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Accuracy of colon cancer lymph node sampling influenced by location
CHICAGO – Clinical guidelines recommend , but those guidelines may need to be revised to take into account which side the cancer is on to accurately stage a subset of patients with colon cancer, according to results of a prospective, multicenter clinical trial presented at the Society of Surgical Oncology Annual Cancer Symposium.
Ahmed Dehal, MD, of John Wayne Canter Institute in Santa Monica, Calif., presented results of the trial that compared nodal staging in right-sided vs. left-sided colon cancer in two cohorts with T3N0 colon cancer who had at least one lymph node examined: a group of 370 patients from the randomized, multicenter prospective trial; and a sampling of 153,945 patients in the National Cancer Database (NCDB). The latter was used to validate findings in the trial group.
The probability of achieving true nodal negativity when 12 lymph nodes were examined was 64% for left and 68% for right colon cancer in the trial group and 72% and 77% in the NCDB cohort, Dr. Dehal said.
The analysis also examined how many nodes would need to be sampled to achieve probabilities of 85%, 90% and 95% true nodal negativity. This analysis found the numbers were consistently lower for right- vs. left-sided disease, Dr. Dehal said. For example, in the trial cohort, 27 lymph nodes would need be sampled in right-sided disease to achieve 85% probability vs. 31 in left-sided. In the NCDB cohort, those numbers were 21 and 25, respectively.
“The current threshold for adequate nodal sampling does not reliably predict the true nodal negativity in this subgroup of patients,” Dr. Dehal said. “In both cohorts – the trial and NCDB – more lymph nodes are needed to predict the true nodal negativity in patients with left compared to right colon cancer.”
These findings may help to inform revisions to existing clinical guidelines, Dr. Dehal said.
“Current guidelines regarding the minimum number of nodes needed to accurately stage patients with node-negative T3 colon cancer may need to be reevaluated given that the decision to give those patients chemotherapy is largely based on the nodal status,” he said. “More studies are needed to improve our understanding of the impact of sidedness on nodal staging in the colon cancer.”
Dr. Dehal and his coauthors reported having no financial disclosures.
SOURCE: Dehal A et al. Society of Surgical Oncology Annual Cancer Symposium. Abstract #23: Accuracy of nodal staging is influenced by sidedness in colon cancer: Results of a multicenter prospective trial.
*CORRECTION, 4/4/2018; a previous version of this story misidentified the cancer type
CHICAGO – Clinical guidelines recommend , but those guidelines may need to be revised to take into account which side the cancer is on to accurately stage a subset of patients with colon cancer, according to results of a prospective, multicenter clinical trial presented at the Society of Surgical Oncology Annual Cancer Symposium.
Ahmed Dehal, MD, of John Wayne Canter Institute in Santa Monica, Calif., presented results of the trial that compared nodal staging in right-sided vs. left-sided colon cancer in two cohorts with T3N0 colon cancer who had at least one lymph node examined: a group of 370 patients from the randomized, multicenter prospective trial; and a sampling of 153,945 patients in the National Cancer Database (NCDB). The latter was used to validate findings in the trial group.
The probability of achieving true nodal negativity when 12 lymph nodes were examined was 64% for left and 68% for right colon cancer in the trial group and 72% and 77% in the NCDB cohort, Dr. Dehal said.
The analysis also examined how many nodes would need to be sampled to achieve probabilities of 85%, 90% and 95% true nodal negativity. This analysis found the numbers were consistently lower for right- vs. left-sided disease, Dr. Dehal said. For example, in the trial cohort, 27 lymph nodes would need be sampled in right-sided disease to achieve 85% probability vs. 31 in left-sided. In the NCDB cohort, those numbers were 21 and 25, respectively.
“The current threshold for adequate nodal sampling does not reliably predict the true nodal negativity in this subgroup of patients,” Dr. Dehal said. “In both cohorts – the trial and NCDB – more lymph nodes are needed to predict the true nodal negativity in patients with left compared to right colon cancer.”
These findings may help to inform revisions to existing clinical guidelines, Dr. Dehal said.
“Current guidelines regarding the minimum number of nodes needed to accurately stage patients with node-negative T3 colon cancer may need to be reevaluated given that the decision to give those patients chemotherapy is largely based on the nodal status,” he said. “More studies are needed to improve our understanding of the impact of sidedness on nodal staging in the colon cancer.”
Dr. Dehal and his coauthors reported having no financial disclosures.
SOURCE: Dehal A et al. Society of Surgical Oncology Annual Cancer Symposium. Abstract #23: Accuracy of nodal staging is influenced by sidedness in colon cancer: Results of a multicenter prospective trial.
*CORRECTION, 4/4/2018; a previous version of this story misidentified the cancer type
CHICAGO – Clinical guidelines recommend , but those guidelines may need to be revised to take into account which side the cancer is on to accurately stage a subset of patients with colon cancer, according to results of a prospective, multicenter clinical trial presented at the Society of Surgical Oncology Annual Cancer Symposium.
Ahmed Dehal, MD, of John Wayne Canter Institute in Santa Monica, Calif., presented results of the trial that compared nodal staging in right-sided vs. left-sided colon cancer in two cohorts with T3N0 colon cancer who had at least one lymph node examined: a group of 370 patients from the randomized, multicenter prospective trial; and a sampling of 153,945 patients in the National Cancer Database (NCDB). The latter was used to validate findings in the trial group.
The probability of achieving true nodal negativity when 12 lymph nodes were examined was 64% for left and 68% for right colon cancer in the trial group and 72% and 77% in the NCDB cohort, Dr. Dehal said.
The analysis also examined how many nodes would need to be sampled to achieve probabilities of 85%, 90% and 95% true nodal negativity. This analysis found the numbers were consistently lower for right- vs. left-sided disease, Dr. Dehal said. For example, in the trial cohort, 27 lymph nodes would need be sampled in right-sided disease to achieve 85% probability vs. 31 in left-sided. In the NCDB cohort, those numbers were 21 and 25, respectively.
“The current threshold for adequate nodal sampling does not reliably predict the true nodal negativity in this subgroup of patients,” Dr. Dehal said. “In both cohorts – the trial and NCDB – more lymph nodes are needed to predict the true nodal negativity in patients with left compared to right colon cancer.”
These findings may help to inform revisions to existing clinical guidelines, Dr. Dehal said.
“Current guidelines regarding the minimum number of nodes needed to accurately stage patients with node-negative T3 colon cancer may need to be reevaluated given that the decision to give those patients chemotherapy is largely based on the nodal status,” he said. “More studies are needed to improve our understanding of the impact of sidedness on nodal staging in the colon cancer.”
Dr. Dehal and his coauthors reported having no financial disclosures.
SOURCE: Dehal A et al. Society of Surgical Oncology Annual Cancer Symposium. Abstract #23: Accuracy of nodal staging is influenced by sidedness in colon cancer: Results of a multicenter prospective trial.
*CORRECTION, 4/4/2018; a previous version of this story misidentified the cancer type
REPORTING FROM SSO 2018
Key clinical point: Sidedness influences the number of lymph nodes needed to predict true nodal negativity in colon cancer.
Major finding: Probability of true nodal negativity when 12 lymph nodes were examined was 64% for left and 68% for right colon cancer.
Study details: Randomized, multicenter trial of ultrastaging in colon cancer in 370 patients and National Cancer Database sampling of 153,945 patients.
Disclosures: Dr. Dehal and his coauthors report having no financial disclosures.
Source: Dehal A et al. Society of Surgical Oncology Annual Cancer Symposium, Abstract 23: Accuracy of nodal staging is influenced by sidedness in colon cancer: Results of a multicenter prospective trial.
New and Noteworthy Information—April 2018
New Genetic Risk Factors for Stroke Determined
New genetic risk factors for stroke have been identified, thereby tripling the number of gene regions known to affect stroke risk, according to a study published online ahead of print March 12 in Nature Genetics. Researchers conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 with stroke) and discovered 22 new stroke risk loci, bringing the total to 32. In addition, the investigators found shared genetic variation with related vascular traits (eg, blood pressure, cardiac traits, and venous thromboembolism) at individual loci and using genetic risk scores and linkage-disequilibrium-score regression. Several loci had distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology. The researchers prioritized risk variants and genes through bioinformatics analyses using functional datasets.
Malik R, Chauhan G, Traylor M, et al. Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes. Nat Genet. 2018 Mar 12 [Epub ahead of print].
MS Medication Withdrawn Because of Safety Concerns
Citing concerns about safety, Biogen and AbbVie announced March 2 that they will be withdrawing daclizumab (Zinbryta) from worldwide markets. Daclizumab has known risks, so it was usually prescribed only for people with relapsing multiple sclerosis who had tried two or more other medications that had not worked well enough. Reports of inflammatory encephalitis and meningoencephalitis led the European Medicines Agency to initiate an Article 20 referral procedure. In such referrals, a medicine or class of medicines are scientifically assessed because of concerns over safety or quality. However, Biogen and AbbVie concluded that, because of the complex nature of these reports and how few patients were taking daclizumab, it would be difficult to characterize the nature of the medication’s harms and benefits, so the companies instead have decided to withdraw the medication from the market.
Many Elderly Patients With Epilepsy Receive Interacting Treatments
Many elderly patients with epilepsy receive combinations of nonepilepsy drugs (NEDs) and antiepileptic drugs (AEDs) that could interact, according to a study published February 7 in Epilepsia. Researchers retrospectively analyzed 2008–2010 Medicare claims for a random sample of beneficiaries age 67 and older. Prevalent cases had a diagnosis of epilepsy and took one or more AEDs. Incident cases had no seizure or epilepsy claim codes or AEDs in the preceding 365 days. Interacting pairs of AEDs and NEDs were identified by literature review. Logistic regression models were used to examine factors affecting the likelihood of interaction risk. Interacting drug pairs affected NED efficacy in 24.5% of incident cases and 39% of prevalent cases. Combinations affected AED efficacy in 20.4% of incident cases and 29.3% of prevalent cases.
Faught E, Szaflarski JP, Richman J, et al. Risk of pharmacokinetic interactions between antiepileptic and other drugs in older persons and factors associated with risk. Epilepsia. 2018;59(3):715-723.
Are Physically Fit Women at Reduced Risk for Dementia?
High cardiovascular fitness in midlife is associated with decreased risk of subsequent dementia, according to a study published online ahead of print March 14 in Neurology. Physicians examined a population-based sample of 1,462 women ages 38 to 60 in 1968. A subsample of 191 women with an average age of 50 took a maximal ergometer cycling test to measure their peak cardiovascular capacity. Over the following 44 years, participants were tested for dementia six times. By 2012, 44 of the women developed dementia. Approximately 5% of the highly fit women developed dementia, compared with 25% of moderately fit women, and 32% of the women with low fitness. The highly fit women were 88% less likely to develop dementia than the moderately fit women.
Hörder H, Johansson L, Guo X, et al. Midlife cardiovascular fitness and dementia: A 44-year longitudinal population study in women. Neurology. 2018 Mar 14 [Epub ahead of print].
Data on Geriatric TBI May Be Inadequate
Many older adults with traumatic brain injury (TBI) respond well to aggressive management and rehabilitation, which suggests that age and TBI severity alone are inadequate prognostic markers, according to a study published online ahead of print February 15 in the Journal of Neurotrauma. Researchers reviewed the literature on incident TBI sustained in older adulthood. They found few geriatric-specific TBI guidelines to assist with complex management decisions and concluded that TBI prognostic models do not perform optimally in this population. Major barriers in management of geriatric TBI include underrepresentation of older adults in TBI research, lack of systematic measurement of preinjury health that may predict outcome and response to treatment, and lack of geriatric-specific TBI common data elements. Investigators need to develop more age-inclusive TBI research protocols, said the authors.
Gardner RC, Dams-O’Connor K, Morrissey MR, Manley GT. Geriatric traumatic brain injury: epidemiology, outcomes, knowledge gaps, and future directions. J Neurotrauma. 2018 Feb 15 [Epub ahead of print].
TDCS Improves Gait in Parkinson’s Disease
Transcranial direct-current stimulation (TDCS) reduces freezing of gait and improves executive function and mobility, according to a study published online ahead of print February 13 in Movement Disorders. Researchers examined 20 patients with Parkinson’s disease and freezing of gait. The patients received 20 minutes of TDCS or sham treatment during three separate visits. TDCS targeted the primary motor cortex and left dorsolateral prefrontal cortex simultaneously or primary motor cortex only. Participants completed the Timed Up and Go and Stroop tests before and after each stimulation session. Performance on the Timed Up and Go and Stroop tests improved after simultaneous stimulation of the primary motor cortex and left dorsolateral prefrontal cortex, but not after stimulation of the primary motor cortex alone or sham stimulation.
Dagan M, Herman T, Harrison R, et al. Multitarget transcranial direct current stimulation for freezing of gait in Parkinson’s disease. Mov Disord. 2018 Feb 13 [Epub ahead of print].
Patients With Major Stroke Need Realistic Planning
Doctors who care for patients with severe stroke should plan with patients and caregivers and discuss the possibility of death or survival with disability, according to a study published March 5 in the Canadian Medical Association Journal. Researchers recruited a purposive sample of people with total anterior circulation stroke at three stroke services and conducted serial, qualitative interviews with participants and their caregivers at six weeks, six months, and one year. Investigators also conducted a data-linkage study of all patients with anterior circulation stroke admitted to the three services over six months. About 57% of patients died within six months. Patients experienced immediate and persistent emotional distress and poor quality of life. Physicians should practice palliative care for these patients, but avoid using that term, said the authors.
Kendall M, Cowey E, Mead G, et al. Outcomes, experiences and palliative care in major stroke: a multicentre, mixed-method, longitudinal study. CMAJ. 2018;190(9):E238-E246.
Dengue Fever Is Associated With Increased Risk of Stroke
Dengue fever is associated with an increased risk of stroke in the first few months after diagnosis, according to a study published March 12 in Canadian Medical Association Journal. Using data from the Taiwan National Health Insurance Research Database, researchers examined 13,787 patients diagnosed with dengue fever between 2000 and 2012. The control cohort consisted of patients matched by demographic characteristics and stroke-related comorbidities who did not have dengue fever. The overall incidence rate of stroke was 5.33 per 1,000 person-years in the dengue fever cohort and 3.72 per 1,000 person-years in the control cohort. The adjusted hazard ratio of stroke was 1.16 in patients with dengue fever. The risk of stroke was 2.49 times higher in patients with dengue fever during the first two months after diagnosis, compared with controls.
Li HM, Huang YK, Su YC, Kao CH. Risk of stroke in patients with dengue fever: a population-based cohort study. CMAJ. 2018;190(10):E285-E290.
Do Survivors of Stroke Need Additional Help Taking Medication?
More than half of patients with stroke need help taking medication, according to a study published March 11 in BMJ Open. Approximately 600 community-dwelling patients with stroke responded to a five-item questionnaire about practical support that they need and receive. Approximately 56% of respondents got help with taking medication, and 11% needed additional help, including help with prescriptions and collection of medicines, getting medicines out of the packaging, and being reminded to take medicines. Being dependent on others was associated with experiencing more unmet needs with daily medicine taking. About 35% of respondents said that they had missed taking medicine in the previous 30 days. Younger patients with stroke were more likely to miss their medicines, possibly because they were less likely to receive help from a caregiver.
Jamison J, Ayerbe L, Di Tanna GL, et al. Evaluating practical support stroke survivors get with medicines and unmet needs in primary care: a survey. BMJ Open. 2018;8(3):e019874.
Sun Exposure Associated With Reduced Risk of MS
Living in areas with high ambient levels of ultraviolet-B light during childhood and the years before multiple sclerosis (MS) onset is associated with a lower MS risk, according to a study published online ahead of print March 7 in Neurology. Researchers identified 151 women with MS and 235 age-matched controls. The average age at MS onset was 40. All participants completed questionnaires about summer, winter, and lifetime sun exposure. Researchers separated the women into three groups representing low, moderate, and high ultraviolet-B ray exposure, based on their residence. Women who lived in sunnier climates with the highest exposure to ultraviolet-B rays had a 45% reduced risk of developing MS across all pre-MS onset age groups, when compared with participants living in areas with the lowest ultraviolet-B ray exposure.
Tremlett H, Zhu F, Ascherio A, Munger KL. Sun exposure over the life course and associations with multiple sclerosis. Neurology. 2018 Mar 7 [Epub ahead of print].
The new blood pressure guidelines could harm certain patients, according to a study published online ahead of print March 2 in the Journal of the American College of Cardiology. Investigators examined the effect of 10-year cardiovascular disease (CVD) risk on primary outcome events and serious adverse events in the Systolic Pressure Intervention Trial, which was a basis for the new guidelines. They stratified patients by quartiles of risk and used Cox proportional hazards models to examine associations. From the first to fourth quartiles, the number needed to treat to prevent primary outcomes decreased from 91 to 38. The number needed to harm for all-cause serious adverse events increased from 62 to 250. Classifying patients by future risk could identify patients who would benefit from intensive treatment, said the authors.
Phillips RA, Xu J, Peterson LE, et al. Impact of cardiovascular risk on the relative benefit and harm of intensive treatment of hypertension. J Am Coll Cardiol. 2018 Mar 2 [Epub ahead of print].
—Kimberly Williams
New Genetic Risk Factors for Stroke Determined
New genetic risk factors for stroke have been identified, thereby tripling the number of gene regions known to affect stroke risk, according to a study published online ahead of print March 12 in Nature Genetics. Researchers conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 with stroke) and discovered 22 new stroke risk loci, bringing the total to 32. In addition, the investigators found shared genetic variation with related vascular traits (eg, blood pressure, cardiac traits, and venous thromboembolism) at individual loci and using genetic risk scores and linkage-disequilibrium-score regression. Several loci had distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology. The researchers prioritized risk variants and genes through bioinformatics analyses using functional datasets.
Malik R, Chauhan G, Traylor M, et al. Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes. Nat Genet. 2018 Mar 12 [Epub ahead of print].
MS Medication Withdrawn Because of Safety Concerns
Citing concerns about safety, Biogen and AbbVie announced March 2 that they will be withdrawing daclizumab (Zinbryta) from worldwide markets. Daclizumab has known risks, so it was usually prescribed only for people with relapsing multiple sclerosis who had tried two or more other medications that had not worked well enough. Reports of inflammatory encephalitis and meningoencephalitis led the European Medicines Agency to initiate an Article 20 referral procedure. In such referrals, a medicine or class of medicines are scientifically assessed because of concerns over safety or quality. However, Biogen and AbbVie concluded that, because of the complex nature of these reports and how few patients were taking daclizumab, it would be difficult to characterize the nature of the medication’s harms and benefits, so the companies instead have decided to withdraw the medication from the market.
Many Elderly Patients With Epilepsy Receive Interacting Treatments
Many elderly patients with epilepsy receive combinations of nonepilepsy drugs (NEDs) and antiepileptic drugs (AEDs) that could interact, according to a study published February 7 in Epilepsia. Researchers retrospectively analyzed 2008–2010 Medicare claims for a random sample of beneficiaries age 67 and older. Prevalent cases had a diagnosis of epilepsy and took one or more AEDs. Incident cases had no seizure or epilepsy claim codes or AEDs in the preceding 365 days. Interacting pairs of AEDs and NEDs were identified by literature review. Logistic regression models were used to examine factors affecting the likelihood of interaction risk. Interacting drug pairs affected NED efficacy in 24.5% of incident cases and 39% of prevalent cases. Combinations affected AED efficacy in 20.4% of incident cases and 29.3% of prevalent cases.
Faught E, Szaflarski JP, Richman J, et al. Risk of pharmacokinetic interactions between antiepileptic and other drugs in older persons and factors associated with risk. Epilepsia. 2018;59(3):715-723.
Are Physically Fit Women at Reduced Risk for Dementia?
High cardiovascular fitness in midlife is associated with decreased risk of subsequent dementia, according to a study published online ahead of print March 14 in Neurology. Physicians examined a population-based sample of 1,462 women ages 38 to 60 in 1968. A subsample of 191 women with an average age of 50 took a maximal ergometer cycling test to measure their peak cardiovascular capacity. Over the following 44 years, participants were tested for dementia six times. By 2012, 44 of the women developed dementia. Approximately 5% of the highly fit women developed dementia, compared with 25% of moderately fit women, and 32% of the women with low fitness. The highly fit women were 88% less likely to develop dementia than the moderately fit women.
Hörder H, Johansson L, Guo X, et al. Midlife cardiovascular fitness and dementia: A 44-year longitudinal population study in women. Neurology. 2018 Mar 14 [Epub ahead of print].
Data on Geriatric TBI May Be Inadequate
Many older adults with traumatic brain injury (TBI) respond well to aggressive management and rehabilitation, which suggests that age and TBI severity alone are inadequate prognostic markers, according to a study published online ahead of print February 15 in the Journal of Neurotrauma. Researchers reviewed the literature on incident TBI sustained in older adulthood. They found few geriatric-specific TBI guidelines to assist with complex management decisions and concluded that TBI prognostic models do not perform optimally in this population. Major barriers in management of geriatric TBI include underrepresentation of older adults in TBI research, lack of systematic measurement of preinjury health that may predict outcome and response to treatment, and lack of geriatric-specific TBI common data elements. Investigators need to develop more age-inclusive TBI research protocols, said the authors.
Gardner RC, Dams-O’Connor K, Morrissey MR, Manley GT. Geriatric traumatic brain injury: epidemiology, outcomes, knowledge gaps, and future directions. J Neurotrauma. 2018 Feb 15 [Epub ahead of print].
TDCS Improves Gait in Parkinson’s Disease
Transcranial direct-current stimulation (TDCS) reduces freezing of gait and improves executive function and mobility, according to a study published online ahead of print February 13 in Movement Disorders. Researchers examined 20 patients with Parkinson’s disease and freezing of gait. The patients received 20 minutes of TDCS or sham treatment during three separate visits. TDCS targeted the primary motor cortex and left dorsolateral prefrontal cortex simultaneously or primary motor cortex only. Participants completed the Timed Up and Go and Stroop tests before and after each stimulation session. Performance on the Timed Up and Go and Stroop tests improved after simultaneous stimulation of the primary motor cortex and left dorsolateral prefrontal cortex, but not after stimulation of the primary motor cortex alone or sham stimulation.
Dagan M, Herman T, Harrison R, et al. Multitarget transcranial direct current stimulation for freezing of gait in Parkinson’s disease. Mov Disord. 2018 Feb 13 [Epub ahead of print].
Patients With Major Stroke Need Realistic Planning
Doctors who care for patients with severe stroke should plan with patients and caregivers and discuss the possibility of death or survival with disability, according to a study published March 5 in the Canadian Medical Association Journal. Researchers recruited a purposive sample of people with total anterior circulation stroke at three stroke services and conducted serial, qualitative interviews with participants and their caregivers at six weeks, six months, and one year. Investigators also conducted a data-linkage study of all patients with anterior circulation stroke admitted to the three services over six months. About 57% of patients died within six months. Patients experienced immediate and persistent emotional distress and poor quality of life. Physicians should practice palliative care for these patients, but avoid using that term, said the authors.
Kendall M, Cowey E, Mead G, et al. Outcomes, experiences and palliative care in major stroke: a multicentre, mixed-method, longitudinal study. CMAJ. 2018;190(9):E238-E246.
Dengue Fever Is Associated With Increased Risk of Stroke
Dengue fever is associated with an increased risk of stroke in the first few months after diagnosis, according to a study published March 12 in Canadian Medical Association Journal. Using data from the Taiwan National Health Insurance Research Database, researchers examined 13,787 patients diagnosed with dengue fever between 2000 and 2012. The control cohort consisted of patients matched by demographic characteristics and stroke-related comorbidities who did not have dengue fever. The overall incidence rate of stroke was 5.33 per 1,000 person-years in the dengue fever cohort and 3.72 per 1,000 person-years in the control cohort. The adjusted hazard ratio of stroke was 1.16 in patients with dengue fever. The risk of stroke was 2.49 times higher in patients with dengue fever during the first two months after diagnosis, compared with controls.
Li HM, Huang YK, Su YC, Kao CH. Risk of stroke in patients with dengue fever: a population-based cohort study. CMAJ. 2018;190(10):E285-E290.
Do Survivors of Stroke Need Additional Help Taking Medication?
More than half of patients with stroke need help taking medication, according to a study published March 11 in BMJ Open. Approximately 600 community-dwelling patients with stroke responded to a five-item questionnaire about practical support that they need and receive. Approximately 56% of respondents got help with taking medication, and 11% needed additional help, including help with prescriptions and collection of medicines, getting medicines out of the packaging, and being reminded to take medicines. Being dependent on others was associated with experiencing more unmet needs with daily medicine taking. About 35% of respondents said that they had missed taking medicine in the previous 30 days. Younger patients with stroke were more likely to miss their medicines, possibly because they were less likely to receive help from a caregiver.
Jamison J, Ayerbe L, Di Tanna GL, et al. Evaluating practical support stroke survivors get with medicines and unmet needs in primary care: a survey. BMJ Open. 2018;8(3):e019874.
Sun Exposure Associated With Reduced Risk of MS
Living in areas with high ambient levels of ultraviolet-B light during childhood and the years before multiple sclerosis (MS) onset is associated with a lower MS risk, according to a study published online ahead of print March 7 in Neurology. Researchers identified 151 women with MS and 235 age-matched controls. The average age at MS onset was 40. All participants completed questionnaires about summer, winter, and lifetime sun exposure. Researchers separated the women into three groups representing low, moderate, and high ultraviolet-B ray exposure, based on their residence. Women who lived in sunnier climates with the highest exposure to ultraviolet-B rays had a 45% reduced risk of developing MS across all pre-MS onset age groups, when compared with participants living in areas with the lowest ultraviolet-B ray exposure.
Tremlett H, Zhu F, Ascherio A, Munger KL. Sun exposure over the life course and associations with multiple sclerosis. Neurology. 2018 Mar 7 [Epub ahead of print].
The new blood pressure guidelines could harm certain patients, according to a study published online ahead of print March 2 in the Journal of the American College of Cardiology. Investigators examined the effect of 10-year cardiovascular disease (CVD) risk on primary outcome events and serious adverse events in the Systolic Pressure Intervention Trial, which was a basis for the new guidelines. They stratified patients by quartiles of risk and used Cox proportional hazards models to examine associations. From the first to fourth quartiles, the number needed to treat to prevent primary outcomes decreased from 91 to 38. The number needed to harm for all-cause serious adverse events increased from 62 to 250. Classifying patients by future risk could identify patients who would benefit from intensive treatment, said the authors.
Phillips RA, Xu J, Peterson LE, et al. Impact of cardiovascular risk on the relative benefit and harm of intensive treatment of hypertension. J Am Coll Cardiol. 2018 Mar 2 [Epub ahead of print].
—Kimberly Williams
New Genetic Risk Factors for Stroke Determined
New genetic risk factors for stroke have been identified, thereby tripling the number of gene regions known to affect stroke risk, according to a study published online ahead of print March 12 in Nature Genetics. Researchers conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 with stroke) and discovered 22 new stroke risk loci, bringing the total to 32. In addition, the investigators found shared genetic variation with related vascular traits (eg, blood pressure, cardiac traits, and venous thromboembolism) at individual loci and using genetic risk scores and linkage-disequilibrium-score regression. Several loci had distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology. The researchers prioritized risk variants and genes through bioinformatics analyses using functional datasets.
Malik R, Chauhan G, Traylor M, et al. Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes. Nat Genet. 2018 Mar 12 [Epub ahead of print].
MS Medication Withdrawn Because of Safety Concerns
Citing concerns about safety, Biogen and AbbVie announced March 2 that they will be withdrawing daclizumab (Zinbryta) from worldwide markets. Daclizumab has known risks, so it was usually prescribed only for people with relapsing multiple sclerosis who had tried two or more other medications that had not worked well enough. Reports of inflammatory encephalitis and meningoencephalitis led the European Medicines Agency to initiate an Article 20 referral procedure. In such referrals, a medicine or class of medicines are scientifically assessed because of concerns over safety or quality. However, Biogen and AbbVie concluded that, because of the complex nature of these reports and how few patients were taking daclizumab, it would be difficult to characterize the nature of the medication’s harms and benefits, so the companies instead have decided to withdraw the medication from the market.
Many Elderly Patients With Epilepsy Receive Interacting Treatments
Many elderly patients with epilepsy receive combinations of nonepilepsy drugs (NEDs) and antiepileptic drugs (AEDs) that could interact, according to a study published February 7 in Epilepsia. Researchers retrospectively analyzed 2008–2010 Medicare claims for a random sample of beneficiaries age 67 and older. Prevalent cases had a diagnosis of epilepsy and took one or more AEDs. Incident cases had no seizure or epilepsy claim codes or AEDs in the preceding 365 days. Interacting pairs of AEDs and NEDs were identified by literature review. Logistic regression models were used to examine factors affecting the likelihood of interaction risk. Interacting drug pairs affected NED efficacy in 24.5% of incident cases and 39% of prevalent cases. Combinations affected AED efficacy in 20.4% of incident cases and 29.3% of prevalent cases.
Faught E, Szaflarski JP, Richman J, et al. Risk of pharmacokinetic interactions between antiepileptic and other drugs in older persons and factors associated with risk. Epilepsia. 2018;59(3):715-723.
Are Physically Fit Women at Reduced Risk for Dementia?
High cardiovascular fitness in midlife is associated with decreased risk of subsequent dementia, according to a study published online ahead of print March 14 in Neurology. Physicians examined a population-based sample of 1,462 women ages 38 to 60 in 1968. A subsample of 191 women with an average age of 50 took a maximal ergometer cycling test to measure their peak cardiovascular capacity. Over the following 44 years, participants were tested for dementia six times. By 2012, 44 of the women developed dementia. Approximately 5% of the highly fit women developed dementia, compared with 25% of moderately fit women, and 32% of the women with low fitness. The highly fit women were 88% less likely to develop dementia than the moderately fit women.
Hörder H, Johansson L, Guo X, et al. Midlife cardiovascular fitness and dementia: A 44-year longitudinal population study in women. Neurology. 2018 Mar 14 [Epub ahead of print].
Data on Geriatric TBI May Be Inadequate
Many older adults with traumatic brain injury (TBI) respond well to aggressive management and rehabilitation, which suggests that age and TBI severity alone are inadequate prognostic markers, according to a study published online ahead of print February 15 in the Journal of Neurotrauma. Researchers reviewed the literature on incident TBI sustained in older adulthood. They found few geriatric-specific TBI guidelines to assist with complex management decisions and concluded that TBI prognostic models do not perform optimally in this population. Major barriers in management of geriatric TBI include underrepresentation of older adults in TBI research, lack of systematic measurement of preinjury health that may predict outcome and response to treatment, and lack of geriatric-specific TBI common data elements. Investigators need to develop more age-inclusive TBI research protocols, said the authors.
Gardner RC, Dams-O’Connor K, Morrissey MR, Manley GT. Geriatric traumatic brain injury: epidemiology, outcomes, knowledge gaps, and future directions. J Neurotrauma. 2018 Feb 15 [Epub ahead of print].
TDCS Improves Gait in Parkinson’s Disease
Transcranial direct-current stimulation (TDCS) reduces freezing of gait and improves executive function and mobility, according to a study published online ahead of print February 13 in Movement Disorders. Researchers examined 20 patients with Parkinson’s disease and freezing of gait. The patients received 20 minutes of TDCS or sham treatment during three separate visits. TDCS targeted the primary motor cortex and left dorsolateral prefrontal cortex simultaneously or primary motor cortex only. Participants completed the Timed Up and Go and Stroop tests before and after each stimulation session. Performance on the Timed Up and Go and Stroop tests improved after simultaneous stimulation of the primary motor cortex and left dorsolateral prefrontal cortex, but not after stimulation of the primary motor cortex alone or sham stimulation.
Dagan M, Herman T, Harrison R, et al. Multitarget transcranial direct current stimulation for freezing of gait in Parkinson’s disease. Mov Disord. 2018 Feb 13 [Epub ahead of print].
Patients With Major Stroke Need Realistic Planning
Doctors who care for patients with severe stroke should plan with patients and caregivers and discuss the possibility of death or survival with disability, according to a study published March 5 in the Canadian Medical Association Journal. Researchers recruited a purposive sample of people with total anterior circulation stroke at three stroke services and conducted serial, qualitative interviews with participants and their caregivers at six weeks, six months, and one year. Investigators also conducted a data-linkage study of all patients with anterior circulation stroke admitted to the three services over six months. About 57% of patients died within six months. Patients experienced immediate and persistent emotional distress and poor quality of life. Physicians should practice palliative care for these patients, but avoid using that term, said the authors.
Kendall M, Cowey E, Mead G, et al. Outcomes, experiences and palliative care in major stroke: a multicentre, mixed-method, longitudinal study. CMAJ. 2018;190(9):E238-E246.
Dengue Fever Is Associated With Increased Risk of Stroke
Dengue fever is associated with an increased risk of stroke in the first few months after diagnosis, according to a study published March 12 in Canadian Medical Association Journal. Using data from the Taiwan National Health Insurance Research Database, researchers examined 13,787 patients diagnosed with dengue fever between 2000 and 2012. The control cohort consisted of patients matched by demographic characteristics and stroke-related comorbidities who did not have dengue fever. The overall incidence rate of stroke was 5.33 per 1,000 person-years in the dengue fever cohort and 3.72 per 1,000 person-years in the control cohort. The adjusted hazard ratio of stroke was 1.16 in patients with dengue fever. The risk of stroke was 2.49 times higher in patients with dengue fever during the first two months after diagnosis, compared with controls.
Li HM, Huang YK, Su YC, Kao CH. Risk of stroke in patients with dengue fever: a population-based cohort study. CMAJ. 2018;190(10):E285-E290.
Do Survivors of Stroke Need Additional Help Taking Medication?
More than half of patients with stroke need help taking medication, according to a study published March 11 in BMJ Open. Approximately 600 community-dwelling patients with stroke responded to a five-item questionnaire about practical support that they need and receive. Approximately 56% of respondents got help with taking medication, and 11% needed additional help, including help with prescriptions and collection of medicines, getting medicines out of the packaging, and being reminded to take medicines. Being dependent on others was associated with experiencing more unmet needs with daily medicine taking. About 35% of respondents said that they had missed taking medicine in the previous 30 days. Younger patients with stroke were more likely to miss their medicines, possibly because they were less likely to receive help from a caregiver.
Jamison J, Ayerbe L, Di Tanna GL, et al. Evaluating practical support stroke survivors get with medicines and unmet needs in primary care: a survey. BMJ Open. 2018;8(3):e019874.
Sun Exposure Associated With Reduced Risk of MS
Living in areas with high ambient levels of ultraviolet-B light during childhood and the years before multiple sclerosis (MS) onset is associated with a lower MS risk, according to a study published online ahead of print March 7 in Neurology. Researchers identified 151 women with MS and 235 age-matched controls. The average age at MS onset was 40. All participants completed questionnaires about summer, winter, and lifetime sun exposure. Researchers separated the women into three groups representing low, moderate, and high ultraviolet-B ray exposure, based on their residence. Women who lived in sunnier climates with the highest exposure to ultraviolet-B rays had a 45% reduced risk of developing MS across all pre-MS onset age groups, when compared with participants living in areas with the lowest ultraviolet-B ray exposure.
Tremlett H, Zhu F, Ascherio A, Munger KL. Sun exposure over the life course and associations with multiple sclerosis. Neurology. 2018 Mar 7 [Epub ahead of print].
The new blood pressure guidelines could harm certain patients, according to a study published online ahead of print March 2 in the Journal of the American College of Cardiology. Investigators examined the effect of 10-year cardiovascular disease (CVD) risk on primary outcome events and serious adverse events in the Systolic Pressure Intervention Trial, which was a basis for the new guidelines. They stratified patients by quartiles of risk and used Cox proportional hazards models to examine associations. From the first to fourth quartiles, the number needed to treat to prevent primary outcomes decreased from 91 to 38. The number needed to harm for all-cause serious adverse events increased from 62 to 250. Classifying patients by future risk could identify patients who would benefit from intensive treatment, said the authors.
Phillips RA, Xu J, Peterson LE, et al. Impact of cardiovascular risk on the relative benefit and harm of intensive treatment of hypertension. J Am Coll Cardiol. 2018 Mar 2 [Epub ahead of print].
—Kimberly Williams
Extended-Interval Dosing of Natalizumab Is Associated With Reduced PML Risk
SAN DIEGO—Among patients with multiple sclerosis (MS) who are positive for the John Cunningham virus (JCV), extended-interval dosing of natalizumab is associated with a clinically and statistically significant reduction in the risk of progressive multifocal leukoencephalopathy (PML), compared with standard-interval dosing, according to a study presented at the ACTRIMS 2018 Forum.
The observed risk reduction may change clinical practice and save lives, said lead study author Lana Zhovtis Ryerson, MD, Assistant Professor of Neurology at the New York University School of Medicine.
Real-World Safety Data
While natalizumab may be an effective medication for relapsing MS at the approved dose of 300 mg IV every four weeks, the treatment is associated with the risk of PML, a rare but potentially deadly brain infection. A prior retrospective study by the researchers suggested that extending the dosing interval to as long as eight weeks does not negatively affect the medication’s efficacy. The impact of extended-interval dosing on PML risk has been inconclusive, however.
To assess whether extended-interval dosing (ie, an average dosing interval of between five and 12 weeks) reduces PML risk, compared with standard-interval dosing (ie, an average dosing interval of between three and five weeks), Dr. Zhovtis Ryerson and colleagues analyzed data through June 1, 2017, from the TOUCH Prescribing Program, a mandatory US risk evaluation and mitigation program for natalizumab. The investigators included only patients who were anti–JCV antibody positive in their analyses. They excluded patients with any gap in treatment of more than 12 weeks.
The investigators analyzed the data using three definitions of standard-interval dosing and extended-interval dosing. Their first analysis defined extended-interval dosing as 15 or fewer infusions in the last 18 months, whereas standard-interval dosing was defined as more than 15 infusions in the last 18 months. The second analysis defined extended-interval dosing as at least six months of consecutive extended-interval infusions at any time in a patient’s dosing history. The third analysis defined extended-interval dosing as an average of 10 or fewer infusions per year during a patient’s total follow-up time, whereas standard-interval dosing was defined as an average of more than 10 infusions per year during a patient’s total follow-up time.
Using the life-table method, the estimated risk of PML per 1,000 patients at the highest number of doses (ie, between 61 doses and 72 doses) was 1.70 in the extended-interval dosing group, versus 4.46 in the standard-interval dosing group, for the first analysis. In the second analysis, the estimated risk was 2.04 in the extended-interval dosing group, versus 4.74 in the standard-interval dosing group.In the first analysis, Kaplan-Meier estimates found “a clinically meaningful and statistically significant divergence of cumulative risk of PML, with a 94% risk reduction” with extended-interval dosing, compared with standard-interval dosing, Dr. Zhovtis Ryerson said. There were three PML cases in the extended-interval dosing group (n = 1,988), versus 89 PML cases in the standard-interval dosing group (n = 13,132). In the second analysis, extended-interval dosing was associated with an 88% risk reduction, with 12 PML cases in the extended-interval dosing cohort (n = 3,331), versus 71 PML cases in the standard-interval dosing group (n = 15,424). In the third analysis, there were no PML cases in the extended-interval dosing group (n = 815), compared with 96 cases in the standard-interval dosing group (n = 23,168).
Parsing the TOUCH Registry
With more than 90,000 patients enrolled as of June 1, 2017, the TOUCH Prescribing Program provided the largest available data source regarding PML risk in patients on extended-interval dosing, the researchers said.
“The TOUCH database provides us with real-world data, which are complicated,” Dr. Zhovtis Ryerson said. “Accidental extended-dose infusions happen. Vacations, sicknesses, and dosing gaps due to pregnancy or other reasons occur. But these are not the patients that we are trying to parse out. We are more interested in patients with consecutive and prolonged treatment on extended dose.”
The complicated nature of the data was part of the rationale for developing the three definitions that enabled the investigators to look at extended-interval dosing in multiple ways. “For the primary definition, we utilized an approach that we see in our own clinics—where patients start out on standard dose and are slowly transitioned to extended dose after some months of treatment,” said Dr. Zhovtis Ryerson.
The methodology may have led to selection biases, however. “The patients in the extended-dosing cohorts spent more time on natalizumab—therefore potentially increasing their risk for PML,” she said. “On the other hand, these patients spent time on standard dose, a median of two years, without getting PML before moving on to the extended-dose schedule,” which could have led to fewer PML cases in the extended-interval dosing cohorts.
The TOUCH registry does not include efficacy data, and prospective studies are needed to determine whether natalizumab’s efficacy is maintained with extended-interval dosing, the researchers said.
—Fred Balzac
Suggested Reading
Bomprezzi R, Pawate S. Extended interval dosing of natalizumab: a two-center, 7-year experience. Ther Adv Neurol Disord. 2014;7(5):227-231.
Fine AJ, Sorbello A, Kortepeter C, et al. Progressive multifocal leukoencephalopathy after natalizumab discontinuation. Ann Neurol. 2014;75(1):108-115.
Ho PR, Koendgen H, Campbell N, et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: a retrospective analysis of data from four clinical studies. Lancet Neurol. 2017;16(11):925-933.
Zhovtis Ryerson L, Frohman TC, Foley J, et al. Extended interval dosing of natalizumab in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2016;87(8):885-889.
SAN DIEGO—Among patients with multiple sclerosis (MS) who are positive for the John Cunningham virus (JCV), extended-interval dosing of natalizumab is associated with a clinically and statistically significant reduction in the risk of progressive multifocal leukoencephalopathy (PML), compared with standard-interval dosing, according to a study presented at the ACTRIMS 2018 Forum.
The observed risk reduction may change clinical practice and save lives, said lead study author Lana Zhovtis Ryerson, MD, Assistant Professor of Neurology at the New York University School of Medicine.
Real-World Safety Data
While natalizumab may be an effective medication for relapsing MS at the approved dose of 300 mg IV every four weeks, the treatment is associated with the risk of PML, a rare but potentially deadly brain infection. A prior retrospective study by the researchers suggested that extending the dosing interval to as long as eight weeks does not negatively affect the medication’s efficacy. The impact of extended-interval dosing on PML risk has been inconclusive, however.
To assess whether extended-interval dosing (ie, an average dosing interval of between five and 12 weeks) reduces PML risk, compared with standard-interval dosing (ie, an average dosing interval of between three and five weeks), Dr. Zhovtis Ryerson and colleagues analyzed data through June 1, 2017, from the TOUCH Prescribing Program, a mandatory US risk evaluation and mitigation program for natalizumab. The investigators included only patients who were anti–JCV antibody positive in their analyses. They excluded patients with any gap in treatment of more than 12 weeks.
The investigators analyzed the data using three definitions of standard-interval dosing and extended-interval dosing. Their first analysis defined extended-interval dosing as 15 or fewer infusions in the last 18 months, whereas standard-interval dosing was defined as more than 15 infusions in the last 18 months. The second analysis defined extended-interval dosing as at least six months of consecutive extended-interval infusions at any time in a patient’s dosing history. The third analysis defined extended-interval dosing as an average of 10 or fewer infusions per year during a patient’s total follow-up time, whereas standard-interval dosing was defined as an average of more than 10 infusions per year during a patient’s total follow-up time.
Using the life-table method, the estimated risk of PML per 1,000 patients at the highest number of doses (ie, between 61 doses and 72 doses) was 1.70 in the extended-interval dosing group, versus 4.46 in the standard-interval dosing group, for the first analysis. In the second analysis, the estimated risk was 2.04 in the extended-interval dosing group, versus 4.74 in the standard-interval dosing group.In the first analysis, Kaplan-Meier estimates found “a clinically meaningful and statistically significant divergence of cumulative risk of PML, with a 94% risk reduction” with extended-interval dosing, compared with standard-interval dosing, Dr. Zhovtis Ryerson said. There were three PML cases in the extended-interval dosing group (n = 1,988), versus 89 PML cases in the standard-interval dosing group (n = 13,132). In the second analysis, extended-interval dosing was associated with an 88% risk reduction, with 12 PML cases in the extended-interval dosing cohort (n = 3,331), versus 71 PML cases in the standard-interval dosing group (n = 15,424). In the third analysis, there were no PML cases in the extended-interval dosing group (n = 815), compared with 96 cases in the standard-interval dosing group (n = 23,168).
Parsing the TOUCH Registry
With more than 90,000 patients enrolled as of June 1, 2017, the TOUCH Prescribing Program provided the largest available data source regarding PML risk in patients on extended-interval dosing, the researchers said.
“The TOUCH database provides us with real-world data, which are complicated,” Dr. Zhovtis Ryerson said. “Accidental extended-dose infusions happen. Vacations, sicknesses, and dosing gaps due to pregnancy or other reasons occur. But these are not the patients that we are trying to parse out. We are more interested in patients with consecutive and prolonged treatment on extended dose.”
The complicated nature of the data was part of the rationale for developing the three definitions that enabled the investigators to look at extended-interval dosing in multiple ways. “For the primary definition, we utilized an approach that we see in our own clinics—where patients start out on standard dose and are slowly transitioned to extended dose after some months of treatment,” said Dr. Zhovtis Ryerson.
The methodology may have led to selection biases, however. “The patients in the extended-dosing cohorts spent more time on natalizumab—therefore potentially increasing their risk for PML,” she said. “On the other hand, these patients spent time on standard dose, a median of two years, without getting PML before moving on to the extended-dose schedule,” which could have led to fewer PML cases in the extended-interval dosing cohorts.
The TOUCH registry does not include efficacy data, and prospective studies are needed to determine whether natalizumab’s efficacy is maintained with extended-interval dosing, the researchers said.
—Fred Balzac
Suggested Reading
Bomprezzi R, Pawate S. Extended interval dosing of natalizumab: a two-center, 7-year experience. Ther Adv Neurol Disord. 2014;7(5):227-231.
Fine AJ, Sorbello A, Kortepeter C, et al. Progressive multifocal leukoencephalopathy after natalizumab discontinuation. Ann Neurol. 2014;75(1):108-115.
Ho PR, Koendgen H, Campbell N, et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: a retrospective analysis of data from four clinical studies. Lancet Neurol. 2017;16(11):925-933.
Zhovtis Ryerson L, Frohman TC, Foley J, et al. Extended interval dosing of natalizumab in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2016;87(8):885-889.
SAN DIEGO—Among patients with multiple sclerosis (MS) who are positive for the John Cunningham virus (JCV), extended-interval dosing of natalizumab is associated with a clinically and statistically significant reduction in the risk of progressive multifocal leukoencephalopathy (PML), compared with standard-interval dosing, according to a study presented at the ACTRIMS 2018 Forum.
The observed risk reduction may change clinical practice and save lives, said lead study author Lana Zhovtis Ryerson, MD, Assistant Professor of Neurology at the New York University School of Medicine.
Real-World Safety Data
While natalizumab may be an effective medication for relapsing MS at the approved dose of 300 mg IV every four weeks, the treatment is associated with the risk of PML, a rare but potentially deadly brain infection. A prior retrospective study by the researchers suggested that extending the dosing interval to as long as eight weeks does not negatively affect the medication’s efficacy. The impact of extended-interval dosing on PML risk has been inconclusive, however.
To assess whether extended-interval dosing (ie, an average dosing interval of between five and 12 weeks) reduces PML risk, compared with standard-interval dosing (ie, an average dosing interval of between three and five weeks), Dr. Zhovtis Ryerson and colleagues analyzed data through June 1, 2017, from the TOUCH Prescribing Program, a mandatory US risk evaluation and mitigation program for natalizumab. The investigators included only patients who were anti–JCV antibody positive in their analyses. They excluded patients with any gap in treatment of more than 12 weeks.
The investigators analyzed the data using three definitions of standard-interval dosing and extended-interval dosing. Their first analysis defined extended-interval dosing as 15 or fewer infusions in the last 18 months, whereas standard-interval dosing was defined as more than 15 infusions in the last 18 months. The second analysis defined extended-interval dosing as at least six months of consecutive extended-interval infusions at any time in a patient’s dosing history. The third analysis defined extended-interval dosing as an average of 10 or fewer infusions per year during a patient’s total follow-up time, whereas standard-interval dosing was defined as an average of more than 10 infusions per year during a patient’s total follow-up time.
Using the life-table method, the estimated risk of PML per 1,000 patients at the highest number of doses (ie, between 61 doses and 72 doses) was 1.70 in the extended-interval dosing group, versus 4.46 in the standard-interval dosing group, for the first analysis. In the second analysis, the estimated risk was 2.04 in the extended-interval dosing group, versus 4.74 in the standard-interval dosing group.In the first analysis, Kaplan-Meier estimates found “a clinically meaningful and statistically significant divergence of cumulative risk of PML, with a 94% risk reduction” with extended-interval dosing, compared with standard-interval dosing, Dr. Zhovtis Ryerson said. There were three PML cases in the extended-interval dosing group (n = 1,988), versus 89 PML cases in the standard-interval dosing group (n = 13,132). In the second analysis, extended-interval dosing was associated with an 88% risk reduction, with 12 PML cases in the extended-interval dosing cohort (n = 3,331), versus 71 PML cases in the standard-interval dosing group (n = 15,424). In the third analysis, there were no PML cases in the extended-interval dosing group (n = 815), compared with 96 cases in the standard-interval dosing group (n = 23,168).
Parsing the TOUCH Registry
With more than 90,000 patients enrolled as of June 1, 2017, the TOUCH Prescribing Program provided the largest available data source regarding PML risk in patients on extended-interval dosing, the researchers said.
“The TOUCH database provides us with real-world data, which are complicated,” Dr. Zhovtis Ryerson said. “Accidental extended-dose infusions happen. Vacations, sicknesses, and dosing gaps due to pregnancy or other reasons occur. But these are not the patients that we are trying to parse out. We are more interested in patients with consecutive and prolonged treatment on extended dose.”
The complicated nature of the data was part of the rationale for developing the three definitions that enabled the investigators to look at extended-interval dosing in multiple ways. “For the primary definition, we utilized an approach that we see in our own clinics—where patients start out on standard dose and are slowly transitioned to extended dose after some months of treatment,” said Dr. Zhovtis Ryerson.
The methodology may have led to selection biases, however. “The patients in the extended-dosing cohorts spent more time on natalizumab—therefore potentially increasing their risk for PML,” she said. “On the other hand, these patients spent time on standard dose, a median of two years, without getting PML before moving on to the extended-dose schedule,” which could have led to fewer PML cases in the extended-interval dosing cohorts.
The TOUCH registry does not include efficacy data, and prospective studies are needed to determine whether natalizumab’s efficacy is maintained with extended-interval dosing, the researchers said.
—Fred Balzac
Suggested Reading
Bomprezzi R, Pawate S. Extended interval dosing of natalizumab: a two-center, 7-year experience. Ther Adv Neurol Disord. 2014;7(5):227-231.
Fine AJ, Sorbello A, Kortepeter C, et al. Progressive multifocal leukoencephalopathy after natalizumab discontinuation. Ann Neurol. 2014;75(1):108-115.
Ho PR, Koendgen H, Campbell N, et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: a retrospective analysis of data from four clinical studies. Lancet Neurol. 2017;16(11):925-933.
Zhovtis Ryerson L, Frohman TC, Foley J, et al. Extended interval dosing of natalizumab in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2016;87(8):885-889.
Current Options in Migraine Prevention
STOWE, VT—The development of monoclonal antibodies targeting calcitonin gene-related peptide (CGRP) has made migraine prevention a hot topic. Although FDA approval of these therapies could transform the field in the months ahead, the guiding principles and mainstays of preventive therapy remain unchanged. At the Headache Cooperative of New England’s 28th Annual Stowe Headache Symposium, Robert E. Shapiro, MD, PhD, reviewed the goals, principles, and current options for preventive migraine therapy. Dr. Shapiro is Professor of Neurological Sciences at the Larner College of Medicine at the University of Vermont in Burlington.
The goals of migraine prevention, Dr. Shapiro said, are to decrease attack frequency, severity, and duration; improve responsiveness to acute treatment; improve function and reduce disability; prevent acute analgesic overuse; and possibly reduce the total cost of treatment. “Achieving zero headaches and zero symptoms of migraine,” he said, “is an emerging goal … but we are not there yet.”
First Things First
Before considering what to prescribe, a neurologist should keep certain guiding principles in mind. Using headache calendars to follow treatment compliance and effects is essential, said Dr. Shapiro. To prevent patients from fixating on their symptoms, Dr. Shapiro advised that documentation be kept to a minimum. He asks his patients to record at the end of each day whether they had a headache and what the severity of the headache was at its worst.
Behavioral therapies also are essential. “Part of this [regimen] is simple cognitive restructuring,” Dr. Shapiro said. He recommended stabilizing bedtime and waking hours, mealtime, and exercise time. “Keep surprises to a minimum, in terms of daily schedule.” Avoiding exposures such as odors or food triggers can be helpful, as long as patients do not obsess over these exposures.
Cognitive behavioral therapy, yoga, and other types of behavioral therapies have demonstrated significant benefit. Likewise, sleep modification can be helpful. Incorporating these techniques into a prevention plan is important, Dr. Shapiro said. It also is important to treat relevant comorbid conditions. Dr. Shapiro also recommends tapering analgesics and caffeine.
Keeping Things in Perspective
There are several “inconvenient truths” about what can be achieved with preventive medications, Dr. Shapiro said. “Only four medications are FDA-approved for prevention of episodic migraine, and one for chronic migraine. None of them were developed for migraine. We are hopeful that later this year there will be FDA-approved medications that were developed for the prevention of migraine.” Additionally, the FDA cleared a few devices for migraine prevention. The caveat is that the standards for approval differ between drugs and devices. “Whenever a device is cleared … it is important to go back and look with some level of higher scrutiny at what the evidence base is for efficacy,” Dr. Shapiro advised.
All available drugs have limited tolerability. There is no clear and obviously superior medication, from the standpoint of efficacy. “A 50% reduction in headache days in half the patients is considered a pretty good outcome,” Dr. Shapiro said. Treatment choice needs to take efficacy, comorbid conditions, cost, side effects, convenient formulations, patient preferences, and prior history into account.
Another basic principle is slow titration to the optimal dose. The dose–response curve for some medications reaches a plateau, Dr. Shapiro said. If the therapeutic window is exceeded, the efficacy begins to decrease. Analgesic overuse is another potential problem. “It is important to have a trial at the appropriate dose for at least two months before you can make a judgment as to whether the medication is helpful. Individual responses are hard to predict.” Finally, Dr. Shapiro suggested tapering a medication off after 12 months. “There is some sense that with a reduction in the frequency of events, there may be a stabilizing effect. That is not based on a lot of evidence. It is based, rather, on clinical experience. Successful preventive medications may be tapered off, and there may be a durable benefit after it has been there for a while,” he said.
The most sobering fact about preventive medications, Dr. Shapiro said, is that “83% of patients started on a preventive medication are not taking it one year later.”
Starting Preventive Treatment
The consensus among a panel of experts was that headache at six days or more per month should be the threshold for offering a patient a preventive therapy, whereas it should be considered for patients experiencing four to five days with headache per month. “Based on this [principle], a 2007 study found that 13% of migraine patients were on preventive medications, while an additional 26% should be offered preventive medications, and in 13% preventives should be considered,” Dr. Shapiro said.
Based on the 2012 American Headache Society/American Academy of Neurology guideline for episodic migraine preventive drugs, there is Level A (established as effective) evidence for divalproex sodium ER (1,000 mg daily), topiramate (50 mg bid), propranolol (120 mg to 160 mg daily), timolol (10 mg to 15 mg bid), metoprolol (100 mg bid), and petasites (ie, butterbur). The first four medicines are FDA-approved for migraine, and metoprolol is included based on the evidence available, even though it is not FDA-approved for this indication. “Butterbur is effective, but there is an almost universal sense that we should not be offering this to patients because of the concern about potential liver toxicity and insufficient assurance from manufacturers that the agents that might cause that toxicity have been removed,” Dr. Shapiro said.
Several studies comparing efficacy, defined as the 50% responder rate, have indicated that valproate, topiramate, and propranolol all have approximately the same level of efficacy. Approximately 45% of patients receiving these therapies had 50% reduction in attack frequency or severity.
Level B (probably effective) evidence exists for several agents that are in common use, such as amitriptyline, candesartan, lisinopril, amlodipine and zonisamide. Other agents with Level B evidence include nutraceuticals and vitamin agents, such as megadoses of riboflavin and magnesium.
As previously mentioned, selection of a preventive agent may be guided by comorbidity. If a patient has hypertension, for example, angiotensin receptor blockers, ACE inhibitors, beta blockers, or calcium channel blockers are worth considering. In its evaluation of medications for migraine prevention, the Agency for Healthcare Research and Quality issued its own evaluation of medications for migraine prevention and suggested that even though angiotensin receptor blockers such as candesartan, or angiotensin converting enzyme inhibitors such as lisinopril, are not FDA-approved to treat migraine, their relative tolerability suggests that they could be first-line agents for this purpose. For depression, venlafaxine could be an appropriate choice. If a patient is obese, topiramate or zonisamide should be considered. If epilepsy is comorbid with migraine, obvious choices would be topiramate, divalproate, or zonisamide. For neuropathic pain or insomnia, tricyclic antidepressants are appropriate.
Game Changer?
“We are all excited about the new developments” related to the CGRP agents in clinical trials, Dr. Shapiro said, “but how much these drugs may improve clinical outcomes remains to be seen.” Independent lines of evidence suggest that CGRP is involved during migraine attacks and that blocking the effects of CGRP can have therapeutic benefit.
The four medications in late-stage clinical development are erenumab, fremanezumab, galcanezumab, and eptinezumab. Three of them have been submitted to the FDA for review. They are all either fully human or humanized antibodies. All of them have been studied in clinical trials for episodic and chronic migraine. Galcanezumab and fremanezumab are being studied for episodic and chronic cluster headache. Erenumab is an antibody directed against the CGRP receptor, whereas the other three treatments target CGRP itself. Erenumab, fremanezumab, and galcanezumab are delivered by monthly or quarterly subcutaneous injections. Eptinezumab has been studied as a quarterly IV infusion. The dosage and frequency of administration will remain uncertain until the FDA approves specific regimens for these therapies, Dr. Shapiro said.
Regulatory news is pending. The PDUFA date for FDA reporting on erenumab is May 17, 2018. Unexpected problems at the manufacturing plant in South Korea have raised questions about the timing of fremanezumab availability, but the FDA is still expected to render a judgment on its approvability by this summer. For galcanezumab, an FDA decision is expected by late September 2018. Eptinezumab has not yet been submitted for approval.
Other Options
Botox is approved for prevention of chronic migraine. Neurologists administer 155 units to 31 injection sites. In clinical trials, baseline monthly headache frequency of 20 days was reduced to 11.5 days among patients receiving onabotulinumtoxinA and to 13 days among controls. The therapeutic gain was about 9%, or about 1.7 days, during the 28-day trial period. At least 78% of the improvement associated with Botox was attributed to the placebo effect, Dr. Shapiro noted. “But that does not mean that this is not a helpful thing to do…. This helps a lot of people, even though the placebo effect is substantial.”
The Cefaly transcutaneous electrical nerve stimulation (TENS) device has been cleared for marketing by the FDA. In clinical trials, the device did not significantly reduce the number of headache days at three months, compared with sham treatment, but the FDA cleared the device nevertheless. “This [treatment] is of variable benefit,” Dr. Shapiro said. “Evidence of that is that only about half of the patients who tried it were willing to buy the device after two months.”
The sTMS mini transcranial magnetic stimulation device was cleared for marketing in the summer of 2017. In clinical trials, this device reduced headache frequency by two to three days per month when used for prevention of episodic or chronic migraine. The clinical trial, however, was open-label and used a “performance goal” comparator that was estimated from placebo responses in several other clinical trials, rather than a sham control; this design raises concerns about the validity of the efficacy claims. “This [device] is another potential option, but again, the evidence that the FDA accepted for clearing this device was not what we would prefer,” Dr. Shapiro said.
—Glenn S. Williams
Shamliyan TA, Choi JY, Ramakrishnan R, et al. Preventive pharmacologic treatments for episodic migraine in adults. J Gen Intern Med. 2013;28(9):1225-1237.
Silberstein SD, Holland S, Freitag F, et al. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012;78(17):1337-1345.
STOWE, VT—The development of monoclonal antibodies targeting calcitonin gene-related peptide (CGRP) has made migraine prevention a hot topic. Although FDA approval of these therapies could transform the field in the months ahead, the guiding principles and mainstays of preventive therapy remain unchanged. At the Headache Cooperative of New England’s 28th Annual Stowe Headache Symposium, Robert E. Shapiro, MD, PhD, reviewed the goals, principles, and current options for preventive migraine therapy. Dr. Shapiro is Professor of Neurological Sciences at the Larner College of Medicine at the University of Vermont in Burlington.
The goals of migraine prevention, Dr. Shapiro said, are to decrease attack frequency, severity, and duration; improve responsiveness to acute treatment; improve function and reduce disability; prevent acute analgesic overuse; and possibly reduce the total cost of treatment. “Achieving zero headaches and zero symptoms of migraine,” he said, “is an emerging goal … but we are not there yet.”
First Things First
Before considering what to prescribe, a neurologist should keep certain guiding principles in mind. Using headache calendars to follow treatment compliance and effects is essential, said Dr. Shapiro. To prevent patients from fixating on their symptoms, Dr. Shapiro advised that documentation be kept to a minimum. He asks his patients to record at the end of each day whether they had a headache and what the severity of the headache was at its worst.
Behavioral therapies also are essential. “Part of this [regimen] is simple cognitive restructuring,” Dr. Shapiro said. He recommended stabilizing bedtime and waking hours, mealtime, and exercise time. “Keep surprises to a minimum, in terms of daily schedule.” Avoiding exposures such as odors or food triggers can be helpful, as long as patients do not obsess over these exposures.
Cognitive behavioral therapy, yoga, and other types of behavioral therapies have demonstrated significant benefit. Likewise, sleep modification can be helpful. Incorporating these techniques into a prevention plan is important, Dr. Shapiro said. It also is important to treat relevant comorbid conditions. Dr. Shapiro also recommends tapering analgesics and caffeine.
Keeping Things in Perspective
There are several “inconvenient truths” about what can be achieved with preventive medications, Dr. Shapiro said. “Only four medications are FDA-approved for prevention of episodic migraine, and one for chronic migraine. None of them were developed for migraine. We are hopeful that later this year there will be FDA-approved medications that were developed for the prevention of migraine.” Additionally, the FDA cleared a few devices for migraine prevention. The caveat is that the standards for approval differ between drugs and devices. “Whenever a device is cleared … it is important to go back and look with some level of higher scrutiny at what the evidence base is for efficacy,” Dr. Shapiro advised.
All available drugs have limited tolerability. There is no clear and obviously superior medication, from the standpoint of efficacy. “A 50% reduction in headache days in half the patients is considered a pretty good outcome,” Dr. Shapiro said. Treatment choice needs to take efficacy, comorbid conditions, cost, side effects, convenient formulations, patient preferences, and prior history into account.
Another basic principle is slow titration to the optimal dose. The dose–response curve for some medications reaches a plateau, Dr. Shapiro said. If the therapeutic window is exceeded, the efficacy begins to decrease. Analgesic overuse is another potential problem. “It is important to have a trial at the appropriate dose for at least two months before you can make a judgment as to whether the medication is helpful. Individual responses are hard to predict.” Finally, Dr. Shapiro suggested tapering a medication off after 12 months. “There is some sense that with a reduction in the frequency of events, there may be a stabilizing effect. That is not based on a lot of evidence. It is based, rather, on clinical experience. Successful preventive medications may be tapered off, and there may be a durable benefit after it has been there for a while,” he said.
The most sobering fact about preventive medications, Dr. Shapiro said, is that “83% of patients started on a preventive medication are not taking it one year later.”
Starting Preventive Treatment
The consensus among a panel of experts was that headache at six days or more per month should be the threshold for offering a patient a preventive therapy, whereas it should be considered for patients experiencing four to five days with headache per month. “Based on this [principle], a 2007 study found that 13% of migraine patients were on preventive medications, while an additional 26% should be offered preventive medications, and in 13% preventives should be considered,” Dr. Shapiro said.
Based on the 2012 American Headache Society/American Academy of Neurology guideline for episodic migraine preventive drugs, there is Level A (established as effective) evidence for divalproex sodium ER (1,000 mg daily), topiramate (50 mg bid), propranolol (120 mg to 160 mg daily), timolol (10 mg to 15 mg bid), metoprolol (100 mg bid), and petasites (ie, butterbur). The first four medicines are FDA-approved for migraine, and metoprolol is included based on the evidence available, even though it is not FDA-approved for this indication. “Butterbur is effective, but there is an almost universal sense that we should not be offering this to patients because of the concern about potential liver toxicity and insufficient assurance from manufacturers that the agents that might cause that toxicity have been removed,” Dr. Shapiro said.
Several studies comparing efficacy, defined as the 50% responder rate, have indicated that valproate, topiramate, and propranolol all have approximately the same level of efficacy. Approximately 45% of patients receiving these therapies had 50% reduction in attack frequency or severity.
Level B (probably effective) evidence exists for several agents that are in common use, such as amitriptyline, candesartan, lisinopril, amlodipine and zonisamide. Other agents with Level B evidence include nutraceuticals and vitamin agents, such as megadoses of riboflavin and magnesium.
As previously mentioned, selection of a preventive agent may be guided by comorbidity. If a patient has hypertension, for example, angiotensin receptor blockers, ACE inhibitors, beta blockers, or calcium channel blockers are worth considering. In its evaluation of medications for migraine prevention, the Agency for Healthcare Research and Quality issued its own evaluation of medications for migraine prevention and suggested that even though angiotensin receptor blockers such as candesartan, or angiotensin converting enzyme inhibitors such as lisinopril, are not FDA-approved to treat migraine, their relative tolerability suggests that they could be first-line agents for this purpose. For depression, venlafaxine could be an appropriate choice. If a patient is obese, topiramate or zonisamide should be considered. If epilepsy is comorbid with migraine, obvious choices would be topiramate, divalproate, or zonisamide. For neuropathic pain or insomnia, tricyclic antidepressants are appropriate.
Game Changer?
“We are all excited about the new developments” related to the CGRP agents in clinical trials, Dr. Shapiro said, “but how much these drugs may improve clinical outcomes remains to be seen.” Independent lines of evidence suggest that CGRP is involved during migraine attacks and that blocking the effects of CGRP can have therapeutic benefit.
The four medications in late-stage clinical development are erenumab, fremanezumab, galcanezumab, and eptinezumab. Three of them have been submitted to the FDA for review. They are all either fully human or humanized antibodies. All of them have been studied in clinical trials for episodic and chronic migraine. Galcanezumab and fremanezumab are being studied for episodic and chronic cluster headache. Erenumab is an antibody directed against the CGRP receptor, whereas the other three treatments target CGRP itself. Erenumab, fremanezumab, and galcanezumab are delivered by monthly or quarterly subcutaneous injections. Eptinezumab has been studied as a quarterly IV infusion. The dosage and frequency of administration will remain uncertain until the FDA approves specific regimens for these therapies, Dr. Shapiro said.
Regulatory news is pending. The PDUFA date for FDA reporting on erenumab is May 17, 2018. Unexpected problems at the manufacturing plant in South Korea have raised questions about the timing of fremanezumab availability, but the FDA is still expected to render a judgment on its approvability by this summer. For galcanezumab, an FDA decision is expected by late September 2018. Eptinezumab has not yet been submitted for approval.
Other Options
Botox is approved for prevention of chronic migraine. Neurologists administer 155 units to 31 injection sites. In clinical trials, baseline monthly headache frequency of 20 days was reduced to 11.5 days among patients receiving onabotulinumtoxinA and to 13 days among controls. The therapeutic gain was about 9%, or about 1.7 days, during the 28-day trial period. At least 78% of the improvement associated with Botox was attributed to the placebo effect, Dr. Shapiro noted. “But that does not mean that this is not a helpful thing to do…. This helps a lot of people, even though the placebo effect is substantial.”
The Cefaly transcutaneous electrical nerve stimulation (TENS) device has been cleared for marketing by the FDA. In clinical trials, the device did not significantly reduce the number of headache days at three months, compared with sham treatment, but the FDA cleared the device nevertheless. “This [treatment] is of variable benefit,” Dr. Shapiro said. “Evidence of that is that only about half of the patients who tried it were willing to buy the device after two months.”
The sTMS mini transcranial magnetic stimulation device was cleared for marketing in the summer of 2017. In clinical trials, this device reduced headache frequency by two to three days per month when used for prevention of episodic or chronic migraine. The clinical trial, however, was open-label and used a “performance goal” comparator that was estimated from placebo responses in several other clinical trials, rather than a sham control; this design raises concerns about the validity of the efficacy claims. “This [device] is another potential option, but again, the evidence that the FDA accepted for clearing this device was not what we would prefer,” Dr. Shapiro said.
—Glenn S. Williams
Shamliyan TA, Choi JY, Ramakrishnan R, et al. Preventive pharmacologic treatments for episodic migraine in adults. J Gen Intern Med. 2013;28(9):1225-1237.
Silberstein SD, Holland S, Freitag F, et al. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012;78(17):1337-1345.
STOWE, VT—The development of monoclonal antibodies targeting calcitonin gene-related peptide (CGRP) has made migraine prevention a hot topic. Although FDA approval of these therapies could transform the field in the months ahead, the guiding principles and mainstays of preventive therapy remain unchanged. At the Headache Cooperative of New England’s 28th Annual Stowe Headache Symposium, Robert E. Shapiro, MD, PhD, reviewed the goals, principles, and current options for preventive migraine therapy. Dr. Shapiro is Professor of Neurological Sciences at the Larner College of Medicine at the University of Vermont in Burlington.
The goals of migraine prevention, Dr. Shapiro said, are to decrease attack frequency, severity, and duration; improve responsiveness to acute treatment; improve function and reduce disability; prevent acute analgesic overuse; and possibly reduce the total cost of treatment. “Achieving zero headaches and zero symptoms of migraine,” he said, “is an emerging goal … but we are not there yet.”
First Things First
Before considering what to prescribe, a neurologist should keep certain guiding principles in mind. Using headache calendars to follow treatment compliance and effects is essential, said Dr. Shapiro. To prevent patients from fixating on their symptoms, Dr. Shapiro advised that documentation be kept to a minimum. He asks his patients to record at the end of each day whether they had a headache and what the severity of the headache was at its worst.
Behavioral therapies also are essential. “Part of this [regimen] is simple cognitive restructuring,” Dr. Shapiro said. He recommended stabilizing bedtime and waking hours, mealtime, and exercise time. “Keep surprises to a minimum, in terms of daily schedule.” Avoiding exposures such as odors or food triggers can be helpful, as long as patients do not obsess over these exposures.
Cognitive behavioral therapy, yoga, and other types of behavioral therapies have demonstrated significant benefit. Likewise, sleep modification can be helpful. Incorporating these techniques into a prevention plan is important, Dr. Shapiro said. It also is important to treat relevant comorbid conditions. Dr. Shapiro also recommends tapering analgesics and caffeine.
Keeping Things in Perspective
There are several “inconvenient truths” about what can be achieved with preventive medications, Dr. Shapiro said. “Only four medications are FDA-approved for prevention of episodic migraine, and one for chronic migraine. None of them were developed for migraine. We are hopeful that later this year there will be FDA-approved medications that were developed for the prevention of migraine.” Additionally, the FDA cleared a few devices for migraine prevention. The caveat is that the standards for approval differ between drugs and devices. “Whenever a device is cleared … it is important to go back and look with some level of higher scrutiny at what the evidence base is for efficacy,” Dr. Shapiro advised.
All available drugs have limited tolerability. There is no clear and obviously superior medication, from the standpoint of efficacy. “A 50% reduction in headache days in half the patients is considered a pretty good outcome,” Dr. Shapiro said. Treatment choice needs to take efficacy, comorbid conditions, cost, side effects, convenient formulations, patient preferences, and prior history into account.
Another basic principle is slow titration to the optimal dose. The dose–response curve for some medications reaches a plateau, Dr. Shapiro said. If the therapeutic window is exceeded, the efficacy begins to decrease. Analgesic overuse is another potential problem. “It is important to have a trial at the appropriate dose for at least two months before you can make a judgment as to whether the medication is helpful. Individual responses are hard to predict.” Finally, Dr. Shapiro suggested tapering a medication off after 12 months. “There is some sense that with a reduction in the frequency of events, there may be a stabilizing effect. That is not based on a lot of evidence. It is based, rather, on clinical experience. Successful preventive medications may be tapered off, and there may be a durable benefit after it has been there for a while,” he said.
The most sobering fact about preventive medications, Dr. Shapiro said, is that “83% of patients started on a preventive medication are not taking it one year later.”
Starting Preventive Treatment
The consensus among a panel of experts was that headache at six days or more per month should be the threshold for offering a patient a preventive therapy, whereas it should be considered for patients experiencing four to five days with headache per month. “Based on this [principle], a 2007 study found that 13% of migraine patients were on preventive medications, while an additional 26% should be offered preventive medications, and in 13% preventives should be considered,” Dr. Shapiro said.
Based on the 2012 American Headache Society/American Academy of Neurology guideline for episodic migraine preventive drugs, there is Level A (established as effective) evidence for divalproex sodium ER (1,000 mg daily), topiramate (50 mg bid), propranolol (120 mg to 160 mg daily), timolol (10 mg to 15 mg bid), metoprolol (100 mg bid), and petasites (ie, butterbur). The first four medicines are FDA-approved for migraine, and metoprolol is included based on the evidence available, even though it is not FDA-approved for this indication. “Butterbur is effective, but there is an almost universal sense that we should not be offering this to patients because of the concern about potential liver toxicity and insufficient assurance from manufacturers that the agents that might cause that toxicity have been removed,” Dr. Shapiro said.
Several studies comparing efficacy, defined as the 50% responder rate, have indicated that valproate, topiramate, and propranolol all have approximately the same level of efficacy. Approximately 45% of patients receiving these therapies had 50% reduction in attack frequency or severity.
Level B (probably effective) evidence exists for several agents that are in common use, such as amitriptyline, candesartan, lisinopril, amlodipine and zonisamide. Other agents with Level B evidence include nutraceuticals and vitamin agents, such as megadoses of riboflavin and magnesium.
As previously mentioned, selection of a preventive agent may be guided by comorbidity. If a patient has hypertension, for example, angiotensin receptor blockers, ACE inhibitors, beta blockers, or calcium channel blockers are worth considering. In its evaluation of medications for migraine prevention, the Agency for Healthcare Research and Quality issued its own evaluation of medications for migraine prevention and suggested that even though angiotensin receptor blockers such as candesartan, or angiotensin converting enzyme inhibitors such as lisinopril, are not FDA-approved to treat migraine, their relative tolerability suggests that they could be first-line agents for this purpose. For depression, venlafaxine could be an appropriate choice. If a patient is obese, topiramate or zonisamide should be considered. If epilepsy is comorbid with migraine, obvious choices would be topiramate, divalproate, or zonisamide. For neuropathic pain or insomnia, tricyclic antidepressants are appropriate.
Game Changer?
“We are all excited about the new developments” related to the CGRP agents in clinical trials, Dr. Shapiro said, “but how much these drugs may improve clinical outcomes remains to be seen.” Independent lines of evidence suggest that CGRP is involved during migraine attacks and that blocking the effects of CGRP can have therapeutic benefit.
The four medications in late-stage clinical development are erenumab, fremanezumab, galcanezumab, and eptinezumab. Three of them have been submitted to the FDA for review. They are all either fully human or humanized antibodies. All of them have been studied in clinical trials for episodic and chronic migraine. Galcanezumab and fremanezumab are being studied for episodic and chronic cluster headache. Erenumab is an antibody directed against the CGRP receptor, whereas the other three treatments target CGRP itself. Erenumab, fremanezumab, and galcanezumab are delivered by monthly or quarterly subcutaneous injections. Eptinezumab has been studied as a quarterly IV infusion. The dosage and frequency of administration will remain uncertain until the FDA approves specific regimens for these therapies, Dr. Shapiro said.
Regulatory news is pending. The PDUFA date for FDA reporting on erenumab is May 17, 2018. Unexpected problems at the manufacturing plant in South Korea have raised questions about the timing of fremanezumab availability, but the FDA is still expected to render a judgment on its approvability by this summer. For galcanezumab, an FDA decision is expected by late September 2018. Eptinezumab has not yet been submitted for approval.
Other Options
Botox is approved for prevention of chronic migraine. Neurologists administer 155 units to 31 injection sites. In clinical trials, baseline monthly headache frequency of 20 days was reduced to 11.5 days among patients receiving onabotulinumtoxinA and to 13 days among controls. The therapeutic gain was about 9%, or about 1.7 days, during the 28-day trial period. At least 78% of the improvement associated with Botox was attributed to the placebo effect, Dr. Shapiro noted. “But that does not mean that this is not a helpful thing to do…. This helps a lot of people, even though the placebo effect is substantial.”
The Cefaly transcutaneous electrical nerve stimulation (TENS) device has been cleared for marketing by the FDA. In clinical trials, the device did not significantly reduce the number of headache days at three months, compared with sham treatment, but the FDA cleared the device nevertheless. “This [treatment] is of variable benefit,” Dr. Shapiro said. “Evidence of that is that only about half of the patients who tried it were willing to buy the device after two months.”
The sTMS mini transcranial magnetic stimulation device was cleared for marketing in the summer of 2017. In clinical trials, this device reduced headache frequency by two to three days per month when used for prevention of episodic or chronic migraine. The clinical trial, however, was open-label and used a “performance goal” comparator that was estimated from placebo responses in several other clinical trials, rather than a sham control; this design raises concerns about the validity of the efficacy claims. “This [device] is another potential option, but again, the evidence that the FDA accepted for clearing this device was not what we would prefer,” Dr. Shapiro said.
—Glenn S. Williams
Shamliyan TA, Choi JY, Ramakrishnan R, et al. Preventive pharmacologic treatments for episodic migraine in adults. J Gen Intern Med. 2013;28(9):1225-1237.
Silberstein SD, Holland S, Freitag F, et al. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012;78(17):1337-1345.
Lenalidomide yields responses in a rare cutaneous lymphoma
The oral immunomodulatory drug lenalidomide is active and may provide prolonged responses in certain patients with a rare and aggressive subtype of primary cutaneous lymphoma, according to results of a phase 2 study.
In the study, which comprised 19 patients with primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL, LT), 5 patients (26.3%) had a response at 6 months, and there were still 3 patients in response at 12 months. The findings were reported in the Journal of Investigative Dermatology.
In an exploratory analysis, reducing the dose of lenalidomide was associated with prolonged response and improved survival, noted lead author Marie Beylot-Barry, MD, of the dermatology department, Hôpital Saint-André, CHU Bordeaux, France, and her colleagues.
“Lenalidomide at reduced doses may allow prolonged responses in few patients, and represents a therapeutic option in relapsing/refractory PCDLBCL, LT,” the researchers wrote.
Found mostly on the lower limbs of elderly patients, PCDLBCL, LT exhibits aggressive behavior and is associated with a high rate of skin recurrences. First-line therapy for the cutaneous lymphoma is typically rituximab and chemotherapy, regardless of clinical stage or patient age, the researchers wrote, though primary resistance or recurrence after treatment occurs in about half of patients. “In such relapsing or refractory cases, no treatment has demonstrated a sustained benefit thus far,” they noted.
Lenalidomide has already demonstrated efficacy in relapsed/refractory diffuse large B-cell lymphoma (DLBCL) and it induces inhibition of cell signaling, engaging NF-kappaB signaling. PCDLBCL, LT is marked by genetic alterations leading to the NF-kappaB pathway, which represents a therapeutic target.
Dr. Beylot-Barry and her colleagues initiated a multicenter, single-arm, phase 2 trial of 19 patients refractory/relapsing PCDLBCL, LT. Median progression-free survival in the trial was 4.9 months. The 6-month overall response rate – the primary endpoint of the trial – was 26.3%, which was not significantly superior to a prespecified 20% minimal response rate, according to the researchers.
“However, it was a stringent goal, and other secondary evaluations have to be considered in this context, such as a 6-month disease control rate at 42%,” they wrote.
Reduced doses were associated with improved outcomes, they added. Comparing the nine patients who had lenalidomide dose reductions to those who did not, there was a higher likelihood of 6- to 11-month overall response rate (44.4% vs. 10.0%; P = .11) and lower risk of disease progression or death (hazard ratio, 0.54; 95% confidence interval, 0.19-1.59; P = .27).
Grade 3 adverse events were primarily hematologic, and two deaths occurred (pulmonary embolism and sepsis).
Taken together, the encouraging results at reduced doses, the advanced age of the patients, and the high rate of adverse events suggests a role for lenalidomide as a part of combination treatment for PCDLBCL, LT in future trials, the researchers concluded.
The study was supported by grants from the French Ministry of Health and Celgene. The researchers reported having no financial disclosures.
SOURCE: Beylot-Barry M et al. J Invest Dermatol. 2018 Mar 26. doi: 10.1016/j.jid.2018.03.1516.
The oral immunomodulatory drug lenalidomide is active and may provide prolonged responses in certain patients with a rare and aggressive subtype of primary cutaneous lymphoma, according to results of a phase 2 study.
In the study, which comprised 19 patients with primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL, LT), 5 patients (26.3%) had a response at 6 months, and there were still 3 patients in response at 12 months. The findings were reported in the Journal of Investigative Dermatology.
In an exploratory analysis, reducing the dose of lenalidomide was associated with prolonged response and improved survival, noted lead author Marie Beylot-Barry, MD, of the dermatology department, Hôpital Saint-André, CHU Bordeaux, France, and her colleagues.
“Lenalidomide at reduced doses may allow prolonged responses in few patients, and represents a therapeutic option in relapsing/refractory PCDLBCL, LT,” the researchers wrote.
Found mostly on the lower limbs of elderly patients, PCDLBCL, LT exhibits aggressive behavior and is associated with a high rate of skin recurrences. First-line therapy for the cutaneous lymphoma is typically rituximab and chemotherapy, regardless of clinical stage or patient age, the researchers wrote, though primary resistance or recurrence after treatment occurs in about half of patients. “In such relapsing or refractory cases, no treatment has demonstrated a sustained benefit thus far,” they noted.
Lenalidomide has already demonstrated efficacy in relapsed/refractory diffuse large B-cell lymphoma (DLBCL) and it induces inhibition of cell signaling, engaging NF-kappaB signaling. PCDLBCL, LT is marked by genetic alterations leading to the NF-kappaB pathway, which represents a therapeutic target.
Dr. Beylot-Barry and her colleagues initiated a multicenter, single-arm, phase 2 trial of 19 patients refractory/relapsing PCDLBCL, LT. Median progression-free survival in the trial was 4.9 months. The 6-month overall response rate – the primary endpoint of the trial – was 26.3%, which was not significantly superior to a prespecified 20% minimal response rate, according to the researchers.
“However, it was a stringent goal, and other secondary evaluations have to be considered in this context, such as a 6-month disease control rate at 42%,” they wrote.
Reduced doses were associated with improved outcomes, they added. Comparing the nine patients who had lenalidomide dose reductions to those who did not, there was a higher likelihood of 6- to 11-month overall response rate (44.4% vs. 10.0%; P = .11) and lower risk of disease progression or death (hazard ratio, 0.54; 95% confidence interval, 0.19-1.59; P = .27).
Grade 3 adverse events were primarily hematologic, and two deaths occurred (pulmonary embolism and sepsis).
Taken together, the encouraging results at reduced doses, the advanced age of the patients, and the high rate of adverse events suggests a role for lenalidomide as a part of combination treatment for PCDLBCL, LT in future trials, the researchers concluded.
The study was supported by grants from the French Ministry of Health and Celgene. The researchers reported having no financial disclosures.
SOURCE: Beylot-Barry M et al. J Invest Dermatol. 2018 Mar 26. doi: 10.1016/j.jid.2018.03.1516.
The oral immunomodulatory drug lenalidomide is active and may provide prolonged responses in certain patients with a rare and aggressive subtype of primary cutaneous lymphoma, according to results of a phase 2 study.
In the study, which comprised 19 patients with primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL, LT), 5 patients (26.3%) had a response at 6 months, and there were still 3 patients in response at 12 months. The findings were reported in the Journal of Investigative Dermatology.
In an exploratory analysis, reducing the dose of lenalidomide was associated with prolonged response and improved survival, noted lead author Marie Beylot-Barry, MD, of the dermatology department, Hôpital Saint-André, CHU Bordeaux, France, and her colleagues.
“Lenalidomide at reduced doses may allow prolonged responses in few patients, and represents a therapeutic option in relapsing/refractory PCDLBCL, LT,” the researchers wrote.
Found mostly on the lower limbs of elderly patients, PCDLBCL, LT exhibits aggressive behavior and is associated with a high rate of skin recurrences. First-line therapy for the cutaneous lymphoma is typically rituximab and chemotherapy, regardless of clinical stage or patient age, the researchers wrote, though primary resistance or recurrence after treatment occurs in about half of patients. “In such relapsing or refractory cases, no treatment has demonstrated a sustained benefit thus far,” they noted.
Lenalidomide has already demonstrated efficacy in relapsed/refractory diffuse large B-cell lymphoma (DLBCL) and it induces inhibition of cell signaling, engaging NF-kappaB signaling. PCDLBCL, LT is marked by genetic alterations leading to the NF-kappaB pathway, which represents a therapeutic target.
Dr. Beylot-Barry and her colleagues initiated a multicenter, single-arm, phase 2 trial of 19 patients refractory/relapsing PCDLBCL, LT. Median progression-free survival in the trial was 4.9 months. The 6-month overall response rate – the primary endpoint of the trial – was 26.3%, which was not significantly superior to a prespecified 20% minimal response rate, according to the researchers.
“However, it was a stringent goal, and other secondary evaluations have to be considered in this context, such as a 6-month disease control rate at 42%,” they wrote.
Reduced doses were associated with improved outcomes, they added. Comparing the nine patients who had lenalidomide dose reductions to those who did not, there was a higher likelihood of 6- to 11-month overall response rate (44.4% vs. 10.0%; P = .11) and lower risk of disease progression or death (hazard ratio, 0.54; 95% confidence interval, 0.19-1.59; P = .27).
Grade 3 adverse events were primarily hematologic, and two deaths occurred (pulmonary embolism and sepsis).
Taken together, the encouraging results at reduced doses, the advanced age of the patients, and the high rate of adverse events suggests a role for lenalidomide as a part of combination treatment for PCDLBCL, LT in future trials, the researchers concluded.
The study was supported by grants from the French Ministry of Health and Celgene. The researchers reported having no financial disclosures.
SOURCE: Beylot-Barry M et al. J Invest Dermatol. 2018 Mar 26. doi: 10.1016/j.jid.2018.03.1516.
FROM THE JOURNAL OF INVESTIGATIVE DERMATOLOGY
Key clinical point:
Major finding: Five of 19 patients (26.3%) had a response at 6 months, and there were still 3 patients in response at 12 months.
Study details: A multicenter, single-arm, phase 2 trial of 19 patients refractory/relapsing PCDLBCL, LT.
Disclosures: The study was supported by grants from the French Ministry of Health and Celgene. The researchers reported having no financial disclosures.
Source: Beylot-Barry M et al. J Invest Dermatol. 2018 Mar 26. doi: 10.1016/j.jid.2018.03.1516.
Pediatric Dermatology Consult - March 2018
Rosacea is a chronic inflammatory skin disorder characterized by flushing, telangiectasia, erythema, papules, and pustules, most classically of the central face. Fair-skinned individuals and women are more commonly affected than are men, with age of onset typically around 30 years and older.1 In children and adolescents, rosacea is rare, especially among prepubertal children, so other papulopustular disorders should be considered when a rosacealike picture is present.2 Recurrent chalazia are seen with ocular rosacea and may be a clue to the diagnosis of acne rosacea. An individual’s subtype of rosacea also may transform with time to a different or an additional subtype.
Papulopustular rosacea (subtype II) is characterized by the presence of erythematous, dome-shaped papules distributed in crops in the central facial region. Cheeks, nasolabial folds, and the chin are most commonly affected. Pustules may or may not be present, but comedones are notably absent in an exclusively rosacea disease process. If comedones are present, a diagnosis of acne vulgaris should be considered instead of, or in addition to, rosacea. Pediatric patients with rosacea frequently present with papules and/or pustules, following the development of flushing.2
Ocular rosacea (subtype IV) may range in severity from mild blepharitis to severe keratitis and corneal vascularization. Patients may complain of a foreign body sensation. On external exam, lid margin telangiectasias, blepharitis, conjunctivitis, conjunctival injection, and recurrent chalazia may be frequently seen.3 Ocular rosacea may present without any signs of cutaneous disease; it may be the only form of rosacea (15% of patients in one study of 20 patients had only ocular rosacea)4 or may herald the development of cutaneous involvement. In fact, in children, ocular rosacea is frequently the first sign of disease. (A total of 55% of patients in the same study had both ocular and cutaneous rosacea, with ocular symptoms manifesting before the cutaneous disease). Thus an index of suspicion for rosacea should be maintained when a child presents with ocular findings.2
Other dermatitides resembling rosacea include steroid rosacea, perioral dermatitis, and idiopathic facial aseptic granuloma. Steroid rosacea, also known as iatrosacea, describes an eruption of erythema, papules, and telangiectasias that is clinically indistinguishable from rosacea.6 It results from chronic use of topical steroids, generally high potency, or abrupt withdrawal of steroids. Steroid rosacea should be treated by discontinuation of the steroid via tapered withdrawal.7 Perioral dermatitis, also known as periorificial dermatitis, may also appear rosacea-form. It usually is located around the perioral and perinasal areas, but may extend to the periocular area.8 Idiopathic facial septic granuloma describes erythematous to violaceous nodules of the cheeks and eyelid in children, with chalazia frequently present; it is thought to be associated with rosacea.9
Although the exact pathophysiology of rosacea is unknown, it is clear that the dysregulation of the innate immune system plays a key role in the pathogenesis of rosacea. Studies have found that patients with rosacea have increased expression of cathelicidin, and its activating serine protease, kallikrein.5 Interestingly, UV light, a known trigger of rosacea, induces expression of cathelicidin and its inflammatory cascade.5 Neurovascular signaling is also aberrantly upregulated; vanilloid and ankyrin receptors have been shown to be active in rosacea, and are activated by rosacea-exacerbating stimuli, such as heat, inflammation, and spices. Higher levels of Demodex folliculorum and Staphylococcus epidermis also have been consistently found on the skin of rosacea patients, compared with healthy subjects, though it is unclear what role these pathogens play in the development of rosacea.
Treatment of rosacea is very important given its profound impact on quality of life; one study found that the odds ratio for depression in individuals with rosacea is 4.81.10 Patient education is essential, and patients should be encouraged to identify specific triggers so they can minimize exposure when feasible. Common triggers include hot and cold temperature, sunlight, wind, spicy foods, alcohol, exercise, emotional stress, and certain medications such as niacin. Topical steroids frequently are exacerbating, so patients should be encouraged to avoid them and use moisturizers often, given their skin’s increased transepidermal water loss and susceptibility to irritation. In addition, sunscreens are essential to reduce inflammation from reactive oxygen species, which aggravate rosacea.11 For pharmaceutical therapeutics, topical sodium sulfacetamide, metronidazole, and azelaic acid have been shown to be effective in rosacea. For persistent erythema, topical alpha-adrenergic receptor agonists including brimonidine tartrate and oxymetazoline have been shown to reduce erythema by vasoconstricting blood vessels, although some products are associated with a rebound erythema on treatment discontinuation. For moderate to severe rosacea, low-dose oral doxycycline at anti-inflammatory doses (less than 50 mg daily) is the mainstay of therapy. Other oral antibiotics and topical permethrin have been used, and topical ivermectin 1% cream has been approved for inflammatory rosacea.11 Oral beta-blockers also have been successfully used in some patients to reduce erythema and flushing, as well as isotretinoin for refractory, severe rosacea with improvement.
Allison Han is a medical student at the University of California, San Diego. Dr. Eichenfield is chief of pediatric and adolescent dermatology at Rady Children’s Hospital–San Diego. He is vice chair of the department of dermatology and professor of dermatology and pediatrics at the University of California, San Diego. There are no conflicts of interest or financial disclosures for Ms. Han or Dr. Eichenfield.
References
1. J Am Acad Dermatol. 2018 Jan;78(1):148-55.
2. Cutis. 2016 Jul;98(1):49-53.
3. J Eur Acad Dermatol Venereol. 2017 Oct;31(10):1732-8.
4. J Fr Ophtalmol. 2011 Dec;34(10):703-10.
5. J Am Acad Dermatol. 2015 May;72(5):749-58.
6. Indian J Dermatol. 2011 Jan;56(1):30-2.
7. Cutis, 2004. 74(2):99-103.
8. Pediatr Dermatol. 1992 Mar;9(1):22-6.
9. Pediatr Dermatol. 2015 Jul-Aug;32(4):e136-9.
10. Br J Dermatol. 2005 Dec;153(6):1176-81.
11. J Am Acad Dermatol. 2015 May;72(5):761-70.
Rosacea is a chronic inflammatory skin disorder characterized by flushing, telangiectasia, erythema, papules, and pustules, most classically of the central face. Fair-skinned individuals and women are more commonly affected than are men, with age of onset typically around 30 years and older.1 In children and adolescents, rosacea is rare, especially among prepubertal children, so other papulopustular disorders should be considered when a rosacealike picture is present.2 Recurrent chalazia are seen with ocular rosacea and may be a clue to the diagnosis of acne rosacea. An individual’s subtype of rosacea also may transform with time to a different or an additional subtype.
Papulopustular rosacea (subtype II) is characterized by the presence of erythematous, dome-shaped papules distributed in crops in the central facial region. Cheeks, nasolabial folds, and the chin are most commonly affected. Pustules may or may not be present, but comedones are notably absent in an exclusively rosacea disease process. If comedones are present, a diagnosis of acne vulgaris should be considered instead of, or in addition to, rosacea. Pediatric patients with rosacea frequently present with papules and/or pustules, following the development of flushing.2
Ocular rosacea (subtype IV) may range in severity from mild blepharitis to severe keratitis and corneal vascularization. Patients may complain of a foreign body sensation. On external exam, lid margin telangiectasias, blepharitis, conjunctivitis, conjunctival injection, and recurrent chalazia may be frequently seen.3 Ocular rosacea may present without any signs of cutaneous disease; it may be the only form of rosacea (15% of patients in one study of 20 patients had only ocular rosacea)4 or may herald the development of cutaneous involvement. In fact, in children, ocular rosacea is frequently the first sign of disease. (A total of 55% of patients in the same study had both ocular and cutaneous rosacea, with ocular symptoms manifesting before the cutaneous disease). Thus an index of suspicion for rosacea should be maintained when a child presents with ocular findings.2
Other dermatitides resembling rosacea include steroid rosacea, perioral dermatitis, and idiopathic facial aseptic granuloma. Steroid rosacea, also known as iatrosacea, describes an eruption of erythema, papules, and telangiectasias that is clinically indistinguishable from rosacea.6 It results from chronic use of topical steroids, generally high potency, or abrupt withdrawal of steroids. Steroid rosacea should be treated by discontinuation of the steroid via tapered withdrawal.7 Perioral dermatitis, also known as periorificial dermatitis, may also appear rosacea-form. It usually is located around the perioral and perinasal areas, but may extend to the periocular area.8 Idiopathic facial septic granuloma describes erythematous to violaceous nodules of the cheeks and eyelid in children, with chalazia frequently present; it is thought to be associated with rosacea.9
Although the exact pathophysiology of rosacea is unknown, it is clear that the dysregulation of the innate immune system plays a key role in the pathogenesis of rosacea. Studies have found that patients with rosacea have increased expression of cathelicidin, and its activating serine protease, kallikrein.5 Interestingly, UV light, a known trigger of rosacea, induces expression of cathelicidin and its inflammatory cascade.5 Neurovascular signaling is also aberrantly upregulated; vanilloid and ankyrin receptors have been shown to be active in rosacea, and are activated by rosacea-exacerbating stimuli, such as heat, inflammation, and spices. Higher levels of Demodex folliculorum and Staphylococcus epidermis also have been consistently found on the skin of rosacea patients, compared with healthy subjects, though it is unclear what role these pathogens play in the development of rosacea.
Treatment of rosacea is very important given its profound impact on quality of life; one study found that the odds ratio for depression in individuals with rosacea is 4.81.10 Patient education is essential, and patients should be encouraged to identify specific triggers so they can minimize exposure when feasible. Common triggers include hot and cold temperature, sunlight, wind, spicy foods, alcohol, exercise, emotional stress, and certain medications such as niacin. Topical steroids frequently are exacerbating, so patients should be encouraged to avoid them and use moisturizers often, given their skin’s increased transepidermal water loss and susceptibility to irritation. In addition, sunscreens are essential to reduce inflammation from reactive oxygen species, which aggravate rosacea.11 For pharmaceutical therapeutics, topical sodium sulfacetamide, metronidazole, and azelaic acid have been shown to be effective in rosacea. For persistent erythema, topical alpha-adrenergic receptor agonists including brimonidine tartrate and oxymetazoline have been shown to reduce erythema by vasoconstricting blood vessels, although some products are associated with a rebound erythema on treatment discontinuation. For moderate to severe rosacea, low-dose oral doxycycline at anti-inflammatory doses (less than 50 mg daily) is the mainstay of therapy. Other oral antibiotics and topical permethrin have been used, and topical ivermectin 1% cream has been approved for inflammatory rosacea.11 Oral beta-blockers also have been successfully used in some patients to reduce erythema and flushing, as well as isotretinoin for refractory, severe rosacea with improvement.
Allison Han is a medical student at the University of California, San Diego. Dr. Eichenfield is chief of pediatric and adolescent dermatology at Rady Children’s Hospital–San Diego. He is vice chair of the department of dermatology and professor of dermatology and pediatrics at the University of California, San Diego. There are no conflicts of interest or financial disclosures for Ms. Han or Dr. Eichenfield.
References
1. J Am Acad Dermatol. 2018 Jan;78(1):148-55.
2. Cutis. 2016 Jul;98(1):49-53.
3. J Eur Acad Dermatol Venereol. 2017 Oct;31(10):1732-8.
4. J Fr Ophtalmol. 2011 Dec;34(10):703-10.
5. J Am Acad Dermatol. 2015 May;72(5):749-58.
6. Indian J Dermatol. 2011 Jan;56(1):30-2.
7. Cutis, 2004. 74(2):99-103.
8. Pediatr Dermatol. 1992 Mar;9(1):22-6.
9. Pediatr Dermatol. 2015 Jul-Aug;32(4):e136-9.
10. Br J Dermatol. 2005 Dec;153(6):1176-81.
11. J Am Acad Dermatol. 2015 May;72(5):761-70.
Rosacea is a chronic inflammatory skin disorder characterized by flushing, telangiectasia, erythema, papules, and pustules, most classically of the central face. Fair-skinned individuals and women are more commonly affected than are men, with age of onset typically around 30 years and older.1 In children and adolescents, rosacea is rare, especially among prepubertal children, so other papulopustular disorders should be considered when a rosacealike picture is present.2 Recurrent chalazia are seen with ocular rosacea and may be a clue to the diagnosis of acne rosacea. An individual’s subtype of rosacea also may transform with time to a different or an additional subtype.
Papulopustular rosacea (subtype II) is characterized by the presence of erythematous, dome-shaped papules distributed in crops in the central facial region. Cheeks, nasolabial folds, and the chin are most commonly affected. Pustules may or may not be present, but comedones are notably absent in an exclusively rosacea disease process. If comedones are present, a diagnosis of acne vulgaris should be considered instead of, or in addition to, rosacea. Pediatric patients with rosacea frequently present with papules and/or pustules, following the development of flushing.2
Ocular rosacea (subtype IV) may range in severity from mild blepharitis to severe keratitis and corneal vascularization. Patients may complain of a foreign body sensation. On external exam, lid margin telangiectasias, blepharitis, conjunctivitis, conjunctival injection, and recurrent chalazia may be frequently seen.3 Ocular rosacea may present without any signs of cutaneous disease; it may be the only form of rosacea (15% of patients in one study of 20 patients had only ocular rosacea)4 or may herald the development of cutaneous involvement. In fact, in children, ocular rosacea is frequently the first sign of disease. (A total of 55% of patients in the same study had both ocular and cutaneous rosacea, with ocular symptoms manifesting before the cutaneous disease). Thus an index of suspicion for rosacea should be maintained when a child presents with ocular findings.2
Other dermatitides resembling rosacea include steroid rosacea, perioral dermatitis, and idiopathic facial aseptic granuloma. Steroid rosacea, also known as iatrosacea, describes an eruption of erythema, papules, and telangiectasias that is clinically indistinguishable from rosacea.6 It results from chronic use of topical steroids, generally high potency, or abrupt withdrawal of steroids. Steroid rosacea should be treated by discontinuation of the steroid via tapered withdrawal.7 Perioral dermatitis, also known as periorificial dermatitis, may also appear rosacea-form. It usually is located around the perioral and perinasal areas, but may extend to the periocular area.8 Idiopathic facial septic granuloma describes erythematous to violaceous nodules of the cheeks and eyelid in children, with chalazia frequently present; it is thought to be associated with rosacea.9
Although the exact pathophysiology of rosacea is unknown, it is clear that the dysregulation of the innate immune system plays a key role in the pathogenesis of rosacea. Studies have found that patients with rosacea have increased expression of cathelicidin, and its activating serine protease, kallikrein.5 Interestingly, UV light, a known trigger of rosacea, induces expression of cathelicidin and its inflammatory cascade.5 Neurovascular signaling is also aberrantly upregulated; vanilloid and ankyrin receptors have been shown to be active in rosacea, and are activated by rosacea-exacerbating stimuli, such as heat, inflammation, and spices. Higher levels of Demodex folliculorum and Staphylococcus epidermis also have been consistently found on the skin of rosacea patients, compared with healthy subjects, though it is unclear what role these pathogens play in the development of rosacea.
Treatment of rosacea is very important given its profound impact on quality of life; one study found that the odds ratio for depression in individuals with rosacea is 4.81.10 Patient education is essential, and patients should be encouraged to identify specific triggers so they can minimize exposure when feasible. Common triggers include hot and cold temperature, sunlight, wind, spicy foods, alcohol, exercise, emotional stress, and certain medications such as niacin. Topical steroids frequently are exacerbating, so patients should be encouraged to avoid them and use moisturizers often, given their skin’s increased transepidermal water loss and susceptibility to irritation. In addition, sunscreens are essential to reduce inflammation from reactive oxygen species, which aggravate rosacea.11 For pharmaceutical therapeutics, topical sodium sulfacetamide, metronidazole, and azelaic acid have been shown to be effective in rosacea. For persistent erythema, topical alpha-adrenergic receptor agonists including brimonidine tartrate and oxymetazoline have been shown to reduce erythema by vasoconstricting blood vessels, although some products are associated with a rebound erythema on treatment discontinuation. For moderate to severe rosacea, low-dose oral doxycycline at anti-inflammatory doses (less than 50 mg daily) is the mainstay of therapy. Other oral antibiotics and topical permethrin have been used, and topical ivermectin 1% cream has been approved for inflammatory rosacea.11 Oral beta-blockers also have been successfully used in some patients to reduce erythema and flushing, as well as isotretinoin for refractory, severe rosacea with improvement.
Allison Han is a medical student at the University of California, San Diego. Dr. Eichenfield is chief of pediatric and adolescent dermatology at Rady Children’s Hospital–San Diego. He is vice chair of the department of dermatology and professor of dermatology and pediatrics at the University of California, San Diego. There are no conflicts of interest or financial disclosures for Ms. Han or Dr. Eichenfield.
References
1. J Am Acad Dermatol. 2018 Jan;78(1):148-55.
2. Cutis. 2016 Jul;98(1):49-53.
3. J Eur Acad Dermatol Venereol. 2017 Oct;31(10):1732-8.
4. J Fr Ophtalmol. 2011 Dec;34(10):703-10.
5. J Am Acad Dermatol. 2015 May;72(5):749-58.
6. Indian J Dermatol. 2011 Jan;56(1):30-2.
7. Cutis, 2004. 74(2):99-103.
8. Pediatr Dermatol. 1992 Mar;9(1):22-6.
9. Pediatr Dermatol. 2015 Jul-Aug;32(4):e136-9.
10. Br J Dermatol. 2005 Dec;153(6):1176-81.
11. J Am Acad Dermatol. 2015 May;72(5):761-70.
A 16-year-old girl presented with a 6-month history of an erythematous eruption of small papules and pustules around the cheeks and nose. She states the erythema had started first, with periods of feeling flushed that became worse with sun exposure. She saw her primary care physician who prescribed topical steroids. After using the steroids, the rash became worse, and she developed papules and pustules.
A creative diversion
Do you have a creative diversion – a hobby for lack of a better word? One frequently hears of physicians who have creative skills not directly related to their professional careers. Furniture-building surgeons, fly-tying orthopedists, pediatrician poets, painting dermatologists ... I have even heard unsubstantiated claims that the traits that encourage individuals to become physicians make it more likely that they will have creative skills. Another one of those left brain/right brain things that probably doesn’t hold water.
If you do have a hobby or have the seed of a creative impulse you think could blossom into a hobby, I bet you wish that you could have an unlimited amount of time to invest in that activity. I am going to argue that this is another example of a situation in which you should be careful what you wish for.
When I was 9 or 10 years old, I bought a small carving of a sandpiper in a gift shop on Cape Cod. I still have it with its chipped bill and yellowed paper label on its driftwood base. That little bird triggered my interest in carving, and with gaps sometimes measured in decades I have been a self-taught bird carver. Some are attempts at realism with burned in feathers that takes weeks to complete. Others are free form painted whimsically, and are created in a few hours. They aren’t for sale, but to keep my inventory in check I distribute them as birthday and hostess gifts.
Ten years ago, after decades of visiting art galleries and grumbling to my wife, “I could do that,” I decided to try my hand at two-dimensional landscape painting. It was a fun challenge, and after a year or 2, I was ready to see what other people thought of my work. The first show that I entered stipulated that all of the entries be for sale. With no intention of parting with my work, I priced mine several orders of magnitude above what I thought they were worth.
One sold, and with that began a 7-year period during which pretty much anything I painted with a maritime theme sold for hundreds of dollars. It was a nice ego trip, but it took me down a dark path in which I began to choose my subjects and style based on what I knew would sell. Creating was no longer something I did for a change of pace. I was now retired, but painting had become my job. I felt burdened by the obligation to paint enough to cover the walls of the restaurant that graciously hung my work.
Luckily, the epiphany that I had sacrificed my creative diversion, which began with that little sandpiper, coincided with the restaurant’s decision to redecorate and the loss of much of my hanging space. I was now free to paint subjects I was interested in, and return to the comfort of carving when I felt the need to create.
If you already have a creative diversion, remember that a large part of its appeal is that it plays counterpoint to your job. Even if you are retired, a hobby provides a change of pace from which we can all benefit.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].
Do you have a creative diversion – a hobby for lack of a better word? One frequently hears of physicians who have creative skills not directly related to their professional careers. Furniture-building surgeons, fly-tying orthopedists, pediatrician poets, painting dermatologists ... I have even heard unsubstantiated claims that the traits that encourage individuals to become physicians make it more likely that they will have creative skills. Another one of those left brain/right brain things that probably doesn’t hold water.
If you do have a hobby or have the seed of a creative impulse you think could blossom into a hobby, I bet you wish that you could have an unlimited amount of time to invest in that activity. I am going to argue that this is another example of a situation in which you should be careful what you wish for.
When I was 9 or 10 years old, I bought a small carving of a sandpiper in a gift shop on Cape Cod. I still have it with its chipped bill and yellowed paper label on its driftwood base. That little bird triggered my interest in carving, and with gaps sometimes measured in decades I have been a self-taught bird carver. Some are attempts at realism with burned in feathers that takes weeks to complete. Others are free form painted whimsically, and are created in a few hours. They aren’t for sale, but to keep my inventory in check I distribute them as birthday and hostess gifts.
Ten years ago, after decades of visiting art galleries and grumbling to my wife, “I could do that,” I decided to try my hand at two-dimensional landscape painting. It was a fun challenge, and after a year or 2, I was ready to see what other people thought of my work. The first show that I entered stipulated that all of the entries be for sale. With no intention of parting with my work, I priced mine several orders of magnitude above what I thought they were worth.
One sold, and with that began a 7-year period during which pretty much anything I painted with a maritime theme sold for hundreds of dollars. It was a nice ego trip, but it took me down a dark path in which I began to choose my subjects and style based on what I knew would sell. Creating was no longer something I did for a change of pace. I was now retired, but painting had become my job. I felt burdened by the obligation to paint enough to cover the walls of the restaurant that graciously hung my work.
Luckily, the epiphany that I had sacrificed my creative diversion, which began with that little sandpiper, coincided with the restaurant’s decision to redecorate and the loss of much of my hanging space. I was now free to paint subjects I was interested in, and return to the comfort of carving when I felt the need to create.
If you already have a creative diversion, remember that a large part of its appeal is that it plays counterpoint to your job. Even if you are retired, a hobby provides a change of pace from which we can all benefit.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].
Do you have a creative diversion – a hobby for lack of a better word? One frequently hears of physicians who have creative skills not directly related to their professional careers. Furniture-building surgeons, fly-tying orthopedists, pediatrician poets, painting dermatologists ... I have even heard unsubstantiated claims that the traits that encourage individuals to become physicians make it more likely that they will have creative skills. Another one of those left brain/right brain things that probably doesn’t hold water.
If you do have a hobby or have the seed of a creative impulse you think could blossom into a hobby, I bet you wish that you could have an unlimited amount of time to invest in that activity. I am going to argue that this is another example of a situation in which you should be careful what you wish for.
When I was 9 or 10 years old, I bought a small carving of a sandpiper in a gift shop on Cape Cod. I still have it with its chipped bill and yellowed paper label on its driftwood base. That little bird triggered my interest in carving, and with gaps sometimes measured in decades I have been a self-taught bird carver. Some are attempts at realism with burned in feathers that takes weeks to complete. Others are free form painted whimsically, and are created in a few hours. They aren’t for sale, but to keep my inventory in check I distribute them as birthday and hostess gifts.
Ten years ago, after decades of visiting art galleries and grumbling to my wife, “I could do that,” I decided to try my hand at two-dimensional landscape painting. It was a fun challenge, and after a year or 2, I was ready to see what other people thought of my work. The first show that I entered stipulated that all of the entries be for sale. With no intention of parting with my work, I priced mine several orders of magnitude above what I thought they were worth.
One sold, and with that began a 7-year period during which pretty much anything I painted with a maritime theme sold for hundreds of dollars. It was a nice ego trip, but it took me down a dark path in which I began to choose my subjects and style based on what I knew would sell. Creating was no longer something I did for a change of pace. I was now retired, but painting had become my job. I felt burdened by the obligation to paint enough to cover the walls of the restaurant that graciously hung my work.
Luckily, the epiphany that I had sacrificed my creative diversion, which began with that little sandpiper, coincided with the restaurant’s decision to redecorate and the loss of much of my hanging space. I was now free to paint subjects I was interested in, and return to the comfort of carving when I felt the need to create.
If you already have a creative diversion, remember that a large part of its appeal is that it plays counterpoint to your job. Even if you are retired, a hobby provides a change of pace from which we can all benefit.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].
Ibrutinib preserves immune memory while fighting cGVHD
SALT LAKE CITY – Ibrutinib’s effectiveness in inhibiting chronic graft versus host disease (cGVHD) may hinge in part on inhibition of pre–germinal center B cells and follicular helper cells, according to a new analysis of clinical trial data.
The analysis also showed that ibrutinib preserved immune memory and type 1 T-helper cells.
Bita Sahaf, PhD, presented results of a “comprehensive and high dimensional proteomic approach” to data from 42 patients who were enrolled in a phase 1/2 clinical trial of ibrutinib for cGVHD (NCT02195869).
In that study, 80% of patients who had two or more organs affected by cGVHD responded in at least two organs; overall, two-thirds of patients had a complete or partial response with ibrutinib. The highest response rates were seen in disease affecting the skin, mouth, and gastrointestinal tract.
The new analysis used blood samples from trial participants collected before and during ibrutinib therapy to look for soluble plasma factors known to be related to inflammation, fibrosis, and cGVHD.
“A heat map of cytokines, chemokines, and factors associated with fibrosis shows a significant decrease following ibrutinib treatment,” Dr. Sahaf said during a top abstracts session at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
In addition, inflammatory gene expression was reduced with ibrutinib use, with reductions in the chemokines nuclear factor kappa-B-1, CXCL10, CCL7, and CCL3 dropping by 2.6-fold, 2.3-fold, 25-fold, and 1.8-fold, respectively, after 3 months of ibrutinib therapy, Dr. Sahaf and her colleagues reported.
The investigators used several different techniques to tease apart the mechanisms behind ibrutinib’s effectiveness. Immunophenotyping was accomplished with cytometry by time of flight (CyTOF), a technique that uses transition element isotopes to tag antibodies, which are then analyzed on a cell-by-cell basis by a time-of-flight mass spectrometer.
Ibrutinib inhibits CD19+CD38+CD27+IgD+ pre–germinal center B cells as well as pathogenic CD4+ T follicular helper cells, both implicated in cGVHD, the investigators found. However, Th1 T cells were preserved in a patient-by-patient analysis.
The CyTOF technique also allowed a phosphorylation analysis showing ibrutinib’s blocking effect on Bruton’s tyrosine kinase (BTK) as well as IL-2 inducible T-cell kinase (ITK), with subsequent effects on the signaling molecule PLCgamma2. In individual patients, this inhibition was confirmed when BTK-activated B-cell populations were eliminated after ibrutinib therapy, Dr. Sahaf said.
Ibrutinib also decreased phosphorylation of ITK, with subsequent depletion of CD4+, CD185+, and BCL6+ follicular helper T cells, and of other T cell populations still to be characterized. However, neither CD4+Tbet+Th1 cells nor CD4+CD25+CD127dim Treg cells saw depletion.
Importantly, “CD8+ cytotoxic T cells persist,” said Dr. Sahaf. Phosphorylation of ITK, she said, “appears heterogeneous across most T-cell populations.
“These data support the clinical efficacy of ibrutinib in cGVHD and highlight ibrutinib’s multifactorial mechanism of action in this disease,” Dr. Sahaf, of Stanford (Calif.) University, and her collaborators wrote in the abstract accompanying the presentation.
In August 2017, ibrutinib became the first treatment approved by the Food and Drug Administration for cGVHD. It is indicated for adults who have failed at least one other therapy.
“These correlative studies suggest that ibrutinib impacts a number of the immunologic mechanisms underlying the development of chronic graft versus host disease,” Dr. Sahaf said. Taken together, her team’s work has shown a reduction in expression of inflammatory genes and cytokines, and a decrease in plasma levels of chemotactic, inflammatory, and fibrotic cytokines that all have been implicated in cGVHD pathogenesis. The selective inhibition of pre–germinal center B cells and the trend toward reduced follicular helper T cells also plays a role in ibrutinib’s effectiveness, she said.
Ibrutinib’s efficacy in damping down inflammatory pathways that lead to cGVHD does not come at the expense of other immune function, however. Immune memory and Th 1 cells were not affected by ibrutinib administration in the study population, Dr. Sahaf said. Comparing 33 ibrutinib-receiving patients who received intravenous immune globulin with three patients who did not, the investigators saw no differences in relative antibody concentrations for tetanus or Epstein-Barr virus between the two groups.
“Protective antibodies against tetanus and Epstein-Barr virus persist following ibrutinib therapy,” Dr. Sahaf said.
Next up is the iNTEGRATE trial (NCT02959944), a phase 3 study that will test ibrutinib plus prednisone as first-line therapy for cGVHD, Dr. Sahaf said. The research team will continue its extensive proteomics work in this study as well, she said.
Dr. Sahaf reported research funding from Pharmacyclics LLC, an AbbVie company, which markets ibrutinib. She also reported having patent, royalty, or intellectual property arrangements with Stanford University.
SOURCE: Sahaf, B et al. BMT Tandem Meetings, Abstract 2.
SALT LAKE CITY – Ibrutinib’s effectiveness in inhibiting chronic graft versus host disease (cGVHD) may hinge in part on inhibition of pre–germinal center B cells and follicular helper cells, according to a new analysis of clinical trial data.
The analysis also showed that ibrutinib preserved immune memory and type 1 T-helper cells.
Bita Sahaf, PhD, presented results of a “comprehensive and high dimensional proteomic approach” to data from 42 patients who were enrolled in a phase 1/2 clinical trial of ibrutinib for cGVHD (NCT02195869).
In that study, 80% of patients who had two or more organs affected by cGVHD responded in at least two organs; overall, two-thirds of patients had a complete or partial response with ibrutinib. The highest response rates were seen in disease affecting the skin, mouth, and gastrointestinal tract.
The new analysis used blood samples from trial participants collected before and during ibrutinib therapy to look for soluble plasma factors known to be related to inflammation, fibrosis, and cGVHD.
“A heat map of cytokines, chemokines, and factors associated with fibrosis shows a significant decrease following ibrutinib treatment,” Dr. Sahaf said during a top abstracts session at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
In addition, inflammatory gene expression was reduced with ibrutinib use, with reductions in the chemokines nuclear factor kappa-B-1, CXCL10, CCL7, and CCL3 dropping by 2.6-fold, 2.3-fold, 25-fold, and 1.8-fold, respectively, after 3 months of ibrutinib therapy, Dr. Sahaf and her colleagues reported.
The investigators used several different techniques to tease apart the mechanisms behind ibrutinib’s effectiveness. Immunophenotyping was accomplished with cytometry by time of flight (CyTOF), a technique that uses transition element isotopes to tag antibodies, which are then analyzed on a cell-by-cell basis by a time-of-flight mass spectrometer.
Ibrutinib inhibits CD19+CD38+CD27+IgD+ pre–germinal center B cells as well as pathogenic CD4+ T follicular helper cells, both implicated in cGVHD, the investigators found. However, Th1 T cells were preserved in a patient-by-patient analysis.
The CyTOF technique also allowed a phosphorylation analysis showing ibrutinib’s blocking effect on Bruton’s tyrosine kinase (BTK) as well as IL-2 inducible T-cell kinase (ITK), with subsequent effects on the signaling molecule PLCgamma2. In individual patients, this inhibition was confirmed when BTK-activated B-cell populations were eliminated after ibrutinib therapy, Dr. Sahaf said.
Ibrutinib also decreased phosphorylation of ITK, with subsequent depletion of CD4+, CD185+, and BCL6+ follicular helper T cells, and of other T cell populations still to be characterized. However, neither CD4+Tbet+Th1 cells nor CD4+CD25+CD127dim Treg cells saw depletion.
Importantly, “CD8+ cytotoxic T cells persist,” said Dr. Sahaf. Phosphorylation of ITK, she said, “appears heterogeneous across most T-cell populations.
“These data support the clinical efficacy of ibrutinib in cGVHD and highlight ibrutinib’s multifactorial mechanism of action in this disease,” Dr. Sahaf, of Stanford (Calif.) University, and her collaborators wrote in the abstract accompanying the presentation.
In August 2017, ibrutinib became the first treatment approved by the Food and Drug Administration for cGVHD. It is indicated for adults who have failed at least one other therapy.
“These correlative studies suggest that ibrutinib impacts a number of the immunologic mechanisms underlying the development of chronic graft versus host disease,” Dr. Sahaf said. Taken together, her team’s work has shown a reduction in expression of inflammatory genes and cytokines, and a decrease in plasma levels of chemotactic, inflammatory, and fibrotic cytokines that all have been implicated in cGVHD pathogenesis. The selective inhibition of pre–germinal center B cells and the trend toward reduced follicular helper T cells also plays a role in ibrutinib’s effectiveness, she said.
Ibrutinib’s efficacy in damping down inflammatory pathways that lead to cGVHD does not come at the expense of other immune function, however. Immune memory and Th 1 cells were not affected by ibrutinib administration in the study population, Dr. Sahaf said. Comparing 33 ibrutinib-receiving patients who received intravenous immune globulin with three patients who did not, the investigators saw no differences in relative antibody concentrations for tetanus or Epstein-Barr virus between the two groups.
“Protective antibodies against tetanus and Epstein-Barr virus persist following ibrutinib therapy,” Dr. Sahaf said.
Next up is the iNTEGRATE trial (NCT02959944), a phase 3 study that will test ibrutinib plus prednisone as first-line therapy for cGVHD, Dr. Sahaf said. The research team will continue its extensive proteomics work in this study as well, she said.
Dr. Sahaf reported research funding from Pharmacyclics LLC, an AbbVie company, which markets ibrutinib. She also reported having patent, royalty, or intellectual property arrangements with Stanford University.
SOURCE: Sahaf, B et al. BMT Tandem Meetings, Abstract 2.
SALT LAKE CITY – Ibrutinib’s effectiveness in inhibiting chronic graft versus host disease (cGVHD) may hinge in part on inhibition of pre–germinal center B cells and follicular helper cells, according to a new analysis of clinical trial data.
The analysis also showed that ibrutinib preserved immune memory and type 1 T-helper cells.
Bita Sahaf, PhD, presented results of a “comprehensive and high dimensional proteomic approach” to data from 42 patients who were enrolled in a phase 1/2 clinical trial of ibrutinib for cGVHD (NCT02195869).
In that study, 80% of patients who had two or more organs affected by cGVHD responded in at least two organs; overall, two-thirds of patients had a complete or partial response with ibrutinib. The highest response rates were seen in disease affecting the skin, mouth, and gastrointestinal tract.
The new analysis used blood samples from trial participants collected before and during ibrutinib therapy to look for soluble plasma factors known to be related to inflammation, fibrosis, and cGVHD.
“A heat map of cytokines, chemokines, and factors associated with fibrosis shows a significant decrease following ibrutinib treatment,” Dr. Sahaf said during a top abstracts session at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
In addition, inflammatory gene expression was reduced with ibrutinib use, with reductions in the chemokines nuclear factor kappa-B-1, CXCL10, CCL7, and CCL3 dropping by 2.6-fold, 2.3-fold, 25-fold, and 1.8-fold, respectively, after 3 months of ibrutinib therapy, Dr. Sahaf and her colleagues reported.
The investigators used several different techniques to tease apart the mechanisms behind ibrutinib’s effectiveness. Immunophenotyping was accomplished with cytometry by time of flight (CyTOF), a technique that uses transition element isotopes to tag antibodies, which are then analyzed on a cell-by-cell basis by a time-of-flight mass spectrometer.
Ibrutinib inhibits CD19+CD38+CD27+IgD+ pre–germinal center B cells as well as pathogenic CD4+ T follicular helper cells, both implicated in cGVHD, the investigators found. However, Th1 T cells were preserved in a patient-by-patient analysis.
The CyTOF technique also allowed a phosphorylation analysis showing ibrutinib’s blocking effect on Bruton’s tyrosine kinase (BTK) as well as IL-2 inducible T-cell kinase (ITK), with subsequent effects on the signaling molecule PLCgamma2. In individual patients, this inhibition was confirmed when BTK-activated B-cell populations were eliminated after ibrutinib therapy, Dr. Sahaf said.
Ibrutinib also decreased phosphorylation of ITK, with subsequent depletion of CD4+, CD185+, and BCL6+ follicular helper T cells, and of other T cell populations still to be characterized. However, neither CD4+Tbet+Th1 cells nor CD4+CD25+CD127dim Treg cells saw depletion.
Importantly, “CD8+ cytotoxic T cells persist,” said Dr. Sahaf. Phosphorylation of ITK, she said, “appears heterogeneous across most T-cell populations.
“These data support the clinical efficacy of ibrutinib in cGVHD and highlight ibrutinib’s multifactorial mechanism of action in this disease,” Dr. Sahaf, of Stanford (Calif.) University, and her collaborators wrote in the abstract accompanying the presentation.
In August 2017, ibrutinib became the first treatment approved by the Food and Drug Administration for cGVHD. It is indicated for adults who have failed at least one other therapy.
“These correlative studies suggest that ibrutinib impacts a number of the immunologic mechanisms underlying the development of chronic graft versus host disease,” Dr. Sahaf said. Taken together, her team’s work has shown a reduction in expression of inflammatory genes and cytokines, and a decrease in plasma levels of chemotactic, inflammatory, and fibrotic cytokines that all have been implicated in cGVHD pathogenesis. The selective inhibition of pre–germinal center B cells and the trend toward reduced follicular helper T cells also plays a role in ibrutinib’s effectiveness, she said.
Ibrutinib’s efficacy in damping down inflammatory pathways that lead to cGVHD does not come at the expense of other immune function, however. Immune memory and Th 1 cells were not affected by ibrutinib administration in the study population, Dr. Sahaf said. Comparing 33 ibrutinib-receiving patients who received intravenous immune globulin with three patients who did not, the investigators saw no differences in relative antibody concentrations for tetanus or Epstein-Barr virus between the two groups.
“Protective antibodies against tetanus and Epstein-Barr virus persist following ibrutinib therapy,” Dr. Sahaf said.
Next up is the iNTEGRATE trial (NCT02959944), a phase 3 study that will test ibrutinib plus prednisone as first-line therapy for cGVHD, Dr. Sahaf said. The research team will continue its extensive proteomics work in this study as well, she said.
Dr. Sahaf reported research funding from Pharmacyclics LLC, an AbbVie company, which markets ibrutinib. She also reported having patent, royalty, or intellectual property arrangements with Stanford University.
SOURCE: Sahaf, B et al. BMT Tandem Meetings, Abstract 2.
REPORTING FROM THE 2018 BMT TANDEM MEETINGS
Key clinical point:
Major finding: Inflammatory gene expression dropped between 1.8-fold and 25-fold for individual chemokines after ibrutinib treatment.
Study details: Comprehensive proteomics analysis of data from a phase 1/2 clinical trial of ibrutinib as second-line therapy for cGVHD.
Disclosures: The clinical trial was sponsored by Pharmacyclics LLC, an Abbvie company. Dr. Sahaf reported having patent, royalty, or intellectual property arrangements with Stanford University.
Source: Sahaf B et al. 2018 BMT Tandem Meetings. Abstract 2.
21-gene assay predicts survival in male and female breast cancer
A study of the molecular and genomic features of breast cancer in men, compared with those in women, highlights the prognostic value of a 21-gene breast recurrence score in both sexes, investigators say.
Men and women with estrogen receptor (ER)–positive breast cancer who had recurrence scores (RS) of 0 to 30 on the 21-gene assay (Oncotype DX) had excellent breast cancer–specific survival rates, which suggests that such patients could be spared from more aggressive treatments, such as chemotherapy, according to Suleiman Alfred Massarweh, MD, of Stanford (Calif.) University and his colleagues.
“Future adjuvant trials in ER-positive breast cancer may need to focus on targeting endocrine resistance in those patients with RS greater than 31 and may need to consider the weight of competing mortality risk when investigating the value of any additional treatment beyond endocrine therapy,” they wrote in the Journal of Clinical Oncology.
In 2016, an estimated 2,600 men were diagnosed with breast cancer in the United States.
“Approximately 95% of breast cancers diagnosed in men express the estrogen receptor and progesterone receptor (PR), which is a higher percentage than in women and suggests a key role for ER in the biology of breast cancer in men,” the investigators noted.
Although treatment of men with breast cancer has traditionally been extrapolated from treatment of women with breast cancer, genomic studies have suggested some key differences, the investigators noted, citing a study of the genomic landscape of male breast cancers presented at the 2014 San Antonio Breast Cancer Symposium.
In that study, investigators from the Memorial Sloan Kettering Cancer Center in New York and other institutions found that all male breast cancers in their sample of 64 patients were ER+ and human epidermal growth factor receptor 2 (HER2)–negative, predominantly of the luminal B subtype, and that the genetic alterations seen in male breast cancers frequently target DNA-repair fibroblast growth factor pathways. However, the pathways that are known to drive luminal cancers when mutated in women are seen less often among men, said Salvatore Piscuoglio, PhD, then a research fellow at MSKCC.
The current study helps to confirm and expand on the findings from that study, commented Steven J. Isakoff, MD, PhD, of the Massachusetts General Hospital Cancer Center in Boston, who was not involved in either study.
“I think it’s helpful to see in a larger dataset what the spectrum of oncotypes [Oncotype DX] looks like in men. In general, as the study described, we have a real lack of large-scale data in men and certainly no prospective data with oncotypes,” he said in an interview.
To get a better idea of the molecular characteristics of breast cancer in men and how they relate to breast cancer–specific mortality, Dr. Massarweh and his associates looked at deidentified 21-gene assay data from the Genomic Health Laboratory database on 3,806 men and 571,115 women with breast cancer with either no nodal involvement, micrometastases only, or one to three involved lymph nodes.
They also looked at survival data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) population of patients with breast cancer diagnosed during 2004-2012, which included data on 332 men and 55,842 women with ER-positive and/or PR-positive invasive breast cancer.
Among the entire 21-gene assay sample, they found that men were significantly older than women at the time of diagnosis, at a mean age of 64.2 vs. 59.1 years (P less than .001).
Both men and women had infiltrating ductal carcinoma as the most common histology; the prevalence was slightly higher among men at 87.6% versus 81.3% for women.
The average recurrence score in men was 16.8 versus 17.0 in women, a difference that was not statistically significant. A majority of both men and women had RS scores below 18 (65.8% and 58.2%, respectively), although significantly more men than women had RS scores of 31 or higher (12.4% vs. 7.4%; P less than .001).
“This relative predominance of high RS results in men was encountered across age groups but was most prominent in men younger than 40 years of age,” the investigators wrote.
At the other end of the scale, RS lower than 11, especially RS 0, were seen more frequently in men than in women, except among those younger than 40 years.
Looking at individual gene expression profiles, the authors found that mean gene expression was higher in men for genes associated with ER, proliferation, and invasion. ER expression was lowest and PR expression was highest in women younger than 50 years, but ER expression increased progressively with age.
Among men, those younger than 50 years had slightly lower ER and PR expression than did older men.
In the analysis of SEER survival data, they found that 5-year breast cancer severity score (BCSS) was 99% for men with RS below 18, 95.7% for those with RS between18 and 30, and 81% for those with RS of 31 or higher. Among women, 5-year BCSS was 99.5% for those with RS under 18, 98.6% for those with RS between 18 and 30, and 94.9% for those with RS of 31 or higher.
Five-year overall survival estimates were 92.6% for men with RS below 18, 86% for those with RS between 18 and 30, and 69% for those with RS of 31 or higher. Respective 5-year OS rates for women were 95%, 94.2%, and 89.9%.
“The 21-gene RS provided clear prognostic information in our cohort, with a significantly different 5-year BCSS determined by RS in both men and women,” the investigators wrote.
They noted that patients with low and intermediate RS have excellent prognoses regardless of nodal status, which suggests that these patients have more indolent disease and better outcomes than do patients with higher RS.
The more frequent use of adjuvant chemotherapy in the RS 31 and higher group indicates that “the prognostic utility of RS results is evident despite adjuvant chemotherapy use,” they wrote.
Dr. Isakoff pointed out, however, that the population in the study is from a registry of patients eligible for the 21-gene assay, which can only be used for patients with ER-positive and HER2-negative tumors.
“In other words, this is not a random sample. This is a sample of patients for whom the treating physician was on the fence about chemotherapy and in some way thought that getting an oncotype might be helpful,” he said.
He added that although the study findings “don’t change anything we have been doing, they provide reassurance that oncotype is a reasonable test to consider in patients with male breast cancer for whom we’re considering including or avoiding chemotherapy,” he said.
A funding source for the study was not reported. Dr. Massarweh disclosed stock or ownership in Radius Health, consulting for Novartis, and institutional research funding from multiple companies. Three coauthors are employees and stockholders of Genomic Health, maker of the Oncotype DX assay used in the study. Dr. Isakoff reported no conflicts of interest related to the study
SOURCE: Massarweh SA et al. 2018 Mar 27. doi: 10.1200/JCO.2017.76.8861.
A study of the molecular and genomic features of breast cancer in men, compared with those in women, highlights the prognostic value of a 21-gene breast recurrence score in both sexes, investigators say.
Men and women with estrogen receptor (ER)–positive breast cancer who had recurrence scores (RS) of 0 to 30 on the 21-gene assay (Oncotype DX) had excellent breast cancer–specific survival rates, which suggests that such patients could be spared from more aggressive treatments, such as chemotherapy, according to Suleiman Alfred Massarweh, MD, of Stanford (Calif.) University and his colleagues.
“Future adjuvant trials in ER-positive breast cancer may need to focus on targeting endocrine resistance in those patients with RS greater than 31 and may need to consider the weight of competing mortality risk when investigating the value of any additional treatment beyond endocrine therapy,” they wrote in the Journal of Clinical Oncology.
In 2016, an estimated 2,600 men were diagnosed with breast cancer in the United States.
“Approximately 95% of breast cancers diagnosed in men express the estrogen receptor and progesterone receptor (PR), which is a higher percentage than in women and suggests a key role for ER in the biology of breast cancer in men,” the investigators noted.
Although treatment of men with breast cancer has traditionally been extrapolated from treatment of women with breast cancer, genomic studies have suggested some key differences, the investigators noted, citing a study of the genomic landscape of male breast cancers presented at the 2014 San Antonio Breast Cancer Symposium.
In that study, investigators from the Memorial Sloan Kettering Cancer Center in New York and other institutions found that all male breast cancers in their sample of 64 patients were ER+ and human epidermal growth factor receptor 2 (HER2)–negative, predominantly of the luminal B subtype, and that the genetic alterations seen in male breast cancers frequently target DNA-repair fibroblast growth factor pathways. However, the pathways that are known to drive luminal cancers when mutated in women are seen less often among men, said Salvatore Piscuoglio, PhD, then a research fellow at MSKCC.
The current study helps to confirm and expand on the findings from that study, commented Steven J. Isakoff, MD, PhD, of the Massachusetts General Hospital Cancer Center in Boston, who was not involved in either study.
“I think it’s helpful to see in a larger dataset what the spectrum of oncotypes [Oncotype DX] looks like in men. In general, as the study described, we have a real lack of large-scale data in men and certainly no prospective data with oncotypes,” he said in an interview.
To get a better idea of the molecular characteristics of breast cancer in men and how they relate to breast cancer–specific mortality, Dr. Massarweh and his associates looked at deidentified 21-gene assay data from the Genomic Health Laboratory database on 3,806 men and 571,115 women with breast cancer with either no nodal involvement, micrometastases only, or one to three involved lymph nodes.
They also looked at survival data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) population of patients with breast cancer diagnosed during 2004-2012, which included data on 332 men and 55,842 women with ER-positive and/or PR-positive invasive breast cancer.
Among the entire 21-gene assay sample, they found that men were significantly older than women at the time of diagnosis, at a mean age of 64.2 vs. 59.1 years (P less than .001).
Both men and women had infiltrating ductal carcinoma as the most common histology; the prevalence was slightly higher among men at 87.6% versus 81.3% for women.
The average recurrence score in men was 16.8 versus 17.0 in women, a difference that was not statistically significant. A majority of both men and women had RS scores below 18 (65.8% and 58.2%, respectively), although significantly more men than women had RS scores of 31 or higher (12.4% vs. 7.4%; P less than .001).
“This relative predominance of high RS results in men was encountered across age groups but was most prominent in men younger than 40 years of age,” the investigators wrote.
At the other end of the scale, RS lower than 11, especially RS 0, were seen more frequently in men than in women, except among those younger than 40 years.
Looking at individual gene expression profiles, the authors found that mean gene expression was higher in men for genes associated with ER, proliferation, and invasion. ER expression was lowest and PR expression was highest in women younger than 50 years, but ER expression increased progressively with age.
Among men, those younger than 50 years had slightly lower ER and PR expression than did older men.
In the analysis of SEER survival data, they found that 5-year breast cancer severity score (BCSS) was 99% for men with RS below 18, 95.7% for those with RS between18 and 30, and 81% for those with RS of 31 or higher. Among women, 5-year BCSS was 99.5% for those with RS under 18, 98.6% for those with RS between 18 and 30, and 94.9% for those with RS of 31 or higher.
Five-year overall survival estimates were 92.6% for men with RS below 18, 86% for those with RS between 18 and 30, and 69% for those with RS of 31 or higher. Respective 5-year OS rates for women were 95%, 94.2%, and 89.9%.
“The 21-gene RS provided clear prognostic information in our cohort, with a significantly different 5-year BCSS determined by RS in both men and women,” the investigators wrote.
They noted that patients with low and intermediate RS have excellent prognoses regardless of nodal status, which suggests that these patients have more indolent disease and better outcomes than do patients with higher RS.
The more frequent use of adjuvant chemotherapy in the RS 31 and higher group indicates that “the prognostic utility of RS results is evident despite adjuvant chemotherapy use,” they wrote.
Dr. Isakoff pointed out, however, that the population in the study is from a registry of patients eligible for the 21-gene assay, which can only be used for patients with ER-positive and HER2-negative tumors.
“In other words, this is not a random sample. This is a sample of patients for whom the treating physician was on the fence about chemotherapy and in some way thought that getting an oncotype might be helpful,” he said.
He added that although the study findings “don’t change anything we have been doing, they provide reassurance that oncotype is a reasonable test to consider in patients with male breast cancer for whom we’re considering including or avoiding chemotherapy,” he said.
A funding source for the study was not reported. Dr. Massarweh disclosed stock or ownership in Radius Health, consulting for Novartis, and institutional research funding from multiple companies. Three coauthors are employees and stockholders of Genomic Health, maker of the Oncotype DX assay used in the study. Dr. Isakoff reported no conflicts of interest related to the study
SOURCE: Massarweh SA et al. 2018 Mar 27. doi: 10.1200/JCO.2017.76.8861.
A study of the molecular and genomic features of breast cancer in men, compared with those in women, highlights the prognostic value of a 21-gene breast recurrence score in both sexes, investigators say.
Men and women with estrogen receptor (ER)–positive breast cancer who had recurrence scores (RS) of 0 to 30 on the 21-gene assay (Oncotype DX) had excellent breast cancer–specific survival rates, which suggests that such patients could be spared from more aggressive treatments, such as chemotherapy, according to Suleiman Alfred Massarweh, MD, of Stanford (Calif.) University and his colleagues.
“Future adjuvant trials in ER-positive breast cancer may need to focus on targeting endocrine resistance in those patients with RS greater than 31 and may need to consider the weight of competing mortality risk when investigating the value of any additional treatment beyond endocrine therapy,” they wrote in the Journal of Clinical Oncology.
In 2016, an estimated 2,600 men were diagnosed with breast cancer in the United States.
“Approximately 95% of breast cancers diagnosed in men express the estrogen receptor and progesterone receptor (PR), which is a higher percentage than in women and suggests a key role for ER in the biology of breast cancer in men,” the investigators noted.
Although treatment of men with breast cancer has traditionally been extrapolated from treatment of women with breast cancer, genomic studies have suggested some key differences, the investigators noted, citing a study of the genomic landscape of male breast cancers presented at the 2014 San Antonio Breast Cancer Symposium.
In that study, investigators from the Memorial Sloan Kettering Cancer Center in New York and other institutions found that all male breast cancers in their sample of 64 patients were ER+ and human epidermal growth factor receptor 2 (HER2)–negative, predominantly of the luminal B subtype, and that the genetic alterations seen in male breast cancers frequently target DNA-repair fibroblast growth factor pathways. However, the pathways that are known to drive luminal cancers when mutated in women are seen less often among men, said Salvatore Piscuoglio, PhD, then a research fellow at MSKCC.
The current study helps to confirm and expand on the findings from that study, commented Steven J. Isakoff, MD, PhD, of the Massachusetts General Hospital Cancer Center in Boston, who was not involved in either study.
“I think it’s helpful to see in a larger dataset what the spectrum of oncotypes [Oncotype DX] looks like in men. In general, as the study described, we have a real lack of large-scale data in men and certainly no prospective data with oncotypes,” he said in an interview.
To get a better idea of the molecular characteristics of breast cancer in men and how they relate to breast cancer–specific mortality, Dr. Massarweh and his associates looked at deidentified 21-gene assay data from the Genomic Health Laboratory database on 3,806 men and 571,115 women with breast cancer with either no nodal involvement, micrometastases only, or one to three involved lymph nodes.
They also looked at survival data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) population of patients with breast cancer diagnosed during 2004-2012, which included data on 332 men and 55,842 women with ER-positive and/or PR-positive invasive breast cancer.
Among the entire 21-gene assay sample, they found that men were significantly older than women at the time of diagnosis, at a mean age of 64.2 vs. 59.1 years (P less than .001).
Both men and women had infiltrating ductal carcinoma as the most common histology; the prevalence was slightly higher among men at 87.6% versus 81.3% for women.
The average recurrence score in men was 16.8 versus 17.0 in women, a difference that was not statistically significant. A majority of both men and women had RS scores below 18 (65.8% and 58.2%, respectively), although significantly more men than women had RS scores of 31 or higher (12.4% vs. 7.4%; P less than .001).
“This relative predominance of high RS results in men was encountered across age groups but was most prominent in men younger than 40 years of age,” the investigators wrote.
At the other end of the scale, RS lower than 11, especially RS 0, were seen more frequently in men than in women, except among those younger than 40 years.
Looking at individual gene expression profiles, the authors found that mean gene expression was higher in men for genes associated with ER, proliferation, and invasion. ER expression was lowest and PR expression was highest in women younger than 50 years, but ER expression increased progressively with age.
Among men, those younger than 50 years had slightly lower ER and PR expression than did older men.
In the analysis of SEER survival data, they found that 5-year breast cancer severity score (BCSS) was 99% for men with RS below 18, 95.7% for those with RS between18 and 30, and 81% for those with RS of 31 or higher. Among women, 5-year BCSS was 99.5% for those with RS under 18, 98.6% for those with RS between 18 and 30, and 94.9% for those with RS of 31 or higher.
Five-year overall survival estimates were 92.6% for men with RS below 18, 86% for those with RS between 18 and 30, and 69% for those with RS of 31 or higher. Respective 5-year OS rates for women were 95%, 94.2%, and 89.9%.
“The 21-gene RS provided clear prognostic information in our cohort, with a significantly different 5-year BCSS determined by RS in both men and women,” the investigators wrote.
They noted that patients with low and intermediate RS have excellent prognoses regardless of nodal status, which suggests that these patients have more indolent disease and better outcomes than do patients with higher RS.
The more frequent use of adjuvant chemotherapy in the RS 31 and higher group indicates that “the prognostic utility of RS results is evident despite adjuvant chemotherapy use,” they wrote.
Dr. Isakoff pointed out, however, that the population in the study is from a registry of patients eligible for the 21-gene assay, which can only be used for patients with ER-positive and HER2-negative tumors.
“In other words, this is not a random sample. This is a sample of patients for whom the treating physician was on the fence about chemotherapy and in some way thought that getting an oncotype might be helpful,” he said.
He added that although the study findings “don’t change anything we have been doing, they provide reassurance that oncotype is a reasonable test to consider in patients with male breast cancer for whom we’re considering including or avoiding chemotherapy,” he said.
A funding source for the study was not reported. Dr. Massarweh disclosed stock or ownership in Radius Health, consulting for Novartis, and institutional research funding from multiple companies. Three coauthors are employees and stockholders of Genomic Health, maker of the Oncotype DX assay used in the study. Dr. Isakoff reported no conflicts of interest related to the study
SOURCE: Massarweh SA et al. 2018 Mar 27. doi: 10.1200/JCO.2017.76.8861.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Key clinical point: A 21-gene assay provides useful information about survival odds for men and women with breast cancer.
Major finding: A recurrence score of 31 or greater was associated with worse survival, particularly in men.
Study details: Retrospective review of genomic and surveillance data on 3,806 men and 571,115 women with breast cancer.
Disclosures: A funding source for the study was not reported. Dr. Massarweh disclosed stock or ownership in Radius Health, consulting for Novartis, and institutional research funding from multiple companies. Three coauthors are employees and stockholders of Genomic Health, maker of the Oncotype DX assay used in the study. Dr. Isakoff reported no conflicts of interest related to the study.
Source: Massarweh SA et al. 2018 Mar 27. doi: 10.1200/JCO.2017.76.8861.
FDA recalls kratom products for salmonella contamination
The Food and Drug Administration on April 3 recalled all products containing kratom manufactured by Triangle Pharmanaturals LLC, after a number of supplements tested positive for salmonella.
The FDA advises consumers to get rid of products including Raw Form Organics Maeng Da Kratom Emerald Green, Raw Form Organics Maeng Da Kratom Ivory White, and Raw Form Organics Maeng Da Kratom Ruby Red.
Evidence of the contamination was found after two samples were collected from a retail store in Oregon by the Oregon Public Health Division and tested positive for salmonella.
The recall was ordered after Triangle Pharmanaturals did not comply with a March 30 formal request from the FDA to voluntarily recall their products.
“This action is based on the imminent health risk posed by the contamination of this product with salmonella, and the refusal of this company to voluntarily act to protect its customers and issue a recall, despite our repeated requests and actions,” said FDA Commissioner Scott Gottlieb, M.D., said in a statement. “The action today is based on the risks posed by the contamination of this particular product with a potentially dangerous pathogen.”
At press time, Triangle Pharmanaturals did not respond to a request for comment.
This is the most recent in a list recalls of kratom products as part of an ongoing investigation of a salmonella outbreak by the FDA; however Triangle Pharmanaturals’ noncompliance is unique to the agency, according to an FDA representative.
“This is the first time the agency has issued a mandatory recall order to protect Americans from contaminated food products,” Michael Felberbaum, an FDA press officer, said in an interview. “This is the third time the FDA has invoked its mandatory recall authority, but the first time the agency ordered a mandatory recall because a company has opted not to voluntarily recall after the FDA’s notification of an opportunity to initiate a voluntary recall.”
Earlier in March, the CDC reported 87 people in 35 states infected with either Salmonella Javiana, Salmonela Okatie, or Salmonella Thompson, which have been associated with the outbreak.
While salmonella was identified in Triangle Pharmanaturals’ products, the strains identified are not currently linked to the outbreak.
Kratom, a plant that commonly grows in South East Asian countries like Thailand, Malaysia, Indonesia, and Papua New Guinea, has recently been used to produce food supplements and marketed as an alternative to addictive pain medication like opioids, as well as used to help treat opioid withdrawal symptoms.
Use of the food supplement has fired debate among physicians, patients, and public officials as all sides continue to determine its efficacy and how, or whether, it should be given a drug classification.
The Food and Drug Administration on April 3 recalled all products containing kratom manufactured by Triangle Pharmanaturals LLC, after a number of supplements tested positive for salmonella.
The FDA advises consumers to get rid of products including Raw Form Organics Maeng Da Kratom Emerald Green, Raw Form Organics Maeng Da Kratom Ivory White, and Raw Form Organics Maeng Da Kratom Ruby Red.
Evidence of the contamination was found after two samples were collected from a retail store in Oregon by the Oregon Public Health Division and tested positive for salmonella.
The recall was ordered after Triangle Pharmanaturals did not comply with a March 30 formal request from the FDA to voluntarily recall their products.
“This action is based on the imminent health risk posed by the contamination of this product with salmonella, and the refusal of this company to voluntarily act to protect its customers and issue a recall, despite our repeated requests and actions,” said FDA Commissioner Scott Gottlieb, M.D., said in a statement. “The action today is based on the risks posed by the contamination of this particular product with a potentially dangerous pathogen.”
At press time, Triangle Pharmanaturals did not respond to a request for comment.
This is the most recent in a list recalls of kratom products as part of an ongoing investigation of a salmonella outbreak by the FDA; however Triangle Pharmanaturals’ noncompliance is unique to the agency, according to an FDA representative.
“This is the first time the agency has issued a mandatory recall order to protect Americans from contaminated food products,” Michael Felberbaum, an FDA press officer, said in an interview. “This is the third time the FDA has invoked its mandatory recall authority, but the first time the agency ordered a mandatory recall because a company has opted not to voluntarily recall after the FDA’s notification of an opportunity to initiate a voluntary recall.”
Earlier in March, the CDC reported 87 people in 35 states infected with either Salmonella Javiana, Salmonela Okatie, or Salmonella Thompson, which have been associated with the outbreak.
While salmonella was identified in Triangle Pharmanaturals’ products, the strains identified are not currently linked to the outbreak.
Kratom, a plant that commonly grows in South East Asian countries like Thailand, Malaysia, Indonesia, and Papua New Guinea, has recently been used to produce food supplements and marketed as an alternative to addictive pain medication like opioids, as well as used to help treat opioid withdrawal symptoms.
Use of the food supplement has fired debate among physicians, patients, and public officials as all sides continue to determine its efficacy and how, or whether, it should be given a drug classification.
The Food and Drug Administration on April 3 recalled all products containing kratom manufactured by Triangle Pharmanaturals LLC, after a number of supplements tested positive for salmonella.
The FDA advises consumers to get rid of products including Raw Form Organics Maeng Da Kratom Emerald Green, Raw Form Organics Maeng Da Kratom Ivory White, and Raw Form Organics Maeng Da Kratom Ruby Red.
Evidence of the contamination was found after two samples were collected from a retail store in Oregon by the Oregon Public Health Division and tested positive for salmonella.
The recall was ordered after Triangle Pharmanaturals did not comply with a March 30 formal request from the FDA to voluntarily recall their products.
“This action is based on the imminent health risk posed by the contamination of this product with salmonella, and the refusal of this company to voluntarily act to protect its customers and issue a recall, despite our repeated requests and actions,” said FDA Commissioner Scott Gottlieb, M.D., said in a statement. “The action today is based on the risks posed by the contamination of this particular product with a potentially dangerous pathogen.”
At press time, Triangle Pharmanaturals did not respond to a request for comment.
This is the most recent in a list recalls of kratom products as part of an ongoing investigation of a salmonella outbreak by the FDA; however Triangle Pharmanaturals’ noncompliance is unique to the agency, according to an FDA representative.
“This is the first time the agency has issued a mandatory recall order to protect Americans from contaminated food products,” Michael Felberbaum, an FDA press officer, said in an interview. “This is the third time the FDA has invoked its mandatory recall authority, but the first time the agency ordered a mandatory recall because a company has opted not to voluntarily recall after the FDA’s notification of an opportunity to initiate a voluntary recall.”
Earlier in March, the CDC reported 87 people in 35 states infected with either Salmonella Javiana, Salmonela Okatie, or Salmonella Thompson, which have been associated with the outbreak.
While salmonella was identified in Triangle Pharmanaturals’ products, the strains identified are not currently linked to the outbreak.
Kratom, a plant that commonly grows in South East Asian countries like Thailand, Malaysia, Indonesia, and Papua New Guinea, has recently been used to produce food supplements and marketed as an alternative to addictive pain medication like opioids, as well as used to help treat opioid withdrawal symptoms.
Use of the food supplement has fired debate among physicians, patients, and public officials as all sides continue to determine its efficacy and how, or whether, it should be given a drug classification.