User login
Scans Detect Brain Damage in "Mild" Blast-Related TBI
Evidence of diffuse axonal injury has been detected using an advanced form of MRI in military personnel who were clinically diagnosed as having only mild blast-related traumatic brain injury, according to a report in the June 2 issue of the New England Journal of Medicine.
This is the first time that widespread structural brain damage reflecting axonal injury has been identified in "mild" blast-related traumatic brain injury (TBI). In addition, the study confirms that axonal injury might be a primary feature of such wounds, as animal studies and computer simulations have suggested, said Christine L. MacDonald, Ph.D., of Washington University in St. Louis, and her associates.
The findings, however, cannot yet be considered definitive because all of the subjects in this study also sustained another mechanism of head injury simultaneously with the blast-related injury. All of them experienced additional head injury from a fall or motor vehicle crash, or from being struck by blunt objects at the time of the explosion, so the effects of the blast cannot be differentiated from the effects of these traumas, the investigators noted.
They studied 84 members of the military who were injured in explosions in Iraq or Afghanistan during a 5-month period. A total of 63 had blast-related TBI that was judged on clinical assessment to be mild and uncomplicated, and 21 who had other injuries, chiefly orthopedic or soft-tissue wounds in the arms or legs, served as controls.
The study subjects underwent initial brain MRI when they were evacuated to Landstuhl Regional Medical Center in Germany immediately after they were wounded and follow-up MRI 6-12 months later at Washington University.
In addition to regular MRI, the subjects’ brains were scanned using diffusion tensor imaging (DTI), an advanced MRI method that measures water diffusion in many directions. Reduced anisotropy (directional asymmetry) of water diffusion on DTI is a marker of traumatic axonal injury.
Conventional MRI revealed abnormalities in only one of the TBI subjects, but DTI demonstrated reduced anisotropy in 18 (29%) of these subjects, across several of the 17 brain regions assessed in each subject. An additional 20 TBI subjects (32%) showed an abnormality within a single brain region on DTI.
"Quantitative analyses indicated significant reductions in relative anisotropy in the group of subjects with TBI as compared with the control group," Dr. MacDonald and her colleagues said (N. Engl. J. Med. 2011;364:2091-100).
Compared with control subjects, the TBI patients showed marked abnormalities in the middle cerebral peduncles, in cingulum bundles, and in the right orbitofrontal white matter – areas that have been predicted by computer simulations to sustain the most intense stresses during a blast. These are not the same regions of the brain that are commonly injured in civilian cases of TBI that do not involve blast exposure, they noted.
"The characteristics of the abnormal DTI signals changed between initial scanning and follow-up scanning, in a fashion that was consistent with the evolution of relatively acute injuries," the researchers said.
The follow-up scans indicated that the edema and cellular inflammation accompanying the axonal injury was resolving while the axonal injury itself persisted.
The investigators said that DTI assessments "may be useful in diagnosis, triage, and treatment planning in clinical practice" since the method "can be performed relatively quickly on the MRI scanners at U.S. military facilities and civilian hospitals."
Dr. MacDonald and her associates emphasized, however, that the findings in this study are preliminary and that TBI remains primarily a clinical diagnosis. "Normal findings on a DTI scan do not rule out TBI, nor are DTI findings in isolation sufficient to make this diagnosis with certainty," they noted.
The investigators noted several limitations of the study, including a moderate sample size and an all-male study population. Several studies of the relationship between DTI abnormalities and clinical outcomes are currently under way, they added.
This study was supported by the Congressionally Directed Medical Research Program and the National Institutes of Health. Dr. MacDonald’s associate, Dr. David L. Brody, reported ties to Wuestling and James Medicolegal Consulting, Burroughs Wellcome Fund, Thrasher Research Fund, the Hope Center for Neurological Disorders, the International Neurotrauma Society, and the Defense and Veterans Brain Injury Center. Dr. Ropper reported no financial conflicts of interest relevant to his commentary.
Until now, "there has been skepticism as to whether a blast that has occurred at a distance and inflicted no visible wound can penetrate the skull and damage the brain," said Dr. Allan Ropper.
"We now have tentative validation in mild TBI of the disruption of cerebral axons by blasts from improvised explosive devices," he said.
There are two key findings by Christine L. MacDonald, Ph.D., and her colleagues: The first is "the contrast between the results of imaging performed with DTI, which shows many regions of axonal disruption, and those achieved with conventional MRI, which usually shows little or no evidence of such disruption."
The second crucial finding is "the evolution of the imaging abnormalities detected on DTI during study follow-up in a manner that suggests the injury occurred at the time of the blast and was not the result of some indeterminate previous head injury," he said.
Dr. Ropper is with the department of neurology at Brigham and Women’s Hospital, Boston. He reported no financial conflicts of interest relevant to this commentary. These remarks were taken from his editorial accompanying Dr. MacDonald’s report (N. Engl. J. Med. 2011;364:2156-7).
Until now, "there has been skepticism as to whether a blast that has occurred at a distance and inflicted no visible wound can penetrate the skull and damage the brain," said Dr. Allan Ropper.
"We now have tentative validation in mild TBI of the disruption of cerebral axons by blasts from improvised explosive devices," he said.
There are two key findings by Christine L. MacDonald, Ph.D., and her colleagues: The first is "the contrast between the results of imaging performed with DTI, which shows many regions of axonal disruption, and those achieved with conventional MRI, which usually shows little or no evidence of such disruption."
The second crucial finding is "the evolution of the imaging abnormalities detected on DTI during study follow-up in a manner that suggests the injury occurred at the time of the blast and was not the result of some indeterminate previous head injury," he said.
Dr. Ropper is with the department of neurology at Brigham and Women’s Hospital, Boston. He reported no financial conflicts of interest relevant to this commentary. These remarks were taken from his editorial accompanying Dr. MacDonald’s report (N. Engl. J. Med. 2011;364:2156-7).
Until now, "there has been skepticism as to whether a blast that has occurred at a distance and inflicted no visible wound can penetrate the skull and damage the brain," said Dr. Allan Ropper.
"We now have tentative validation in mild TBI of the disruption of cerebral axons by blasts from improvised explosive devices," he said.
There are two key findings by Christine L. MacDonald, Ph.D., and her colleagues: The first is "the contrast between the results of imaging performed with DTI, which shows many regions of axonal disruption, and those achieved with conventional MRI, which usually shows little or no evidence of such disruption."
The second crucial finding is "the evolution of the imaging abnormalities detected on DTI during study follow-up in a manner that suggests the injury occurred at the time of the blast and was not the result of some indeterminate previous head injury," he said.
Dr. Ropper is with the department of neurology at Brigham and Women’s Hospital, Boston. He reported no financial conflicts of interest relevant to this commentary. These remarks were taken from his editorial accompanying Dr. MacDonald’s report (N. Engl. J. Med. 2011;364:2156-7).
Evidence of diffuse axonal injury has been detected using an advanced form of MRI in military personnel who were clinically diagnosed as having only mild blast-related traumatic brain injury, according to a report in the June 2 issue of the New England Journal of Medicine.
This is the first time that widespread structural brain damage reflecting axonal injury has been identified in "mild" blast-related traumatic brain injury (TBI). In addition, the study confirms that axonal injury might be a primary feature of such wounds, as animal studies and computer simulations have suggested, said Christine L. MacDonald, Ph.D., of Washington University in St. Louis, and her associates.
The findings, however, cannot yet be considered definitive because all of the subjects in this study also sustained another mechanism of head injury simultaneously with the blast-related injury. All of them experienced additional head injury from a fall or motor vehicle crash, or from being struck by blunt objects at the time of the explosion, so the effects of the blast cannot be differentiated from the effects of these traumas, the investigators noted.
They studied 84 members of the military who were injured in explosions in Iraq or Afghanistan during a 5-month period. A total of 63 had blast-related TBI that was judged on clinical assessment to be mild and uncomplicated, and 21 who had other injuries, chiefly orthopedic or soft-tissue wounds in the arms or legs, served as controls.
The study subjects underwent initial brain MRI when they were evacuated to Landstuhl Regional Medical Center in Germany immediately after they were wounded and follow-up MRI 6-12 months later at Washington University.
In addition to regular MRI, the subjects’ brains were scanned using diffusion tensor imaging (DTI), an advanced MRI method that measures water diffusion in many directions. Reduced anisotropy (directional asymmetry) of water diffusion on DTI is a marker of traumatic axonal injury.
Conventional MRI revealed abnormalities in only one of the TBI subjects, but DTI demonstrated reduced anisotropy in 18 (29%) of these subjects, across several of the 17 brain regions assessed in each subject. An additional 20 TBI subjects (32%) showed an abnormality within a single brain region on DTI.
"Quantitative analyses indicated significant reductions in relative anisotropy in the group of subjects with TBI as compared with the control group," Dr. MacDonald and her colleagues said (N. Engl. J. Med. 2011;364:2091-100).
Compared with control subjects, the TBI patients showed marked abnormalities in the middle cerebral peduncles, in cingulum bundles, and in the right orbitofrontal white matter – areas that have been predicted by computer simulations to sustain the most intense stresses during a blast. These are not the same regions of the brain that are commonly injured in civilian cases of TBI that do not involve blast exposure, they noted.
"The characteristics of the abnormal DTI signals changed between initial scanning and follow-up scanning, in a fashion that was consistent with the evolution of relatively acute injuries," the researchers said.
The follow-up scans indicated that the edema and cellular inflammation accompanying the axonal injury was resolving while the axonal injury itself persisted.
The investigators said that DTI assessments "may be useful in diagnosis, triage, and treatment planning in clinical practice" since the method "can be performed relatively quickly on the MRI scanners at U.S. military facilities and civilian hospitals."
Dr. MacDonald and her associates emphasized, however, that the findings in this study are preliminary and that TBI remains primarily a clinical diagnosis. "Normal findings on a DTI scan do not rule out TBI, nor are DTI findings in isolation sufficient to make this diagnosis with certainty," they noted.
The investigators noted several limitations of the study, including a moderate sample size and an all-male study population. Several studies of the relationship between DTI abnormalities and clinical outcomes are currently under way, they added.
This study was supported by the Congressionally Directed Medical Research Program and the National Institutes of Health. Dr. MacDonald’s associate, Dr. David L. Brody, reported ties to Wuestling and James Medicolegal Consulting, Burroughs Wellcome Fund, Thrasher Research Fund, the Hope Center for Neurological Disorders, the International Neurotrauma Society, and the Defense and Veterans Brain Injury Center. Dr. Ropper reported no financial conflicts of interest relevant to his commentary.
Evidence of diffuse axonal injury has been detected using an advanced form of MRI in military personnel who were clinically diagnosed as having only mild blast-related traumatic brain injury, according to a report in the June 2 issue of the New England Journal of Medicine.
This is the first time that widespread structural brain damage reflecting axonal injury has been identified in "mild" blast-related traumatic brain injury (TBI). In addition, the study confirms that axonal injury might be a primary feature of such wounds, as animal studies and computer simulations have suggested, said Christine L. MacDonald, Ph.D., of Washington University in St. Louis, and her associates.
The findings, however, cannot yet be considered definitive because all of the subjects in this study also sustained another mechanism of head injury simultaneously with the blast-related injury. All of them experienced additional head injury from a fall or motor vehicle crash, or from being struck by blunt objects at the time of the explosion, so the effects of the blast cannot be differentiated from the effects of these traumas, the investigators noted.
They studied 84 members of the military who were injured in explosions in Iraq or Afghanistan during a 5-month period. A total of 63 had blast-related TBI that was judged on clinical assessment to be mild and uncomplicated, and 21 who had other injuries, chiefly orthopedic or soft-tissue wounds in the arms or legs, served as controls.
The study subjects underwent initial brain MRI when they were evacuated to Landstuhl Regional Medical Center in Germany immediately after they were wounded and follow-up MRI 6-12 months later at Washington University.
In addition to regular MRI, the subjects’ brains were scanned using diffusion tensor imaging (DTI), an advanced MRI method that measures water diffusion in many directions. Reduced anisotropy (directional asymmetry) of water diffusion on DTI is a marker of traumatic axonal injury.
Conventional MRI revealed abnormalities in only one of the TBI subjects, but DTI demonstrated reduced anisotropy in 18 (29%) of these subjects, across several of the 17 brain regions assessed in each subject. An additional 20 TBI subjects (32%) showed an abnormality within a single brain region on DTI.
"Quantitative analyses indicated significant reductions in relative anisotropy in the group of subjects with TBI as compared with the control group," Dr. MacDonald and her colleagues said (N. Engl. J. Med. 2011;364:2091-100).
Compared with control subjects, the TBI patients showed marked abnormalities in the middle cerebral peduncles, in cingulum bundles, and in the right orbitofrontal white matter – areas that have been predicted by computer simulations to sustain the most intense stresses during a blast. These are not the same regions of the brain that are commonly injured in civilian cases of TBI that do not involve blast exposure, they noted.
"The characteristics of the abnormal DTI signals changed between initial scanning and follow-up scanning, in a fashion that was consistent with the evolution of relatively acute injuries," the researchers said.
The follow-up scans indicated that the edema and cellular inflammation accompanying the axonal injury was resolving while the axonal injury itself persisted.
The investigators said that DTI assessments "may be useful in diagnosis, triage, and treatment planning in clinical practice" since the method "can be performed relatively quickly on the MRI scanners at U.S. military facilities and civilian hospitals."
Dr. MacDonald and her associates emphasized, however, that the findings in this study are preliminary and that TBI remains primarily a clinical diagnosis. "Normal findings on a DTI scan do not rule out TBI, nor are DTI findings in isolation sufficient to make this diagnosis with certainty," they noted.
The investigators noted several limitations of the study, including a moderate sample size and an all-male study population. Several studies of the relationship between DTI abnormalities and clinical outcomes are currently under way, they added.
This study was supported by the Congressionally Directed Medical Research Program and the National Institutes of Health. Dr. MacDonald’s associate, Dr. David L. Brody, reported ties to Wuestling and James Medicolegal Consulting, Burroughs Wellcome Fund, Thrasher Research Fund, the Hope Center for Neurological Disorders, the International Neurotrauma Society, and the Defense and Veterans Brain Injury Center. Dr. Ropper reported no financial conflicts of interest relevant to his commentary.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Major Finding: Diffusion tensor imaging demonstrated widespread axonal injury in 18 of 63 military personnel with mild blast-related TBI and axonal injury in a single brain region in an additional 20. Conventional MRI revealed abnormalities in only one of the TBI subjects.
Data Source: An assessment of axonal injury using DTI in 63 U.S. military personnel with a clinical diagnosis of mild, uncomplicated TBI.
Disclosures: This study was supported by the Congressionally Directed Medical Research Program and the National Institutes of Health. Dr. MacDonald’s associate, Dr. David L. Brody, reported ties to Wuestling and James Medicolegal Consulting, Burroughs Wellcome Fund, Thrasher Research Fund, the Hope Center for Neurological Disorders, the International Neurotrauma Society, and the Defense and Veterans Brain Injury Center.
Scans Detect Brain Damage in "Mild" Blast-Related TBI
Evidence of diffuse axonal injury has been detected using an advanced form of MRI in military personnel who were clinically diagnosed as having only mild blast-related traumatic brain injury, according to a report in the June 2 issue of the New England Journal of Medicine.
This is the first time that widespread structural brain damage reflecting axonal injury has been identified in "mild" blast-related traumatic brain injury (TBI). In addition, the study confirms that axonal injury might be a primary feature of such wounds, as animal studies and computer simulations have suggested, said Christine L. MacDonald, Ph.D., of Washington University in St. Louis, and her associates.
The findings, however, cannot yet be considered definitive because all of the subjects in this study also sustained another mechanism of head injury simultaneously with the blast-related injury. All of them experienced additional head injury from a fall or motor vehicle crash, or from being struck by blunt objects at the time of the explosion, so the effects of the blast cannot be differentiated from the effects of these traumas, the investigators noted.
They studied 84 members of the military who were injured in explosions in Iraq or Afghanistan during a 5-month period. A total of 63 had blast-related TBI that was judged on clinical assessment to be mild and uncomplicated, and 21 who had other injuries, chiefly orthopedic or soft-tissue wounds in the arms or legs, served as controls.
The study subjects underwent initial brain MRI when they were evacuated to Landstuhl Regional Medical Center in Germany immediately after they were wounded and follow-up MRI 6-12 months later at Washington University.
In addition to regular MRI, the subjects’ brains were scanned using diffusion tensor imaging (DTI), an advanced MRI method that measures water diffusion in many directions. Reduced anisotropy (directional asymmetry) of water diffusion on DTI is a marker of traumatic axonal injury.
Conventional MRI revealed abnormalities in only one of the TBI subjects, but DTI demonstrated reduced anisotropy in 18 (29%) of these subjects, across several of the 17 brain regions assessed in each subject. An additional 20 TBI subjects (32%) showed an abnormality within a single brain region on DTI.
"Quantitative analyses indicated significant reductions in relative anisotropy in the group of subjects with TBI as compared with the control group," Dr. MacDonald and her colleagues said (N. Engl. J. Med. 2011;364:2091-100).
Compared with control subjects, the TBI patients showed marked abnormalities in the middle cerebral peduncles, in cingulum bundles, and in the right orbitofrontal white matter – areas that have been predicted by computer simulations to sustain the most intense stresses during a blast. These are not the same regions of the brain that are commonly injured in civilian cases of TBI that do not involve blast exposure, they noted.
"The characteristics of the abnormal DTI signals changed between initial scanning and follow-up scanning, in a fashion that was consistent with the evolution of relatively acute injuries," the researchers said.
The follow-up scans indicated that the edema and cellular inflammation accompanying the axonal injury was resolving while the axonal injury itself persisted.
The investigators said that DTI assessments "may be useful in diagnosis, triage, and treatment planning in clinical practice" since the method "can be performed relatively quickly on the MRI scanners at U.S. military facilities and civilian hospitals."
Dr. MacDonald and her associates emphasized, however, that the findings in this study are preliminary and that TBI remains primarily a clinical diagnosis. "Normal findings on a DTI scan do not rule out TBI, nor are DTI findings in isolation sufficient to make this diagnosis with certainty," they noted.
The investigators noted several limitations of the study, including a moderate sample size and an all-male study population. Several studies of the relationship between DTI abnormalities and clinical outcomes are currently under way, they added.
This study was supported by the Congressionally Directed Medical Research Program and the National Institutes of Health. Dr. MacDonald’s associate, Dr. David L. Brody, reported ties to Wuestling and James Medicolegal Consulting, Burroughs Wellcome Fund, Thrasher Research Fund, the Hope Center for Neurological Disorders, the International Neurotrauma Society, and the Defense and Veterans Brain Injury Center. Dr. Ropper reported no financial conflicts of interest relevant to his commentary.
Until now, "there has been skepticism as to whether a blast that has occurred at a distance and inflicted no visible wound can penetrate the skull and damage the brain," said Dr. Allan Ropper.
"We now have tentative validation in mild TBI of the disruption of cerebral axons by blasts from improvised explosive devices," he said.
There are two key findings by Christine L. MacDonald, Ph.D., and her colleagues: The first is "the contrast between the results of imaging performed with DTI, which shows many regions of axonal disruption, and those achieved with conventional MRI, which usually shows little or no evidence of such disruption."
The second crucial finding is "the evolution of the imaging abnormalities detected on DTI during study follow-up in a manner that suggests the injury occurred at the time of the blast and was not the result of some indeterminate previous head injury," he said.
Dr. Ropper is with the department of neurology at Brigham and Women’s Hospital, Boston. He reported no financial conflicts of interest relevant to this commentary. These remarks were taken from his editorial accompanying Dr. MacDonald’s report (N. Engl. J. Med. 2011;364:2156-7).
Until now, "there has been skepticism as to whether a blast that has occurred at a distance and inflicted no visible wound can penetrate the skull and damage the brain," said Dr. Allan Ropper.
"We now have tentative validation in mild TBI of the disruption of cerebral axons by blasts from improvised explosive devices," he said.
There are two key findings by Christine L. MacDonald, Ph.D., and her colleagues: The first is "the contrast between the results of imaging performed with DTI, which shows many regions of axonal disruption, and those achieved with conventional MRI, which usually shows little or no evidence of such disruption."
The second crucial finding is "the evolution of the imaging abnormalities detected on DTI during study follow-up in a manner that suggests the injury occurred at the time of the blast and was not the result of some indeterminate previous head injury," he said.
Dr. Ropper is with the department of neurology at Brigham and Women’s Hospital, Boston. He reported no financial conflicts of interest relevant to this commentary. These remarks were taken from his editorial accompanying Dr. MacDonald’s report (N. Engl. J. Med. 2011;364:2156-7).
Until now, "there has been skepticism as to whether a blast that has occurred at a distance and inflicted no visible wound can penetrate the skull and damage the brain," said Dr. Allan Ropper.
"We now have tentative validation in mild TBI of the disruption of cerebral axons by blasts from improvised explosive devices," he said.
There are two key findings by Christine L. MacDonald, Ph.D., and her colleagues: The first is "the contrast between the results of imaging performed with DTI, which shows many regions of axonal disruption, and those achieved with conventional MRI, which usually shows little or no evidence of such disruption."
The second crucial finding is "the evolution of the imaging abnormalities detected on DTI during study follow-up in a manner that suggests the injury occurred at the time of the blast and was not the result of some indeterminate previous head injury," he said.
Dr. Ropper is with the department of neurology at Brigham and Women’s Hospital, Boston. He reported no financial conflicts of interest relevant to this commentary. These remarks were taken from his editorial accompanying Dr. MacDonald’s report (N. Engl. J. Med. 2011;364:2156-7).
Evidence of diffuse axonal injury has been detected using an advanced form of MRI in military personnel who were clinically diagnosed as having only mild blast-related traumatic brain injury, according to a report in the June 2 issue of the New England Journal of Medicine.
This is the first time that widespread structural brain damage reflecting axonal injury has been identified in "mild" blast-related traumatic brain injury (TBI). In addition, the study confirms that axonal injury might be a primary feature of such wounds, as animal studies and computer simulations have suggested, said Christine L. MacDonald, Ph.D., of Washington University in St. Louis, and her associates.
The findings, however, cannot yet be considered definitive because all of the subjects in this study also sustained another mechanism of head injury simultaneously with the blast-related injury. All of them experienced additional head injury from a fall or motor vehicle crash, or from being struck by blunt objects at the time of the explosion, so the effects of the blast cannot be differentiated from the effects of these traumas, the investigators noted.
They studied 84 members of the military who were injured in explosions in Iraq or Afghanistan during a 5-month period. A total of 63 had blast-related TBI that was judged on clinical assessment to be mild and uncomplicated, and 21 who had other injuries, chiefly orthopedic or soft-tissue wounds in the arms or legs, served as controls.
The study subjects underwent initial brain MRI when they were evacuated to Landstuhl Regional Medical Center in Germany immediately after they were wounded and follow-up MRI 6-12 months later at Washington University.
In addition to regular MRI, the subjects’ brains were scanned using diffusion tensor imaging (DTI), an advanced MRI method that measures water diffusion in many directions. Reduced anisotropy (directional asymmetry) of water diffusion on DTI is a marker of traumatic axonal injury.
Conventional MRI revealed abnormalities in only one of the TBI subjects, but DTI demonstrated reduced anisotropy in 18 (29%) of these subjects, across several of the 17 brain regions assessed in each subject. An additional 20 TBI subjects (32%) showed an abnormality within a single brain region on DTI.
"Quantitative analyses indicated significant reductions in relative anisotropy in the group of subjects with TBI as compared with the control group," Dr. MacDonald and her colleagues said (N. Engl. J. Med. 2011;364:2091-100).
Compared with control subjects, the TBI patients showed marked abnormalities in the middle cerebral peduncles, in cingulum bundles, and in the right orbitofrontal white matter – areas that have been predicted by computer simulations to sustain the most intense stresses during a blast. These are not the same regions of the brain that are commonly injured in civilian cases of TBI that do not involve blast exposure, they noted.
"The characteristics of the abnormal DTI signals changed between initial scanning and follow-up scanning, in a fashion that was consistent with the evolution of relatively acute injuries," the researchers said.
The follow-up scans indicated that the edema and cellular inflammation accompanying the axonal injury was resolving while the axonal injury itself persisted.
The investigators said that DTI assessments "may be useful in diagnosis, triage, and treatment planning in clinical practice" since the method "can be performed relatively quickly on the MRI scanners at U.S. military facilities and civilian hospitals."
Dr. MacDonald and her associates emphasized, however, that the findings in this study are preliminary and that TBI remains primarily a clinical diagnosis. "Normal findings on a DTI scan do not rule out TBI, nor are DTI findings in isolation sufficient to make this diagnosis with certainty," they noted.
The investigators noted several limitations of the study, including a moderate sample size and an all-male study population. Several studies of the relationship between DTI abnormalities and clinical outcomes are currently under way, they added.
This study was supported by the Congressionally Directed Medical Research Program and the National Institutes of Health. Dr. MacDonald’s associate, Dr. David L. Brody, reported ties to Wuestling and James Medicolegal Consulting, Burroughs Wellcome Fund, Thrasher Research Fund, the Hope Center for Neurological Disorders, the International Neurotrauma Society, and the Defense and Veterans Brain Injury Center. Dr. Ropper reported no financial conflicts of interest relevant to his commentary.
Evidence of diffuse axonal injury has been detected using an advanced form of MRI in military personnel who were clinically diagnosed as having only mild blast-related traumatic brain injury, according to a report in the June 2 issue of the New England Journal of Medicine.
This is the first time that widespread structural brain damage reflecting axonal injury has been identified in "mild" blast-related traumatic brain injury (TBI). In addition, the study confirms that axonal injury might be a primary feature of such wounds, as animal studies and computer simulations have suggested, said Christine L. MacDonald, Ph.D., of Washington University in St. Louis, and her associates.
The findings, however, cannot yet be considered definitive because all of the subjects in this study also sustained another mechanism of head injury simultaneously with the blast-related injury. All of them experienced additional head injury from a fall or motor vehicle crash, or from being struck by blunt objects at the time of the explosion, so the effects of the blast cannot be differentiated from the effects of these traumas, the investigators noted.
They studied 84 members of the military who were injured in explosions in Iraq or Afghanistan during a 5-month period. A total of 63 had blast-related TBI that was judged on clinical assessment to be mild and uncomplicated, and 21 who had other injuries, chiefly orthopedic or soft-tissue wounds in the arms or legs, served as controls.
The study subjects underwent initial brain MRI when they were evacuated to Landstuhl Regional Medical Center in Germany immediately after they were wounded and follow-up MRI 6-12 months later at Washington University.
In addition to regular MRI, the subjects’ brains were scanned using diffusion tensor imaging (DTI), an advanced MRI method that measures water diffusion in many directions. Reduced anisotropy (directional asymmetry) of water diffusion on DTI is a marker of traumatic axonal injury.
Conventional MRI revealed abnormalities in only one of the TBI subjects, but DTI demonstrated reduced anisotropy in 18 (29%) of these subjects, across several of the 17 brain regions assessed in each subject. An additional 20 TBI subjects (32%) showed an abnormality within a single brain region on DTI.
"Quantitative analyses indicated significant reductions in relative anisotropy in the group of subjects with TBI as compared with the control group," Dr. MacDonald and her colleagues said (N. Engl. J. Med. 2011;364:2091-100).
Compared with control subjects, the TBI patients showed marked abnormalities in the middle cerebral peduncles, in cingulum bundles, and in the right orbitofrontal white matter – areas that have been predicted by computer simulations to sustain the most intense stresses during a blast. These are not the same regions of the brain that are commonly injured in civilian cases of TBI that do not involve blast exposure, they noted.
"The characteristics of the abnormal DTI signals changed between initial scanning and follow-up scanning, in a fashion that was consistent with the evolution of relatively acute injuries," the researchers said.
The follow-up scans indicated that the edema and cellular inflammation accompanying the axonal injury was resolving while the axonal injury itself persisted.
The investigators said that DTI assessments "may be useful in diagnosis, triage, and treatment planning in clinical practice" since the method "can be performed relatively quickly on the MRI scanners at U.S. military facilities and civilian hospitals."
Dr. MacDonald and her associates emphasized, however, that the findings in this study are preliminary and that TBI remains primarily a clinical diagnosis. "Normal findings on a DTI scan do not rule out TBI, nor are DTI findings in isolation sufficient to make this diagnosis with certainty," they noted.
The investigators noted several limitations of the study, including a moderate sample size and an all-male study population. Several studies of the relationship between DTI abnormalities and clinical outcomes are currently under way, they added.
This study was supported by the Congressionally Directed Medical Research Program and the National Institutes of Health. Dr. MacDonald’s associate, Dr. David L. Brody, reported ties to Wuestling and James Medicolegal Consulting, Burroughs Wellcome Fund, Thrasher Research Fund, the Hope Center for Neurological Disorders, the International Neurotrauma Society, and the Defense and Veterans Brain Injury Center. Dr. Ropper reported no financial conflicts of interest relevant to his commentary.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Major Finding: Diffusion tensor imaging demonstrated widespread axonal injury in 18 of 63 military personnel with mild blast-related TBI and axonal injury in a single brain region in an additional 20. Conventional MRI revealed abnormalities in only one of the TBI subjects.
Data Source: An assessment of axonal injury using DTI in 63 U.S. military personnel with a clinical diagnosis of mild, uncomplicated TBI.
Disclosures: This study was supported by the Congressionally Directed Medical Research Program and the National Institutes of Health. Dr. MacDonald’s associate, Dr. David L. Brody, reported ties to Wuestling and James Medicolegal Consulting, Burroughs Wellcome Fund, Thrasher Research Fund, the Hope Center for Neurological Disorders, the International Neurotrauma Society, and the Defense and Veterans Brain Injury Center.
Scans Detect Brain Damage in "Mild" Blast-Related TBI
Evidence of diffuse axonal injury has been detected using an advanced form of MRI in military personnel who were clinically diagnosed as having only mild blast-related traumatic brain injury, according to a report in the June 2 issue of the New England Journal of Medicine.
This is the first time that widespread structural brain damage reflecting axonal injury has been identified in "mild" blast-related traumatic brain injury (TBI). In addition, the study confirms that axonal injury might be a primary feature of such wounds, as animal studies and computer simulations have suggested, said Christine L. MacDonald, Ph.D., of Washington University in St. Louis, and her associates.
The findings, however, cannot yet be considered definitive because all of the subjects in this study also sustained another mechanism of head injury simultaneously with the blast-related injury. All of them experienced additional head injury from a fall or motor vehicle crash, or from being struck by blunt objects at the time of the explosion, so the effects of the blast cannot be differentiated from the effects of these traumas, the investigators noted.
They studied 84 members of the military who were injured in explosions in Iraq or Afghanistan during a 5-month period. A total of 63 had blast-related TBI that was judged on clinical assessment to be mild and uncomplicated, and 21 who had other injuries, chiefly orthopedic or soft-tissue wounds in the arms or legs, served as controls.
The study subjects underwent initial brain MRI when they were evacuated to Landstuhl Regional Medical Center in Germany immediately after they were wounded and follow-up MRI 6-12 months later at Washington University.
In addition to regular MRI, the subjects’ brains were scanned using diffusion tensor imaging (DTI), an advanced MRI method that measures water diffusion in many directions. Reduced anisotropy (directional asymmetry) of water diffusion on DTI is a marker of traumatic axonal injury.
Conventional MRI revealed abnormalities in only one of the TBI subjects, but DTI demonstrated reduced anisotropy in 18 (29%) of these subjects, across several of the 17 brain regions assessed in each subject. An additional 20 TBI subjects (32%) showed an abnormality within a single brain region on DTI.
"Quantitative analyses indicated significant reductions in relative anisotropy in the group of subjects with TBI as compared with the control group," Dr. MacDonald and her colleagues said (N. Engl. J. Med. 2011;364:2091-100).
Compared with control subjects, the TBI patients showed marked abnormalities in the middle cerebral peduncles, in cingulum bundles, and in the right orbitofrontal white matter – areas that have been predicted by computer simulations to sustain the most intense stresses during a blast. These are not the same regions of the brain that are commonly injured in civilian cases of TBI that do not involve blast exposure, they noted.
"The characteristics of the abnormal DTI signals changed between initial scanning and follow-up scanning, in a fashion that was consistent with the evolution of relatively acute injuries," the researchers said.
The follow-up scans indicated that the edema and cellular inflammation accompanying the axonal injury was resolving while the axonal injury itself persisted.
The investigators said that DTI assessments "may be useful in diagnosis, triage, and treatment planning in clinical practice" since the method "can be performed relatively quickly on the MRI scanners at U.S. military facilities and civilian hospitals."
Dr. MacDonald and her associates emphasized, however, that the findings in this study are preliminary and that TBI remains primarily a clinical diagnosis. "Normal findings on a DTI scan do not rule out TBI, nor are DTI findings in isolation sufficient to make this diagnosis with certainty," they noted.
The investigators noted several limitations of the study, including a moderate sample size and an all-male study population. Several studies of the relationship between DTI abnormalities and clinical outcomes are currently under way, they added.
This study was supported by the Congressionally Directed Medical Research Program and the National Institutes of Health. Dr. MacDonald’s associate, Dr. David L. Brody, reported ties to Wuestling and James Medicolegal Consulting, Burroughs Wellcome Fund, Thrasher Research Fund, the Hope Center for Neurological Disorders, the International Neurotrauma Society, and the Defense and Veterans Brain Injury Center. Dr. Ropper reported no financial conflicts of interest relevant to his commentary.
Until now, "there has been skepticism as to whether a blast that has occurred at a distance and inflicted no visible wound can penetrate the skull and damage the brain," said Dr. Allan Ropper.
"We now have tentative validation in mild TBI of the disruption of cerebral axons by blasts from improvised explosive devices," he said.
There are two key findings by Christine L. MacDonald, Ph.D., and her colleagues: The first is "the contrast between the results of imaging performed with DTI, which shows many regions of axonal disruption, and those achieved with conventional MRI, which usually shows little or no evidence of such disruption."
The second crucial finding is "the evolution of the imaging abnormalities detected on DTI during study follow-up in a manner that suggests the injury occurred at the time of the blast and was not the result of some indeterminate previous head injury," he said.
Dr. Ropper is with the department of neurology at Brigham and Women’s Hospital, Boston. He reported no financial conflicts of interest relevant to this commentary. These remarks were taken from his editorial accompanying Dr. MacDonald’s report (N. Engl. J. Med. 2011;364:2156-7).
Until now, "there has been skepticism as to whether a blast that has occurred at a distance and inflicted no visible wound can penetrate the skull and damage the brain," said Dr. Allan Ropper.
"We now have tentative validation in mild TBI of the disruption of cerebral axons by blasts from improvised explosive devices," he said.
There are two key findings by Christine L. MacDonald, Ph.D., and her colleagues: The first is "the contrast between the results of imaging performed with DTI, which shows many regions of axonal disruption, and those achieved with conventional MRI, which usually shows little or no evidence of such disruption."
The second crucial finding is "the evolution of the imaging abnormalities detected on DTI during study follow-up in a manner that suggests the injury occurred at the time of the blast and was not the result of some indeterminate previous head injury," he said.
Dr. Ropper is with the department of neurology at Brigham and Women’s Hospital, Boston. He reported no financial conflicts of interest relevant to this commentary. These remarks were taken from his editorial accompanying Dr. MacDonald’s report (N. Engl. J. Med. 2011;364:2156-7).
Until now, "there has been skepticism as to whether a blast that has occurred at a distance and inflicted no visible wound can penetrate the skull and damage the brain," said Dr. Allan Ropper.
"We now have tentative validation in mild TBI of the disruption of cerebral axons by blasts from improvised explosive devices," he said.
There are two key findings by Christine L. MacDonald, Ph.D., and her colleagues: The first is "the contrast between the results of imaging performed with DTI, which shows many regions of axonal disruption, and those achieved with conventional MRI, which usually shows little or no evidence of such disruption."
The second crucial finding is "the evolution of the imaging abnormalities detected on DTI during study follow-up in a manner that suggests the injury occurred at the time of the blast and was not the result of some indeterminate previous head injury," he said.
Dr. Ropper is with the department of neurology at Brigham and Women’s Hospital, Boston. He reported no financial conflicts of interest relevant to this commentary. These remarks were taken from his editorial accompanying Dr. MacDonald’s report (N. Engl. J. Med. 2011;364:2156-7).
Evidence of diffuse axonal injury has been detected using an advanced form of MRI in military personnel who were clinically diagnosed as having only mild blast-related traumatic brain injury, according to a report in the June 2 issue of the New England Journal of Medicine.
This is the first time that widespread structural brain damage reflecting axonal injury has been identified in "mild" blast-related traumatic brain injury (TBI). In addition, the study confirms that axonal injury might be a primary feature of such wounds, as animal studies and computer simulations have suggested, said Christine L. MacDonald, Ph.D., of Washington University in St. Louis, and her associates.
The findings, however, cannot yet be considered definitive because all of the subjects in this study also sustained another mechanism of head injury simultaneously with the blast-related injury. All of them experienced additional head injury from a fall or motor vehicle crash, or from being struck by blunt objects at the time of the explosion, so the effects of the blast cannot be differentiated from the effects of these traumas, the investigators noted.
They studied 84 members of the military who were injured in explosions in Iraq or Afghanistan during a 5-month period. A total of 63 had blast-related TBI that was judged on clinical assessment to be mild and uncomplicated, and 21 who had other injuries, chiefly orthopedic or soft-tissue wounds in the arms or legs, served as controls.
The study subjects underwent initial brain MRI when they were evacuated to Landstuhl Regional Medical Center in Germany immediately after they were wounded and follow-up MRI 6-12 months later at Washington University.
In addition to regular MRI, the subjects’ brains were scanned using diffusion tensor imaging (DTI), an advanced MRI method that measures water diffusion in many directions. Reduced anisotropy (directional asymmetry) of water diffusion on DTI is a marker of traumatic axonal injury.
Conventional MRI revealed abnormalities in only one of the TBI subjects, but DTI demonstrated reduced anisotropy in 18 (29%) of these subjects, across several of the 17 brain regions assessed in each subject. An additional 20 TBI subjects (32%) showed an abnormality within a single brain region on DTI.
"Quantitative analyses indicated significant reductions in relative anisotropy in the group of subjects with TBI as compared with the control group," Dr. MacDonald and her colleagues said (N. Engl. J. Med. 2011;364:2091-100).
Compared with control subjects, the TBI patients showed marked abnormalities in the middle cerebral peduncles, in cingulum bundles, and in the right orbitofrontal white matter – areas that have been predicted by computer simulations to sustain the most intense stresses during a blast. These are not the same regions of the brain that are commonly injured in civilian cases of TBI that do not involve blast exposure, they noted.
"The characteristics of the abnormal DTI signals changed between initial scanning and follow-up scanning, in a fashion that was consistent with the evolution of relatively acute injuries," the researchers said.
The follow-up scans indicated that the edema and cellular inflammation accompanying the axonal injury was resolving while the axonal injury itself persisted.
The investigators said that DTI assessments "may be useful in diagnosis, triage, and treatment planning in clinical practice" since the method "can be performed relatively quickly on the MRI scanners at U.S. military facilities and civilian hospitals."
Dr. MacDonald and her associates emphasized, however, that the findings in this study are preliminary and that TBI remains primarily a clinical diagnosis. "Normal findings on a DTI scan do not rule out TBI, nor are DTI findings in isolation sufficient to make this diagnosis with certainty," they noted.
The investigators noted several limitations of the study, including a moderate sample size and an all-male study population. Several studies of the relationship between DTI abnormalities and clinical outcomes are currently under way, they added.
This study was supported by the Congressionally Directed Medical Research Program and the National Institutes of Health. Dr. MacDonald’s associate, Dr. David L. Brody, reported ties to Wuestling and James Medicolegal Consulting, Burroughs Wellcome Fund, Thrasher Research Fund, the Hope Center for Neurological Disorders, the International Neurotrauma Society, and the Defense and Veterans Brain Injury Center. Dr. Ropper reported no financial conflicts of interest relevant to his commentary.
Evidence of diffuse axonal injury has been detected using an advanced form of MRI in military personnel who were clinically diagnosed as having only mild blast-related traumatic brain injury, according to a report in the June 2 issue of the New England Journal of Medicine.
This is the first time that widespread structural brain damage reflecting axonal injury has been identified in "mild" blast-related traumatic brain injury (TBI). In addition, the study confirms that axonal injury might be a primary feature of such wounds, as animal studies and computer simulations have suggested, said Christine L. MacDonald, Ph.D., of Washington University in St. Louis, and her associates.
The findings, however, cannot yet be considered definitive because all of the subjects in this study also sustained another mechanism of head injury simultaneously with the blast-related injury. All of them experienced additional head injury from a fall or motor vehicle crash, or from being struck by blunt objects at the time of the explosion, so the effects of the blast cannot be differentiated from the effects of these traumas, the investigators noted.
They studied 84 members of the military who were injured in explosions in Iraq or Afghanistan during a 5-month period. A total of 63 had blast-related TBI that was judged on clinical assessment to be mild and uncomplicated, and 21 who had other injuries, chiefly orthopedic or soft-tissue wounds in the arms or legs, served as controls.
The study subjects underwent initial brain MRI when they were evacuated to Landstuhl Regional Medical Center in Germany immediately after they were wounded and follow-up MRI 6-12 months later at Washington University.
In addition to regular MRI, the subjects’ brains were scanned using diffusion tensor imaging (DTI), an advanced MRI method that measures water diffusion in many directions. Reduced anisotropy (directional asymmetry) of water diffusion on DTI is a marker of traumatic axonal injury.
Conventional MRI revealed abnormalities in only one of the TBI subjects, but DTI demonstrated reduced anisotropy in 18 (29%) of these subjects, across several of the 17 brain regions assessed in each subject. An additional 20 TBI subjects (32%) showed an abnormality within a single brain region on DTI.
"Quantitative analyses indicated significant reductions in relative anisotropy in the group of subjects with TBI as compared with the control group," Dr. MacDonald and her colleagues said (N. Engl. J. Med. 2011;364:2091-100).
Compared with control subjects, the TBI patients showed marked abnormalities in the middle cerebral peduncles, in cingulum bundles, and in the right orbitofrontal white matter – areas that have been predicted by computer simulations to sustain the most intense stresses during a blast. These are not the same regions of the brain that are commonly injured in civilian cases of TBI that do not involve blast exposure, they noted.
"The characteristics of the abnormal DTI signals changed between initial scanning and follow-up scanning, in a fashion that was consistent with the evolution of relatively acute injuries," the researchers said.
The follow-up scans indicated that the edema and cellular inflammation accompanying the axonal injury was resolving while the axonal injury itself persisted.
The investigators said that DTI assessments "may be useful in diagnosis, triage, and treatment planning in clinical practice" since the method "can be performed relatively quickly on the MRI scanners at U.S. military facilities and civilian hospitals."
Dr. MacDonald and her associates emphasized, however, that the findings in this study are preliminary and that TBI remains primarily a clinical diagnosis. "Normal findings on a DTI scan do not rule out TBI, nor are DTI findings in isolation sufficient to make this diagnosis with certainty," they noted.
The investigators noted several limitations of the study, including a moderate sample size and an all-male study population. Several studies of the relationship between DTI abnormalities and clinical outcomes are currently under way, they added.
This study was supported by the Congressionally Directed Medical Research Program and the National Institutes of Health. Dr. MacDonald’s associate, Dr. David L. Brody, reported ties to Wuestling and James Medicolegal Consulting, Burroughs Wellcome Fund, Thrasher Research Fund, the Hope Center for Neurological Disorders, the International Neurotrauma Society, and the Defense and Veterans Brain Injury Center. Dr. Ropper reported no financial conflicts of interest relevant to his commentary.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Major Finding: Diffusion tensor imaging demonstrated widespread axonal injury in 18 of 63 military personnel with mild blast-related TBI and axonal injury in a single brain region in an additional 20. Conventional MRI revealed abnormalities in only one of the TBI subjects.
Data Source: An assessment of axonal injury using DTI in 63 U.S. military personnel with a clinical diagnosis of mild, uncomplicated TBI.
Disclosures: This study was supported by the Congressionally Directed Medical Research Program and the National Institutes of Health. Dr. MacDonald’s associate, Dr. David L. Brody, reported ties to Wuestling and James Medicolegal Consulting, Burroughs Wellcome Fund, Thrasher Research Fund, the Hope Center for Neurological Disorders, the International Neurotrauma Society, and the Defense and Veterans Brain Injury Center.
Heavy Coffee Consumption Linked to Better Hep C Treatment Response
Patients with advanced hepatitis C virus–related liver disease who drank three or more cups of coffee per day were three times more likely to respond to therapy with peginterferon alfa-2a plus ribavirin at four time points than were patients who didn’t drink coffee, Neal David Freedman, Ph.D., and his colleagues reported in the June issue of Gastroenterology.
The reason for this benefit is not yet known, but it appears that coffee drinkers’ improved response was independent of other factors known to influence hepatitis C virus (HCV) virologic response to therapy, such as the patient’s race, serum HCV RNA level, the presence or absence of cirrhosis, and the AST/ALT (aspartate aminotransferase/alanine aminotransferase) ratio, said Dr. Freedman of the National Cancer Institute and his associates.
In previous studies of hepatic disease, coffee drinking has been associated with lower levels of liver enzymes, a reduced progression of chronic liver disease, and a decreased incidence of hepatocellular carcinoma. But coffee’s effect in chronic HCV infection has not been studied until now.
The investigators examined coffee intake and virologic response to treatment using data from the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) trial, which involved patients with chronic hepatitis C who had fibrosis or cirrhosis at baseline, showed no sign of hepatic decompensation or hepatocellular carcinoma, and had failed to respond to interferon therapy.
For this study, Dr. Freedman and his colleagues assessed 885 subjects who completed a food frequency questionnaire at the beginning of the study. This included a measure of the portion size and frequency of coffee and tea intake, but did not distinguish between caffeinated and decaffeinated drinks and did not differentiate black tea from green tea.
A total of 85% of the subjects were coffee drinkers, and 15% of subjects drank three or more cups per day, which was defined as heavy coffee consumption.
The data showed that 61% of the heavy coffee drinkers tolerated the full dose of peginterferon alfa-2a plus ribavirin, while only 50% of the non–coffee drinkers did so (P = .0015). Heavy coffee drinkers also were less likely to require a dose reduction because of either a low neutrophil count or a low platelet count.
The decline in serum HCV RNA levels during treatment was greater with higher coffee intake. In addition, the absolute levels of HCV RNA were lower in heavy coffee drinkers than in nondrinkers at weeks 12, 20, and 24 of treatment. These benefits were seen even though higher coffee consumption had been associated with higher initial HCV RNA levels at baseline, the researchers noted.
In addition, heavy coffee drinkers were more likely than nondrinkers to show a virologic response early in the course of treatment (73% vs. 46%), to show no detectable serum HCV RNA at week 20 (52% vs. 26%), to show no detectable serum HCV RNA at week 48 (49% vs. 22%), and to have a sustained virologic response (26% vs. 11%).
Adjustment of the data to account for potential confounding factors such as age, sex, race, alcohol use, the presence of cirrhosis, the AST/ALT ratio, the baseline HCV RNA level, and the HCV genotype attenuated the associations with coffee somewhat, but the correlations remained significant at each virologic response end point.
The association between heavy coffee drinking and improved virologic response persisted in a subgroup analysis of only white patients, and it was actually stronger in patients with an unfavorable genotype (positive for the IL28B SNP rs12979860) than in those with a favorable genotype (negative for that SNP).
In contrast to these findings for coffee, there were no associations between tea drinking and treatment response.
Coffee contains more than 1,000 compounds, "any one of which could be involved in the virologic response." This study could not differentiate any possible role for caffeine, a major constituent of coffee.
However, "it is unlikely that coffee or its constituents have a direct antiviral effect. If so, HCV RNA levels at baseline would have been expected to be lower with greater coffee consumption," when in fact they were higher. It is more likely that coffee facilitates the response to peginterferon and ribavirin by some mechanism that is not yet understood, perhaps related to its association with cholesterol or with insulin resistance.
"As in all observational studies, we cannot exclude unmeasured or residual confounding as an explanation for our results. Observed associations could also simply be due to chance," Dr. Freedman and his associates said.
For that reason, further studies are needed to replicate these results in other populations, they added.
This study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases, the National Cancer Institute, the National Center for Minority Health and Health Disparities, the National Center for Research Resources, and Hoffman–La Roche. One of Dr. Freedman’s associates reported ties to Hoffmann–La Roche (now Genentech) and Tibotec.
Patients with advanced hepatitis C virus–related liver disease who drank three or more cups of coffee per day were three times more likely to respond to therapy with peginterferon alfa-2a plus ribavirin at four time points than were patients who didn’t drink coffee, Neal David Freedman, Ph.D., and his colleagues reported in the June issue of Gastroenterology.
The reason for this benefit is not yet known, but it appears that coffee drinkers’ improved response was independent of other factors known to influence hepatitis C virus (HCV) virologic response to therapy, such as the patient’s race, serum HCV RNA level, the presence or absence of cirrhosis, and the AST/ALT (aspartate aminotransferase/alanine aminotransferase) ratio, said Dr. Freedman of the National Cancer Institute and his associates.
In previous studies of hepatic disease, coffee drinking has been associated with lower levels of liver enzymes, a reduced progression of chronic liver disease, and a decreased incidence of hepatocellular carcinoma. But coffee’s effect in chronic HCV infection has not been studied until now.
The investigators examined coffee intake and virologic response to treatment using data from the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) trial, which involved patients with chronic hepatitis C who had fibrosis or cirrhosis at baseline, showed no sign of hepatic decompensation or hepatocellular carcinoma, and had failed to respond to interferon therapy.
For this study, Dr. Freedman and his colleagues assessed 885 subjects who completed a food frequency questionnaire at the beginning of the study. This included a measure of the portion size and frequency of coffee and tea intake, but did not distinguish between caffeinated and decaffeinated drinks and did not differentiate black tea from green tea.
A total of 85% of the subjects were coffee drinkers, and 15% of subjects drank three or more cups per day, which was defined as heavy coffee consumption.
The data showed that 61% of the heavy coffee drinkers tolerated the full dose of peginterferon alfa-2a plus ribavirin, while only 50% of the non–coffee drinkers did so (P = .0015). Heavy coffee drinkers also were less likely to require a dose reduction because of either a low neutrophil count or a low platelet count.
The decline in serum HCV RNA levels during treatment was greater with higher coffee intake. In addition, the absolute levels of HCV RNA were lower in heavy coffee drinkers than in nondrinkers at weeks 12, 20, and 24 of treatment. These benefits were seen even though higher coffee consumption had been associated with higher initial HCV RNA levels at baseline, the researchers noted.
In addition, heavy coffee drinkers were more likely than nondrinkers to show a virologic response early in the course of treatment (73% vs. 46%), to show no detectable serum HCV RNA at week 20 (52% vs. 26%), to show no detectable serum HCV RNA at week 48 (49% vs. 22%), and to have a sustained virologic response (26% vs. 11%).
Adjustment of the data to account for potential confounding factors such as age, sex, race, alcohol use, the presence of cirrhosis, the AST/ALT ratio, the baseline HCV RNA level, and the HCV genotype attenuated the associations with coffee somewhat, but the correlations remained significant at each virologic response end point.
The association between heavy coffee drinking and improved virologic response persisted in a subgroup analysis of only white patients, and it was actually stronger in patients with an unfavorable genotype (positive for the IL28B SNP rs12979860) than in those with a favorable genotype (negative for that SNP).
In contrast to these findings for coffee, there were no associations between tea drinking and treatment response.
Coffee contains more than 1,000 compounds, "any one of which could be involved in the virologic response." This study could not differentiate any possible role for caffeine, a major constituent of coffee.
However, "it is unlikely that coffee or its constituents have a direct antiviral effect. If so, HCV RNA levels at baseline would have been expected to be lower with greater coffee consumption," when in fact they were higher. It is more likely that coffee facilitates the response to peginterferon and ribavirin by some mechanism that is not yet understood, perhaps related to its association with cholesterol or with insulin resistance.
"As in all observational studies, we cannot exclude unmeasured or residual confounding as an explanation for our results. Observed associations could also simply be due to chance," Dr. Freedman and his associates said.
For that reason, further studies are needed to replicate these results in other populations, they added.
This study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases, the National Cancer Institute, the National Center for Minority Health and Health Disparities, the National Center for Research Resources, and Hoffman–La Roche. One of Dr. Freedman’s associates reported ties to Hoffmann–La Roche (now Genentech) and Tibotec.
Patients with advanced hepatitis C virus–related liver disease who drank three or more cups of coffee per day were three times more likely to respond to therapy with peginterferon alfa-2a plus ribavirin at four time points than were patients who didn’t drink coffee, Neal David Freedman, Ph.D., and his colleagues reported in the June issue of Gastroenterology.
The reason for this benefit is not yet known, but it appears that coffee drinkers’ improved response was independent of other factors known to influence hepatitis C virus (HCV) virologic response to therapy, such as the patient’s race, serum HCV RNA level, the presence or absence of cirrhosis, and the AST/ALT (aspartate aminotransferase/alanine aminotransferase) ratio, said Dr. Freedman of the National Cancer Institute and his associates.
In previous studies of hepatic disease, coffee drinking has been associated with lower levels of liver enzymes, a reduced progression of chronic liver disease, and a decreased incidence of hepatocellular carcinoma. But coffee’s effect in chronic HCV infection has not been studied until now.
The investigators examined coffee intake and virologic response to treatment using data from the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) trial, which involved patients with chronic hepatitis C who had fibrosis or cirrhosis at baseline, showed no sign of hepatic decompensation or hepatocellular carcinoma, and had failed to respond to interferon therapy.
For this study, Dr. Freedman and his colleagues assessed 885 subjects who completed a food frequency questionnaire at the beginning of the study. This included a measure of the portion size and frequency of coffee and tea intake, but did not distinguish between caffeinated and decaffeinated drinks and did not differentiate black tea from green tea.
A total of 85% of the subjects were coffee drinkers, and 15% of subjects drank three or more cups per day, which was defined as heavy coffee consumption.
The data showed that 61% of the heavy coffee drinkers tolerated the full dose of peginterferon alfa-2a plus ribavirin, while only 50% of the non–coffee drinkers did so (P = .0015). Heavy coffee drinkers also were less likely to require a dose reduction because of either a low neutrophil count or a low platelet count.
The decline in serum HCV RNA levels during treatment was greater with higher coffee intake. In addition, the absolute levels of HCV RNA were lower in heavy coffee drinkers than in nondrinkers at weeks 12, 20, and 24 of treatment. These benefits were seen even though higher coffee consumption had been associated with higher initial HCV RNA levels at baseline, the researchers noted.
In addition, heavy coffee drinkers were more likely than nondrinkers to show a virologic response early in the course of treatment (73% vs. 46%), to show no detectable serum HCV RNA at week 20 (52% vs. 26%), to show no detectable serum HCV RNA at week 48 (49% vs. 22%), and to have a sustained virologic response (26% vs. 11%).
Adjustment of the data to account for potential confounding factors such as age, sex, race, alcohol use, the presence of cirrhosis, the AST/ALT ratio, the baseline HCV RNA level, and the HCV genotype attenuated the associations with coffee somewhat, but the correlations remained significant at each virologic response end point.
The association between heavy coffee drinking and improved virologic response persisted in a subgroup analysis of only white patients, and it was actually stronger in patients with an unfavorable genotype (positive for the IL28B SNP rs12979860) than in those with a favorable genotype (negative for that SNP).
In contrast to these findings for coffee, there were no associations between tea drinking and treatment response.
Coffee contains more than 1,000 compounds, "any one of which could be involved in the virologic response." This study could not differentiate any possible role for caffeine, a major constituent of coffee.
However, "it is unlikely that coffee or its constituents have a direct antiviral effect. If so, HCV RNA levels at baseline would have been expected to be lower with greater coffee consumption," when in fact they were higher. It is more likely that coffee facilitates the response to peginterferon and ribavirin by some mechanism that is not yet understood, perhaps related to its association with cholesterol or with insulin resistance.
"As in all observational studies, we cannot exclude unmeasured or residual confounding as an explanation for our results. Observed associations could also simply be due to chance," Dr. Freedman and his associates said.
For that reason, further studies are needed to replicate these results in other populations, they added.
This study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases, the National Cancer Institute, the National Center for Minority Health and Health Disparities, the National Center for Research Resources, and Hoffman–La Roche. One of Dr. Freedman’s associates reported ties to Hoffmann–La Roche (now Genentech) and Tibotec.
FROM GASTROENTEROLOGY
Heavy Coffee Consumption Linked to Better Hep C Treatment Response
Patients with advanced hepatitis C virus–related liver disease who drank three or more cups of coffee per day were three times more likely to respond to therapy with peginterferon alfa-2a plus ribavirin at four time points than were patients who didn’t drink coffee, Neal David Freedman, Ph.D., and his colleagues reported in the June issue of Gastroenterology.
The reason for this benefit is not yet known, but it appears that coffee drinkers’ improved response was independent of other factors known to influence hepatitis C virus (HCV) virologic response to therapy, such as the patient’s race, serum HCV RNA level, the presence or absence of cirrhosis, and the AST/ALT (aspartate aminotransferase/alanine aminotransferase) ratio, said Dr. Freedman of the National Cancer Institute and his associates.
In previous studies of hepatic disease, coffee drinking has been associated with lower levels of liver enzymes, a reduced progression of chronic liver disease, and a decreased incidence of hepatocellular carcinoma. But coffee’s effect in chronic HCV infection has not been studied until now.
The investigators examined coffee intake and virologic response to treatment using data from the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) trial, which involved patients with chronic hepatitis C who had fibrosis or cirrhosis at baseline, showed no sign of hepatic decompensation or hepatocellular carcinoma, and had failed to respond to interferon therapy.
For this study, Dr. Freedman and his colleagues assessed 885 subjects who completed a food frequency questionnaire at the beginning of the study. This included a measure of the portion size and frequency of coffee and tea intake, but did not distinguish between caffeinated and decaffeinated drinks and did not differentiate black tea from green tea.
A total of 85% of the subjects were coffee drinkers, and 15% of subjects drank three or more cups per day, which was defined as heavy coffee consumption.
The data showed that 61% of the heavy coffee drinkers tolerated the full dose of peginterferon alfa-2a plus ribavirin, while only 50% of the non–coffee drinkers did so (P = .0015). Heavy coffee drinkers also were less likely to require a dose reduction because of either a low neutrophil count or a low platelet count.
The decline in serum HCV RNA levels during treatment was greater with higher coffee intake. In addition, the absolute levels of HCV RNA were lower in heavy coffee drinkers than in nondrinkers at weeks 12, 20, and 24 of treatment. These benefits were seen even though higher coffee consumption had been associated with higher initial HCV RNA levels at baseline, the researchers noted.
In addition, heavy coffee drinkers were more likely than nondrinkers to show a virologic response early in the course of treatment (73% vs. 46%), to show no detectable serum HCV RNA at week 20 (52% vs. 26%), to show no detectable serum HCV RNA at week 48 (49% vs. 22%), and to have a sustained virologic response (26% vs. 11%).
Adjustment of the data to account for potential confounding factors such as age, sex, race, alcohol use, the presence of cirrhosis, the AST/ALT ratio, the baseline HCV RNA level, and the HCV genotype attenuated the associations with coffee somewhat, but the correlations remained significant at each virologic response end point.
The association between heavy coffee drinking and improved virologic response persisted in a subgroup analysis of only white patients, and it was actually stronger in patients with an unfavorable genotype (positive for the IL28B SNP rs12979860) than in those with a favorable genotype (negative for that SNP).
In contrast to these findings for coffee, there were no associations between tea drinking and treatment response.
Coffee contains more than 1,000 compounds, "any one of which could be involved in the virologic response." This study could not differentiate any possible role for caffeine, a major constituent of coffee.
However, "it is unlikely that coffee or its constituents have a direct antiviral effect. If so, HCV RNA levels at baseline would have been expected to be lower with greater coffee consumption," when in fact they were higher. It is more likely that coffee facilitates the response to peginterferon and ribavirin by some mechanism that is not yet understood, perhaps related to its association with cholesterol or with insulin resistance.
"As in all observational studies, we cannot exclude unmeasured or residual confounding as an explanation for our results. Observed associations could also simply be due to chance," Dr. Freedman and his associates said.
For that reason, further studies are needed to replicate these results in other populations, they added.
This study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases, the National Cancer Institute, the National Center for Minority Health and Health Disparities, the National Center for Research Resources, and Hoffman–La Roche. One of Dr. Freedman’s associates reported ties to Hoffmann–La Roche (now Genentech) and Tibotec.
Patients with advanced hepatitis C virus–related liver disease who drank three or more cups of coffee per day were three times more likely to respond to therapy with peginterferon alfa-2a plus ribavirin at four time points than were patients who didn’t drink coffee, Neal David Freedman, Ph.D., and his colleagues reported in the June issue of Gastroenterology.
The reason for this benefit is not yet known, but it appears that coffee drinkers’ improved response was independent of other factors known to influence hepatitis C virus (HCV) virologic response to therapy, such as the patient’s race, serum HCV RNA level, the presence or absence of cirrhosis, and the AST/ALT (aspartate aminotransferase/alanine aminotransferase) ratio, said Dr. Freedman of the National Cancer Institute and his associates.
In previous studies of hepatic disease, coffee drinking has been associated with lower levels of liver enzymes, a reduced progression of chronic liver disease, and a decreased incidence of hepatocellular carcinoma. But coffee’s effect in chronic HCV infection has not been studied until now.
The investigators examined coffee intake and virologic response to treatment using data from the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) trial, which involved patients with chronic hepatitis C who had fibrosis or cirrhosis at baseline, showed no sign of hepatic decompensation or hepatocellular carcinoma, and had failed to respond to interferon therapy.
For this study, Dr. Freedman and his colleagues assessed 885 subjects who completed a food frequency questionnaire at the beginning of the study. This included a measure of the portion size and frequency of coffee and tea intake, but did not distinguish between caffeinated and decaffeinated drinks and did not differentiate black tea from green tea.
A total of 85% of the subjects were coffee drinkers, and 15% of subjects drank three or more cups per day, which was defined as heavy coffee consumption.
The data showed that 61% of the heavy coffee drinkers tolerated the full dose of peginterferon alfa-2a plus ribavirin, while only 50% of the non–coffee drinkers did so (P = .0015). Heavy coffee drinkers also were less likely to require a dose reduction because of either a low neutrophil count or a low platelet count.
The decline in serum HCV RNA levels during treatment was greater with higher coffee intake. In addition, the absolute levels of HCV RNA were lower in heavy coffee drinkers than in nondrinkers at weeks 12, 20, and 24 of treatment. These benefits were seen even though higher coffee consumption had been associated with higher initial HCV RNA levels at baseline, the researchers noted.
In addition, heavy coffee drinkers were more likely than nondrinkers to show a virologic response early in the course of treatment (73% vs. 46%), to show no detectable serum HCV RNA at week 20 (52% vs. 26%), to show no detectable serum HCV RNA at week 48 (49% vs. 22%), and to have a sustained virologic response (26% vs. 11%).
Adjustment of the data to account for potential confounding factors such as age, sex, race, alcohol use, the presence of cirrhosis, the AST/ALT ratio, the baseline HCV RNA level, and the HCV genotype attenuated the associations with coffee somewhat, but the correlations remained significant at each virologic response end point.
The association between heavy coffee drinking and improved virologic response persisted in a subgroup analysis of only white patients, and it was actually stronger in patients with an unfavorable genotype (positive for the IL28B SNP rs12979860) than in those with a favorable genotype (negative for that SNP).
In contrast to these findings for coffee, there were no associations between tea drinking and treatment response.
Coffee contains more than 1,000 compounds, "any one of which could be involved in the virologic response." This study could not differentiate any possible role for caffeine, a major constituent of coffee.
However, "it is unlikely that coffee or its constituents have a direct antiviral effect. If so, HCV RNA levels at baseline would have been expected to be lower with greater coffee consumption," when in fact they were higher. It is more likely that coffee facilitates the response to peginterferon and ribavirin by some mechanism that is not yet understood, perhaps related to its association with cholesterol or with insulin resistance.
"As in all observational studies, we cannot exclude unmeasured or residual confounding as an explanation for our results. Observed associations could also simply be due to chance," Dr. Freedman and his associates said.
For that reason, further studies are needed to replicate these results in other populations, they added.
This study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases, the National Cancer Institute, the National Center for Minority Health and Health Disparities, the National Center for Research Resources, and Hoffman–La Roche. One of Dr. Freedman’s associates reported ties to Hoffmann–La Roche (now Genentech) and Tibotec.
Patients with advanced hepatitis C virus–related liver disease who drank three or more cups of coffee per day were three times more likely to respond to therapy with peginterferon alfa-2a plus ribavirin at four time points than were patients who didn’t drink coffee, Neal David Freedman, Ph.D., and his colleagues reported in the June issue of Gastroenterology.
The reason for this benefit is not yet known, but it appears that coffee drinkers’ improved response was independent of other factors known to influence hepatitis C virus (HCV) virologic response to therapy, such as the patient’s race, serum HCV RNA level, the presence or absence of cirrhosis, and the AST/ALT (aspartate aminotransferase/alanine aminotransferase) ratio, said Dr. Freedman of the National Cancer Institute and his associates.
In previous studies of hepatic disease, coffee drinking has been associated with lower levels of liver enzymes, a reduced progression of chronic liver disease, and a decreased incidence of hepatocellular carcinoma. But coffee’s effect in chronic HCV infection has not been studied until now.
The investigators examined coffee intake and virologic response to treatment using data from the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) trial, which involved patients with chronic hepatitis C who had fibrosis or cirrhosis at baseline, showed no sign of hepatic decompensation or hepatocellular carcinoma, and had failed to respond to interferon therapy.
For this study, Dr. Freedman and his colleagues assessed 885 subjects who completed a food frequency questionnaire at the beginning of the study. This included a measure of the portion size and frequency of coffee and tea intake, but did not distinguish between caffeinated and decaffeinated drinks and did not differentiate black tea from green tea.
A total of 85% of the subjects were coffee drinkers, and 15% of subjects drank three or more cups per day, which was defined as heavy coffee consumption.
The data showed that 61% of the heavy coffee drinkers tolerated the full dose of peginterferon alfa-2a plus ribavirin, while only 50% of the non–coffee drinkers did so (P = .0015). Heavy coffee drinkers also were less likely to require a dose reduction because of either a low neutrophil count or a low platelet count.
The decline in serum HCV RNA levels during treatment was greater with higher coffee intake. In addition, the absolute levels of HCV RNA were lower in heavy coffee drinkers than in nondrinkers at weeks 12, 20, and 24 of treatment. These benefits were seen even though higher coffee consumption had been associated with higher initial HCV RNA levels at baseline, the researchers noted.
In addition, heavy coffee drinkers were more likely than nondrinkers to show a virologic response early in the course of treatment (73% vs. 46%), to show no detectable serum HCV RNA at week 20 (52% vs. 26%), to show no detectable serum HCV RNA at week 48 (49% vs. 22%), and to have a sustained virologic response (26% vs. 11%).
Adjustment of the data to account for potential confounding factors such as age, sex, race, alcohol use, the presence of cirrhosis, the AST/ALT ratio, the baseline HCV RNA level, and the HCV genotype attenuated the associations with coffee somewhat, but the correlations remained significant at each virologic response end point.
The association between heavy coffee drinking and improved virologic response persisted in a subgroup analysis of only white patients, and it was actually stronger in patients with an unfavorable genotype (positive for the IL28B SNP rs12979860) than in those with a favorable genotype (negative for that SNP).
In contrast to these findings for coffee, there were no associations between tea drinking and treatment response.
Coffee contains more than 1,000 compounds, "any one of which could be involved in the virologic response." This study could not differentiate any possible role for caffeine, a major constituent of coffee.
However, "it is unlikely that coffee or its constituents have a direct antiviral effect. If so, HCV RNA levels at baseline would have been expected to be lower with greater coffee consumption," when in fact they were higher. It is more likely that coffee facilitates the response to peginterferon and ribavirin by some mechanism that is not yet understood, perhaps related to its association with cholesterol or with insulin resistance.
"As in all observational studies, we cannot exclude unmeasured or residual confounding as an explanation for our results. Observed associations could also simply be due to chance," Dr. Freedman and his associates said.
For that reason, further studies are needed to replicate these results in other populations, they added.
This study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases, the National Cancer Institute, the National Center for Minority Health and Health Disparities, the National Center for Research Resources, and Hoffman–La Roche. One of Dr. Freedman’s associates reported ties to Hoffmann–La Roche (now Genentech) and Tibotec.
FROM GASTROENTEROLOGY
NAFLD Rising, Already Accounts for 75% of Chronic Liver Disease
Nonalcoholic fatty liver disease may soon become the most important cause of chronic liver disease in the United States, "with a substantial clinical and economic impact," Dr. Zobair M. Younossi, AGAF, and his colleagues reported in the June issue of Clinical Gastroenterology and Hepatology.
In what they described as the first population-based study to assess changes in the prevalence of chronic liver diseases over the past 20 years, the authors found that the prevalence is steadily rising in only one major category: nonalcoholic fatty liver disease (NAFLD). In contrast, rates of chronic liver disease related to hepatitis B virus, hepatitis C virus, and alcohol use have remained stable (Clin. Gastroenterol. Hepatol. 2011 June [doi: 10.1016/j.cgh.2011.03.020]).
The rise in NAFLD correlates with the well-known increases in obesity and type 2 diabetes, and the study findings suggest that liver disease "will remain among the major causes of mortality and morbidity in the U.S. and will be responsible for substantial medical resource utilization."
"This issue becomes especially important as we face a potential decline in the availability of resources dedicated to the care of patients with chronic diseases, as well as the expected shortage of individuals trained in hepatology who are available to care for these patients," said Dr. Younossi, executive director of the Center for Liver Diseases at Inova Fairfax (Va.) Hospital, and his associates.
The investigators used data from the National Health and Nutrition Examination Survey (NHANES), the CDC’s assessments of health and nutrition in nationally representative samples of the adult population, to track trends in chronic liver disease during three periods: 1988-1994 (15,855 subjects), 1999-2004 (13,970 subjects), and 2005-2008 (9,670 subjects).
The prevalence of the four types of chronic liver disease combined increased during this 20-year interval, from 12% to 15%. However, that was driven entirely by the increasing prevalence of NAFLD-related liver disease alone, which rose from 5.5% in 1988-1994, to 9.8% in 1999-2004, to 11.0% in 2005-2008.
In contrast, the prevalence of chronic liver disease related to hepatitis B remained stable (0.4%, 0.3%, and 0.3%, respectively), as did that related to hepatitis C (2%, 2%, and 2%, respectively). The prevalence of alcohol-related chronic liver disease also remained stable over the 3 time periods, at 1.4%, 2%, and 2%, respectively.
In a further analysis of the data, the researchers found that the proportion of chronic liver disease attributable to NAFLD also rose significantly during these three time periods. NAFLD accounted for 47% of chronic liver disease in 1988-1994, which increased to 63% in 1999-2004 and to 75% in 2005-2008.
To assess the underlying causes of this increase in NAFLD, the investigators studied changes in the rates of metabolic syndrome components, all of which are known to be risk factors for NAFLD.
Significant increases during this same time span were found for prevalence of obesity, visceral obesity, type 2 diabetes, insulin resistance, and hypertension. Hypercholesterolemia was the only component of the metabolic syndrome that did not rise significantly.
"We postulate that by treating components of the metabolic syndrome in patients with chronic liver disease, we may be able to ameliorate the anticipated wave of liver disease complications in the U.S.," the investigators said.
To do so, "we must expand patients’ access to care and the availability of insurance coverage, encourage more targeted treatment strategies, and increase the training of experts and health care extenders capable of delivering care to these patients," they added.
This study included only adults, but "given the reports from other databases and tertiary care centers regarding children with liver disease, we suspect that our findings are applicable to children and adolescents in the U.S."
"The increasing prevalence of obesity and NAFLD among U.S. children and adolescents makes the future projections even direr," the authors wrote.
"As this young population ages, they are expected to become more obese and more likely to develop type 2 diabetes, both of which can lead to even higher rates of NAFLD. This cohort will certainly contribute to the future burden of chronic liver disease ... which could potentially become overwhelming," they said.
Dr. Younossi and his associates reported that they have no conflicts of interest. The study was conducted with internal funds only.
Nonalcoholic fatty liver disease may soon become the most important cause of chronic liver disease in the United States, "with a substantial clinical and economic impact," Dr. Zobair M. Younossi, AGAF, and his colleagues reported in the June issue of Clinical Gastroenterology and Hepatology.
In what they described as the first population-based study to assess changes in the prevalence of chronic liver diseases over the past 20 years, the authors found that the prevalence is steadily rising in only one major category: nonalcoholic fatty liver disease (NAFLD). In contrast, rates of chronic liver disease related to hepatitis B virus, hepatitis C virus, and alcohol use have remained stable (Clin. Gastroenterol. Hepatol. 2011 June [doi: 10.1016/j.cgh.2011.03.020]).
The rise in NAFLD correlates with the well-known increases in obesity and type 2 diabetes, and the study findings suggest that liver disease "will remain among the major causes of mortality and morbidity in the U.S. and will be responsible for substantial medical resource utilization."
"This issue becomes especially important as we face a potential decline in the availability of resources dedicated to the care of patients with chronic diseases, as well as the expected shortage of individuals trained in hepatology who are available to care for these patients," said Dr. Younossi, executive director of the Center for Liver Diseases at Inova Fairfax (Va.) Hospital, and his associates.
The investigators used data from the National Health and Nutrition Examination Survey (NHANES), the CDC’s assessments of health and nutrition in nationally representative samples of the adult population, to track trends in chronic liver disease during three periods: 1988-1994 (15,855 subjects), 1999-2004 (13,970 subjects), and 2005-2008 (9,670 subjects).
The prevalence of the four types of chronic liver disease combined increased during this 20-year interval, from 12% to 15%. However, that was driven entirely by the increasing prevalence of NAFLD-related liver disease alone, which rose from 5.5% in 1988-1994, to 9.8% in 1999-2004, to 11.0% in 2005-2008.
In contrast, the prevalence of chronic liver disease related to hepatitis B remained stable (0.4%, 0.3%, and 0.3%, respectively), as did that related to hepatitis C (2%, 2%, and 2%, respectively). The prevalence of alcohol-related chronic liver disease also remained stable over the 3 time periods, at 1.4%, 2%, and 2%, respectively.
In a further analysis of the data, the researchers found that the proportion of chronic liver disease attributable to NAFLD also rose significantly during these three time periods. NAFLD accounted for 47% of chronic liver disease in 1988-1994, which increased to 63% in 1999-2004 and to 75% in 2005-2008.
To assess the underlying causes of this increase in NAFLD, the investigators studied changes in the rates of metabolic syndrome components, all of which are known to be risk factors for NAFLD.
Significant increases during this same time span were found for prevalence of obesity, visceral obesity, type 2 diabetes, insulin resistance, and hypertension. Hypercholesterolemia was the only component of the metabolic syndrome that did not rise significantly.
"We postulate that by treating components of the metabolic syndrome in patients with chronic liver disease, we may be able to ameliorate the anticipated wave of liver disease complications in the U.S.," the investigators said.
To do so, "we must expand patients’ access to care and the availability of insurance coverage, encourage more targeted treatment strategies, and increase the training of experts and health care extenders capable of delivering care to these patients," they added.
This study included only adults, but "given the reports from other databases and tertiary care centers regarding children with liver disease, we suspect that our findings are applicable to children and adolescents in the U.S."
"The increasing prevalence of obesity and NAFLD among U.S. children and adolescents makes the future projections even direr," the authors wrote.
"As this young population ages, they are expected to become more obese and more likely to develop type 2 diabetes, both of which can lead to even higher rates of NAFLD. This cohort will certainly contribute to the future burden of chronic liver disease ... which could potentially become overwhelming," they said.
Dr. Younossi and his associates reported that they have no conflicts of interest. The study was conducted with internal funds only.
Nonalcoholic fatty liver disease may soon become the most important cause of chronic liver disease in the United States, "with a substantial clinical and economic impact," Dr. Zobair M. Younossi, AGAF, and his colleagues reported in the June issue of Clinical Gastroenterology and Hepatology.
In what they described as the first population-based study to assess changes in the prevalence of chronic liver diseases over the past 20 years, the authors found that the prevalence is steadily rising in only one major category: nonalcoholic fatty liver disease (NAFLD). In contrast, rates of chronic liver disease related to hepatitis B virus, hepatitis C virus, and alcohol use have remained stable (Clin. Gastroenterol. Hepatol. 2011 June [doi: 10.1016/j.cgh.2011.03.020]).
The rise in NAFLD correlates with the well-known increases in obesity and type 2 diabetes, and the study findings suggest that liver disease "will remain among the major causes of mortality and morbidity in the U.S. and will be responsible for substantial medical resource utilization."
"This issue becomes especially important as we face a potential decline in the availability of resources dedicated to the care of patients with chronic diseases, as well as the expected shortage of individuals trained in hepatology who are available to care for these patients," said Dr. Younossi, executive director of the Center for Liver Diseases at Inova Fairfax (Va.) Hospital, and his associates.
The investigators used data from the National Health and Nutrition Examination Survey (NHANES), the CDC’s assessments of health and nutrition in nationally representative samples of the adult population, to track trends in chronic liver disease during three periods: 1988-1994 (15,855 subjects), 1999-2004 (13,970 subjects), and 2005-2008 (9,670 subjects).
The prevalence of the four types of chronic liver disease combined increased during this 20-year interval, from 12% to 15%. However, that was driven entirely by the increasing prevalence of NAFLD-related liver disease alone, which rose from 5.5% in 1988-1994, to 9.8% in 1999-2004, to 11.0% in 2005-2008.
In contrast, the prevalence of chronic liver disease related to hepatitis B remained stable (0.4%, 0.3%, and 0.3%, respectively), as did that related to hepatitis C (2%, 2%, and 2%, respectively). The prevalence of alcohol-related chronic liver disease also remained stable over the 3 time periods, at 1.4%, 2%, and 2%, respectively.
In a further analysis of the data, the researchers found that the proportion of chronic liver disease attributable to NAFLD also rose significantly during these three time periods. NAFLD accounted for 47% of chronic liver disease in 1988-1994, which increased to 63% in 1999-2004 and to 75% in 2005-2008.
To assess the underlying causes of this increase in NAFLD, the investigators studied changes in the rates of metabolic syndrome components, all of which are known to be risk factors for NAFLD.
Significant increases during this same time span were found for prevalence of obesity, visceral obesity, type 2 diabetes, insulin resistance, and hypertension. Hypercholesterolemia was the only component of the metabolic syndrome that did not rise significantly.
"We postulate that by treating components of the metabolic syndrome in patients with chronic liver disease, we may be able to ameliorate the anticipated wave of liver disease complications in the U.S.," the investigators said.
To do so, "we must expand patients’ access to care and the availability of insurance coverage, encourage more targeted treatment strategies, and increase the training of experts and health care extenders capable of delivering care to these patients," they added.
This study included only adults, but "given the reports from other databases and tertiary care centers regarding children with liver disease, we suspect that our findings are applicable to children and adolescents in the U.S."
"The increasing prevalence of obesity and NAFLD among U.S. children and adolescents makes the future projections even direr," the authors wrote.
"As this young population ages, they are expected to become more obese and more likely to develop type 2 diabetes, both of which can lead to even higher rates of NAFLD. This cohort will certainly contribute to the future burden of chronic liver disease ... which could potentially become overwhelming," they said.
Dr. Younossi and his associates reported that they have no conflicts of interest. The study was conducted with internal funds only.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
NAFLD Rising, Already Accounts for 75% of Chronic Liver Disease
Nonalcoholic fatty liver disease may soon become the most important cause of chronic liver disease in the United States, "with a substantial clinical and economic impact," Dr. Zobair M. Younossi, AGAF, and his colleagues reported in the June issue of Clinical Gastroenterology and Hepatology.
In what they described as the first population-based study to assess changes in the prevalence of chronic liver diseases over the past 20 years, the authors found that the prevalence is steadily rising in only one major category: nonalcoholic fatty liver disease (NAFLD). In contrast, rates of chronic liver disease related to hepatitis B virus, hepatitis C virus, and alcohol use have remained stable (Clin. Gastroenterol. Hepatol. 2011 June [doi: 10.1016/j.cgh.2011.03.020]).
The rise in NAFLD correlates with the well-known increases in obesity and type 2 diabetes, and the study findings suggest that liver disease "will remain among the major causes of mortality and morbidity in the U.S. and will be responsible for substantial medical resource utilization."
"This issue becomes especially important as we face a potential decline in the availability of resources dedicated to the care of patients with chronic diseases, as well as the expected shortage of individuals trained in hepatology who are available to care for these patients," said Dr. Younossi, executive director of the Center for Liver Diseases at Inova Fairfax (Va.) Hospital, and his associates.
The investigators used data from the National Health and Nutrition Examination Survey (NHANES), the CDC’s assessments of health and nutrition in nationally representative samples of the adult population, to track trends in chronic liver disease during three periods: 1988-1994 (15,855 subjects), 1999-2004 (13,970 subjects), and 2005-2008 (9,670 subjects).
The prevalence of the four types of chronic liver disease combined increased during this 20-year interval, from 12% to 15%. However, that was driven entirely by the increasing prevalence of NAFLD-related liver disease alone, which rose from 5.5% in 1988-1994, to 9.8% in 1999-2004, to 11.0% in 2005-2008.
In contrast, the prevalence of chronic liver disease related to hepatitis B remained stable (0.4%, 0.3%, and 0.3%, respectively), as did that related to hepatitis C (2%, 2%, and 2%, respectively). The prevalence of alcohol-related chronic liver disease also remained stable over the 3 time periods, at 1.4%, 2%, and 2%, respectively.
In a further analysis of the data, the researchers found that the proportion of chronic liver disease attributable to NAFLD also rose significantly during these three time periods. NAFLD accounted for 47% of chronic liver disease in 1988-1994, which increased to 63% in 1999-2004 and to 75% in 2005-2008.
To assess the underlying causes of this increase in NAFLD, the investigators studied changes in the rates of metabolic syndrome components, all of which are known to be risk factors for NAFLD.
Significant increases during this same time span were found for prevalence of obesity, visceral obesity, type 2 diabetes, insulin resistance, and hypertension. Hypercholesterolemia was the only component of the metabolic syndrome that did not rise significantly.
"We postulate that by treating components of the metabolic syndrome in patients with chronic liver disease, we may be able to ameliorate the anticipated wave of liver disease complications in the U.S.," the investigators said.
To do so, "we must expand patients’ access to care and the availability of insurance coverage, encourage more targeted treatment strategies, and increase the training of experts and health care extenders capable of delivering care to these patients," they added.
This study included only adults, but "given the reports from other databases and tertiary care centers regarding children with liver disease, we suspect that our findings are applicable to children and adolescents in the U.S."
"The increasing prevalence of obesity and NAFLD among U.S. children and adolescents makes the future projections even direr," the authors wrote.
"As this young population ages, they are expected to become more obese and more likely to develop type 2 diabetes, both of which can lead to even higher rates of NAFLD. This cohort will certainly contribute to the future burden of chronic liver disease ... which could potentially become overwhelming," they said.
Dr. Younossi and his associates reported that they have no conflicts of interest. The study was conducted with internal funds only.
Nonalcoholic fatty liver disease may soon become the most important cause of chronic liver disease in the United States, "with a substantial clinical and economic impact," Dr. Zobair M. Younossi, AGAF, and his colleagues reported in the June issue of Clinical Gastroenterology and Hepatology.
In what they described as the first population-based study to assess changes in the prevalence of chronic liver diseases over the past 20 years, the authors found that the prevalence is steadily rising in only one major category: nonalcoholic fatty liver disease (NAFLD). In contrast, rates of chronic liver disease related to hepatitis B virus, hepatitis C virus, and alcohol use have remained stable (Clin. Gastroenterol. Hepatol. 2011 June [doi: 10.1016/j.cgh.2011.03.020]).
The rise in NAFLD correlates with the well-known increases in obesity and type 2 diabetes, and the study findings suggest that liver disease "will remain among the major causes of mortality and morbidity in the U.S. and will be responsible for substantial medical resource utilization."
"This issue becomes especially important as we face a potential decline in the availability of resources dedicated to the care of patients with chronic diseases, as well as the expected shortage of individuals trained in hepatology who are available to care for these patients," said Dr. Younossi, executive director of the Center for Liver Diseases at Inova Fairfax (Va.) Hospital, and his associates.
The investigators used data from the National Health and Nutrition Examination Survey (NHANES), the CDC’s assessments of health and nutrition in nationally representative samples of the adult population, to track trends in chronic liver disease during three periods: 1988-1994 (15,855 subjects), 1999-2004 (13,970 subjects), and 2005-2008 (9,670 subjects).
The prevalence of the four types of chronic liver disease combined increased during this 20-year interval, from 12% to 15%. However, that was driven entirely by the increasing prevalence of NAFLD-related liver disease alone, which rose from 5.5% in 1988-1994, to 9.8% in 1999-2004, to 11.0% in 2005-2008.
In contrast, the prevalence of chronic liver disease related to hepatitis B remained stable (0.4%, 0.3%, and 0.3%, respectively), as did that related to hepatitis C (2%, 2%, and 2%, respectively). The prevalence of alcohol-related chronic liver disease also remained stable over the 3 time periods, at 1.4%, 2%, and 2%, respectively.
In a further analysis of the data, the researchers found that the proportion of chronic liver disease attributable to NAFLD also rose significantly during these three time periods. NAFLD accounted for 47% of chronic liver disease in 1988-1994, which increased to 63% in 1999-2004 and to 75% in 2005-2008.
To assess the underlying causes of this increase in NAFLD, the investigators studied changes in the rates of metabolic syndrome components, all of which are known to be risk factors for NAFLD.
Significant increases during this same time span were found for prevalence of obesity, visceral obesity, type 2 diabetes, insulin resistance, and hypertension. Hypercholesterolemia was the only component of the metabolic syndrome that did not rise significantly.
"We postulate that by treating components of the metabolic syndrome in patients with chronic liver disease, we may be able to ameliorate the anticipated wave of liver disease complications in the U.S.," the investigators said.
To do so, "we must expand patients’ access to care and the availability of insurance coverage, encourage more targeted treatment strategies, and increase the training of experts and health care extenders capable of delivering care to these patients," they added.
This study included only adults, but "given the reports from other databases and tertiary care centers regarding children with liver disease, we suspect that our findings are applicable to children and adolescents in the U.S."
"The increasing prevalence of obesity and NAFLD among U.S. children and adolescents makes the future projections even direr," the authors wrote.
"As this young population ages, they are expected to become more obese and more likely to develop type 2 diabetes, both of which can lead to even higher rates of NAFLD. This cohort will certainly contribute to the future burden of chronic liver disease ... which could potentially become overwhelming," they said.
Dr. Younossi and his associates reported that they have no conflicts of interest. The study was conducted with internal funds only.
Nonalcoholic fatty liver disease may soon become the most important cause of chronic liver disease in the United States, "with a substantial clinical and economic impact," Dr. Zobair M. Younossi, AGAF, and his colleagues reported in the June issue of Clinical Gastroenterology and Hepatology.
In what they described as the first population-based study to assess changes in the prevalence of chronic liver diseases over the past 20 years, the authors found that the prevalence is steadily rising in only one major category: nonalcoholic fatty liver disease (NAFLD). In contrast, rates of chronic liver disease related to hepatitis B virus, hepatitis C virus, and alcohol use have remained stable (Clin. Gastroenterol. Hepatol. 2011 June [doi: 10.1016/j.cgh.2011.03.020]).
The rise in NAFLD correlates with the well-known increases in obesity and type 2 diabetes, and the study findings suggest that liver disease "will remain among the major causes of mortality and morbidity in the U.S. and will be responsible for substantial medical resource utilization."
"This issue becomes especially important as we face a potential decline in the availability of resources dedicated to the care of patients with chronic diseases, as well as the expected shortage of individuals trained in hepatology who are available to care for these patients," said Dr. Younossi, executive director of the Center for Liver Diseases at Inova Fairfax (Va.) Hospital, and his associates.
The investigators used data from the National Health and Nutrition Examination Survey (NHANES), the CDC’s assessments of health and nutrition in nationally representative samples of the adult population, to track trends in chronic liver disease during three periods: 1988-1994 (15,855 subjects), 1999-2004 (13,970 subjects), and 2005-2008 (9,670 subjects).
The prevalence of the four types of chronic liver disease combined increased during this 20-year interval, from 12% to 15%. However, that was driven entirely by the increasing prevalence of NAFLD-related liver disease alone, which rose from 5.5% in 1988-1994, to 9.8% in 1999-2004, to 11.0% in 2005-2008.
In contrast, the prevalence of chronic liver disease related to hepatitis B remained stable (0.4%, 0.3%, and 0.3%, respectively), as did that related to hepatitis C (2%, 2%, and 2%, respectively). The prevalence of alcohol-related chronic liver disease also remained stable over the 3 time periods, at 1.4%, 2%, and 2%, respectively.
In a further analysis of the data, the researchers found that the proportion of chronic liver disease attributable to NAFLD also rose significantly during these three time periods. NAFLD accounted for 47% of chronic liver disease in 1988-1994, which increased to 63% in 1999-2004 and to 75% in 2005-2008.
To assess the underlying causes of this increase in NAFLD, the investigators studied changes in the rates of metabolic syndrome components, all of which are known to be risk factors for NAFLD.
Significant increases during this same time span were found for prevalence of obesity, visceral obesity, type 2 diabetes, insulin resistance, and hypertension. Hypercholesterolemia was the only component of the metabolic syndrome that did not rise significantly.
"We postulate that by treating components of the metabolic syndrome in patients with chronic liver disease, we may be able to ameliorate the anticipated wave of liver disease complications in the U.S.," the investigators said.
To do so, "we must expand patients’ access to care and the availability of insurance coverage, encourage more targeted treatment strategies, and increase the training of experts and health care extenders capable of delivering care to these patients," they added.
This study included only adults, but "given the reports from other databases and tertiary care centers regarding children with liver disease, we suspect that our findings are applicable to children and adolescents in the U.S."
"The increasing prevalence of obesity and NAFLD among U.S. children and adolescents makes the future projections even direr," the authors wrote.
"As this young population ages, they are expected to become more obese and more likely to develop type 2 diabetes, both of which can lead to even higher rates of NAFLD. This cohort will certainly contribute to the future burden of chronic liver disease ... which could potentially become overwhelming," they said.
Dr. Younossi and his associates reported that they have no conflicts of interest. The study was conducted with internal funds only.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Abiraterone Prolonged Life in Prostate Cancer
Abiraterone acetate, a selective inhibitor of androgen biosynthesis, prolonged overall survival, reduced mortality risk by 35%, and delayed time to disease progression in men with metastatic castration-resistant prostate cancer who had already undergone chemotherapy.
“These results show that continued androgen-receptor signaling contributes to disease progression, and they provide support for the evaluation of other endocrine therapies in this [advanced] stage of the disease,” wrote Dr. Johann S. de Bono of the Institute of Cancer Research and Royal Marsden Hospital, Sutton (England), and his associates.
Several previous studies have demonstrated that, despite medical or surgical castration, prostate cancers continue to have sufficient levels of androgens, perhaps from synthesis within the tumor itself, to propel tumor growth. In phase I and phase II trials, abiraterone acetate – which potently blocks cytochrome P450 c17 (CYP17), an enzyme critical to testosterone synthesis – has shown promising antitumor activity even in advanced prostate cancer.
Dr. de Bono and his colleagues performed this international phase III randomized double-blind trial at 147 sites to compare daily oral therapy with four 250-mg abiraterone acetate tablets plus low-dose prednisone against placebo plus low-dose prednisone. They enrolled 1,195 men who had previously received docetaxel and showed disease progression despite ongoing androgen deprivation. The primary end point of the study was overall survival.
At a preplanned interim analysis, active treatment was found to reduce the risk of death by 35%, compared with placebo.
Mortality was 42% with active treatment, compared with 55% with placebo. Median overall survival was 14.8 months with abiraterone, compared with 10.9 months with placebo, the investigators reported (N. Engl J. Med. 2011;364:1995-2005).
This survival benefit “was consistent across all subgroups, and … robust after adjustment for stratification factors in a multivariate analysis,” they said. Based on these findings, the trial was unblinded and patients in the placebo group were allowed to switch to active treatment.
“All the secondary end points analyzed provided support for the superiority of abiraterone acetate over placebo,” Dr. de Bono and his associates said. Time to PSA progression was longer (10.2 months vs. 6.6 months), as was median progression-free survival on radiography (5.6 vs. 3.6 months).
Active treatment reduced the risk of disease progression by 42% when assessed by PSA levels and by 33% when assessed by radiographic imaging.
“As our study shows, blocking androgen synthesis by inhibiting CYP17 can produce tumor responses in patients who no longer have a response to standard hormonal therapies and who had received docetaxel-based chemotherapy,” the researchers said.
This study was sponsored by Cougar Biotechnology, with further support provided by the U.K. Medical Research Council, the Experimental Cancer Medical Centre, the National Institute for Health Research Biomedical Research Centre, and the Prostate Cancer Foundation.
Dr. de Bono is employed by the Institute of Cancer Research, where abiraterone was designed and synthesized, and which has a commercial interest in the drug. He and his associates reported ties to numerous drug and biotechnology companies.
'Continued androgen-receptor signaling contributes to disease progression.'
Source DR. DE BONO
Abiraterone acetate, a selective inhibitor of androgen biosynthesis, prolonged overall survival, reduced mortality risk by 35%, and delayed time to disease progression in men with metastatic castration-resistant prostate cancer who had already undergone chemotherapy.
“These results show that continued androgen-receptor signaling contributes to disease progression, and they provide support for the evaluation of other endocrine therapies in this [advanced] stage of the disease,” wrote Dr. Johann S. de Bono of the Institute of Cancer Research and Royal Marsden Hospital, Sutton (England), and his associates.
Several previous studies have demonstrated that, despite medical or surgical castration, prostate cancers continue to have sufficient levels of androgens, perhaps from synthesis within the tumor itself, to propel tumor growth. In phase I and phase II trials, abiraterone acetate – which potently blocks cytochrome P450 c17 (CYP17), an enzyme critical to testosterone synthesis – has shown promising antitumor activity even in advanced prostate cancer.
Dr. de Bono and his colleagues performed this international phase III randomized double-blind trial at 147 sites to compare daily oral therapy with four 250-mg abiraterone acetate tablets plus low-dose prednisone against placebo plus low-dose prednisone. They enrolled 1,195 men who had previously received docetaxel and showed disease progression despite ongoing androgen deprivation. The primary end point of the study was overall survival.
At a preplanned interim analysis, active treatment was found to reduce the risk of death by 35%, compared with placebo.
Mortality was 42% with active treatment, compared with 55% with placebo. Median overall survival was 14.8 months with abiraterone, compared with 10.9 months with placebo, the investigators reported (N. Engl J. Med. 2011;364:1995-2005).
This survival benefit “was consistent across all subgroups, and … robust after adjustment for stratification factors in a multivariate analysis,” they said. Based on these findings, the trial was unblinded and patients in the placebo group were allowed to switch to active treatment.
“All the secondary end points analyzed provided support for the superiority of abiraterone acetate over placebo,” Dr. de Bono and his associates said. Time to PSA progression was longer (10.2 months vs. 6.6 months), as was median progression-free survival on radiography (5.6 vs. 3.6 months).
Active treatment reduced the risk of disease progression by 42% when assessed by PSA levels and by 33% when assessed by radiographic imaging.
“As our study shows, blocking androgen synthesis by inhibiting CYP17 can produce tumor responses in patients who no longer have a response to standard hormonal therapies and who had received docetaxel-based chemotherapy,” the researchers said.
This study was sponsored by Cougar Biotechnology, with further support provided by the U.K. Medical Research Council, the Experimental Cancer Medical Centre, the National Institute for Health Research Biomedical Research Centre, and the Prostate Cancer Foundation.
Dr. de Bono is employed by the Institute of Cancer Research, where abiraterone was designed and synthesized, and which has a commercial interest in the drug. He and his associates reported ties to numerous drug and biotechnology companies.
'Continued androgen-receptor signaling contributes to disease progression.'
Source DR. DE BONO
Abiraterone acetate, a selective inhibitor of androgen biosynthesis, prolonged overall survival, reduced mortality risk by 35%, and delayed time to disease progression in men with metastatic castration-resistant prostate cancer who had already undergone chemotherapy.
“These results show that continued androgen-receptor signaling contributes to disease progression, and they provide support for the evaluation of other endocrine therapies in this [advanced] stage of the disease,” wrote Dr. Johann S. de Bono of the Institute of Cancer Research and Royal Marsden Hospital, Sutton (England), and his associates.
Several previous studies have demonstrated that, despite medical or surgical castration, prostate cancers continue to have sufficient levels of androgens, perhaps from synthesis within the tumor itself, to propel tumor growth. In phase I and phase II trials, abiraterone acetate – which potently blocks cytochrome P450 c17 (CYP17), an enzyme critical to testosterone synthesis – has shown promising antitumor activity even in advanced prostate cancer.
Dr. de Bono and his colleagues performed this international phase III randomized double-blind trial at 147 sites to compare daily oral therapy with four 250-mg abiraterone acetate tablets plus low-dose prednisone against placebo plus low-dose prednisone. They enrolled 1,195 men who had previously received docetaxel and showed disease progression despite ongoing androgen deprivation. The primary end point of the study was overall survival.
At a preplanned interim analysis, active treatment was found to reduce the risk of death by 35%, compared with placebo.
Mortality was 42% with active treatment, compared with 55% with placebo. Median overall survival was 14.8 months with abiraterone, compared with 10.9 months with placebo, the investigators reported (N. Engl J. Med. 2011;364:1995-2005).
This survival benefit “was consistent across all subgroups, and … robust after adjustment for stratification factors in a multivariate analysis,” they said. Based on these findings, the trial was unblinded and patients in the placebo group were allowed to switch to active treatment.
“All the secondary end points analyzed provided support for the superiority of abiraterone acetate over placebo,” Dr. de Bono and his associates said. Time to PSA progression was longer (10.2 months vs. 6.6 months), as was median progression-free survival on radiography (5.6 vs. 3.6 months).
Active treatment reduced the risk of disease progression by 42% when assessed by PSA levels and by 33% when assessed by radiographic imaging.
“As our study shows, blocking androgen synthesis by inhibiting CYP17 can produce tumor responses in patients who no longer have a response to standard hormonal therapies and who had received docetaxel-based chemotherapy,” the researchers said.
This study was sponsored by Cougar Biotechnology, with further support provided by the U.K. Medical Research Council, the Experimental Cancer Medical Centre, the National Institute for Health Research Biomedical Research Centre, and the Prostate Cancer Foundation.
Dr. de Bono is employed by the Institute of Cancer Research, where abiraterone was designed and synthesized, and which has a commercial interest in the drug. He and his associates reported ties to numerous drug and biotechnology companies.
'Continued androgen-receptor signaling contributes to disease progression.'
Source DR. DE BONO
From the New England Journal of Medicine
BMD, FRAX Underestimate Risk in Diabetes
Major Finding: In older adults with diabetes, any given BMD T score or FRAX score carried a higher fracture risk than did the same score in those without diabetes. The risk of hip fracture in a woman with diabetes was equivalent to that of a nondiabetic woman with a T score of about 0.5 units lower.
Data Source: Analysis of data from three prospective observational studies involving more than 16,000 older subjects in whom fractures were tracked for about 10 years.
Disclosures: This study was funded by an investigator-initiated grant from Amgen to Dr. Schwartz. She and her associates also reported receiving support from Novartis, Merck, Pfizer, Nycomed, and Roche.
Two measures of fracture risk – bone mineral density T score and FRAX score – are clinically useful in patients with type 2 diabetes, even though they tend to underestimate the increased fracture risk in this patient population, according to the results of a large study.
But to be more accurate for older adults with diabetes, these treatment and diagnostic algorithms should undergo “refinements,” said Ann V. Schwartz, Ph.D., of the department of epidemiology and biostatistics, University of California, San Francisco, and her associates (JAMA 2011;305:2184-92).
Type 2 diabetes is known to be associated with a higher bone mineral density (BMD) but, paradoxically, also with a higher risk of fracture. There has been concern that established methods for predicting fractures “may not perform adequately in patients with type 2 diabetes,” the researchers said.
In what they described as the first study to prospectively examine the relationship between BMD and fractures in older adults with type 2 diabetes, Dr. Schwartz and her colleagues analyzed data from three large, prospective, observational studies that all used radiology reports and radiographs to confirm fracture diagnoses. The three studies also ascertained subjects' diabetes status.
The Study of Osteoporotic Fractures (SOF) involved 7,926 white women at four U.S. clinical centers who underwent femoral neck-hip BMD measurement and were followed for the occurrence of fractures from 1988 through 2008. The Osteoporotic Fractures in Men Study (MrOS) involved 5,994 men at six U.S. clinical centers who underwent hip BMD measurement and were followed from 2000 through 2009. And the Health, Aging, and Body Composition (Health ABC) study involved 1,523 women and 1,442 men in their 70s, approximately half of whom were white and half black, who underwent hip BMD measurement and were followed from 1997 through 2007.
The FRAX (Fracture Risk Algorithm) scores were calculated for subjects in the SOF and MrOS studies by the World Health Organization (WHO) Collaborating Center for Metabolic Bone Disease, but not for subjects in the Health ABC study.
Dr. Schwartz and her associates found that both low BMD T score and high FRAX score were predictive of hip and nonspinal fracture in patients with diabetes. “However, for a given T score and age, those adults with diabetes had a higher risk of fracture than those without diabetes,” they said.
For example, the risk of hip fracture in a woman with diabetes was equivalent to that of a nondiabetic woman with a T score of about 0.5 units lower.
The subjects with diabetes showed higher rates of fracture at any given FRAX score than did subjects who did not have diabetes, they noted.
“Interpretation of T score or FRAX score in an older patient with diabetes must take into account the higher fracture risk associated with diabetes. For example, … a T score in a woman with diabetes is associated with hip fracture risk equivalent to a woman without diabetes with a T score of approximately 0.5 units lower,” the investigators said.
“The FRAX score has been incorporated into U.S. guidelines for prevention and treatment of osteoporosis. The FRAX algorithm does not currently include type 2 diabetes as a risk factor for fracture, and our results indicate that use of the FRAX score in patients with diabetes will likely underestimate risk.
“An adjustment of this algorithm for type 2 diabetes seems justified, given the prevalence of diabetes among older adults,” Dr. Schwartz and her associates said.
The reason diabetes raises fracture risk even as it appears to protect against loss of BMD is not understood. “Bone strength may be compromised through changes that are not captured with dual-energy x-ray absorptiometry, such as higher levels of advanced glycation end products in bone collagen. More frequent falls in older adults with diabetes could also increase fracture risk for a given BMD,” they said.
This study was funded by an investigator-initiated grant from Amgen to Dr. Schwartz. She and her associates also reported receiving support from Novartis, Merck, Pfizer, Nycomed, and Roche.
Major Finding: In older adults with diabetes, any given BMD T score or FRAX score carried a higher fracture risk than did the same score in those without diabetes. The risk of hip fracture in a woman with diabetes was equivalent to that of a nondiabetic woman with a T score of about 0.5 units lower.
Data Source: Analysis of data from three prospective observational studies involving more than 16,000 older subjects in whom fractures were tracked for about 10 years.
Disclosures: This study was funded by an investigator-initiated grant from Amgen to Dr. Schwartz. She and her associates also reported receiving support from Novartis, Merck, Pfizer, Nycomed, and Roche.
Two measures of fracture risk – bone mineral density T score and FRAX score – are clinically useful in patients with type 2 diabetes, even though they tend to underestimate the increased fracture risk in this patient population, according to the results of a large study.
But to be more accurate for older adults with diabetes, these treatment and diagnostic algorithms should undergo “refinements,” said Ann V. Schwartz, Ph.D., of the department of epidemiology and biostatistics, University of California, San Francisco, and her associates (JAMA 2011;305:2184-92).
Type 2 diabetes is known to be associated with a higher bone mineral density (BMD) but, paradoxically, also with a higher risk of fracture. There has been concern that established methods for predicting fractures “may not perform adequately in patients with type 2 diabetes,” the researchers said.
In what they described as the first study to prospectively examine the relationship between BMD and fractures in older adults with type 2 diabetes, Dr. Schwartz and her colleagues analyzed data from three large, prospective, observational studies that all used radiology reports and radiographs to confirm fracture diagnoses. The three studies also ascertained subjects' diabetes status.
The Study of Osteoporotic Fractures (SOF) involved 7,926 white women at four U.S. clinical centers who underwent femoral neck-hip BMD measurement and were followed for the occurrence of fractures from 1988 through 2008. The Osteoporotic Fractures in Men Study (MrOS) involved 5,994 men at six U.S. clinical centers who underwent hip BMD measurement and were followed from 2000 through 2009. And the Health, Aging, and Body Composition (Health ABC) study involved 1,523 women and 1,442 men in their 70s, approximately half of whom were white and half black, who underwent hip BMD measurement and were followed from 1997 through 2007.
The FRAX (Fracture Risk Algorithm) scores were calculated for subjects in the SOF and MrOS studies by the World Health Organization (WHO) Collaborating Center for Metabolic Bone Disease, but not for subjects in the Health ABC study.
Dr. Schwartz and her associates found that both low BMD T score and high FRAX score were predictive of hip and nonspinal fracture in patients with diabetes. “However, for a given T score and age, those adults with diabetes had a higher risk of fracture than those without diabetes,” they said.
For example, the risk of hip fracture in a woman with diabetes was equivalent to that of a nondiabetic woman with a T score of about 0.5 units lower.
The subjects with diabetes showed higher rates of fracture at any given FRAX score than did subjects who did not have diabetes, they noted.
“Interpretation of T score or FRAX score in an older patient with diabetes must take into account the higher fracture risk associated with diabetes. For example, … a T score in a woman with diabetes is associated with hip fracture risk equivalent to a woman without diabetes with a T score of approximately 0.5 units lower,” the investigators said.
“The FRAX score has been incorporated into U.S. guidelines for prevention and treatment of osteoporosis. The FRAX algorithm does not currently include type 2 diabetes as a risk factor for fracture, and our results indicate that use of the FRAX score in patients with diabetes will likely underestimate risk.
“An adjustment of this algorithm for type 2 diabetes seems justified, given the prevalence of diabetes among older adults,” Dr. Schwartz and her associates said.
The reason diabetes raises fracture risk even as it appears to protect against loss of BMD is not understood. “Bone strength may be compromised through changes that are not captured with dual-energy x-ray absorptiometry, such as higher levels of advanced glycation end products in bone collagen. More frequent falls in older adults with diabetes could also increase fracture risk for a given BMD,” they said.
This study was funded by an investigator-initiated grant from Amgen to Dr. Schwartz. She and her associates also reported receiving support from Novartis, Merck, Pfizer, Nycomed, and Roche.
Major Finding: In older adults with diabetes, any given BMD T score or FRAX score carried a higher fracture risk than did the same score in those without diabetes. The risk of hip fracture in a woman with diabetes was equivalent to that of a nondiabetic woman with a T score of about 0.5 units lower.
Data Source: Analysis of data from three prospective observational studies involving more than 16,000 older subjects in whom fractures were tracked for about 10 years.
Disclosures: This study was funded by an investigator-initiated grant from Amgen to Dr. Schwartz. She and her associates also reported receiving support from Novartis, Merck, Pfizer, Nycomed, and Roche.
Two measures of fracture risk – bone mineral density T score and FRAX score – are clinically useful in patients with type 2 diabetes, even though they tend to underestimate the increased fracture risk in this patient population, according to the results of a large study.
But to be more accurate for older adults with diabetes, these treatment and diagnostic algorithms should undergo “refinements,” said Ann V. Schwartz, Ph.D., of the department of epidemiology and biostatistics, University of California, San Francisco, and her associates (JAMA 2011;305:2184-92).
Type 2 diabetes is known to be associated with a higher bone mineral density (BMD) but, paradoxically, also with a higher risk of fracture. There has been concern that established methods for predicting fractures “may not perform adequately in patients with type 2 diabetes,” the researchers said.
In what they described as the first study to prospectively examine the relationship between BMD and fractures in older adults with type 2 diabetes, Dr. Schwartz and her colleagues analyzed data from three large, prospective, observational studies that all used radiology reports and radiographs to confirm fracture diagnoses. The three studies also ascertained subjects' diabetes status.
The Study of Osteoporotic Fractures (SOF) involved 7,926 white women at four U.S. clinical centers who underwent femoral neck-hip BMD measurement and were followed for the occurrence of fractures from 1988 through 2008. The Osteoporotic Fractures in Men Study (MrOS) involved 5,994 men at six U.S. clinical centers who underwent hip BMD measurement and were followed from 2000 through 2009. And the Health, Aging, and Body Composition (Health ABC) study involved 1,523 women and 1,442 men in their 70s, approximately half of whom were white and half black, who underwent hip BMD measurement and were followed from 1997 through 2007.
The FRAX (Fracture Risk Algorithm) scores were calculated for subjects in the SOF and MrOS studies by the World Health Organization (WHO) Collaborating Center for Metabolic Bone Disease, but not for subjects in the Health ABC study.
Dr. Schwartz and her associates found that both low BMD T score and high FRAX score were predictive of hip and nonspinal fracture in patients with diabetes. “However, for a given T score and age, those adults with diabetes had a higher risk of fracture than those without diabetes,” they said.
For example, the risk of hip fracture in a woman with diabetes was equivalent to that of a nondiabetic woman with a T score of about 0.5 units lower.
The subjects with diabetes showed higher rates of fracture at any given FRAX score than did subjects who did not have diabetes, they noted.
“Interpretation of T score or FRAX score in an older patient with diabetes must take into account the higher fracture risk associated with diabetes. For example, … a T score in a woman with diabetes is associated with hip fracture risk equivalent to a woman without diabetes with a T score of approximately 0.5 units lower,” the investigators said.
“The FRAX score has been incorporated into U.S. guidelines for prevention and treatment of osteoporosis. The FRAX algorithm does not currently include type 2 diabetes as a risk factor for fracture, and our results indicate that use of the FRAX score in patients with diabetes will likely underestimate risk.
“An adjustment of this algorithm for type 2 diabetes seems justified, given the prevalence of diabetes among older adults,” Dr. Schwartz and her associates said.
The reason diabetes raises fracture risk even as it appears to protect against loss of BMD is not understood. “Bone strength may be compromised through changes that are not captured with dual-energy x-ray absorptiometry, such as higher levels of advanced glycation end products in bone collagen. More frequent falls in older adults with diabetes could also increase fracture risk for a given BMD,” they said.
This study was funded by an investigator-initiated grant from Amgen to Dr. Schwartz. She and her associates also reported receiving support from Novartis, Merck, Pfizer, Nycomed, and Roche.
From JAMA
Rituximab Use Associated With PML in Arthritis
Major Finding: Patients given rituximab for refractory RA are at “modest” risk of developing progressive multifocal leukoencephalopathy, with an estimated incidence of 1 case of PML per 25,000 drug exposures.
Data Source: Case studies of five RA patients who developed PML after receiving rituximab.
Disclosures: This study was supported by the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, and the National Institute of Allergy and Infectious Diseases. Dr. Clifford and his associates reported ties to Bavarian Nordic, Biogen Idec, Bristol-Myers Squibb, Genentech (maker of rituximab), Genzyme, GlaxoSmithKline, Lilly, Millennium, NeurogesX, Novartis, Pfizer, Schering-Plough, Tibotec, and Wyeth.
Physicians considering the use of rituximab treatment of rheumatic diseases including rheumatoid arthritis should be aware that there is “a potential, albeit modest, risk of developing progressive multifocal leukoencephalopathy,” a study has shown.
In addition, rheumatology patients who are already taking the drug should undergo “aggressive evaluation of new and progressing neurologic deficits … to allow early diagnosis” of progressive multifocal leukoencephalopathy (PML), said Dr. David B. Clifford, professor of neurology and medicine at Washington University in St. Louis, and his associates.
PML is a serious, often fatal demyelinating infection of the brain, usually caused by reactivation of latent JC virus in people who are immunocompromised. It also has been reported as a complication of treatment with monoclonal antibodies such as natalizumab and efalizumab, among patients taking the drugs for disorders including multiple sclerosis, inflammatory bowel disease, and chronic plaque psoriasis.
The mechanism by which these agents facilitate the development of PML is not yet known, but it is presumed that some suppressive effect they exert on the immune system allows latent JC virus to reactivate. Primary JC virus infection usually occurs unnoticed during childhood and is very widespread; most adults are seropositive for JC virus, and many carry latent virus in kidney epithelial cells, lymphoid tissues, bone marrow, and possibly the brain.
“Until very recently, treatment of RA with rituximab had not been associated with development of PML,” the investigators wrote. There was one case reported in 2009, but that “was complicated by a history of malignancy that had been treated with chemotherapy and irradiation a short time before PML onset,” so the connection with rituximab was unclear, they noted.
Dr. Clifford and his colleagues now report four additional cases of PML in RA patients treated with rituximab. To characterize the disorder in this patient population, they summarized their findings along with those for the previously reported case.
All of the patients were women aged 51–73 years who had moderate to severe RA of at least 3 years' duration. All began taking rituximab after failing to respond adequately to other interventions including methotrexate, other biologics, or corticosteroids.
In all cases, rituximab was given at the recommended dose for refractory RA: Each course comprised two 1,000-mg infusions administered 2 weeks apart. Two patients received only a single course, and the maximal number of courses was five. In two cases, patients may have been at increased risk of PML because of cancer. One woman had a history of breast cancer treated with surgery and chemotherapy; the other was the previously reported case in which the patient developed superficial squamous cell carcinoma of the oropharynx and received chemotherapy and irradiation after rituximab had been administered.
Symptom onset occurred at 5–7 months after a rituximab infusion in three cases. This timing is “interesting” because it occurs during the process of immune reconstitution, rather than earlier, when CD20 cells reach their nadir.
In a fourth case, PML onset was delayed until 16 months after rituximab infusion. However this also proved to be during immune reconstitution, as this patient had an unusually prolonged interval of CD-cell suppression. This suppression “only began to normalize after PML onset, when a clear immune reconstitution inflammatory syndrome (IRIS) was well documented on MR scans,” the investigators said.
It appears that the immune reconstitution inflammatory syndrome may often complicate rituximab-associated PML, as it developed in three of these five cases. “This factor is critical for clinicians, since it impacts diagnosis and management,” they added.
These five patients presented with a variety of central nervous system symptoms including dysesthesias, ataxia, dysphasia, cognitive decline, focal dystonic tremor, and segmental myoclonus. JC virus DNA frequently was not detectable in the cerebrospinal fluid at presentation, “and was found only after repeated lumbar punctures as the disease progressed.” In fact, one case required a brain biopsy to confirm PML.
Genentech, the maker of rituximab, estimates that these five cases of PML occurred against a background of approximately 129,000 exposures among RA patients. This puts the incidence of rituximab-associated PML at 1 in 25,000 exposed RA patients, Dr. Clifford and his associates said (Arch. Neurol. 2011 May 9 [doi:10.1001/archneurol.2011.103]).
This may be an underestimate because it's likely that more patients have not been accurately diagnosed or reported to the company, they added.
This “modest” incidence is lower than that reported for natalizumab-associated PML (1 in 1,000 patients exposed for more than 2 years) or for efalizumab-associated PML (1 in 400 exposed patients).
The need for effective treatments of rituximab-associated PML is “urgent.” Antiviral therapy has not been shown to be effective. Some clinicians still try using cytosine arabinoside and cidofovir, “in spite of significant evidence that they are not effective.”
Mefloquine hydrochloride has shown in vitro activity against JC virus and was used “in several of our cases,” but failed to show efficacy in a recent clinical trial. “Similarly, clinicians continue to prescribe mirtazapine on a theoretical basis, related to its potential efficacy in blocking serotonin receptors used for viral entry, despite absence of documented clinical efficacy,” they said.
Plasma exchange has become standard practice for natalizumab-associated PML, but it is only likely to speed immune recovery in RA patients taking rituximab if PML is discovered shortly after an infusion of the drug.
If patients develop immune reconstitution inflammatory syndrome, that “provides an additional potential therapeutic avenue.” High-dose corticosteroid pulses – “often 1 g of IV methylprednisolone daily for 5 days, which is repeated if symptoms respond and then recur” – may halt neurologic decline and initiate recovery. “Physicians should be aware that this may be required even when the CD20 count suggests ongoing immune compromise” from the rituximab therapy, they added.
Major Finding: Patients given rituximab for refractory RA are at “modest” risk of developing progressive multifocal leukoencephalopathy, with an estimated incidence of 1 case of PML per 25,000 drug exposures.
Data Source: Case studies of five RA patients who developed PML after receiving rituximab.
Disclosures: This study was supported by the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, and the National Institute of Allergy and Infectious Diseases. Dr. Clifford and his associates reported ties to Bavarian Nordic, Biogen Idec, Bristol-Myers Squibb, Genentech (maker of rituximab), Genzyme, GlaxoSmithKline, Lilly, Millennium, NeurogesX, Novartis, Pfizer, Schering-Plough, Tibotec, and Wyeth.
Physicians considering the use of rituximab treatment of rheumatic diseases including rheumatoid arthritis should be aware that there is “a potential, albeit modest, risk of developing progressive multifocal leukoencephalopathy,” a study has shown.
In addition, rheumatology patients who are already taking the drug should undergo “aggressive evaluation of new and progressing neurologic deficits … to allow early diagnosis” of progressive multifocal leukoencephalopathy (PML), said Dr. David B. Clifford, professor of neurology and medicine at Washington University in St. Louis, and his associates.
PML is a serious, often fatal demyelinating infection of the brain, usually caused by reactivation of latent JC virus in people who are immunocompromised. It also has been reported as a complication of treatment with monoclonal antibodies such as natalizumab and efalizumab, among patients taking the drugs for disorders including multiple sclerosis, inflammatory bowel disease, and chronic plaque psoriasis.
The mechanism by which these agents facilitate the development of PML is not yet known, but it is presumed that some suppressive effect they exert on the immune system allows latent JC virus to reactivate. Primary JC virus infection usually occurs unnoticed during childhood and is very widespread; most adults are seropositive for JC virus, and many carry latent virus in kidney epithelial cells, lymphoid tissues, bone marrow, and possibly the brain.
“Until very recently, treatment of RA with rituximab had not been associated with development of PML,” the investigators wrote. There was one case reported in 2009, but that “was complicated by a history of malignancy that had been treated with chemotherapy and irradiation a short time before PML onset,” so the connection with rituximab was unclear, they noted.
Dr. Clifford and his colleagues now report four additional cases of PML in RA patients treated with rituximab. To characterize the disorder in this patient population, they summarized their findings along with those for the previously reported case.
All of the patients were women aged 51–73 years who had moderate to severe RA of at least 3 years' duration. All began taking rituximab after failing to respond adequately to other interventions including methotrexate, other biologics, or corticosteroids.
In all cases, rituximab was given at the recommended dose for refractory RA: Each course comprised two 1,000-mg infusions administered 2 weeks apart. Two patients received only a single course, and the maximal number of courses was five. In two cases, patients may have been at increased risk of PML because of cancer. One woman had a history of breast cancer treated with surgery and chemotherapy; the other was the previously reported case in which the patient developed superficial squamous cell carcinoma of the oropharynx and received chemotherapy and irradiation after rituximab had been administered.
Symptom onset occurred at 5–7 months after a rituximab infusion in three cases. This timing is “interesting” because it occurs during the process of immune reconstitution, rather than earlier, when CD20 cells reach their nadir.
In a fourth case, PML onset was delayed until 16 months after rituximab infusion. However this also proved to be during immune reconstitution, as this patient had an unusually prolonged interval of CD-cell suppression. This suppression “only began to normalize after PML onset, when a clear immune reconstitution inflammatory syndrome (IRIS) was well documented on MR scans,” the investigators said.
It appears that the immune reconstitution inflammatory syndrome may often complicate rituximab-associated PML, as it developed in three of these five cases. “This factor is critical for clinicians, since it impacts diagnosis and management,” they added.
These five patients presented with a variety of central nervous system symptoms including dysesthesias, ataxia, dysphasia, cognitive decline, focal dystonic tremor, and segmental myoclonus. JC virus DNA frequently was not detectable in the cerebrospinal fluid at presentation, “and was found only after repeated lumbar punctures as the disease progressed.” In fact, one case required a brain biopsy to confirm PML.
Genentech, the maker of rituximab, estimates that these five cases of PML occurred against a background of approximately 129,000 exposures among RA patients. This puts the incidence of rituximab-associated PML at 1 in 25,000 exposed RA patients, Dr. Clifford and his associates said (Arch. Neurol. 2011 May 9 [doi:10.1001/archneurol.2011.103]).
This may be an underestimate because it's likely that more patients have not been accurately diagnosed or reported to the company, they added.
This “modest” incidence is lower than that reported for natalizumab-associated PML (1 in 1,000 patients exposed for more than 2 years) or for efalizumab-associated PML (1 in 400 exposed patients).
The need for effective treatments of rituximab-associated PML is “urgent.” Antiviral therapy has not been shown to be effective. Some clinicians still try using cytosine arabinoside and cidofovir, “in spite of significant evidence that they are not effective.”
Mefloquine hydrochloride has shown in vitro activity against JC virus and was used “in several of our cases,” but failed to show efficacy in a recent clinical trial. “Similarly, clinicians continue to prescribe mirtazapine on a theoretical basis, related to its potential efficacy in blocking serotonin receptors used for viral entry, despite absence of documented clinical efficacy,” they said.
Plasma exchange has become standard practice for natalizumab-associated PML, but it is only likely to speed immune recovery in RA patients taking rituximab if PML is discovered shortly after an infusion of the drug.
If patients develop immune reconstitution inflammatory syndrome, that “provides an additional potential therapeutic avenue.” High-dose corticosteroid pulses – “often 1 g of IV methylprednisolone daily for 5 days, which is repeated if symptoms respond and then recur” – may halt neurologic decline and initiate recovery. “Physicians should be aware that this may be required even when the CD20 count suggests ongoing immune compromise” from the rituximab therapy, they added.
Major Finding: Patients given rituximab for refractory RA are at “modest” risk of developing progressive multifocal leukoencephalopathy, with an estimated incidence of 1 case of PML per 25,000 drug exposures.
Data Source: Case studies of five RA patients who developed PML after receiving rituximab.
Disclosures: This study was supported by the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, and the National Institute of Allergy and Infectious Diseases. Dr. Clifford and his associates reported ties to Bavarian Nordic, Biogen Idec, Bristol-Myers Squibb, Genentech (maker of rituximab), Genzyme, GlaxoSmithKline, Lilly, Millennium, NeurogesX, Novartis, Pfizer, Schering-Plough, Tibotec, and Wyeth.
Physicians considering the use of rituximab treatment of rheumatic diseases including rheumatoid arthritis should be aware that there is “a potential, albeit modest, risk of developing progressive multifocal leukoencephalopathy,” a study has shown.
In addition, rheumatology patients who are already taking the drug should undergo “aggressive evaluation of new and progressing neurologic deficits … to allow early diagnosis” of progressive multifocal leukoencephalopathy (PML), said Dr. David B. Clifford, professor of neurology and medicine at Washington University in St. Louis, and his associates.
PML is a serious, often fatal demyelinating infection of the brain, usually caused by reactivation of latent JC virus in people who are immunocompromised. It also has been reported as a complication of treatment with monoclonal antibodies such as natalizumab and efalizumab, among patients taking the drugs for disorders including multiple sclerosis, inflammatory bowel disease, and chronic plaque psoriasis.
The mechanism by which these agents facilitate the development of PML is not yet known, but it is presumed that some suppressive effect they exert on the immune system allows latent JC virus to reactivate. Primary JC virus infection usually occurs unnoticed during childhood and is very widespread; most adults are seropositive for JC virus, and many carry latent virus in kidney epithelial cells, lymphoid tissues, bone marrow, and possibly the brain.
“Until very recently, treatment of RA with rituximab had not been associated with development of PML,” the investigators wrote. There was one case reported in 2009, but that “was complicated by a history of malignancy that had been treated with chemotherapy and irradiation a short time before PML onset,” so the connection with rituximab was unclear, they noted.
Dr. Clifford and his colleagues now report four additional cases of PML in RA patients treated with rituximab. To characterize the disorder in this patient population, they summarized their findings along with those for the previously reported case.
All of the patients were women aged 51–73 years who had moderate to severe RA of at least 3 years' duration. All began taking rituximab after failing to respond adequately to other interventions including methotrexate, other biologics, or corticosteroids.
In all cases, rituximab was given at the recommended dose for refractory RA: Each course comprised two 1,000-mg infusions administered 2 weeks apart. Two patients received only a single course, and the maximal number of courses was five. In two cases, patients may have been at increased risk of PML because of cancer. One woman had a history of breast cancer treated with surgery and chemotherapy; the other was the previously reported case in which the patient developed superficial squamous cell carcinoma of the oropharynx and received chemotherapy and irradiation after rituximab had been administered.
Symptom onset occurred at 5–7 months after a rituximab infusion in three cases. This timing is “interesting” because it occurs during the process of immune reconstitution, rather than earlier, when CD20 cells reach their nadir.
In a fourth case, PML onset was delayed until 16 months after rituximab infusion. However this also proved to be during immune reconstitution, as this patient had an unusually prolonged interval of CD-cell suppression. This suppression “only began to normalize after PML onset, when a clear immune reconstitution inflammatory syndrome (IRIS) was well documented on MR scans,” the investigators said.
It appears that the immune reconstitution inflammatory syndrome may often complicate rituximab-associated PML, as it developed in three of these five cases. “This factor is critical for clinicians, since it impacts diagnosis and management,” they added.
These five patients presented with a variety of central nervous system symptoms including dysesthesias, ataxia, dysphasia, cognitive decline, focal dystonic tremor, and segmental myoclonus. JC virus DNA frequently was not detectable in the cerebrospinal fluid at presentation, “and was found only after repeated lumbar punctures as the disease progressed.” In fact, one case required a brain biopsy to confirm PML.
Genentech, the maker of rituximab, estimates that these five cases of PML occurred against a background of approximately 129,000 exposures among RA patients. This puts the incidence of rituximab-associated PML at 1 in 25,000 exposed RA patients, Dr. Clifford and his associates said (Arch. Neurol. 2011 May 9 [doi:10.1001/archneurol.2011.103]).
This may be an underestimate because it's likely that more patients have not been accurately diagnosed or reported to the company, they added.
This “modest” incidence is lower than that reported for natalizumab-associated PML (1 in 1,000 patients exposed for more than 2 years) or for efalizumab-associated PML (1 in 400 exposed patients).
The need for effective treatments of rituximab-associated PML is “urgent.” Antiviral therapy has not been shown to be effective. Some clinicians still try using cytosine arabinoside and cidofovir, “in spite of significant evidence that they are not effective.”
Mefloquine hydrochloride has shown in vitro activity against JC virus and was used “in several of our cases,” but failed to show efficacy in a recent clinical trial. “Similarly, clinicians continue to prescribe mirtazapine on a theoretical basis, related to its potential efficacy in blocking serotonin receptors used for viral entry, despite absence of documented clinical efficacy,” they said.
Plasma exchange has become standard practice for natalizumab-associated PML, but it is only likely to speed immune recovery in RA patients taking rituximab if PML is discovered shortly after an infusion of the drug.
If patients develop immune reconstitution inflammatory syndrome, that “provides an additional potential therapeutic avenue.” High-dose corticosteroid pulses – “often 1 g of IV methylprednisolone daily for 5 days, which is repeated if symptoms respond and then recur” – may halt neurologic decline and initiate recovery. “Physicians should be aware that this may be required even when the CD20 count suggests ongoing immune compromise” from the rituximab therapy, they added.