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Much work to be done in optimizing treatment for transgender children
ORLANDO – Janet Y. Lee, MD, MPH, said at the annual meeting of the American Society for Bone and Mineral Research.
According to a report from The Williams Institute in 2017, there were approximately 150,000 youth in the United States who identified as transgender, and among studies that measured transgender identity among youth, the percentage who identified as transgender ranged between 1.3% and 3.2% (Herman J et al. “Age of Individuals who Identify as Transgender in the United States.” Los Angeles: The Williams Institute, January 2017).
“If you’ve not seen one of these patients yet, you probably will in your career,” said Dr. Lee of the University of California, San Francisco.
At UCSF, Dr. Lee said the focus of care for transgender youth in early childhood to late childhood is on school resources and social transition, with puberty blockers such as gonadotropin-releasing hormone agents (GnRHa) beginning in late childhood and early puberty at Tanner stage 2. When patients reach early puberty and move to late puberty and adulthood, they usually begin gender-affirming sex hormones such as testosterone for masculinizing hormone therapy or estrogen and spironolactone or bicalutamide for feminizing hormone therapy in transgender women, and consideration of fertility preservation is undertaken. In adulthood, patients can begin gender-affirming surgery.
Dr. Lee said the specific timing of gender-affirming sex hormones is controversial and “seems to be a moving target in our field.” The average age to begin gender-affirming sex hormones at UCSF is 14 years old, but sometimes younger, said Dr. Lee. There also is a question of when to start gender-affirming sex hormones in gender diverse youth. “[They] may not want full adult doses of testosterone or full adult doses of estradiol,” said Dr. Lee. “It’s been very challenging to figure out [appropriate] treatment for these youth.”
In Europe, some studies have shown transwomen have lower bone mineral density (BMD) scores at baseline even after 2.5 years to 5 years of treatment with estradiol, compared with male reference standards. A study by Vlot et al. found transwomen had lower bone turnover markers and bone mineral apparent density in cohorts younger than 15 years old, compared with cohorts 15 years or older (Bone. 2017 Feb. doi: 10.1016/j.bone.2016.11.008).
As in the case of when to start gender-affirming sex hormones, how to approach treatment for gender diverse youth who have a low baseline BMD but are eligible for puberty blockers is debated. “We could go into a whole other talk about this because we have many [patients] who present with low baseline BMD,” said Dr. Lee. “We have to figure out a way to apply treatment without impairing their bone.”
Other questions that have yet to be answered are what dual x-ray absorptiometry standards to be used for transgender individuals and how body composition and height growth are affected by gender-affirming medical therapy, which is currently “really modeled after hypergonadic children,” said Dr. Lee.
Results from a National Institutes of Health–funded longitudinal observational study of transgender youth at UCSF, Children’s Hospital Los Angeles, Boston Children’s Hospital, and Ann & Robert H. Lurie Children’s Hospital of Chicago is currently examining the effect of using gender-affirming medical treatment for patients in early and late puberty and assessing factors such as mental health, psychological well-being, and bone health measures such as dual x-ray absorptiometry and quantitative computed tomography, as well as investigating dietary intake, physical activity and exercise, and vitamin D status. Preliminary findings from the study have shown low BMD z-scores in designated males at birth when compared with designated females at birth, with suboptimal dietary calcium intake in both designated males and designated females.
Dr. Lee reported no relevant conflicts of interest.
ORLANDO – Janet Y. Lee, MD, MPH, said at the annual meeting of the American Society for Bone and Mineral Research.
According to a report from The Williams Institute in 2017, there were approximately 150,000 youth in the United States who identified as transgender, and among studies that measured transgender identity among youth, the percentage who identified as transgender ranged between 1.3% and 3.2% (Herman J et al. “Age of Individuals who Identify as Transgender in the United States.” Los Angeles: The Williams Institute, January 2017).
“If you’ve not seen one of these patients yet, you probably will in your career,” said Dr. Lee of the University of California, San Francisco.
At UCSF, Dr. Lee said the focus of care for transgender youth in early childhood to late childhood is on school resources and social transition, with puberty blockers such as gonadotropin-releasing hormone agents (GnRHa) beginning in late childhood and early puberty at Tanner stage 2. When patients reach early puberty and move to late puberty and adulthood, they usually begin gender-affirming sex hormones such as testosterone for masculinizing hormone therapy or estrogen and spironolactone or bicalutamide for feminizing hormone therapy in transgender women, and consideration of fertility preservation is undertaken. In adulthood, patients can begin gender-affirming surgery.
Dr. Lee said the specific timing of gender-affirming sex hormones is controversial and “seems to be a moving target in our field.” The average age to begin gender-affirming sex hormones at UCSF is 14 years old, but sometimes younger, said Dr. Lee. There also is a question of when to start gender-affirming sex hormones in gender diverse youth. “[They] may not want full adult doses of testosterone or full adult doses of estradiol,” said Dr. Lee. “It’s been very challenging to figure out [appropriate] treatment for these youth.”
In Europe, some studies have shown transwomen have lower bone mineral density (BMD) scores at baseline even after 2.5 years to 5 years of treatment with estradiol, compared with male reference standards. A study by Vlot et al. found transwomen had lower bone turnover markers and bone mineral apparent density in cohorts younger than 15 years old, compared with cohorts 15 years or older (Bone. 2017 Feb. doi: 10.1016/j.bone.2016.11.008).
As in the case of when to start gender-affirming sex hormones, how to approach treatment for gender diverse youth who have a low baseline BMD but are eligible for puberty blockers is debated. “We could go into a whole other talk about this because we have many [patients] who present with low baseline BMD,” said Dr. Lee. “We have to figure out a way to apply treatment without impairing their bone.”
Other questions that have yet to be answered are what dual x-ray absorptiometry standards to be used for transgender individuals and how body composition and height growth are affected by gender-affirming medical therapy, which is currently “really modeled after hypergonadic children,” said Dr. Lee.
Results from a National Institutes of Health–funded longitudinal observational study of transgender youth at UCSF, Children’s Hospital Los Angeles, Boston Children’s Hospital, and Ann & Robert H. Lurie Children’s Hospital of Chicago is currently examining the effect of using gender-affirming medical treatment for patients in early and late puberty and assessing factors such as mental health, psychological well-being, and bone health measures such as dual x-ray absorptiometry and quantitative computed tomography, as well as investigating dietary intake, physical activity and exercise, and vitamin D status. Preliminary findings from the study have shown low BMD z-scores in designated males at birth when compared with designated females at birth, with suboptimal dietary calcium intake in both designated males and designated females.
Dr. Lee reported no relevant conflicts of interest.
ORLANDO – Janet Y. Lee, MD, MPH, said at the annual meeting of the American Society for Bone and Mineral Research.
According to a report from The Williams Institute in 2017, there were approximately 150,000 youth in the United States who identified as transgender, and among studies that measured transgender identity among youth, the percentage who identified as transgender ranged between 1.3% and 3.2% (Herman J et al. “Age of Individuals who Identify as Transgender in the United States.” Los Angeles: The Williams Institute, January 2017).
“If you’ve not seen one of these patients yet, you probably will in your career,” said Dr. Lee of the University of California, San Francisco.
At UCSF, Dr. Lee said the focus of care for transgender youth in early childhood to late childhood is on school resources and social transition, with puberty blockers such as gonadotropin-releasing hormone agents (GnRHa) beginning in late childhood and early puberty at Tanner stage 2. When patients reach early puberty and move to late puberty and adulthood, they usually begin gender-affirming sex hormones such as testosterone for masculinizing hormone therapy or estrogen and spironolactone or bicalutamide for feminizing hormone therapy in transgender women, and consideration of fertility preservation is undertaken. In adulthood, patients can begin gender-affirming surgery.
Dr. Lee said the specific timing of gender-affirming sex hormones is controversial and “seems to be a moving target in our field.” The average age to begin gender-affirming sex hormones at UCSF is 14 years old, but sometimes younger, said Dr. Lee. There also is a question of when to start gender-affirming sex hormones in gender diverse youth. “[They] may not want full adult doses of testosterone or full adult doses of estradiol,” said Dr. Lee. “It’s been very challenging to figure out [appropriate] treatment for these youth.”
In Europe, some studies have shown transwomen have lower bone mineral density (BMD) scores at baseline even after 2.5 years to 5 years of treatment with estradiol, compared with male reference standards. A study by Vlot et al. found transwomen had lower bone turnover markers and bone mineral apparent density in cohorts younger than 15 years old, compared with cohorts 15 years or older (Bone. 2017 Feb. doi: 10.1016/j.bone.2016.11.008).
As in the case of when to start gender-affirming sex hormones, how to approach treatment for gender diverse youth who have a low baseline BMD but are eligible for puberty blockers is debated. “We could go into a whole other talk about this because we have many [patients] who present with low baseline BMD,” said Dr. Lee. “We have to figure out a way to apply treatment without impairing their bone.”
Other questions that have yet to be answered are what dual x-ray absorptiometry standards to be used for transgender individuals and how body composition and height growth are affected by gender-affirming medical therapy, which is currently “really modeled after hypergonadic children,” said Dr. Lee.
Results from a National Institutes of Health–funded longitudinal observational study of transgender youth at UCSF, Children’s Hospital Los Angeles, Boston Children’s Hospital, and Ann & Robert H. Lurie Children’s Hospital of Chicago is currently examining the effect of using gender-affirming medical treatment for patients in early and late puberty and assessing factors such as mental health, psychological well-being, and bone health measures such as dual x-ray absorptiometry and quantitative computed tomography, as well as investigating dietary intake, physical activity and exercise, and vitamin D status. Preliminary findings from the study have shown low BMD z-scores in designated males at birth when compared with designated females at birth, with suboptimal dietary calcium intake in both designated males and designated females.
Dr. Lee reported no relevant conflicts of interest.
EXPERT ANALYSIS FROM ASBMR 2019
Hemophilia prevalence is nearly three times higher than previously reported
The number of people with hemophilia worldwide is higher than previously estimated, and patients still face a shortened life expectancy, according to an international meta-analysis of registry data.
Approximately 1.125 million people have hemophilia worldwide, compared with the previous estimate of 400,000, reported lead author Alfonso Iorio, MD, PhD, of McMaster University, Hamilton, Ont., and colleagues.
The previous estimate, from the early 2000s, was based on prevalence in the United States and the global population at the time, the investigators explained. Their report is in Annals of Internal Medicine.
They noted a lack of clarity in prior estimates concerning type and severity of hemophilia, and aimed to correct this knowledge gap with the present meta-analysis.
Prevalence was estimated using data from registries in Australia, Canada, Italy, France, the United Kingdom, and New Zealand, which are all high-income countries. Prevalence at birth was estimated using the Canadian, French, and British registries, as these are the most established databases, according to the investigators. The World Federation of Hemophilia Annual Global survey was used to estimate the total global number of patients with hemophilia, while national statistics databases were used to determine the number of males and live male births.
Of the 1.125 million cases of hemophilia worldwide, the investigators estimated that 418,000 are likely severe. Proportionally, 17.1 out of 100,000 males have hemophilia A, with 6.0 out of 100,000 males exhibiting severe hemophilia A. Hemophilia B is less common, occurring in 3.8 out of 100,000 males, with a 1.1 out of 100,000 classified as severe.
Turning to prevalence at birth, the investigators estimated that there are 24.6 cases of hemophilia A per 100,000 male births and 5.0 cases of hemophilia B per 100,000 male births.
The associated life expectancy disadvantage in high-income countries is highest for severe hemophilia A (37%), followed by all severities of hemophilia A (30%), severe hemophilia B (27%), and all severities of hemophilia B (24%).
“Having 1,125,000 persons with hemophilia worldwide, of whom about 418,000 have severe and mostly undiagnosed disease, constitutes a formidable challenge and burden for researchers and health care systems, especially because only 196,706 patients have been identified and reported globally,” the investigators wrote. “More efficient diagnostic approaches are needed in less wealthy countries to take advantage of current and future treatment modalities, including gene therapy. Increased demand for care should drive new policy planning and spur renewed effort toward the development and manufacture of new drugs.”
The updated prevalence figures will serve as a valuable roadmap for the future, according to J. Michael Soucie, PhD, of the Centers for Disease Control and Prevention, Atlanta.
“Although the magnitude of the global gaps in care for persons with hemophilia is daunting, country specific data generated by application of the prevalence estimates reported by Iorio and colleagues are an important step toward prioritizing efforts to address these gaps,” Dr. Soucie wrote in an accompanying editorial. “Having more accurate prevalence data might also allow identification of ways in which regional efforts to improve care access could generate considerable benefits for patients and cost savings for countries. Armed with these data for action, we can hope to make substantial progress toward the goal of improving the lives of persons with hemophilia wherever they live.”
The study received no financial support. The investigators reported relationships with Pfizer, Roche, Novo Nordisk, and others. Dr. Soucie reported having no conflicts of interest.
SOURCE: Iorio A et al. Ann Intern Med. 2019 Sept 10. doi: 10.7326/M19-1208.
The number of people with hemophilia worldwide is higher than previously estimated, and patients still face a shortened life expectancy, according to an international meta-analysis of registry data.
Approximately 1.125 million people have hemophilia worldwide, compared with the previous estimate of 400,000, reported lead author Alfonso Iorio, MD, PhD, of McMaster University, Hamilton, Ont., and colleagues.
The previous estimate, from the early 2000s, was based on prevalence in the United States and the global population at the time, the investigators explained. Their report is in Annals of Internal Medicine.
They noted a lack of clarity in prior estimates concerning type and severity of hemophilia, and aimed to correct this knowledge gap with the present meta-analysis.
Prevalence was estimated using data from registries in Australia, Canada, Italy, France, the United Kingdom, and New Zealand, which are all high-income countries. Prevalence at birth was estimated using the Canadian, French, and British registries, as these are the most established databases, according to the investigators. The World Federation of Hemophilia Annual Global survey was used to estimate the total global number of patients with hemophilia, while national statistics databases were used to determine the number of males and live male births.
Of the 1.125 million cases of hemophilia worldwide, the investigators estimated that 418,000 are likely severe. Proportionally, 17.1 out of 100,000 males have hemophilia A, with 6.0 out of 100,000 males exhibiting severe hemophilia A. Hemophilia B is less common, occurring in 3.8 out of 100,000 males, with a 1.1 out of 100,000 classified as severe.
Turning to prevalence at birth, the investigators estimated that there are 24.6 cases of hemophilia A per 100,000 male births and 5.0 cases of hemophilia B per 100,000 male births.
The associated life expectancy disadvantage in high-income countries is highest for severe hemophilia A (37%), followed by all severities of hemophilia A (30%), severe hemophilia B (27%), and all severities of hemophilia B (24%).
“Having 1,125,000 persons with hemophilia worldwide, of whom about 418,000 have severe and mostly undiagnosed disease, constitutes a formidable challenge and burden for researchers and health care systems, especially because only 196,706 patients have been identified and reported globally,” the investigators wrote. “More efficient diagnostic approaches are needed in less wealthy countries to take advantage of current and future treatment modalities, including gene therapy. Increased demand for care should drive new policy planning and spur renewed effort toward the development and manufacture of new drugs.”
The updated prevalence figures will serve as a valuable roadmap for the future, according to J. Michael Soucie, PhD, of the Centers for Disease Control and Prevention, Atlanta.
“Although the magnitude of the global gaps in care for persons with hemophilia is daunting, country specific data generated by application of the prevalence estimates reported by Iorio and colleagues are an important step toward prioritizing efforts to address these gaps,” Dr. Soucie wrote in an accompanying editorial. “Having more accurate prevalence data might also allow identification of ways in which regional efforts to improve care access could generate considerable benefits for patients and cost savings for countries. Armed with these data for action, we can hope to make substantial progress toward the goal of improving the lives of persons with hemophilia wherever they live.”
The study received no financial support. The investigators reported relationships with Pfizer, Roche, Novo Nordisk, and others. Dr. Soucie reported having no conflicts of interest.
SOURCE: Iorio A et al. Ann Intern Med. 2019 Sept 10. doi: 10.7326/M19-1208.
The number of people with hemophilia worldwide is higher than previously estimated, and patients still face a shortened life expectancy, according to an international meta-analysis of registry data.
Approximately 1.125 million people have hemophilia worldwide, compared with the previous estimate of 400,000, reported lead author Alfonso Iorio, MD, PhD, of McMaster University, Hamilton, Ont., and colleagues.
The previous estimate, from the early 2000s, was based on prevalence in the United States and the global population at the time, the investigators explained. Their report is in Annals of Internal Medicine.
They noted a lack of clarity in prior estimates concerning type and severity of hemophilia, and aimed to correct this knowledge gap with the present meta-analysis.
Prevalence was estimated using data from registries in Australia, Canada, Italy, France, the United Kingdom, and New Zealand, which are all high-income countries. Prevalence at birth was estimated using the Canadian, French, and British registries, as these are the most established databases, according to the investigators. The World Federation of Hemophilia Annual Global survey was used to estimate the total global number of patients with hemophilia, while national statistics databases were used to determine the number of males and live male births.
Of the 1.125 million cases of hemophilia worldwide, the investigators estimated that 418,000 are likely severe. Proportionally, 17.1 out of 100,000 males have hemophilia A, with 6.0 out of 100,000 males exhibiting severe hemophilia A. Hemophilia B is less common, occurring in 3.8 out of 100,000 males, with a 1.1 out of 100,000 classified as severe.
Turning to prevalence at birth, the investigators estimated that there are 24.6 cases of hemophilia A per 100,000 male births and 5.0 cases of hemophilia B per 100,000 male births.
The associated life expectancy disadvantage in high-income countries is highest for severe hemophilia A (37%), followed by all severities of hemophilia A (30%), severe hemophilia B (27%), and all severities of hemophilia B (24%).
“Having 1,125,000 persons with hemophilia worldwide, of whom about 418,000 have severe and mostly undiagnosed disease, constitutes a formidable challenge and burden for researchers and health care systems, especially because only 196,706 patients have been identified and reported globally,” the investigators wrote. “More efficient diagnostic approaches are needed in less wealthy countries to take advantage of current and future treatment modalities, including gene therapy. Increased demand for care should drive new policy planning and spur renewed effort toward the development and manufacture of new drugs.”
The updated prevalence figures will serve as a valuable roadmap for the future, according to J. Michael Soucie, PhD, of the Centers for Disease Control and Prevention, Atlanta.
“Although the magnitude of the global gaps in care for persons with hemophilia is daunting, country specific data generated by application of the prevalence estimates reported by Iorio and colleagues are an important step toward prioritizing efforts to address these gaps,” Dr. Soucie wrote in an accompanying editorial. “Having more accurate prevalence data might also allow identification of ways in which regional efforts to improve care access could generate considerable benefits for patients and cost savings for countries. Armed with these data for action, we can hope to make substantial progress toward the goal of improving the lives of persons with hemophilia wherever they live.”
The study received no financial support. The investigators reported relationships with Pfizer, Roche, Novo Nordisk, and others. Dr. Soucie reported having no conflicts of interest.
SOURCE: Iorio A et al. Ann Intern Med. 2019 Sept 10. doi: 10.7326/M19-1208.
FROM ANNALS OF INTERNAL MEDICINE
Pilot program benefits gynecologic cancer patients with malignant bowel obstruction
A pilot program that aims to optimize the care of patients with malignant bowel obstruction is associated with longer survival and shorter cumulative hospital length of stay in the first 60 days after a malignant bowel obstruction diagnosis, according to research published in Journal of Oncology Practice.
Yeh Chen Lee, MBBS, of Princess Margaret Cancer Centre in Toronto, and colleagues retrospectively compared the outcomes of 106 women with advanced gynecologic cancer who were admitted to the hospital with malignant bowel obstruction before the program was implemented, with those of 63 women who were admitted after the program was implemented.
Patients’ median age at diagnosis of malignant bowel obstruction was 62 years (range, 31-91 years). Primary cancer diagnoses included ovarian cancer (73%), uterine cancer (18%), and cervical cancer (9%), and most patients had stage III-IV disease. Most patients had small-bowel obstruction (78%).
In the 2 years before the program, women had an average cumulative length of stay in the hospital of 22 days within the first 60 days of malignant bowel obstruction diagnosis. In the 2 years after, the average length of stay was 13 days. Furthermore, median overall survival, adjusted for initial cancer stage and lines of chemotherapy, increased by about 5 months, from 99 days before the program to 243 days after the program was implemented.
Patients who were treated during the malignant bowel obstruction program were more likely than were patients in the baseline group to receive chemotherapy (83% vs. 56%) and to receive two or more interventions for malignant bowel obstruction, such as surgery, chemotherapy, or total parenteral nutrition (42% vs. 33%). Complications included bowel perforation (13% in the program group vs. 5% in the baseline group) and fistulizing disease (6% in the program group vs. 12% in the baseline group).
In addition, the program was associated with lower costs.
The pilot program was designed “to provide a systematic framework to coordinate care and consensus decision-making among different specialties relevant to [malignant bowel obstruction] management,” Dr. Lee and colleagues said. It includes outpatient care led by oncology nurses through telephone consultations. “Standardized clinical processes, assessment tools, and documentation in the electronic medical record are incorporated to facilitate seamless transition between in- and outpatient care,” the authors said. “Patient educational materials have been developed to empower patients to recognize and effectively communicate their symptoms.”
It is unclear whether other institutions could implement this program, Dr. Lee and colleagues noted. It also is not possible to determine whether differences in survival relate to earlier recognition of malignant bowel obstruction, more effective management, or other factors.
Dr. Lee was supported by funding from Princess Margaret Cancer Foundation and an Australian Government Research Training Program Scholarship. Coauthors disclosed financial relationships with pharmaceutical companies and pending patents related to percutaneous procedures and a surgical device.
SOURCE: Lee YC et al. J Oncol Pract. 2019 Sep 24. doi: 10.1200/JOP.18.00793.
A pilot program that aims to optimize the care of patients with malignant bowel obstruction is associated with longer survival and shorter cumulative hospital length of stay in the first 60 days after a malignant bowel obstruction diagnosis, according to research published in Journal of Oncology Practice.
Yeh Chen Lee, MBBS, of Princess Margaret Cancer Centre in Toronto, and colleagues retrospectively compared the outcomes of 106 women with advanced gynecologic cancer who were admitted to the hospital with malignant bowel obstruction before the program was implemented, with those of 63 women who were admitted after the program was implemented.
Patients’ median age at diagnosis of malignant bowel obstruction was 62 years (range, 31-91 years). Primary cancer diagnoses included ovarian cancer (73%), uterine cancer (18%), and cervical cancer (9%), and most patients had stage III-IV disease. Most patients had small-bowel obstruction (78%).
In the 2 years before the program, women had an average cumulative length of stay in the hospital of 22 days within the first 60 days of malignant bowel obstruction diagnosis. In the 2 years after, the average length of stay was 13 days. Furthermore, median overall survival, adjusted for initial cancer stage and lines of chemotherapy, increased by about 5 months, from 99 days before the program to 243 days after the program was implemented.
Patients who were treated during the malignant bowel obstruction program were more likely than were patients in the baseline group to receive chemotherapy (83% vs. 56%) and to receive two or more interventions for malignant bowel obstruction, such as surgery, chemotherapy, or total parenteral nutrition (42% vs. 33%). Complications included bowel perforation (13% in the program group vs. 5% in the baseline group) and fistulizing disease (6% in the program group vs. 12% in the baseline group).
In addition, the program was associated with lower costs.
The pilot program was designed “to provide a systematic framework to coordinate care and consensus decision-making among different specialties relevant to [malignant bowel obstruction] management,” Dr. Lee and colleagues said. It includes outpatient care led by oncology nurses through telephone consultations. “Standardized clinical processes, assessment tools, and documentation in the electronic medical record are incorporated to facilitate seamless transition between in- and outpatient care,” the authors said. “Patient educational materials have been developed to empower patients to recognize and effectively communicate their symptoms.”
It is unclear whether other institutions could implement this program, Dr. Lee and colleagues noted. It also is not possible to determine whether differences in survival relate to earlier recognition of malignant bowel obstruction, more effective management, or other factors.
Dr. Lee was supported by funding from Princess Margaret Cancer Foundation and an Australian Government Research Training Program Scholarship. Coauthors disclosed financial relationships with pharmaceutical companies and pending patents related to percutaneous procedures and a surgical device.
SOURCE: Lee YC et al. J Oncol Pract. 2019 Sep 24. doi: 10.1200/JOP.18.00793.
A pilot program that aims to optimize the care of patients with malignant bowel obstruction is associated with longer survival and shorter cumulative hospital length of stay in the first 60 days after a malignant bowel obstruction diagnosis, according to research published in Journal of Oncology Practice.
Yeh Chen Lee, MBBS, of Princess Margaret Cancer Centre in Toronto, and colleagues retrospectively compared the outcomes of 106 women with advanced gynecologic cancer who were admitted to the hospital with malignant bowel obstruction before the program was implemented, with those of 63 women who were admitted after the program was implemented.
Patients’ median age at diagnosis of malignant bowel obstruction was 62 years (range, 31-91 years). Primary cancer diagnoses included ovarian cancer (73%), uterine cancer (18%), and cervical cancer (9%), and most patients had stage III-IV disease. Most patients had small-bowel obstruction (78%).
In the 2 years before the program, women had an average cumulative length of stay in the hospital of 22 days within the first 60 days of malignant bowel obstruction diagnosis. In the 2 years after, the average length of stay was 13 days. Furthermore, median overall survival, adjusted for initial cancer stage and lines of chemotherapy, increased by about 5 months, from 99 days before the program to 243 days after the program was implemented.
Patients who were treated during the malignant bowel obstruction program were more likely than were patients in the baseline group to receive chemotherapy (83% vs. 56%) and to receive two or more interventions for malignant bowel obstruction, such as surgery, chemotherapy, or total parenteral nutrition (42% vs. 33%). Complications included bowel perforation (13% in the program group vs. 5% in the baseline group) and fistulizing disease (6% in the program group vs. 12% in the baseline group).
In addition, the program was associated with lower costs.
The pilot program was designed “to provide a systematic framework to coordinate care and consensus decision-making among different specialties relevant to [malignant bowel obstruction] management,” Dr. Lee and colleagues said. It includes outpatient care led by oncology nurses through telephone consultations. “Standardized clinical processes, assessment tools, and documentation in the electronic medical record are incorporated to facilitate seamless transition between in- and outpatient care,” the authors said. “Patient educational materials have been developed to empower patients to recognize and effectively communicate their symptoms.”
It is unclear whether other institutions could implement this program, Dr. Lee and colleagues noted. It also is not possible to determine whether differences in survival relate to earlier recognition of malignant bowel obstruction, more effective management, or other factors.
Dr. Lee was supported by funding from Princess Margaret Cancer Foundation and an Australian Government Research Training Program Scholarship. Coauthors disclosed financial relationships with pharmaceutical companies and pending patents related to percutaneous procedures and a surgical device.
SOURCE: Lee YC et al. J Oncol Pract. 2019 Sep 24. doi: 10.1200/JOP.18.00793.
FROM JOURNAL OF ONCOLOGY PRACTICE
Newly described lung disorder strikes children with systemic juvenile idiopathic arthritis
An uncommon but potentially deadly inflammatory lung disease is emerging among children with systemic juvenile idiopathic arthritis, and its history appears to coincide with the rise of powerful biologics as first-line therapy for children with the disease.
Most confirmed cases of systemic juvenile idiopathic arthritis with lung disease (sJIA-LD) are in the United States. But it’s popping up in other places that have adopted early biologic treatment for sJIA – including Canada, South America, Europe, and the Middle East.
The respiratory symptoms are relatively subtle, so by the time of lung disease detection, the amount of affected lung can be extensive, said Elizabeth Mellins, MD, a Stanford (Calif.) University researcher who, along with first author Vivian Saper, MD, recently published the largest case series comprising reports from 37 institutions (Ann Rheum Dis. 2019 Sep 27. doi: 10.1136/annrheumdis-2019-216040). By the end of follow-up, 22 of the 61 children in her cohort had died, including all 12 patients who demonstrated excessively high neutrophil levels in bronchoalveolar lavage samples.
Another recent report, authored by Grant Schulert, MD, PhD, and colleagues of the Cincinnati Children’s Hospital Medical Center, described 18 patients, 9 of whom were also included in the Stanford cohort (Arthritis Rheumatol. 2019 Aug 5. doi: 10.1002/art.41073).
Both investigators have now identified new patients.
“We are aware of 60 additional cases beyond what were included in our series,” Dr. Mellins said in an interview, bringing her entire cohort to 121. Dr. Schulert also continues to expand his group, detailing nine new cases at a recent private meeting.
“We are up to 27 now,” he said. “The features of these new patients are all very similar: The children are very young, all have had macrophage activation syndrome in the past and very-difficult-to-control JIA. Reactions to tocilizumab [Actemra] were also not uncommon in this group.”
Dr. Mellins also saw this association with allergic-type tocilizumab reactions, severe delayed hypersensitivity reactions to anakinra (Kineret) or canakinumab (Ilaris). Although serious lung disease in sJIA patients is not unheard of, this phenotype was virtually unknown until about a decade ago. Both investigators said that it’s been rising steadily since 2010 – just about the time that powerful cytokine-inhibiting biologics were changing these patients’ world for the better. After decades of relying almost solely on steroids and methotrexate, with rather poor results and significant long-term side effects, children were not only improving, but thriving. Gone was the life-changing glucocorticoid-related growth inhibition. Biologics could halt fevers, rash, and joint destruction in their tracks.
“For the first time in history, these kids could look forward to a more or less normal life,” Dr. Schulert said.
But the emergence of this particular type of lung disease could throw a pall over that success story, he said. If sJIA-LD is temporally associated with increasing reliance on long-term interleukin-1/IL-6 inhibition in children with early-onset disease, could these drugs actually be the causative agent? The picture remains unclear.
Some of the 18 in his initial series have improved, while 36% of those in the Stanford series died. Most who do recover stay on their IL-1 or IL-6 blocking therapy with good disease control without further lung problems. Both investigators found compelling genetic hints, but nothing conclusive. Children with trisomy 21 appear especially vulnerable. Most patients are very young – around 2 years old – but others are school aged. Some had a history of macrophage activation syndrome. Some had hard-to-control disease and some were clinically well controlled when the lung disease presented.
There are simply no answers yet.
With so many potential links, all unproven, clinicians may question the wisdom of embarking on long-term biologic therapy for their children with sJIA. Peter Nigrovic, MD, of Boston Children’s Hospital, addressed this in an accompanying editorial (Arthritis Rheumatol. 2019 Aug 7. doi: 10.1002/art.41071).
“My take on this is that it’s a very worrisome trend,” he said in an interview. “We’ve been going full bore toward early biologic therapy in sJIA and at the same time we are seeing more of this lung disease. Is it guilt by association? Or is there something more? The challenge for us is not to jump too soon to that conclusion.”
Although the association is there, he said, association does not equal causation. And there’s no doubt that biologics have vastly improved the lives of sJIA patients. “The drugs might be causal, and I worry about that and think we need to study it. But we absolutely need stronger evidence before we change practice.”
“This is a new manifestation of the disease, and it’s coming at the same time we are changing the treatment paradigm,” Dr. Nigrovic continued. “It could be because of interleukin-1 or interleukin-6 blockade. There is biological plausibility for such a link. It could also be related to the fact that we are using less steroids and methotrexate, which might have been preventing this. The appearance of sJIA lung disease could also be that a distinct secular trend unrelated to treatment, just as we saw amyloid come and go in this population in Europe. These other therapies were actually preventing this. We just don’t know.”
Clinical characteristics
Children presented with similar symptoms. Respiratory symptoms are usually subtle and mild. These can include tachypnea, hypoxia (43% in the Stanford series), and pulmonary hypertension (30% in the Stanford series).
Digital clubbing, often with erythema, was a common finding. Some children showed pruritic, nonevanescent rashes. Eosinophilia occurred in 37% of the Stanford series and severe abdominal pain in 16%, although Dr. Mellins noted that belly pain may be underestimated, as it was only volunteered, not queried, information.
“There are some red flags that should raise suspicion even without obvious respiratory symptoms,” Dr. Mellins said. These include lymphopenia, unexplained abdominal pain, eosinophilia, an unusual rash, and finger clubbing with or without erythema.
Findings on imaging were consistent in both series. Several key clinic features emerged: pleural thickening, septal thickening, bronchial wall or peribronchovascular thickening, “tree-in-bud” opacities, “ground-glass” opacities, peripheral consolidation, and lymphadenopathy.
“The imaging findings correspond to two things,” Dr. Schulert said. “The first is inflammation in the interstitium, which is evidence of chronic and ongoing inflammation. The other thing is that the alveoli are filled with a lipoproteinaceous material which is actually surfactant that’s not being normally recycled by the lung macrophages. You can see these features in other conditions where there’s a problem with lung macrophages, like pulmonary alveolar proteinosis, genetic and autoimmune disorders, infections, or inhalants.”
Pathology showed alveolar filling – a location in the lung that hides usual symptoms until the lung disease is advanced. Prior drug reactions were common. Tocilizumab anaphylaxis occurred in close to 40% of the Stanford series – a surprising finding given the 0.6% reaction incidence in the drug’s sJIA trials. Dr. Schulert saw a similar story.
“In our cohort we also observed a striking number of adverse events to cytokine-targeted biologics exposure,” Dr. Schulert said. “Most of these reactions were to tocilizumab, and were described variously from pain and feeling unwell, to difficulty breathing, to anaphylaxis.”
In a risk analysis, Dr. Schulert determined that adverse events to cytokine-targeting biologics increased the likelihood of lung disease more than 13 times (odds ratio, 13.6).
“We also identified a statistically significant association with history of macrophage activation syndrome when compared to controls (OR, 14.5),” Dr. Schulert and associates wrote.
Genetics
Both the Cincinnati and Stanford teams conducted genetic analyses on some of their patients.
Among eight lung biopsy samples, Dr. Schulert found 37 differentially expressed genes: 36 with increased expression and 1 with decreased expression. Many of the up-regulated genes are involved in interferon-gamma response. Two (CXCL10 and CXCL9) are interferon-induced chemokines associated with macrophage activation syndrome. The down-regulated gene, PADI4, modulates immune response in lupus, and has been associated with the risk of interstitial lung disease in RA.
Dr. Mellins and her team analyzed whole-exome sequencing data from 20 patients and found some rare protein-altering gene variants in genes related to pulmonary alveolar proteinosis, all of which were heterozygous and shared with a healthy parent. But none of them could be directly tied to the disorder.
Another genetic puzzle demands attention, she said. About 10% of the children had trisomy 21 – a stark contrast to the typical 0.2% prevalence among a control group of sJIA patients without any known lung disease in the Childhood Arthritis and Rheumatology Research Alliance Registry cohort, similar to the background population rate. There were suggestions of more aggressive lung disease in all six of these children. Four presented with hypoxia, and two showed advanced interstitial fibrosis. Children with trisomy 21 also seemed more susceptible to infections; 83% had a viral or fungal lung infection at diagnosis, compared with 29% of those without trisomy 21.
Prior exposure to cytokine inhibitors
Parenchymal lung disease and pulmonary hypertension complicating sJIA was first highlighted in a series of 25 cases reported by Kimura et al. in 2013. These authors raised the question of the possible relationship of this and the increasing use of anti–IL-1 and anti–IL-6 biologics in sJIA treatment.
Following this lead, Dr. Mellins started looking into this new clinical entity in 2015. By then, she was identifying some past cases by autopsy records and current cases by clinical presentation. She saw a dramatic shift over time. From 2002 to 2011, she identified four cases, half of which had been exposed to IL-1/IL-6 inhibitors. From 2012 to 2014, eight new cases came to light, and seven had been exposed to those drugs. The crescendo continued from 2015 to 2017. During those years, Dr. Mellins and associates identified 10 new patients, 7 of whom had taken interleukin-inhibiting biologics. The mean time from initial drug exposure to diagnosis was a little more than 1 year.
An adjusted analysis comparing sJIA-LD patients and sJIA patients without lung disease didn’t find any significant difference in drug exposure. However, children with lung disease were more likely to have taken anakinra before the symptoms developed. Additionally, the symptoms of clubbing, abdominal pain, eosinophilia, hyperenhancing lymph nodes, and pulmonary alveolar proteinosis were much more common in children who’d taken the drugs.
The authors pointed out that this association does not prove causality and is confounded by the concomitant reduction in glucocorticoids with IL-1/IL-6 inhibitor use. And the vast majority of children with sJIA take cytokine inhibitors with no problems.
“Possibly, drug exposure may promote lung disease in a subset of children with sJIA, among the substantially larger group of patients who derive striking benefit from these drugs,” Dr. Mellins said, “Importantly, our results argue strongly for more investigation into a possible connection.”
Survival
After a mean follow-up of 1.7 years, the Stanford group saw high mortality. The 5-year survival rate translated to a mortality incidence of 159 deaths per 1,000 person-years, compared with 3.9 per 1,000 person-years in a historical cohort of sJIA patients who required biologic therapy.
Diffuse lung disease was the cause of 12 deaths; 5 of these patients also had macrophage activation syndrome at the time of death. Factors significantly associated with shortened survival included male sex, hypoxia at presentation, and neutrophilic bronchoalveolar lavage with more than 10 times the normal count. In an adjusted analysis, all of these variables fell out. However, none of the children with excessively high neutrophilic bronchoalveolar lavage survived.
Does it affect adults?
Could adults be experiencing the same disorder? There is some evidence to support it: The Food and Drug Administration adverse event website shows alveolar disease or pulmonary hypertension in 39 adults who have been exposed to IL-1 or IL-6 inhibition. Of these, 23 had RA, 11 adult-onset Still’s disease, and 5 unclassified rheumatic disorders.
The research groups were supported by grants from the sJIA Foundation, the Lucile Packard Foundation for Children’s Health, Stanford graduate fellowships, the Life Sciences Research Foundation, the Bill & Melinda Gates Foundation, Cincinnati Children’s Research Foundation, the Childhood Arthritis and Rheumatology Research Alliance, the Arthritis Foundation, and the National Institutes of Health. Many authors on both papers reported financial ties to Genentech, which markets tocilizumab, and other pharmaceutical companies*. Dr. Nigrovic reported receiving consulting fees and research support from Novartis and other companies.
SOURCES: Saper V et al. Ann Rheum Dis. 2019 Sep 27. doi: 10.1136/annrheumdis-2019-216040; Schulert GS et al. Arthritis Rheumatol. 2019 Aug 5. doi: 10.1002/art.41073; Nigrovic PA. Arthritis Rheumatol. 2019 Aug 7. doi: 10.1002/art.41071.
*Correction, 10/12/19: An earlier version of this article misstated the manufacturer of Actemra (tocilizumab).
This article was updated 10/14/19.
An uncommon but potentially deadly inflammatory lung disease is emerging among children with systemic juvenile idiopathic arthritis, and its history appears to coincide with the rise of powerful biologics as first-line therapy for children with the disease.
Most confirmed cases of systemic juvenile idiopathic arthritis with lung disease (sJIA-LD) are in the United States. But it’s popping up in other places that have adopted early biologic treatment for sJIA – including Canada, South America, Europe, and the Middle East.
The respiratory symptoms are relatively subtle, so by the time of lung disease detection, the amount of affected lung can be extensive, said Elizabeth Mellins, MD, a Stanford (Calif.) University researcher who, along with first author Vivian Saper, MD, recently published the largest case series comprising reports from 37 institutions (Ann Rheum Dis. 2019 Sep 27. doi: 10.1136/annrheumdis-2019-216040). By the end of follow-up, 22 of the 61 children in her cohort had died, including all 12 patients who demonstrated excessively high neutrophil levels in bronchoalveolar lavage samples.
Another recent report, authored by Grant Schulert, MD, PhD, and colleagues of the Cincinnati Children’s Hospital Medical Center, described 18 patients, 9 of whom were also included in the Stanford cohort (Arthritis Rheumatol. 2019 Aug 5. doi: 10.1002/art.41073).
Both investigators have now identified new patients.
“We are aware of 60 additional cases beyond what were included in our series,” Dr. Mellins said in an interview, bringing her entire cohort to 121. Dr. Schulert also continues to expand his group, detailing nine new cases at a recent private meeting.
“We are up to 27 now,” he said. “The features of these new patients are all very similar: The children are very young, all have had macrophage activation syndrome in the past and very-difficult-to-control JIA. Reactions to tocilizumab [Actemra] were also not uncommon in this group.”
Dr. Mellins also saw this association with allergic-type tocilizumab reactions, severe delayed hypersensitivity reactions to anakinra (Kineret) or canakinumab (Ilaris). Although serious lung disease in sJIA patients is not unheard of, this phenotype was virtually unknown until about a decade ago. Both investigators said that it’s been rising steadily since 2010 – just about the time that powerful cytokine-inhibiting biologics were changing these patients’ world for the better. After decades of relying almost solely on steroids and methotrexate, with rather poor results and significant long-term side effects, children were not only improving, but thriving. Gone was the life-changing glucocorticoid-related growth inhibition. Biologics could halt fevers, rash, and joint destruction in their tracks.
“For the first time in history, these kids could look forward to a more or less normal life,” Dr. Schulert said.
But the emergence of this particular type of lung disease could throw a pall over that success story, he said. If sJIA-LD is temporally associated with increasing reliance on long-term interleukin-1/IL-6 inhibition in children with early-onset disease, could these drugs actually be the causative agent? The picture remains unclear.
Some of the 18 in his initial series have improved, while 36% of those in the Stanford series died. Most who do recover stay on their IL-1 or IL-6 blocking therapy with good disease control without further lung problems. Both investigators found compelling genetic hints, but nothing conclusive. Children with trisomy 21 appear especially vulnerable. Most patients are very young – around 2 years old – but others are school aged. Some had a history of macrophage activation syndrome. Some had hard-to-control disease and some were clinically well controlled when the lung disease presented.
There are simply no answers yet.
With so many potential links, all unproven, clinicians may question the wisdom of embarking on long-term biologic therapy for their children with sJIA. Peter Nigrovic, MD, of Boston Children’s Hospital, addressed this in an accompanying editorial (Arthritis Rheumatol. 2019 Aug 7. doi: 10.1002/art.41071).
“My take on this is that it’s a very worrisome trend,” he said in an interview. “We’ve been going full bore toward early biologic therapy in sJIA and at the same time we are seeing more of this lung disease. Is it guilt by association? Or is there something more? The challenge for us is not to jump too soon to that conclusion.”
Although the association is there, he said, association does not equal causation. And there’s no doubt that biologics have vastly improved the lives of sJIA patients. “The drugs might be causal, and I worry about that and think we need to study it. But we absolutely need stronger evidence before we change practice.”
“This is a new manifestation of the disease, and it’s coming at the same time we are changing the treatment paradigm,” Dr. Nigrovic continued. “It could be because of interleukin-1 or interleukin-6 blockade. There is biological plausibility for such a link. It could also be related to the fact that we are using less steroids and methotrexate, which might have been preventing this. The appearance of sJIA lung disease could also be that a distinct secular trend unrelated to treatment, just as we saw amyloid come and go in this population in Europe. These other therapies were actually preventing this. We just don’t know.”
Clinical characteristics
Children presented with similar symptoms. Respiratory symptoms are usually subtle and mild. These can include tachypnea, hypoxia (43% in the Stanford series), and pulmonary hypertension (30% in the Stanford series).
Digital clubbing, often with erythema, was a common finding. Some children showed pruritic, nonevanescent rashes. Eosinophilia occurred in 37% of the Stanford series and severe abdominal pain in 16%, although Dr. Mellins noted that belly pain may be underestimated, as it was only volunteered, not queried, information.
“There are some red flags that should raise suspicion even without obvious respiratory symptoms,” Dr. Mellins said. These include lymphopenia, unexplained abdominal pain, eosinophilia, an unusual rash, and finger clubbing with or without erythema.
Findings on imaging were consistent in both series. Several key clinic features emerged: pleural thickening, septal thickening, bronchial wall or peribronchovascular thickening, “tree-in-bud” opacities, “ground-glass” opacities, peripheral consolidation, and lymphadenopathy.
“The imaging findings correspond to two things,” Dr. Schulert said. “The first is inflammation in the interstitium, which is evidence of chronic and ongoing inflammation. The other thing is that the alveoli are filled with a lipoproteinaceous material which is actually surfactant that’s not being normally recycled by the lung macrophages. You can see these features in other conditions where there’s a problem with lung macrophages, like pulmonary alveolar proteinosis, genetic and autoimmune disorders, infections, or inhalants.”
Pathology showed alveolar filling – a location in the lung that hides usual symptoms until the lung disease is advanced. Prior drug reactions were common. Tocilizumab anaphylaxis occurred in close to 40% of the Stanford series – a surprising finding given the 0.6% reaction incidence in the drug’s sJIA trials. Dr. Schulert saw a similar story.
“In our cohort we also observed a striking number of adverse events to cytokine-targeted biologics exposure,” Dr. Schulert said. “Most of these reactions were to tocilizumab, and were described variously from pain and feeling unwell, to difficulty breathing, to anaphylaxis.”
In a risk analysis, Dr. Schulert determined that adverse events to cytokine-targeting biologics increased the likelihood of lung disease more than 13 times (odds ratio, 13.6).
“We also identified a statistically significant association with history of macrophage activation syndrome when compared to controls (OR, 14.5),” Dr. Schulert and associates wrote.
Genetics
Both the Cincinnati and Stanford teams conducted genetic analyses on some of their patients.
Among eight lung biopsy samples, Dr. Schulert found 37 differentially expressed genes: 36 with increased expression and 1 with decreased expression. Many of the up-regulated genes are involved in interferon-gamma response. Two (CXCL10 and CXCL9) are interferon-induced chemokines associated with macrophage activation syndrome. The down-regulated gene, PADI4, modulates immune response in lupus, and has been associated with the risk of interstitial lung disease in RA.
Dr. Mellins and her team analyzed whole-exome sequencing data from 20 patients and found some rare protein-altering gene variants in genes related to pulmonary alveolar proteinosis, all of which were heterozygous and shared with a healthy parent. But none of them could be directly tied to the disorder.
Another genetic puzzle demands attention, she said. About 10% of the children had trisomy 21 – a stark contrast to the typical 0.2% prevalence among a control group of sJIA patients without any known lung disease in the Childhood Arthritis and Rheumatology Research Alliance Registry cohort, similar to the background population rate. There were suggestions of more aggressive lung disease in all six of these children. Four presented with hypoxia, and two showed advanced interstitial fibrosis. Children with trisomy 21 also seemed more susceptible to infections; 83% had a viral or fungal lung infection at diagnosis, compared with 29% of those without trisomy 21.
Prior exposure to cytokine inhibitors
Parenchymal lung disease and pulmonary hypertension complicating sJIA was first highlighted in a series of 25 cases reported by Kimura et al. in 2013. These authors raised the question of the possible relationship of this and the increasing use of anti–IL-1 and anti–IL-6 biologics in sJIA treatment.
Following this lead, Dr. Mellins started looking into this new clinical entity in 2015. By then, she was identifying some past cases by autopsy records and current cases by clinical presentation. She saw a dramatic shift over time. From 2002 to 2011, she identified four cases, half of which had been exposed to IL-1/IL-6 inhibitors. From 2012 to 2014, eight new cases came to light, and seven had been exposed to those drugs. The crescendo continued from 2015 to 2017. During those years, Dr. Mellins and associates identified 10 new patients, 7 of whom had taken interleukin-inhibiting biologics. The mean time from initial drug exposure to diagnosis was a little more than 1 year.
An adjusted analysis comparing sJIA-LD patients and sJIA patients without lung disease didn’t find any significant difference in drug exposure. However, children with lung disease were more likely to have taken anakinra before the symptoms developed. Additionally, the symptoms of clubbing, abdominal pain, eosinophilia, hyperenhancing lymph nodes, and pulmonary alveolar proteinosis were much more common in children who’d taken the drugs.
The authors pointed out that this association does not prove causality and is confounded by the concomitant reduction in glucocorticoids with IL-1/IL-6 inhibitor use. And the vast majority of children with sJIA take cytokine inhibitors with no problems.
“Possibly, drug exposure may promote lung disease in a subset of children with sJIA, among the substantially larger group of patients who derive striking benefit from these drugs,” Dr. Mellins said, “Importantly, our results argue strongly for more investigation into a possible connection.”
Survival
After a mean follow-up of 1.7 years, the Stanford group saw high mortality. The 5-year survival rate translated to a mortality incidence of 159 deaths per 1,000 person-years, compared with 3.9 per 1,000 person-years in a historical cohort of sJIA patients who required biologic therapy.
Diffuse lung disease was the cause of 12 deaths; 5 of these patients also had macrophage activation syndrome at the time of death. Factors significantly associated with shortened survival included male sex, hypoxia at presentation, and neutrophilic bronchoalveolar lavage with more than 10 times the normal count. In an adjusted analysis, all of these variables fell out. However, none of the children with excessively high neutrophilic bronchoalveolar lavage survived.
Does it affect adults?
Could adults be experiencing the same disorder? There is some evidence to support it: The Food and Drug Administration adverse event website shows alveolar disease or pulmonary hypertension in 39 adults who have been exposed to IL-1 or IL-6 inhibition. Of these, 23 had RA, 11 adult-onset Still’s disease, and 5 unclassified rheumatic disorders.
The research groups were supported by grants from the sJIA Foundation, the Lucile Packard Foundation for Children’s Health, Stanford graduate fellowships, the Life Sciences Research Foundation, the Bill & Melinda Gates Foundation, Cincinnati Children’s Research Foundation, the Childhood Arthritis and Rheumatology Research Alliance, the Arthritis Foundation, and the National Institutes of Health. Many authors on both papers reported financial ties to Genentech, which markets tocilizumab, and other pharmaceutical companies*. Dr. Nigrovic reported receiving consulting fees and research support from Novartis and other companies.
SOURCES: Saper V et al. Ann Rheum Dis. 2019 Sep 27. doi: 10.1136/annrheumdis-2019-216040; Schulert GS et al. Arthritis Rheumatol. 2019 Aug 5. doi: 10.1002/art.41073; Nigrovic PA. Arthritis Rheumatol. 2019 Aug 7. doi: 10.1002/art.41071.
*Correction, 10/12/19: An earlier version of this article misstated the manufacturer of Actemra (tocilizumab).
This article was updated 10/14/19.
An uncommon but potentially deadly inflammatory lung disease is emerging among children with systemic juvenile idiopathic arthritis, and its history appears to coincide with the rise of powerful biologics as first-line therapy for children with the disease.
Most confirmed cases of systemic juvenile idiopathic arthritis with lung disease (sJIA-LD) are in the United States. But it’s popping up in other places that have adopted early biologic treatment for sJIA – including Canada, South America, Europe, and the Middle East.
The respiratory symptoms are relatively subtle, so by the time of lung disease detection, the amount of affected lung can be extensive, said Elizabeth Mellins, MD, a Stanford (Calif.) University researcher who, along with first author Vivian Saper, MD, recently published the largest case series comprising reports from 37 institutions (Ann Rheum Dis. 2019 Sep 27. doi: 10.1136/annrheumdis-2019-216040). By the end of follow-up, 22 of the 61 children in her cohort had died, including all 12 patients who demonstrated excessively high neutrophil levels in bronchoalveolar lavage samples.
Another recent report, authored by Grant Schulert, MD, PhD, and colleagues of the Cincinnati Children’s Hospital Medical Center, described 18 patients, 9 of whom were also included in the Stanford cohort (Arthritis Rheumatol. 2019 Aug 5. doi: 10.1002/art.41073).
Both investigators have now identified new patients.
“We are aware of 60 additional cases beyond what were included in our series,” Dr. Mellins said in an interview, bringing her entire cohort to 121. Dr. Schulert also continues to expand his group, detailing nine new cases at a recent private meeting.
“We are up to 27 now,” he said. “The features of these new patients are all very similar: The children are very young, all have had macrophage activation syndrome in the past and very-difficult-to-control JIA. Reactions to tocilizumab [Actemra] were also not uncommon in this group.”
Dr. Mellins also saw this association with allergic-type tocilizumab reactions, severe delayed hypersensitivity reactions to anakinra (Kineret) or canakinumab (Ilaris). Although serious lung disease in sJIA patients is not unheard of, this phenotype was virtually unknown until about a decade ago. Both investigators said that it’s been rising steadily since 2010 – just about the time that powerful cytokine-inhibiting biologics were changing these patients’ world for the better. After decades of relying almost solely on steroids and methotrexate, with rather poor results and significant long-term side effects, children were not only improving, but thriving. Gone was the life-changing glucocorticoid-related growth inhibition. Biologics could halt fevers, rash, and joint destruction in their tracks.
“For the first time in history, these kids could look forward to a more or less normal life,” Dr. Schulert said.
But the emergence of this particular type of lung disease could throw a pall over that success story, he said. If sJIA-LD is temporally associated with increasing reliance on long-term interleukin-1/IL-6 inhibition in children with early-onset disease, could these drugs actually be the causative agent? The picture remains unclear.
Some of the 18 in his initial series have improved, while 36% of those in the Stanford series died. Most who do recover stay on their IL-1 or IL-6 blocking therapy with good disease control without further lung problems. Both investigators found compelling genetic hints, but nothing conclusive. Children with trisomy 21 appear especially vulnerable. Most patients are very young – around 2 years old – but others are school aged. Some had a history of macrophage activation syndrome. Some had hard-to-control disease and some were clinically well controlled when the lung disease presented.
There are simply no answers yet.
With so many potential links, all unproven, clinicians may question the wisdom of embarking on long-term biologic therapy for their children with sJIA. Peter Nigrovic, MD, of Boston Children’s Hospital, addressed this in an accompanying editorial (Arthritis Rheumatol. 2019 Aug 7. doi: 10.1002/art.41071).
“My take on this is that it’s a very worrisome trend,” he said in an interview. “We’ve been going full bore toward early biologic therapy in sJIA and at the same time we are seeing more of this lung disease. Is it guilt by association? Or is there something more? The challenge for us is not to jump too soon to that conclusion.”
Although the association is there, he said, association does not equal causation. And there’s no doubt that biologics have vastly improved the lives of sJIA patients. “The drugs might be causal, and I worry about that and think we need to study it. But we absolutely need stronger evidence before we change practice.”
“This is a new manifestation of the disease, and it’s coming at the same time we are changing the treatment paradigm,” Dr. Nigrovic continued. “It could be because of interleukin-1 or interleukin-6 blockade. There is biological plausibility for such a link. It could also be related to the fact that we are using less steroids and methotrexate, which might have been preventing this. The appearance of sJIA lung disease could also be that a distinct secular trend unrelated to treatment, just as we saw amyloid come and go in this population in Europe. These other therapies were actually preventing this. We just don’t know.”
Clinical characteristics
Children presented with similar symptoms. Respiratory symptoms are usually subtle and mild. These can include tachypnea, hypoxia (43% in the Stanford series), and pulmonary hypertension (30% in the Stanford series).
Digital clubbing, often with erythema, was a common finding. Some children showed pruritic, nonevanescent rashes. Eosinophilia occurred in 37% of the Stanford series and severe abdominal pain in 16%, although Dr. Mellins noted that belly pain may be underestimated, as it was only volunteered, not queried, information.
“There are some red flags that should raise suspicion even without obvious respiratory symptoms,” Dr. Mellins said. These include lymphopenia, unexplained abdominal pain, eosinophilia, an unusual rash, and finger clubbing with or without erythema.
Findings on imaging were consistent in both series. Several key clinic features emerged: pleural thickening, septal thickening, bronchial wall or peribronchovascular thickening, “tree-in-bud” opacities, “ground-glass” opacities, peripheral consolidation, and lymphadenopathy.
“The imaging findings correspond to two things,” Dr. Schulert said. “The first is inflammation in the interstitium, which is evidence of chronic and ongoing inflammation. The other thing is that the alveoli are filled with a lipoproteinaceous material which is actually surfactant that’s not being normally recycled by the lung macrophages. You can see these features in other conditions where there’s a problem with lung macrophages, like pulmonary alveolar proteinosis, genetic and autoimmune disorders, infections, or inhalants.”
Pathology showed alveolar filling – a location in the lung that hides usual symptoms until the lung disease is advanced. Prior drug reactions were common. Tocilizumab anaphylaxis occurred in close to 40% of the Stanford series – a surprising finding given the 0.6% reaction incidence in the drug’s sJIA trials. Dr. Schulert saw a similar story.
“In our cohort we also observed a striking number of adverse events to cytokine-targeted biologics exposure,” Dr. Schulert said. “Most of these reactions were to tocilizumab, and were described variously from pain and feeling unwell, to difficulty breathing, to anaphylaxis.”
In a risk analysis, Dr. Schulert determined that adverse events to cytokine-targeting biologics increased the likelihood of lung disease more than 13 times (odds ratio, 13.6).
“We also identified a statistically significant association with history of macrophage activation syndrome when compared to controls (OR, 14.5),” Dr. Schulert and associates wrote.
Genetics
Both the Cincinnati and Stanford teams conducted genetic analyses on some of their patients.
Among eight lung biopsy samples, Dr. Schulert found 37 differentially expressed genes: 36 with increased expression and 1 with decreased expression. Many of the up-regulated genes are involved in interferon-gamma response. Two (CXCL10 and CXCL9) are interferon-induced chemokines associated with macrophage activation syndrome. The down-regulated gene, PADI4, modulates immune response in lupus, and has been associated with the risk of interstitial lung disease in RA.
Dr. Mellins and her team analyzed whole-exome sequencing data from 20 patients and found some rare protein-altering gene variants in genes related to pulmonary alveolar proteinosis, all of which were heterozygous and shared with a healthy parent. But none of them could be directly tied to the disorder.
Another genetic puzzle demands attention, she said. About 10% of the children had trisomy 21 – a stark contrast to the typical 0.2% prevalence among a control group of sJIA patients without any known lung disease in the Childhood Arthritis and Rheumatology Research Alliance Registry cohort, similar to the background population rate. There were suggestions of more aggressive lung disease in all six of these children. Four presented with hypoxia, and two showed advanced interstitial fibrosis. Children with trisomy 21 also seemed more susceptible to infections; 83% had a viral or fungal lung infection at diagnosis, compared with 29% of those without trisomy 21.
Prior exposure to cytokine inhibitors
Parenchymal lung disease and pulmonary hypertension complicating sJIA was first highlighted in a series of 25 cases reported by Kimura et al. in 2013. These authors raised the question of the possible relationship of this and the increasing use of anti–IL-1 and anti–IL-6 biologics in sJIA treatment.
Following this lead, Dr. Mellins started looking into this new clinical entity in 2015. By then, she was identifying some past cases by autopsy records and current cases by clinical presentation. She saw a dramatic shift over time. From 2002 to 2011, she identified four cases, half of which had been exposed to IL-1/IL-6 inhibitors. From 2012 to 2014, eight new cases came to light, and seven had been exposed to those drugs. The crescendo continued from 2015 to 2017. During those years, Dr. Mellins and associates identified 10 new patients, 7 of whom had taken interleukin-inhibiting biologics. The mean time from initial drug exposure to diagnosis was a little more than 1 year.
An adjusted analysis comparing sJIA-LD patients and sJIA patients without lung disease didn’t find any significant difference in drug exposure. However, children with lung disease were more likely to have taken anakinra before the symptoms developed. Additionally, the symptoms of clubbing, abdominal pain, eosinophilia, hyperenhancing lymph nodes, and pulmonary alveolar proteinosis were much more common in children who’d taken the drugs.
The authors pointed out that this association does not prove causality and is confounded by the concomitant reduction in glucocorticoids with IL-1/IL-6 inhibitor use. And the vast majority of children with sJIA take cytokine inhibitors with no problems.
“Possibly, drug exposure may promote lung disease in a subset of children with sJIA, among the substantially larger group of patients who derive striking benefit from these drugs,” Dr. Mellins said, “Importantly, our results argue strongly for more investigation into a possible connection.”
Survival
After a mean follow-up of 1.7 years, the Stanford group saw high mortality. The 5-year survival rate translated to a mortality incidence of 159 deaths per 1,000 person-years, compared with 3.9 per 1,000 person-years in a historical cohort of sJIA patients who required biologic therapy.
Diffuse lung disease was the cause of 12 deaths; 5 of these patients also had macrophage activation syndrome at the time of death. Factors significantly associated with shortened survival included male sex, hypoxia at presentation, and neutrophilic bronchoalveolar lavage with more than 10 times the normal count. In an adjusted analysis, all of these variables fell out. However, none of the children with excessively high neutrophilic bronchoalveolar lavage survived.
Does it affect adults?
Could adults be experiencing the same disorder? There is some evidence to support it: The Food and Drug Administration adverse event website shows alveolar disease or pulmonary hypertension in 39 adults who have been exposed to IL-1 or IL-6 inhibition. Of these, 23 had RA, 11 adult-onset Still’s disease, and 5 unclassified rheumatic disorders.
The research groups were supported by grants from the sJIA Foundation, the Lucile Packard Foundation for Children’s Health, Stanford graduate fellowships, the Life Sciences Research Foundation, the Bill & Melinda Gates Foundation, Cincinnati Children’s Research Foundation, the Childhood Arthritis and Rheumatology Research Alliance, the Arthritis Foundation, and the National Institutes of Health. Many authors on both papers reported financial ties to Genentech, which markets tocilizumab, and other pharmaceutical companies*. Dr. Nigrovic reported receiving consulting fees and research support from Novartis and other companies.
SOURCES: Saper V et al. Ann Rheum Dis. 2019 Sep 27. doi: 10.1136/annrheumdis-2019-216040; Schulert GS et al. Arthritis Rheumatol. 2019 Aug 5. doi: 10.1002/art.41073; Nigrovic PA. Arthritis Rheumatol. 2019 Aug 7. doi: 10.1002/art.41071.
*Correction, 10/12/19: An earlier version of this article misstated the manufacturer of Actemra (tocilizumab).
This article was updated 10/14/19.
Patients with nonaffective psychosis offer treatment target preferences
‘Worrying less,’ ‘feeling happier,’ and sleeping better were among top targets identified
Patients with nonaffective psychosis want the “causal mechanisms” for their psychotic experiences treated, according to a study conducted by researchers at the University of Oxford (England).
“The findings indicate a need to adopt into services for people with severe mental health difficulties interventions shown by research to treat anxious avoidance, worry, low self-esteem, insomnia, and other such transdiagnostic mechanisms and evaluate the outcomes,” wrote Daniel Freeman, PhD, DClinPsy, of the department of psychiatry at Oxford, and colleagues. The study was published in Schizophrenia Research.
In previous research, Dr. Freeman and colleagues identified factors that appear to maintain symptoms of nonaffective psychosis, such as paranoia (Behav Cogn Psychother. 2016 Sep;44[5]:539-52).Those factors include anxious avoidance, worry, low self-esteem, insomnia, and reasoning bias. In additional research, the researchers demonstrated that addressing those targets can lead to led to reductions in paranoia.
In the current study, 1,809 patients were recruited from 39 National Health Services mental health trusts across England. The researchers analyzed responses to eight clinical assessment tools and a patient-reported questionnaire about treatment preferences.
Dr. Freeman and colleagues found consistency in the relationships observed among the factors and nonaffective psychosis with the theoretical model they had developed, such as positive correlations between paranoia and anxious avoidance (correlation coefficient [r] = 0.37), worry (r = 0.40), and hallucinations (r = 0.54). They found negative correlations between paranoia and levels of positive self-beliefs (r = –0.17), rational reasoning (r = –0.14), and psychological wellbeing (r = –0.29). Those correlations were all statistically significant with P values less than .001.
Most of the patients (90.3%) wanted at least one of the eight problem areas assessed in the study treated, and on average, they wanted more than four (mean, 4.5) treated. The most frequently identified top treatment priorities identified by patients were worrying (50.8%), feeling happier (42.9%), and sleeping better (41.2%).
the researchers wrote.
Among the study limitations: The assessments selected were based on the theoretical model the researchers had developed and therefore may not have captured all difficulties experienced by the patients. Furthermore, although the sample was large, it’s unclear whether it was truly representative because they were drawn from certain mental health services that, for example, patients with milder symptoms might not seek out.
Dr. Freeman is a cofounder and chief clinical officer of Oxford VR. He has received funding from the National Institute of Health Research, Medical Research Council, and Wellcome Trust. No other authors reported conflicts of interest.
SOURCE: Freeman D et al. Schizophr Res. 2019. doi: 10.1016/j.schres.2019.07.016.
‘Worrying less,’ ‘feeling happier,’ and sleeping better were among top targets identified
‘Worrying less,’ ‘feeling happier,’ and sleeping better were among top targets identified
Patients with nonaffective psychosis want the “causal mechanisms” for their psychotic experiences treated, according to a study conducted by researchers at the University of Oxford (England).
“The findings indicate a need to adopt into services for people with severe mental health difficulties interventions shown by research to treat anxious avoidance, worry, low self-esteem, insomnia, and other such transdiagnostic mechanisms and evaluate the outcomes,” wrote Daniel Freeman, PhD, DClinPsy, of the department of psychiatry at Oxford, and colleagues. The study was published in Schizophrenia Research.
In previous research, Dr. Freeman and colleagues identified factors that appear to maintain symptoms of nonaffective psychosis, such as paranoia (Behav Cogn Psychother. 2016 Sep;44[5]:539-52).Those factors include anxious avoidance, worry, low self-esteem, insomnia, and reasoning bias. In additional research, the researchers demonstrated that addressing those targets can lead to led to reductions in paranoia.
In the current study, 1,809 patients were recruited from 39 National Health Services mental health trusts across England. The researchers analyzed responses to eight clinical assessment tools and a patient-reported questionnaire about treatment preferences.
Dr. Freeman and colleagues found consistency in the relationships observed among the factors and nonaffective psychosis with the theoretical model they had developed, such as positive correlations between paranoia and anxious avoidance (correlation coefficient [r] = 0.37), worry (r = 0.40), and hallucinations (r = 0.54). They found negative correlations between paranoia and levels of positive self-beliefs (r = –0.17), rational reasoning (r = –0.14), and psychological wellbeing (r = –0.29). Those correlations were all statistically significant with P values less than .001.
Most of the patients (90.3%) wanted at least one of the eight problem areas assessed in the study treated, and on average, they wanted more than four (mean, 4.5) treated. The most frequently identified top treatment priorities identified by patients were worrying (50.8%), feeling happier (42.9%), and sleeping better (41.2%).
the researchers wrote.
Among the study limitations: The assessments selected were based on the theoretical model the researchers had developed and therefore may not have captured all difficulties experienced by the patients. Furthermore, although the sample was large, it’s unclear whether it was truly representative because they were drawn from certain mental health services that, for example, patients with milder symptoms might not seek out.
Dr. Freeman is a cofounder and chief clinical officer of Oxford VR. He has received funding from the National Institute of Health Research, Medical Research Council, and Wellcome Trust. No other authors reported conflicts of interest.
SOURCE: Freeman D et al. Schizophr Res. 2019. doi: 10.1016/j.schres.2019.07.016.
Patients with nonaffective psychosis want the “causal mechanisms” for their psychotic experiences treated, according to a study conducted by researchers at the University of Oxford (England).
“The findings indicate a need to adopt into services for people with severe mental health difficulties interventions shown by research to treat anxious avoidance, worry, low self-esteem, insomnia, and other such transdiagnostic mechanisms and evaluate the outcomes,” wrote Daniel Freeman, PhD, DClinPsy, of the department of psychiatry at Oxford, and colleagues. The study was published in Schizophrenia Research.
In previous research, Dr. Freeman and colleagues identified factors that appear to maintain symptoms of nonaffective psychosis, such as paranoia (Behav Cogn Psychother. 2016 Sep;44[5]:539-52).Those factors include anxious avoidance, worry, low self-esteem, insomnia, and reasoning bias. In additional research, the researchers demonstrated that addressing those targets can lead to led to reductions in paranoia.
In the current study, 1,809 patients were recruited from 39 National Health Services mental health trusts across England. The researchers analyzed responses to eight clinical assessment tools and a patient-reported questionnaire about treatment preferences.
Dr. Freeman and colleagues found consistency in the relationships observed among the factors and nonaffective psychosis with the theoretical model they had developed, such as positive correlations between paranoia and anxious avoidance (correlation coefficient [r] = 0.37), worry (r = 0.40), and hallucinations (r = 0.54). They found negative correlations between paranoia and levels of positive self-beliefs (r = –0.17), rational reasoning (r = –0.14), and psychological wellbeing (r = –0.29). Those correlations were all statistically significant with P values less than .001.
Most of the patients (90.3%) wanted at least one of the eight problem areas assessed in the study treated, and on average, they wanted more than four (mean, 4.5) treated. The most frequently identified top treatment priorities identified by patients were worrying (50.8%), feeling happier (42.9%), and sleeping better (41.2%).
the researchers wrote.
Among the study limitations: The assessments selected were based on the theoretical model the researchers had developed and therefore may not have captured all difficulties experienced by the patients. Furthermore, although the sample was large, it’s unclear whether it was truly representative because they were drawn from certain mental health services that, for example, patients with milder symptoms might not seek out.
Dr. Freeman is a cofounder and chief clinical officer of Oxford VR. He has received funding from the National Institute of Health Research, Medical Research Council, and Wellcome Trust. No other authors reported conflicts of interest.
SOURCE: Freeman D et al. Schizophr Res. 2019. doi: 10.1016/j.schres.2019.07.016.
FROM SCHIZOPHRENIA RESEARCH
Start From Scratch
A 50-year-old man presents with complaints of a rash on his right leg that manifested 20 years ago. Although the rash is worrisome, he says the associated pruritus is worse. During the workday, he is able to ignore the itching—but the minute he gets home, he begins to scratch.
He knows the scratching is counterproductive in the long run, but the urge to do it is quite compelling. Sometimes he uses a wet washcloth; other times, he will actually use a hair brush to satiate the itching. The relief is intensely satisfying albeit short lived.
The rash has persisted despite multiple treatment attempts. Tried products include OTC moisturizers and antifungal creams, as well as prescription antifungal creams. None has had an effect.
The patient denies any other skin problems. He does recall having eczema as a child. Although that has long since resolved, he remains quite allergy prone and is particularly sensitive to airborne allergens—a trait that runs strongly in his family.
EXAMINATION
A pink, oval rash covers most of the patient’s right lateral calf. It has a thickened, faintly scaly surface that is uniform and sharply circumscribed. There is no increased warmth or tenderness on palpation. No lymph nodes can be felt in the right groin. A check of the patient’s knees, elbows, scalp, nails, and trunk show no sign of rash or other changes.
What’s the diagnosis?
DISCUSSION
Lichen simplex chronicus (LSC), previously known as neurodermatitis, is quite common but frequently misdiagnosed. Patients often report that their condition started with a bug bite or poison ivy—a provocation that gets the patient in the habit of scratching, which continues long after the initial outbreak has subsided. Thus, LSC is often associated with significant chronicity, as typified by this case.
What patients seldom understand is their own role in the perpetuation of their condition. The urge to scratch is so unbearable that few can resist it. Over time, the scratching creates more nerves that have a lower threshold for itching, and thus the itch-scratch-itch cycle is born. Many LSC patients are atopic, which predisposes them to itching in general and to xerosis especially.
The literature asserts that LSC affects the genders equally, but this ignores the fact that it can present significantly differently in men and women. This patient’s area of involvement is quite typical for men, most of whom never moisturize and for whom the lateral calf is readily accessible. In the author’s experience, the most common location for LSC in women is the nuchal scalp, where heat and sweat appear to play a role, along with ready accessibility to fingernails or the sharp end of a pencil. Other common areas of involvement include the dorsal forearms and the scrotum or vulvae.
Biopsy is seldom necessary, but if performed, it will show a marked thickening of the epidermis, orthokeratosis (normal keratinocytes about to shed), and compacted, elongated rete ridges. These and other changes effectively rule out other items in the differential (eg, psoriasis, simple eczema, fungal infection).
Stopping the itch-scratch-itch cycle with mid-strength topical steroid creams or foams is the first step in treating LSC. But then the patient must be convinced of his contribution to the treatment: leaving the affected sites alone. Truth be told, after 20 years of scratching, the best this patient can look forward to is some relief—not only from the itching, but also from concern about all the terrible things he now knows he doesn’t have.
TAKE-HOME LEARNING POINTS
- Lichen simplex chronicus is quite common in both genders and is typified by longstanding severe itching, usually confined to one area.
- Atopy, xerosis, and stress all appear to contribute to the problem.
- Stopping the itch-scratch-itch cycle with topical steroids is a key component of treatment.
- Patient education—on the nature of the problem and the patient’s role in controlling it—is just as important as any prescribed medication.
A 50-year-old man presents with complaints of a rash on his right leg that manifested 20 years ago. Although the rash is worrisome, he says the associated pruritus is worse. During the workday, he is able to ignore the itching—but the minute he gets home, he begins to scratch.
He knows the scratching is counterproductive in the long run, but the urge to do it is quite compelling. Sometimes he uses a wet washcloth; other times, he will actually use a hair brush to satiate the itching. The relief is intensely satisfying albeit short lived.
The rash has persisted despite multiple treatment attempts. Tried products include OTC moisturizers and antifungal creams, as well as prescription antifungal creams. None has had an effect.
The patient denies any other skin problems. He does recall having eczema as a child. Although that has long since resolved, he remains quite allergy prone and is particularly sensitive to airborne allergens—a trait that runs strongly in his family.
EXAMINATION
A pink, oval rash covers most of the patient’s right lateral calf. It has a thickened, faintly scaly surface that is uniform and sharply circumscribed. There is no increased warmth or tenderness on palpation. No lymph nodes can be felt in the right groin. A check of the patient’s knees, elbows, scalp, nails, and trunk show no sign of rash or other changes.
What’s the diagnosis?
DISCUSSION
Lichen simplex chronicus (LSC), previously known as neurodermatitis, is quite common but frequently misdiagnosed. Patients often report that their condition started with a bug bite or poison ivy—a provocation that gets the patient in the habit of scratching, which continues long after the initial outbreak has subsided. Thus, LSC is often associated with significant chronicity, as typified by this case.
What patients seldom understand is their own role in the perpetuation of their condition. The urge to scratch is so unbearable that few can resist it. Over time, the scratching creates more nerves that have a lower threshold for itching, and thus the itch-scratch-itch cycle is born. Many LSC patients are atopic, which predisposes them to itching in general and to xerosis especially.
The literature asserts that LSC affects the genders equally, but this ignores the fact that it can present significantly differently in men and women. This patient’s area of involvement is quite typical for men, most of whom never moisturize and for whom the lateral calf is readily accessible. In the author’s experience, the most common location for LSC in women is the nuchal scalp, where heat and sweat appear to play a role, along with ready accessibility to fingernails or the sharp end of a pencil. Other common areas of involvement include the dorsal forearms and the scrotum or vulvae.
Biopsy is seldom necessary, but if performed, it will show a marked thickening of the epidermis, orthokeratosis (normal keratinocytes about to shed), and compacted, elongated rete ridges. These and other changes effectively rule out other items in the differential (eg, psoriasis, simple eczema, fungal infection).
Stopping the itch-scratch-itch cycle with mid-strength topical steroid creams or foams is the first step in treating LSC. But then the patient must be convinced of his contribution to the treatment: leaving the affected sites alone. Truth be told, after 20 years of scratching, the best this patient can look forward to is some relief—not only from the itching, but also from concern about all the terrible things he now knows he doesn’t have.
TAKE-HOME LEARNING POINTS
- Lichen simplex chronicus is quite common in both genders and is typified by longstanding severe itching, usually confined to one area.
- Atopy, xerosis, and stress all appear to contribute to the problem.
- Stopping the itch-scratch-itch cycle with topical steroids is a key component of treatment.
- Patient education—on the nature of the problem and the patient’s role in controlling it—is just as important as any prescribed medication.
A 50-year-old man presents with complaints of a rash on his right leg that manifested 20 years ago. Although the rash is worrisome, he says the associated pruritus is worse. During the workday, he is able to ignore the itching—but the minute he gets home, he begins to scratch.
He knows the scratching is counterproductive in the long run, but the urge to do it is quite compelling. Sometimes he uses a wet washcloth; other times, he will actually use a hair brush to satiate the itching. The relief is intensely satisfying albeit short lived.
The rash has persisted despite multiple treatment attempts. Tried products include OTC moisturizers and antifungal creams, as well as prescription antifungal creams. None has had an effect.
The patient denies any other skin problems. He does recall having eczema as a child. Although that has long since resolved, he remains quite allergy prone and is particularly sensitive to airborne allergens—a trait that runs strongly in his family.
EXAMINATION
A pink, oval rash covers most of the patient’s right lateral calf. It has a thickened, faintly scaly surface that is uniform and sharply circumscribed. There is no increased warmth or tenderness on palpation. No lymph nodes can be felt in the right groin. A check of the patient’s knees, elbows, scalp, nails, and trunk show no sign of rash or other changes.
What’s the diagnosis?
DISCUSSION
Lichen simplex chronicus (LSC), previously known as neurodermatitis, is quite common but frequently misdiagnosed. Patients often report that their condition started with a bug bite or poison ivy—a provocation that gets the patient in the habit of scratching, which continues long after the initial outbreak has subsided. Thus, LSC is often associated with significant chronicity, as typified by this case.
What patients seldom understand is their own role in the perpetuation of their condition. The urge to scratch is so unbearable that few can resist it. Over time, the scratching creates more nerves that have a lower threshold for itching, and thus the itch-scratch-itch cycle is born. Many LSC patients are atopic, which predisposes them to itching in general and to xerosis especially.
The literature asserts that LSC affects the genders equally, but this ignores the fact that it can present significantly differently in men and women. This patient’s area of involvement is quite typical for men, most of whom never moisturize and for whom the lateral calf is readily accessible. In the author’s experience, the most common location for LSC in women is the nuchal scalp, where heat and sweat appear to play a role, along with ready accessibility to fingernails or the sharp end of a pencil. Other common areas of involvement include the dorsal forearms and the scrotum or vulvae.
Biopsy is seldom necessary, but if performed, it will show a marked thickening of the epidermis, orthokeratosis (normal keratinocytes about to shed), and compacted, elongated rete ridges. These and other changes effectively rule out other items in the differential (eg, psoriasis, simple eczema, fungal infection).
Stopping the itch-scratch-itch cycle with mid-strength topical steroid creams or foams is the first step in treating LSC. But then the patient must be convinced of his contribution to the treatment: leaving the affected sites alone. Truth be told, after 20 years of scratching, the best this patient can look forward to is some relief—not only from the itching, but also from concern about all the terrible things he now knows he doesn’t have.
TAKE-HOME LEARNING POINTS
- Lichen simplex chronicus is quite common in both genders and is typified by longstanding severe itching, usually confined to one area.
- Atopy, xerosis, and stress all appear to contribute to the problem.
- Stopping the itch-scratch-itch cycle with topical steroids is a key component of treatment.
- Patient education—on the nature of the problem and the patient’s role in controlling it—is just as important as any prescribed medication.
Congenital heart disease in children linked to increased autism risk
A new study of children who were born with congenital heart disease (CHD) has found that they have increased odds of developing autism spectrum disorder.
“To our knowledge, this is the only study in which there has been a comparison between [autism spectrum disorder] and multiple CHD subtypes,” wrote Eric R. Sigmon, MD, of Emory University, Atlanta, and coauthors. “Our findings are consistent with previous studies of CHD developmental outcomes, which have shown an increased risk of developmental and academic delay after CHD diagnosis and treatment.” The study was published in Pediatrics.
To further investigate the association between CHD and autism, the researchers performed a case-control study using the Military Health System administrative database. They uncovered 8,760 cases of children with autism spectrum disorder and matched each one with three controls (n = 26,280). From that sample size, they identified 1,063 children with CHD: 401 in the autism spectrum disorder group and 662 in the control group.
Before analysis, children with autism spectrum disorder had an odds ratio of 1.85 of having any form of CHD, compared with controls (95% confidence interval, 1.63-2.10). After adjustment for covariates – including genetic syndromes, maternal age and morbidity, perinatal morbidity, and neonatal complications – the OR was 1.33 (95% CI, 1.16-1.52).
In the sensitivity analysis – which included only 593 children with CHD – the OR was a similar 1.32 (95% CI, 1.10-1.59).
Left heart obstructive lesion was significantly associated with autism spectrum disorder after covariate adjustment (OR, 1.42; 95% CI, 1.04-1.93), but the finding was no longer significant in the sensitivity analysis.
The authors noted the potential limitations of their study, including the general weaknesses of administrative data, which they attempted to counter with the sensitive analysis. In addition, they recognized that children with either autism spectrum disorder or CHD “tend to present for care more frequently,” which could have created an ascertainment bias.
In an accompanying editorial, Johanna Calderon, PhD, David C. Bellinger, PhD, and Jane W. Newburger, MD, MPH, stated that more work needs to be done to further quantify the relationship between CHD and autism spectrum disorder (Pediatrics. 2019 Oct 10. doi: 10.1542/peds.2019-2752). The three authors – all affiliated with Boston Children’s Hospital and Harvard Medical School, also in Boston – reiterated the acknowledgment from Dr. Sigmon and coauthors that the “etiologic pathways that might explain” the link between the two remains unknown. They also noted their surprise that autism spectrum disorder risk appears to be increased in children with modestly severe forms of CHD, stating that this finding required additional investigation.
“Despite the strengths of this study,” they wrote, “it raises more questions than answers.”
The study was funded by the Congressional Directed Medical Research Programs Autism Research Award. The authors reported no conflicts of interest.
SOURCE: Sigmon ER at al. Pediatrics. 2019 Oct 10. doi: 10.1542/peds.2018-4114.
A new study of children who were born with congenital heart disease (CHD) has found that they have increased odds of developing autism spectrum disorder.
“To our knowledge, this is the only study in which there has been a comparison between [autism spectrum disorder] and multiple CHD subtypes,” wrote Eric R. Sigmon, MD, of Emory University, Atlanta, and coauthors. “Our findings are consistent with previous studies of CHD developmental outcomes, which have shown an increased risk of developmental and academic delay after CHD diagnosis and treatment.” The study was published in Pediatrics.
To further investigate the association between CHD and autism, the researchers performed a case-control study using the Military Health System administrative database. They uncovered 8,760 cases of children with autism spectrum disorder and matched each one with three controls (n = 26,280). From that sample size, they identified 1,063 children with CHD: 401 in the autism spectrum disorder group and 662 in the control group.
Before analysis, children with autism spectrum disorder had an odds ratio of 1.85 of having any form of CHD, compared with controls (95% confidence interval, 1.63-2.10). After adjustment for covariates – including genetic syndromes, maternal age and morbidity, perinatal morbidity, and neonatal complications – the OR was 1.33 (95% CI, 1.16-1.52).
In the sensitivity analysis – which included only 593 children with CHD – the OR was a similar 1.32 (95% CI, 1.10-1.59).
Left heart obstructive lesion was significantly associated with autism spectrum disorder after covariate adjustment (OR, 1.42; 95% CI, 1.04-1.93), but the finding was no longer significant in the sensitivity analysis.
The authors noted the potential limitations of their study, including the general weaknesses of administrative data, which they attempted to counter with the sensitive analysis. In addition, they recognized that children with either autism spectrum disorder or CHD “tend to present for care more frequently,” which could have created an ascertainment bias.
In an accompanying editorial, Johanna Calderon, PhD, David C. Bellinger, PhD, and Jane W. Newburger, MD, MPH, stated that more work needs to be done to further quantify the relationship between CHD and autism spectrum disorder (Pediatrics. 2019 Oct 10. doi: 10.1542/peds.2019-2752). The three authors – all affiliated with Boston Children’s Hospital and Harvard Medical School, also in Boston – reiterated the acknowledgment from Dr. Sigmon and coauthors that the “etiologic pathways that might explain” the link between the two remains unknown. They also noted their surprise that autism spectrum disorder risk appears to be increased in children with modestly severe forms of CHD, stating that this finding required additional investigation.
“Despite the strengths of this study,” they wrote, “it raises more questions than answers.”
The study was funded by the Congressional Directed Medical Research Programs Autism Research Award. The authors reported no conflicts of interest.
SOURCE: Sigmon ER at al. Pediatrics. 2019 Oct 10. doi: 10.1542/peds.2018-4114.
A new study of children who were born with congenital heart disease (CHD) has found that they have increased odds of developing autism spectrum disorder.
“To our knowledge, this is the only study in which there has been a comparison between [autism spectrum disorder] and multiple CHD subtypes,” wrote Eric R. Sigmon, MD, of Emory University, Atlanta, and coauthors. “Our findings are consistent with previous studies of CHD developmental outcomes, which have shown an increased risk of developmental and academic delay after CHD diagnosis and treatment.” The study was published in Pediatrics.
To further investigate the association between CHD and autism, the researchers performed a case-control study using the Military Health System administrative database. They uncovered 8,760 cases of children with autism spectrum disorder and matched each one with three controls (n = 26,280). From that sample size, they identified 1,063 children with CHD: 401 in the autism spectrum disorder group and 662 in the control group.
Before analysis, children with autism spectrum disorder had an odds ratio of 1.85 of having any form of CHD, compared with controls (95% confidence interval, 1.63-2.10). After adjustment for covariates – including genetic syndromes, maternal age and morbidity, perinatal morbidity, and neonatal complications – the OR was 1.33 (95% CI, 1.16-1.52).
In the sensitivity analysis – which included only 593 children with CHD – the OR was a similar 1.32 (95% CI, 1.10-1.59).
Left heart obstructive lesion was significantly associated with autism spectrum disorder after covariate adjustment (OR, 1.42; 95% CI, 1.04-1.93), but the finding was no longer significant in the sensitivity analysis.
The authors noted the potential limitations of their study, including the general weaknesses of administrative data, which they attempted to counter with the sensitive analysis. In addition, they recognized that children with either autism spectrum disorder or CHD “tend to present for care more frequently,” which could have created an ascertainment bias.
In an accompanying editorial, Johanna Calderon, PhD, David C. Bellinger, PhD, and Jane W. Newburger, MD, MPH, stated that more work needs to be done to further quantify the relationship between CHD and autism spectrum disorder (Pediatrics. 2019 Oct 10. doi: 10.1542/peds.2019-2752). The three authors – all affiliated with Boston Children’s Hospital and Harvard Medical School, also in Boston – reiterated the acknowledgment from Dr. Sigmon and coauthors that the “etiologic pathways that might explain” the link between the two remains unknown. They also noted their surprise that autism spectrum disorder risk appears to be increased in children with modestly severe forms of CHD, stating that this finding required additional investigation.
“Despite the strengths of this study,” they wrote, “it raises more questions than answers.”
The study was funded by the Congressional Directed Medical Research Programs Autism Research Award. The authors reported no conflicts of interest.
SOURCE: Sigmon ER at al. Pediatrics. 2019 Oct 10. doi: 10.1542/peds.2018-4114.
FROM PEDIATRICS
Key clinical point: Children born with congenital heart disease have higher odds of developing autism, especially with certain forms of CHD, such as atrial and ventricular septal defects.
Major finding: After sensitivity analysis, children with congenital heart disease had increased odds of autism, compared with controls (odds ratio, 1.32; 95% confidence interval, 1.10-1.59).
Study details: A case-control study of children enrolled in the U.S. Military Health System from 2001 to 2013.
Disclosures: The study was funded by the Congressional Directed Medical Research Programs Autism Research Award. The authors reported no conflicts of interest.
Source: Sigmon ER at al. Pediatrics. 2019 Oct 10. doi: 10.1542/peds.2018-4114.
Appeals court to hear prescription drug privacy rights case
An appeals court may soon decide whether federal authorities can access a patient’s medical records through a statewide prescription drug monitoring database without a warrant or if such searches infringe upon privacy rights.
On Oct. 10, the 1st U.S. Circuit Court of Appeals will hear arguments in U.S. Department of Justice v. Jonas, which centers on an investigatory subpoena issued by the U.S. Drug Enforcement Agency in 2018 that sought records about a certain patient from New Hampshire’s Prescription Drug Monitoring Program (PDMP). The subpoena’s recipient, PDMP program manager Michelle Ricco-Jonas, refused to comply, citing state law that prohibits law enforcement from accessing the database without a court order based on probable cause. Releasing PDMP records to authorities without cause violate patients’ privacy protections under the Fourth Amendment, Ms. Jonas and the New Hampshire Attorney General’s Office argued.
The U.S. Department of Justice sued to enforce the subpoena, contending that the DEA’s authority to investigate suspected criminal drug activity preempts New Hampshire’s law under the Supremacy Clause. In November 2018, U.S. Magistrate Judge Andrea K. Johnstone agreed with the DOJ and recommended the district judge grant the government’s motion to enforce the subpoena, a decision affirmed by the U.S. District Court for the District of New Hampshire in January 2019. The court ruled the government met its burden to satisfy the modest requirements for enforcement of the subpoena. Attorneys for New Hampshire appealed to the 1st Circuit.
The case is being closely watched by states, physician groups, pharmacies, and patient advocacy groups. In a joint court brief by the New Hampshire Medical Society and the American Civil Liberties Union, the organizations urged the appeals court to protect patient privacy by finding in favor of New Hampshire.
“The DEA has sought to enforce a subpoena that both injures Jonas and threatens to invade the Fourth Amendment privacy rights of individuals whose private medical information resides in the database, and whose privacy and confidentiality Jonas is statutorily charged with protecting. ... but who have no ability to challenge that impending harm,” the groups wrote in the brief. “The prescription records at issue in this case reveal intimate, private, and potentially stigmatizing details about patients’ health, including details of those patients’ underlying medical conditions. For that reason, as with other medical records, people have a reasonable expectation of privacy in them.”
Oregon’s PDMP faced a similar legal challenge in 2012. In that case, the DEA attempted to access the records of one patient and two prescribing physicians from Oregon’s prescription database. The state sued to prevent release of the records, and the ACLU intervened as a plaintiff on behalf of several unnamed patients and a doctor. A district court ruled in favor of the plaintiffs, finding that the DEA’s actions constituted a Fourth Amendment violation. However, the 9th U.S. Circuit Court in 2017 overturned the decision, ruling that federal law regarding administrative subpoenas trumps Oregon law. In addition, the appeals court ruled that the ACLU lacked standing to intervene and seek relief different from that sought by Oregon. By invalidating ACLU from the suit, the Fourth Amendment argument was never resolved by the 9th Circuit.
New Hampshire is one of 49 states that have Prescription Drug Monitoring Programs in addition to the District of Columbia. The programs collect, monitor, and analyze electronically transmitted prescribing and dispensing data submitted by physicians and pharmacies with the aim of reducing prescription drug abuse and diversion.
An appeals court may soon decide whether federal authorities can access a patient’s medical records through a statewide prescription drug monitoring database without a warrant or if such searches infringe upon privacy rights.
On Oct. 10, the 1st U.S. Circuit Court of Appeals will hear arguments in U.S. Department of Justice v. Jonas, which centers on an investigatory subpoena issued by the U.S. Drug Enforcement Agency in 2018 that sought records about a certain patient from New Hampshire’s Prescription Drug Monitoring Program (PDMP). The subpoena’s recipient, PDMP program manager Michelle Ricco-Jonas, refused to comply, citing state law that prohibits law enforcement from accessing the database without a court order based on probable cause. Releasing PDMP records to authorities without cause violate patients’ privacy protections under the Fourth Amendment, Ms. Jonas and the New Hampshire Attorney General’s Office argued.
The U.S. Department of Justice sued to enforce the subpoena, contending that the DEA’s authority to investigate suspected criminal drug activity preempts New Hampshire’s law under the Supremacy Clause. In November 2018, U.S. Magistrate Judge Andrea K. Johnstone agreed with the DOJ and recommended the district judge grant the government’s motion to enforce the subpoena, a decision affirmed by the U.S. District Court for the District of New Hampshire in January 2019. The court ruled the government met its burden to satisfy the modest requirements for enforcement of the subpoena. Attorneys for New Hampshire appealed to the 1st Circuit.
The case is being closely watched by states, physician groups, pharmacies, and patient advocacy groups. In a joint court brief by the New Hampshire Medical Society and the American Civil Liberties Union, the organizations urged the appeals court to protect patient privacy by finding in favor of New Hampshire.
“The DEA has sought to enforce a subpoena that both injures Jonas and threatens to invade the Fourth Amendment privacy rights of individuals whose private medical information resides in the database, and whose privacy and confidentiality Jonas is statutorily charged with protecting. ... but who have no ability to challenge that impending harm,” the groups wrote in the brief. “The prescription records at issue in this case reveal intimate, private, and potentially stigmatizing details about patients’ health, including details of those patients’ underlying medical conditions. For that reason, as with other medical records, people have a reasonable expectation of privacy in them.”
Oregon’s PDMP faced a similar legal challenge in 2012. In that case, the DEA attempted to access the records of one patient and two prescribing physicians from Oregon’s prescription database. The state sued to prevent release of the records, and the ACLU intervened as a plaintiff on behalf of several unnamed patients and a doctor. A district court ruled in favor of the plaintiffs, finding that the DEA’s actions constituted a Fourth Amendment violation. However, the 9th U.S. Circuit Court in 2017 overturned the decision, ruling that federal law regarding administrative subpoenas trumps Oregon law. In addition, the appeals court ruled that the ACLU lacked standing to intervene and seek relief different from that sought by Oregon. By invalidating ACLU from the suit, the Fourth Amendment argument was never resolved by the 9th Circuit.
New Hampshire is one of 49 states that have Prescription Drug Monitoring Programs in addition to the District of Columbia. The programs collect, monitor, and analyze electronically transmitted prescribing and dispensing data submitted by physicians and pharmacies with the aim of reducing prescription drug abuse and diversion.
An appeals court may soon decide whether federal authorities can access a patient’s medical records through a statewide prescription drug monitoring database without a warrant or if such searches infringe upon privacy rights.
On Oct. 10, the 1st U.S. Circuit Court of Appeals will hear arguments in U.S. Department of Justice v. Jonas, which centers on an investigatory subpoena issued by the U.S. Drug Enforcement Agency in 2018 that sought records about a certain patient from New Hampshire’s Prescription Drug Monitoring Program (PDMP). The subpoena’s recipient, PDMP program manager Michelle Ricco-Jonas, refused to comply, citing state law that prohibits law enforcement from accessing the database without a court order based on probable cause. Releasing PDMP records to authorities without cause violate patients’ privacy protections under the Fourth Amendment, Ms. Jonas and the New Hampshire Attorney General’s Office argued.
The U.S. Department of Justice sued to enforce the subpoena, contending that the DEA’s authority to investigate suspected criminal drug activity preempts New Hampshire’s law under the Supremacy Clause. In November 2018, U.S. Magistrate Judge Andrea K. Johnstone agreed with the DOJ and recommended the district judge grant the government’s motion to enforce the subpoena, a decision affirmed by the U.S. District Court for the District of New Hampshire in January 2019. The court ruled the government met its burden to satisfy the modest requirements for enforcement of the subpoena. Attorneys for New Hampshire appealed to the 1st Circuit.
The case is being closely watched by states, physician groups, pharmacies, and patient advocacy groups. In a joint court brief by the New Hampshire Medical Society and the American Civil Liberties Union, the organizations urged the appeals court to protect patient privacy by finding in favor of New Hampshire.
“The DEA has sought to enforce a subpoena that both injures Jonas and threatens to invade the Fourth Amendment privacy rights of individuals whose private medical information resides in the database, and whose privacy and confidentiality Jonas is statutorily charged with protecting. ... but who have no ability to challenge that impending harm,” the groups wrote in the brief. “The prescription records at issue in this case reveal intimate, private, and potentially stigmatizing details about patients’ health, including details of those patients’ underlying medical conditions. For that reason, as with other medical records, people have a reasonable expectation of privacy in them.”
Oregon’s PDMP faced a similar legal challenge in 2012. In that case, the DEA attempted to access the records of one patient and two prescribing physicians from Oregon’s prescription database. The state sued to prevent release of the records, and the ACLU intervened as a plaintiff on behalf of several unnamed patients and a doctor. A district court ruled in favor of the plaintiffs, finding that the DEA’s actions constituted a Fourth Amendment violation. However, the 9th U.S. Circuit Court in 2017 overturned the decision, ruling that federal law regarding administrative subpoenas trumps Oregon law. In addition, the appeals court ruled that the ACLU lacked standing to intervene and seek relief different from that sought by Oregon. By invalidating ACLU from the suit, the Fourth Amendment argument was never resolved by the 9th Circuit.
New Hampshire is one of 49 states that have Prescription Drug Monitoring Programs in addition to the District of Columbia. The programs collect, monitor, and analyze electronically transmitted prescribing and dispensing data submitted by physicians and pharmacies with the aim of reducing prescription drug abuse and diversion.
Influenza vaccination modestly reduces risk of hospitalizations in patients with COPD
(COPD), according to data published in the Journal of Infectious Diseases.
“To the best of our knowledge, this is the first large, real-world population study to examine vaccine effectiveness in people with COPD using the test-negative design and influenza-specific study outcomes,” wrote Andrea S. Gershon, MD, of Sunnybrook Health Sciences Center in Toronto and colleagues. “These findings emphasize the need for more effective influenza vaccines for older COPD patients and other preventive strategies.”
A test-negative study design
Data suggest that 70% of COPD exacerbations are caused by infection, and influenza often is identified as the cause. Although all major COPD practice guidelines recommend seasonal influenza vaccination, the evidence indicating that vaccination reduces hospitalizations and death is limited. The inherent or corticosteroid-induced decrease in immune response to vaccination and respiratory infection among patients with COPD may reduce the effectiveness of influenza vaccination, wrote Dr. Gershon and colleagues.
The investigators used a test-negative design to evaluate how effectively influenza vaccination prevents laboratory-confirmed influenza–associated hospitalizations in community-dwelling older patients with COPD. They chose this design because it attenuates biases resulting from misclassification of infection and from differences in health care–seeking behavior between vaccinated and unvaccinated patients.
Dr. Gershon and colleagues examined health care administrative data and respiratory specimens collected from patients who had been tested for influenza during the 2010-2011 to 2015-2016 influenza seasons. Eligible patients were aged 66 years or older, had physician-diagnosed COPD, and had been tested for influenza within 3 days before and during an acute care hospitalization. The researchers determined influenza vaccination status using physician and pharmacist billing claims. They obtained demographic information through linkage with the provincial health insurance database. Multivariable logistic regression allowed Dr. Gershon and colleagues to estimate the adjusted odds ratio of influenza vaccination in people with laboratory-confirmed influenza, compared with those without.
Effectiveness did not vary by demographic factors
The investigators included 21,748 patients in their analysis. Of this population, 3,636 (16.7%) patients tested positive for influenza. Vaccinated patients were less likely than unvaccinated patients to test positive for influenza (15.3% vs. 18.6%). Vaccinated patients also were more likely to be older; live in an urban area; live in a higher income neighborhood; have had more outpatient visits with a physician in the previous year; have received a prescription for a COPD medication in the previous 6 months; have diabetes, asthma, or immunocompromising conditions; have a longer duration of COPD; and have had an outpatient COPD exacerbation in the previous year.
The overall unadjusted estimate of vaccine effectiveness against laboratory-confirmed influenza–associated hospitalizations was 21%. Multivariable adjustment yielded an effectiveness of 22%. When Dr. Gershon and colleagues corrected for misclassification of vaccination status among people with COPD, the effectiveness was estimated to be 43%. Vaccine effectiveness did not vary significantly according to influenza season, nor did it vary significantly by patient-specific factors such as age, sex, influenza subtype, codiagnosis of asthma, duration of COPD, previous outpatient COPD exacerbations, previous COPD hospitalization, previous receipt of inhaled corticosteroids, and previous pneumonia.
One limitation of the study was the possibility that COPD was misclassified because not all participants underwent pulmonary function testing. In addition, the estimates of vaccine effectiveness in the present study are specific to the outcome of influenza hospitalization and may not be generalizable to vaccine effectiveness estimates of outpatient outcomes, said the investigators. Finally, Dr. Gershon and colleagues could not identify the type of vaccine received.
“Given that a large pragmatic randomized controlled trial evaluating influenza vaccination would be unethical, this is likely the most robust estimate of vaccine effectiveness for hospitalizations in the COPD population to guide influenza vaccine recommendations for patients with COPD,” wrote Dr. Gershon and colleagues.
An Ontario Ministry of Health and Long-Term Care Health Systems Research Fund Capacity Grant and a Canadian Institutes of Health Research operating grant funded this research. One investigator received grants from the Canadian Institutes of Health Research during the study, and others received grants from pharmaceutical companies that were unrelated to this study.
SOURCE: Gershon AS et al. J Infect Dis. 2019 Sep 24. doi: 10.1093/infdis/jiz419.
(COPD), according to data published in the Journal of Infectious Diseases.
“To the best of our knowledge, this is the first large, real-world population study to examine vaccine effectiveness in people with COPD using the test-negative design and influenza-specific study outcomes,” wrote Andrea S. Gershon, MD, of Sunnybrook Health Sciences Center in Toronto and colleagues. “These findings emphasize the need for more effective influenza vaccines for older COPD patients and other preventive strategies.”
A test-negative study design
Data suggest that 70% of COPD exacerbations are caused by infection, and influenza often is identified as the cause. Although all major COPD practice guidelines recommend seasonal influenza vaccination, the evidence indicating that vaccination reduces hospitalizations and death is limited. The inherent or corticosteroid-induced decrease in immune response to vaccination and respiratory infection among patients with COPD may reduce the effectiveness of influenza vaccination, wrote Dr. Gershon and colleagues.
The investigators used a test-negative design to evaluate how effectively influenza vaccination prevents laboratory-confirmed influenza–associated hospitalizations in community-dwelling older patients with COPD. They chose this design because it attenuates biases resulting from misclassification of infection and from differences in health care–seeking behavior between vaccinated and unvaccinated patients.
Dr. Gershon and colleagues examined health care administrative data and respiratory specimens collected from patients who had been tested for influenza during the 2010-2011 to 2015-2016 influenza seasons. Eligible patients were aged 66 years or older, had physician-diagnosed COPD, and had been tested for influenza within 3 days before and during an acute care hospitalization. The researchers determined influenza vaccination status using physician and pharmacist billing claims. They obtained demographic information through linkage with the provincial health insurance database. Multivariable logistic regression allowed Dr. Gershon and colleagues to estimate the adjusted odds ratio of influenza vaccination in people with laboratory-confirmed influenza, compared with those without.
Effectiveness did not vary by demographic factors
The investigators included 21,748 patients in their analysis. Of this population, 3,636 (16.7%) patients tested positive for influenza. Vaccinated patients were less likely than unvaccinated patients to test positive for influenza (15.3% vs. 18.6%). Vaccinated patients also were more likely to be older; live in an urban area; live in a higher income neighborhood; have had more outpatient visits with a physician in the previous year; have received a prescription for a COPD medication in the previous 6 months; have diabetes, asthma, or immunocompromising conditions; have a longer duration of COPD; and have had an outpatient COPD exacerbation in the previous year.
The overall unadjusted estimate of vaccine effectiveness against laboratory-confirmed influenza–associated hospitalizations was 21%. Multivariable adjustment yielded an effectiveness of 22%. When Dr. Gershon and colleagues corrected for misclassification of vaccination status among people with COPD, the effectiveness was estimated to be 43%. Vaccine effectiveness did not vary significantly according to influenza season, nor did it vary significantly by patient-specific factors such as age, sex, influenza subtype, codiagnosis of asthma, duration of COPD, previous outpatient COPD exacerbations, previous COPD hospitalization, previous receipt of inhaled corticosteroids, and previous pneumonia.
One limitation of the study was the possibility that COPD was misclassified because not all participants underwent pulmonary function testing. In addition, the estimates of vaccine effectiveness in the present study are specific to the outcome of influenza hospitalization and may not be generalizable to vaccine effectiveness estimates of outpatient outcomes, said the investigators. Finally, Dr. Gershon and colleagues could not identify the type of vaccine received.
“Given that a large pragmatic randomized controlled trial evaluating influenza vaccination would be unethical, this is likely the most robust estimate of vaccine effectiveness for hospitalizations in the COPD population to guide influenza vaccine recommendations for patients with COPD,” wrote Dr. Gershon and colleagues.
An Ontario Ministry of Health and Long-Term Care Health Systems Research Fund Capacity Grant and a Canadian Institutes of Health Research operating grant funded this research. One investigator received grants from the Canadian Institutes of Health Research during the study, and others received grants from pharmaceutical companies that were unrelated to this study.
SOURCE: Gershon AS et al. J Infect Dis. 2019 Sep 24. doi: 10.1093/infdis/jiz419.
(COPD), according to data published in the Journal of Infectious Diseases.
“To the best of our knowledge, this is the first large, real-world population study to examine vaccine effectiveness in people with COPD using the test-negative design and influenza-specific study outcomes,” wrote Andrea S. Gershon, MD, of Sunnybrook Health Sciences Center in Toronto and colleagues. “These findings emphasize the need for more effective influenza vaccines for older COPD patients and other preventive strategies.”
A test-negative study design
Data suggest that 70% of COPD exacerbations are caused by infection, and influenza often is identified as the cause. Although all major COPD practice guidelines recommend seasonal influenza vaccination, the evidence indicating that vaccination reduces hospitalizations and death is limited. The inherent or corticosteroid-induced decrease in immune response to vaccination and respiratory infection among patients with COPD may reduce the effectiveness of influenza vaccination, wrote Dr. Gershon and colleagues.
The investigators used a test-negative design to evaluate how effectively influenza vaccination prevents laboratory-confirmed influenza–associated hospitalizations in community-dwelling older patients with COPD. They chose this design because it attenuates biases resulting from misclassification of infection and from differences in health care–seeking behavior between vaccinated and unvaccinated patients.
Dr. Gershon and colleagues examined health care administrative data and respiratory specimens collected from patients who had been tested for influenza during the 2010-2011 to 2015-2016 influenza seasons. Eligible patients were aged 66 years or older, had physician-diagnosed COPD, and had been tested for influenza within 3 days before and during an acute care hospitalization. The researchers determined influenza vaccination status using physician and pharmacist billing claims. They obtained demographic information through linkage with the provincial health insurance database. Multivariable logistic regression allowed Dr. Gershon and colleagues to estimate the adjusted odds ratio of influenza vaccination in people with laboratory-confirmed influenza, compared with those without.
Effectiveness did not vary by demographic factors
The investigators included 21,748 patients in their analysis. Of this population, 3,636 (16.7%) patients tested positive for influenza. Vaccinated patients were less likely than unvaccinated patients to test positive for influenza (15.3% vs. 18.6%). Vaccinated patients also were more likely to be older; live in an urban area; live in a higher income neighborhood; have had more outpatient visits with a physician in the previous year; have received a prescription for a COPD medication in the previous 6 months; have diabetes, asthma, or immunocompromising conditions; have a longer duration of COPD; and have had an outpatient COPD exacerbation in the previous year.
The overall unadjusted estimate of vaccine effectiveness against laboratory-confirmed influenza–associated hospitalizations was 21%. Multivariable adjustment yielded an effectiveness of 22%. When Dr. Gershon and colleagues corrected for misclassification of vaccination status among people with COPD, the effectiveness was estimated to be 43%. Vaccine effectiveness did not vary significantly according to influenza season, nor did it vary significantly by patient-specific factors such as age, sex, influenza subtype, codiagnosis of asthma, duration of COPD, previous outpatient COPD exacerbations, previous COPD hospitalization, previous receipt of inhaled corticosteroids, and previous pneumonia.
One limitation of the study was the possibility that COPD was misclassified because not all participants underwent pulmonary function testing. In addition, the estimates of vaccine effectiveness in the present study are specific to the outcome of influenza hospitalization and may not be generalizable to vaccine effectiveness estimates of outpatient outcomes, said the investigators. Finally, Dr. Gershon and colleagues could not identify the type of vaccine received.
“Given that a large pragmatic randomized controlled trial evaluating influenza vaccination would be unethical, this is likely the most robust estimate of vaccine effectiveness for hospitalizations in the COPD population to guide influenza vaccine recommendations for patients with COPD,” wrote Dr. Gershon and colleagues.
An Ontario Ministry of Health and Long-Term Care Health Systems Research Fund Capacity Grant and a Canadian Institutes of Health Research operating grant funded this research. One investigator received grants from the Canadian Institutes of Health Research during the study, and others received grants from pharmaceutical companies that were unrelated to this study.
SOURCE: Gershon AS et al. J Infect Dis. 2019 Sep 24. doi: 10.1093/infdis/jiz419.
FROM JOURNAL OF INFECTIOUS DISEASES
Printed meat in space and diesel-pattern baldness
If at first you don’t succeed …
Dozens of new drugs are approved every year, but for every promising new medication, there are far more that fail to get past the clinical trial stage. The causes can vary: The drug didn’t do enough, it caused too many adverse events, and so on.
DNA topoisomerase inhibitors have been extensively researched as an anticancer agent, but many examples failed their clinical trials. These molecules are flat and made up of neatly stacked columns of electrically conductive rings, and operate by inserting themselves into DNA to stop replication.
That molecular structure is what interested a team of researchers from the University of Illinois at Urbana-Champaign. In research published in Nature Communications, the researchers noted that DNA topoisomerase inhibitors are structured much like organic semiconductors, but with a bonus. Those columns that make up the molecule are linked by hydrogen bonds, which allow bridges to form across the entire molecule, transforming the entire thing into a semiconductor.
That property, along with their easy printability and their high-specificity interactions with biological material, make the inhibitors an excellent candidate for use in biosensors or biotransistors.
A word to the manufacturer of those topoisomerase inhibitors, though, now that we’ve gotten you all excited again: We doubt you’ll be able to charge as much for the molecule. Semiconductors are hardly as glamorous as treating cancer.
Houston, we have a cultivated meat product
The Delmonico brothers didn’t do it. Ronald McDonald didn’t do it. Neil Armstrong never even tried. Same goes for Julia Child.
None of these culinary giants or astronauts ever grew beef in space. That honor belongs to Aleph Farms of Rehovot, Israel. The company, a self-proclaimed “global leader in the cultivated meat industry,” collaborated with 3D Bioprinting Solutions of Moscow and others to produce slaughter-free beef in the Russian segment of the International Space Station in September.
The actual process of growing a steak mimics natural “muscle-tissue regeneration occurring inside the cow’s body” and somehow uses a 3-D bioprinter to assemble “a small-scale muscle tissue.” We don’t really understand it, but the scientists and engineers here at LOTME Co. assure us it makes sense.
But why, you may ask, did they do it on the space station? Think of it as a stand-in for New York City. You know … if you can make it there, you can make it anywhere. We’ll let Didier Toubia, cofounder and CEO of Aleph Farms, explain: “In space, we don’t have 10,000 or 15,000 liter (3962.58 gallon) of water available to produce 1 kilogram (2.205 pounds) of beef.” It’s all about sustainable food production.
The next phase of the project, we think, is going to be even more interesting. For a proper fine dining experience in space, they’re going to grow a snooty French waiter to serve cultivated steak to the astronauts.
Pollution Hair Club for Men
By now, most people are well aware that air pollution is linked with cancer. And chronic obstructive pulmonary disease. And asthma. And cardiovascular disease. And Germanic automotive emissions system cheating. Yawn.
But there’s a newly revealed association sure to make even the most jaded health news consumer’s hair stand on end: Exposure to pollution’s particulate matter is linked to ... hair loss.
Researchers from the Future Science Research Center in South Korea exposed cells from the base of human hair follicles to assorted concentrations of diesel and dust particulates. After 24 hours, the pollutants had suppressed production of beta-catenin, the primary protein crucial to the maintenance of George Clooney’s luxurious mane. And three other proteins supporting hair growth and hair retention also went AWOL in the presence of pollutants. Plus more particulate matter meant fewer hair-restoring proteins.
Diesel particulates and baldness? It all makes so much more sense now. Given the pollutant-rich Big Apple air in which lollipop-loving TV detective Theo Kojak’s smooth pate was steeped, is it any wonder he was famously so follicularly challenged? The Clean Air Act – who loves ya, baby?
If at first you don’t succeed …
Dozens of new drugs are approved every year, but for every promising new medication, there are far more that fail to get past the clinical trial stage. The causes can vary: The drug didn’t do enough, it caused too many adverse events, and so on.
DNA topoisomerase inhibitors have been extensively researched as an anticancer agent, but many examples failed their clinical trials. These molecules are flat and made up of neatly stacked columns of electrically conductive rings, and operate by inserting themselves into DNA to stop replication.
That molecular structure is what interested a team of researchers from the University of Illinois at Urbana-Champaign. In research published in Nature Communications, the researchers noted that DNA topoisomerase inhibitors are structured much like organic semiconductors, but with a bonus. Those columns that make up the molecule are linked by hydrogen bonds, which allow bridges to form across the entire molecule, transforming the entire thing into a semiconductor.
That property, along with their easy printability and their high-specificity interactions with biological material, make the inhibitors an excellent candidate for use in biosensors or biotransistors.
A word to the manufacturer of those topoisomerase inhibitors, though, now that we’ve gotten you all excited again: We doubt you’ll be able to charge as much for the molecule. Semiconductors are hardly as glamorous as treating cancer.
Houston, we have a cultivated meat product
The Delmonico brothers didn’t do it. Ronald McDonald didn’t do it. Neil Armstrong never even tried. Same goes for Julia Child.
None of these culinary giants or astronauts ever grew beef in space. That honor belongs to Aleph Farms of Rehovot, Israel. The company, a self-proclaimed “global leader in the cultivated meat industry,” collaborated with 3D Bioprinting Solutions of Moscow and others to produce slaughter-free beef in the Russian segment of the International Space Station in September.
The actual process of growing a steak mimics natural “muscle-tissue regeneration occurring inside the cow’s body” and somehow uses a 3-D bioprinter to assemble “a small-scale muscle tissue.” We don’t really understand it, but the scientists and engineers here at LOTME Co. assure us it makes sense.
But why, you may ask, did they do it on the space station? Think of it as a stand-in for New York City. You know … if you can make it there, you can make it anywhere. We’ll let Didier Toubia, cofounder and CEO of Aleph Farms, explain: “In space, we don’t have 10,000 or 15,000 liter (3962.58 gallon) of water available to produce 1 kilogram (2.205 pounds) of beef.” It’s all about sustainable food production.
The next phase of the project, we think, is going to be even more interesting. For a proper fine dining experience in space, they’re going to grow a snooty French waiter to serve cultivated steak to the astronauts.
Pollution Hair Club for Men
By now, most people are well aware that air pollution is linked with cancer. And chronic obstructive pulmonary disease. And asthma. And cardiovascular disease. And Germanic automotive emissions system cheating. Yawn.
But there’s a newly revealed association sure to make even the most jaded health news consumer’s hair stand on end: Exposure to pollution’s particulate matter is linked to ... hair loss.
Researchers from the Future Science Research Center in South Korea exposed cells from the base of human hair follicles to assorted concentrations of diesel and dust particulates. After 24 hours, the pollutants had suppressed production of beta-catenin, the primary protein crucial to the maintenance of George Clooney’s luxurious mane. And three other proteins supporting hair growth and hair retention also went AWOL in the presence of pollutants. Plus more particulate matter meant fewer hair-restoring proteins.
Diesel particulates and baldness? It all makes so much more sense now. Given the pollutant-rich Big Apple air in which lollipop-loving TV detective Theo Kojak’s smooth pate was steeped, is it any wonder he was famously so follicularly challenged? The Clean Air Act – who loves ya, baby?
If at first you don’t succeed …
Dozens of new drugs are approved every year, but for every promising new medication, there are far more that fail to get past the clinical trial stage. The causes can vary: The drug didn’t do enough, it caused too many adverse events, and so on.
DNA topoisomerase inhibitors have been extensively researched as an anticancer agent, but many examples failed their clinical trials. These molecules are flat and made up of neatly stacked columns of electrically conductive rings, and operate by inserting themselves into DNA to stop replication.
That molecular structure is what interested a team of researchers from the University of Illinois at Urbana-Champaign. In research published in Nature Communications, the researchers noted that DNA topoisomerase inhibitors are structured much like organic semiconductors, but with a bonus. Those columns that make up the molecule are linked by hydrogen bonds, which allow bridges to form across the entire molecule, transforming the entire thing into a semiconductor.
That property, along with their easy printability and their high-specificity interactions with biological material, make the inhibitors an excellent candidate for use in biosensors or biotransistors.
A word to the manufacturer of those topoisomerase inhibitors, though, now that we’ve gotten you all excited again: We doubt you’ll be able to charge as much for the molecule. Semiconductors are hardly as glamorous as treating cancer.
Houston, we have a cultivated meat product
The Delmonico brothers didn’t do it. Ronald McDonald didn’t do it. Neil Armstrong never even tried. Same goes for Julia Child.
None of these culinary giants or astronauts ever grew beef in space. That honor belongs to Aleph Farms of Rehovot, Israel. The company, a self-proclaimed “global leader in the cultivated meat industry,” collaborated with 3D Bioprinting Solutions of Moscow and others to produce slaughter-free beef in the Russian segment of the International Space Station in September.
The actual process of growing a steak mimics natural “muscle-tissue regeneration occurring inside the cow’s body” and somehow uses a 3-D bioprinter to assemble “a small-scale muscle tissue.” We don’t really understand it, but the scientists and engineers here at LOTME Co. assure us it makes sense.
But why, you may ask, did they do it on the space station? Think of it as a stand-in for New York City. You know … if you can make it there, you can make it anywhere. We’ll let Didier Toubia, cofounder and CEO of Aleph Farms, explain: “In space, we don’t have 10,000 or 15,000 liter (3962.58 gallon) of water available to produce 1 kilogram (2.205 pounds) of beef.” It’s all about sustainable food production.
The next phase of the project, we think, is going to be even more interesting. For a proper fine dining experience in space, they’re going to grow a snooty French waiter to serve cultivated steak to the astronauts.
Pollution Hair Club for Men
By now, most people are well aware that air pollution is linked with cancer. And chronic obstructive pulmonary disease. And asthma. And cardiovascular disease. And Germanic automotive emissions system cheating. Yawn.
But there’s a newly revealed association sure to make even the most jaded health news consumer’s hair stand on end: Exposure to pollution’s particulate matter is linked to ... hair loss.
Researchers from the Future Science Research Center in South Korea exposed cells from the base of human hair follicles to assorted concentrations of diesel and dust particulates. After 24 hours, the pollutants had suppressed production of beta-catenin, the primary protein crucial to the maintenance of George Clooney’s luxurious mane. And three other proteins supporting hair growth and hair retention also went AWOL in the presence of pollutants. Plus more particulate matter meant fewer hair-restoring proteins.
Diesel particulates and baldness? It all makes so much more sense now. Given the pollutant-rich Big Apple air in which lollipop-loving TV detective Theo Kojak’s smooth pate was steeped, is it any wonder he was famously so follicularly challenged? The Clean Air Act – who loves ya, baby?