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Armored CAR T cells elicit responses in NHL patients
NATIONAL HARBOR, MD – An armored chimeric antigen receptor (CAR) T-cell therapy has demonstrated efficacy in vitro and in patients with relapsed or refractory non-Hodgkin lymphoma (NHL), according to findings presented at the annual meeting of the Society for Immunotherapy of Cancer.
ICTCAR014, a dominant negative PD-1 armored CAR T-cell therapy, proved more cytotoxic than traditional CAR T-cell therapy in vitro and produced responses in 12 of 13 NHL patients who received it.
Xiaobin Victor Lu, PhD, of Innovative Cellular Therapeutics, Shanghai, China, presented results with ICTCAR014 at the meeting.
Dr. Lu explained that ICTCAR014 consists of CD19-targeted CAR T cells genetically engineered to overexpress a PD-1 dominant negative protein with an altered intracellular signaling domain. The dominant negative protein can act as a “decoy receptor” to bind and block the PD-L1/2 inhibitory signal, thereby enhancing the efficacy of CAR T cells.
Innovative Cellular Therapeutics is developing ICTCAR014 because there is “some room to improve” with commercially available CAR T-cell products, Dr. Lu said. Specifically, tisagenlecleucel produced a 52% response rate in the JULIET trial (N Engl J Med. 2019;380:45-56), and axicabtagene ciloleucel produced an 82% response rate in the ZUMA-1 trial (N Engl J Med. 2017;377:2531-44).
There is also evidence to suggest that PD-1 blockade can modulate and “refuel” CAR T cells in relapsed/refractory NHL patients who fail or relapse after traditional anti-CD19 CAR T-cell therapy (Blood. 2017 Feb 23;129[8]:1039-41). This finding has prompted researchers to conduct trials of PD-1 inhibitors in combination with CAR T-cell therapies. But this combination approach may be expensive and cause more side effects than the armored CAR T-cell approach, Dr. Lu said.
In preclinical studies, Dr. Lu and colleagues found that ICTCAR014 was more effective than traditional anti-CD19 CAR T cells in killing Nalm6-PDL1 cells. In addition, the PD-1 dominant negative protein protected CAR T cells from exhaustion.
Dr. Lu also presented results in 13 NHL patients who have received ICTCAR014 in a phase 1 trial in China. Eleven patients had diffuse large B-cell lymphoma (DLBCL), and two had follicular lymphoma.
The objective response rate was 92.3% (12/13), which included five partial responses (38.5%) and seven complete responses (53.8%). Both follicular lymphoma patients and five DLBCL patients achieved a complete response. Five DLBCL patients achieved a partial response, and the remaining DLBCL patient did not respond.
Dr. Lu did not present safety data. However, he reported that there was no increased incidence of cytokine release syndrome or neurotoxicity in these patients, compared with patients receiving traditional CAR T-cell therapy.
Dr. Lu is employed by Innovative Cellular Therapeutics, which funded the research and is developing ICTCAR014.
SOURCE: Lu V et al. SITC 2019, Abstract O25.
NATIONAL HARBOR, MD – An armored chimeric antigen receptor (CAR) T-cell therapy has demonstrated efficacy in vitro and in patients with relapsed or refractory non-Hodgkin lymphoma (NHL), according to findings presented at the annual meeting of the Society for Immunotherapy of Cancer.
ICTCAR014, a dominant negative PD-1 armored CAR T-cell therapy, proved more cytotoxic than traditional CAR T-cell therapy in vitro and produced responses in 12 of 13 NHL patients who received it.
Xiaobin Victor Lu, PhD, of Innovative Cellular Therapeutics, Shanghai, China, presented results with ICTCAR014 at the meeting.
Dr. Lu explained that ICTCAR014 consists of CD19-targeted CAR T cells genetically engineered to overexpress a PD-1 dominant negative protein with an altered intracellular signaling domain. The dominant negative protein can act as a “decoy receptor” to bind and block the PD-L1/2 inhibitory signal, thereby enhancing the efficacy of CAR T cells.
Innovative Cellular Therapeutics is developing ICTCAR014 because there is “some room to improve” with commercially available CAR T-cell products, Dr. Lu said. Specifically, tisagenlecleucel produced a 52% response rate in the JULIET trial (N Engl J Med. 2019;380:45-56), and axicabtagene ciloleucel produced an 82% response rate in the ZUMA-1 trial (N Engl J Med. 2017;377:2531-44).
There is also evidence to suggest that PD-1 blockade can modulate and “refuel” CAR T cells in relapsed/refractory NHL patients who fail or relapse after traditional anti-CD19 CAR T-cell therapy (Blood. 2017 Feb 23;129[8]:1039-41). This finding has prompted researchers to conduct trials of PD-1 inhibitors in combination with CAR T-cell therapies. But this combination approach may be expensive and cause more side effects than the armored CAR T-cell approach, Dr. Lu said.
In preclinical studies, Dr. Lu and colleagues found that ICTCAR014 was more effective than traditional anti-CD19 CAR T cells in killing Nalm6-PDL1 cells. In addition, the PD-1 dominant negative protein protected CAR T cells from exhaustion.
Dr. Lu also presented results in 13 NHL patients who have received ICTCAR014 in a phase 1 trial in China. Eleven patients had diffuse large B-cell lymphoma (DLBCL), and two had follicular lymphoma.
The objective response rate was 92.3% (12/13), which included five partial responses (38.5%) and seven complete responses (53.8%). Both follicular lymphoma patients and five DLBCL patients achieved a complete response. Five DLBCL patients achieved a partial response, and the remaining DLBCL patient did not respond.
Dr. Lu did not present safety data. However, he reported that there was no increased incidence of cytokine release syndrome or neurotoxicity in these patients, compared with patients receiving traditional CAR T-cell therapy.
Dr. Lu is employed by Innovative Cellular Therapeutics, which funded the research and is developing ICTCAR014.
SOURCE: Lu V et al. SITC 2019, Abstract O25.
NATIONAL HARBOR, MD – An armored chimeric antigen receptor (CAR) T-cell therapy has demonstrated efficacy in vitro and in patients with relapsed or refractory non-Hodgkin lymphoma (NHL), according to findings presented at the annual meeting of the Society for Immunotherapy of Cancer.
ICTCAR014, a dominant negative PD-1 armored CAR T-cell therapy, proved more cytotoxic than traditional CAR T-cell therapy in vitro and produced responses in 12 of 13 NHL patients who received it.
Xiaobin Victor Lu, PhD, of Innovative Cellular Therapeutics, Shanghai, China, presented results with ICTCAR014 at the meeting.
Dr. Lu explained that ICTCAR014 consists of CD19-targeted CAR T cells genetically engineered to overexpress a PD-1 dominant negative protein with an altered intracellular signaling domain. The dominant negative protein can act as a “decoy receptor” to bind and block the PD-L1/2 inhibitory signal, thereby enhancing the efficacy of CAR T cells.
Innovative Cellular Therapeutics is developing ICTCAR014 because there is “some room to improve” with commercially available CAR T-cell products, Dr. Lu said. Specifically, tisagenlecleucel produced a 52% response rate in the JULIET trial (N Engl J Med. 2019;380:45-56), and axicabtagene ciloleucel produced an 82% response rate in the ZUMA-1 trial (N Engl J Med. 2017;377:2531-44).
There is also evidence to suggest that PD-1 blockade can modulate and “refuel” CAR T cells in relapsed/refractory NHL patients who fail or relapse after traditional anti-CD19 CAR T-cell therapy (Blood. 2017 Feb 23;129[8]:1039-41). This finding has prompted researchers to conduct trials of PD-1 inhibitors in combination with CAR T-cell therapies. But this combination approach may be expensive and cause more side effects than the armored CAR T-cell approach, Dr. Lu said.
In preclinical studies, Dr. Lu and colleagues found that ICTCAR014 was more effective than traditional anti-CD19 CAR T cells in killing Nalm6-PDL1 cells. In addition, the PD-1 dominant negative protein protected CAR T cells from exhaustion.
Dr. Lu also presented results in 13 NHL patients who have received ICTCAR014 in a phase 1 trial in China. Eleven patients had diffuse large B-cell lymphoma (DLBCL), and two had follicular lymphoma.
The objective response rate was 92.3% (12/13), which included five partial responses (38.5%) and seven complete responses (53.8%). Both follicular lymphoma patients and five DLBCL patients achieved a complete response. Five DLBCL patients achieved a partial response, and the remaining DLBCL patient did not respond.
Dr. Lu did not present safety data. However, he reported that there was no increased incidence of cytokine release syndrome or neurotoxicity in these patients, compared with patients receiving traditional CAR T-cell therapy.
Dr. Lu is employed by Innovative Cellular Therapeutics, which funded the research and is developing ICTCAR014.
SOURCE: Lu V et al. SITC 2019, Abstract O25.
REPORTING FROM SITC 2019
Combo shows promise for checkpoint inhibitor-refractory urothelial carcinoma
NATIONAL HARBOR, MD. – Sitravatinib may “restore or enhance” the activity of anti-PD-1 therapy in patients with checkpoint inhibitor–refractory urothelial carcinoma, an investigator reported at the annual meeting of the Society for Immunotherapy of Cancer.
Clinical activity was observed with combination sitravatinib and nivolumab in patients with urothelial carcinoma who had disease progression on or after an immune checkpoint inhibitor and were previously treated with platinum-based chemotherapy.
“Up until a few years ago, the only therapies we had [for urothelial carcinoma] were cytotoxic, platinum-based chemotherapies,” said Pavlos Msaouel, MD, PhD, of the University of Texas MD Anderson Cancer Center, Houston.
“Thankfully, since 2016, immune checkpoint therapy has become part of our toolbox. But even with single-agent, approved immune checkpoint therapies, anti-PD-1/anti-PD-L1, the response rates are still low, around 20%, and durable responses are only seen in a subset of patients. So we have to do better, if possible, potentially by combining immune checkpoint therapies with other immunotherapies such as sitravatinib.”
Dr. Msaouel explained that sitravatinib inhibits a spectrum of related receptor tyrosine kinases, including TAM family receptors (TYRO3, Axl, and Mer), split family receptors (VEGFR2/PDGFR and c-KIT), and c-Met. Researchers are investigating sitravatinib in combination with nivolumab in a phase 2 trial of patients with urothelial carcinoma (NCT03606174). Dr. Msaouel presented results from one cohort on this trial – 33 patients who had previously received platinum-based chemotherapy and a PD-1/PD-L1 inhibitor.
At baseline, the patients’ median age was 68 years (range, 47-83 years), and 70% were male. Patients had metastatic (n = 30) or locally advanced (n = 3) disease. They had received a median of two (range, one to four) prior systemic therapies.
For this study, patients received oral sitravatinib at 120 mg daily and intravenous nivolumab at 240 mg every 2 weeks or 480 mg every 4 weeks on continuous 28-day cycles. Tumor assessments were performed every 8 weeks.
Results
Of the 22 patients evaluable for efficacy, 1 patient achieved a complete response, 5 had a partial response, 15 had stable disease, and 1 progressed. Eight patients had tumor regression greater than 30%.
Treatment duration exceeded 26 weeks in six patients. Nine patients, including four responders, were still on study at the data cutoff in mid-October.
“This ongoing trial continues to show promising clinical activity, including tumor regression and prolonged duration on treatment,” Dr. Msaouel said.
He added that combination sitravatinib and nivolumab has “an acceptable side effect profile, with manageable adverse events.”
Common treatment-related adverse events, in all 33 patients, were fatigue (58%), diarrhea (48%), decreased appetite (33%), dysphonia (33%), nausea (33%), and alanine aminotransferase increase (21%).
Grade 3 treatment-related adverse events included fatigue (12%), hypertension (12%), diarrhea (9%), lipase increase (9%), decreased appetite (3%), and palmar-plantar erythrodysesthesia syndrome (3%). There were no grade 4 or 5 treatment-related events.
Mirati Therapeutics sponsored the trial. Dr. Msaouel disclosed relationships with Mirati, Bristol-Myers Squibb, Exelixis, Pfizer, and Takeda.
SOURCE: Msaouel P et al. SITC 2019. Abstract O23.
NATIONAL HARBOR, MD. – Sitravatinib may “restore or enhance” the activity of anti-PD-1 therapy in patients with checkpoint inhibitor–refractory urothelial carcinoma, an investigator reported at the annual meeting of the Society for Immunotherapy of Cancer.
Clinical activity was observed with combination sitravatinib and nivolumab in patients with urothelial carcinoma who had disease progression on or after an immune checkpoint inhibitor and were previously treated with platinum-based chemotherapy.
“Up until a few years ago, the only therapies we had [for urothelial carcinoma] were cytotoxic, platinum-based chemotherapies,” said Pavlos Msaouel, MD, PhD, of the University of Texas MD Anderson Cancer Center, Houston.
“Thankfully, since 2016, immune checkpoint therapy has become part of our toolbox. But even with single-agent, approved immune checkpoint therapies, anti-PD-1/anti-PD-L1, the response rates are still low, around 20%, and durable responses are only seen in a subset of patients. So we have to do better, if possible, potentially by combining immune checkpoint therapies with other immunotherapies such as sitravatinib.”
Dr. Msaouel explained that sitravatinib inhibits a spectrum of related receptor tyrosine kinases, including TAM family receptors (TYRO3, Axl, and Mer), split family receptors (VEGFR2/PDGFR and c-KIT), and c-Met. Researchers are investigating sitravatinib in combination with nivolumab in a phase 2 trial of patients with urothelial carcinoma (NCT03606174). Dr. Msaouel presented results from one cohort on this trial – 33 patients who had previously received platinum-based chemotherapy and a PD-1/PD-L1 inhibitor.
At baseline, the patients’ median age was 68 years (range, 47-83 years), and 70% were male. Patients had metastatic (n = 30) or locally advanced (n = 3) disease. They had received a median of two (range, one to four) prior systemic therapies.
For this study, patients received oral sitravatinib at 120 mg daily and intravenous nivolumab at 240 mg every 2 weeks or 480 mg every 4 weeks on continuous 28-day cycles. Tumor assessments were performed every 8 weeks.
Results
Of the 22 patients evaluable for efficacy, 1 patient achieved a complete response, 5 had a partial response, 15 had stable disease, and 1 progressed. Eight patients had tumor regression greater than 30%.
Treatment duration exceeded 26 weeks in six patients. Nine patients, including four responders, were still on study at the data cutoff in mid-October.
“This ongoing trial continues to show promising clinical activity, including tumor regression and prolonged duration on treatment,” Dr. Msaouel said.
He added that combination sitravatinib and nivolumab has “an acceptable side effect profile, with manageable adverse events.”
Common treatment-related adverse events, in all 33 patients, were fatigue (58%), diarrhea (48%), decreased appetite (33%), dysphonia (33%), nausea (33%), and alanine aminotransferase increase (21%).
Grade 3 treatment-related adverse events included fatigue (12%), hypertension (12%), diarrhea (9%), lipase increase (9%), decreased appetite (3%), and palmar-plantar erythrodysesthesia syndrome (3%). There were no grade 4 or 5 treatment-related events.
Mirati Therapeutics sponsored the trial. Dr. Msaouel disclosed relationships with Mirati, Bristol-Myers Squibb, Exelixis, Pfizer, and Takeda.
SOURCE: Msaouel P et al. SITC 2019. Abstract O23.
NATIONAL HARBOR, MD. – Sitravatinib may “restore or enhance” the activity of anti-PD-1 therapy in patients with checkpoint inhibitor–refractory urothelial carcinoma, an investigator reported at the annual meeting of the Society for Immunotherapy of Cancer.
Clinical activity was observed with combination sitravatinib and nivolumab in patients with urothelial carcinoma who had disease progression on or after an immune checkpoint inhibitor and were previously treated with platinum-based chemotherapy.
“Up until a few years ago, the only therapies we had [for urothelial carcinoma] were cytotoxic, platinum-based chemotherapies,” said Pavlos Msaouel, MD, PhD, of the University of Texas MD Anderson Cancer Center, Houston.
“Thankfully, since 2016, immune checkpoint therapy has become part of our toolbox. But even with single-agent, approved immune checkpoint therapies, anti-PD-1/anti-PD-L1, the response rates are still low, around 20%, and durable responses are only seen in a subset of patients. So we have to do better, if possible, potentially by combining immune checkpoint therapies with other immunotherapies such as sitravatinib.”
Dr. Msaouel explained that sitravatinib inhibits a spectrum of related receptor tyrosine kinases, including TAM family receptors (TYRO3, Axl, and Mer), split family receptors (VEGFR2/PDGFR and c-KIT), and c-Met. Researchers are investigating sitravatinib in combination with nivolumab in a phase 2 trial of patients with urothelial carcinoma (NCT03606174). Dr. Msaouel presented results from one cohort on this trial – 33 patients who had previously received platinum-based chemotherapy and a PD-1/PD-L1 inhibitor.
At baseline, the patients’ median age was 68 years (range, 47-83 years), and 70% were male. Patients had metastatic (n = 30) or locally advanced (n = 3) disease. They had received a median of two (range, one to four) prior systemic therapies.
For this study, patients received oral sitravatinib at 120 mg daily and intravenous nivolumab at 240 mg every 2 weeks or 480 mg every 4 weeks on continuous 28-day cycles. Tumor assessments were performed every 8 weeks.
Results
Of the 22 patients evaluable for efficacy, 1 patient achieved a complete response, 5 had a partial response, 15 had stable disease, and 1 progressed. Eight patients had tumor regression greater than 30%.
Treatment duration exceeded 26 weeks in six patients. Nine patients, including four responders, were still on study at the data cutoff in mid-October.
“This ongoing trial continues to show promising clinical activity, including tumor regression and prolonged duration on treatment,” Dr. Msaouel said.
He added that combination sitravatinib and nivolumab has “an acceptable side effect profile, with manageable adverse events.”
Common treatment-related adverse events, in all 33 patients, were fatigue (58%), diarrhea (48%), decreased appetite (33%), dysphonia (33%), nausea (33%), and alanine aminotransferase increase (21%).
Grade 3 treatment-related adverse events included fatigue (12%), hypertension (12%), diarrhea (9%), lipase increase (9%), decreased appetite (3%), and palmar-plantar erythrodysesthesia syndrome (3%). There were no grade 4 or 5 treatment-related events.
Mirati Therapeutics sponsored the trial. Dr. Msaouel disclosed relationships with Mirati, Bristol-Myers Squibb, Exelixis, Pfizer, and Takeda.
SOURCE: Msaouel P et al. SITC 2019. Abstract O23.
REPORTING FROM SITC 2019
Short-course DAA therapy may prevent hepatitis transmission in transplant patients
BOSTON – A short course of results of a recent study show.
The regimen, given right before transplantation and for 7 days afterward, reduced the cost of direct-acting antiviral (DAA) therapy and allowed patients to complete hepatitis C virus (HCV) therapy before hospital discharge, according to authors of the study, which was presented at the annual meeting of the American Association for the Study of Liver Diseases.
If confirmed in subsequent studies, this regimen could become the standard of care for donor-positive, recipient-negative transplantation, said lead study author Jordan J. Feld, MD, R. Phelan Chair in translational liver disease research at the University of Toronto and research director at the Toronto Centre for Liver Disease.
“Transplant recipients are understandably nervous about accepting organs from people with HCV infection,” said Dr. Feld in a press release. “This very short therapy allows them to leave hospital free of HCV, which is a huge benefit. Not only is it cheaper and likely safer, but the patients really prefer not having to worry about HCV with all of the other challenges after a transplant.”
Results of this study come at a time when the proportion of overdose death organ donors is on the rise, from just 1% in 2000 to 15% in 2016, according to Dr. Feld. Overdose deaths account for the largest percentage of HCV-infected donors, most of whom are young and often otherwise healthy, he added.
Recipients of HCV-infected organs can be cured after transplant as a number of studies have previously shown. However, preventing transmission would be better than cure, Dr. Feld said, in part because of issues with drug-drug interactions, potential for relapse, and issues with procuring the drugs after transplant.
Accordingly, Dr. Feld and colleagues sought to evaluate “preemptive” treatment with DAA therapy combined with ezetimibe, which they said has been shown to inhibit HCV entry blockers. The recipients, who were listed for heart, lung, kidney, or kidney-pancreas transplant, were given glecaprevir/pibrentasvir plus ezetimibe starting 6-12 hours prior to transplantation, and then daily for 7 days.
The median age was 36 years for the 16 donors reported, and 61 years for the 25 recipients. Most recipients (12 patients) had a lung transplant, while 8 had a heart transplant, 4 had a kidney transplant, and 1 had a kidney-pancreas transplant.
There were no virologic failures, according to the investigators, with sustained virologic response (SVR) after 6 weeks in 7 patients, and SVR after 12 weeks in the remaining 18. Three recipients did have detectable HCV RNA, though all cleared and had SVR at 6 weeks in one case, and SVR at 12 weeks in the other two, according to the investigators’ report.
Of 22 serious adverse events noted in the study, 1 was considered treatment related, according to the report, and there were 2 deaths among lung transplant patients, caused by sepsis in 1 case to sepsis and subarachnoid hemorrhage in another.
It’s not clear whether ezetimibe is needed in this short-duration regimen, but in any case, it is well tolerated and inexpensive, and so there is “minimal downside” to include it, Dr. Feld and coinvestigators wrote in their report.
Dr. Feld reported disclosures related to Abbvie, Abbott, Enanta Pharmaceuticals, Gilead, Janssen, Merck, and Roche.
SOURCE: Feld JJ et al. The Liver Meeting 2019, Abstract 38.
BOSTON – A short course of results of a recent study show.
The regimen, given right before transplantation and for 7 days afterward, reduced the cost of direct-acting antiviral (DAA) therapy and allowed patients to complete hepatitis C virus (HCV) therapy before hospital discharge, according to authors of the study, which was presented at the annual meeting of the American Association for the Study of Liver Diseases.
If confirmed in subsequent studies, this regimen could become the standard of care for donor-positive, recipient-negative transplantation, said lead study author Jordan J. Feld, MD, R. Phelan Chair in translational liver disease research at the University of Toronto and research director at the Toronto Centre for Liver Disease.
“Transplant recipients are understandably nervous about accepting organs from people with HCV infection,” said Dr. Feld in a press release. “This very short therapy allows them to leave hospital free of HCV, which is a huge benefit. Not only is it cheaper and likely safer, but the patients really prefer not having to worry about HCV with all of the other challenges after a transplant.”
Results of this study come at a time when the proportion of overdose death organ donors is on the rise, from just 1% in 2000 to 15% in 2016, according to Dr. Feld. Overdose deaths account for the largest percentage of HCV-infected donors, most of whom are young and often otherwise healthy, he added.
Recipients of HCV-infected organs can be cured after transplant as a number of studies have previously shown. However, preventing transmission would be better than cure, Dr. Feld said, in part because of issues with drug-drug interactions, potential for relapse, and issues with procuring the drugs after transplant.
Accordingly, Dr. Feld and colleagues sought to evaluate “preemptive” treatment with DAA therapy combined with ezetimibe, which they said has been shown to inhibit HCV entry blockers. The recipients, who were listed for heart, lung, kidney, or kidney-pancreas transplant, were given glecaprevir/pibrentasvir plus ezetimibe starting 6-12 hours prior to transplantation, and then daily for 7 days.
The median age was 36 years for the 16 donors reported, and 61 years for the 25 recipients. Most recipients (12 patients) had a lung transplant, while 8 had a heart transplant, 4 had a kidney transplant, and 1 had a kidney-pancreas transplant.
There were no virologic failures, according to the investigators, with sustained virologic response (SVR) after 6 weeks in 7 patients, and SVR after 12 weeks in the remaining 18. Three recipients did have detectable HCV RNA, though all cleared and had SVR at 6 weeks in one case, and SVR at 12 weeks in the other two, according to the investigators’ report.
Of 22 serious adverse events noted in the study, 1 was considered treatment related, according to the report, and there were 2 deaths among lung transplant patients, caused by sepsis in 1 case to sepsis and subarachnoid hemorrhage in another.
It’s not clear whether ezetimibe is needed in this short-duration regimen, but in any case, it is well tolerated and inexpensive, and so there is “minimal downside” to include it, Dr. Feld and coinvestigators wrote in their report.
Dr. Feld reported disclosures related to Abbvie, Abbott, Enanta Pharmaceuticals, Gilead, Janssen, Merck, and Roche.
SOURCE: Feld JJ et al. The Liver Meeting 2019, Abstract 38.
BOSTON – A short course of results of a recent study show.
The regimen, given right before transplantation and for 7 days afterward, reduced the cost of direct-acting antiviral (DAA) therapy and allowed patients to complete hepatitis C virus (HCV) therapy before hospital discharge, according to authors of the study, which was presented at the annual meeting of the American Association for the Study of Liver Diseases.
If confirmed in subsequent studies, this regimen could become the standard of care for donor-positive, recipient-negative transplantation, said lead study author Jordan J. Feld, MD, R. Phelan Chair in translational liver disease research at the University of Toronto and research director at the Toronto Centre for Liver Disease.
“Transplant recipients are understandably nervous about accepting organs from people with HCV infection,” said Dr. Feld in a press release. “This very short therapy allows them to leave hospital free of HCV, which is a huge benefit. Not only is it cheaper and likely safer, but the patients really prefer not having to worry about HCV with all of the other challenges after a transplant.”
Results of this study come at a time when the proportion of overdose death organ donors is on the rise, from just 1% in 2000 to 15% in 2016, according to Dr. Feld. Overdose deaths account for the largest percentage of HCV-infected donors, most of whom are young and often otherwise healthy, he added.
Recipients of HCV-infected organs can be cured after transplant as a number of studies have previously shown. However, preventing transmission would be better than cure, Dr. Feld said, in part because of issues with drug-drug interactions, potential for relapse, and issues with procuring the drugs after transplant.
Accordingly, Dr. Feld and colleagues sought to evaluate “preemptive” treatment with DAA therapy combined with ezetimibe, which they said has been shown to inhibit HCV entry blockers. The recipients, who were listed for heart, lung, kidney, or kidney-pancreas transplant, were given glecaprevir/pibrentasvir plus ezetimibe starting 6-12 hours prior to transplantation, and then daily for 7 days.
The median age was 36 years for the 16 donors reported, and 61 years for the 25 recipients. Most recipients (12 patients) had a lung transplant, while 8 had a heart transplant, 4 had a kidney transplant, and 1 had a kidney-pancreas transplant.
There were no virologic failures, according to the investigators, with sustained virologic response (SVR) after 6 weeks in 7 patients, and SVR after 12 weeks in the remaining 18. Three recipients did have detectable HCV RNA, though all cleared and had SVR at 6 weeks in one case, and SVR at 12 weeks in the other two, according to the investigators’ report.
Of 22 serious adverse events noted in the study, 1 was considered treatment related, according to the report, and there were 2 deaths among lung transplant patients, caused by sepsis in 1 case to sepsis and subarachnoid hemorrhage in another.
It’s not clear whether ezetimibe is needed in this short-duration regimen, but in any case, it is well tolerated and inexpensive, and so there is “minimal downside” to include it, Dr. Feld and coinvestigators wrote in their report.
Dr. Feld reported disclosures related to Abbvie, Abbott, Enanta Pharmaceuticals, Gilead, Janssen, Merck, and Roche.
SOURCE: Feld JJ et al. The Liver Meeting 2019, Abstract 38.
REPORTING FROM THE LIVER MEETING 2019
Dextromethorphan/bupropion combo is remarkably fast-acting antidepressant
COPENHAGEN – A novel investigational oral combination of dextromethorphan and bupropion achieved a strikingly rapid and clinically meaningful reduction in depressive symptoms in patients with major depressive disorder in a phase 2, active comparator–controlled study, Cedric O’Gorman, MD, reported at the annual congress of the European College of Neuropsychopharmacology.
– and the between-group difference continued to grow over the course of the 6-week, double-blind randomized trial. Thus, AXS-05 shows the potential to help meet the widely recognized need for faster-acting, higher-response antidepressant therapies than are currently available, observed Dr. O’Gorman, senior vice president for clinical development and medical affairs at Axsome Therapeutics in New York.
AXS-05 has multimodal mechanisms of action. As a result, it is not only in late-stage clinical development for major depressive disorder, but also for nicotine dependence and agitation in patients with Alzheimer’s disease.
Dextromethorphan is an NMDA (N-methyl-D-aspartate)–receptor antagonist, a serotonin and norepinephrine reuptake inhibitor, a sigma-1–receptor agonist, and a nicotinic-receptor antagonist. Bupropion, too, is a nicotinic-receptor antagonist. In addition, it’s a dopamine and norepinephrine reuptake inhibitor, and it boosts plasma levels of dextromethorphan by inhibiting its metabolism, the psychiatrist explained.
The phase 2, double-blind clinical trial included 80 patients with confirmed major depressive disorder who were experiencing an acute moderate to severe depressive episode. Slightly more than half of them had a history of three or more prior depressive episodes. Their mean baseline Montgomery-Åsberg Depression Rating Scale (MADRS) total score was 32, with a mean Clinical Global Impressions-Severity (CGI-S) score of 4.5 on a 1-7 scale. Participants were randomized to 45 mg dextromethorphan/105 mg bupropion or to 105 mg of bupropion-only, twice daily for 6 weeks.
The primary study endpoint was the average weekly change in MADRS score from baseline to week 6. The difference was highly significant: 13.7 points in the AXS-05 group, 8.8 with bupropion. At week 6, the AXS-05 group averaged a 17.2-point reduction from baseline in MADRS total score, compared with a 12.1-point decrease in controls. The between-group difference numerically favored AXS-05 at week 1, achieving statistically significant superiority from week 2 on. At week 6, 47% of the AXS-05 group had achieved clinical remission as defined by a MADRS score of 10 or less, as did 16% of the bupropion group.
At week 1 – again, the earliest assessment – 18% of AXS-05-treated patients were rated much or very much improved on the CGI, as were 3% of bupropion-treated controls. At week 6, 59% of the AXS-05 group and 27% of controls were rated very much improved.
Twelve percent of patients in both study arms discontinued treatment because of adverse events, none serious. The most common adverse events in the dextromethorphan/bupropion group were nausea, dizziness, dry mouth, reduced appetite, and anxiety. There were no instances of weight gain, sexual dysfunction, or psychomimetic effects.
Two phase 3, double-blind, 6-week RCTs of AXS-05 in depression are ongoing. STRIDE 1 includes 250 patients with treatment-resistant depression randomized to AXS-05 or bupropion. GEMINI is a study of 300 patients with major depressive disorder assigned to AXS-05 or placebo.
COPENHAGEN – A novel investigational oral combination of dextromethorphan and bupropion achieved a strikingly rapid and clinically meaningful reduction in depressive symptoms in patients with major depressive disorder in a phase 2, active comparator–controlled study, Cedric O’Gorman, MD, reported at the annual congress of the European College of Neuropsychopharmacology.
– and the between-group difference continued to grow over the course of the 6-week, double-blind randomized trial. Thus, AXS-05 shows the potential to help meet the widely recognized need for faster-acting, higher-response antidepressant therapies than are currently available, observed Dr. O’Gorman, senior vice president for clinical development and medical affairs at Axsome Therapeutics in New York.
AXS-05 has multimodal mechanisms of action. As a result, it is not only in late-stage clinical development for major depressive disorder, but also for nicotine dependence and agitation in patients with Alzheimer’s disease.
Dextromethorphan is an NMDA (N-methyl-D-aspartate)–receptor antagonist, a serotonin and norepinephrine reuptake inhibitor, a sigma-1–receptor agonist, and a nicotinic-receptor antagonist. Bupropion, too, is a nicotinic-receptor antagonist. In addition, it’s a dopamine and norepinephrine reuptake inhibitor, and it boosts plasma levels of dextromethorphan by inhibiting its metabolism, the psychiatrist explained.
The phase 2, double-blind clinical trial included 80 patients with confirmed major depressive disorder who were experiencing an acute moderate to severe depressive episode. Slightly more than half of them had a history of three or more prior depressive episodes. Their mean baseline Montgomery-Åsberg Depression Rating Scale (MADRS) total score was 32, with a mean Clinical Global Impressions-Severity (CGI-S) score of 4.5 on a 1-7 scale. Participants were randomized to 45 mg dextromethorphan/105 mg bupropion or to 105 mg of bupropion-only, twice daily for 6 weeks.
The primary study endpoint was the average weekly change in MADRS score from baseline to week 6. The difference was highly significant: 13.7 points in the AXS-05 group, 8.8 with bupropion. At week 6, the AXS-05 group averaged a 17.2-point reduction from baseline in MADRS total score, compared with a 12.1-point decrease in controls. The between-group difference numerically favored AXS-05 at week 1, achieving statistically significant superiority from week 2 on. At week 6, 47% of the AXS-05 group had achieved clinical remission as defined by a MADRS score of 10 or less, as did 16% of the bupropion group.
At week 1 – again, the earliest assessment – 18% of AXS-05-treated patients were rated much or very much improved on the CGI, as were 3% of bupropion-treated controls. At week 6, 59% of the AXS-05 group and 27% of controls were rated very much improved.
Twelve percent of patients in both study arms discontinued treatment because of adverse events, none serious. The most common adverse events in the dextromethorphan/bupropion group were nausea, dizziness, dry mouth, reduced appetite, and anxiety. There were no instances of weight gain, sexual dysfunction, or psychomimetic effects.
Two phase 3, double-blind, 6-week RCTs of AXS-05 in depression are ongoing. STRIDE 1 includes 250 patients with treatment-resistant depression randomized to AXS-05 or bupropion. GEMINI is a study of 300 patients with major depressive disorder assigned to AXS-05 or placebo.
COPENHAGEN – A novel investigational oral combination of dextromethorphan and bupropion achieved a strikingly rapid and clinically meaningful reduction in depressive symptoms in patients with major depressive disorder in a phase 2, active comparator–controlled study, Cedric O’Gorman, MD, reported at the annual congress of the European College of Neuropsychopharmacology.
– and the between-group difference continued to grow over the course of the 6-week, double-blind randomized trial. Thus, AXS-05 shows the potential to help meet the widely recognized need for faster-acting, higher-response antidepressant therapies than are currently available, observed Dr. O’Gorman, senior vice president for clinical development and medical affairs at Axsome Therapeutics in New York.
AXS-05 has multimodal mechanisms of action. As a result, it is not only in late-stage clinical development for major depressive disorder, but also for nicotine dependence and agitation in patients with Alzheimer’s disease.
Dextromethorphan is an NMDA (N-methyl-D-aspartate)–receptor antagonist, a serotonin and norepinephrine reuptake inhibitor, a sigma-1–receptor agonist, and a nicotinic-receptor antagonist. Bupropion, too, is a nicotinic-receptor antagonist. In addition, it’s a dopamine and norepinephrine reuptake inhibitor, and it boosts plasma levels of dextromethorphan by inhibiting its metabolism, the psychiatrist explained.
The phase 2, double-blind clinical trial included 80 patients with confirmed major depressive disorder who were experiencing an acute moderate to severe depressive episode. Slightly more than half of them had a history of three or more prior depressive episodes. Their mean baseline Montgomery-Åsberg Depression Rating Scale (MADRS) total score was 32, with a mean Clinical Global Impressions-Severity (CGI-S) score of 4.5 on a 1-7 scale. Participants were randomized to 45 mg dextromethorphan/105 mg bupropion or to 105 mg of bupropion-only, twice daily for 6 weeks.
The primary study endpoint was the average weekly change in MADRS score from baseline to week 6. The difference was highly significant: 13.7 points in the AXS-05 group, 8.8 with bupropion. At week 6, the AXS-05 group averaged a 17.2-point reduction from baseline in MADRS total score, compared with a 12.1-point decrease in controls. The between-group difference numerically favored AXS-05 at week 1, achieving statistically significant superiority from week 2 on. At week 6, 47% of the AXS-05 group had achieved clinical remission as defined by a MADRS score of 10 or less, as did 16% of the bupropion group.
At week 1 – again, the earliest assessment – 18% of AXS-05-treated patients were rated much or very much improved on the CGI, as were 3% of bupropion-treated controls. At week 6, 59% of the AXS-05 group and 27% of controls were rated very much improved.
Twelve percent of patients in both study arms discontinued treatment because of adverse events, none serious. The most common adverse events in the dextromethorphan/bupropion group were nausea, dizziness, dry mouth, reduced appetite, and anxiety. There were no instances of weight gain, sexual dysfunction, or psychomimetic effects.
Two phase 3, double-blind, 6-week RCTs of AXS-05 in depression are ongoing. STRIDE 1 includes 250 patients with treatment-resistant depression randomized to AXS-05 or bupropion. GEMINI is a study of 300 patients with major depressive disorder assigned to AXS-05 or placebo.
REPORTING FROM ECNP 2019
TLR9 agonist may overcome resistance to anti–PD-1 therapy in melanoma
NATIONAL HARBOR, MD. – A TLR9 agonist called CMP-001 can reverse resistance to anti–programmed death-1 (PD-1) therapy in patients with melanoma, a phase 1 trial suggests.
Combination CMP-001 and pembrolizumab produced durable responses in patients who had progressed on prior anti–PD-1 therapy, and the combination was considered well tolerated.
CMP-001 is a CpG-A TLR9 agonist packaged in a viruslike particle, John Kirkwood, MD, of University of Pittsburgh Medical Center, explained in a late-breaking abstract at the annual meeting of the Society for Immunotherapy of Cancer. CMP-001 activates tumor-associated plasmacytoid dendritic cells and induces systemic tumor-specific CD8+ T-cell responses.
Dr. Kirkwood and associates are investigating CMP-001, given alone or in combination with pembrolizumab, in a phase 1 trial (NCT02680184) of patients with metastatic or unresectable melanoma who are refractory to anti–PD-1 therapy.
Data were presented on 144 patients who received CMP-001 in combination with pembrolizumab. About 40% of patients (39.6%) had elevated lactate dehydrogenase at baseline, and 32.6% had BRAF mutations.
All patients had received prior anti–PD-1 therapy alone (75%) and/or in combination (50%). For most patients (93.1%), their last response to anti–PD-1 therapy was progression.
For this study, the patients received intratumoral CMP-001 injections at a range of doses (1 mg, 3 mg, 5 mg, 7.5 mg, and 10 mg). CMP-001 was given weekly for either 2 weeks or 7 weeks, then every 3 weeks until discontinuation. There were two different formulations of CMP-001 given – 0.01% polysorbate 20 (PS20; n = 83) and 0.00167% PS20 (n = 61).
Safety
“CMP-001 in combination with pembrolizumab is very well tolerated, with no apparent increase in autoimmune toxicities associated with anti–PD-1,” Dr. Kirkwood said.
The most common treatment-related adverse events were flulike symptoms, including chills (72%), pyrexia (56%), fatigue (51%), nausea (45%), vomiting (29%), and headache (28%). Another common event was injection-site pain (28%).
The most common grade 3 adverse events were hypotension (n = 9) and hypertension (n = 7). Grade 4 events included hypotension, aspartate aminotransferase increase, and alanine aminotransferase increase (n = 1 for all). There were no grade 5 events.
Six patients discontinued treatment because of adverse events.
Response
The overall response rate was 25% (21/83) among patients who received the 0.01% PS20 formulation of CMP-001 and 11.5% (7/61) among patients who received the 0.00167% PS20 formulation.
Responses were similar in injected and noninjected target lesions. The median duration of response has not been reached at a median follow-up of 16.9 months.
“Intratumoral CMP-001 reverses resistance to anti–PD-1 in patients who have progressed on prior anti–PD-1 therapy,” Dr. Kirkwood said, adding that these data support further clinical development of CMP-001.
The research is sponsored by Checkmate Pharmaceuticals. Dr. Kirkwood disclosed relationships with Amgen, BMS, Immunocore, Iovance, Novartis, Elsevier, Castle, Merck, and Checkmate.
SOURCE: Kirkwood J et al. SITC 2019, Abstract O85.
NATIONAL HARBOR, MD. – A TLR9 agonist called CMP-001 can reverse resistance to anti–programmed death-1 (PD-1) therapy in patients with melanoma, a phase 1 trial suggests.
Combination CMP-001 and pembrolizumab produced durable responses in patients who had progressed on prior anti–PD-1 therapy, and the combination was considered well tolerated.
CMP-001 is a CpG-A TLR9 agonist packaged in a viruslike particle, John Kirkwood, MD, of University of Pittsburgh Medical Center, explained in a late-breaking abstract at the annual meeting of the Society for Immunotherapy of Cancer. CMP-001 activates tumor-associated plasmacytoid dendritic cells and induces systemic tumor-specific CD8+ T-cell responses.
Dr. Kirkwood and associates are investigating CMP-001, given alone or in combination with pembrolizumab, in a phase 1 trial (NCT02680184) of patients with metastatic or unresectable melanoma who are refractory to anti–PD-1 therapy.
Data were presented on 144 patients who received CMP-001 in combination with pembrolizumab. About 40% of patients (39.6%) had elevated lactate dehydrogenase at baseline, and 32.6% had BRAF mutations.
All patients had received prior anti–PD-1 therapy alone (75%) and/or in combination (50%). For most patients (93.1%), their last response to anti–PD-1 therapy was progression.
For this study, the patients received intratumoral CMP-001 injections at a range of doses (1 mg, 3 mg, 5 mg, 7.5 mg, and 10 mg). CMP-001 was given weekly for either 2 weeks or 7 weeks, then every 3 weeks until discontinuation. There were two different formulations of CMP-001 given – 0.01% polysorbate 20 (PS20; n = 83) and 0.00167% PS20 (n = 61).
Safety
“CMP-001 in combination with pembrolizumab is very well tolerated, with no apparent increase in autoimmune toxicities associated with anti–PD-1,” Dr. Kirkwood said.
The most common treatment-related adverse events were flulike symptoms, including chills (72%), pyrexia (56%), fatigue (51%), nausea (45%), vomiting (29%), and headache (28%). Another common event was injection-site pain (28%).
The most common grade 3 adverse events were hypotension (n = 9) and hypertension (n = 7). Grade 4 events included hypotension, aspartate aminotransferase increase, and alanine aminotransferase increase (n = 1 for all). There were no grade 5 events.
Six patients discontinued treatment because of adverse events.
Response
The overall response rate was 25% (21/83) among patients who received the 0.01% PS20 formulation of CMP-001 and 11.5% (7/61) among patients who received the 0.00167% PS20 formulation.
Responses were similar in injected and noninjected target lesions. The median duration of response has not been reached at a median follow-up of 16.9 months.
“Intratumoral CMP-001 reverses resistance to anti–PD-1 in patients who have progressed on prior anti–PD-1 therapy,” Dr. Kirkwood said, adding that these data support further clinical development of CMP-001.
The research is sponsored by Checkmate Pharmaceuticals. Dr. Kirkwood disclosed relationships with Amgen, BMS, Immunocore, Iovance, Novartis, Elsevier, Castle, Merck, and Checkmate.
SOURCE: Kirkwood J et al. SITC 2019, Abstract O85.
NATIONAL HARBOR, MD. – A TLR9 agonist called CMP-001 can reverse resistance to anti–programmed death-1 (PD-1) therapy in patients with melanoma, a phase 1 trial suggests.
Combination CMP-001 and pembrolizumab produced durable responses in patients who had progressed on prior anti–PD-1 therapy, and the combination was considered well tolerated.
CMP-001 is a CpG-A TLR9 agonist packaged in a viruslike particle, John Kirkwood, MD, of University of Pittsburgh Medical Center, explained in a late-breaking abstract at the annual meeting of the Society for Immunotherapy of Cancer. CMP-001 activates tumor-associated plasmacytoid dendritic cells and induces systemic tumor-specific CD8+ T-cell responses.
Dr. Kirkwood and associates are investigating CMP-001, given alone or in combination with pembrolizumab, in a phase 1 trial (NCT02680184) of patients with metastatic or unresectable melanoma who are refractory to anti–PD-1 therapy.
Data were presented on 144 patients who received CMP-001 in combination with pembrolizumab. About 40% of patients (39.6%) had elevated lactate dehydrogenase at baseline, and 32.6% had BRAF mutations.
All patients had received prior anti–PD-1 therapy alone (75%) and/or in combination (50%). For most patients (93.1%), their last response to anti–PD-1 therapy was progression.
For this study, the patients received intratumoral CMP-001 injections at a range of doses (1 mg, 3 mg, 5 mg, 7.5 mg, and 10 mg). CMP-001 was given weekly for either 2 weeks or 7 weeks, then every 3 weeks until discontinuation. There were two different formulations of CMP-001 given – 0.01% polysorbate 20 (PS20; n = 83) and 0.00167% PS20 (n = 61).
Safety
“CMP-001 in combination with pembrolizumab is very well tolerated, with no apparent increase in autoimmune toxicities associated with anti–PD-1,” Dr. Kirkwood said.
The most common treatment-related adverse events were flulike symptoms, including chills (72%), pyrexia (56%), fatigue (51%), nausea (45%), vomiting (29%), and headache (28%). Another common event was injection-site pain (28%).
The most common grade 3 adverse events were hypotension (n = 9) and hypertension (n = 7). Grade 4 events included hypotension, aspartate aminotransferase increase, and alanine aminotransferase increase (n = 1 for all). There were no grade 5 events.
Six patients discontinued treatment because of adverse events.
Response
The overall response rate was 25% (21/83) among patients who received the 0.01% PS20 formulation of CMP-001 and 11.5% (7/61) among patients who received the 0.00167% PS20 formulation.
Responses were similar in injected and noninjected target lesions. The median duration of response has not been reached at a median follow-up of 16.9 months.
“Intratumoral CMP-001 reverses resistance to anti–PD-1 in patients who have progressed on prior anti–PD-1 therapy,” Dr. Kirkwood said, adding that these data support further clinical development of CMP-001.
The research is sponsored by Checkmate Pharmaceuticals. Dr. Kirkwood disclosed relationships with Amgen, BMS, Immunocore, Iovance, Novartis, Elsevier, Castle, Merck, and Checkmate.
SOURCE: Kirkwood J et al. SITC 2019, Abstract O85.
REPORTING FROM SITC 2019
Veterans at higher risk of sleep behavior disorders
Veterans may be at higher risk of idiopathic rapid eye movement sleep behavior disorders, particularly if they have traumatic brain injury (TBI) or posttraumatic stress disorder (PTSD) according to a paper published in Sleep.
In a prospective, cross-sectional study, researchers recruited 394 veterans – 94% of whom were male – who underwent in-lab video-polysomnography and questionnaires about REM sleep behavior disorder (RBD), as well as assessment of their trauma status and medical history.
Overall, 9% of subjects had RBD, a figure considerably higher than has been estimated in the general population (prevalence of 0.38%-1.0%). Seven percent had REM sleep without atonia, 31% had other parasomnias such as a history of dream enactment behavior, and 53% were classified as normal.
The majority of subjects determined to have RBD (n = 34) had either PTSD or comorbid TBI+PTSD (n = 19, 56%). The combined overall crude prevalence of RBD in subjects with either PTSD alone or TBI+PTSD was 16.8% (n = 19 out of 113).
The individuals with PTSD had a 2.81-fold greater odds of RBD and 3.13-fold greater odds of other parasomnias compared with those without PTSD.
Those with both traumatic brain injury and PTSD had 3.43-fold greater odds of RBD and 3.22-fold greater odds of other parasomnias compared with individuals without.
“Interestingly, the neuropathology underpinning PTSD shares common features with RBD, raising the question as to whether or not PTSD has a causal role in the development of RBD, or if a single pathophysiologic process generates two clinical entities,” wrote Jonathan E. Elliott, PhD, of the VA Portland Health Care System, and coauthors.
The researchers also looked for evidence of trauma-associated sleep disorder (TASD), a recently proposed phenomenological sleep disorder whose diagnostic criteria overlaps with REM sleep behavior disorder but includes subjects reporting having an inciting traumatic experience and a history of dreaming related to this experience as well as evidence of autonomic hyperarousal.
The researchers found 22 of the subjects with REM behavior disorder had a traumatic brain injury and/or PTSD, and 9 of these subjects reported evidence of altered dream mentation related to that prior traumatic experience. However, none showed evidence of autonomic nervous system hyperarousal that coincided with abnormal REM sleep activity.
The investigators noted that although the sample of 394 subjects with in-lab video-polysomnography is large, the study is underpowered to draw broader conclusions about prevalence of RBD among veterans. In addition, the study did not establish whether or not trauma exposure preceded, and contributed to, the development of parasomnias and this question should be pursued in further studies.
“Given the purported relationships between TBI, PTSD, RBD, and neurodegeneration, we sought to determine the crude prevalence and related associations of RBD following TBI and PTSD among veterans. Our data show that the prevalence of RBD and related parasomnias is significantly higher in veterans with PTSD and TBI+PTSD compared to veterans without a history of neuropsychiatric trauma,” the authors wrote.
No funding or conflicts of interest were declared.
SOURCE: Elliott JE et al. Sleep 2019 Oct 7. doi: 10.1093/sleep/zsz237.
Veterans may be at higher risk of idiopathic rapid eye movement sleep behavior disorders, particularly if they have traumatic brain injury (TBI) or posttraumatic stress disorder (PTSD) according to a paper published in Sleep.
In a prospective, cross-sectional study, researchers recruited 394 veterans – 94% of whom were male – who underwent in-lab video-polysomnography and questionnaires about REM sleep behavior disorder (RBD), as well as assessment of their trauma status and medical history.
Overall, 9% of subjects had RBD, a figure considerably higher than has been estimated in the general population (prevalence of 0.38%-1.0%). Seven percent had REM sleep without atonia, 31% had other parasomnias such as a history of dream enactment behavior, and 53% were classified as normal.
The majority of subjects determined to have RBD (n = 34) had either PTSD or comorbid TBI+PTSD (n = 19, 56%). The combined overall crude prevalence of RBD in subjects with either PTSD alone or TBI+PTSD was 16.8% (n = 19 out of 113).
The individuals with PTSD had a 2.81-fold greater odds of RBD and 3.13-fold greater odds of other parasomnias compared with those without PTSD.
Those with both traumatic brain injury and PTSD had 3.43-fold greater odds of RBD and 3.22-fold greater odds of other parasomnias compared with individuals without.
“Interestingly, the neuropathology underpinning PTSD shares common features with RBD, raising the question as to whether or not PTSD has a causal role in the development of RBD, or if a single pathophysiologic process generates two clinical entities,” wrote Jonathan E. Elliott, PhD, of the VA Portland Health Care System, and coauthors.
The researchers also looked for evidence of trauma-associated sleep disorder (TASD), a recently proposed phenomenological sleep disorder whose diagnostic criteria overlaps with REM sleep behavior disorder but includes subjects reporting having an inciting traumatic experience and a history of dreaming related to this experience as well as evidence of autonomic hyperarousal.
The researchers found 22 of the subjects with REM behavior disorder had a traumatic brain injury and/or PTSD, and 9 of these subjects reported evidence of altered dream mentation related to that prior traumatic experience. However, none showed evidence of autonomic nervous system hyperarousal that coincided with abnormal REM sleep activity.
The investigators noted that although the sample of 394 subjects with in-lab video-polysomnography is large, the study is underpowered to draw broader conclusions about prevalence of RBD among veterans. In addition, the study did not establish whether or not trauma exposure preceded, and contributed to, the development of parasomnias and this question should be pursued in further studies.
“Given the purported relationships between TBI, PTSD, RBD, and neurodegeneration, we sought to determine the crude prevalence and related associations of RBD following TBI and PTSD among veterans. Our data show that the prevalence of RBD and related parasomnias is significantly higher in veterans with PTSD and TBI+PTSD compared to veterans without a history of neuropsychiatric trauma,” the authors wrote.
No funding or conflicts of interest were declared.
SOURCE: Elliott JE et al. Sleep 2019 Oct 7. doi: 10.1093/sleep/zsz237.
Veterans may be at higher risk of idiopathic rapid eye movement sleep behavior disorders, particularly if they have traumatic brain injury (TBI) or posttraumatic stress disorder (PTSD) according to a paper published in Sleep.
In a prospective, cross-sectional study, researchers recruited 394 veterans – 94% of whom were male – who underwent in-lab video-polysomnography and questionnaires about REM sleep behavior disorder (RBD), as well as assessment of their trauma status and medical history.
Overall, 9% of subjects had RBD, a figure considerably higher than has been estimated in the general population (prevalence of 0.38%-1.0%). Seven percent had REM sleep without atonia, 31% had other parasomnias such as a history of dream enactment behavior, and 53% were classified as normal.
The majority of subjects determined to have RBD (n = 34) had either PTSD or comorbid TBI+PTSD (n = 19, 56%). The combined overall crude prevalence of RBD in subjects with either PTSD alone or TBI+PTSD was 16.8% (n = 19 out of 113).
The individuals with PTSD had a 2.81-fold greater odds of RBD and 3.13-fold greater odds of other parasomnias compared with those without PTSD.
Those with both traumatic brain injury and PTSD had 3.43-fold greater odds of RBD and 3.22-fold greater odds of other parasomnias compared with individuals without.
“Interestingly, the neuropathology underpinning PTSD shares common features with RBD, raising the question as to whether or not PTSD has a causal role in the development of RBD, or if a single pathophysiologic process generates two clinical entities,” wrote Jonathan E. Elliott, PhD, of the VA Portland Health Care System, and coauthors.
The researchers also looked for evidence of trauma-associated sleep disorder (TASD), a recently proposed phenomenological sleep disorder whose diagnostic criteria overlaps with REM sleep behavior disorder but includes subjects reporting having an inciting traumatic experience and a history of dreaming related to this experience as well as evidence of autonomic hyperarousal.
The researchers found 22 of the subjects with REM behavior disorder had a traumatic brain injury and/or PTSD, and 9 of these subjects reported evidence of altered dream mentation related to that prior traumatic experience. However, none showed evidence of autonomic nervous system hyperarousal that coincided with abnormal REM sleep activity.
The investigators noted that although the sample of 394 subjects with in-lab video-polysomnography is large, the study is underpowered to draw broader conclusions about prevalence of RBD among veterans. In addition, the study did not establish whether or not trauma exposure preceded, and contributed to, the development of parasomnias and this question should be pursued in further studies.
“Given the purported relationships between TBI, PTSD, RBD, and neurodegeneration, we sought to determine the crude prevalence and related associations of RBD following TBI and PTSD among veterans. Our data show that the prevalence of RBD and related parasomnias is significantly higher in veterans with PTSD and TBI+PTSD compared to veterans without a history of neuropsychiatric trauma,” the authors wrote.
No funding or conflicts of interest were declared.
SOURCE: Elliott JE et al. Sleep 2019 Oct 7. doi: 10.1093/sleep/zsz237.
FROM SLEEP
Resting-state cerebral blood flow tied to apathy in schizophrenia
Regional resting-state cerebral blood flow (rCBF) in the ventral and dorsal striatum is associated with apathy in patients with schizophrenia – but not with diminished expression, results of a small study suggest.
“This distinction is of high relevance when investigating striatal rCBF,” wrote Karoline Schneider, MD, and colleagues. “The paucity of reported associations beween striatal rCBF and negative symptoms could result from the fact that until now apathy and diminished expression have not been addressed separately.” The study was published in the Journal of Psychiatry & Neuroscience.
Dr. Schneider and colleagues used arterial spin labeling MRI to measure rCBF in 29 patients with schizophrenia from outpatient and inpatient units affiliated with the University of Zürich and in 20 controls without schizophrenia. Negative symptoms were assessed via the Brief Negative Symptom Scale and were divided into those of apathy or those of diminished expression.
, and between severity and higher rCBF in the left and right dorsal striatum (r = 0.48; P = .008). However, the correlations were nonsignificant for symptoms of diminished expression, reported Dr. Schneider, of the university’s department of psychiatry, psychotherapy, and psychosomatics.
“The association between increased striatal rCBF and the negative symptom dimension of apathy, but not diminished expression, provides further evidence for the assumption of different underlying neural bases,” Dr. Schneider and colleagues concluded. “These dimensions should be considered separately in future research on negative symptoms.”
Limitations of the study include its sample size. Another limitation is that all patients with schizophrenia in the study were taking second-generation antipsychotics, which in some research appears to influence striatal rCBF.
Grants from the Swiss National Science Foundation funded the study. Dr. Schneider reported no conflicts of interest. Two authors disclosed receiving grant support or honoraria from pharmaceutical companies but said those activities were unrelated to this study.
SOURCE: Schneider K et al. J Psychiatry Neurosci. 2019;44(2):102-10.
Regional resting-state cerebral blood flow (rCBF) in the ventral and dorsal striatum is associated with apathy in patients with schizophrenia – but not with diminished expression, results of a small study suggest.
“This distinction is of high relevance when investigating striatal rCBF,” wrote Karoline Schneider, MD, and colleagues. “The paucity of reported associations beween striatal rCBF and negative symptoms could result from the fact that until now apathy and diminished expression have not been addressed separately.” The study was published in the Journal of Psychiatry & Neuroscience.
Dr. Schneider and colleagues used arterial spin labeling MRI to measure rCBF in 29 patients with schizophrenia from outpatient and inpatient units affiliated with the University of Zürich and in 20 controls without schizophrenia. Negative symptoms were assessed via the Brief Negative Symptom Scale and were divided into those of apathy or those of diminished expression.
, and between severity and higher rCBF in the left and right dorsal striatum (r = 0.48; P = .008). However, the correlations were nonsignificant for symptoms of diminished expression, reported Dr. Schneider, of the university’s department of psychiatry, psychotherapy, and psychosomatics.
“The association between increased striatal rCBF and the negative symptom dimension of apathy, but not diminished expression, provides further evidence for the assumption of different underlying neural bases,” Dr. Schneider and colleagues concluded. “These dimensions should be considered separately in future research on negative symptoms.”
Limitations of the study include its sample size. Another limitation is that all patients with schizophrenia in the study were taking second-generation antipsychotics, which in some research appears to influence striatal rCBF.
Grants from the Swiss National Science Foundation funded the study. Dr. Schneider reported no conflicts of interest. Two authors disclosed receiving grant support or honoraria from pharmaceutical companies but said those activities were unrelated to this study.
SOURCE: Schneider K et al. J Psychiatry Neurosci. 2019;44(2):102-10.
Regional resting-state cerebral blood flow (rCBF) in the ventral and dorsal striatum is associated with apathy in patients with schizophrenia – but not with diminished expression, results of a small study suggest.
“This distinction is of high relevance when investigating striatal rCBF,” wrote Karoline Schneider, MD, and colleagues. “The paucity of reported associations beween striatal rCBF and negative symptoms could result from the fact that until now apathy and diminished expression have not been addressed separately.” The study was published in the Journal of Psychiatry & Neuroscience.
Dr. Schneider and colleagues used arterial spin labeling MRI to measure rCBF in 29 patients with schizophrenia from outpatient and inpatient units affiliated with the University of Zürich and in 20 controls without schizophrenia. Negative symptoms were assessed via the Brief Negative Symptom Scale and were divided into those of apathy or those of diminished expression.
, and between severity and higher rCBF in the left and right dorsal striatum (r = 0.48; P = .008). However, the correlations were nonsignificant for symptoms of diminished expression, reported Dr. Schneider, of the university’s department of psychiatry, psychotherapy, and psychosomatics.
“The association between increased striatal rCBF and the negative symptom dimension of apathy, but not diminished expression, provides further evidence for the assumption of different underlying neural bases,” Dr. Schneider and colleagues concluded. “These dimensions should be considered separately in future research on negative symptoms.”
Limitations of the study include its sample size. Another limitation is that all patients with schizophrenia in the study were taking second-generation antipsychotics, which in some research appears to influence striatal rCBF.
Grants from the Swiss National Science Foundation funded the study. Dr. Schneider reported no conflicts of interest. Two authors disclosed receiving grant support or honoraria from pharmaceutical companies but said those activities were unrelated to this study.
SOURCE: Schneider K et al. J Psychiatry Neurosci. 2019;44(2):102-10.
FROM THE JOURNAL OF PSYCHIATRY & NEUROSCIENCE
B-cell-poor RA responds better to tocilizumab than to rituximab
ATLANTA – Tocilizumab proved more effective than rituximab in B-cell-poor but not in B-cell-rich patients with RA who have had an inadequate response to disease-modifying antirheumatic drugs (DMARDs) and tumor necrosis factor inhibition in the randomized, open-label, 48-week, phase 4 R4-RA trial.
If validated, the findings of the trial – the first randomized, controlled, biopsy-driven trial in RA – could have “massive implications” for treatment selection and improved outcomes, Constantino Pitzalis, MD, reported during a press conference at the annual meeting of the American College of Rheumatology.
Of 164 RA patients who were failing or intolerant to conventional synthetic (cs) DMARD therapy and at least one tumor necrosis factor inhibitor (TNFi), 83 were randomized to receive rituximab and 81 received tocilizumab. Of those patients, 49.1% were considered B-cell poor (BCP) based on synovial tissue biopsies obtained at trial entry.
The BCP patients treated with tocilizumab were numerically more likely than those treated with rituximab to achieve the coprimary endpoint of Clinical Disease Activity Index (CDAI) improvement of at least 50% from baseline at 16 weeks (56.1% vs. 44.7%), and they were significantly more likely – twice as likely, in fact – to achieve the coprimary endpoint of CDAI improvement of at least 50% from baseline at 16 weeks as well as CDAI score less than 10, indicating a major treatment response (46.3% vs. 23.7%), said Dr. Pitzalis, head of the Centre for Experimental Medicine & Rheumatology at Queen Mary University of London.
BCP patients receiving tocilizumab also were significantly more likely to achieve a number of secondary endpoints, he noted.
In the B-cell-rich (BCR) population, no significant differences were seen in the majority of endpoints with tocilizumab versus rituximab, he said.
Study participants had a mean age of 55-56 years and were intolerant of or refractory to csDMARDs and at least one TNFi. They were recruited from 19 centers in Europe, were randomized and treated with standard doses of rituximab or tocilizumab, and were stratified based on histologic classification (BCP vs. BCR). Baseline characteristics were comparable among the treatment groups, Dr. Pitzalis said.
Adverse events occurred in 62 and 68 patients in the rituximab and tocilizumab groups, respectively, and serious adverse events occurred in 8 and 12 patients, respectively, thus 40% of all serious adverse events occurred in the rituximab group and 60% in the tocilizumab group. Infections and serious infections each occurred in three patients in each group, and two patients in each group discontinued treatment because of adverse events.
B cells are pivotal to RA pathogenesis, as demonstrated by the efficacy of the B-cell-depleting agent, rituximab. However, rituximab, which is licensed for use following failure of csDMARDs and TNFi therapy, is only effective for achieving a 50% improvement in ACR response criteria at 6 months in about 30% of such patients, Dr. Pitzalis noted. In a recent early RA cohort, he and his colleagues found synovial heterogeneity, with more than half of patients showing low or no synovial B-cell infiltration.
“So why would you give them rituximab?” he asked, explaining the rationale for the R4-RA trial: The hypothesis was that alternative biologic agents targeting alternative pathways may be more effective in BCP patients.
“The results showed quite clearly that rituximab was inferior to tocilizumab in this patient group,” he said. “We demonstrated that tocilizumab is more effective than rituximab in achieving low disease activity in patients who had, on synovial biopsy, low levels of B-cell infiltration.
“The study really highlights the importance of integrating molecular pathology into the clinical algorithms, because making the diagnosis is not sufficient. We really need to know what the pathology of the patient is so we can give the right drug to the right patients.”
Donald Thomas, MD, a rheumatologist in private practice in Silver Spring, Md., called the study “fascinating,” and noted during a question-and-answer period during the press conference that, during his lifetime, he “has probably wasted tens of thousands to hundreds of thousands of dollars,” using the trial-and-error approach to treatment.
“We can only treat by trial and error ... so being able to pinpoint therapy is just phenomenal,” he added, further noting in an interview after the press conference that finding the right treatment can be “such a struggle.”
“I literally have patients who have gone through 10 medicines and wasted thousands of dollars,” he said.
In response to a question from Dr. Thomas about the potential for rheumatologists to do their own synovial biopsies to help guide treatment in the event the findings are validated, Dr. Pitzalis said that is both feasible and an important goal.
“All the biopsies [in the study] were carried out by rheumatologists,” he noted. “We have trained over 150 rheumatologists worldwide, including at 15 centers in the United States. ... We want to empower the rheumatologists to do it.”
He added that “this is early data ... and will require validation in larger trials,” but said the point is that “we can’t continue to just give these drugs and see if the patient responds.”
R4-RA is funded by the National Institute of Health Research Efficacy and Mechanism Evaluation program. Dr. Pitzalis and some of the other study authors reported financial relationships with Roche/Genentech, which markets tocilizumab and rituximab, and other pharmaceutical companies.
SOURCE: Pitzalis C et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 2911.
ATLANTA – Tocilizumab proved more effective than rituximab in B-cell-poor but not in B-cell-rich patients with RA who have had an inadequate response to disease-modifying antirheumatic drugs (DMARDs) and tumor necrosis factor inhibition in the randomized, open-label, 48-week, phase 4 R4-RA trial.
If validated, the findings of the trial – the first randomized, controlled, biopsy-driven trial in RA – could have “massive implications” for treatment selection and improved outcomes, Constantino Pitzalis, MD, reported during a press conference at the annual meeting of the American College of Rheumatology.
Of 164 RA patients who were failing or intolerant to conventional synthetic (cs) DMARD therapy and at least one tumor necrosis factor inhibitor (TNFi), 83 were randomized to receive rituximab and 81 received tocilizumab. Of those patients, 49.1% were considered B-cell poor (BCP) based on synovial tissue biopsies obtained at trial entry.
The BCP patients treated with tocilizumab were numerically more likely than those treated with rituximab to achieve the coprimary endpoint of Clinical Disease Activity Index (CDAI) improvement of at least 50% from baseline at 16 weeks (56.1% vs. 44.7%), and they were significantly more likely – twice as likely, in fact – to achieve the coprimary endpoint of CDAI improvement of at least 50% from baseline at 16 weeks as well as CDAI score less than 10, indicating a major treatment response (46.3% vs. 23.7%), said Dr. Pitzalis, head of the Centre for Experimental Medicine & Rheumatology at Queen Mary University of London.
BCP patients receiving tocilizumab also were significantly more likely to achieve a number of secondary endpoints, he noted.
In the B-cell-rich (BCR) population, no significant differences were seen in the majority of endpoints with tocilizumab versus rituximab, he said.
Study participants had a mean age of 55-56 years and were intolerant of or refractory to csDMARDs and at least one TNFi. They were recruited from 19 centers in Europe, were randomized and treated with standard doses of rituximab or tocilizumab, and were stratified based on histologic classification (BCP vs. BCR). Baseline characteristics were comparable among the treatment groups, Dr. Pitzalis said.
Adverse events occurred in 62 and 68 patients in the rituximab and tocilizumab groups, respectively, and serious adverse events occurred in 8 and 12 patients, respectively, thus 40% of all serious adverse events occurred in the rituximab group and 60% in the tocilizumab group. Infections and serious infections each occurred in three patients in each group, and two patients in each group discontinued treatment because of adverse events.
B cells are pivotal to RA pathogenesis, as demonstrated by the efficacy of the B-cell-depleting agent, rituximab. However, rituximab, which is licensed for use following failure of csDMARDs and TNFi therapy, is only effective for achieving a 50% improvement in ACR response criteria at 6 months in about 30% of such patients, Dr. Pitzalis noted. In a recent early RA cohort, he and his colleagues found synovial heterogeneity, with more than half of patients showing low or no synovial B-cell infiltration.
“So why would you give them rituximab?” he asked, explaining the rationale for the R4-RA trial: The hypothesis was that alternative biologic agents targeting alternative pathways may be more effective in BCP patients.
“The results showed quite clearly that rituximab was inferior to tocilizumab in this patient group,” he said. “We demonstrated that tocilizumab is more effective than rituximab in achieving low disease activity in patients who had, on synovial biopsy, low levels of B-cell infiltration.
“The study really highlights the importance of integrating molecular pathology into the clinical algorithms, because making the diagnosis is not sufficient. We really need to know what the pathology of the patient is so we can give the right drug to the right patients.”
Donald Thomas, MD, a rheumatologist in private practice in Silver Spring, Md., called the study “fascinating,” and noted during a question-and-answer period during the press conference that, during his lifetime, he “has probably wasted tens of thousands to hundreds of thousands of dollars,” using the trial-and-error approach to treatment.
“We can only treat by trial and error ... so being able to pinpoint therapy is just phenomenal,” he added, further noting in an interview after the press conference that finding the right treatment can be “such a struggle.”
“I literally have patients who have gone through 10 medicines and wasted thousands of dollars,” he said.
In response to a question from Dr. Thomas about the potential for rheumatologists to do their own synovial biopsies to help guide treatment in the event the findings are validated, Dr. Pitzalis said that is both feasible and an important goal.
“All the biopsies [in the study] were carried out by rheumatologists,” he noted. “We have trained over 150 rheumatologists worldwide, including at 15 centers in the United States. ... We want to empower the rheumatologists to do it.”
He added that “this is early data ... and will require validation in larger trials,” but said the point is that “we can’t continue to just give these drugs and see if the patient responds.”
R4-RA is funded by the National Institute of Health Research Efficacy and Mechanism Evaluation program. Dr. Pitzalis and some of the other study authors reported financial relationships with Roche/Genentech, which markets tocilizumab and rituximab, and other pharmaceutical companies.
SOURCE: Pitzalis C et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 2911.
ATLANTA – Tocilizumab proved more effective than rituximab in B-cell-poor but not in B-cell-rich patients with RA who have had an inadequate response to disease-modifying antirheumatic drugs (DMARDs) and tumor necrosis factor inhibition in the randomized, open-label, 48-week, phase 4 R4-RA trial.
If validated, the findings of the trial – the first randomized, controlled, biopsy-driven trial in RA – could have “massive implications” for treatment selection and improved outcomes, Constantino Pitzalis, MD, reported during a press conference at the annual meeting of the American College of Rheumatology.
Of 164 RA patients who were failing or intolerant to conventional synthetic (cs) DMARD therapy and at least one tumor necrosis factor inhibitor (TNFi), 83 were randomized to receive rituximab and 81 received tocilizumab. Of those patients, 49.1% were considered B-cell poor (BCP) based on synovial tissue biopsies obtained at trial entry.
The BCP patients treated with tocilizumab were numerically more likely than those treated with rituximab to achieve the coprimary endpoint of Clinical Disease Activity Index (CDAI) improvement of at least 50% from baseline at 16 weeks (56.1% vs. 44.7%), and they were significantly more likely – twice as likely, in fact – to achieve the coprimary endpoint of CDAI improvement of at least 50% from baseline at 16 weeks as well as CDAI score less than 10, indicating a major treatment response (46.3% vs. 23.7%), said Dr. Pitzalis, head of the Centre for Experimental Medicine & Rheumatology at Queen Mary University of London.
BCP patients receiving tocilizumab also were significantly more likely to achieve a number of secondary endpoints, he noted.
In the B-cell-rich (BCR) population, no significant differences were seen in the majority of endpoints with tocilizumab versus rituximab, he said.
Study participants had a mean age of 55-56 years and were intolerant of or refractory to csDMARDs and at least one TNFi. They were recruited from 19 centers in Europe, were randomized and treated with standard doses of rituximab or tocilizumab, and were stratified based on histologic classification (BCP vs. BCR). Baseline characteristics were comparable among the treatment groups, Dr. Pitzalis said.
Adverse events occurred in 62 and 68 patients in the rituximab and tocilizumab groups, respectively, and serious adverse events occurred in 8 and 12 patients, respectively, thus 40% of all serious adverse events occurred in the rituximab group and 60% in the tocilizumab group. Infections and serious infections each occurred in three patients in each group, and two patients in each group discontinued treatment because of adverse events.
B cells are pivotal to RA pathogenesis, as demonstrated by the efficacy of the B-cell-depleting agent, rituximab. However, rituximab, which is licensed for use following failure of csDMARDs and TNFi therapy, is only effective for achieving a 50% improvement in ACR response criteria at 6 months in about 30% of such patients, Dr. Pitzalis noted. In a recent early RA cohort, he and his colleagues found synovial heterogeneity, with more than half of patients showing low or no synovial B-cell infiltration.
“So why would you give them rituximab?” he asked, explaining the rationale for the R4-RA trial: The hypothesis was that alternative biologic agents targeting alternative pathways may be more effective in BCP patients.
“The results showed quite clearly that rituximab was inferior to tocilizumab in this patient group,” he said. “We demonstrated that tocilizumab is more effective than rituximab in achieving low disease activity in patients who had, on synovial biopsy, low levels of B-cell infiltration.
“The study really highlights the importance of integrating molecular pathology into the clinical algorithms, because making the diagnosis is not sufficient. We really need to know what the pathology of the patient is so we can give the right drug to the right patients.”
Donald Thomas, MD, a rheumatologist in private practice in Silver Spring, Md., called the study “fascinating,” and noted during a question-and-answer period during the press conference that, during his lifetime, he “has probably wasted tens of thousands to hundreds of thousands of dollars,” using the trial-and-error approach to treatment.
“We can only treat by trial and error ... so being able to pinpoint therapy is just phenomenal,” he added, further noting in an interview after the press conference that finding the right treatment can be “such a struggle.”
“I literally have patients who have gone through 10 medicines and wasted thousands of dollars,” he said.
In response to a question from Dr. Thomas about the potential for rheumatologists to do their own synovial biopsies to help guide treatment in the event the findings are validated, Dr. Pitzalis said that is both feasible and an important goal.
“All the biopsies [in the study] were carried out by rheumatologists,” he noted. “We have trained over 150 rheumatologists worldwide, including at 15 centers in the United States. ... We want to empower the rheumatologists to do it.”
He added that “this is early data ... and will require validation in larger trials,” but said the point is that “we can’t continue to just give these drugs and see if the patient responds.”
R4-RA is funded by the National Institute of Health Research Efficacy and Mechanism Evaluation program. Dr. Pitzalis and some of the other study authors reported financial relationships with Roche/Genentech, which markets tocilizumab and rituximab, and other pharmaceutical companies.
SOURCE: Pitzalis C et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 2911.
REPORTING FROM ACR 2019
Worse air quality linked to premature deaths
, according to a working paper issued by the National Bureau of Economic Research.
The increase in air pollution, defined as the amount of fine particulate matter (PM2.5) in the air, was associated with an additional 9,700 premature deaths from 2016 to 2018, representing damages totaling $89 billion, wrote Karen Clay and Nicholas C. Miller of Carnegie Mellon University, Pittsburgh. The increase may reflect in part the impact of the a major wildfire that occurred in the fall of 2018.
“These increases are worrisome, because previous studies have shown that PM2.5 increases premature mortality risk,” the researchers wrote. To assess the changes in air quality, they reviewed data from the Air Quality System (AQS) database including total PM2.5 and three PM2.5 species: ammonium nitrate, sulfate, and elemental carbon.
To examine the impact of pollution on public health, the researchers used data from the damage function approach used in the Environmental Protection Agency’s Benefit-Cost Analysis of the Clean Air Act, the Regulatory Impact Analysis for PM2.5, and multiple academic studies.
The number of premature deaths linked to PM2.5 increased by approximately 4,900 between 2016 and 2017 and by 9,700 from 2016 to 2018 in U.S. counties with monitors.
Elderly individuals are especially vulnerable to particulate matter exposure and experience approximately 80% of the burden of disease related to pollution, the researchers said.
“While some deaths among the elderly are shifted by days or weeks, recent research suggests that the burden is ‘concentrated among the elderly with 5-10 years of remaining life expectancy, followed by those with 2-5 years remaining, because these groups represent a large fraction of the Medicare population and are also vulnerable to acute particulate matter exposure,’” they said.
Overall, pollution levels across the United States stopped declining in 2016. When broken down by four Census regions, no change in PM2.5 levels occurred in the Northeast and South between 2016 and 2018; the Midwest and West showed increases in PM2.5 of 9.3% and 11.5%, respectively.
The researchers suggested three possible factors affecting the increase in pollution: economic activity, wildfires, and air quality enforcement. They noted that increases in PM2.5 were especially high in California, and that California accounted for 43% of the increase in pollution-related premature deaths nationwide between 2016 and 2018. When the researchers examined PM2.5 month by month, “November 2018 had an outsized effect on our mortality calculations,” largely because the devastating Camp Fire occurred in California at that time, they said.
With regard to the impact of economic activity on pollution, the researchers reviewed data from the National Highway Administration and Energy Information Administration that showed increased use of natural gas and increased vehicle travel as contributing to higher levels of nitrate and elemental carbon in the air.
Finally, the researchers reported that enforcement of the Clean Air Act appeared to have declined since 2013, and this decline, although it might reflect increased compliance in some areas “is concerning in light of the increases in air pollution in both attainment and nonattainment counties after 2016,” they said.
The researchers had no financial conflicts to disclose.
SOURCE: Clay K, Miller NZ. NBER 2019. Working Paper 26381. doi: 10.3386/w26381.
, according to a working paper issued by the National Bureau of Economic Research.
The increase in air pollution, defined as the amount of fine particulate matter (PM2.5) in the air, was associated with an additional 9,700 premature deaths from 2016 to 2018, representing damages totaling $89 billion, wrote Karen Clay and Nicholas C. Miller of Carnegie Mellon University, Pittsburgh. The increase may reflect in part the impact of the a major wildfire that occurred in the fall of 2018.
“These increases are worrisome, because previous studies have shown that PM2.5 increases premature mortality risk,” the researchers wrote. To assess the changes in air quality, they reviewed data from the Air Quality System (AQS) database including total PM2.5 and three PM2.5 species: ammonium nitrate, sulfate, and elemental carbon.
To examine the impact of pollution on public health, the researchers used data from the damage function approach used in the Environmental Protection Agency’s Benefit-Cost Analysis of the Clean Air Act, the Regulatory Impact Analysis for PM2.5, and multiple academic studies.
The number of premature deaths linked to PM2.5 increased by approximately 4,900 between 2016 and 2017 and by 9,700 from 2016 to 2018 in U.S. counties with monitors.
Elderly individuals are especially vulnerable to particulate matter exposure and experience approximately 80% of the burden of disease related to pollution, the researchers said.
“While some deaths among the elderly are shifted by days or weeks, recent research suggests that the burden is ‘concentrated among the elderly with 5-10 years of remaining life expectancy, followed by those with 2-5 years remaining, because these groups represent a large fraction of the Medicare population and are also vulnerable to acute particulate matter exposure,’” they said.
Overall, pollution levels across the United States stopped declining in 2016. When broken down by four Census regions, no change in PM2.5 levels occurred in the Northeast and South between 2016 and 2018; the Midwest and West showed increases in PM2.5 of 9.3% and 11.5%, respectively.
The researchers suggested three possible factors affecting the increase in pollution: economic activity, wildfires, and air quality enforcement. They noted that increases in PM2.5 were especially high in California, and that California accounted for 43% of the increase in pollution-related premature deaths nationwide between 2016 and 2018. When the researchers examined PM2.5 month by month, “November 2018 had an outsized effect on our mortality calculations,” largely because the devastating Camp Fire occurred in California at that time, they said.
With regard to the impact of economic activity on pollution, the researchers reviewed data from the National Highway Administration and Energy Information Administration that showed increased use of natural gas and increased vehicle travel as contributing to higher levels of nitrate and elemental carbon in the air.
Finally, the researchers reported that enforcement of the Clean Air Act appeared to have declined since 2013, and this decline, although it might reflect increased compliance in some areas “is concerning in light of the increases in air pollution in both attainment and nonattainment counties after 2016,” they said.
The researchers had no financial conflicts to disclose.
SOURCE: Clay K, Miller NZ. NBER 2019. Working Paper 26381. doi: 10.3386/w26381.
, according to a working paper issued by the National Bureau of Economic Research.
The increase in air pollution, defined as the amount of fine particulate matter (PM2.5) in the air, was associated with an additional 9,700 premature deaths from 2016 to 2018, representing damages totaling $89 billion, wrote Karen Clay and Nicholas C. Miller of Carnegie Mellon University, Pittsburgh. The increase may reflect in part the impact of the a major wildfire that occurred in the fall of 2018.
“These increases are worrisome, because previous studies have shown that PM2.5 increases premature mortality risk,” the researchers wrote. To assess the changes in air quality, they reviewed data from the Air Quality System (AQS) database including total PM2.5 and three PM2.5 species: ammonium nitrate, sulfate, and elemental carbon.
To examine the impact of pollution on public health, the researchers used data from the damage function approach used in the Environmental Protection Agency’s Benefit-Cost Analysis of the Clean Air Act, the Regulatory Impact Analysis for PM2.5, and multiple academic studies.
The number of premature deaths linked to PM2.5 increased by approximately 4,900 between 2016 and 2017 and by 9,700 from 2016 to 2018 in U.S. counties with monitors.
Elderly individuals are especially vulnerable to particulate matter exposure and experience approximately 80% of the burden of disease related to pollution, the researchers said.
“While some deaths among the elderly are shifted by days or weeks, recent research suggests that the burden is ‘concentrated among the elderly with 5-10 years of remaining life expectancy, followed by those with 2-5 years remaining, because these groups represent a large fraction of the Medicare population and are also vulnerable to acute particulate matter exposure,’” they said.
Overall, pollution levels across the United States stopped declining in 2016. When broken down by four Census regions, no change in PM2.5 levels occurred in the Northeast and South between 2016 and 2018; the Midwest and West showed increases in PM2.5 of 9.3% and 11.5%, respectively.
The researchers suggested three possible factors affecting the increase in pollution: economic activity, wildfires, and air quality enforcement. They noted that increases in PM2.5 were especially high in California, and that California accounted for 43% of the increase in pollution-related premature deaths nationwide between 2016 and 2018. When the researchers examined PM2.5 month by month, “November 2018 had an outsized effect on our mortality calculations,” largely because the devastating Camp Fire occurred in California at that time, they said.
With regard to the impact of economic activity on pollution, the researchers reviewed data from the National Highway Administration and Energy Information Administration that showed increased use of natural gas and increased vehicle travel as contributing to higher levels of nitrate and elemental carbon in the air.
Finally, the researchers reported that enforcement of the Clean Air Act appeared to have declined since 2013, and this decline, although it might reflect increased compliance in some areas “is concerning in light of the increases in air pollution in both attainment and nonattainment counties after 2016,” they said.
The researchers had no financial conflicts to disclose.
SOURCE: Clay K, Miller NZ. NBER 2019. Working Paper 26381. doi: 10.3386/w26381.
FROM AN NBER AIR QUALITY STUDY
Don’t leave dermatomyositis to the rheumatologists
LAS VEGAS – When she brings up dermatomyositis in the context of dermatology, Alisa Femia, MD, often hears from trainees and medical students who assume that this is a condition for rheumatologists to diagnose and treat. That’s not true: Dermatologists need to watch for this potentially fatal connective tissue disorder because they may see it first, she said at Skin Disease Education Foundation’s annual Las Vegas Dermatology Seminar.
“A fifth are clinically amyopathic,” and they may not initially see a rheumatologist, said Dr. Femia, director of inpatient dermatology at the department of dermatology, New York University. “They have normal muscle enzymes and no muscle weakness. It really puts them in our care as dermatologists.”
The challenge is that patient presentations can be subtle, but the stakes may be high, she added. “If we catch them early and treat some of these patients aggressively, we can save their lives.”
During the presentation, :
- Don’t rely on tests like biopsies to absolutely tell you what’s going on. “Clinical examination is the most important test to establish the diagnosis,” she said. “If you’re suspecting dermatomyositis ... get the patient in a gown [for a full-body exam] and look for all the signs that might not be as prominent as they are in our textbooks.”
- Look for the “butterfly” rash on the midface that is unique because it spares the nasolabial folds. “It looks like someone took an eraser and wiped out those areas,” Dr. Femia said. “This is important to help us nail down the diagnosis.”
- Other telltale signs, she said, include erythema on the extensor surfaces of digits, severe itching in the scalp, and a rash on the eyelids.
- Be aware of pulmonary involvement, including interstitial lung disease. In some cases, patients and their physicians wrongly believe that patients with dermatomyositis have asthma or pneumonia. “Pulmonologists are not necessarily aware of lung disease associated with dermatomyositis,” she said.
It’s wise to refer patients with dermatomyositis for malignancy and lung disease screening even if they don’t show signs of muscular involvement. “There’s no significant difference in rates of malignancy or lung disease in classic versus amyopathic dermatomyositis.”
Keep the MDA5 form of dermatomyositis in mind, Dr. Femia said. Anti–melanoma differentiation–associated gene 5 dermatomyositis is linked to rapidly progressive interstitial lung disease, alopecia, arthritis and oral lacerations. “Initially, it can have features of lupus, and the patient can be on immunosuppressive therapy, which mitigates diagnostic findings.”
Dr. Femia disclosed serving as principal investigator for a clinical trial in cutaneous dermatomyositis therapy.
SDEF and this news organization are owned by the same parent company.
LAS VEGAS – When she brings up dermatomyositis in the context of dermatology, Alisa Femia, MD, often hears from trainees and medical students who assume that this is a condition for rheumatologists to diagnose and treat. That’s not true: Dermatologists need to watch for this potentially fatal connective tissue disorder because they may see it first, she said at Skin Disease Education Foundation’s annual Las Vegas Dermatology Seminar.
“A fifth are clinically amyopathic,” and they may not initially see a rheumatologist, said Dr. Femia, director of inpatient dermatology at the department of dermatology, New York University. “They have normal muscle enzymes and no muscle weakness. It really puts them in our care as dermatologists.”
The challenge is that patient presentations can be subtle, but the stakes may be high, she added. “If we catch them early and treat some of these patients aggressively, we can save their lives.”
During the presentation, :
- Don’t rely on tests like biopsies to absolutely tell you what’s going on. “Clinical examination is the most important test to establish the diagnosis,” she said. “If you’re suspecting dermatomyositis ... get the patient in a gown [for a full-body exam] and look for all the signs that might not be as prominent as they are in our textbooks.”
- Look for the “butterfly” rash on the midface that is unique because it spares the nasolabial folds. “It looks like someone took an eraser and wiped out those areas,” Dr. Femia said. “This is important to help us nail down the diagnosis.”
- Other telltale signs, she said, include erythema on the extensor surfaces of digits, severe itching in the scalp, and a rash on the eyelids.
- Be aware of pulmonary involvement, including interstitial lung disease. In some cases, patients and their physicians wrongly believe that patients with dermatomyositis have asthma or pneumonia. “Pulmonologists are not necessarily aware of lung disease associated with dermatomyositis,” she said.
It’s wise to refer patients with dermatomyositis for malignancy and lung disease screening even if they don’t show signs of muscular involvement. “There’s no significant difference in rates of malignancy or lung disease in classic versus amyopathic dermatomyositis.”
Keep the MDA5 form of dermatomyositis in mind, Dr. Femia said. Anti–melanoma differentiation–associated gene 5 dermatomyositis is linked to rapidly progressive interstitial lung disease, alopecia, arthritis and oral lacerations. “Initially, it can have features of lupus, and the patient can be on immunosuppressive therapy, which mitigates diagnostic findings.”
Dr. Femia disclosed serving as principal investigator for a clinical trial in cutaneous dermatomyositis therapy.
SDEF and this news organization are owned by the same parent company.
LAS VEGAS – When she brings up dermatomyositis in the context of dermatology, Alisa Femia, MD, often hears from trainees and medical students who assume that this is a condition for rheumatologists to diagnose and treat. That’s not true: Dermatologists need to watch for this potentially fatal connective tissue disorder because they may see it first, she said at Skin Disease Education Foundation’s annual Las Vegas Dermatology Seminar.
“A fifth are clinically amyopathic,” and they may not initially see a rheumatologist, said Dr. Femia, director of inpatient dermatology at the department of dermatology, New York University. “They have normal muscle enzymes and no muscle weakness. It really puts them in our care as dermatologists.”
The challenge is that patient presentations can be subtle, but the stakes may be high, she added. “If we catch them early and treat some of these patients aggressively, we can save their lives.”
During the presentation, :
- Don’t rely on tests like biopsies to absolutely tell you what’s going on. “Clinical examination is the most important test to establish the diagnosis,” she said. “If you’re suspecting dermatomyositis ... get the patient in a gown [for a full-body exam] and look for all the signs that might not be as prominent as they are in our textbooks.”
- Look for the “butterfly” rash on the midface that is unique because it spares the nasolabial folds. “It looks like someone took an eraser and wiped out those areas,” Dr. Femia said. “This is important to help us nail down the diagnosis.”
- Other telltale signs, she said, include erythema on the extensor surfaces of digits, severe itching in the scalp, and a rash on the eyelids.
- Be aware of pulmonary involvement, including interstitial lung disease. In some cases, patients and their physicians wrongly believe that patients with dermatomyositis have asthma or pneumonia. “Pulmonologists are not necessarily aware of lung disease associated with dermatomyositis,” she said.
It’s wise to refer patients with dermatomyositis for malignancy and lung disease screening even if they don’t show signs of muscular involvement. “There’s no significant difference in rates of malignancy or lung disease in classic versus amyopathic dermatomyositis.”
Keep the MDA5 form of dermatomyositis in mind, Dr. Femia said. Anti–melanoma differentiation–associated gene 5 dermatomyositis is linked to rapidly progressive interstitial lung disease, alopecia, arthritis and oral lacerations. “Initially, it can have features of lupus, and the patient can be on immunosuppressive therapy, which mitigates diagnostic findings.”
Dr. Femia disclosed serving as principal investigator for a clinical trial in cutaneous dermatomyositis therapy.
SDEF and this news organization are owned by the same parent company.
REPORTING FROM SDEF LAS VEGAS DERMATOLOGY SEMINAR