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Blunted cardiac reserve strongly predicts incident hepatorenal syndrome
VIENNA – Patients with cirrhosis and undergoing work-up for a possible liver transplant who had low cardiac reserve had a nearly fourfold increased rate of developing hepatorenal syndrome (HRS) during an average 17 months of follow-up, compared with patients with normal cardiac reserve, in a review of 560 Australian patients assessed for a possible liver transplant.
The findings suggest that patients with advanced liver disease should routinely undergo assessment for low cardiac reserve, Anoop N. Koshy, MBBS, said at the meeting sponsored by the European Association for the Study of the Liver.
said Dr. Koshy, a cardiologist with Austin Health in Melbourne. “We propose that it’s not low cardiac output that leads to HRS, but an inability of patients to increase their cardiac output” in response to usual stimuli.
The findings also add to the concerns about using nonselective beta-blocker drugs in patients with cirrhosis because of the potential of these drugs to further blunt increases in cardiac output; they also suggest that noninvasive measurement of cardiac reserve could identify patients with low cardiac reserve who could benefit from closer monitoring and new approaches to treatment, he suggested. About 10%-30% of patients with cirrhosis develop HRS, and the new finding suggests a noninvasive way to identify patients with the highest risk for this complication.
The study included 560 consecutive patients with cirrhosis and end-stage liver disease who were awaiting a liver transplant at the Victoria Liver Transplant Unit in Melbourne and underwent assessment by stress echocardiography using low-dose dobutamine (10 mcg/kg per min) during 2010-2017 as part of their standard pretransplant work-up. Exclusion of patients with known cardiac disease prior to their stress echo examination or incomplete measurement left 488 patients, of whom 424 were free from HRS at baseline. Patients with HRS at the time of their stress echo assessment had on average a cardiac output that was about 25% higher than patients without HRS, a statistically significant difference driven by both a significantly increased heart rate and stroke volume.
Among the 424 patients free from HRS at baseline, 85 developed HRS during an average 17-month follow-up. Patients with low cardiac reserve after dobutamine challenge, defined as an increase in cardiac output of less than 25%, had a 3.9-fold increased rate of incident HRS during follow-up, compared with patients who had a larger rise in their cardiac output after adjustment for several clinical and echocardiographic baseline variables, Dr. Koshy reported. In this analysis low cardiac reserve was the strongest predictor of subsequent HRS, he said.
Dr. Koshy had no disclosures.
SOURCE: Koshy AN et al. J Hepatol. 2019 April;70(1):e56.
Cardiovascular abnormalities develop in patients with advanced chronic liver disease to produce a hyperdynamic systemic circulation with splanchnic vasodilation, decreased systemic vascular resistance, and increased cardiac output (J Hepatol. 2018;69[4]:958-60). The term cirrhotic cardiomyopathy has also been used for the changes of systolic dysfunction with impaired cardiac contractile response to stress and altered diastolic relaxation that develops in patients with cirrhosis (J Hepatol. 2010;53[1]:179-90).
In this study by Dr. Koshy and colleagues, the inability to increase cardiac output during dobutamine stress echo (DSE) was associated with a greater subsequent risk for hepatorenal syndrome (J Hepatol. 2019;70:e56).
All patients in the study were undergoing pretransplant liver evaluation. Those who developed hepatorenal syndrome (HRS) in follow-up had a higher mean cardiac output with a reduction of the increase in cardiac output that follows dobutamine administration when compared with those who did not develop HRS. A multivariate analysis that adjusted for age, gender, MELD score, and Child-Pugh score found that “impaired contractile response was the strongest predictor of hepatorenal syndrome” as defined by a less than 22% increase in cardiac output following dobutamine. Overall, 40% of those with impaired contractile reserve developed hepatorenal syndrome, compared with 25% of those with normal contractile reserve following dobutamine (P = .006). It is of interest that cirrhotic patients with HRS at the time of initial dobutamine stress echo had a 25% higher average cardiac output than those without HRS. Patients who subsequently developed hepatorenal syndrome also had higher average cardiac output at initial evaluation than those who did not.
This study continues to raise important questions about the role of cardiovascular dysfunction and the risk of hepatorenal syndrome. Additional studies seem warranted to evaluate progression of cardiac changes and dobutamine response throughout follow-up of end-stage liver disease patients, including at the development of hepatorenal syndrome. Studies of HRS patients with specific associations such as sepsis, spontaneous bacterial peritonitis, and gastrointestinal bleeding may also provide information on the role of systolic and diastolic dysfunction during such events.
This article also draws attention to “concerns about using nonselective beta-blocker drugs in patients with cirrhosis.” Current data indicate that nonselective beta-blockers reduce all-cause mortality and the risk of first variceal hemorrhage in patients with advanced liver disease (Hepatology. 2019;69[4]:1657-75). Until we have studies that reveal a clear association between beta-blockers and development of hepatorenal syndrome, I will continue to recommend the use of beta-blockers in cirrhotic patients at risk for first variceal hemorrhage.
Rowen K. Zetterman, MD, is dean emeritus of the Creighton University School of Medicine in Omaha, Neb. He serves as the Associate Vice Chancellor for Academic Affairs and the Associate Vice Chancellor for Planning at the University of Nebraska Medical Center in Omaha. Dr. Zetterman, a gastroenterologist and hepatologist, is also a member of the editorial advisory board of Internal Medicine News.
Cardiovascular abnormalities develop in patients with advanced chronic liver disease to produce a hyperdynamic systemic circulation with splanchnic vasodilation, decreased systemic vascular resistance, and increased cardiac output (J Hepatol. 2018;69[4]:958-60). The term cirrhotic cardiomyopathy has also been used for the changes of systolic dysfunction with impaired cardiac contractile response to stress and altered diastolic relaxation that develops in patients with cirrhosis (J Hepatol. 2010;53[1]:179-90).
In this study by Dr. Koshy and colleagues, the inability to increase cardiac output during dobutamine stress echo (DSE) was associated with a greater subsequent risk for hepatorenal syndrome (J Hepatol. 2019;70:e56).
All patients in the study were undergoing pretransplant liver evaluation. Those who developed hepatorenal syndrome (HRS) in follow-up had a higher mean cardiac output with a reduction of the increase in cardiac output that follows dobutamine administration when compared with those who did not develop HRS. A multivariate analysis that adjusted for age, gender, MELD score, and Child-Pugh score found that “impaired contractile response was the strongest predictor of hepatorenal syndrome” as defined by a less than 22% increase in cardiac output following dobutamine. Overall, 40% of those with impaired contractile reserve developed hepatorenal syndrome, compared with 25% of those with normal contractile reserve following dobutamine (P = .006). It is of interest that cirrhotic patients with HRS at the time of initial dobutamine stress echo had a 25% higher average cardiac output than those without HRS. Patients who subsequently developed hepatorenal syndrome also had higher average cardiac output at initial evaluation than those who did not.
This study continues to raise important questions about the role of cardiovascular dysfunction and the risk of hepatorenal syndrome. Additional studies seem warranted to evaluate progression of cardiac changes and dobutamine response throughout follow-up of end-stage liver disease patients, including at the development of hepatorenal syndrome. Studies of HRS patients with specific associations such as sepsis, spontaneous bacterial peritonitis, and gastrointestinal bleeding may also provide information on the role of systolic and diastolic dysfunction during such events.
This article also draws attention to “concerns about using nonselective beta-blocker drugs in patients with cirrhosis.” Current data indicate that nonselective beta-blockers reduce all-cause mortality and the risk of first variceal hemorrhage in patients with advanced liver disease (Hepatology. 2019;69[4]:1657-75). Until we have studies that reveal a clear association between beta-blockers and development of hepatorenal syndrome, I will continue to recommend the use of beta-blockers in cirrhotic patients at risk for first variceal hemorrhage.
Rowen K. Zetterman, MD, is dean emeritus of the Creighton University School of Medicine in Omaha, Neb. He serves as the Associate Vice Chancellor for Academic Affairs and the Associate Vice Chancellor for Planning at the University of Nebraska Medical Center in Omaha. Dr. Zetterman, a gastroenterologist and hepatologist, is also a member of the editorial advisory board of Internal Medicine News.
Cardiovascular abnormalities develop in patients with advanced chronic liver disease to produce a hyperdynamic systemic circulation with splanchnic vasodilation, decreased systemic vascular resistance, and increased cardiac output (J Hepatol. 2018;69[4]:958-60). The term cirrhotic cardiomyopathy has also been used for the changes of systolic dysfunction with impaired cardiac contractile response to stress and altered diastolic relaxation that develops in patients with cirrhosis (J Hepatol. 2010;53[1]:179-90).
In this study by Dr. Koshy and colleagues, the inability to increase cardiac output during dobutamine stress echo (DSE) was associated with a greater subsequent risk for hepatorenal syndrome (J Hepatol. 2019;70:e56).
All patients in the study were undergoing pretransplant liver evaluation. Those who developed hepatorenal syndrome (HRS) in follow-up had a higher mean cardiac output with a reduction of the increase in cardiac output that follows dobutamine administration when compared with those who did not develop HRS. A multivariate analysis that adjusted for age, gender, MELD score, and Child-Pugh score found that “impaired contractile response was the strongest predictor of hepatorenal syndrome” as defined by a less than 22% increase in cardiac output following dobutamine. Overall, 40% of those with impaired contractile reserve developed hepatorenal syndrome, compared with 25% of those with normal contractile reserve following dobutamine (P = .006). It is of interest that cirrhotic patients with HRS at the time of initial dobutamine stress echo had a 25% higher average cardiac output than those without HRS. Patients who subsequently developed hepatorenal syndrome also had higher average cardiac output at initial evaluation than those who did not.
This study continues to raise important questions about the role of cardiovascular dysfunction and the risk of hepatorenal syndrome. Additional studies seem warranted to evaluate progression of cardiac changes and dobutamine response throughout follow-up of end-stage liver disease patients, including at the development of hepatorenal syndrome. Studies of HRS patients with specific associations such as sepsis, spontaneous bacterial peritonitis, and gastrointestinal bleeding may also provide information on the role of systolic and diastolic dysfunction during such events.
This article also draws attention to “concerns about using nonselective beta-blocker drugs in patients with cirrhosis.” Current data indicate that nonselective beta-blockers reduce all-cause mortality and the risk of first variceal hemorrhage in patients with advanced liver disease (Hepatology. 2019;69[4]:1657-75). Until we have studies that reveal a clear association between beta-blockers and development of hepatorenal syndrome, I will continue to recommend the use of beta-blockers in cirrhotic patients at risk for first variceal hemorrhage.
Rowen K. Zetterman, MD, is dean emeritus of the Creighton University School of Medicine in Omaha, Neb. He serves as the Associate Vice Chancellor for Academic Affairs and the Associate Vice Chancellor for Planning at the University of Nebraska Medical Center in Omaha. Dr. Zetterman, a gastroenterologist and hepatologist, is also a member of the editorial advisory board of Internal Medicine News.
VIENNA – Patients with cirrhosis and undergoing work-up for a possible liver transplant who had low cardiac reserve had a nearly fourfold increased rate of developing hepatorenal syndrome (HRS) during an average 17 months of follow-up, compared with patients with normal cardiac reserve, in a review of 560 Australian patients assessed for a possible liver transplant.
The findings suggest that patients with advanced liver disease should routinely undergo assessment for low cardiac reserve, Anoop N. Koshy, MBBS, said at the meeting sponsored by the European Association for the Study of the Liver.
said Dr. Koshy, a cardiologist with Austin Health in Melbourne. “We propose that it’s not low cardiac output that leads to HRS, but an inability of patients to increase their cardiac output” in response to usual stimuli.
The findings also add to the concerns about using nonselective beta-blocker drugs in patients with cirrhosis because of the potential of these drugs to further blunt increases in cardiac output; they also suggest that noninvasive measurement of cardiac reserve could identify patients with low cardiac reserve who could benefit from closer monitoring and new approaches to treatment, he suggested. About 10%-30% of patients with cirrhosis develop HRS, and the new finding suggests a noninvasive way to identify patients with the highest risk for this complication.
The study included 560 consecutive patients with cirrhosis and end-stage liver disease who were awaiting a liver transplant at the Victoria Liver Transplant Unit in Melbourne and underwent assessment by stress echocardiography using low-dose dobutamine (10 mcg/kg per min) during 2010-2017 as part of their standard pretransplant work-up. Exclusion of patients with known cardiac disease prior to their stress echo examination or incomplete measurement left 488 patients, of whom 424 were free from HRS at baseline. Patients with HRS at the time of their stress echo assessment had on average a cardiac output that was about 25% higher than patients without HRS, a statistically significant difference driven by both a significantly increased heart rate and stroke volume.
Among the 424 patients free from HRS at baseline, 85 developed HRS during an average 17-month follow-up. Patients with low cardiac reserve after dobutamine challenge, defined as an increase in cardiac output of less than 25%, had a 3.9-fold increased rate of incident HRS during follow-up, compared with patients who had a larger rise in their cardiac output after adjustment for several clinical and echocardiographic baseline variables, Dr. Koshy reported. In this analysis low cardiac reserve was the strongest predictor of subsequent HRS, he said.
Dr. Koshy had no disclosures.
SOURCE: Koshy AN et al. J Hepatol. 2019 April;70(1):e56.
VIENNA – Patients with cirrhosis and undergoing work-up for a possible liver transplant who had low cardiac reserve had a nearly fourfold increased rate of developing hepatorenal syndrome (HRS) during an average 17 months of follow-up, compared with patients with normal cardiac reserve, in a review of 560 Australian patients assessed for a possible liver transplant.
The findings suggest that patients with advanced liver disease should routinely undergo assessment for low cardiac reserve, Anoop N. Koshy, MBBS, said at the meeting sponsored by the European Association for the Study of the Liver.
said Dr. Koshy, a cardiologist with Austin Health in Melbourne. “We propose that it’s not low cardiac output that leads to HRS, but an inability of patients to increase their cardiac output” in response to usual stimuli.
The findings also add to the concerns about using nonselective beta-blocker drugs in patients with cirrhosis because of the potential of these drugs to further blunt increases in cardiac output; they also suggest that noninvasive measurement of cardiac reserve could identify patients with low cardiac reserve who could benefit from closer monitoring and new approaches to treatment, he suggested. About 10%-30% of patients with cirrhosis develop HRS, and the new finding suggests a noninvasive way to identify patients with the highest risk for this complication.
The study included 560 consecutive patients with cirrhosis and end-stage liver disease who were awaiting a liver transplant at the Victoria Liver Transplant Unit in Melbourne and underwent assessment by stress echocardiography using low-dose dobutamine (10 mcg/kg per min) during 2010-2017 as part of their standard pretransplant work-up. Exclusion of patients with known cardiac disease prior to their stress echo examination or incomplete measurement left 488 patients, of whom 424 were free from HRS at baseline. Patients with HRS at the time of their stress echo assessment had on average a cardiac output that was about 25% higher than patients without HRS, a statistically significant difference driven by both a significantly increased heart rate and stroke volume.
Among the 424 patients free from HRS at baseline, 85 developed HRS during an average 17-month follow-up. Patients with low cardiac reserve after dobutamine challenge, defined as an increase in cardiac output of less than 25%, had a 3.9-fold increased rate of incident HRS during follow-up, compared with patients who had a larger rise in their cardiac output after adjustment for several clinical and echocardiographic baseline variables, Dr. Koshy reported. In this analysis low cardiac reserve was the strongest predictor of subsequent HRS, he said.
Dr. Koshy had no disclosures.
SOURCE: Koshy AN et al. J Hepatol. 2019 April;70(1):e56.
REPORTING FROM ILC 2019
Are you offering vaccines to adults for these 5 conditions?
References
1. Grohskopf LA, Sokolow LZ, Broder KR, et al. Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices—United States, 2018-19 influenza season. MMWR Recomm Rep. 2018;67:1-20.
2. Liang JL, Tiwari T, Moro P, et al. Prevention of pertussis, tetanus, and diphtheria with vaccines in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2018;67:1-44.
3. Dooling KL, Guo A, Patel M, et al. Recommendations of the Advisory Committee on Immunization Practices for use of herpes zoster vaccines. MMWR Morb Mortal Wkly Rep. 2018;67:103-108.
4. Kobayashi M, Bennett NM, Gierke R, et al. Intervals between PCV13 and PPSV23 vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep. 2015;64;944-947.
5. Meites E, Kempe A, Markowitz LE. Use of a 2-dose schedule for human papillomavirus vaccination—updated recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep. 2016;65:1405-1408.
6. Adult immunization schedule. Centers for Disease Control and Prevention website. https://www.cdc.gov/vaccines/schedules/hcp/imz/adult.html. Reviewed February 5, 2019. Accessed April 23, 2019.
References
1. Grohskopf LA, Sokolow LZ, Broder KR, et al. Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices—United States, 2018-19 influenza season. MMWR Recomm Rep. 2018;67:1-20.
2. Liang JL, Tiwari T, Moro P, et al. Prevention of pertussis, tetanus, and diphtheria with vaccines in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2018;67:1-44.
3. Dooling KL, Guo A, Patel M, et al. Recommendations of the Advisory Committee on Immunization Practices for use of herpes zoster vaccines. MMWR Morb Mortal Wkly Rep. 2018;67:103-108.
4. Kobayashi M, Bennett NM, Gierke R, et al. Intervals between PCV13 and PPSV23 vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep. 2015;64;944-947.
5. Meites E, Kempe A, Markowitz LE. Use of a 2-dose schedule for human papillomavirus vaccination—updated recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep. 2016;65:1405-1408.
6. Adult immunization schedule. Centers for Disease Control and Prevention website. https://www.cdc.gov/vaccines/schedules/hcp/imz/adult.html. Reviewed February 5, 2019. Accessed April 23, 2019.
References
1. Grohskopf LA, Sokolow LZ, Broder KR, et al. Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices—United States, 2018-19 influenza season. MMWR Recomm Rep. 2018;67:1-20.
2. Liang JL, Tiwari T, Moro P, et al. Prevention of pertussis, tetanus, and diphtheria with vaccines in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2018;67:1-44.
3. Dooling KL, Guo A, Patel M, et al. Recommendations of the Advisory Committee on Immunization Practices for use of herpes zoster vaccines. MMWR Morb Mortal Wkly Rep. 2018;67:103-108.
4. Kobayashi M, Bennett NM, Gierke R, et al. Intervals between PCV13 and PPSV23 vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep. 2015;64;944-947.
5. Meites E, Kempe A, Markowitz LE. Use of a 2-dose schedule for human papillomavirus vaccination—updated recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep. 2016;65:1405-1408.
6. Adult immunization schedule. Centers for Disease Control and Prevention website. https://www.cdc.gov/vaccines/schedules/hcp/imz/adult.html. Reviewed February 5, 2019. Accessed April 23, 2019.
Gene therapy restored immunity in newly diagnosed SCID-X1
For infants with newly diagnosed X-linked severe combined immunodeficiency (SCID-X1), lentiviral gene therapy and targeted busulfan conditioning successfully induced multilineage engraftment of transduced cells, researchers reported.
By 3-4 months after infusion, seven of eight patients had normal numbers of CD3+, CD4+, and naive CD4+ T cells; normal counts of natural killer (NK) cells; and vector marking of T cells, B cells, NK cells, myeloid cells, and bone marrow progenitors, Ewelina Mamcarz, MD, of St. Jude Children’s Research Hospital in Memphis, and her associates reported in the New England Journal of Medicine.
The eighth infant at first lacked a sufficient T-cell response but responded to a boost of gene-corrected cells without busulfan conditioning.
By 6-12 months after infusion, IgM levels also had normalized in seven of the eight infants and showed polyclonal patterns without clonal dominance, according to the investigators. Among four infants who were able to stop intravenous immunoglobulin therapy, three responded to vaccinations with tetanus, diphtheria, pertussis, polio, and pneumococcal polysaccharide. Such restoration of humoral immunity “has not been achieved in previously reported trials of gene therapy for infants with newly diagnosed SCID-X1,” wrote the investigators of this dual-center, phase 1/2 study.
X-linked severe combined immunodeficiency – “bubble boy disease” – is characterized by a lack of T cells, NK cells, and B cells, and is caused by mutations in IL2RG. Some 80% of affected infants have no matched sibling donor for hematopoietic stem cell transplantation, and transplantation from other donors can produce an inadequate response and graft-versus-host disease. Prior attempts at gene therapy with gamma-retroviral vectors had led to vector-induced leukemia or had failed to induce humoral immunity or normal NK cell production.
“Our new lentiviral vector gene therapy combined with nonmyeloablative busulfan conditioning has been successful in restoring immunity in five patients 7-23 years of age in whom a previous allogeneic hematopoietic stem cell transplantation for SCID-X1 had failed,” the investigators wrote. “We hypothesized that the combination of this lentiviral vector and low-exposure busulfan administered by means of pharmacokinetic dose targeting would be safe and effective as the primary treatment in infants with newly diagnosed SCID-X1.”
Their protocol included one to two daily intravenous doses of busulfan, targeting a cumulative area under the curve of 22 mg per hr/L. They calculated the first dose by weight and age using a population-based pharmacokinetic model and adjusted the second dose based on first-dose pharmacokinetics.
After a median of 16.4 months, all infants continued to grow normally and cleared previous infections, and there were no unanticipated side effects from bone marrow harvest, busulfan conditioning, or cell infusion.
“It is hoped that durable, complete adaptive immunity will be achieved in the majority of the patients over time,” the researchers wrote.
They continue to follow the patients to assess therapeutic safety, immune durability, and persistence of the transferred gene in hematopoietic and immune cells.
Study funders included the American Lebanese Syrian Associated Charities, the National Institutes of Health, the California Institute of Regenerative Medicine, and the Assisi Foundation of Memphis. St. Jude Children’s Research Hospital has licensed the gene therapy and partnered with Mustang Bio to develop and commercialize it. Dr. Mamcarz reported receiving grant support from the study funders.
SOURCE: Mamcarz E et al. N Engl J Med. 2019; 380:1525-34.
For infants with newly diagnosed X-linked severe combined immunodeficiency (SCID-X1), lentiviral gene therapy and targeted busulfan conditioning successfully induced multilineage engraftment of transduced cells, researchers reported.
By 3-4 months after infusion, seven of eight patients had normal numbers of CD3+, CD4+, and naive CD4+ T cells; normal counts of natural killer (NK) cells; and vector marking of T cells, B cells, NK cells, myeloid cells, and bone marrow progenitors, Ewelina Mamcarz, MD, of St. Jude Children’s Research Hospital in Memphis, and her associates reported in the New England Journal of Medicine.
The eighth infant at first lacked a sufficient T-cell response but responded to a boost of gene-corrected cells without busulfan conditioning.
By 6-12 months after infusion, IgM levels also had normalized in seven of the eight infants and showed polyclonal patterns without clonal dominance, according to the investigators. Among four infants who were able to stop intravenous immunoglobulin therapy, three responded to vaccinations with tetanus, diphtheria, pertussis, polio, and pneumococcal polysaccharide. Such restoration of humoral immunity “has not been achieved in previously reported trials of gene therapy for infants with newly diagnosed SCID-X1,” wrote the investigators of this dual-center, phase 1/2 study.
X-linked severe combined immunodeficiency – “bubble boy disease” – is characterized by a lack of T cells, NK cells, and B cells, and is caused by mutations in IL2RG. Some 80% of affected infants have no matched sibling donor for hematopoietic stem cell transplantation, and transplantation from other donors can produce an inadequate response and graft-versus-host disease. Prior attempts at gene therapy with gamma-retroviral vectors had led to vector-induced leukemia or had failed to induce humoral immunity or normal NK cell production.
“Our new lentiviral vector gene therapy combined with nonmyeloablative busulfan conditioning has been successful in restoring immunity in five patients 7-23 years of age in whom a previous allogeneic hematopoietic stem cell transplantation for SCID-X1 had failed,” the investigators wrote. “We hypothesized that the combination of this lentiviral vector and low-exposure busulfan administered by means of pharmacokinetic dose targeting would be safe and effective as the primary treatment in infants with newly diagnosed SCID-X1.”
Their protocol included one to two daily intravenous doses of busulfan, targeting a cumulative area under the curve of 22 mg per hr/L. They calculated the first dose by weight and age using a population-based pharmacokinetic model and adjusted the second dose based on first-dose pharmacokinetics.
After a median of 16.4 months, all infants continued to grow normally and cleared previous infections, and there were no unanticipated side effects from bone marrow harvest, busulfan conditioning, or cell infusion.
“It is hoped that durable, complete adaptive immunity will be achieved in the majority of the patients over time,” the researchers wrote.
They continue to follow the patients to assess therapeutic safety, immune durability, and persistence of the transferred gene in hematopoietic and immune cells.
Study funders included the American Lebanese Syrian Associated Charities, the National Institutes of Health, the California Institute of Regenerative Medicine, and the Assisi Foundation of Memphis. St. Jude Children’s Research Hospital has licensed the gene therapy and partnered with Mustang Bio to develop and commercialize it. Dr. Mamcarz reported receiving grant support from the study funders.
SOURCE: Mamcarz E et al. N Engl J Med. 2019; 380:1525-34.
For infants with newly diagnosed X-linked severe combined immunodeficiency (SCID-X1), lentiviral gene therapy and targeted busulfan conditioning successfully induced multilineage engraftment of transduced cells, researchers reported.
By 3-4 months after infusion, seven of eight patients had normal numbers of CD3+, CD4+, and naive CD4+ T cells; normal counts of natural killer (NK) cells; and vector marking of T cells, B cells, NK cells, myeloid cells, and bone marrow progenitors, Ewelina Mamcarz, MD, of St. Jude Children’s Research Hospital in Memphis, and her associates reported in the New England Journal of Medicine.
The eighth infant at first lacked a sufficient T-cell response but responded to a boost of gene-corrected cells without busulfan conditioning.
By 6-12 months after infusion, IgM levels also had normalized in seven of the eight infants and showed polyclonal patterns without clonal dominance, according to the investigators. Among four infants who were able to stop intravenous immunoglobulin therapy, three responded to vaccinations with tetanus, diphtheria, pertussis, polio, and pneumococcal polysaccharide. Such restoration of humoral immunity “has not been achieved in previously reported trials of gene therapy for infants with newly diagnosed SCID-X1,” wrote the investigators of this dual-center, phase 1/2 study.
X-linked severe combined immunodeficiency – “bubble boy disease” – is characterized by a lack of T cells, NK cells, and B cells, and is caused by mutations in IL2RG. Some 80% of affected infants have no matched sibling donor for hematopoietic stem cell transplantation, and transplantation from other donors can produce an inadequate response and graft-versus-host disease. Prior attempts at gene therapy with gamma-retroviral vectors had led to vector-induced leukemia or had failed to induce humoral immunity or normal NK cell production.
“Our new lentiviral vector gene therapy combined with nonmyeloablative busulfan conditioning has been successful in restoring immunity in five patients 7-23 years of age in whom a previous allogeneic hematopoietic stem cell transplantation for SCID-X1 had failed,” the investigators wrote. “We hypothesized that the combination of this lentiviral vector and low-exposure busulfan administered by means of pharmacokinetic dose targeting would be safe and effective as the primary treatment in infants with newly diagnosed SCID-X1.”
Their protocol included one to two daily intravenous doses of busulfan, targeting a cumulative area under the curve of 22 mg per hr/L. They calculated the first dose by weight and age using a population-based pharmacokinetic model and adjusted the second dose based on first-dose pharmacokinetics.
After a median of 16.4 months, all infants continued to grow normally and cleared previous infections, and there were no unanticipated side effects from bone marrow harvest, busulfan conditioning, or cell infusion.
“It is hoped that durable, complete adaptive immunity will be achieved in the majority of the patients over time,” the researchers wrote.
They continue to follow the patients to assess therapeutic safety, immune durability, and persistence of the transferred gene in hematopoietic and immune cells.
Study funders included the American Lebanese Syrian Associated Charities, the National Institutes of Health, the California Institute of Regenerative Medicine, and the Assisi Foundation of Memphis. St. Jude Children’s Research Hospital has licensed the gene therapy and partnered with Mustang Bio to develop and commercialize it. Dr. Mamcarz reported receiving grant support from the study funders.
SOURCE: Mamcarz E et al. N Engl J Med. 2019; 380:1525-34.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
TMS is associated with improved recollection in older adults
according to a small pilot study published online ahead of print April 17 in Neurology. Stimulation also increased functional MRI signals associated with recollection throughout the hippocampal-cortical network.
“Disruption and abnormal functioning of the hippocampal-cortical network, the region of the brain involved in memory formation, has been linked to age-related memory decline, so it’s exciting to see that, by targeting this region, magnetic stimulation may help improve memory in older adults,” said Joel L. Voss, PhD, of Northwestern University in Chicago. “These results may help us better understand how this network supports memory.”
Recollection is the type of memory most impaired during normal aging. Other types of memory, such as recognition, are relatively spared. Research indicates that multiple sessions of TMS improve recollection and hippocampal-cortical network function in young adults.
Dr. Voss and colleagues performed a pilot study to evaluate whether TMS could improve recollection in older adults. They enrolled 15 cognitively normal older adults (mean age, 72.46 years) into a sham-controlled, single-blind, counterbalanced experiment. Eleven subjects were women. Participants underwent fMRI while learning objects paired with scenes and locations. Investigators administered TMS to lateral parietal locations that were based on each participant’s fMRI connectivity with the hippocampus. Using a within-subjects crossover design, Dr. Voss’s group assessed participants’ recollection and recognition memory at baseline and 24 hours and also 1 week after five consecutive daily sessions of full-intensity stimulation, compared with low-intensity sham stimulation.
At baseline, participants had impaired recollection, but not impaired recognition, compared with a historical sample of younger adults. At 24 hours, TMS provided robust recollection improvement and weak recognition improvement, compared with sham. TMS improved recollection by 31.1% from baseline, and sham yielded a nonsignificant change of −3.1%. Recollection improvements after TMS were consistent across participants. Recognition changed by a nonsignificant 2.8% following TMS and by a nonsignificant −2.9% following sham.
The investigators also found a significant and consistent increase in fMRI recollection activity for the targeted hippocampal-cortical network, but not for the control frontal-parietal network. They observed no increased fMRI activity for recognition.
“These findings demonstrate a causal link between recollection and the hippocampal-cortical network in older adults,” said Dr. Voss. “While our small study examined age-related memory loss, it did not examine this stimulation in people with memory loss from more serious conditions such as mild cognitive impairment or Alzheimer’s disease.” Furthermore, the study was designed to test for neural and behavioral target engagement, but not clinical efficacy, he added.
The study’s limitations included its small sample size, its single-site design, and its lack of active control stimulation. Nevertheless, it identified specific and consistent effects of stimulation across participants that were consistent with previous findings in younger adults. “These findings motivate future studies to optimize the effectiveness of noninvasive stimulation for treatment of age-related memory impairment and to improve mechanistic understanding of the hippocampal-cortical networks that support episodic memory across the lifespan,” said Dr. Voss.
The National Institute on Aging, as well as the Northwestern University Cognitive Neurology and Alzheimer’s Disease Center, supported the study.
SOURCE: Nilakantan AS et al. Neurology. 2019 Apr 17 doi: 10.1212/WNL.0000000000007502.
according to a small pilot study published online ahead of print April 17 in Neurology. Stimulation also increased functional MRI signals associated with recollection throughout the hippocampal-cortical network.
“Disruption and abnormal functioning of the hippocampal-cortical network, the region of the brain involved in memory formation, has been linked to age-related memory decline, so it’s exciting to see that, by targeting this region, magnetic stimulation may help improve memory in older adults,” said Joel L. Voss, PhD, of Northwestern University in Chicago. “These results may help us better understand how this network supports memory.”
Recollection is the type of memory most impaired during normal aging. Other types of memory, such as recognition, are relatively spared. Research indicates that multiple sessions of TMS improve recollection and hippocampal-cortical network function in young adults.
Dr. Voss and colleagues performed a pilot study to evaluate whether TMS could improve recollection in older adults. They enrolled 15 cognitively normal older adults (mean age, 72.46 years) into a sham-controlled, single-blind, counterbalanced experiment. Eleven subjects were women. Participants underwent fMRI while learning objects paired with scenes and locations. Investigators administered TMS to lateral parietal locations that were based on each participant’s fMRI connectivity with the hippocampus. Using a within-subjects crossover design, Dr. Voss’s group assessed participants’ recollection and recognition memory at baseline and 24 hours and also 1 week after five consecutive daily sessions of full-intensity stimulation, compared with low-intensity sham stimulation.
At baseline, participants had impaired recollection, but not impaired recognition, compared with a historical sample of younger adults. At 24 hours, TMS provided robust recollection improvement and weak recognition improvement, compared with sham. TMS improved recollection by 31.1% from baseline, and sham yielded a nonsignificant change of −3.1%. Recollection improvements after TMS were consistent across participants. Recognition changed by a nonsignificant 2.8% following TMS and by a nonsignificant −2.9% following sham.
The investigators also found a significant and consistent increase in fMRI recollection activity for the targeted hippocampal-cortical network, but not for the control frontal-parietal network. They observed no increased fMRI activity for recognition.
“These findings demonstrate a causal link between recollection and the hippocampal-cortical network in older adults,” said Dr. Voss. “While our small study examined age-related memory loss, it did not examine this stimulation in people with memory loss from more serious conditions such as mild cognitive impairment or Alzheimer’s disease.” Furthermore, the study was designed to test for neural and behavioral target engagement, but not clinical efficacy, he added.
The study’s limitations included its small sample size, its single-site design, and its lack of active control stimulation. Nevertheless, it identified specific and consistent effects of stimulation across participants that were consistent with previous findings in younger adults. “These findings motivate future studies to optimize the effectiveness of noninvasive stimulation for treatment of age-related memory impairment and to improve mechanistic understanding of the hippocampal-cortical networks that support episodic memory across the lifespan,” said Dr. Voss.
The National Institute on Aging, as well as the Northwestern University Cognitive Neurology and Alzheimer’s Disease Center, supported the study.
SOURCE: Nilakantan AS et al. Neurology. 2019 Apr 17 doi: 10.1212/WNL.0000000000007502.
according to a small pilot study published online ahead of print April 17 in Neurology. Stimulation also increased functional MRI signals associated with recollection throughout the hippocampal-cortical network.
“Disruption and abnormal functioning of the hippocampal-cortical network, the region of the brain involved in memory formation, has been linked to age-related memory decline, so it’s exciting to see that, by targeting this region, magnetic stimulation may help improve memory in older adults,” said Joel L. Voss, PhD, of Northwestern University in Chicago. “These results may help us better understand how this network supports memory.”
Recollection is the type of memory most impaired during normal aging. Other types of memory, such as recognition, are relatively spared. Research indicates that multiple sessions of TMS improve recollection and hippocampal-cortical network function in young adults.
Dr. Voss and colleagues performed a pilot study to evaluate whether TMS could improve recollection in older adults. They enrolled 15 cognitively normal older adults (mean age, 72.46 years) into a sham-controlled, single-blind, counterbalanced experiment. Eleven subjects were women. Participants underwent fMRI while learning objects paired with scenes and locations. Investigators administered TMS to lateral parietal locations that were based on each participant’s fMRI connectivity with the hippocampus. Using a within-subjects crossover design, Dr. Voss’s group assessed participants’ recollection and recognition memory at baseline and 24 hours and also 1 week after five consecutive daily sessions of full-intensity stimulation, compared with low-intensity sham stimulation.
At baseline, participants had impaired recollection, but not impaired recognition, compared with a historical sample of younger adults. At 24 hours, TMS provided robust recollection improvement and weak recognition improvement, compared with sham. TMS improved recollection by 31.1% from baseline, and sham yielded a nonsignificant change of −3.1%. Recollection improvements after TMS were consistent across participants. Recognition changed by a nonsignificant 2.8% following TMS and by a nonsignificant −2.9% following sham.
The investigators also found a significant and consistent increase in fMRI recollection activity for the targeted hippocampal-cortical network, but not for the control frontal-parietal network. They observed no increased fMRI activity for recognition.
“These findings demonstrate a causal link between recollection and the hippocampal-cortical network in older adults,” said Dr. Voss. “While our small study examined age-related memory loss, it did not examine this stimulation in people with memory loss from more serious conditions such as mild cognitive impairment or Alzheimer’s disease.” Furthermore, the study was designed to test for neural and behavioral target engagement, but not clinical efficacy, he added.
The study’s limitations included its small sample size, its single-site design, and its lack of active control stimulation. Nevertheless, it identified specific and consistent effects of stimulation across participants that were consistent with previous findings in younger adults. “These findings motivate future studies to optimize the effectiveness of noninvasive stimulation for treatment of age-related memory impairment and to improve mechanistic understanding of the hippocampal-cortical networks that support episodic memory across the lifespan,” said Dr. Voss.
The National Institute on Aging, as well as the Northwestern University Cognitive Neurology and Alzheimer’s Disease Center, supported the study.
SOURCE: Nilakantan AS et al. Neurology. 2019 Apr 17 doi: 10.1212/WNL.0000000000007502.
FROM NEUROLOGY
CMS pushing primary care with two new payment models
“We’re launching CMS Primary Cares, an initiative of two new payment models that will enroll a quarter or more of traditional Medicare beneficiaries and a quarter of providers in arrangements that pay for keeping patients healthy, rather than ordering procedures,” Alex Azar, secretary of Health and Human Services, said April 22 during a press conference.
“Today’s announcement creates innovation in primary care that has the potential to entirely transform our fee-for-service system – which is about 65% of the Medicare program – into one that drives value,” Seema Verma, administrator of the Centers for Medicare & Medicaid Services, said during the press conference.
The voluntary models are an array of “new payment options that are all designed to reward [physicians] for keeping people healthy, improving quality of life and delivering positive health outcomes,” Ms. Verma said. “These models are intended to allow clinicians to focus on patient care, not billing, and to do what they’ve been trained to do.”
One option, the Primary Care First model, is aimed at small and solo primary care practices.
The model will “provide participating practices with a predictable payment stream, including a partial cap and some fee-for-service spend,” Ms. Verma said, adding that payments will be adjusted for performance in reducing hospitalizations.
Under Primary Care First, practices will receive a flat payment per beneficiary, allowing clinicians to focus more on care than on revenue cycle management, according to CMS. Practices will be able to receive bonuses of up to 50% or penalties of up to 10%, based on performance, as an incentive to reduce costs and improve quality. Performance will be assessed and paid quarterly. Specifics on the per-beneficiary payment were not released.
Participation in Primary Care First is limited to primary care professionals certified in internal medicine, general medicine, geriatric medicine, family medicine, and hospice and palliative medicine. Practices must provide services to at least 125 Medicare beneficiaries and primary care services must account for at least 70% of billing revenue. Practices also must have experience in value-based payments.
There also will be an option for enhanced payment for caring for patients with chronic illnesses.
“When a patient stays healthy and out of the hospital, these practices will get paid a bonus,” Secretary Azar said. “But if the patient ends up sicker than expected, these practices will bear responsibility for the extra spending up to a certain share of their practices’ revenue.”
More information about participating in the Primary Care First model will be available later in the spring of 2019, with the model launching in 2020.
A second option, the Direct Contracting model is “more ambitious and aimed at larger practices,” Mr. Azar said – those that serve at least 5,000 Medicare beneficiaries.
“Just like in Primary Care First, when patients have a better experience and stay healthier, these practices will make more money,” he continued. “But if patients end up sicker, Direct Contracting Practices will bear the risk for the extra health spending, not just at their own practice, but throughout the system.”
Options under the Direct Contracting model are designed for organizations ready to take on full financial risk that have experience managing large populations with accountable care organizations or working with Medicare Advantage plans, Ms. Verma explained.
The Direct Contracting model will start with two options. The Professional population-based payment (PBP) model offers a lower risk-sharing arrangement (50% savings/losses), while the Global PBP offers a 100% savings/losses risk-sharing arrangement.
CMS also is requesting information on a third payment model, the Geographic PBP model, which would have a similar risk-sharing arrangement as the Global PBP, but participants would assume responsibility for the total cost of care for all Medicare fee-for-service beneficiaries in a defined region.
This model also will launch in 2020.
The new Medicare primary care options were commended by quarters not always supportive of the current government.
Andy Slavitt, CMS administrator under President Obama, voiced his support for the new models.
“There are several watershed moments in the history of the Medicare program, like the coverage of prescription drugs and the shift to paying for better care,” he tweeted April 22. This announcement is “another one as it eases the connection of Medicare beneficiaries to a primary care physician and gives doctors the freedom, rewards, and tools to keep people healthy.”
He continued: “With this great starting point, even as CMS listens to input, physicians and patient groups should be considering who this helps move ... to a healthier country with a more sustainable system.”
The American Medical Association also voiced its support.
“Providing adequate financial support for high-quality primary care must be an essential element of any strategy to improve the quality and affordability of our country’s health care system, Gerald E. Harmon, MD, immediate past chair of the AMA Board of Trustees, said in a statement. “Many primary care physicians have been struggling to deliver the care their patients need and to financially sustain their practices under current Medicare payments. The new primary care payment models announced today will provide practices with more resources and more flexibility to deliver the highest-quality care to their patients.”
The American College of Physicians also noted their support of the new models.
“ACP is optimistic that the new models will emphasize the important role primary care plays in value-based care delivery, that models are voluntary and have a range of risk options, and that practices should use population health management data to reap potential benefits, Robert McLean, MD, ACP president, said in a statement. “ACP is supportive of the fact that the new models aim to reduce administrative burdens – potentially allowing physicians to spend more time with their patients.
“The success and viability of these models will depend on the extent that they are supported by payers in addition to Medicare and Medicaid, are adequately adjusted for differences in the risk and health status of patients seen by each practice, are provided predictable and adequate payments to support and sustain practices (especially smaller independent ones), are appropriately scaled for the financial risk expected of a practice, are provided meaningful and timely data to support improvement, and are truly able to reduce administrative tasks and costs, among other things,” he noted.
As a primary care physician, these new payment models proposed by the Centers for Medicare and Medicaid Services sound like a dream come true. Professional organizations and advocacy groups seem to unanimously agree this is a step in the right direction. Meanwhile, there are a few caveats for primary care docs wondering how much champagne to pop: These models apply to Medicare and some Medicaid contracts. As with any payment reform, the hope is that, if successful, these precedents set by CMS will be adopted by other payers throughout the market and extend to other patients’ plans. It is unclear how this care will be integrated into practices that serve patients with a large payer mix, though it seems to be a natural progression of the Comprehensive Primary Care Plus (CPC+) model practices.
The plans are currently available only in select regions of the United States and in practices that already have the capacity to perform some less traditional care delivery models, which may include home visits, coordination of hospital discharges, telehealth, and group visits.
The measurement of value-based care will likely rely on checkboxes like hemoglobin A1c targets and prescription of statins for secondary prevention of heart disease - measures we already know may be disproportionately more difficult to achieve in the presence of unfavorable “Social Determinants of Health.” The plans account for this by allowing for additional benefit payments for practices caring for “Seriously Ill Patients” or those with “Complex Chronic” conditions. However, it looks like these patients need to be proactively identified when the plans are contracted, and it is unclear who is responsible for determining these designations and how.
Lastly, and most significantly, like the CPC+ models and other similar direct-payment models of care, the practices must agree to carry most - or all - of the financial risk of these patients. Plain and simple, for some, the cost may still be too high.
Sarah G. Candler, MD, MPH, FACP is a primary care physician in Houston.
As a primary care physician, these new payment models proposed by the Centers for Medicare and Medicaid Services sound like a dream come true. Professional organizations and advocacy groups seem to unanimously agree this is a step in the right direction. Meanwhile, there are a few caveats for primary care docs wondering how much champagne to pop: These models apply to Medicare and some Medicaid contracts. As with any payment reform, the hope is that, if successful, these precedents set by CMS will be adopted by other payers throughout the market and extend to other patients’ plans. It is unclear how this care will be integrated into practices that serve patients with a large payer mix, though it seems to be a natural progression of the Comprehensive Primary Care Plus (CPC+) model practices.
The plans are currently available only in select regions of the United States and in practices that already have the capacity to perform some less traditional care delivery models, which may include home visits, coordination of hospital discharges, telehealth, and group visits.
The measurement of value-based care will likely rely on checkboxes like hemoglobin A1c targets and prescription of statins for secondary prevention of heart disease - measures we already know may be disproportionately more difficult to achieve in the presence of unfavorable “Social Determinants of Health.” The plans account for this by allowing for additional benefit payments for practices caring for “Seriously Ill Patients” or those with “Complex Chronic” conditions. However, it looks like these patients need to be proactively identified when the plans are contracted, and it is unclear who is responsible for determining these designations and how.
Lastly, and most significantly, like the CPC+ models and other similar direct-payment models of care, the practices must agree to carry most - or all - of the financial risk of these patients. Plain and simple, for some, the cost may still be too high.
Sarah G. Candler, MD, MPH, FACP is a primary care physician in Houston.
As a primary care physician, these new payment models proposed by the Centers for Medicare and Medicaid Services sound like a dream come true. Professional organizations and advocacy groups seem to unanimously agree this is a step in the right direction. Meanwhile, there are a few caveats for primary care docs wondering how much champagne to pop: These models apply to Medicare and some Medicaid contracts. As with any payment reform, the hope is that, if successful, these precedents set by CMS will be adopted by other payers throughout the market and extend to other patients’ plans. It is unclear how this care will be integrated into practices that serve patients with a large payer mix, though it seems to be a natural progression of the Comprehensive Primary Care Plus (CPC+) model practices.
The plans are currently available only in select regions of the United States and in practices that already have the capacity to perform some less traditional care delivery models, which may include home visits, coordination of hospital discharges, telehealth, and group visits.
The measurement of value-based care will likely rely on checkboxes like hemoglobin A1c targets and prescription of statins for secondary prevention of heart disease - measures we already know may be disproportionately more difficult to achieve in the presence of unfavorable “Social Determinants of Health.” The plans account for this by allowing for additional benefit payments for practices caring for “Seriously Ill Patients” or those with “Complex Chronic” conditions. However, it looks like these patients need to be proactively identified when the plans are contracted, and it is unclear who is responsible for determining these designations and how.
Lastly, and most significantly, like the CPC+ models and other similar direct-payment models of care, the practices must agree to carry most - or all - of the financial risk of these patients. Plain and simple, for some, the cost may still be too high.
Sarah G. Candler, MD, MPH, FACP is a primary care physician in Houston.
“We’re launching CMS Primary Cares, an initiative of two new payment models that will enroll a quarter or more of traditional Medicare beneficiaries and a quarter of providers in arrangements that pay for keeping patients healthy, rather than ordering procedures,” Alex Azar, secretary of Health and Human Services, said April 22 during a press conference.
“Today’s announcement creates innovation in primary care that has the potential to entirely transform our fee-for-service system – which is about 65% of the Medicare program – into one that drives value,” Seema Verma, administrator of the Centers for Medicare & Medicaid Services, said during the press conference.
The voluntary models are an array of “new payment options that are all designed to reward [physicians] for keeping people healthy, improving quality of life and delivering positive health outcomes,” Ms. Verma said. “These models are intended to allow clinicians to focus on patient care, not billing, and to do what they’ve been trained to do.”
One option, the Primary Care First model, is aimed at small and solo primary care practices.
The model will “provide participating practices with a predictable payment stream, including a partial cap and some fee-for-service spend,” Ms. Verma said, adding that payments will be adjusted for performance in reducing hospitalizations.
Under Primary Care First, practices will receive a flat payment per beneficiary, allowing clinicians to focus more on care than on revenue cycle management, according to CMS. Practices will be able to receive bonuses of up to 50% or penalties of up to 10%, based on performance, as an incentive to reduce costs and improve quality. Performance will be assessed and paid quarterly. Specifics on the per-beneficiary payment were not released.
Participation in Primary Care First is limited to primary care professionals certified in internal medicine, general medicine, geriatric medicine, family medicine, and hospice and palliative medicine. Practices must provide services to at least 125 Medicare beneficiaries and primary care services must account for at least 70% of billing revenue. Practices also must have experience in value-based payments.
There also will be an option for enhanced payment for caring for patients with chronic illnesses.
“When a patient stays healthy and out of the hospital, these practices will get paid a bonus,” Secretary Azar said. “But if the patient ends up sicker than expected, these practices will bear responsibility for the extra spending up to a certain share of their practices’ revenue.”
More information about participating in the Primary Care First model will be available later in the spring of 2019, with the model launching in 2020.
A second option, the Direct Contracting model is “more ambitious and aimed at larger practices,” Mr. Azar said – those that serve at least 5,000 Medicare beneficiaries.
“Just like in Primary Care First, when patients have a better experience and stay healthier, these practices will make more money,” he continued. “But if patients end up sicker, Direct Contracting Practices will bear the risk for the extra health spending, not just at their own practice, but throughout the system.”
Options under the Direct Contracting model are designed for organizations ready to take on full financial risk that have experience managing large populations with accountable care organizations or working with Medicare Advantage plans, Ms. Verma explained.
The Direct Contracting model will start with two options. The Professional population-based payment (PBP) model offers a lower risk-sharing arrangement (50% savings/losses), while the Global PBP offers a 100% savings/losses risk-sharing arrangement.
CMS also is requesting information on a third payment model, the Geographic PBP model, which would have a similar risk-sharing arrangement as the Global PBP, but participants would assume responsibility for the total cost of care for all Medicare fee-for-service beneficiaries in a defined region.
This model also will launch in 2020.
The new Medicare primary care options were commended by quarters not always supportive of the current government.
Andy Slavitt, CMS administrator under President Obama, voiced his support for the new models.
“There are several watershed moments in the history of the Medicare program, like the coverage of prescription drugs and the shift to paying for better care,” he tweeted April 22. This announcement is “another one as it eases the connection of Medicare beneficiaries to a primary care physician and gives doctors the freedom, rewards, and tools to keep people healthy.”
He continued: “With this great starting point, even as CMS listens to input, physicians and patient groups should be considering who this helps move ... to a healthier country with a more sustainable system.”
The American Medical Association also voiced its support.
“Providing adequate financial support for high-quality primary care must be an essential element of any strategy to improve the quality and affordability of our country’s health care system, Gerald E. Harmon, MD, immediate past chair of the AMA Board of Trustees, said in a statement. “Many primary care physicians have been struggling to deliver the care their patients need and to financially sustain their practices under current Medicare payments. The new primary care payment models announced today will provide practices with more resources and more flexibility to deliver the highest-quality care to their patients.”
The American College of Physicians also noted their support of the new models.
“ACP is optimistic that the new models will emphasize the important role primary care plays in value-based care delivery, that models are voluntary and have a range of risk options, and that practices should use population health management data to reap potential benefits, Robert McLean, MD, ACP president, said in a statement. “ACP is supportive of the fact that the new models aim to reduce administrative burdens – potentially allowing physicians to spend more time with their patients.
“The success and viability of these models will depend on the extent that they are supported by payers in addition to Medicare and Medicaid, are adequately adjusted for differences in the risk and health status of patients seen by each practice, are provided predictable and adequate payments to support and sustain practices (especially smaller independent ones), are appropriately scaled for the financial risk expected of a practice, are provided meaningful and timely data to support improvement, and are truly able to reduce administrative tasks and costs, among other things,” he noted.
“We’re launching CMS Primary Cares, an initiative of two new payment models that will enroll a quarter or more of traditional Medicare beneficiaries and a quarter of providers in arrangements that pay for keeping patients healthy, rather than ordering procedures,” Alex Azar, secretary of Health and Human Services, said April 22 during a press conference.
“Today’s announcement creates innovation in primary care that has the potential to entirely transform our fee-for-service system – which is about 65% of the Medicare program – into one that drives value,” Seema Verma, administrator of the Centers for Medicare & Medicaid Services, said during the press conference.
The voluntary models are an array of “new payment options that are all designed to reward [physicians] for keeping people healthy, improving quality of life and delivering positive health outcomes,” Ms. Verma said. “These models are intended to allow clinicians to focus on patient care, not billing, and to do what they’ve been trained to do.”
One option, the Primary Care First model, is aimed at small and solo primary care practices.
The model will “provide participating practices with a predictable payment stream, including a partial cap and some fee-for-service spend,” Ms. Verma said, adding that payments will be adjusted for performance in reducing hospitalizations.
Under Primary Care First, practices will receive a flat payment per beneficiary, allowing clinicians to focus more on care than on revenue cycle management, according to CMS. Practices will be able to receive bonuses of up to 50% or penalties of up to 10%, based on performance, as an incentive to reduce costs and improve quality. Performance will be assessed and paid quarterly. Specifics on the per-beneficiary payment were not released.
Participation in Primary Care First is limited to primary care professionals certified in internal medicine, general medicine, geriatric medicine, family medicine, and hospice and palliative medicine. Practices must provide services to at least 125 Medicare beneficiaries and primary care services must account for at least 70% of billing revenue. Practices also must have experience in value-based payments.
There also will be an option for enhanced payment for caring for patients with chronic illnesses.
“When a patient stays healthy and out of the hospital, these practices will get paid a bonus,” Secretary Azar said. “But if the patient ends up sicker than expected, these practices will bear responsibility for the extra spending up to a certain share of their practices’ revenue.”
More information about participating in the Primary Care First model will be available later in the spring of 2019, with the model launching in 2020.
A second option, the Direct Contracting model is “more ambitious and aimed at larger practices,” Mr. Azar said – those that serve at least 5,000 Medicare beneficiaries.
“Just like in Primary Care First, when patients have a better experience and stay healthier, these practices will make more money,” he continued. “But if patients end up sicker, Direct Contracting Practices will bear the risk for the extra health spending, not just at their own practice, but throughout the system.”
Options under the Direct Contracting model are designed for organizations ready to take on full financial risk that have experience managing large populations with accountable care organizations or working with Medicare Advantage plans, Ms. Verma explained.
The Direct Contracting model will start with two options. The Professional population-based payment (PBP) model offers a lower risk-sharing arrangement (50% savings/losses), while the Global PBP offers a 100% savings/losses risk-sharing arrangement.
CMS also is requesting information on a third payment model, the Geographic PBP model, which would have a similar risk-sharing arrangement as the Global PBP, but participants would assume responsibility for the total cost of care for all Medicare fee-for-service beneficiaries in a defined region.
This model also will launch in 2020.
The new Medicare primary care options were commended by quarters not always supportive of the current government.
Andy Slavitt, CMS administrator under President Obama, voiced his support for the new models.
“There are several watershed moments in the history of the Medicare program, like the coverage of prescription drugs and the shift to paying for better care,” he tweeted April 22. This announcement is “another one as it eases the connection of Medicare beneficiaries to a primary care physician and gives doctors the freedom, rewards, and tools to keep people healthy.”
He continued: “With this great starting point, even as CMS listens to input, physicians and patient groups should be considering who this helps move ... to a healthier country with a more sustainable system.”
The American Medical Association also voiced its support.
“Providing adequate financial support for high-quality primary care must be an essential element of any strategy to improve the quality and affordability of our country’s health care system, Gerald E. Harmon, MD, immediate past chair of the AMA Board of Trustees, said in a statement. “Many primary care physicians have been struggling to deliver the care their patients need and to financially sustain their practices under current Medicare payments. The new primary care payment models announced today will provide practices with more resources and more flexibility to deliver the highest-quality care to their patients.”
The American College of Physicians also noted their support of the new models.
“ACP is optimistic that the new models will emphasize the important role primary care plays in value-based care delivery, that models are voluntary and have a range of risk options, and that practices should use population health management data to reap potential benefits, Robert McLean, MD, ACP president, said in a statement. “ACP is supportive of the fact that the new models aim to reduce administrative burdens – potentially allowing physicians to spend more time with their patients.
“The success and viability of these models will depend on the extent that they are supported by payers in addition to Medicare and Medicaid, are adequately adjusted for differences in the risk and health status of patients seen by each practice, are provided predictable and adequate payments to support and sustain practices (especially smaller independent ones), are appropriately scaled for the financial risk expected of a practice, are provided meaningful and timely data to support improvement, and are truly able to reduce administrative tasks and costs, among other things,” he noted.
Alvogen issues recall for mislabeled fentanyl patches
Alvogen has issued a voluntary recall of two lots of its Fentanyl Transdermal System 12-mcg/h transdermal patches because of a product mislabeling, according to the Food and Drug Administration.
The recall was issued because a small number of cartons labeled as containing 12-mcg/h patches contained 50-mcg/h patches. The 50-mcg/h patches were labeled as such within the package.
Application of a 50-mcg/h patch instead of a 12-mcg/h patch could result in serious, life-threatening, or fatal respiratory depression. Groups at potential risk for such adverse events include first-time users of the patch, children, and the elderly. No reports of serious adverse events have yet been reported.
“Pharmacies are requested not to dispense any product subject to this recall,” the FDA said in a press release. Patients who “have product subject to this recall should immediately remove any patch currently in use and contact their health care provider. Patients with unused product should return it to point of purchase for replacement.”
Find more information on the recall at the FDA website.
Alvogen has issued a voluntary recall of two lots of its Fentanyl Transdermal System 12-mcg/h transdermal patches because of a product mislabeling, according to the Food and Drug Administration.
The recall was issued because a small number of cartons labeled as containing 12-mcg/h patches contained 50-mcg/h patches. The 50-mcg/h patches were labeled as such within the package.
Application of a 50-mcg/h patch instead of a 12-mcg/h patch could result in serious, life-threatening, or fatal respiratory depression. Groups at potential risk for such adverse events include first-time users of the patch, children, and the elderly. No reports of serious adverse events have yet been reported.
“Pharmacies are requested not to dispense any product subject to this recall,” the FDA said in a press release. Patients who “have product subject to this recall should immediately remove any patch currently in use and contact their health care provider. Patients with unused product should return it to point of purchase for replacement.”
Find more information on the recall at the FDA website.
Alvogen has issued a voluntary recall of two lots of its Fentanyl Transdermal System 12-mcg/h transdermal patches because of a product mislabeling, according to the Food and Drug Administration.
The recall was issued because a small number of cartons labeled as containing 12-mcg/h patches contained 50-mcg/h patches. The 50-mcg/h patches were labeled as such within the package.
Application of a 50-mcg/h patch instead of a 12-mcg/h patch could result in serious, life-threatening, or fatal respiratory depression. Groups at potential risk for such adverse events include first-time users of the patch, children, and the elderly. No reports of serious adverse events have yet been reported.
“Pharmacies are requested not to dispense any product subject to this recall,” the FDA said in a press release. Patients who “have product subject to this recall should immediately remove any patch currently in use and contact their health care provider. Patients with unused product should return it to point of purchase for replacement.”
Find more information on the recall at the FDA website.
MS: Partnering With Patients to Improve Health
Sharon, a 19-year-old woman, has a history of right optic neuritis and paraparesis that occurred 2 years ago. At that time, the diagnosis of multiple sclerosis (MS) was confirmed by a brain MRI and lumbar puncture. She has been taking disease-modifying therapy for 2 years and rarely misses a dose. Lately, however, she has experienced worsening symptoms and feels that her MS is progressing. Her neurologist doesn’t agree; he informs her that a recent MRI shows no changes, and her neurologic examination is within normal limits. At his suggestion, she presents to her primary care provider for an annual check-up.
HISTORY & PHYSICAL EXAM
Sharon’s height is 5 ft 2 in and her weight, 170 lb. Her blood pressure is 140/88 mm Hg and pulse, 80 beats/min and regular. Review of systems is remarkable for fatigue, visual changes when she is overheated, and weight gain of about 50 lb during the past year. Her lungs are clear to percussion and auscultation.
Her current medications include oral disease-modifying therapy, which she takes daily; an oral contraceptive (for regulation of her menstrual cycle; she says she is not sexually active); and an occasional pain reliever for headache.
CLINICAL IMPRESSION
Following history-taking and examination, the clinician notes the following impressions about Sharon’s health status:
Obesity: Examination reveals an overweight female with a BMI of 31.1.
Physical inactivity: As a legal secretary, Sharon sits at her desk most of the day. Her exercise is limited to walking to and from the bus to get to work. She has limited time for social activities due to fatigue. She spends most of her time watching television or visiting her parents.
Heat intolerance: While describing her lifestyle, Sharon notes that she does not participate in outdoor activity due to heat intolerance.
Continue to: Ambulation difficulty
Ambulation difficulty: Sharon’s walking and balance are worse than they were 6 months ago—a problem she relates to her MS, not her increased weight. She walks with a wide-based ataxic gait and transfers with difficulty, using the arms of her chair to stand up.
Poor nutritional habits: Sharon reports an irregular diet with an occasional breakfast, a sandwich for lunch, and a microwavable meal for dinner. Between meals, she snacks on nutrition bars, chocolate, and hot and cold coffee.
Smoking: Sharon smokes 1 pack of cigarettes daily.
Headache: As noted, Sharon reports occasional analgesic use for relief of headache pain.
The clinician’s impression is as follows: relapsing MS treated with disease-modifying therapy; obesity; ambulation difficulty; heat intolerance; sedentary lifestyle; and headache. In addition, the patient has the following risk factors: smoking; suboptimal activity and exercise; and poor nutritional habits.
Continue to: DISCUSSION
DISCUSSION
Sharon has relapsing MS treated with disease-modifying therapy. But she also demonstrates or reports several independent risk factors, including borderline hypertension; obesity; inadequate diet; lack of activity and exercise; and possible lack of insight into her disease.1
The plan of care for Sharon should include a review of her MS disease course. As this is explained, it is important to emphasize how adherence to the care plan will yield positive outcomes from the treatment. For example, the patient should understand that the underlying cause of damage in MS is related to the immune system. Providing this education might involve 1 or 2 sessions with written material, simple graphics, and explanation on how disease-modifying therapies work. Even a simple statement such as
The next step is to review Sharon’s risk factors for worsening MS, along with the impact these have on her general health. This might entail a long discussion focusing on the patient’s diet, minimal activity and exercise, and smoking. Sharon’s provider explained how all 3 factors can contribute to poor general health and have been shown to negatively affect MS. There is a general impression that wellness and neurologic diseases such as MS are disconnected. The clinician must “reconnect” the 2 through encouragement, education, and coaching.
By working closely with the patient and providing the education to help her make informed decisions about her health, the clinician can develop a plan to implement that has the patient’s full support. For a patient like Sharon, this includes
- Dietary modifications to improve nutrition and promote healthy weight loss
- A program of daily walking to improve stamina and support the patient’s weight loss program2
- Smoking cessation, including participation in a local support group of former smokers.3
Continue to: In Sharon's case...
In Sharon’s case, both she and her clinician agreed that it was important to meet regularly to assess progress toward their mutually agreed-upon goals. It is not enough to devise a plan—providers need to support patients in their efforts to improve their health. Meeting regularly can motivate patients to stay on track, and it gives providers an opportunity to address problems or concerns that might interfere with the patient’s progress.
1. Dalgas U, Stenager E. Exercise and disease progression in multiple sclerosis: can exercise slow down the progression of multiple sclerosis? Ther Adv Neurol Disord. 2012;5(2):81-95.
2. Gianfrancesco MA, Barcellos LF. Obesity and multiple sclerosis susceptibility: a review. J Neurol Neuromedicine. 2016:1(7):1-5.
3. Healy BC, Eman A, Guttmann CRG, et al. Smoking and disease progression in multiple sclerosis. Arch Neurol. 2009;66(7):858-864.
Clinician Reviews in partnership with
MS Consult is edited by Colleen J. Harris, MN, NP, MSCN, Nurse Practitioner/Manager of the Multiple Sclerosis Clinic at Foothills Medical Centre in Calgary, Alberta, Canada, and Bryan Walker, MHS, PA-C, who is in the Department of Neurology, Division of MS and Neuroimmunology, at Duke University Medical Center in Durham, North Carolina.
June Halper is CEO of the Consortium of Multiple Sclerosis Centers and practices at the MS Center of the New Jersey Medical School, Rutgers University, Newark, and at primary care clinic.
Clinician Reviews in partnership with
MS Consult is edited by Colleen J. Harris, MN, NP, MSCN, Nurse Practitioner/Manager of the Multiple Sclerosis Clinic at Foothills Medical Centre in Calgary, Alberta, Canada, and Bryan Walker, MHS, PA-C, who is in the Department of Neurology, Division of MS and Neuroimmunology, at Duke University Medical Center in Durham, North Carolina.
June Halper is CEO of the Consortium of Multiple Sclerosis Centers and practices at the MS Center of the New Jersey Medical School, Rutgers University, Newark, and at primary care clinic.
Clinician Reviews in partnership with
MS Consult is edited by Colleen J. Harris, MN, NP, MSCN, Nurse Practitioner/Manager of the Multiple Sclerosis Clinic at Foothills Medical Centre in Calgary, Alberta, Canada, and Bryan Walker, MHS, PA-C, who is in the Department of Neurology, Division of MS and Neuroimmunology, at Duke University Medical Center in Durham, North Carolina.
June Halper is CEO of the Consortium of Multiple Sclerosis Centers and practices at the MS Center of the New Jersey Medical School, Rutgers University, Newark, and at primary care clinic.
Sharon, a 19-year-old woman, has a history of right optic neuritis and paraparesis that occurred 2 years ago. At that time, the diagnosis of multiple sclerosis (MS) was confirmed by a brain MRI and lumbar puncture. She has been taking disease-modifying therapy for 2 years and rarely misses a dose. Lately, however, she has experienced worsening symptoms and feels that her MS is progressing. Her neurologist doesn’t agree; he informs her that a recent MRI shows no changes, and her neurologic examination is within normal limits. At his suggestion, she presents to her primary care provider for an annual check-up.
HISTORY & PHYSICAL EXAM
Sharon’s height is 5 ft 2 in and her weight, 170 lb. Her blood pressure is 140/88 mm Hg and pulse, 80 beats/min and regular. Review of systems is remarkable for fatigue, visual changes when she is overheated, and weight gain of about 50 lb during the past year. Her lungs are clear to percussion and auscultation.
Her current medications include oral disease-modifying therapy, which she takes daily; an oral contraceptive (for regulation of her menstrual cycle; she says she is not sexually active); and an occasional pain reliever for headache.
CLINICAL IMPRESSION
Following history-taking and examination, the clinician notes the following impressions about Sharon’s health status:
Obesity: Examination reveals an overweight female with a BMI of 31.1.
Physical inactivity: As a legal secretary, Sharon sits at her desk most of the day. Her exercise is limited to walking to and from the bus to get to work. She has limited time for social activities due to fatigue. She spends most of her time watching television or visiting her parents.
Heat intolerance: While describing her lifestyle, Sharon notes that she does not participate in outdoor activity due to heat intolerance.
Continue to: Ambulation difficulty
Ambulation difficulty: Sharon’s walking and balance are worse than they were 6 months ago—a problem she relates to her MS, not her increased weight. She walks with a wide-based ataxic gait and transfers with difficulty, using the arms of her chair to stand up.
Poor nutritional habits: Sharon reports an irregular diet with an occasional breakfast, a sandwich for lunch, and a microwavable meal for dinner. Between meals, she snacks on nutrition bars, chocolate, and hot and cold coffee.
Smoking: Sharon smokes 1 pack of cigarettes daily.
Headache: As noted, Sharon reports occasional analgesic use for relief of headache pain.
The clinician’s impression is as follows: relapsing MS treated with disease-modifying therapy; obesity; ambulation difficulty; heat intolerance; sedentary lifestyle; and headache. In addition, the patient has the following risk factors: smoking; suboptimal activity and exercise; and poor nutritional habits.
Continue to: DISCUSSION
DISCUSSION
Sharon has relapsing MS treated with disease-modifying therapy. But she also demonstrates or reports several independent risk factors, including borderline hypertension; obesity; inadequate diet; lack of activity and exercise; and possible lack of insight into her disease.1
The plan of care for Sharon should include a review of her MS disease course. As this is explained, it is important to emphasize how adherence to the care plan will yield positive outcomes from the treatment. For example, the patient should understand that the underlying cause of damage in MS is related to the immune system. Providing this education might involve 1 or 2 sessions with written material, simple graphics, and explanation on how disease-modifying therapies work. Even a simple statement such as
The next step is to review Sharon’s risk factors for worsening MS, along with the impact these have on her general health. This might entail a long discussion focusing on the patient’s diet, minimal activity and exercise, and smoking. Sharon’s provider explained how all 3 factors can contribute to poor general health and have been shown to negatively affect MS. There is a general impression that wellness and neurologic diseases such as MS are disconnected. The clinician must “reconnect” the 2 through encouragement, education, and coaching.
By working closely with the patient and providing the education to help her make informed decisions about her health, the clinician can develop a plan to implement that has the patient’s full support. For a patient like Sharon, this includes
- Dietary modifications to improve nutrition and promote healthy weight loss
- A program of daily walking to improve stamina and support the patient’s weight loss program2
- Smoking cessation, including participation in a local support group of former smokers.3
Continue to: In Sharon's case...
In Sharon’s case, both she and her clinician agreed that it was important to meet regularly to assess progress toward their mutually agreed-upon goals. It is not enough to devise a plan—providers need to support patients in their efforts to improve their health. Meeting regularly can motivate patients to stay on track, and it gives providers an opportunity to address problems or concerns that might interfere with the patient’s progress.
Sharon, a 19-year-old woman, has a history of right optic neuritis and paraparesis that occurred 2 years ago. At that time, the diagnosis of multiple sclerosis (MS) was confirmed by a brain MRI and lumbar puncture. She has been taking disease-modifying therapy for 2 years and rarely misses a dose. Lately, however, she has experienced worsening symptoms and feels that her MS is progressing. Her neurologist doesn’t agree; he informs her that a recent MRI shows no changes, and her neurologic examination is within normal limits. At his suggestion, she presents to her primary care provider for an annual check-up.
HISTORY & PHYSICAL EXAM
Sharon’s height is 5 ft 2 in and her weight, 170 lb. Her blood pressure is 140/88 mm Hg and pulse, 80 beats/min and regular. Review of systems is remarkable for fatigue, visual changes when she is overheated, and weight gain of about 50 lb during the past year. Her lungs are clear to percussion and auscultation.
Her current medications include oral disease-modifying therapy, which she takes daily; an oral contraceptive (for regulation of her menstrual cycle; she says she is not sexually active); and an occasional pain reliever for headache.
CLINICAL IMPRESSION
Following history-taking and examination, the clinician notes the following impressions about Sharon’s health status:
Obesity: Examination reveals an overweight female with a BMI of 31.1.
Physical inactivity: As a legal secretary, Sharon sits at her desk most of the day. Her exercise is limited to walking to and from the bus to get to work. She has limited time for social activities due to fatigue. She spends most of her time watching television or visiting her parents.
Heat intolerance: While describing her lifestyle, Sharon notes that she does not participate in outdoor activity due to heat intolerance.
Continue to: Ambulation difficulty
Ambulation difficulty: Sharon’s walking and balance are worse than they were 6 months ago—a problem she relates to her MS, not her increased weight. She walks with a wide-based ataxic gait and transfers with difficulty, using the arms of her chair to stand up.
Poor nutritional habits: Sharon reports an irregular diet with an occasional breakfast, a sandwich for lunch, and a microwavable meal for dinner. Between meals, she snacks on nutrition bars, chocolate, and hot and cold coffee.
Smoking: Sharon smokes 1 pack of cigarettes daily.
Headache: As noted, Sharon reports occasional analgesic use for relief of headache pain.
The clinician’s impression is as follows: relapsing MS treated with disease-modifying therapy; obesity; ambulation difficulty; heat intolerance; sedentary lifestyle; and headache. In addition, the patient has the following risk factors: smoking; suboptimal activity and exercise; and poor nutritional habits.
Continue to: DISCUSSION
DISCUSSION
Sharon has relapsing MS treated with disease-modifying therapy. But she also demonstrates or reports several independent risk factors, including borderline hypertension; obesity; inadequate diet; lack of activity and exercise; and possible lack of insight into her disease.1
The plan of care for Sharon should include a review of her MS disease course. As this is explained, it is important to emphasize how adherence to the care plan will yield positive outcomes from the treatment. For example, the patient should understand that the underlying cause of damage in MS is related to the immune system. Providing this education might involve 1 or 2 sessions with written material, simple graphics, and explanation on how disease-modifying therapies work. Even a simple statement such as
The next step is to review Sharon’s risk factors for worsening MS, along with the impact these have on her general health. This might entail a long discussion focusing on the patient’s diet, minimal activity and exercise, and smoking. Sharon’s provider explained how all 3 factors can contribute to poor general health and have been shown to negatively affect MS. There is a general impression that wellness and neurologic diseases such as MS are disconnected. The clinician must “reconnect” the 2 through encouragement, education, and coaching.
By working closely with the patient and providing the education to help her make informed decisions about her health, the clinician can develop a plan to implement that has the patient’s full support. For a patient like Sharon, this includes
- Dietary modifications to improve nutrition and promote healthy weight loss
- A program of daily walking to improve stamina and support the patient’s weight loss program2
- Smoking cessation, including participation in a local support group of former smokers.3
Continue to: In Sharon's case...
In Sharon’s case, both she and her clinician agreed that it was important to meet regularly to assess progress toward their mutually agreed-upon goals. It is not enough to devise a plan—providers need to support patients in their efforts to improve their health. Meeting regularly can motivate patients to stay on track, and it gives providers an opportunity to address problems or concerns that might interfere with the patient’s progress.
1. Dalgas U, Stenager E. Exercise and disease progression in multiple sclerosis: can exercise slow down the progression of multiple sclerosis? Ther Adv Neurol Disord. 2012;5(2):81-95.
2. Gianfrancesco MA, Barcellos LF. Obesity and multiple sclerosis susceptibility: a review. J Neurol Neuromedicine. 2016:1(7):1-5.
3. Healy BC, Eman A, Guttmann CRG, et al. Smoking and disease progression in multiple sclerosis. Arch Neurol. 2009;66(7):858-864.
1. Dalgas U, Stenager E. Exercise and disease progression in multiple sclerosis: can exercise slow down the progression of multiple sclerosis? Ther Adv Neurol Disord. 2012;5(2):81-95.
2. Gianfrancesco MA, Barcellos LF. Obesity and multiple sclerosis susceptibility: a review. J Neurol Neuromedicine. 2016:1(7):1-5.
3. Healy BC, Eman A, Guttmann CRG, et al. Smoking and disease progression in multiple sclerosis. Arch Neurol. 2009;66(7):858-864.
Model inspired by Netflix, Amazon may help guide MDS treatment
NEWPORT BEACH, CALIF. — A model that mimics the recommender system used by Netflix and Amazon can help predict outcomes of lenalidomide treatment in patients with non–deletion 5q (non-del[5q]) myelodysplastic syndromes (MDS), according to new research.
The model was used to identify genomic biomarkers that were associated with resistance or response to lenalidomide. Researchers found these associations in 39% of patients with non-del(5q) MDS, and the model predicted response or resistance with 82% accuracy.
Yazan Madanat, MD, of the Cleveland Clinic, and his colleagues presented these findings at the Acute Leukemia Forum of Hemedicus.
Dr. Madanat explained that his group’s model is similar to the recommender system used by Netflix and Amazon, which makes suggestions for new products based on customers’ past behavior. Dr. Madanat and his colleagues used their model to show that patients with certain molecular or cytogenetic abnormalities are likely to respond or not respond to lenalidomide.
The researchers began by looking at 139 patients who had received at least two cycles of lenalidomide treatment. There were 118 patients with MDS, and 108 who had received lenalidomide monotherapy. However, the team focused on the 100 patients who had non-del(5q) MDS, 58 of whom had normal karyotype (NK) and 19 of whom had complex karyotype (CK).
The model revealed several combinations of genomic/cytogenetic abnormalities that could predict resistance to lenalidomide, including the following:
- DNMT3A and SF3B1
- EZH2 and NK
- ASXL1, TET2, and NK
- STAG2, IDH1/2, and NK
- TP53, del(5q), and CK
- BCOR/BCORL1 and NK
- JAK2, TET2, and NK
- U2AF1, +/– ETV6, and NK
However, only the following two combinations could predict response to lenalidomide:
- DDX41 and NK
- MECOM and KDM6A/B
These combinations could be applied to 39% of the patients with non-del(5q) MDS, and the model predicted response or resistance to lenalidomide with 82% accuracy.
Although the biomarkers were found in only a subset of patients, Dr. Madanat said these findings may help physicians tailor therapy for MDS patients, given the high level of accuracy the researchers observed.
“It’s really important to validate the results in a prospective manner and to ensure that we’re able to apply them clinically and potentially change the way we’re treating our patients,” he added.
Dr. Madanat and his colleagues reported having no relevant conflicts of interest.
The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.
NEWPORT BEACH, CALIF. — A model that mimics the recommender system used by Netflix and Amazon can help predict outcomes of lenalidomide treatment in patients with non–deletion 5q (non-del[5q]) myelodysplastic syndromes (MDS), according to new research.
The model was used to identify genomic biomarkers that were associated with resistance or response to lenalidomide. Researchers found these associations in 39% of patients with non-del(5q) MDS, and the model predicted response or resistance with 82% accuracy.
Yazan Madanat, MD, of the Cleveland Clinic, and his colleagues presented these findings at the Acute Leukemia Forum of Hemedicus.
Dr. Madanat explained that his group’s model is similar to the recommender system used by Netflix and Amazon, which makes suggestions for new products based on customers’ past behavior. Dr. Madanat and his colleagues used their model to show that patients with certain molecular or cytogenetic abnormalities are likely to respond or not respond to lenalidomide.
The researchers began by looking at 139 patients who had received at least two cycles of lenalidomide treatment. There were 118 patients with MDS, and 108 who had received lenalidomide monotherapy. However, the team focused on the 100 patients who had non-del(5q) MDS, 58 of whom had normal karyotype (NK) and 19 of whom had complex karyotype (CK).
The model revealed several combinations of genomic/cytogenetic abnormalities that could predict resistance to lenalidomide, including the following:
- DNMT3A and SF3B1
- EZH2 and NK
- ASXL1, TET2, and NK
- STAG2, IDH1/2, and NK
- TP53, del(5q), and CK
- BCOR/BCORL1 and NK
- JAK2, TET2, and NK
- U2AF1, +/– ETV6, and NK
However, only the following two combinations could predict response to lenalidomide:
- DDX41 and NK
- MECOM and KDM6A/B
These combinations could be applied to 39% of the patients with non-del(5q) MDS, and the model predicted response or resistance to lenalidomide with 82% accuracy.
Although the biomarkers were found in only a subset of patients, Dr. Madanat said these findings may help physicians tailor therapy for MDS patients, given the high level of accuracy the researchers observed.
“It’s really important to validate the results in a prospective manner and to ensure that we’re able to apply them clinically and potentially change the way we’re treating our patients,” he added.
Dr. Madanat and his colleagues reported having no relevant conflicts of interest.
The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.
NEWPORT BEACH, CALIF. — A model that mimics the recommender system used by Netflix and Amazon can help predict outcomes of lenalidomide treatment in patients with non–deletion 5q (non-del[5q]) myelodysplastic syndromes (MDS), according to new research.
The model was used to identify genomic biomarkers that were associated with resistance or response to lenalidomide. Researchers found these associations in 39% of patients with non-del(5q) MDS, and the model predicted response or resistance with 82% accuracy.
Yazan Madanat, MD, of the Cleveland Clinic, and his colleagues presented these findings at the Acute Leukemia Forum of Hemedicus.
Dr. Madanat explained that his group’s model is similar to the recommender system used by Netflix and Amazon, which makes suggestions for new products based on customers’ past behavior. Dr. Madanat and his colleagues used their model to show that patients with certain molecular or cytogenetic abnormalities are likely to respond or not respond to lenalidomide.
The researchers began by looking at 139 patients who had received at least two cycles of lenalidomide treatment. There were 118 patients with MDS, and 108 who had received lenalidomide monotherapy. However, the team focused on the 100 patients who had non-del(5q) MDS, 58 of whom had normal karyotype (NK) and 19 of whom had complex karyotype (CK).
The model revealed several combinations of genomic/cytogenetic abnormalities that could predict resistance to lenalidomide, including the following:
- DNMT3A and SF3B1
- EZH2 and NK
- ASXL1, TET2, and NK
- STAG2, IDH1/2, and NK
- TP53, del(5q), and CK
- BCOR/BCORL1 and NK
- JAK2, TET2, and NK
- U2AF1, +/– ETV6, and NK
However, only the following two combinations could predict response to lenalidomide:
- DDX41 and NK
- MECOM and KDM6A/B
These combinations could be applied to 39% of the patients with non-del(5q) MDS, and the model predicted response or resistance to lenalidomide with 82% accuracy.
Although the biomarkers were found in only a subset of patients, Dr. Madanat said these findings may help physicians tailor therapy for MDS patients, given the high level of accuracy the researchers observed.
“It’s really important to validate the results in a prospective manner and to ensure that we’re able to apply them clinically and potentially change the way we’re treating our patients,” he added.
Dr. Madanat and his colleagues reported having no relevant conflicts of interest.
The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.
REPORTING FROM ALF 2019
Text messaging may help patients with schizophrenia
A text messaging–based mobile health (mHealth) intervention that relied on lay health supporters improved medication adherence among rural Chinese patients with schizophrenia by 27%, according to results of a study published in PLoS Medicine.
The researchers developed a mHealth protocol intervention that used text messaging and lay health supporters to help patients with schizophrenia to transition from facility-based care to community-based care. The study randomized 278 community-dwelling villagers with schizophrenia to receive care through a community-based free-medicine program either with or without support from the mHealth intervention. Among the 271 patients successfully followed, medication adherence – the primary outcome – was higher in the mHealth group than it was in the control group (adjusted mean difference, 0.12; 95% confidence interval, 0.03-0.22; P = .013).
The investigators wrote that the treatment gaps for schizophrenia in resource-poor areas remain substantial and that text messaging plus lay health support could form a simple and low-cost means of improving the situation in these settings.
SOURCE: Xu D et al. PLoS Med. 2019 Apr 23. doi: 10.1371/journal.pmed.1002785.
A text messaging–based mobile health (mHealth) intervention that relied on lay health supporters improved medication adherence among rural Chinese patients with schizophrenia by 27%, according to results of a study published in PLoS Medicine.
The researchers developed a mHealth protocol intervention that used text messaging and lay health supporters to help patients with schizophrenia to transition from facility-based care to community-based care. The study randomized 278 community-dwelling villagers with schizophrenia to receive care through a community-based free-medicine program either with or without support from the mHealth intervention. Among the 271 patients successfully followed, medication adherence – the primary outcome – was higher in the mHealth group than it was in the control group (adjusted mean difference, 0.12; 95% confidence interval, 0.03-0.22; P = .013).
The investigators wrote that the treatment gaps for schizophrenia in resource-poor areas remain substantial and that text messaging plus lay health support could form a simple and low-cost means of improving the situation in these settings.
SOURCE: Xu D et al. PLoS Med. 2019 Apr 23. doi: 10.1371/journal.pmed.1002785.
A text messaging–based mobile health (mHealth) intervention that relied on lay health supporters improved medication adherence among rural Chinese patients with schizophrenia by 27%, according to results of a study published in PLoS Medicine.
The researchers developed a mHealth protocol intervention that used text messaging and lay health supporters to help patients with schizophrenia to transition from facility-based care to community-based care. The study randomized 278 community-dwelling villagers with schizophrenia to receive care through a community-based free-medicine program either with or without support from the mHealth intervention. Among the 271 patients successfully followed, medication adherence – the primary outcome – was higher in the mHealth group than it was in the control group (adjusted mean difference, 0.12; 95% confidence interval, 0.03-0.22; P = .013).
The investigators wrote that the treatment gaps for schizophrenia in resource-poor areas remain substantial and that text messaging plus lay health support could form a simple and low-cost means of improving the situation in these settings.
SOURCE: Xu D et al. PLoS Med. 2019 Apr 23. doi: 10.1371/journal.pmed.1002785.
FROM PLOS MEDICINE
Plasma levels of neurofilament light track neurodegeneration in MCI and Alzheimer’s disease
Plasma levels of the axonal protein also correlated with its presence in cerebrospinal fluid, and mirrored the changes in amyloid beta (Abeta) 42, Niklas Mattsson, MD, and colleagues wrote in JAMA Neurology.
“Taken together, these findings suggest that the neurofilament light level is a dynamic biomarker that changes throughout the course of Alzheimer’s disease and is sensitive to progressive neurodegeneration,” wrote Dr. Mattsson of Lund (Sweden) University and his coauthors. “This has important implications, given the unmet need for noninvasive blood-based methods to objectively track longitudinal neurodegeneration in Alzheimer’s disease.”
A blood-based biomarker of Alzheimer’s disease progression could open a new door for drug trials, the authors noted. Previously, NfL levels have only been available by lumbar puncture – a invasive and expensive test that many patients resist. If NfL plasma levels do reliably track dementia progression, the test could become a standard part of clinical trials, providing regular drug response data as the study progresses.
Neurofilaments are polypeptides that give structure to the neuronal cytoskeleton and regulate microtubule function. Injured cells release the protein very quickly. Neurofilaments are elevated in traumatic brain injury, multiple sclerosis, and some psychiatric illnesses. Neurofilament levels have even been used to predict neurologic recovery after cardiac arrest.
Dr. Mattsson and his team used data obtained over 11 years from 1,583 subjects enrolled in the Alzheimer’s Disease Neuroimaging Initiative study. The sample comprised three groups: cognitively unimpaired controls (401), patients with MCI (855), and patients with Alzheimer’s dementia (327). The investigators analyzed 4,326 samples.
In addition to the NfL measurements, they tracked Abeta and tau in cerebrospinal fluid (CSF), structural brain changes by 18fluorodeoxyglucose (FDG)–PET and MRI, and cognitive and functional performance. The primary outcome was NfL’s association with these changes. The team set the lower limit of NfL as 6.7 ng/L and the upper, 1,620 ng/L.
At baseline, only advancing age correlated with NfL levels. But it was significantly higher in patients with MCI (37.9 ng/L) and Alzheimer’s dementia (45.9 ng/L) than it was in the control subjects (32.1 ng/L). Over the years of follow-up, levels increased in all groups, but NfL increased more rapidly among patients with MCI and Alzheimer’s dementia than controls (2.7 vs. 2.4 ng/L per year). The difference was most pronounced when comparing levels in patients with Alzheimer’s dementia and MCI with controls. However, control subjects who were Abeta positive by CSF had greater NfL changes than Abeta-negative controls.
Baseline measures of CSF Abeta and tau, as well as hippocampal and ventricular volume and cortical thickness, also correlated with NfL levels, as did cognition and functional scores.
During follow-up, the diagnostic groups showed different NfL trajectories, which correlated strongly with the other measures.
In the control group, NfL increases correlated with lower FDG-PET measures, lower CSF Abeta, reduced hippocampal volume, and higher ventricular volume. Among patients with MCI, NfL increases correlated most strongly with hippocampal volume, temporal region, and cognition. Among patients with Alzheimer’s dementia, the NfL increase most strongly tracked cognitive decline,
When the investigators applied these findings to the A/T/N (amyloid, tau, neurodegeneration) classification system, NfL most often correlated with neurodegeneration, but not always. This might suggest that the neuronal damage occurred separately from Abeta changes. In all three groups, rapid NfL increases mirrored the rate of change in most other measures.
“In controls and patients with MCI and Alzheimer’s dementia, greater rates of NfL were associated with accelerated reduction in FDG-PET measures … expansion of ventricular volume,” and a reduction in cognitive and functional performance, Dr. Mattsson and his colleagues wrote.“ In addition, greater increases in NfL levels were associated with accelerated loss of hippocampal volume and entorhinal cortical thickness in controls and patients with MCI and with accelerated increases in total tau level, phosphorylated tau level, and white matter lesions in patients with MCI. In general, the concentrations of blood-based NfL appears to reflect the intensity of the neuronal injury.”
Dr Mattsson reported being a consultant for the Alzheimer’s Disease Neuroimaging Initiative.
SOURCE: Mattsson N et al. JAMA Neurol. 2019 Apr 22. doi: 10.1001/jamaneurol.2019.0765.
This is an impressive study that convincingly demonstrates the sensitivity of plasma neurofilament light (NfL) to disease progression in patients with mild cognitive impairment and dementia in the Alzheimer’s Disease Neuroimaging Initiative cohort.
It is known that NfL is sensitive to neuronal damage that can result from a variety of pathologies, not limited to Alzheimer’s disease, so it is not diagnostically specific. In the present study there was even overlap of values between the cognitively unimpaired and mild cognitive impairment groups at baseline as well, although the levels separated over time.
In the right setting, NfL might still be a clinically useful diagnostic marker, especially for mild-stage disease when other clinical measures such as mental status scores and structural brain scans are inconclusive, and further study seems warranted for such a possibility.
Its greatest utility, however, will likely be in clinical trials. It would have been of the greatest interest to know how NfL levels changed in the setting of demonstrated cerebral amyloid clearance by agents such as aducanumab that failed to halt dementia progression, or in the setting of BACE1 inhibitor-related worsening of cognition. Did NfL levels remain static in the former and rise in the latter? Looking ahead, it seems likely that this easily accessed biomarker will become an integral part of clinical trial design. Assuming cost is not overly burdensome, it may even find its way eventually into clinical practice.
Dr. Caselli is professor of neurology at the Mayo Clinic Arizona in Scottsdale and associate director and clinical core director of the Arizona Alzheimer’s Disease Center.
This is an impressive study that convincingly demonstrates the sensitivity of plasma neurofilament light (NfL) to disease progression in patients with mild cognitive impairment and dementia in the Alzheimer’s Disease Neuroimaging Initiative cohort.
It is known that NfL is sensitive to neuronal damage that can result from a variety of pathologies, not limited to Alzheimer’s disease, so it is not diagnostically specific. In the present study there was even overlap of values between the cognitively unimpaired and mild cognitive impairment groups at baseline as well, although the levels separated over time.
In the right setting, NfL might still be a clinically useful diagnostic marker, especially for mild-stage disease when other clinical measures such as mental status scores and structural brain scans are inconclusive, and further study seems warranted for such a possibility.
Its greatest utility, however, will likely be in clinical trials. It would have been of the greatest interest to know how NfL levels changed in the setting of demonstrated cerebral amyloid clearance by agents such as aducanumab that failed to halt dementia progression, or in the setting of BACE1 inhibitor-related worsening of cognition. Did NfL levels remain static in the former and rise in the latter? Looking ahead, it seems likely that this easily accessed biomarker will become an integral part of clinical trial design. Assuming cost is not overly burdensome, it may even find its way eventually into clinical practice.
Dr. Caselli is professor of neurology at the Mayo Clinic Arizona in Scottsdale and associate director and clinical core director of the Arizona Alzheimer’s Disease Center.
This is an impressive study that convincingly demonstrates the sensitivity of plasma neurofilament light (NfL) to disease progression in patients with mild cognitive impairment and dementia in the Alzheimer’s Disease Neuroimaging Initiative cohort.
It is known that NfL is sensitive to neuronal damage that can result from a variety of pathologies, not limited to Alzheimer’s disease, so it is not diagnostically specific. In the present study there was even overlap of values between the cognitively unimpaired and mild cognitive impairment groups at baseline as well, although the levels separated over time.
In the right setting, NfL might still be a clinically useful diagnostic marker, especially for mild-stage disease when other clinical measures such as mental status scores and structural brain scans are inconclusive, and further study seems warranted for such a possibility.
Its greatest utility, however, will likely be in clinical trials. It would have been of the greatest interest to know how NfL levels changed in the setting of demonstrated cerebral amyloid clearance by agents such as aducanumab that failed to halt dementia progression, or in the setting of BACE1 inhibitor-related worsening of cognition. Did NfL levels remain static in the former and rise in the latter? Looking ahead, it seems likely that this easily accessed biomarker will become an integral part of clinical trial design. Assuming cost is not overly burdensome, it may even find its way eventually into clinical practice.
Dr. Caselli is professor of neurology at the Mayo Clinic Arizona in Scottsdale and associate director and clinical core director of the Arizona Alzheimer’s Disease Center.
Plasma levels of the axonal protein also correlated with its presence in cerebrospinal fluid, and mirrored the changes in amyloid beta (Abeta) 42, Niklas Mattsson, MD, and colleagues wrote in JAMA Neurology.
“Taken together, these findings suggest that the neurofilament light level is a dynamic biomarker that changes throughout the course of Alzheimer’s disease and is sensitive to progressive neurodegeneration,” wrote Dr. Mattsson of Lund (Sweden) University and his coauthors. “This has important implications, given the unmet need for noninvasive blood-based methods to objectively track longitudinal neurodegeneration in Alzheimer’s disease.”
A blood-based biomarker of Alzheimer’s disease progression could open a new door for drug trials, the authors noted. Previously, NfL levels have only been available by lumbar puncture – a invasive and expensive test that many patients resist. If NfL plasma levels do reliably track dementia progression, the test could become a standard part of clinical trials, providing regular drug response data as the study progresses.
Neurofilaments are polypeptides that give structure to the neuronal cytoskeleton and regulate microtubule function. Injured cells release the protein very quickly. Neurofilaments are elevated in traumatic brain injury, multiple sclerosis, and some psychiatric illnesses. Neurofilament levels have even been used to predict neurologic recovery after cardiac arrest.
Dr. Mattsson and his team used data obtained over 11 years from 1,583 subjects enrolled in the Alzheimer’s Disease Neuroimaging Initiative study. The sample comprised three groups: cognitively unimpaired controls (401), patients with MCI (855), and patients with Alzheimer’s dementia (327). The investigators analyzed 4,326 samples.
In addition to the NfL measurements, they tracked Abeta and tau in cerebrospinal fluid (CSF), structural brain changes by 18fluorodeoxyglucose (FDG)–PET and MRI, and cognitive and functional performance. The primary outcome was NfL’s association with these changes. The team set the lower limit of NfL as 6.7 ng/L and the upper, 1,620 ng/L.
At baseline, only advancing age correlated with NfL levels. But it was significantly higher in patients with MCI (37.9 ng/L) and Alzheimer’s dementia (45.9 ng/L) than it was in the control subjects (32.1 ng/L). Over the years of follow-up, levels increased in all groups, but NfL increased more rapidly among patients with MCI and Alzheimer’s dementia than controls (2.7 vs. 2.4 ng/L per year). The difference was most pronounced when comparing levels in patients with Alzheimer’s dementia and MCI with controls. However, control subjects who were Abeta positive by CSF had greater NfL changes than Abeta-negative controls.
Baseline measures of CSF Abeta and tau, as well as hippocampal and ventricular volume and cortical thickness, also correlated with NfL levels, as did cognition and functional scores.
During follow-up, the diagnostic groups showed different NfL trajectories, which correlated strongly with the other measures.
In the control group, NfL increases correlated with lower FDG-PET measures, lower CSF Abeta, reduced hippocampal volume, and higher ventricular volume. Among patients with MCI, NfL increases correlated most strongly with hippocampal volume, temporal region, and cognition. Among patients with Alzheimer’s dementia, the NfL increase most strongly tracked cognitive decline,
When the investigators applied these findings to the A/T/N (amyloid, tau, neurodegeneration) classification system, NfL most often correlated with neurodegeneration, but not always. This might suggest that the neuronal damage occurred separately from Abeta changes. In all three groups, rapid NfL increases mirrored the rate of change in most other measures.
“In controls and patients with MCI and Alzheimer’s dementia, greater rates of NfL were associated with accelerated reduction in FDG-PET measures … expansion of ventricular volume,” and a reduction in cognitive and functional performance, Dr. Mattsson and his colleagues wrote.“ In addition, greater increases in NfL levels were associated with accelerated loss of hippocampal volume and entorhinal cortical thickness in controls and patients with MCI and with accelerated increases in total tau level, phosphorylated tau level, and white matter lesions in patients with MCI. In general, the concentrations of blood-based NfL appears to reflect the intensity of the neuronal injury.”
Dr Mattsson reported being a consultant for the Alzheimer’s Disease Neuroimaging Initiative.
SOURCE: Mattsson N et al. JAMA Neurol. 2019 Apr 22. doi: 10.1001/jamaneurol.2019.0765.
Plasma levels of the axonal protein also correlated with its presence in cerebrospinal fluid, and mirrored the changes in amyloid beta (Abeta) 42, Niklas Mattsson, MD, and colleagues wrote in JAMA Neurology.
“Taken together, these findings suggest that the neurofilament light level is a dynamic biomarker that changes throughout the course of Alzheimer’s disease and is sensitive to progressive neurodegeneration,” wrote Dr. Mattsson of Lund (Sweden) University and his coauthors. “This has important implications, given the unmet need for noninvasive blood-based methods to objectively track longitudinal neurodegeneration in Alzheimer’s disease.”
A blood-based biomarker of Alzheimer’s disease progression could open a new door for drug trials, the authors noted. Previously, NfL levels have only been available by lumbar puncture – a invasive and expensive test that many patients resist. If NfL plasma levels do reliably track dementia progression, the test could become a standard part of clinical trials, providing regular drug response data as the study progresses.
Neurofilaments are polypeptides that give structure to the neuronal cytoskeleton and regulate microtubule function. Injured cells release the protein very quickly. Neurofilaments are elevated in traumatic brain injury, multiple sclerosis, and some psychiatric illnesses. Neurofilament levels have even been used to predict neurologic recovery after cardiac arrest.
Dr. Mattsson and his team used data obtained over 11 years from 1,583 subjects enrolled in the Alzheimer’s Disease Neuroimaging Initiative study. The sample comprised three groups: cognitively unimpaired controls (401), patients with MCI (855), and patients with Alzheimer’s dementia (327). The investigators analyzed 4,326 samples.
In addition to the NfL measurements, they tracked Abeta and tau in cerebrospinal fluid (CSF), structural brain changes by 18fluorodeoxyglucose (FDG)–PET and MRI, and cognitive and functional performance. The primary outcome was NfL’s association with these changes. The team set the lower limit of NfL as 6.7 ng/L and the upper, 1,620 ng/L.
At baseline, only advancing age correlated with NfL levels. But it was significantly higher in patients with MCI (37.9 ng/L) and Alzheimer’s dementia (45.9 ng/L) than it was in the control subjects (32.1 ng/L). Over the years of follow-up, levels increased in all groups, but NfL increased more rapidly among patients with MCI and Alzheimer’s dementia than controls (2.7 vs. 2.4 ng/L per year). The difference was most pronounced when comparing levels in patients with Alzheimer’s dementia and MCI with controls. However, control subjects who were Abeta positive by CSF had greater NfL changes than Abeta-negative controls.
Baseline measures of CSF Abeta and tau, as well as hippocampal and ventricular volume and cortical thickness, also correlated with NfL levels, as did cognition and functional scores.
During follow-up, the diagnostic groups showed different NfL trajectories, which correlated strongly with the other measures.
In the control group, NfL increases correlated with lower FDG-PET measures, lower CSF Abeta, reduced hippocampal volume, and higher ventricular volume. Among patients with MCI, NfL increases correlated most strongly with hippocampal volume, temporal region, and cognition. Among patients with Alzheimer’s dementia, the NfL increase most strongly tracked cognitive decline,
When the investigators applied these findings to the A/T/N (amyloid, tau, neurodegeneration) classification system, NfL most often correlated with neurodegeneration, but not always. This might suggest that the neuronal damage occurred separately from Abeta changes. In all three groups, rapid NfL increases mirrored the rate of change in most other measures.
“In controls and patients with MCI and Alzheimer’s dementia, greater rates of NfL were associated with accelerated reduction in FDG-PET measures … expansion of ventricular volume,” and a reduction in cognitive and functional performance, Dr. Mattsson and his colleagues wrote.“ In addition, greater increases in NfL levels were associated with accelerated loss of hippocampal volume and entorhinal cortical thickness in controls and patients with MCI and with accelerated increases in total tau level, phosphorylated tau level, and white matter lesions in patients with MCI. In general, the concentrations of blood-based NfL appears to reflect the intensity of the neuronal injury.”
Dr Mattsson reported being a consultant for the Alzheimer’s Disease Neuroimaging Initiative.
SOURCE: Mattsson N et al. JAMA Neurol. 2019 Apr 22. doi: 10.1001/jamaneurol.2019.0765.
FROM JAMA NEUROLOGY