The cost burden of uterine fibroids and endometriosis related to two types of endocrine-disrupting chemicals (EDCs) in Europe is about 1.4 billion euros a year, or more than $1.5 billion, according to an analysis published online March 22 in the Journal of Clinical Endocrinology & Metabolism.

Diphenyldichloroethene, or DDE, is an agricultural pesticide that has been linked to fibroids, while phthalates, used to soften plastics or deliver scent, are ubiquitous in consumer products and have been linked to endometriosis.

Courtesy Wikimedia Commons/Hic et nunc/CC BY-SA 3.0

The true burden of female reproductive disorders linked to endocrine-disrupting chemicals is likely considerably higher than the study’s estimate reflects, says Dr. Leonardo Trasande of New York University Langone Medical Center, the lead investigator.

While Dr. Trasande and his colleagues limited the scope of their study to two reproductive tract abnormalities, others, including polycystic ovarian syndrome and fertility disorders, have increasingly been linked to EDCs. The investigators also limited their focus to the two chemicals for which the evidence was strong and for which the European Union is seeking guidance on regulating.

“We see this as a first step toward a more comprehensive investigation of the role of environmental chemicals and their impact on diseases that unfortunately are all too common in women,” Dr. Trasande said in an interview.

The investigators looked at levels of DDE exposures from cohorts of mothers from whom cord blood was drawn, while phthalate exposures were measured in urine from women who took part in a pan-European biomonitoring survey of mothers and children.

Incidence of fibroids (in women aged 15-54 years) and endometriosis (in women aged 20-44 years) was derived from large national cohorts. Per-patient treatment and lost-work costs were also drawn from national databases, based on 2010 figures. Excess risk of either disease per level of exposure was calculated based on previous findings. The investigators found that fibroids or endometriosis caused by chemical exposure accounted for between 20% and 39% of cases (J Clin Endocrinol Metab. 2016 Mar 22. doi: 10.1210/jc.2015-2873).

The European national health care systems offered the researchers the advantage of large, stable cohorts from which to draw data; a similar study would have been harder to carry out in the United States, Dr. Trasande noted.

Nonetheless, he said, the implications of the study apply broadly. “The greatest takeaway here is prevention related. The findings speak to the substantial health and economic burden of these chemicals both in Europe and other parts of the world.” Exposures are comparable between the United States and Europe, he said, meaning related disease burden and costs may be proportionally consistent. In the developing world, exposures are lower but increasing.

All the chemical exposures measured in Dr. Trasande and his colleagues’ study were of adult women, though much concern over EDCs relates to in utero or early-life exposures affecting adult outcomes.

“Without the data to compare exposure in early life and conditions that occur many years later, we had to rely upon associations that were closer in time,” he said. What’s needed now is “substantial and further investment in studies that leverage banked [early-life] specimens and can be associated with patients with a particular condition.”

The National Institutes of Health’s National Children’s Study was designed to do just this, measuring prenatal environmental exposures and conducting long-term follow-up in some 100,000 subjects. However, it was canceled in late 2014 due to recruitment concerns.

The planned ECHO (Environmental Influences on Child Health Outcomes) study, also under NIH, will attempt to measure long-term outcomes related to prenatal and early postnatal exposures, including through tissue banking. It will rely on existing birth cohorts instead.

Dr. Trasande and his colleagues’ study was funded by the Endocrine Society, the John Merck Fund, the Broad Reach Foundation, and the Oak Foundation. Its authors disclosed no conflicts of interest.

The cost burden of uterine fibroids and endometriosis related to two types of endocrine-disrupting chemicals (EDCs) in Europe is about 1.4 billion euros a year, or more than $1.5 billion, according to an analysis published online March 22 in the Journal of Clinical Endocrinology & Metabolism.

Diphenyldichloroethene, or DDE, is an agricultural pesticide that has been linked to fibroids, while phthalates, used to soften plastics or deliver scent, are ubiquitous in consumer products and have been linked to endometriosis.

Courtesy Wikimedia Commons/Hic et nunc/CC BY-SA 3.0

The true burden of female reproductive disorders linked to endocrine-disrupting chemicals is likely considerably higher than the study’s estimate reflects, says Dr. Leonardo Trasande of New York University Langone Medical Center, the lead investigator.

While Dr. Trasande and his colleagues limited the scope of their study to two reproductive tract abnormalities, others, including polycystic ovarian syndrome and fertility disorders, have increasingly been linked to EDCs. The investigators also limited their focus to the two chemicals for which the evidence was strong and for which the European Union is seeking guidance on regulating.

“We see this as a first step toward a more comprehensive investigation of the role of environmental chemicals and their impact on diseases that unfortunately are all too common in women,” Dr. Trasande said in an interview.

The investigators looked at levels of DDE exposures from cohorts of mothers from whom cord blood was drawn, while phthalate exposures were measured in urine from women who took part in a pan-European biomonitoring survey of mothers and children.

Incidence of fibroids (in women aged 15-54 years) and endometriosis (in women aged 20-44 years) was derived from large national cohorts. Per-patient treatment and lost-work costs were also drawn from national databases, based on 2010 figures. Excess risk of either disease per level of exposure was calculated based on previous findings. The investigators found that fibroids or endometriosis caused by chemical exposure accounted for between 20% and 39% of cases (J Clin Endocrinol Metab. 2016 Mar 22. doi: 10.1210/jc.2015-2873).

The European national health care systems offered the researchers the advantage of large, stable cohorts from which to draw data; a similar study would have been harder to carry out in the United States, Dr. Trasande noted.

Nonetheless, he said, the implications of the study apply broadly. “The greatest takeaway here is prevention related. The findings speak to the substantial health and economic burden of these chemicals both in Europe and other parts of the world.” Exposures are comparable between the United States and Europe, he said, meaning related disease burden and costs may be proportionally consistent. In the developing world, exposures are lower but increasing.

All the chemical exposures measured in Dr. Trasande and his colleagues’ study were of adult women, though much concern over EDCs relates to in utero or early-life exposures affecting adult outcomes.

“Without the data to compare exposure in early life and conditions that occur many years later, we had to rely upon associations that were closer in time,” he said. What’s needed now is “substantial and further investment in studies that leverage banked [early-life] specimens and can be associated with patients with a particular condition.”

The National Institutes of Health’s National Children’s Study was designed to do just this, measuring prenatal environmental exposures and conducting long-term follow-up in some 100,000 subjects. However, it was canceled in late 2014 due to recruitment concerns.

The planned ECHO (Environmental Influences on Child Health Outcomes) study, also under NIH, will attempt to measure long-term outcomes related to prenatal and early postnatal exposures, including through tissue banking. It will rely on existing birth cohorts instead.

Dr. Trasande and his colleagues’ study was funded by the Endocrine Society, the John Merck Fund, the Broad Reach Foundation, and the Oak Foundation. Its authors disclosed no conflicts of interest.

The cost burden of uterine fibroids and endometriosis related to two types of endocrine-disrupting chemicals (EDCs) in Europe is about 1.4 billion euros a year, or more than $1.5 billion, according to an analysis published online March 22 in the Journal of Clinical Endocrinology & Metabolism.

Diphenyldichloroethene, or DDE, is an agricultural pesticide that has been linked to fibroids, while phthalates, used to soften plastics or deliver scent, are ubiquitous in consumer products and have been linked to endometriosis.

Courtesy Wikimedia Commons/Hic et nunc/CC BY-SA 3.0

The true burden of female reproductive disorders linked to endocrine-disrupting chemicals is likely considerably higher than the study’s estimate reflects, says Dr. Leonardo Trasande of New York University Langone Medical Center, the lead investigator.

While Dr. Trasande and his colleagues limited the scope of their study to two reproductive tract abnormalities, others, including polycystic ovarian syndrome and fertility disorders, have increasingly been linked to EDCs. The investigators also limited their focus to the two chemicals for which the evidence was strong and for which the European Union is seeking guidance on regulating.

“We see this as a first step toward a more comprehensive investigation of the role of environmental chemicals and their impact on diseases that unfortunately are all too common in women,” Dr. Trasande said in an interview.

The investigators looked at levels of DDE exposures from cohorts of mothers from whom cord blood was drawn, while phthalate exposures were measured in urine from women who took part in a pan-European biomonitoring survey of mothers and children.

Incidence of fibroids (in women aged 15-54 years) and endometriosis (in women aged 20-44 years) was derived from large national cohorts. Per-patient treatment and lost-work costs were also drawn from national databases, based on 2010 figures. Excess risk of either disease per level of exposure was calculated based on previous findings. The investigators found that fibroids or endometriosis caused by chemical exposure accounted for between 20% and 39% of cases (J Clin Endocrinol Metab. 2016 Mar 22. doi: 10.1210/jc.2015-2873).

The European national health care systems offered the researchers the advantage of large, stable cohorts from which to draw data; a similar study would have been harder to carry out in the United States, Dr. Trasande noted.

Nonetheless, he said, the implications of the study apply broadly. “The greatest takeaway here is prevention related. The findings speak to the substantial health and economic burden of these chemicals both in Europe and other parts of the world.” Exposures are comparable between the United States and Europe, he said, meaning related disease burden and costs may be proportionally consistent. In the developing world, exposures are lower but increasing.

All the chemical exposures measured in Dr. Trasande and his colleagues’ study were of adult women, though much concern over EDCs relates to in utero or early-life exposures affecting adult outcomes.

“Without the data to compare exposure in early life and conditions that occur many years later, we had to rely upon associations that were closer in time,” he said. What’s needed now is “substantial and further investment in studies that leverage banked [early-life] specimens and can be associated with patients with a particular condition.”

The National Institutes of Health’s National Children’s Study was designed to do just this, measuring prenatal environmental exposures and conducting long-term follow-up in some 100,000 subjects. However, it was canceled in late 2014 due to recruitment concerns.

The planned ECHO (Environmental Influences on Child Health Outcomes) study, also under NIH, will attempt to measure long-term outcomes related to prenatal and early postnatal exposures, including through tissue banking. It will rely on existing birth cohorts instead.

Dr. Trasande and his colleagues’ study was funded by the Endocrine Society, the John Merck Fund, the Broad Reach Foundation, and the Oak Foundation. Its authors disclosed no conflicts of interest.

Intranasal ketorolac is superior to placebo and noninferior to intranasal sumatriptan for the acute abortive treatment of moderate to severe migraine, according to data published in the February issue of Headache. Intranasal ketorolac may be appropriate for patients whose nausea makes the use of oral medications difficult, and the formulation also offers an effective alternative for patients who cannot or do not want to use a triptan nasal spray, according to the authors.

Research suggests that parenteral ketorolac may be as effective as or more effective than certain triptans and other acute abortive therapies. No previous study, however, had directly compared intranasal ketorolac with any migraine-specific therapy.

Aruna S. Rao, MD, Instructor of Neurology at Johns Hopkins University School of Medicine in Baltimore, and colleagues conducted a prospective, double-blind, double-dummy trial at an outpatient headache center in Baltimore from March 2013 to December 2014. Eligible patients were age 18 or older, had a history of episodic migraine for at least one year, and had two to 10 migraine attacks per month.

Participants were randomized in groups of equal size to one of six sequences of ketorolac nasal spray (31.5 mg), sumatriptan nasal spray (20 mg), and placebo. Each participant treated three moderate to severe migraine attacks and received a different treatment for each attack. During the 48 hours following the use of each treatment, patients used a four-point scale to assess headache severity, migraine-associated symptoms, and disability.

The study’s primary outcome was two-hour headache relief. Secondary outcomes included two-hour pain freedom, two-hour absence of migraine-associated symptoms, absence of allodynia, disability, and 24- and 48-hour sustained pain relief and sustained pain freedom.

In all, 72 participants were randomized, 54 used at least one dose of study medication, and 49 treated three attacks. A total of 152 attacks were analyzed. Patients’ mean age was 36. Approximately 80% of patients were Caucasian, and 98% were female.

About 73% of patients treated with ketorolac had two-hour pain relief, compared with 69% of patients treated with sumatriptan and 39% of controls. Ketorolac and sumatriptan thus were superior to placebo. In addition, 43% of patients treated with ketorolac had two-hour pain freedom, compared with 37% of patients treated with sumatriptan and 18% of controls. Ketorolac and sumatriptan were superior to placebo for time to pain relief, two-hour freedom from photophobia, and two-to-24-hour sustained pain relief. Only ketorolac was superior to placebo for two-hour freedom from nausea and phonophobia, two-to-24-hour sustained pain freedom, two-to-48-hour sustained pain relief, and two-to-48-hour sustained pain freedom.

The researchers found no statistically significant difference in two-hour freedom from allodynia in participants treated with ketorolac or sumatriptan, compared with placebo. In the first two hours after study treatment, participants who used ketorolac were 61% less likely, and participants who used sumatriptan were 53% less likely, to use rescue medication, compared with placebo. The most common adverse events reported for ketorolac and sumatriptan were nasal burning and an unusual taste. Both were mild to moderate for the majority of patients.

—Erik Greb

Intranasal ketorolac is superior to placebo and noninferior to intranasal sumatriptan for the acute abortive treatment of moderate to severe migraine, according to data published in the February issue of Headache. Intranasal ketorolac may be appropriate for patients whose nausea makes the use of oral medications difficult, and the formulation also offers an effective alternative for patients who cannot or do not want to use a triptan nasal spray, according to the authors.

Research suggests that parenteral ketorolac may be as effective as or more effective than certain triptans and other acute abortive therapies. No previous study, however, had directly compared intranasal ketorolac with any migraine-specific therapy.

Aruna S. Rao, MD, Instructor of Neurology at Johns Hopkins University School of Medicine in Baltimore, and colleagues conducted a prospective, double-blind, double-dummy trial at an outpatient headache center in Baltimore from March 2013 to December 2014. Eligible patients were age 18 or older, had a history of episodic migraine for at least one year, and had two to 10 migraine attacks per month.

Participants were randomized in groups of equal size to one of six sequences of ketorolac nasal spray (31.5 mg), sumatriptan nasal spray (20 mg), and placebo. Each participant treated three moderate to severe migraine attacks and received a different treatment for each attack. During the 48 hours following the use of each treatment, patients used a four-point scale to assess headache severity, migraine-associated symptoms, and disability.

The study’s primary outcome was two-hour headache relief. Secondary outcomes included two-hour pain freedom, two-hour absence of migraine-associated symptoms, absence of allodynia, disability, and 24- and 48-hour sustained pain relief and sustained pain freedom.

In all, 72 participants were randomized, 54 used at least one dose of study medication, and 49 treated three attacks. A total of 152 attacks were analyzed. Patients’ mean age was 36. Approximately 80% of patients were Caucasian, and 98% were female.

About 73% of patients treated with ketorolac had two-hour pain relief, compared with 69% of patients treated with sumatriptan and 39% of controls. Ketorolac and sumatriptan thus were superior to placebo. In addition, 43% of patients treated with ketorolac had two-hour pain freedom, compared with 37% of patients treated with sumatriptan and 18% of controls. Ketorolac and sumatriptan were superior to placebo for time to pain relief, two-hour freedom from photophobia, and two-to-24-hour sustained pain relief. Only ketorolac was superior to placebo for two-hour freedom from nausea and phonophobia, two-to-24-hour sustained pain freedom, two-to-48-hour sustained pain relief, and two-to-48-hour sustained pain freedom.

The researchers found no statistically significant difference in two-hour freedom from allodynia in participants treated with ketorolac or sumatriptan, compared with placebo. In the first two hours after study treatment, participants who used ketorolac were 61% less likely, and participants who used sumatriptan were 53% less likely, to use rescue medication, compared with placebo. The most common adverse events reported for ketorolac and sumatriptan were nasal burning and an unusual taste. Both were mild to moderate for the majority of patients.

—Erik Greb

Intranasal ketorolac is superior to placebo and noninferior to intranasal sumatriptan for the acute abortive treatment of moderate to severe migraine, according to data published in the February issue of Headache. Intranasal ketorolac may be appropriate for patients whose nausea makes the use of oral medications difficult, and the formulation also offers an effective alternative for patients who cannot or do not want to use a triptan nasal spray, according to the authors.

Research suggests that parenteral ketorolac may be as effective as or more effective than certain triptans and other acute abortive therapies. No previous study, however, had directly compared intranasal ketorolac with any migraine-specific therapy.

Aruna S. Rao, MD, Instructor of Neurology at Johns Hopkins University School of Medicine in Baltimore, and colleagues conducted a prospective, double-blind, double-dummy trial at an outpatient headache center in Baltimore from March 2013 to December 2014. Eligible patients were age 18 or older, had a history of episodic migraine for at least one year, and had two to 10 migraine attacks per month.

Participants were randomized in groups of equal size to one of six sequences of ketorolac nasal spray (31.5 mg), sumatriptan nasal spray (20 mg), and placebo. Each participant treated three moderate to severe migraine attacks and received a different treatment for each attack. During the 48 hours following the use of each treatment, patients used a four-point scale to assess headache severity, migraine-associated symptoms, and disability.

The study’s primary outcome was two-hour headache relief. Secondary outcomes included two-hour pain freedom, two-hour absence of migraine-associated symptoms, absence of allodynia, disability, and 24- and 48-hour sustained pain relief and sustained pain freedom.

In all, 72 participants were randomized, 54 used at least one dose of study medication, and 49 treated three attacks. A total of 152 attacks were analyzed. Patients’ mean age was 36. Approximately 80% of patients were Caucasian, and 98% were female.

About 73% of patients treated with ketorolac had two-hour pain relief, compared with 69% of patients treated with sumatriptan and 39% of controls. Ketorolac and sumatriptan thus were superior to placebo. In addition, 43% of patients treated with ketorolac had two-hour pain freedom, compared with 37% of patients treated with sumatriptan and 18% of controls. Ketorolac and sumatriptan were superior to placebo for time to pain relief, two-hour freedom from photophobia, and two-to-24-hour sustained pain relief. Only ketorolac was superior to placebo for two-hour freedom from nausea and phonophobia, two-to-24-hour sustained pain freedom, two-to-48-hour sustained pain relief, and two-to-48-hour sustained pain freedom.

The researchers found no statistically significant difference in two-hour freedom from allodynia in participants treated with ketorolac or sumatriptan, compared with placebo. In the first two hours after study treatment, participants who used ketorolac were 61% less likely, and participants who used sumatriptan were 53% less likely, to use rescue medication, compared with placebo. The most common adverse events reported for ketorolac and sumatriptan were nasal burning and an unusual taste. Both were mild to moderate for the majority of patients.

—Erik Greb

NEW ORLEANS—The lack of a therapy that slows or stops disease progression represents the greatest unmet need among patients with progressive multiple sclerosis (MS), according to a lecture presented at the ACTRIMS 2016 Forum. Future therapeutics for progressive MS will need to address mechanisms such as microglial and macrophage-driven neurodegeneration, mitochondrial dysfunction, and oxidative stress, said Claudia F. Lucchinetti, MD, Professor of Neurology at Mayo Clinic in Rochester, Minnesota.

Research efforts should aim to develop drugs that treat smoldering plaques and meningeal inflammation, she added. Furthermore, patients need a therapy that protects axons and promotes remyelination. “Finally, our therapies are going to need to consider targeting both inflammation and neurodegeneration early and concurrently,” said Dr. Lucchinetti.

White Matter Plaques Indicate Disease Duration

MS progression generally affects the white matter, the axons, the cortex, the meninges, and the deep gray matter. As white matter undergoes demyelination, it may develop any of four types of plaques, including active, inactive, smoldering, and remyelinated shadow plaques. In 2015, Dr. Lucchinetti and colleagues studied autopsy results for 120 patients with MS who had 2,476 white-matter plaques. They found that most plaques in early MS were active, while inactive plaques predominated in chronic MS. Smoldering plaques were rare in early MS, but reached peak levels at 18 to 20 years’ disease duration, which is when many patients convert to secondary progressive MS. The frequency of shadow plaques was similar throughout the disease duration.

In addition, the investigators found that active plaques predominated among patients with ongoing relapses, indicating that the plaques may be “the substrate of the relapse itself,” said Dr. Lucchinetti. Active plaques were less frequent in secondary progressive MS without attacks and in primary progressive MS. Shadow plaques occurred in all clinical forms of the disease, but smoldering plaques occurred only in progressive MS.

Axonal Injury May Promote Progression

Axonal injury in MS mostly occurs in small axons. The main causes of axonal loss are repeated demyelination, lack of trophic support for myelin in oligodendrocytes, Wallerian degeneration, and acute and chronic mitochondrial dysfunction, which may result from enhanced production of reactive oxygen species in macrophages and active microglia.

Mitochondria are especially susceptible to oxidative damage, and microarray gene studies have found mitochondrial dysfunction in MS. Oxidized lipids are common within active plaques and promote calcium accumulation in the axon and, hence, axonal degeneration. In cells such as oligodendrocytes, injury to the mitochondria activates apoptosis-inducible factor, which can be transferred into the nucleus. MS also causes chronic energy failure in axons, which leak current when they have been demyelinated. In a compensatory response, sodium channels increase within the axon, and mitochondria are recruited, but this response eventually fails. Demyelinated axons subsequently undergo neurodegeneration and irreversible injury, potentially leading to disease progression.

Cortical Lesions Predict Disability

“Cortical lesion load is the strongest predictor of MS disability,” said Dr. Lucchinetti. Cortical lesion load correlates with cognitive dysfunction and is present early in the disease. Approximately 40% of patients with clinically isolated syndrome have cortical lesions, which include leukocortical, intracortical, and subpial plaques.

Dr. Lucchinetti and colleagues demonstrated in one investigation that early MS lesions in the cortex are inflammatory, unlike lesions found in chronic MS. Furthermore, they found myelinated macrophages in early cortical plaques. A finding of large numbers of CD68 and CD8 cells near neurons suggests that early neurodegeneration occurs against a background of inflammation, said Dr. Lucchinetti.

Demyelination in the cortex is extensive in chronic MS. It occurs in multiple gyri and mainly affects areas involved in cognition. Research indicates that areas of cortical demyelination often are topographically related to areas in which one finds follicular light structures. “This topographical association of meningeal inflammation and cortical demyelination is striking, and it also seems to be associated with microglial activation in the underlying cortex and neuritic damage, again pointing to the fact that there is a potential soluble myelinotoxic factor mediating this aspect of MS pathology,” said Dr. Lucchinetti.

Meningeal Inflammation and Aggressive Disease

Although meningeal infiltrates may not be true follicles, meningeal inflammation is associated with greater inflammation and a shorter, more aggressive disease course. Data suggest that patients have more aggressive disease and die sooner when they have more meningeal inflammation.

In 2015, Absinta et al found that 3-T postcontrast T2-weighted FLAIR MRI may identify areas of fixed leptomeningeal inflammation. Histopathology indicated that the inflammation included perivascular lymphocytic and mononuclear infiltration in association with nearby subpial cortical demyelination. “When they looked further within these areas, they found prominent, meningeal diffuse inflammation positive for CD45 and CD68 cells,” said Dr. Lucchinetti.

The results indicate that neurologists may now have a marker to track this aspect of MS pathology, she continued. Diffuse and focal meningeal inflammation is present within days to weeks of initial presentation. This inflammation increases the likelihood of cortical demyelination and may contribute to disease progression. In a cohort of patients with early MS, meningeal inflammation was associated with subpial demyelination, similar to the association in chronic MS.

Mainero et al found that sparse areas of abnormality within the upper 25% of the brain tissue correspond with focal myelin loss or iron loss. Deeper areas of the cortex have more extensive involvement (ie, prolonged T2), and these changes are strongly associated with Expanded Disability Status Scale score. This process begins early and is not associated with white matter lesion burden, thus “highlighting the importance of this pathology to some elements of disease progression,” said Dr. Lucchinetti.

Deep Gray Matter Damage

Damage to deep gray matter in MS is focused in the caudate and the hypothalamus. As the disease progresses, it may involve the deep gray matter more extensively. Atrophy of the third ventricle is one potential way to measure the degree to which MS affects the thalamus. This atrophy seems to be associated with cognitive decline, motor deficits, and fatigue. It correlates with cortical demyelination, but not white matter demyelination.

Current approved therapies “are really targeting what we can see, [such as] inflammation and white matter plaques, but there’s much more going on,” concluded Dr. Lucchinetti.

—Erik Greb

NEW ORLEANS—The lack of a therapy that slows or stops disease progression represents the greatest unmet need among patients with progressive multiple sclerosis (MS), according to a lecture presented at the ACTRIMS 2016 Forum. Future therapeutics for progressive MS will need to address mechanisms such as microglial and macrophage-driven neurodegeneration, mitochondrial dysfunction, and oxidative stress, said Claudia F. Lucchinetti, MD, Professor of Neurology at Mayo Clinic in Rochester, Minnesota.

Research efforts should aim to develop drugs that treat smoldering plaques and meningeal inflammation, she added. Furthermore, patients need a therapy that protects axons and promotes remyelination. “Finally, our therapies are going to need to consider targeting both inflammation and neurodegeneration early and concurrently,” said Dr. Lucchinetti.

White Matter Plaques Indicate Disease Duration

MS progression generally affects the white matter, the axons, the cortex, the meninges, and the deep gray matter. As white matter undergoes demyelination, it may develop any of four types of plaques, including active, inactive, smoldering, and remyelinated shadow plaques. In 2015, Dr. Lucchinetti and colleagues studied autopsy results for 120 patients with MS who had 2,476 white-matter plaques. They found that most plaques in early MS were active, while inactive plaques predominated in chronic MS. Smoldering plaques were rare in early MS, but reached peak levels at 18 to 20 years’ disease duration, which is when many patients convert to secondary progressive MS. The frequency of shadow plaques was similar throughout the disease duration.

In addition, the investigators found that active plaques predominated among patients with ongoing relapses, indicating that the plaques may be “the substrate of the relapse itself,” said Dr. Lucchinetti. Active plaques were less frequent in secondary progressive MS without attacks and in primary progressive MS. Shadow plaques occurred in all clinical forms of the disease, but smoldering plaques occurred only in progressive MS.

Axonal Injury May Promote Progression

Axonal injury in MS mostly occurs in small axons. The main causes of axonal loss are repeated demyelination, lack of trophic support for myelin in oligodendrocytes, Wallerian degeneration, and acute and chronic mitochondrial dysfunction, which may result from enhanced production of reactive oxygen species in macrophages and active microglia.

Mitochondria are especially susceptible to oxidative damage, and microarray gene studies have found mitochondrial dysfunction in MS. Oxidized lipids are common within active plaques and promote calcium accumulation in the axon and, hence, axonal degeneration. In cells such as oligodendrocytes, injury to the mitochondria activates apoptosis-inducible factor, which can be transferred into the nucleus. MS also causes chronic energy failure in axons, which leak current when they have been demyelinated. In a compensatory response, sodium channels increase within the axon, and mitochondria are recruited, but this response eventually fails. Demyelinated axons subsequently undergo neurodegeneration and irreversible injury, potentially leading to disease progression.

Cortical Lesions Predict Disability

“Cortical lesion load is the strongest predictor of MS disability,” said Dr. Lucchinetti. Cortical lesion load correlates with cognitive dysfunction and is present early in the disease. Approximately 40% of patients with clinically isolated syndrome have cortical lesions, which include leukocortical, intracortical, and subpial plaques.

Dr. Lucchinetti and colleagues demonstrated in one investigation that early MS lesions in the cortex are inflammatory, unlike lesions found in chronic MS. Furthermore, they found myelinated macrophages in early cortical plaques. A finding of large numbers of CD68 and CD8 cells near neurons suggests that early neurodegeneration occurs against a background of inflammation, said Dr. Lucchinetti.

Demyelination in the cortex is extensive in chronic MS. It occurs in multiple gyri and mainly affects areas involved in cognition. Research indicates that areas of cortical demyelination often are topographically related to areas in which one finds follicular light structures. “This topographical association of meningeal inflammation and cortical demyelination is striking, and it also seems to be associated with microglial activation in the underlying cortex and neuritic damage, again pointing to the fact that there is a potential soluble myelinotoxic factor mediating this aspect of MS pathology,” said Dr. Lucchinetti.

Meningeal Inflammation and Aggressive Disease

Although meningeal infiltrates may not be true follicles, meningeal inflammation is associated with greater inflammation and a shorter, more aggressive disease course. Data suggest that patients have more aggressive disease and die sooner when they have more meningeal inflammation.

In 2015, Absinta et al found that 3-T postcontrast T2-weighted FLAIR MRI may identify areas of fixed leptomeningeal inflammation. Histopathology indicated that the inflammation included perivascular lymphocytic and mononuclear infiltration in association with nearby subpial cortical demyelination. “When they looked further within these areas, they found prominent, meningeal diffuse inflammation positive for CD45 and CD68 cells,” said Dr. Lucchinetti.

The results indicate that neurologists may now have a marker to track this aspect of MS pathology, she continued. Diffuse and focal meningeal inflammation is present within days to weeks of initial presentation. This inflammation increases the likelihood of cortical demyelination and may contribute to disease progression. In a cohort of patients with early MS, meningeal inflammation was associated with subpial demyelination, similar to the association in chronic MS.

Mainero et al found that sparse areas of abnormality within the upper 25% of the brain tissue correspond with focal myelin loss or iron loss. Deeper areas of the cortex have more extensive involvement (ie, prolonged T2), and these changes are strongly associated with Expanded Disability Status Scale score. This process begins early and is not associated with white matter lesion burden, thus “highlighting the importance of this pathology to some elements of disease progression,” said Dr. Lucchinetti.

Deep Gray Matter Damage

Damage to deep gray matter in MS is focused in the caudate and the hypothalamus. As the disease progresses, it may involve the deep gray matter more extensively. Atrophy of the third ventricle is one potential way to measure the degree to which MS affects the thalamus. This atrophy seems to be associated with cognitive decline, motor deficits, and fatigue. It correlates with cortical demyelination, but not white matter demyelination.

Current approved therapies “are really targeting what we can see, [such as] inflammation and white matter plaques, but there’s much more going on,” concluded Dr. Lucchinetti.

—Erik Greb

NEW ORLEANS—The lack of a therapy that slows or stops disease progression represents the greatest unmet need among patients with progressive multiple sclerosis (MS), according to a lecture presented at the ACTRIMS 2016 Forum. Future therapeutics for progressive MS will need to address mechanisms such as microglial and macrophage-driven neurodegeneration, mitochondrial dysfunction, and oxidative stress, said Claudia F. Lucchinetti, MD, Professor of Neurology at Mayo Clinic in Rochester, Minnesota.

Research efforts should aim to develop drugs that treat smoldering plaques and meningeal inflammation, she added. Furthermore, patients need a therapy that protects axons and promotes remyelination. “Finally, our therapies are going to need to consider targeting both inflammation and neurodegeneration early and concurrently,” said Dr. Lucchinetti.

White Matter Plaques Indicate Disease Duration

MS progression generally affects the white matter, the axons, the cortex, the meninges, and the deep gray matter. As white matter undergoes demyelination, it may develop any of four types of plaques, including active, inactive, smoldering, and remyelinated shadow plaques. In 2015, Dr. Lucchinetti and colleagues studied autopsy results for 120 patients with MS who had 2,476 white-matter plaques. They found that most plaques in early MS were active, while inactive plaques predominated in chronic MS. Smoldering plaques were rare in early MS, but reached peak levels at 18 to 20 years’ disease duration, which is when many patients convert to secondary progressive MS. The frequency of shadow plaques was similar throughout the disease duration.

In addition, the investigators found that active plaques predominated among patients with ongoing relapses, indicating that the plaques may be “the substrate of the relapse itself,” said Dr. Lucchinetti. Active plaques were less frequent in secondary progressive MS without attacks and in primary progressive MS. Shadow plaques occurred in all clinical forms of the disease, but smoldering plaques occurred only in progressive MS.

Axonal Injury May Promote Progression

Axonal injury in MS mostly occurs in small axons. The main causes of axonal loss are repeated demyelination, lack of trophic support for myelin in oligodendrocytes, Wallerian degeneration, and acute and chronic mitochondrial dysfunction, which may result from enhanced production of reactive oxygen species in macrophages and active microglia.

Mitochondria are especially susceptible to oxidative damage, and microarray gene studies have found mitochondrial dysfunction in MS. Oxidized lipids are common within active plaques and promote calcium accumulation in the axon and, hence, axonal degeneration. In cells such as oligodendrocytes, injury to the mitochondria activates apoptosis-inducible factor, which can be transferred into the nucleus. MS also causes chronic energy failure in axons, which leak current when they have been demyelinated. In a compensatory response, sodium channels increase within the axon, and mitochondria are recruited, but this response eventually fails. Demyelinated axons subsequently undergo neurodegeneration and irreversible injury, potentially leading to disease progression.

Cortical Lesions Predict Disability

“Cortical lesion load is the strongest predictor of MS disability,” said Dr. Lucchinetti. Cortical lesion load correlates with cognitive dysfunction and is present early in the disease. Approximately 40% of patients with clinically isolated syndrome have cortical lesions, which include leukocortical, intracortical, and subpial plaques.

Dr. Lucchinetti and colleagues demonstrated in one investigation that early MS lesions in the cortex are inflammatory, unlike lesions found in chronic MS. Furthermore, they found myelinated macrophages in early cortical plaques. A finding of large numbers of CD68 and CD8 cells near neurons suggests that early neurodegeneration occurs against a background of inflammation, said Dr. Lucchinetti.

Demyelination in the cortex is extensive in chronic MS. It occurs in multiple gyri and mainly affects areas involved in cognition. Research indicates that areas of cortical demyelination often are topographically related to areas in which one finds follicular light structures. “This topographical association of meningeal inflammation and cortical demyelination is striking, and it also seems to be associated with microglial activation in the underlying cortex and neuritic damage, again pointing to the fact that there is a potential soluble myelinotoxic factor mediating this aspect of MS pathology,” said Dr. Lucchinetti.

Meningeal Inflammation and Aggressive Disease

Although meningeal infiltrates may not be true follicles, meningeal inflammation is associated with greater inflammation and a shorter, more aggressive disease course. Data suggest that patients have more aggressive disease and die sooner when they have more meningeal inflammation.

In 2015, Absinta et al found that 3-T postcontrast T2-weighted FLAIR MRI may identify areas of fixed leptomeningeal inflammation. Histopathology indicated that the inflammation included perivascular lymphocytic and mononuclear infiltration in association with nearby subpial cortical demyelination. “When they looked further within these areas, they found prominent, meningeal diffuse inflammation positive for CD45 and CD68 cells,” said Dr. Lucchinetti.

The results indicate that neurologists may now have a marker to track this aspect of MS pathology, she continued. Diffuse and focal meningeal inflammation is present within days to weeks of initial presentation. This inflammation increases the likelihood of cortical demyelination and may contribute to disease progression. In a cohort of patients with early MS, meningeal inflammation was associated with subpial demyelination, similar to the association in chronic MS.

Mainero et al found that sparse areas of abnormality within the upper 25% of the brain tissue correspond with focal myelin loss or iron loss. Deeper areas of the cortex have more extensive involvement (ie, prolonged T2), and these changes are strongly associated with Expanded Disability Status Scale score. This process begins early and is not associated with white matter lesion burden, thus “highlighting the importance of this pathology to some elements of disease progression,” said Dr. Lucchinetti.

Deep Gray Matter Damage

Damage to deep gray matter in MS is focused in the caudate and the hypothalamus. As the disease progresses, it may involve the deep gray matter more extensively. Atrophy of the third ventricle is one potential way to measure the degree to which MS affects the thalamus. This atrophy seems to be associated with cognitive decline, motor deficits, and fatigue. It correlates with cortical demyelination, but not white matter demyelination.

Current approved therapies “are really targeting what we can see, [such as] inflammation and white matter plaques, but there’s much more going on,” concluded Dr. Lucchinetti.

—Erik Greb

Targeting insulin resistance (IR) may be an important strategy to reduce cardiovascular events in patients infected with HIV, say researchers from Johns Hopkins University in Baltimore, Maryland, and Northwestern University in Chicago, Illinois.

Related: Homelessness, HIV, and HCV

To find out whether IR was greater in men infected with HIV and, consequently, whether coronary artery disease would be amplified in those patients, the researchers analyzed data collected over 10 years from 448 men infected with HIV and 306 uninfected men in the Multicenter AIDS Cohort Study. They measured fasting serum insulin and glucose and computed the homeostatic model assessment of IR. At the end of the study, they assessed atherosclerotic disease with computed tomographic angiography (CTA).

Insulin resistance was higher in men infected with HIV when averaged over the course of the study and when measured with CTA. The prevalence of coronary stenosis ≥ 50% was similar between both groups. Men with mean IR values in the highest tertile had nearly 3 times the odds of coronary stenosis than men in the lowest tertile.

Men infected with HIV (of whom about 11% also had hepatitis C infection) were more insulin resistant than those without HIV. Insulin resistance was associated in all the study participants with common cardiovascular disease (CVD) risk factors, such as hypertension, but also with hepatitis C infection. The association between IR and coronary artery stenosis remained after adjustment for multiple CVD risk factors as well as HIV-related variables. That may mean the association is independent of the severity of immune suppression or HIV control.

Related: HIV Antibody Infusion Safely Reduces Viral Load

Coronary artery stenosis was associated with IR in both groups, particularly when IR values were assessed over the 10 years rather than at the time of the angiography. The researchers say this suggests that long-standing IR is an important contributor to CVD in patients infected with HIV.

Source: Brener MI, Post WS, Haberlen SA, et al. Am J Cardiol. 2016;117(6):993-1000.doi: 10.1016/j.amjcard.2015.12.037. 

Targeting insulin resistance (IR) may be an important strategy to reduce cardiovascular events in patients infected with HIV, say researchers from Johns Hopkins University in Baltimore, Maryland, and Northwestern University in Chicago, Illinois.

Related: Homelessness, HIV, and HCV

To find out whether IR was greater in men infected with HIV and, consequently, whether coronary artery disease would be amplified in those patients, the researchers analyzed data collected over 10 years from 448 men infected with HIV and 306 uninfected men in the Multicenter AIDS Cohort Study. They measured fasting serum insulin and glucose and computed the homeostatic model assessment of IR. At the end of the study, they assessed atherosclerotic disease with computed tomographic angiography (CTA).

Insulin resistance was higher in men infected with HIV when averaged over the course of the study and when measured with CTA. The prevalence of coronary stenosis ≥ 50% was similar between both groups. Men with mean IR values in the highest tertile had nearly 3 times the odds of coronary stenosis than men in the lowest tertile.

Men infected with HIV (of whom about 11% also had hepatitis C infection) were more insulin resistant than those without HIV. Insulin resistance was associated in all the study participants with common cardiovascular disease (CVD) risk factors, such as hypertension, but also with hepatitis C infection. The association between IR and coronary artery stenosis remained after adjustment for multiple CVD risk factors as well as HIV-related variables. That may mean the association is independent of the severity of immune suppression or HIV control.

Related: HIV Antibody Infusion Safely Reduces Viral Load

Coronary artery stenosis was associated with IR in both groups, particularly when IR values were assessed over the 10 years rather than at the time of the angiography. The researchers say this suggests that long-standing IR is an important contributor to CVD in patients infected with HIV.

Source: Brener MI, Post WS, Haberlen SA, et al. Am J Cardiol. 2016;117(6):993-1000.doi: 10.1016/j.amjcard.2015.12.037. 

Targeting insulin resistance (IR) may be an important strategy to reduce cardiovascular events in patients infected with HIV, say researchers from Johns Hopkins University in Baltimore, Maryland, and Northwestern University in Chicago, Illinois.

Related: Homelessness, HIV, and HCV

To find out whether IR was greater in men infected with HIV and, consequently, whether coronary artery disease would be amplified in those patients, the researchers analyzed data collected over 10 years from 448 men infected with HIV and 306 uninfected men in the Multicenter AIDS Cohort Study. They measured fasting serum insulin and glucose and computed the homeostatic model assessment of IR. At the end of the study, they assessed atherosclerotic disease with computed tomographic angiography (CTA).

Insulin resistance was higher in men infected with HIV when averaged over the course of the study and when measured with CTA. The prevalence of coronary stenosis ≥ 50% was similar between both groups. Men with mean IR values in the highest tertile had nearly 3 times the odds of coronary stenosis than men in the lowest tertile.

Men infected with HIV (of whom about 11% also had hepatitis C infection) were more insulin resistant than those without HIV. Insulin resistance was associated in all the study participants with common cardiovascular disease (CVD) risk factors, such as hypertension, but also with hepatitis C infection. The association between IR and coronary artery stenosis remained after adjustment for multiple CVD risk factors as well as HIV-related variables. That may mean the association is independent of the severity of immune suppression or HIV control.

Related: HIV Antibody Infusion Safely Reduces Viral Load

Coronary artery stenosis was associated with IR in both groups, particularly when IR values were assessed over the 10 years rather than at the time of the angiography. The researchers say this suggests that long-standing IR is an important contributor to CVD in patients infected with HIV.

Source: Brener MI, Post WS, Haberlen SA, et al. Am J Cardiol. 2016;117(6):993-1000.doi: 10.1016/j.amjcard.2015.12.037. 

Headache worsening after treatment with IV dihydroergotamine (DHE) does not predict poor headache outcome in the medium term among patients with chronic migraine, according to research published March 1 in Neurology. Headache exacerbation thus is not a sufficient reason to stop treatment. Instead, neurologists should focus on controlling nausea, which is the most important modifiable factor in achieving a good headache outcome, according to the researchers.

Neurologists have used IV DHE to treat patients with migraine for decades. After receiving this therapy, some patients have transient headache worsening, and this development may be interpreted as a reason to stop the infusions. Michael Eller, MD, Assistant Clinical Professor of Neurology at the University of California, San Francisco (UCSF), and colleagues performed a retrospective chart review to determine whether transient headache worsening after IV DHE infusion predicts medium-term headache outcome in patients with chronic migraine.

The investigators included all patients with chronic migraine admitted by the UCSF Headache Service between January 1, 2008, and December 31, 2012, in their analysis. All patients received IV DHE according to a standard protocol, which included 1-mg doses administered over five days to a typical target dose of 11.25 mg. In addition, patients were premedicated with ondansetron, domperidone, or both. Participants with medication overuse (approximately 30% of the population) also received IV aspirin before receiving IV DHE.

Dr. Eller and colleagues retrospectively analyzed the prospectively collected inpatient headache diaries, progress notes, and discharge summaries. Physicians did not routinely ask patients whether they had headache exacerbation. The researchers defined DHE worsening as headache (typically, exacerbation of the underlying phenotype) or nausea increase within 30 minutes of the infusion. The treating clinician assessed and recorded medium-term headache outcome at follow-up approximately six weeks after discharge.

During the study period, 274 patients with chronic migraine had inpatient treatment with DHE. Mean age was 44, and 77% of the population was female. In all, 153 patients had been receiving migraine preventives. Headache outcome information was available for 214 patients, and patients with missing outcome data did not differ from the others in terms of age, sex, or likelihood of having nausea or medication overuse. Approximately 78% of patients with follow-up data had medium-term headache benefit following IV DHE.

Forty-one participants (19%) had headache worsening with DHE infusions. Of these patients, 66% had medium-term headache benefit, compared with 82% of patients who did not have headache exacerbation. A univariate analysis indicated that headache exacerbation with DHE infusion was associated with reduced odds of medium-term headache benefit. Multivariate logistic regression analysis adjusted for nausea, leg cramping, medication overuse, sex, and age, however, indicated that headache exacerbation with DHE was not an independent predictor of medium-term headache benefit.

Nausea was the modifiable risk factor with the greatest effect on headache outcome. In an adjusted model, nausea was significantly associated with headache exacerbation with DHE infusion. Nausea also was an independent predictor of decreased likelihood of medium-term headache benefit in the fully adjusted model, as was medication overuse. Older age was strongly associated with increased odds of headache benefit.

The results suggest that adequate nausea control might help prevent headache exacerbation, said the authors. “Clinicians in all settings should focus their efforts on aggressive nausea control during a course of IV DHE for chronic migraine,” they added. Younger patients with chronic migraine were less likely to benefit from an inpatient course of IV DHE, and this finding “highlights an even greater need for nausea control in that population.”

The study’s retrospective design was a limitation, said Dr. Eller. Some exacerbations of headache may have gone unreported, and future studies should systematically query patients for this symptom, he added.

Data Improve the Understanding of DHE

The investigation by Dr. Eller and colleagues improves our current understanding of the effects of DHE, said Andrew Charles, MD, Director of the Headache Research and Treatment Program at the University of California, Los Angeles, in an accompanying editorial. The careful documentation and systematic reporting of patient experience, although retrospective, can be valuable in characterizing common patient-management issues, he added.

In population studies, persistent frequent nausea has been associated with increased risk of progression from episodic migraine to chronic migraine. “Whether or not treatment of nausea as a ‘modifiable risk factor’ actually changes the clinical course of migraine remains unclear,” said Dr. Charles. “What is clear, however, is that nausea is a frequently disabling component of migraine that warrants aggressive therapy.” Various therapeutic options exist, but no evidence clearly supports one option over the others. “This study underscores the importance of optimizing therapy of migraine-related nausea, and of coming to a better understanding of the role of nausea and its treatment in the short- and long-term outcomes of patients with migraine,” Dr. Charles concluded.

—Erik Greb

Headache worsening after treatment with IV dihydroergotamine (DHE) does not predict poor headache outcome in the medium term among patients with chronic migraine, according to research published March 1 in Neurology. Headache exacerbation thus is not a sufficient reason to stop treatment. Instead, neurologists should focus on controlling nausea, which is the most important modifiable factor in achieving a good headache outcome, according to the researchers.

Neurologists have used IV DHE to treat patients with migraine for decades. After receiving this therapy, some patients have transient headache worsening, and this development may be interpreted as a reason to stop the infusions. Michael Eller, MD, Assistant Clinical Professor of Neurology at the University of California, San Francisco (UCSF), and colleagues performed a retrospective chart review to determine whether transient headache worsening after IV DHE infusion predicts medium-term headache outcome in patients with chronic migraine.

The investigators included all patients with chronic migraine admitted by the UCSF Headache Service between January 1, 2008, and December 31, 2012, in their analysis. All patients received IV DHE according to a standard protocol, which included 1-mg doses administered over five days to a typical target dose of 11.25 mg. In addition, patients were premedicated with ondansetron, domperidone, or both. Participants with medication overuse (approximately 30% of the population) also received IV aspirin before receiving IV DHE.

Dr. Eller and colleagues retrospectively analyzed the prospectively collected inpatient headache diaries, progress notes, and discharge summaries. Physicians did not routinely ask patients whether they had headache exacerbation. The researchers defined DHE worsening as headache (typically, exacerbation of the underlying phenotype) or nausea increase within 30 minutes of the infusion. The treating clinician assessed and recorded medium-term headache outcome at follow-up approximately six weeks after discharge.

During the study period, 274 patients with chronic migraine had inpatient treatment with DHE. Mean age was 44, and 77% of the population was female. In all, 153 patients had been receiving migraine preventives. Headache outcome information was available for 214 patients, and patients with missing outcome data did not differ from the others in terms of age, sex, or likelihood of having nausea or medication overuse. Approximately 78% of patients with follow-up data had medium-term headache benefit following IV DHE.

Forty-one participants (19%) had headache worsening with DHE infusions. Of these patients, 66% had medium-term headache benefit, compared with 82% of patients who did not have headache exacerbation. A univariate analysis indicated that headache exacerbation with DHE infusion was associated with reduced odds of medium-term headache benefit. Multivariate logistic regression analysis adjusted for nausea, leg cramping, medication overuse, sex, and age, however, indicated that headache exacerbation with DHE was not an independent predictor of medium-term headache benefit.

Nausea was the modifiable risk factor with the greatest effect on headache outcome. In an adjusted model, nausea was significantly associated with headache exacerbation with DHE infusion. Nausea also was an independent predictor of decreased likelihood of medium-term headache benefit in the fully adjusted model, as was medication overuse. Older age was strongly associated with increased odds of headache benefit.

The results suggest that adequate nausea control might help prevent headache exacerbation, said the authors. “Clinicians in all settings should focus their efforts on aggressive nausea control during a course of IV DHE for chronic migraine,” they added. Younger patients with chronic migraine were less likely to benefit from an inpatient course of IV DHE, and this finding “highlights an even greater need for nausea control in that population.”

The study’s retrospective design was a limitation, said Dr. Eller. Some exacerbations of headache may have gone unreported, and future studies should systematically query patients for this symptom, he added.

Data Improve the Understanding of DHE

The investigation by Dr. Eller and colleagues improves our current understanding of the effects of DHE, said Andrew Charles, MD, Director of the Headache Research and Treatment Program at the University of California, Los Angeles, in an accompanying editorial. The careful documentation and systematic reporting of patient experience, although retrospective, can be valuable in characterizing common patient-management issues, he added.

In population studies, persistent frequent nausea has been associated with increased risk of progression from episodic migraine to chronic migraine. “Whether or not treatment of nausea as a ‘modifiable risk factor’ actually changes the clinical course of migraine remains unclear,” said Dr. Charles. “What is clear, however, is that nausea is a frequently disabling component of migraine that warrants aggressive therapy.” Various therapeutic options exist, but no evidence clearly supports one option over the others. “This study underscores the importance of optimizing therapy of migraine-related nausea, and of coming to a better understanding of the role of nausea and its treatment in the short- and long-term outcomes of patients with migraine,” Dr. Charles concluded.

—Erik Greb

Headache worsening after treatment with IV dihydroergotamine (DHE) does not predict poor headache outcome in the medium term among patients with chronic migraine, according to research published March 1 in Neurology. Headache exacerbation thus is not a sufficient reason to stop treatment. Instead, neurologists should focus on controlling nausea, which is the most important modifiable factor in achieving a good headache outcome, according to the researchers.

Neurologists have used IV DHE to treat patients with migraine for decades. After receiving this therapy, some patients have transient headache worsening, and this development may be interpreted as a reason to stop the infusions. Michael Eller, MD, Assistant Clinical Professor of Neurology at the University of California, San Francisco (UCSF), and colleagues performed a retrospective chart review to determine whether transient headache worsening after IV DHE infusion predicts medium-term headache outcome in patients with chronic migraine.

The investigators included all patients with chronic migraine admitted by the UCSF Headache Service between January 1, 2008, and December 31, 2012, in their analysis. All patients received IV DHE according to a standard protocol, which included 1-mg doses administered over five days to a typical target dose of 11.25 mg. In addition, patients were premedicated with ondansetron, domperidone, or both. Participants with medication overuse (approximately 30% of the population) also received IV aspirin before receiving IV DHE.

Dr. Eller and colleagues retrospectively analyzed the prospectively collected inpatient headache diaries, progress notes, and discharge summaries. Physicians did not routinely ask patients whether they had headache exacerbation. The researchers defined DHE worsening as headache (typically, exacerbation of the underlying phenotype) or nausea increase within 30 minutes of the infusion. The treating clinician assessed and recorded medium-term headache outcome at follow-up approximately six weeks after discharge.

During the study period, 274 patients with chronic migraine had inpatient treatment with DHE. Mean age was 44, and 77% of the population was female. In all, 153 patients had been receiving migraine preventives. Headache outcome information was available for 214 patients, and patients with missing outcome data did not differ from the others in terms of age, sex, or likelihood of having nausea or medication overuse. Approximately 78% of patients with follow-up data had medium-term headache benefit following IV DHE.

Forty-one participants (19%) had headache worsening with DHE infusions. Of these patients, 66% had medium-term headache benefit, compared with 82% of patients who did not have headache exacerbation. A univariate analysis indicated that headache exacerbation with DHE infusion was associated with reduced odds of medium-term headache benefit. Multivariate logistic regression analysis adjusted for nausea, leg cramping, medication overuse, sex, and age, however, indicated that headache exacerbation with DHE was not an independent predictor of medium-term headache benefit.

Nausea was the modifiable risk factor with the greatest effect on headache outcome. In an adjusted model, nausea was significantly associated with headache exacerbation with DHE infusion. Nausea also was an independent predictor of decreased likelihood of medium-term headache benefit in the fully adjusted model, as was medication overuse. Older age was strongly associated with increased odds of headache benefit.

The results suggest that adequate nausea control might help prevent headache exacerbation, said the authors. “Clinicians in all settings should focus their efforts on aggressive nausea control during a course of IV DHE for chronic migraine,” they added. Younger patients with chronic migraine were less likely to benefit from an inpatient course of IV DHE, and this finding “highlights an even greater need for nausea control in that population.”

The study’s retrospective design was a limitation, said Dr. Eller. Some exacerbations of headache may have gone unreported, and future studies should systematically query patients for this symptom, he added.

Data Improve the Understanding of DHE

The investigation by Dr. Eller and colleagues improves our current understanding of the effects of DHE, said Andrew Charles, MD, Director of the Headache Research and Treatment Program at the University of California, Los Angeles, in an accompanying editorial. The careful documentation and systematic reporting of patient experience, although retrospective, can be valuable in characterizing common patient-management issues, he added.

In population studies, persistent frequent nausea has been associated with increased risk of progression from episodic migraine to chronic migraine. “Whether or not treatment of nausea as a ‘modifiable risk factor’ actually changes the clinical course of migraine remains unclear,” said Dr. Charles. “What is clear, however, is that nausea is a frequently disabling component of migraine that warrants aggressive therapy.” Various therapeutic options exist, but no evidence clearly supports one option over the others. “This study underscores the importance of optimizing therapy of migraine-related nausea, and of coming to a better understanding of the role of nausea and its treatment in the short- and long-term outcomes of patients with migraine,” Dr. Charles concluded.

—Erik Greb

Engaged hospitalists drive quality care, and SHM has the tools to help you assess the level of engagement of hospitalists in your hospital medicine group. SHM offered a Hospitalist Engagement Benchmarking Service in 2015 and analyzed engagement of approximately 1,500 hospitalists. Organizational climate, care quality, autonomy, effective motivation, and burnout risk are just a few of the domains that were benchmarked.

“The engagement survey opened conversations about everything from how we relate to the C-suite to what we can do to sustain teamwork,” says Erin Stucky Fisher, MD, MHM, pediatric hospitalist at Rady Children’s Hospital-San Diego. “[It] highlighted what was working well and identified what needs work.”

More than 80% of respondents indicated that they will utilize the service again and plan to recommend it to a colleague. Help ensure hospitalists are engaged in your hospital medicine group by registering now for the next cohort at www.hospitalmedicine.org/engage. TH

Brett Radler is SHM’s communications coordinator.

Engaged hospitalists drive quality care, and SHM has the tools to help you assess the level of engagement of hospitalists in your hospital medicine group. SHM offered a Hospitalist Engagement Benchmarking Service in 2015 and analyzed engagement of approximately 1,500 hospitalists. Organizational climate, care quality, autonomy, effective motivation, and burnout risk are just a few of the domains that were benchmarked.

“The engagement survey opened conversations about everything from how we relate to the C-suite to what we can do to sustain teamwork,” says Erin Stucky Fisher, MD, MHM, pediatric hospitalist at Rady Children’s Hospital-San Diego. “[It] highlighted what was working well and identified what needs work.”

More than 80% of respondents indicated that they will utilize the service again and plan to recommend it to a colleague. Help ensure hospitalists are engaged in your hospital medicine group by registering now for the next cohort at www.hospitalmedicine.org/engage. TH

Brett Radler is SHM’s communications coordinator.

Engaged hospitalists drive quality care, and SHM has the tools to help you assess the level of engagement of hospitalists in your hospital medicine group. SHM offered a Hospitalist Engagement Benchmarking Service in 2015 and analyzed engagement of approximately 1,500 hospitalists. Organizational climate, care quality, autonomy, effective motivation, and burnout risk are just a few of the domains that were benchmarked.

“The engagement survey opened conversations about everything from how we relate to the C-suite to what we can do to sustain teamwork,” says Erin Stucky Fisher, MD, MHM, pediatric hospitalist at Rady Children’s Hospital-San Diego. “[It] highlighted what was working well and identified what needs work.”

More than 80% of respondents indicated that they will utilize the service again and plan to recommend it to a colleague. Help ensure hospitalists are engaged in your hospital medicine group by registering now for the next cohort at www.hospitalmedicine.org/engage. TH

Brett Radler is SHM’s communications coordinator.

Ever wish you had more leadership training in medical school or your residency programs? Feel a bit overwhelmed when developing operational plans for your hospital or negotiating important contracts? Join SHM in sunny Lake Buena Vista, Fla., October 24–27, for its esteemed Leadership Academy (www.shmleadershipacademy.org). SHM Leadership Academy prepares clinicians, academicians, and administrators with vital leadership skills traditionally not taught throughout the course of medical training, tailored specifically to hospital medicine.

“SHM’s Leadership Academy teaches leadership skills for individuals all across the spectrum of the hospital team. My experience helped me to raise the bar not only to benefit myself but also my institution and especially my patients,” says Ron Greeno, MD, MHM. “I highly recommend this experience to any hospital medicine professionals who aspire to take their leadership skills to the next level.”

All three courses run concurrently over the span of the four days and are led by world-renowned faculty. This expanded meeting will provide attendees with unprecedented networking opportunities with hundreds of colleagues and enhanced career development.

Available Leadership Academy courses include:

• Leadership Foundations, a four-day course that serves as the first step in your leadership journey. Attendees learn how to evaluate personal leadership strengths and weaknesses, create and execute a communication strategy for key team members, understand key hospital drivers, examine how hospital metrics are derived, and much more. Attendees are divided into smaller moderated groups to ensure meaningful, relevant application of concepts to hands-on activities.
• Advanced Leadership: Influential Management, a course that builds skills around driving culture change through specific leadership behaviors and actions, financial storytelling, engaging in effective professional negotiation activities with proven techniques, and more through world-renowned faculty and applied exercises.

  (Prerequisite: Leadership Foundations or an advanced management degree upon course director approval)

• Advanced Leadership: Mastering Teamwork, a course developed in response to high demand from previous Leadership Academy attendees. Participants learn how to critically assess program growth opportunities and develop operational plans; utilize the principles of SWARM intelligence; lead, manage, and motivate teams in complex hospital environments; and develop effective communication strategies.

  (Prerequisite: Leadership Foundations or an advanced management degree upon course director approval.)

SHM members receive reduced rates for course tuition. For more information on how to register, visit www.SHMLeadershipAcademy.org.

Ever wish you had more leadership training in medical school or your residency programs? Feel a bit overwhelmed when developing operational plans for your hospital or negotiating important contracts? Join SHM in sunny Lake Buena Vista, Fla., October 24–27, for its esteemed Leadership Academy (www.shmleadershipacademy.org). SHM Leadership Academy prepares clinicians, academicians, and administrators with vital leadership skills traditionally not taught throughout the course of medical training, tailored specifically to hospital medicine.

“SHM’s Leadership Academy teaches leadership skills for individuals all across the spectrum of the hospital team. My experience helped me to raise the bar not only to benefit myself but also my institution and especially my patients,” says Ron Greeno, MD, MHM. “I highly recommend this experience to any hospital medicine professionals who aspire to take their leadership skills to the next level.”

All three courses run concurrently over the span of the four days and are led by world-renowned faculty. This expanded meeting will provide attendees with unprecedented networking opportunities with hundreds of colleagues and enhanced career development.

Available Leadership Academy courses include:

• Leadership Foundations, a four-day course that serves as the first step in your leadership journey. Attendees learn how to evaluate personal leadership strengths and weaknesses, create and execute a communication strategy for key team members, understand key hospital drivers, examine how hospital metrics are derived, and much more. Attendees are divided into smaller moderated groups to ensure meaningful, relevant application of concepts to hands-on activities.
• Advanced Leadership: Influential Management, a course that builds skills around driving culture change through specific leadership behaviors and actions, financial storytelling, engaging in effective professional negotiation activities with proven techniques, and more through world-renowned faculty and applied exercises.

  (Prerequisite: Leadership Foundations or an advanced management degree upon course director approval)

• Advanced Leadership: Mastering Teamwork, a course developed in response to high demand from previous Leadership Academy attendees. Participants learn how to critically assess program growth opportunities and develop operational plans; utilize the principles of SWARM intelligence; lead, manage, and motivate teams in complex hospital environments; and develop effective communication strategies.

  (Prerequisite: Leadership Foundations or an advanced management degree upon course director approval.)

SHM members receive reduced rates for course tuition. For more information on how to register, visit www.SHMLeadershipAcademy.org.

Ever wish you had more leadership training in medical school or your residency programs? Feel a bit overwhelmed when developing operational plans for your hospital or negotiating important contracts? Join SHM in sunny Lake Buena Vista, Fla., October 24–27, for its esteemed Leadership Academy (www.shmleadershipacademy.org). SHM Leadership Academy prepares clinicians, academicians, and administrators with vital leadership skills traditionally not taught throughout the course of medical training, tailored specifically to hospital medicine.

“SHM’s Leadership Academy teaches leadership skills for individuals all across the spectrum of the hospital team. My experience helped me to raise the bar not only to benefit myself but also my institution and especially my patients,” says Ron Greeno, MD, MHM. “I highly recommend this experience to any hospital medicine professionals who aspire to take their leadership skills to the next level.”

All three courses run concurrently over the span of the four days and are led by world-renowned faculty. This expanded meeting will provide attendees with unprecedented networking opportunities with hundreds of colleagues and enhanced career development.

Available Leadership Academy courses include:

• Leadership Foundations, a four-day course that serves as the first step in your leadership journey. Attendees learn how to evaluate personal leadership strengths and weaknesses, create and execute a communication strategy for key team members, understand key hospital drivers, examine how hospital metrics are derived, and much more. Attendees are divided into smaller moderated groups to ensure meaningful, relevant application of concepts to hands-on activities.
• Advanced Leadership: Influential Management, a course that builds skills around driving culture change through specific leadership behaviors and actions, financial storytelling, engaging in effective professional negotiation activities with proven techniques, and more through world-renowned faculty and applied exercises.

  (Prerequisite: Leadership Foundations or an advanced management degree upon course director approval)

• Advanced Leadership: Mastering Teamwork, a course developed in response to high demand from previous Leadership Academy attendees. Participants learn how to critically assess program growth opportunities and develop operational plans; utilize the principles of SWARM intelligence; lead, manage, and motivate teams in complex hospital environments; and develop effective communication strategies.

  (Prerequisite: Leadership Foundations or an advanced management degree upon course director approval.)

SHM members receive reduced rates for course tuition. For more information on how to register, visit www.SHMLeadershipAcademy.org.

NEW YORK (Reuters Health) - Use of the marker procalcitonin to guide antibacterial therapy in the critically ill is associated with shorter treatment and reduced mortality, according to Dutch researchers.

As Dr. Evelien de Jong told Reuters Health by email, "Antibiotic overconsumption is one of the largest threats to medicine in the near future. Our study is the largest randomized controlled trial of antibiotic reduction in intensive care units (ICUs) and will, hopefully, contribute to a more individualized antibiotic duration per patient and an overall reduction of antibiotic use."

In a February 29 online paper in the Lancet Infectious Diseases, Dr. de Jong, of VU University Medical Center, Amsterdam, and colleagues noted that a "drop in procalcitonin concentration might help (clinicians) to discontinue antibiotic use in a more timely fashion" than reliance on biomarkers such as C-reactive protein.

To investigate, the researchers studied 1,575 ICU patients who received antibiotics and were randomized to procalcitonin-guided antibiotic discontinuation or standard of care. Fifteen were excluded from the procalcitonin group and 14 were excluded from the standard care group.

"In the procalcitonin-guided group, a non-binding advice to discontinue antibiotics was provided if procalcitonin concentration had decreased by 80% or more of its peak value or to 0.5 ug/L or lower," the authors reported.

In all, 538 (71%) of 761 patients in the procalcitonin-guided group and 457 (58%) of 785 patients in the standard-of-care group completed their antibiotic treatment in the ICU.

Median consumption of antibiotics was 7.5 daily defined doses in the procalcitonin group, significantly less than the 9.3 daily defined doses in the standard-of-care group, for a mean group absolute difference of 2.69 (p<0.0001).

Median duration of treatment was also significantly shorter in the procalcitonin-guided group (five versus seven days), for a mean group absolute difference of 1.22 (p<0.0001).

Mortality at 28 days was also significantly less than in the standard-of-care group. This was 20% versus 27% in intention-to-treat analysis. At one year, corresponding per protocol proportions were 36% and 43%.

Overall, the researchers concluded, "Procalcitonin concentrations might help physicians in deciding whether or not the presumed infection is truly bacterial, leading to more adequate diagnosis and treatment, the cornerstones of antibiotic stewardship."

Commenting by email, Dr. Philipp Schuetz, coauthor of an accompanying editorial, told Reuters Health, "This well-done and large landmark trial proves that procalcitonin-guided care reduces unnecessary antibiotic courses in critical care patients with assumed or proven infection and thereby improves patient outcomes, namely overall survival."

Dr. Schuetz, of the University of Basel, Switzerland, concluded, "We should now adapt our guidelines and start to (adopt) more widespread use of procalcitonin protocols in clinical practice to slow emergence of bacterial resistance and improve sepsis care."

NEW YORK (Reuters Health) - Use of the marker procalcitonin to guide antibacterial therapy in the critically ill is associated with shorter treatment and reduced mortality, according to Dutch researchers.

As Dr. Evelien de Jong told Reuters Health by email, "Antibiotic overconsumption is one of the largest threats to medicine in the near future. Our study is the largest randomized controlled trial of antibiotic reduction in intensive care units (ICUs) and will, hopefully, contribute to a more individualized antibiotic duration per patient and an overall reduction of antibiotic use."

In a February 29 online paper in the Lancet Infectious Diseases, Dr. de Jong, of VU University Medical Center, Amsterdam, and colleagues noted that a "drop in procalcitonin concentration might help (clinicians) to discontinue antibiotic use in a more timely fashion" than reliance on biomarkers such as C-reactive protein.

To investigate, the researchers studied 1,575 ICU patients who received antibiotics and were randomized to procalcitonin-guided antibiotic discontinuation or standard of care. Fifteen were excluded from the procalcitonin group and 14 were excluded from the standard care group.

"In the procalcitonin-guided group, a non-binding advice to discontinue antibiotics was provided if procalcitonin concentration had decreased by 80% or more of its peak value or to 0.5 ug/L or lower," the authors reported.

In all, 538 (71%) of 761 patients in the procalcitonin-guided group and 457 (58%) of 785 patients in the standard-of-care group completed their antibiotic treatment in the ICU.

Median consumption of antibiotics was 7.5 daily defined doses in the procalcitonin group, significantly less than the 9.3 daily defined doses in the standard-of-care group, for a mean group absolute difference of 2.69 (p<0.0001).

Median duration of treatment was also significantly shorter in the procalcitonin-guided group (five versus seven days), for a mean group absolute difference of 1.22 (p<0.0001).

Mortality at 28 days was also significantly less than in the standard-of-care group. This was 20% versus 27% in intention-to-treat analysis. At one year, corresponding per protocol proportions were 36% and 43%.

Overall, the researchers concluded, "Procalcitonin concentrations might help physicians in deciding whether or not the presumed infection is truly bacterial, leading to more adequate diagnosis and treatment, the cornerstones of antibiotic stewardship."

Commenting by email, Dr. Philipp Schuetz, coauthor of an accompanying editorial, told Reuters Health, "This well-done and large landmark trial proves that procalcitonin-guided care reduces unnecessary antibiotic courses in critical care patients with assumed or proven infection and thereby improves patient outcomes, namely overall survival."

Dr. Schuetz, of the University of Basel, Switzerland, concluded, "We should now adapt our guidelines and start to (adopt) more widespread use of procalcitonin protocols in clinical practice to slow emergence of bacterial resistance and improve sepsis care."

NEW YORK (Reuters Health) - Use of the marker procalcitonin to guide antibacterial therapy in the critically ill is associated with shorter treatment and reduced mortality, according to Dutch researchers.

As Dr. Evelien de Jong told Reuters Health by email, "Antibiotic overconsumption is one of the largest threats to medicine in the near future. Our study is the largest randomized controlled trial of antibiotic reduction in intensive care units (ICUs) and will, hopefully, contribute to a more individualized antibiotic duration per patient and an overall reduction of antibiotic use."

In a February 29 online paper in the Lancet Infectious Diseases, Dr. de Jong, of VU University Medical Center, Amsterdam, and colleagues noted that a "drop in procalcitonin concentration might help (clinicians) to discontinue antibiotic use in a more timely fashion" than reliance on biomarkers such as C-reactive protein.

To investigate, the researchers studied 1,575 ICU patients who received antibiotics and were randomized to procalcitonin-guided antibiotic discontinuation or standard of care. Fifteen were excluded from the procalcitonin group and 14 were excluded from the standard care group.

"In the procalcitonin-guided group, a non-binding advice to discontinue antibiotics was provided if procalcitonin concentration had decreased by 80% or more of its peak value or to 0.5 ug/L or lower," the authors reported.

In all, 538 (71%) of 761 patients in the procalcitonin-guided group and 457 (58%) of 785 patients in the standard-of-care group completed their antibiotic treatment in the ICU.

Median consumption of antibiotics was 7.5 daily defined doses in the procalcitonin group, significantly less than the 9.3 daily defined doses in the standard-of-care group, for a mean group absolute difference of 2.69 (p<0.0001).

Median duration of treatment was also significantly shorter in the procalcitonin-guided group (five versus seven days), for a mean group absolute difference of 1.22 (p<0.0001).

Mortality at 28 days was also significantly less than in the standard-of-care group. This was 20% versus 27% in intention-to-treat analysis. At one year, corresponding per protocol proportions were 36% and 43%.

Overall, the researchers concluded, "Procalcitonin concentrations might help physicians in deciding whether or not the presumed infection is truly bacterial, leading to more adequate diagnosis and treatment, the cornerstones of antibiotic stewardship."

Commenting by email, Dr. Philipp Schuetz, coauthor of an accompanying editorial, told Reuters Health, "This well-done and large landmark trial proves that procalcitonin-guided care reduces unnecessary antibiotic courses in critical care patients with assumed or proven infection and thereby improves patient outcomes, namely overall survival."

Dr. Schuetz, of the University of Basel, Switzerland, concluded, "We should now adapt our guidelines and start to (adopt) more widespread use of procalcitonin protocols in clinical practice to slow emergence of bacterial resistance and improve sepsis care."

Lab mice

Photo by Aaron Logan

Increasing levels of a gut microbiome-derived metabolite could help prevent graft-versus-host disease (GVHD) after hematopoietic stem cell transplant (HSCT), according to preclinical research published in Nature Immunology.

For this study, researchers searched for alterations in the gut microbiome to see whether metabolites could impact outcomes after HSCT.

They found that levels of a metabolite called butyrate were significantly reduced in the intestinal tract of mice that received a transplant.

When the researchers increased butyrate levels in these mice, they saw a decrease in the incidence and severity of GVHD.

“Our findings suggest we can prevent graft-vs-host disease by bolstering the amount of the microbiome-derived metabolite butyrate,” said study author Pavan Reddy, MD, of the University of Michigan Comprehensive Cancer Center in Ann Arbor.

He and his colleagues found they could mitigate GVHD by administering butyrate to mice or by altering the composition of indigenous gastrointestinal microbiota so they produced high levels of butyrate.

The team noted that diet is another way to control butyrate production by the gut microbiome—specifically, through resistant starch such as that found in potatoes.

The researchers hope to begin a clinical trial later this year in which they will combine resistant starch with current methods of preventing GVHD to assess whether they can increase butyrate and reduce the incidence and severity of GVHD in HSCT recipients.

“This is a whole new approach,” Dr Reddy said. “The idea is to make the host cells stronger, to be able to withstand the assault of the donor immune cells while reducing the risk of infection or [disease] relapse.” 

Lab mice

Photo by Aaron Logan

Increasing levels of a gut microbiome-derived metabolite could help prevent graft-versus-host disease (GVHD) after hematopoietic stem cell transplant (HSCT), according to preclinical research published in Nature Immunology.

For this study, researchers searched for alterations in the gut microbiome to see whether metabolites could impact outcomes after HSCT.

They found that levels of a metabolite called butyrate were significantly reduced in the intestinal tract of mice that received a transplant.

When the researchers increased butyrate levels in these mice, they saw a decrease in the incidence and severity of GVHD.

“Our findings suggest we can prevent graft-vs-host disease by bolstering the amount of the microbiome-derived metabolite butyrate,” said study author Pavan Reddy, MD, of the University of Michigan Comprehensive Cancer Center in Ann Arbor.

He and his colleagues found they could mitigate GVHD by administering butyrate to mice or by altering the composition of indigenous gastrointestinal microbiota so they produced high levels of butyrate.

The team noted that diet is another way to control butyrate production by the gut microbiome—specifically, through resistant starch such as that found in potatoes.

The researchers hope to begin a clinical trial later this year in which they will combine resistant starch with current methods of preventing GVHD to assess whether they can increase butyrate and reduce the incidence and severity of GVHD in HSCT recipients.

“This is a whole new approach,” Dr Reddy said. “The idea is to make the host cells stronger, to be able to withstand the assault of the donor immune cells while reducing the risk of infection or [disease] relapse.” 

Lab mice

Photo by Aaron Logan

Increasing levels of a gut microbiome-derived metabolite could help prevent graft-versus-host disease (GVHD) after hematopoietic stem cell transplant (HSCT), according to preclinical research published in Nature Immunology.

For this study, researchers searched for alterations in the gut microbiome to see whether metabolites could impact outcomes after HSCT.

They found that levels of a metabolite called butyrate were significantly reduced in the intestinal tract of mice that received a transplant.

When the researchers increased butyrate levels in these mice, they saw a decrease in the incidence and severity of GVHD.

“Our findings suggest we can prevent graft-vs-host disease by bolstering the amount of the microbiome-derived metabolite butyrate,” said study author Pavan Reddy, MD, of the University of Michigan Comprehensive Cancer Center in Ann Arbor.

He and his colleagues found they could mitigate GVHD by administering butyrate to mice or by altering the composition of indigenous gastrointestinal microbiota so they produced high levels of butyrate.

The team noted that diet is another way to control butyrate production by the gut microbiome—specifically, through resistant starch such as that found in potatoes.

The researchers hope to begin a clinical trial later this year in which they will combine resistant starch with current methods of preventing GVHD to assess whether they can increase butyrate and reduce the incidence and severity of GVHD in HSCT recipients.

“This is a whole new approach,” Dr Reddy said. “The idea is to make the host cells stronger, to be able to withstand the assault of the donor immune cells while reducing the risk of infection or [disease] relapse.” 

 

 

Idelalisib (Zydelig)

Photo courtesy of

Gilead Sciences, Inc.

 

In light of recently reported safety concerns, the European Medicines Agency’s (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) has issued provisional advice for doctors and patients using idelalisib (Zydelig).

The EMA recently began reviewing the safety of idelalisib because of serious adverse events, most of which were infection-related, that were reported in 3 clinical trials investigating idelalisib in combination with other drugs.

These trials have since been stopped.

Now, the PRAC is making provisional recommendations to ensure idelalisib is used as safely as possible outside of clinical trials.

These recommendations will be forwarded to the European Commission, which will issue a provisional legally binding decision applicable in all European Union (EU) member states.

In the EU, idelalisib is approved as monotherapy for adults with follicular lymphoma that is refractory to 2 prior lines of treatment.

Idelalisib is also approved for use in combination with rituximab to treat adults with chronic lymphocytic leukemia (CLL) who have received at least 1 prior therapy or as first-line treatment in the presence of 17p deletion or TP53 mutation in CLL patients considered unsuitable for chemo-immunotherapy.

Recommendations

The PRAC is recommending that previously untreated CLL patients with 17p deletion or TP53 mutation do not begin treatment with idelalisib. In addition, doctors should re-evaluate each patient taking idelalisib as first-line treatment for CLL and only continue treatment if the benefits outweigh the risks.

Idelalisib can continue to be used in combination, only with rituximab, in CLL patients who have received at least 1 prior therapy and as monotherapy in patients with follicular lymphoma that is refractory to 2 lines of treatment.

Patients with any evidence of ongoing systemic infection should not be started on treatment with idelalisib.

And patients should be informed about the risk of serious infections with idelalisib.

All patients who do receive idelalisib should take antibiotics to prevent Pneumocystis jirovecii pneumonia, and they should be monitored for respiratory signs and symptoms. Regular clinical and laboratory monitoring for cytomegalovirus infection is also recommended.

Patients should have regular blood tests to detect neutropenia. In case a patient has moderate or severe neutropenia, treatment with idelalisib may have to be interrupted, in line with the updated summary of product characteristics.

The EMA said further details on these provisional measures will be provided in writing to healthcare professionals, and the product information will be updated accordingly.

Likewise, further information on the review of idelalisib will be provided as necessary and once the review is finished.

About the review

The EMA’s review of idelalisib started after a higher rate of serious adverse events, including deaths, was seen in 3 clinical trials evaluating the addition of idelalisib to standard therapy in first-line CLL and relapsed indolent non-Hodgkin lymphoma (NHL).

Most of the deaths were related to infections such as Pneumocystis jirovecii pneumonia and cytomegalovirus infection. Other excess deaths were related mainly to respiratory events.

The NHL studies (NCT01732926 and NCT01732913) included patients with disease characteristics different from those covered by the currently approved indication for idelalisib and investigated combinations of drugs that are not currently approved in the EU—idelalisib plus rituximab for NHL and idelalisib plus bendamustine and rituximab for NHL.

The CLL trial (NCT01980888) involved patients who had not received previous treatment, some of whom had the 17p deletion or TP53 mutation. However, the trial also investigated a combination of drugs not currently approved in the EU—idelalisib plus bendamustine and rituximab.

At present, the PRAC is conducting the review. Once the PRAC is finished, its recommendations will be forwarded to the EMA’s Committee for Medicinal Products for Human Use, which will adopt a final opinion.

The European Commission will take this opinion into account and adopt a legally binding decision that is applicable in all EU member states.

 

 

Idelalisib (Zydelig)

Photo courtesy of

Gilead Sciences, Inc.

 

In light of recently reported safety concerns, the European Medicines Agency’s (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) has issued provisional advice for doctors and patients using idelalisib (Zydelig).

The EMA recently began reviewing the safety of idelalisib because of serious adverse events, most of which were infection-related, that were reported in 3 clinical trials investigating idelalisib in combination with other drugs.

These trials have since been stopped.

Now, the PRAC is making provisional recommendations to ensure idelalisib is used as safely as possible outside of clinical trials.

These recommendations will be forwarded to the European Commission, which will issue a provisional legally binding decision applicable in all European Union (EU) member states.

In the EU, idelalisib is approved as monotherapy for adults with follicular lymphoma that is refractory to 2 prior lines of treatment.

Idelalisib is also approved for use in combination with rituximab to treat adults with chronic lymphocytic leukemia (CLL) who have received at least 1 prior therapy or as first-line treatment in the presence of 17p deletion or TP53 mutation in CLL patients considered unsuitable for chemo-immunotherapy.

Recommendations

The PRAC is recommending that previously untreated CLL patients with 17p deletion or TP53 mutation do not begin treatment with idelalisib. In addition, doctors should re-evaluate each patient taking idelalisib as first-line treatment for CLL and only continue treatment if the benefits outweigh the risks.

Idelalisib can continue to be used in combination, only with rituximab, in CLL patients who have received at least 1 prior therapy and as monotherapy in patients with follicular lymphoma that is refractory to 2 lines of treatment.

Patients with any evidence of ongoing systemic infection should not be started on treatment with idelalisib.

And patients should be informed about the risk of serious infections with idelalisib.

All patients who do receive idelalisib should take antibiotics to prevent Pneumocystis jirovecii pneumonia, and they should be monitored for respiratory signs and symptoms. Regular clinical and laboratory monitoring for cytomegalovirus infection is also recommended.

Patients should have regular blood tests to detect neutropenia. In case a patient has moderate or severe neutropenia, treatment with idelalisib may have to be interrupted, in line with the updated summary of product characteristics.

The EMA said further details on these provisional measures will be provided in writing to healthcare professionals, and the product information will be updated accordingly.

Likewise, further information on the review of idelalisib will be provided as necessary and once the review is finished.

About the review

The EMA’s review of idelalisib started after a higher rate of serious adverse events, including deaths, was seen in 3 clinical trials evaluating the addition of idelalisib to standard therapy in first-line CLL and relapsed indolent non-Hodgkin lymphoma (NHL).

Most of the deaths were related to infections such as Pneumocystis jirovecii pneumonia and cytomegalovirus infection. Other excess deaths were related mainly to respiratory events.

The NHL studies (NCT01732926 and NCT01732913) included patients with disease characteristics different from those covered by the currently approved indication for idelalisib and investigated combinations of drugs that are not currently approved in the EU—idelalisib plus rituximab for NHL and idelalisib plus bendamustine and rituximab for NHL.

The CLL trial (NCT01980888) involved patients who had not received previous treatment, some of whom had the 17p deletion or TP53 mutation. However, the trial also investigated a combination of drugs not currently approved in the EU—idelalisib plus bendamustine and rituximab.

At present, the PRAC is conducting the review. Once the PRAC is finished, its recommendations will be forwarded to the EMA’s Committee for Medicinal Products for Human Use, which will adopt a final opinion.

The European Commission will take this opinion into account and adopt a legally binding decision that is applicable in all EU member states.

 

 

Idelalisib (Zydelig)

Photo courtesy of

Gilead Sciences, Inc.

 

In light of recently reported safety concerns, the European Medicines Agency’s (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) has issued provisional advice for doctors and patients using idelalisib (Zydelig).

The EMA recently began reviewing the safety of idelalisib because of serious adverse events, most of which were infection-related, that were reported in 3 clinical trials investigating idelalisib in combination with other drugs.

These trials have since been stopped.

Now, the PRAC is making provisional recommendations to ensure idelalisib is used as safely as possible outside of clinical trials.

These recommendations will be forwarded to the European Commission, which will issue a provisional legally binding decision applicable in all European Union (EU) member states.

In the EU, idelalisib is approved as monotherapy for adults with follicular lymphoma that is refractory to 2 prior lines of treatment.

Idelalisib is also approved for use in combination with rituximab to treat adults with chronic lymphocytic leukemia (CLL) who have received at least 1 prior therapy or as first-line treatment in the presence of 17p deletion or TP53 mutation in CLL patients considered unsuitable for chemo-immunotherapy.

Recommendations

The PRAC is recommending that previously untreated CLL patients with 17p deletion or TP53 mutation do not begin treatment with idelalisib. In addition, doctors should re-evaluate each patient taking idelalisib as first-line treatment for CLL and only continue treatment if the benefits outweigh the risks.

Idelalisib can continue to be used in combination, only with rituximab, in CLL patients who have received at least 1 prior therapy and as monotherapy in patients with follicular lymphoma that is refractory to 2 lines of treatment.

Patients with any evidence of ongoing systemic infection should not be started on treatment with idelalisib.

And patients should be informed about the risk of serious infections with idelalisib.

All patients who do receive idelalisib should take antibiotics to prevent Pneumocystis jirovecii pneumonia, and they should be monitored for respiratory signs and symptoms. Regular clinical and laboratory monitoring for cytomegalovirus infection is also recommended.

Patients should have regular blood tests to detect neutropenia. In case a patient has moderate or severe neutropenia, treatment with idelalisib may have to be interrupted, in line with the updated summary of product characteristics.

The EMA said further details on these provisional measures will be provided in writing to healthcare professionals, and the product information will be updated accordingly.

Likewise, further information on the review of idelalisib will be provided as necessary and once the review is finished.

About the review

The EMA’s review of idelalisib started after a higher rate of serious adverse events, including deaths, was seen in 3 clinical trials evaluating the addition of idelalisib to standard therapy in first-line CLL and relapsed indolent non-Hodgkin lymphoma (NHL).

Most of the deaths were related to infections such as Pneumocystis jirovecii pneumonia and cytomegalovirus infection. Other excess deaths were related mainly to respiratory events.

The NHL studies (NCT01732926 and NCT01732913) included patients with disease characteristics different from those covered by the currently approved indication for idelalisib and investigated combinations of drugs that are not currently approved in the EU—idelalisib plus rituximab for NHL and idelalisib plus bendamustine and rituximab for NHL.

The CLL trial (NCT01980888) involved patients who had not received previous treatment, some of whom had the 17p deletion or TP53 mutation. However, the trial also investigated a combination of drugs not currently approved in the EU—idelalisib plus bendamustine and rituximab.

At present, the PRAC is conducting the review. Once the PRAC is finished, its recommendations will be forwarded to the EMA’s Committee for Medicinal Products for Human Use, which will adopt a final opinion.

The European Commission will take this opinion into account and adopt a legally binding decision that is applicable in all EU member states.