b2 vaccine candidate is a joint effort between Pfizer and BioNTech. “The study results mark an important step in this historic 8-month journey to bring forward a vaccine capable of helping to end this devastating pandemic,” Albert Bourla, DVM, PhD, Pfizer chairman and CEO, said in a statement. “With hundreds of thousands of people around the globe infected every day, we urgently need to get a safe and effective vaccine to the world.”

Ugur Sahin, MD, PhD, cofounder and CEO of BioNTech, added, “we are grateful that the first global trial to reach the final efficacy analysis mark indicates that a high rate of protection against COVID-19 can be achieved very fast after the first 30-mcg dose, underscoring the power of BNT162 in providing early protection.”

The two companies expect to produce up to 50 million vaccine doses in 2020 for global distribution. Projections for 2021 include up to 1.3 billion doses.

The companies also designed temperature-controlled thermal shipping containers with dry ice to maintain the required, approximate –70° C (–94° F) conditions. Clinicians can use the containers as temporary storage units for up to 15 days by replacing the dry ice.

This article first appeared on Medscape.com.

Patients with primary biliary cholangitis experienced rapid improvements in itch and quality of life after treatment with linerixibat in a randomized, placebo-controlled trial of the safety, efficacy, and tolerability of the small-molecule drug.

Moderate to severe pruritus “affects patients’ quality of life and is a huge burden for them,” said investigator Cynthia Levy, MD, from the University of Miami Health System.

“Finally having a medication that controls those symptoms is really important,” she said in an interview.

With a twice-daily mid-range dose of the drug for 12 weeks, patients with moderate to severe itch reported significantly less itch and better social and emotional quality of life, Dr. Levy reported at the Liver Meeting, where she presented findings from the phase 2 GLIMMER trial.

After a single-blind 4-week placebo run-in period for patients with itch scores of at least 4 on a 10-point rating scale, those with itch scores of at least 3 were then randomly assigned to one of five treatment regimens – once-daily linerixibat at doses of 20 mg, 90 mg, or 180 mg, or twice-daily doses of 40 mg or 90 mg – or to placebo.

After 12 weeks of treatment, all 147 participants once again received placebo for 4 weeks.

During the trial, participants recorded itch levels twice daily. The worst of these daily scores was averaged every 7 days to determine the mean worst daily itch.

The primary study endpoint was the change in worst daily itch from baseline after 12 weeks of treatment. Participants whose self-rated itch improved by 2 points on the 10-point scale were considered to have had a response to the drug.

Participants also completed the PBC-40, an instrument to measure quality of life in patients with primary biliary cholangitis, answering questions about itch and social and emotional status.

Reductions in worst daily itch from baseline to 12 weeks were steepest in the 40-mg twice-daily group, at 2.86 points, and in the 90-mg twice-daily group, at 2.25 points. In the placebo group, the mean decrease was 1.73 points.

During the subsequent 4 weeks of placebo, after treatment ended, the itch relief faded in all groups.

Scores on the PBC-40 itch domain improved significantly in every group, including placebo. However, only those in the twice-daily 40-mg group saw significant improvements on the social (P = .0016) and emotional (P = .0025) domains.
 

‘Between incremental and revolutionary’

The results are on a “kind of continuum between incremental and revolutionary,” said Jonathan A. Dranoff, MD, from the University of Arkansas for Medical Sciences, Little Rock, who was not involved in the study. “It doesn’t hit either extreme, but it’s the first new drug for this purpose in forever, which by itself is a good thing.”

The placebo effect suggests that “maybe the actual contribution of the noncognitive brain to pruritus is bigger than we thought, and that’s worth noting,” he added. Nevertheless, “the drug still appears to have effects that are statistically different from placebo.”

The placebo effect in itching studies is always high but tends to wane over time, said Dr. Levy. This trial had a 4-week placebo run-in period to allow that effect to fade somewhat, she explained.

About 10% of the study cohort experienced drug-related diarrhea, which was expected, and about 10% dropped out of the trial because of drug-related adverse events.

Linerixibat is an ileal sodium-dependent bile acid transporter inhibitor, so the gut has to deal with the excess bile acid fallout, but the diarrhea is likely manageable with antidiarrheals, said Dr. Levy.

It is unlikely that diarrhea will deter patients with severe itch from using an effective drug when other drugs have failed them. “These patients are consumed by itch most of the time,” said Dr. Dranoff. “I think for people who don’t regularly treat patients with primary biliary cholangitis, it’s one of the underappreciated aspects of the disease.”

The improvements in social and emotional quality of life seen with linerixibat are not only statistically significant, they are also clinically significant, said Dr. Levy. “We are really expecting this to impact the lives of our patients and are looking forward to phase 3.”

Dr. Levy disclosed support from GlaxoSmithKline. Dr. Dranoff disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Patients with primary biliary cholangitis experienced rapid improvements in itch and quality of life after treatment with linerixibat in a randomized, placebo-controlled trial of the safety, efficacy, and tolerability of the small-molecule drug.

Moderate to severe pruritus “affects patients’ quality of life and is a huge burden for them,” said investigator Cynthia Levy, MD, from the University of Miami Health System.

“Finally having a medication that controls those symptoms is really important,” she said in an interview.

With a twice-daily mid-range dose of the drug for 12 weeks, patients with moderate to severe itch reported significantly less itch and better social and emotional quality of life, Dr. Levy reported at the Liver Meeting, where she presented findings from the phase 2 GLIMMER trial.

After a single-blind 4-week placebo run-in period for patients with itch scores of at least 4 on a 10-point rating scale, those with itch scores of at least 3 were then randomly assigned to one of five treatment regimens – once-daily linerixibat at doses of 20 mg, 90 mg, or 180 mg, or twice-daily doses of 40 mg or 90 mg – or to placebo.

After 12 weeks of treatment, all 147 participants once again received placebo for 4 weeks.

During the trial, participants recorded itch levels twice daily. The worst of these daily scores was averaged every 7 days to determine the mean worst daily itch.

The primary study endpoint was the change in worst daily itch from baseline after 12 weeks of treatment. Participants whose self-rated itch improved by 2 points on the 10-point scale were considered to have had a response to the drug.

Participants also completed the PBC-40, an instrument to measure quality of life in patients with primary biliary cholangitis, answering questions about itch and social and emotional status.

Reductions in worst daily itch from baseline to 12 weeks were steepest in the 40-mg twice-daily group, at 2.86 points, and in the 90-mg twice-daily group, at 2.25 points. In the placebo group, the mean decrease was 1.73 points.

During the subsequent 4 weeks of placebo, after treatment ended, the itch relief faded in all groups.

Scores on the PBC-40 itch domain improved significantly in every group, including placebo. However, only those in the twice-daily 40-mg group saw significant improvements on the social (P = .0016) and emotional (P = .0025) domains.
 

‘Between incremental and revolutionary’

The results are on a “kind of continuum between incremental and revolutionary,” said Jonathan A. Dranoff, MD, from the University of Arkansas for Medical Sciences, Little Rock, who was not involved in the study. “It doesn’t hit either extreme, but it’s the first new drug for this purpose in forever, which by itself is a good thing.”

The placebo effect suggests that “maybe the actual contribution of the noncognitive brain to pruritus is bigger than we thought, and that’s worth noting,” he added. Nevertheless, “the drug still appears to have effects that are statistically different from placebo.”

The placebo effect in itching studies is always high but tends to wane over time, said Dr. Levy. This trial had a 4-week placebo run-in period to allow that effect to fade somewhat, she explained.

About 10% of the study cohort experienced drug-related diarrhea, which was expected, and about 10% dropped out of the trial because of drug-related adverse events.

Linerixibat is an ileal sodium-dependent bile acid transporter inhibitor, so the gut has to deal with the excess bile acid fallout, but the diarrhea is likely manageable with antidiarrheals, said Dr. Levy.

It is unlikely that diarrhea will deter patients with severe itch from using an effective drug when other drugs have failed them. “These patients are consumed by itch most of the time,” said Dr. Dranoff. “I think for people who don’t regularly treat patients with primary biliary cholangitis, it’s one of the underappreciated aspects of the disease.”

The improvements in social and emotional quality of life seen with linerixibat are not only statistically significant, they are also clinically significant, said Dr. Levy. “We are really expecting this to impact the lives of our patients and are looking forward to phase 3.”

Dr. Levy disclosed support from GlaxoSmithKline. Dr. Dranoff disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Patients with primary biliary cholangitis experienced rapid improvements in itch and quality of life after treatment with linerixibat in a randomized, placebo-controlled trial of the safety, efficacy, and tolerability of the small-molecule drug.

Moderate to severe pruritus “affects patients’ quality of life and is a huge burden for them,” said investigator Cynthia Levy, MD, from the University of Miami Health System.

“Finally having a medication that controls those symptoms is really important,” she said in an interview.

With a twice-daily mid-range dose of the drug for 12 weeks, patients with moderate to severe itch reported significantly less itch and better social and emotional quality of life, Dr. Levy reported at the Liver Meeting, where she presented findings from the phase 2 GLIMMER trial.

After a single-blind 4-week placebo run-in period for patients with itch scores of at least 4 on a 10-point rating scale, those with itch scores of at least 3 were then randomly assigned to one of five treatment regimens – once-daily linerixibat at doses of 20 mg, 90 mg, or 180 mg, or twice-daily doses of 40 mg or 90 mg – or to placebo.

After 12 weeks of treatment, all 147 participants once again received placebo for 4 weeks.

During the trial, participants recorded itch levels twice daily. The worst of these daily scores was averaged every 7 days to determine the mean worst daily itch.

The primary study endpoint was the change in worst daily itch from baseline after 12 weeks of treatment. Participants whose self-rated itch improved by 2 points on the 10-point scale were considered to have had a response to the drug.

Participants also completed the PBC-40, an instrument to measure quality of life in patients with primary biliary cholangitis, answering questions about itch and social and emotional status.

Reductions in worst daily itch from baseline to 12 weeks were steepest in the 40-mg twice-daily group, at 2.86 points, and in the 90-mg twice-daily group, at 2.25 points. In the placebo group, the mean decrease was 1.73 points.

During the subsequent 4 weeks of placebo, after treatment ended, the itch relief faded in all groups.

Scores on the PBC-40 itch domain improved significantly in every group, including placebo. However, only those in the twice-daily 40-mg group saw significant improvements on the social (P = .0016) and emotional (P = .0025) domains.
 

‘Between incremental and revolutionary’

The results are on a “kind of continuum between incremental and revolutionary,” said Jonathan A. Dranoff, MD, from the University of Arkansas for Medical Sciences, Little Rock, who was not involved in the study. “It doesn’t hit either extreme, but it’s the first new drug for this purpose in forever, which by itself is a good thing.”

The placebo effect suggests that “maybe the actual contribution of the noncognitive brain to pruritus is bigger than we thought, and that’s worth noting,” he added. Nevertheless, “the drug still appears to have effects that are statistically different from placebo.”

The placebo effect in itching studies is always high but tends to wane over time, said Dr. Levy. This trial had a 4-week placebo run-in period to allow that effect to fade somewhat, she explained.

About 10% of the study cohort experienced drug-related diarrhea, which was expected, and about 10% dropped out of the trial because of drug-related adverse events.

Linerixibat is an ileal sodium-dependent bile acid transporter inhibitor, so the gut has to deal with the excess bile acid fallout, but the diarrhea is likely manageable with antidiarrheals, said Dr. Levy.

It is unlikely that diarrhea will deter patients with severe itch from using an effective drug when other drugs have failed them. “These patients are consumed by itch most of the time,” said Dr. Dranoff. “I think for people who don’t regularly treat patients with primary biliary cholangitis, it’s one of the underappreciated aspects of the disease.”

The improvements in social and emotional quality of life seen with linerixibat are not only statistically significant, they are also clinically significant, said Dr. Levy. “We are really expecting this to impact the lives of our patients and are looking forward to phase 3.”

Dr. Levy disclosed support from GlaxoSmithKline. Dr. Dranoff disclosed no relevant financial relationships.

This article first appeared on Medscape.com.