User login
Hospitalists: Leading health care innovation
As I begin my year as SHM president, I continue to be energized by the opportunity to be part of an organization that has such a positive impact on our nation’s health care system. From the beginning of my medical career to now, never have I witnessed a health care movement quite like hospital medicine.
Even when I first arrived in Southern California as a pulmonary/critical-care physician in 1987, there were groups of physicians who had taken financial risk on populations of managed-care patients and were paid using an “alternative payment model” called capitation. One of the innovations they had utilized since the early ’80s to successfully manage their risk – and their patients’ – was to have dedicated inpatient physicians caring for their hospitalized patients 24/7, while most of their primary care partners managed the group’s patients in the outpatient setting.
This year will see a continued reshaping of our delivery system, driven by emerging federal policy like the Medicare Access and CHIP Reauthorization Act (MACRA). All of this policy is designed to create a health care system that delivers high-quality care in a much more cost effective way. Many of these policies will result in groups of providers being pushed away from fee-for-service payment toward alternative payment models that involve higher levels of risk and opportunity. If we, as providers, are going to be successful in managing our “at risk” populations, we are going to have to be as innovative as our managed care forefathers. If we are not, we, as a society, are not going to be able to afford to deliver high-quality care to our nations sickest citizens.
At the center of much of this innovation will be hospitalists. After all, by its very nature, our model is a delivery system reform. The drive to deliver more-efficient quality care is in the very DNA of our specialty.
As decisions are made, they will have a significant impact on our patients and our careers. It will continue to be a priority for SHM to make sure that the voice of hospital medicine is heard loud and clear. We will continue to ask our members to ensure that the hospital medicine community has a prominent place in these conversations. Those who step up in this effort will lead us as we insist on having a prominent seat at the table and as new models of care emerge and new incentives are created for the provider community. We will continue to strive to make sure that our patients get the care they deserve and that we continue to help build a sustainable health care delivery system.
This year, you will also see a focused effort to strengthen SHM’s system of state and local chapters. The vitality of these local organizations is important to our efforts to effectively serve our members by engaging them with their colleagues at the local level. In our attempts to further connect our members with others who share similar interests and focuses, we will be rolling out a new structure of special interest groups. These local chapters and these interest groups will fuel new ideas that will continue to improve our specialty and the effectiveness of the society to speak for hospital medicine with a strong voice.
Of course, SHM will continue to be the only organization that was created to represent our nation’s hospitalists and will be totally committed to providing our members with clinical and administrative education, dedicated publications, leadership training, research opportunities, and advocacy. I look forward to serving you and helping you get the most from your SHM experience. Together, we will continue to move the hospital medicine movement forward, shaping our health care system and improving patient care.
Dr. Greeno is the incoming president of the Society of Hospital Medicine and senior adviser for medical affairs at TeamHealth.
As I begin my year as SHM president, I continue to be energized by the opportunity to be part of an organization that has such a positive impact on our nation’s health care system. From the beginning of my medical career to now, never have I witnessed a health care movement quite like hospital medicine.
Even when I first arrived in Southern California as a pulmonary/critical-care physician in 1987, there were groups of physicians who had taken financial risk on populations of managed-care patients and were paid using an “alternative payment model” called capitation. One of the innovations they had utilized since the early ’80s to successfully manage their risk – and their patients’ – was to have dedicated inpatient physicians caring for their hospitalized patients 24/7, while most of their primary care partners managed the group’s patients in the outpatient setting.
This year will see a continued reshaping of our delivery system, driven by emerging federal policy like the Medicare Access and CHIP Reauthorization Act (MACRA). All of this policy is designed to create a health care system that delivers high-quality care in a much more cost effective way. Many of these policies will result in groups of providers being pushed away from fee-for-service payment toward alternative payment models that involve higher levels of risk and opportunity. If we, as providers, are going to be successful in managing our “at risk” populations, we are going to have to be as innovative as our managed care forefathers. If we are not, we, as a society, are not going to be able to afford to deliver high-quality care to our nations sickest citizens.
At the center of much of this innovation will be hospitalists. After all, by its very nature, our model is a delivery system reform. The drive to deliver more-efficient quality care is in the very DNA of our specialty.
As decisions are made, they will have a significant impact on our patients and our careers. It will continue to be a priority for SHM to make sure that the voice of hospital medicine is heard loud and clear. We will continue to ask our members to ensure that the hospital medicine community has a prominent place in these conversations. Those who step up in this effort will lead us as we insist on having a prominent seat at the table and as new models of care emerge and new incentives are created for the provider community. We will continue to strive to make sure that our patients get the care they deserve and that we continue to help build a sustainable health care delivery system.
This year, you will also see a focused effort to strengthen SHM’s system of state and local chapters. The vitality of these local organizations is important to our efforts to effectively serve our members by engaging them with their colleagues at the local level. In our attempts to further connect our members with others who share similar interests and focuses, we will be rolling out a new structure of special interest groups. These local chapters and these interest groups will fuel new ideas that will continue to improve our specialty and the effectiveness of the society to speak for hospital medicine with a strong voice.
Of course, SHM will continue to be the only organization that was created to represent our nation’s hospitalists and will be totally committed to providing our members with clinical and administrative education, dedicated publications, leadership training, research opportunities, and advocacy. I look forward to serving you and helping you get the most from your SHM experience. Together, we will continue to move the hospital medicine movement forward, shaping our health care system and improving patient care.
Dr. Greeno is the incoming president of the Society of Hospital Medicine and senior adviser for medical affairs at TeamHealth.
As I begin my year as SHM president, I continue to be energized by the opportunity to be part of an organization that has such a positive impact on our nation’s health care system. From the beginning of my medical career to now, never have I witnessed a health care movement quite like hospital medicine.
Even when I first arrived in Southern California as a pulmonary/critical-care physician in 1987, there were groups of physicians who had taken financial risk on populations of managed-care patients and were paid using an “alternative payment model” called capitation. One of the innovations they had utilized since the early ’80s to successfully manage their risk – and their patients’ – was to have dedicated inpatient physicians caring for their hospitalized patients 24/7, while most of their primary care partners managed the group’s patients in the outpatient setting.
This year will see a continued reshaping of our delivery system, driven by emerging federal policy like the Medicare Access and CHIP Reauthorization Act (MACRA). All of this policy is designed to create a health care system that delivers high-quality care in a much more cost effective way. Many of these policies will result in groups of providers being pushed away from fee-for-service payment toward alternative payment models that involve higher levels of risk and opportunity. If we, as providers, are going to be successful in managing our “at risk” populations, we are going to have to be as innovative as our managed care forefathers. If we are not, we, as a society, are not going to be able to afford to deliver high-quality care to our nations sickest citizens.
At the center of much of this innovation will be hospitalists. After all, by its very nature, our model is a delivery system reform. The drive to deliver more-efficient quality care is in the very DNA of our specialty.
As decisions are made, they will have a significant impact on our patients and our careers. It will continue to be a priority for SHM to make sure that the voice of hospital medicine is heard loud and clear. We will continue to ask our members to ensure that the hospital medicine community has a prominent place in these conversations. Those who step up in this effort will lead us as we insist on having a prominent seat at the table and as new models of care emerge and new incentives are created for the provider community. We will continue to strive to make sure that our patients get the care they deserve and that we continue to help build a sustainable health care delivery system.
This year, you will also see a focused effort to strengthen SHM’s system of state and local chapters. The vitality of these local organizations is important to our efforts to effectively serve our members by engaging them with their colleagues at the local level. In our attempts to further connect our members with others who share similar interests and focuses, we will be rolling out a new structure of special interest groups. These local chapters and these interest groups will fuel new ideas that will continue to improve our specialty and the effectiveness of the society to speak for hospital medicine with a strong voice.
Of course, SHM will continue to be the only organization that was created to represent our nation’s hospitalists and will be totally committed to providing our members with clinical and administrative education, dedicated publications, leadership training, research opportunities, and advocacy. I look forward to serving you and helping you get the most from your SHM experience. Together, we will continue to move the hospital medicine movement forward, shaping our health care system and improving patient care.
Dr. Greeno is the incoming president of the Society of Hospital Medicine and senior adviser for medical affairs at TeamHealth.
Study Reveals Tumor Blood Vessels Cluster in Beltlike Zones
Digital pathology has made it possible to measure microscopic objects, such as blood vessels in tumor tissue and then visualize them in density maps, showing hotspot regions. But for many applications in histopathology, there is no clear-cut definition of the hotspots, say researchers from Heidelberg University in Germany. Thus, most tumor models “implicitly assume” that blood vessels are equally abundant in different parts of a tumor. But the researchers’ new computational approach to mapping angiogenesis in colorectal cancer (CRC) could change that assumption.
Related: In Rare Case Colorectal Cancer Causes Thrombus
Their method analyzes blood vessels based on spatial statistics, identifying all hotspot areas that are unlikely to occur by chance. The researchers found that in nearly all cases, the blood vessels grouped in a distinctive beltlike pattern. In 33 of 34 untreated colorectal tumor samples, the blood vessels were aggregated at the interface of tumor tissue to the intestinal wall. The researchers found similar “hypervascularized” zones at the boundaries of liver tissue in 100% of the samples of CRC liver metastases. Ultimately, they describe a new model of tumor vascularization: a highly vascularized zone about 1.5-mm wide close to the intestinal lumen in CRC primary tumors and a highly vascularized zone approximately 1-mm wide close to the invasion front in CRC liver metastases.
Related: Colorectal Screening: Available but Underused
Their model has immediate and far-reaching implications, the researchers say. For instance, because vascular patterns determine how chemotherapeutic drugs are distributed in tumor tissue, it is likely that these drugs reach the luminal side of CRC tumors much easier than they reach the the basolateral side. Their new information also could be used in timing surgery, since the tumor parts of the deep invasion front may be less sensitive to chemotherapy. The researchers suggest that using their model could help optimize treatment in any number of ways: explaining early symptoms like gastrointestinal bleeding, the architecture of CRC, metastasis, and opening new pathways for investigation.
Source:
Kather JN, Zöllner FG, Schad LR. PLoS One. 2017;12(3):e0171378.
doi: 10.1371/journal.pone.0171378.
Digital pathology has made it possible to measure microscopic objects, such as blood vessels in tumor tissue and then visualize them in density maps, showing hotspot regions. But for many applications in histopathology, there is no clear-cut definition of the hotspots, say researchers from Heidelberg University in Germany. Thus, most tumor models “implicitly assume” that blood vessels are equally abundant in different parts of a tumor. But the researchers’ new computational approach to mapping angiogenesis in colorectal cancer (CRC) could change that assumption.
Related: In Rare Case Colorectal Cancer Causes Thrombus
Their method analyzes blood vessels based on spatial statistics, identifying all hotspot areas that are unlikely to occur by chance. The researchers found that in nearly all cases, the blood vessels grouped in a distinctive beltlike pattern. In 33 of 34 untreated colorectal tumor samples, the blood vessels were aggregated at the interface of tumor tissue to the intestinal wall. The researchers found similar “hypervascularized” zones at the boundaries of liver tissue in 100% of the samples of CRC liver metastases. Ultimately, they describe a new model of tumor vascularization: a highly vascularized zone about 1.5-mm wide close to the intestinal lumen in CRC primary tumors and a highly vascularized zone approximately 1-mm wide close to the invasion front in CRC liver metastases.
Related: Colorectal Screening: Available but Underused
Their model has immediate and far-reaching implications, the researchers say. For instance, because vascular patterns determine how chemotherapeutic drugs are distributed in tumor tissue, it is likely that these drugs reach the luminal side of CRC tumors much easier than they reach the the basolateral side. Their new information also could be used in timing surgery, since the tumor parts of the deep invasion front may be less sensitive to chemotherapy. The researchers suggest that using their model could help optimize treatment in any number of ways: explaining early symptoms like gastrointestinal bleeding, the architecture of CRC, metastasis, and opening new pathways for investigation.
Source:
Kather JN, Zöllner FG, Schad LR. PLoS One. 2017;12(3):e0171378.
doi: 10.1371/journal.pone.0171378.
Digital pathology has made it possible to measure microscopic objects, such as blood vessels in tumor tissue and then visualize them in density maps, showing hotspot regions. But for many applications in histopathology, there is no clear-cut definition of the hotspots, say researchers from Heidelberg University in Germany. Thus, most tumor models “implicitly assume” that blood vessels are equally abundant in different parts of a tumor. But the researchers’ new computational approach to mapping angiogenesis in colorectal cancer (CRC) could change that assumption.
Related: In Rare Case Colorectal Cancer Causes Thrombus
Their method analyzes blood vessels based on spatial statistics, identifying all hotspot areas that are unlikely to occur by chance. The researchers found that in nearly all cases, the blood vessels grouped in a distinctive beltlike pattern. In 33 of 34 untreated colorectal tumor samples, the blood vessels were aggregated at the interface of tumor tissue to the intestinal wall. The researchers found similar “hypervascularized” zones at the boundaries of liver tissue in 100% of the samples of CRC liver metastases. Ultimately, they describe a new model of tumor vascularization: a highly vascularized zone about 1.5-mm wide close to the intestinal lumen in CRC primary tumors and a highly vascularized zone approximately 1-mm wide close to the invasion front in CRC liver metastases.
Related: Colorectal Screening: Available but Underused
Their model has immediate and far-reaching implications, the researchers say. For instance, because vascular patterns determine how chemotherapeutic drugs are distributed in tumor tissue, it is likely that these drugs reach the luminal side of CRC tumors much easier than they reach the the basolateral side. Their new information also could be used in timing surgery, since the tumor parts of the deep invasion front may be less sensitive to chemotherapy. The researchers suggest that using their model could help optimize treatment in any number of ways: explaining early symptoms like gastrointestinal bleeding, the architecture of CRC, metastasis, and opening new pathways for investigation.
Source:
Kather JN, Zöllner FG, Schad LR. PLoS One. 2017;12(3):e0171378.
doi: 10.1371/journal.pone.0171378.
Fertility treatments linked to risk of pediatric cancers
Children born to mothers who underwent fertility treatments have an increased risk of developing pediatric neoplasms, according to research published in the American Journal of Obstetrics & Gynecology.
The study showed an increased risk of malignancies and benign tumors among children conceived after fertility treatments.
However, the risk of leukemias and lymphomas among these children was not significantly different from the risk among children who were conceived spontaneously.
The study was a population-based cohort analysis of babies born between 1991 and 2013 at Soroka University Medical Center in Beer-Sheva, Israel, with follow-up to age 18.
Of the 242,187 newborn infants in the study, 237,863 (98.3%) were conceived spontaneously, 2603 (1.1%) were conceived after in vitro fertilization (IVF), and 1721 (0.7%) were conceived after ovulation induction (OI) treatments.
During a median follow-up of 10.55 years, there were 1498 neoplasms reported, including 1074 benign tumors and 429 malignancies.
The rate of neoplasms per 10,000 children was 61.85 for the entire study cohort, 111.41 for the IVF group, 110.40 for the OI group, and 60.96 for the spontaneous conception group (P<0.001 for the comparison between spontaneous conception and both types of fertility treatments).
The rate of benign tumors per 10,000 children was 44.35 for the entire study cohort, 84.51 for the IVF group, 69.73 for the OI group, and 43.72 for the spontaneous conception group (P=0.002).
The rate of malignancies per 10,000 children was 17.71 for the entire study cohort, 26.89 for the IVF group, 40.67 for the OI group, and 17.44 for the spontaneous conception group (P=0.038).
The rate of leukemia per 10,000 children was 3.72 for the entire study cohort (n=90 leukemia cases total), 0 for the IVF group (n=0), 5.81 for the OI group (n=1), and 3.74 for the spontaneous conception group (n=89, P=0.56).
The rate of lymphoma per 10,000 children was 2.27 for the entire study cohort (n=55), 7.68 for the IVF group (n=2), 0 for the OI group (n=0), and 2.23 for the spontaneous conception group (n=53, P=0.15).
The researchers said the association between fertility treatments and total pediatric neoplasms or total malignancies remained significant in analyses controlled for confounders such as gestational diabetes mellitus, hypertensive disorders, preterm birth, and maternal age.
For any fertility treatment, the adjusted hazard ratio (aHR) for all neoplasms was 1.97, and the aHR for all malignancies was 1.96.
For IVF, the aHR was 2.48 for all neoplasms and 1.89 for all malignancies. For OI, the aHR was 1.51 for all neoplasms and 2.03 for all malignancies.
“The research concludes that the association between IVF and total pediatric neoplasms and malignancies is significant,” said study author Eyal Sheiner, MD, PhD, of Ben-Gurion University of the Negev in Beer-Sheva, Israel.
“With increasing numbers of offspring conceived after fertility treatments, it is important to follow up on their health.” 
Children born to mothers who underwent fertility treatments have an increased risk of developing pediatric neoplasms, according to research published in the American Journal of Obstetrics & Gynecology.
The study showed an increased risk of malignancies and benign tumors among children conceived after fertility treatments.
However, the risk of leukemias and lymphomas among these children was not significantly different from the risk among children who were conceived spontaneously.
The study was a population-based cohort analysis of babies born between 1991 and 2013 at Soroka University Medical Center in Beer-Sheva, Israel, with follow-up to age 18.
Of the 242,187 newborn infants in the study, 237,863 (98.3%) were conceived spontaneously, 2603 (1.1%) were conceived after in vitro fertilization (IVF), and 1721 (0.7%) were conceived after ovulation induction (OI) treatments.
During a median follow-up of 10.55 years, there were 1498 neoplasms reported, including 1074 benign tumors and 429 malignancies.
The rate of neoplasms per 10,000 children was 61.85 for the entire study cohort, 111.41 for the IVF group, 110.40 for the OI group, and 60.96 for the spontaneous conception group (P<0.001 for the comparison between spontaneous conception and both types of fertility treatments).
The rate of benign tumors per 10,000 children was 44.35 for the entire study cohort, 84.51 for the IVF group, 69.73 for the OI group, and 43.72 for the spontaneous conception group (P=0.002).
The rate of malignancies per 10,000 children was 17.71 for the entire study cohort, 26.89 for the IVF group, 40.67 for the OI group, and 17.44 for the spontaneous conception group (P=0.038).
The rate of leukemia per 10,000 children was 3.72 for the entire study cohort (n=90 leukemia cases total), 0 for the IVF group (n=0), 5.81 for the OI group (n=1), and 3.74 for the spontaneous conception group (n=89, P=0.56).
The rate of lymphoma per 10,000 children was 2.27 for the entire study cohort (n=55), 7.68 for the IVF group (n=2), 0 for the OI group (n=0), and 2.23 for the spontaneous conception group (n=53, P=0.15).
The researchers said the association between fertility treatments and total pediatric neoplasms or total malignancies remained significant in analyses controlled for confounders such as gestational diabetes mellitus, hypertensive disorders, preterm birth, and maternal age.
For any fertility treatment, the adjusted hazard ratio (aHR) for all neoplasms was 1.97, and the aHR for all malignancies was 1.96.
For IVF, the aHR was 2.48 for all neoplasms and 1.89 for all malignancies. For OI, the aHR was 1.51 for all neoplasms and 2.03 for all malignancies.
“The research concludes that the association between IVF and total pediatric neoplasms and malignancies is significant,” said study author Eyal Sheiner, MD, PhD, of Ben-Gurion University of the Negev in Beer-Sheva, Israel.
“With increasing numbers of offspring conceived after fertility treatments, it is important to follow up on their health.”
Children born to mothers who underwent fertility treatments have an increased risk of developing pediatric neoplasms, according to research published in the American Journal of Obstetrics & Gynecology.
The study showed an increased risk of malignancies and benign tumors among children conceived after fertility treatments.
However, the risk of leukemias and lymphomas among these children was not significantly different from the risk among children who were conceived spontaneously.
The study was a population-based cohort analysis of babies born between 1991 and 2013 at Soroka University Medical Center in Beer-Sheva, Israel, with follow-up to age 18.
Of the 242,187 newborn infants in the study, 237,863 (98.3%) were conceived spontaneously, 2603 (1.1%) were conceived after in vitro fertilization (IVF), and 1721 (0.7%) were conceived after ovulation induction (OI) treatments.
During a median follow-up of 10.55 years, there were 1498 neoplasms reported, including 1074 benign tumors and 429 malignancies.
The rate of neoplasms per 10,000 children was 61.85 for the entire study cohort, 111.41 for the IVF group, 110.40 for the OI group, and 60.96 for the spontaneous conception group (P<0.001 for the comparison between spontaneous conception and both types of fertility treatments).
The rate of benign tumors per 10,000 children was 44.35 for the entire study cohort, 84.51 for the IVF group, 69.73 for the OI group, and 43.72 for the spontaneous conception group (P=0.002).
The rate of malignancies per 10,000 children was 17.71 for the entire study cohort, 26.89 for the IVF group, 40.67 for the OI group, and 17.44 for the spontaneous conception group (P=0.038).
The rate of leukemia per 10,000 children was 3.72 for the entire study cohort (n=90 leukemia cases total), 0 for the IVF group (n=0), 5.81 for the OI group (n=1), and 3.74 for the spontaneous conception group (n=89, P=0.56).
The rate of lymphoma per 10,000 children was 2.27 for the entire study cohort (n=55), 7.68 for the IVF group (n=2), 0 for the OI group (n=0), and 2.23 for the spontaneous conception group (n=53, P=0.15).
The researchers said the association between fertility treatments and total pediatric neoplasms or total malignancies remained significant in analyses controlled for confounders such as gestational diabetes mellitus, hypertensive disorders, preterm birth, and maternal age.
For any fertility treatment, the adjusted hazard ratio (aHR) for all neoplasms was 1.97, and the aHR for all malignancies was 1.96.
For IVF, the aHR was 2.48 for all neoplasms and 1.89 for all malignancies. For OI, the aHR was 1.51 for all neoplasms and 2.03 for all malignancies.
“The research concludes that the association between IVF and total pediatric neoplasms and malignancies is significant,” said study author Eyal Sheiner, MD, PhD, of Ben-Gurion University of the Negev in Beer-Sheva, Israel.
“With increasing numbers of offspring conceived after fertility treatments, it is important to follow up on their health.”
TXA lowers risk of death from post-partum hemorrhage
Treatment with tranexamic acid (TXA) should become the frontline response to major bleeding after childbirth, according to researchers.
Results of a global study showed that TXA can reduce death due to bleeding in women with post-partum hemorrhage, particularly when the drug is given early.
TXA reduced deaths from bleeding by 19% overall and by 31% when patients received TXA within 3 hours of giving birth.
In addition, there was no significant difference in adverse events for women who received TXA and those who received placebo.
Researchers reported these results in The Lancet.
Funds to support the drug and placebo costs in the run-in phase of the trial were provided by Pfizer. The trial was also funded by the London School of Hygiene & Tropical Medicine, UK Department of Health, Wellcome Trust, and Bill & Melinda Gates Foundation.
The trial included 20,060 mothers, age 16 and older, who were treated at 193 hospitals in 21 countries.
All of the women had a clinical diagnosis of post-partum hemorrhage—defined as a blood loss of more than 500 ml within 24 hours of giving birth—after a vaginal birth or caesarean section.
The women were randomized to receive either 1 g of intravenous TXA (n=10,051) or matching placebo (n=10,009) in addition to standard care. The patients could receive a second dose of TXA or placebo if their bleeding continued after 30 minutes or stopped and restarted within 24 hours of the first dose.
The patients and their caregivers were blinded to randomization.
Results
In the final analysis, there were 10,036 women in the TXA arm and 9985 in the placebo arm.
TXA significantly reduced the risk of death from bleeding. The incidence of death from bleeding was 1.5% (n=155) among women who received TXA and 1.9% (n=191) in the placebo group. The risk ratio (RR) was 0.81 (P=0.045).
The incidence of death due to bleeding was 1.2% (n=89) among women who received TXA within 3 hours of giving birth and 1.7% (n=127) among women who received placebo within the same time period. The RR was 0.69 (P=0.008).
There was no significant difference between the treatment groups for other causes of death, and there was no significant difference in the use of hysterectomy.
Likewise, there was no significant difference between the treatment groups when it came to the composite endpoint of death from all causes or hysterectomy within 42 days of giving birth. This endpoint occurred in 5.3% (n=534) of patients in the TXA group and 5.6% (n=546) of those in the placebo group. The RR was 0.97 (P=0.65).
There was no significant difference between the treatment groups in the use of blood products. Fifty-four percent of patients in each group received blood transfusions. Among women who received transfusions, there was no significant difference in the mean number of units received.
On the other hand, there was a significant reduction in laparotomy to control bleeding for patients who received TXA (0.8%, n=82) compared to placebo (1.3%, n=127), with an RR of 0.64 (P=0.002).
There was no significant difference between the treatment groups (TXA and placebo, respectively) with regard to thromboembolic events (0.3% vs 0.3%), renal failure (1.3% vs 1.2%), cardiac failure (1.1% vs 1.2%), respiratory failure (1.1% vs 1.2%), hepatic failure (0.3% vs 0.3%), sepsis (1.8% vs 1.9%), or seizure (0.3% vs 0.4%).
And there was no significant difference between the treatment groups in quality of life measures, such as pain/discomfort, anxiety/depression, and mobility.
“We now have important evidence that the early use of tranexamic acid can save women’s lives and ensure more children grow up with a mother,” said study author Haleema Shakur, of the London School of Hygiene & Tropical Medicine in the UK.
“[TXA is] safe, affordable, and easy to administer, and we hope that doctors will use it as early as possible following the onset of severe bleeding after childbirth.”
Current World Health Organization guidelines recommend the use of TXA in post-partum hemorrhage as a treatment option if uterotonics fail to control the bleeding or if the bleeding is thought to be due to trauma.
Treatment with tranexamic acid (TXA) should become the frontline response to major bleeding after childbirth, according to researchers.
Results of a global study showed that TXA can reduce death due to bleeding in women with post-partum hemorrhage, particularly when the drug is given early.
TXA reduced deaths from bleeding by 19% overall and by 31% when patients received TXA within 3 hours of giving birth.
In addition, there was no significant difference in adverse events for women who received TXA and those who received placebo.
Researchers reported these results in The Lancet.
Funds to support the drug and placebo costs in the run-in phase of the trial were provided by Pfizer. The trial was also funded by the London School of Hygiene & Tropical Medicine, UK Department of Health, Wellcome Trust, and Bill & Melinda Gates Foundation.
The trial included 20,060 mothers, age 16 and older, who were treated at 193 hospitals in 21 countries.
All of the women had a clinical diagnosis of post-partum hemorrhage—defined as a blood loss of more than 500 ml within 24 hours of giving birth—after a vaginal birth or caesarean section.
The women were randomized to receive either 1 g of intravenous TXA (n=10,051) or matching placebo (n=10,009) in addition to standard care. The patients could receive a second dose of TXA or placebo if their bleeding continued after 30 minutes or stopped and restarted within 24 hours of the first dose.
The patients and their caregivers were blinded to randomization.
Results
In the final analysis, there were 10,036 women in the TXA arm and 9985 in the placebo arm.
TXA significantly reduced the risk of death from bleeding. The incidence of death from bleeding was 1.5% (n=155) among women who received TXA and 1.9% (n=191) in the placebo group. The risk ratio (RR) was 0.81 (P=0.045).
The incidence of death due to bleeding was 1.2% (n=89) among women who received TXA within 3 hours of giving birth and 1.7% (n=127) among women who received placebo within the same time period. The RR was 0.69 (P=0.008).
There was no significant difference between the treatment groups for other causes of death, and there was no significant difference in the use of hysterectomy.
Likewise, there was no significant difference between the treatment groups when it came to the composite endpoint of death from all causes or hysterectomy within 42 days of giving birth. This endpoint occurred in 5.3% (n=534) of patients in the TXA group and 5.6% (n=546) of those in the placebo group. The RR was 0.97 (P=0.65).
There was no significant difference between the treatment groups in the use of blood products. Fifty-four percent of patients in each group received blood transfusions. Among women who received transfusions, there was no significant difference in the mean number of units received.
On the other hand, there was a significant reduction in laparotomy to control bleeding for patients who received TXA (0.8%, n=82) compared to placebo (1.3%, n=127), with an RR of 0.64 (P=0.002).
There was no significant difference between the treatment groups (TXA and placebo, respectively) with regard to thromboembolic events (0.3% vs 0.3%), renal failure (1.3% vs 1.2%), cardiac failure (1.1% vs 1.2%), respiratory failure (1.1% vs 1.2%), hepatic failure (0.3% vs 0.3%), sepsis (1.8% vs 1.9%), or seizure (0.3% vs 0.4%).
And there was no significant difference between the treatment groups in quality of life measures, such as pain/discomfort, anxiety/depression, and mobility.
“We now have important evidence that the early use of tranexamic acid can save women’s lives and ensure more children grow up with a mother,” said study author Haleema Shakur, of the London School of Hygiene & Tropical Medicine in the UK.
“[TXA is] safe, affordable, and easy to administer, and we hope that doctors will use it as early as possible following the onset of severe bleeding after childbirth.”
Current World Health Organization guidelines recommend the use of TXA in post-partum hemorrhage as a treatment option if uterotonics fail to control the bleeding or if the bleeding is thought to be due to trauma.
Treatment with tranexamic acid (TXA) should become the frontline response to major bleeding after childbirth, according to researchers.
Results of a global study showed that TXA can reduce death due to bleeding in women with post-partum hemorrhage, particularly when the drug is given early.
TXA reduced deaths from bleeding by 19% overall and by 31% when patients received TXA within 3 hours of giving birth.
In addition, there was no significant difference in adverse events for women who received TXA and those who received placebo.
Researchers reported these results in The Lancet.
Funds to support the drug and placebo costs in the run-in phase of the trial were provided by Pfizer. The trial was also funded by the London School of Hygiene & Tropical Medicine, UK Department of Health, Wellcome Trust, and Bill & Melinda Gates Foundation.
The trial included 20,060 mothers, age 16 and older, who were treated at 193 hospitals in 21 countries.
All of the women had a clinical diagnosis of post-partum hemorrhage—defined as a blood loss of more than 500 ml within 24 hours of giving birth—after a vaginal birth or caesarean section.
The women were randomized to receive either 1 g of intravenous TXA (n=10,051) or matching placebo (n=10,009) in addition to standard care. The patients could receive a second dose of TXA or placebo if their bleeding continued after 30 minutes or stopped and restarted within 24 hours of the first dose.
The patients and their caregivers were blinded to randomization.
Results
In the final analysis, there were 10,036 women in the TXA arm and 9985 in the placebo arm.
TXA significantly reduced the risk of death from bleeding. The incidence of death from bleeding was 1.5% (n=155) among women who received TXA and 1.9% (n=191) in the placebo group. The risk ratio (RR) was 0.81 (P=0.045).
The incidence of death due to bleeding was 1.2% (n=89) among women who received TXA within 3 hours of giving birth and 1.7% (n=127) among women who received placebo within the same time period. The RR was 0.69 (P=0.008).
There was no significant difference between the treatment groups for other causes of death, and there was no significant difference in the use of hysterectomy.
Likewise, there was no significant difference between the treatment groups when it came to the composite endpoint of death from all causes or hysterectomy within 42 days of giving birth. This endpoint occurred in 5.3% (n=534) of patients in the TXA group and 5.6% (n=546) of those in the placebo group. The RR was 0.97 (P=0.65).
There was no significant difference between the treatment groups in the use of blood products. Fifty-four percent of patients in each group received blood transfusions. Among women who received transfusions, there was no significant difference in the mean number of units received.
On the other hand, there was a significant reduction in laparotomy to control bleeding for patients who received TXA (0.8%, n=82) compared to placebo (1.3%, n=127), with an RR of 0.64 (P=0.002).
There was no significant difference between the treatment groups (TXA and placebo, respectively) with regard to thromboembolic events (0.3% vs 0.3%), renal failure (1.3% vs 1.2%), cardiac failure (1.1% vs 1.2%), respiratory failure (1.1% vs 1.2%), hepatic failure (0.3% vs 0.3%), sepsis (1.8% vs 1.9%), or seizure (0.3% vs 0.4%).
And there was no significant difference between the treatment groups in quality of life measures, such as pain/discomfort, anxiety/depression, and mobility.
“We now have important evidence that the early use of tranexamic acid can save women’s lives and ensure more children grow up with a mother,” said study author Haleema Shakur, of the London School of Hygiene & Tropical Medicine in the UK.
“[TXA is] safe, affordable, and easy to administer, and we hope that doctors will use it as early as possible following the onset of severe bleeding after childbirth.”
Current World Health Organization guidelines recommend the use of TXA in post-partum hemorrhage as a treatment option if uterotonics fail to control the bleeding or if the bleeding is thought to be due to trauma.
Program allows select Europeans access to belinostat
A managed access program is making the histone deacetylase inhibitor belinostat (Beleodaq®) available to patients in Europe who have relapsed or refractory peripheral T-cell lymphoma (PTCL).
The program allows physicians to request belinostat for individual PTCL patients who have no alternative treatment options.
This enables patients to use belinostat ahead of a potential European approval. There are currently no approved treatments for PTCL in Europe.
The program will provide access to belinostat for patients in the UK, Germany, France, Spain, Italy, Denmark, Sweden, Norway, Finland, Belgium, The Netherlands, Luxembourg, and Austria.
The managed access program was made possible via an agreement between Onxeo, the company developing belinostat, and Clinigen Group plc., a company focused on providing access to medicines.
Healthcare professionals can obtain details about the belinostat managed access program by calling a Clinigen representative at +44 (0) 1283 44 347 or emailing [email protected].
A managed access program is making the histone deacetylase inhibitor belinostat (Beleodaq®) available to patients in Europe who have relapsed or refractory peripheral T-cell lymphoma (PTCL).
The program allows physicians to request belinostat for individual PTCL patients who have no alternative treatment options.
This enables patients to use belinostat ahead of a potential European approval. There are currently no approved treatments for PTCL in Europe.
The program will provide access to belinostat for patients in the UK, Germany, France, Spain, Italy, Denmark, Sweden, Norway, Finland, Belgium, The Netherlands, Luxembourg, and Austria.
The managed access program was made possible via an agreement between Onxeo, the company developing belinostat, and Clinigen Group plc., a company focused on providing access to medicines.
Healthcare professionals can obtain details about the belinostat managed access program by calling a Clinigen representative at +44 (0) 1283 44 347 or emailing [email protected].
A managed access program is making the histone deacetylase inhibitor belinostat (Beleodaq®) available to patients in Europe who have relapsed or refractory peripheral T-cell lymphoma (PTCL).
The program allows physicians to request belinostat for individual PTCL patients who have no alternative treatment options.
This enables patients to use belinostat ahead of a potential European approval. There are currently no approved treatments for PTCL in Europe.
The program will provide access to belinostat for patients in the UK, Germany, France, Spain, Italy, Denmark, Sweden, Norway, Finland, Belgium, The Netherlands, Luxembourg, and Austria.
The managed access program was made possible via an agreement between Onxeo, the company developing belinostat, and Clinigen Group plc., a company focused on providing access to medicines.
Healthcare professionals can obtain details about the belinostat managed access program by calling a Clinigen representative at +44 (0) 1283 44 347 or emailing [email protected].
DLA tablets cure drug-resistant malaria
Researchers have reported that tablets made from dried leaves of the Artemisia annua plant were able to cure malaria in 18 critically ill patients in a clinic in Africa.
When standard malaria medications failed to help the patients, the attending physician at the clinic acted under the compassionate use doctrine and prescribed the unapproved therapy, known as dried-leaf Artemisia (DLA).
Within 5 days, all 18 patients had fully recovered, with lab tests showing no parasites in their blood.
Details on this small trial were published in Phytomedicine.
The trial included 18 patients in the North Kivu province of the Democratic Republic of Congo who showed symptoms of malaria and were originally treated with artemisinin-based combination therapy (ACT).
The patients, who ranged in age from 14 months to 60 years, did not respond to ACT and lapsed into severe malaria.
Seven of the patients had anemia, 6 had convulsions, and 4 had vomiting and diarrhea. One patient, a 5-year-old child, became comatose.
All of the patients were then treated with intravenous artesunate, but they showed no improvement.
As a last resort, doctors turned to DLA. After 5 days of treatment with DLA tablets, all 18 patients fully recovered. Tests showed they had no parasites remaining in their blood.
The researchers said the DLA tablets were well-tolerated, as there were no side effects observed.
“These 18 patients were dying,” said study author Pamela Weathers, PhD, of Worcester Polytechnic Institute in Massachusetts.
“So to see 100% recover, even the child who had lapsed into a coma, was just amazing. It’s a small study, but the results are powerful.”
Dr Weathers noted that more than 100 other drug-resistant patients have been successfully treated with DLA tablets.
She said the superior performance of DLA in comparison to ACT, as well as DLA’s ability to kill drug-resistant parasites and avoid the resistance trap itself, is likely due to the synergistic effects of a complex array of phytochemicals contained in the plant’s leaves.
Several of these phytochemicals are known to have antimalarial properties, and others may act both to enhance the absorption of artemisinin into the bloodstream and bolster its effectiveness against malaria.
In effect, the dried leaves constitute a robust natural combination therapy, one whose benefits surpass those of ACT and other combination drugs.
“We have done a lot of work to understand the biochemistry of these compounds, which include a number of flavonoids and terpenes, so we can better understand the role they play in the pharmacological activity of the dried leaves,” Dr Weathers said.
“The more we learn, the more excited we become about the potential for DLA to be the medication of choice for combating malaria worldwide. Artemisia annua is known to be efficacious against a range of other diseases, including other tropical maladies and certain cancers. So, in our lab, we are already at work investigating the effectiveness of DLA with other diseases.”
Another advantage of DLA over conventional malaria treatments is its low cost and the relative simplicity of its manufacture, Dr Weathers said. When compared to ACT, producing DLA tablets can be accomplished with simpler equipment and a modest amount of training.
Growing Artemisia annua and producing and testing the tablets, Dr Weathers noted, are ideal local business ventures that can provide jobs in impoverished areas and greatly expand access to antimalarial therapy.
In fact, she has already established a supply chain in Africa that includes growing and harvesting high-producing cultivars in East Africa, along with Good Manufacturing Practice processing operations in Uganda where the leaves are dried, pulverized, and homogenized; the powder is compacted into tablets; and the tablets are tested to verify their dosage.
This supply chain helped produce the tablets used to treat the 18 patients in the Democratic Republic of Congo.
Researchers have reported that tablets made from dried leaves of the Artemisia annua plant were able to cure malaria in 18 critically ill patients in a clinic in Africa.
When standard malaria medications failed to help the patients, the attending physician at the clinic acted under the compassionate use doctrine and prescribed the unapproved therapy, known as dried-leaf Artemisia (DLA).
Within 5 days, all 18 patients had fully recovered, with lab tests showing no parasites in their blood.
Details on this small trial were published in Phytomedicine.
The trial included 18 patients in the North Kivu province of the Democratic Republic of Congo who showed symptoms of malaria and were originally treated with artemisinin-based combination therapy (ACT).
The patients, who ranged in age from 14 months to 60 years, did not respond to ACT and lapsed into severe malaria.
Seven of the patients had anemia, 6 had convulsions, and 4 had vomiting and diarrhea. One patient, a 5-year-old child, became comatose.
All of the patients were then treated with intravenous artesunate, but they showed no improvement.
As a last resort, doctors turned to DLA. After 5 days of treatment with DLA tablets, all 18 patients fully recovered. Tests showed they had no parasites remaining in their blood.
The researchers said the DLA tablets were well-tolerated, as there were no side effects observed.
“These 18 patients were dying,” said study author Pamela Weathers, PhD, of Worcester Polytechnic Institute in Massachusetts.
“So to see 100% recover, even the child who had lapsed into a coma, was just amazing. It’s a small study, but the results are powerful.”
Dr Weathers noted that more than 100 other drug-resistant patients have been successfully treated with DLA tablets.
She said the superior performance of DLA in comparison to ACT, as well as DLA’s ability to kill drug-resistant parasites and avoid the resistance trap itself, is likely due to the synergistic effects of a complex array of phytochemicals contained in the plant’s leaves.
Several of these phytochemicals are known to have antimalarial properties, and others may act both to enhance the absorption of artemisinin into the bloodstream and bolster its effectiveness against malaria.
In effect, the dried leaves constitute a robust natural combination therapy, one whose benefits surpass those of ACT and other combination drugs.
“We have done a lot of work to understand the biochemistry of these compounds, which include a number of flavonoids and terpenes, so we can better understand the role they play in the pharmacological activity of the dried leaves,” Dr Weathers said.
“The more we learn, the more excited we become about the potential for DLA to be the medication of choice for combating malaria worldwide. Artemisia annua is known to be efficacious against a range of other diseases, including other tropical maladies and certain cancers. So, in our lab, we are already at work investigating the effectiveness of DLA with other diseases.”
Another advantage of DLA over conventional malaria treatments is its low cost and the relative simplicity of its manufacture, Dr Weathers said. When compared to ACT, producing DLA tablets can be accomplished with simpler equipment and a modest amount of training.
Growing Artemisia annua and producing and testing the tablets, Dr Weathers noted, are ideal local business ventures that can provide jobs in impoverished areas and greatly expand access to antimalarial therapy.
In fact, she has already established a supply chain in Africa that includes growing and harvesting high-producing cultivars in East Africa, along with Good Manufacturing Practice processing operations in Uganda where the leaves are dried, pulverized, and homogenized; the powder is compacted into tablets; and the tablets are tested to verify their dosage.
This supply chain helped produce the tablets used to treat the 18 patients in the Democratic Republic of Congo.
Researchers have reported that tablets made from dried leaves of the Artemisia annua plant were able to cure malaria in 18 critically ill patients in a clinic in Africa.
When standard malaria medications failed to help the patients, the attending physician at the clinic acted under the compassionate use doctrine and prescribed the unapproved therapy, known as dried-leaf Artemisia (DLA).
Within 5 days, all 18 patients had fully recovered, with lab tests showing no parasites in their blood.
Details on this small trial were published in Phytomedicine.
The trial included 18 patients in the North Kivu province of the Democratic Republic of Congo who showed symptoms of malaria and were originally treated with artemisinin-based combination therapy (ACT).
The patients, who ranged in age from 14 months to 60 years, did not respond to ACT and lapsed into severe malaria.
Seven of the patients had anemia, 6 had convulsions, and 4 had vomiting and diarrhea. One patient, a 5-year-old child, became comatose.
All of the patients were then treated with intravenous artesunate, but they showed no improvement.
As a last resort, doctors turned to DLA. After 5 days of treatment with DLA tablets, all 18 patients fully recovered. Tests showed they had no parasites remaining in their blood.
The researchers said the DLA tablets were well-tolerated, as there were no side effects observed.
“These 18 patients were dying,” said study author Pamela Weathers, PhD, of Worcester Polytechnic Institute in Massachusetts.
“So to see 100% recover, even the child who had lapsed into a coma, was just amazing. It’s a small study, but the results are powerful.”
Dr Weathers noted that more than 100 other drug-resistant patients have been successfully treated with DLA tablets.
She said the superior performance of DLA in comparison to ACT, as well as DLA’s ability to kill drug-resistant parasites and avoid the resistance trap itself, is likely due to the synergistic effects of a complex array of phytochemicals contained in the plant’s leaves.
Several of these phytochemicals are known to have antimalarial properties, and others may act both to enhance the absorption of artemisinin into the bloodstream and bolster its effectiveness against malaria.
In effect, the dried leaves constitute a robust natural combination therapy, one whose benefits surpass those of ACT and other combination drugs.
“We have done a lot of work to understand the biochemistry of these compounds, which include a number of flavonoids and terpenes, so we can better understand the role they play in the pharmacological activity of the dried leaves,” Dr Weathers said.
“The more we learn, the more excited we become about the potential for DLA to be the medication of choice for combating malaria worldwide. Artemisia annua is known to be efficacious against a range of other diseases, including other tropical maladies and certain cancers. So, in our lab, we are already at work investigating the effectiveness of DLA with other diseases.”
Another advantage of DLA over conventional malaria treatments is its low cost and the relative simplicity of its manufacture, Dr Weathers said. When compared to ACT, producing DLA tablets can be accomplished with simpler equipment and a modest amount of training.
Growing Artemisia annua and producing and testing the tablets, Dr Weathers noted, are ideal local business ventures that can provide jobs in impoverished areas and greatly expand access to antimalarial therapy.
In fact, she has already established a supply chain in Africa that includes growing and harvesting high-producing cultivars in East Africa, along with Good Manufacturing Practice processing operations in Uganda where the leaves are dried, pulverized, and homogenized; the powder is compacted into tablets; and the tablets are tested to verify their dosage.
This supply chain helped produce the tablets used to treat the 18 patients in the Democratic Republic of Congo.
Severely painful vesicular rash
The family physician (FP) recognized the multiple vesicles on the patient’s hands as pompholyx, also known as dyshidrotic eczema. The term “pompholyx” means bubble, while the term “dyshidrotic” means "difficult sweating," as problems with sweating were once believed to be the cause of this condition. Some dermatologists prefer the name “vesicular hand dermatitis.” Regardless of the terminology, this can be a mild condition that is a minor nuisance or a severe chronic condition that impairs the patient's quality of life.
The FP prescribed 0.1% triamcinolone cream to be applied twice daily and gave the patient a referral to a dermatologist. While waiting for the dermatology appointment, the patient was not improving, so she went to an emergency room, where she received a prescription for oral prednisone.
When she arrived at the dermatology office, she stated that neither the topical cream nor the oral prednisone helped to improve the rash on her hands. The dermatologist performed patch testing and discovered that she had a contact allergy to topical steroids. He withdrew the steroids and started her on oral cyclosporine, which cleared the rash.
One major lesson from this case is that patients can actually be allergic to topical steroids. Referral to Dermatology was appropriate as the complexity of this case was beyond the scope of family medicine.
Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Usatine R. Hand eczema. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013:597-602.
To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/
You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com
The family physician (FP) recognized the multiple vesicles on the patient’s hands as pompholyx, also known as dyshidrotic eczema. The term “pompholyx” means bubble, while the term “dyshidrotic” means "difficult sweating," as problems with sweating were once believed to be the cause of this condition. Some dermatologists prefer the name “vesicular hand dermatitis.” Regardless of the terminology, this can be a mild condition that is a minor nuisance or a severe chronic condition that impairs the patient's quality of life.
The FP prescribed 0.1% triamcinolone cream to be applied twice daily and gave the patient a referral to a dermatologist. While waiting for the dermatology appointment, the patient was not improving, so she went to an emergency room, where she received a prescription for oral prednisone.
When she arrived at the dermatology office, she stated that neither the topical cream nor the oral prednisone helped to improve the rash on her hands. The dermatologist performed patch testing and discovered that she had a contact allergy to topical steroids. He withdrew the steroids and started her on oral cyclosporine, which cleared the rash.
One major lesson from this case is that patients can actually be allergic to topical steroids. Referral to Dermatology was appropriate as the complexity of this case was beyond the scope of family medicine.
Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Usatine R. Hand eczema. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013:597-602.
To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/
You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com
The family physician (FP) recognized the multiple vesicles on the patient’s hands as pompholyx, also known as dyshidrotic eczema. The term “pompholyx” means bubble, while the term “dyshidrotic” means "difficult sweating," as problems with sweating were once believed to be the cause of this condition. Some dermatologists prefer the name “vesicular hand dermatitis.” Regardless of the terminology, this can be a mild condition that is a minor nuisance or a severe chronic condition that impairs the patient's quality of life.
The FP prescribed 0.1% triamcinolone cream to be applied twice daily and gave the patient a referral to a dermatologist. While waiting for the dermatology appointment, the patient was not improving, so she went to an emergency room, where she received a prescription for oral prednisone.
When she arrived at the dermatology office, she stated that neither the topical cream nor the oral prednisone helped to improve the rash on her hands. The dermatologist performed patch testing and discovered that she had a contact allergy to topical steroids. He withdrew the steroids and started her on oral cyclosporine, which cleared the rash.
One major lesson from this case is that patients can actually be allergic to topical steroids. Referral to Dermatology was appropriate as the complexity of this case was beyond the scope of family medicine.
Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Usatine R. Hand eczema. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013:597-602.
To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/
You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com
Trial supports naproxen over low-dose colchicine for acute gout
BIRMINGHAM, ENGLAND – Naproxen may be considered the first-choice treatment for patients with acute gout in primary care, based on the results of the CONTACT (Colchicine or Naproxen Treatment for Acute Gout) trial.
“Our findings suggest that both naproxen and low-dose colchicine are effective treatments for acute gout,” Edward Roddy, MD, said at the British Society for Rheumatology annual conference.
The trial results showed, however, that there might be “a small, early treatment difference” favoring naproxen, and that the nonsteroidal anti-inflammatory drug “appeared to be associated with fewer side effects and less use of rescue analgesia for gout than low-dose colchicine,” said Dr. Roddy, a rheumatologist at Keele University, Staffordshire, England.
CONTACT was a multicenter, randomized, open-label trial involving 399 patients recruited at 100 primary care practices. Participants were mostly men (87%) and had a mean age of 59 years.
“The eligibility criteria were designed to reflect the pragmatic nature of the trial, but also to enable us to recruit the sorts of patients in whom either treatment option would be appropriate in routine practice,” Dr. Roddy explained.
Patients were eligible for inclusion if they had consulted a general practitioner for gout in the preceding 2 years and had a recent attack of acute gout that had been clinically assessed. Patients with medical or other contraindications to using either drug were excluded.
After giving their informed consent and completing a baseline questionnaire, patients were randomized to receive either naproxen as a single 750-mg dose, then as 250 mg three times a day for a maximum of 7 days, which is the licensed dose for gout in the United Kingdom, or 500 mcg of colchicine three times a day for 4 days. Patients completed a daily diary for 1 week, noting any pain, side effects, and analgesic drug use and then completed a follow-up questionnaire 4 weeks later.
The primary outcome was the worst pain intensity experienced in the preceding 24 hours, assessed on days 1-7 with a 10-point numeric rating scale (where 10 was the worst pain experienced).
The results showed that pain was reduced to a similar extent in both groups, with a mean difference in pain score between the treatments of 0.20 (95% confidence interval, –0.60 to 0.20) at 7 days and 0.08 (95% CI, –0.54 to 0.39) at 4 weeks’ follow-up, after adjustment for patients’ age, sex, and individual pain scores at baseline.
Greater mean improvement in pain intensity was seen with naproxen than colchicine on the second day of treatment, with a mean difference in pain scores between the groups of 0.48 (95% CI, –0.86 to –0.09) but not on any other day.
During the first 7 days of the study, diarrhea was the most commonly reported side effect occurring in the low-dose colchicine arm, reported by 43.2% of patients vs. 18.0% of those treated with naproxen (adjusted odds ratio, 3.04; 95% CI, 1.75-5.27). Conversely, constipation was a less frequently reported side effect occurring in 4.8% and 18.7% of patients, respectively (OR, 0.20; 95% CI, 0.08-0.49).
Patients treated with low-dose colchicine were also more likely than those treated with naproxen to report headache during the first 7 days (20.5% vs. 10.7%; OR, 1.90; 95% CI, 1.01-3.58).
There were no deaths in the study, and the three serious adverse events that occurred were thought to be unrelated to the study treatment. One NSAID-treated patient developed hospital-acquired pneumonia after elective heart valve surgery, and another NSAID-treated patient had noncardiac chest pain needing hospital treatment. One patient in the colchicine arm developed osteomyelitis that required hospitalization, but it was later thought that the patient might not have had gout to start with.
Between days 1 and 7 of the study, patients treated with low-dose colchicine were more likely to use other analgesic medications than were those treated with naproxen. This included the use of acetaminophen (23.6% vs. 13.4%; adjusted OR, 2.04; 95% CI, 1.10-3.78) and codeine (14.6% vs. 4.7%; aOR, 3.38; 95% CI, 1.45-7.91).
Patients in the low-dose colchicine group were also more likely to use an NSAID other than naproxen at week 4 than were those in the naproxen arm (24.0% vs. 13.4%; aOR, 1.93; 95% CI, 1.05-3.55).
Other secondary endpoints assessed showed no significant difference between the treatments, including changes in global assessment of response, acute gout recurrence, number of health care consultations, and ability to work.
The study was funded by the National Institute for Health Research School for Primary Care Research. Dr. Roddy had no conflicts of interest.
It’s not surprising that a relatively high dose of an NSAID like naproxen worked well for acute gout in the CONTACT study. That has been shown for multiple NSAIDs, although the quality of that evidence has been questioned (Cochrane Database Syst Rev. 2014 Sep 16;[9]:CD010120). What’s surprising is that colchicine did so well. It would have been informative to include the percentage of patients that responded to each treatment based on a predefined criterion, such as a 50% or greater reduction in pain scores at a given time point. The total colchicine dose used is on the high end of the “low dose” protocols, at 6.0 mg over 4 days, identical to the maximum low-dose over 4 days using current U.S. guidelines (Arthritis Care Res. 2012;64:1447-61). The higher dose may account for its efficacy, but also undoubtedly contributed to the high diarrhea rate of 43% (Arthritis Rheum. 2010;62:1060-8).
Christopher M. Burns, MD, is a rheumatologist at Dartmouth-Hitchcock Medical Center, Lebanon, N.H. He has no relevant disclosures.
It’s not surprising that a relatively high dose of an NSAID like naproxen worked well for acute gout in the CONTACT study. That has been shown for multiple NSAIDs, although the quality of that evidence has been questioned (Cochrane Database Syst Rev. 2014 Sep 16;[9]:CD010120). What’s surprising is that colchicine did so well. It would have been informative to include the percentage of patients that responded to each treatment based on a predefined criterion, such as a 50% or greater reduction in pain scores at a given time point. The total colchicine dose used is on the high end of the “low dose” protocols, at 6.0 mg over 4 days, identical to the maximum low-dose over 4 days using current U.S. guidelines (Arthritis Care Res. 2012;64:1447-61). The higher dose may account for its efficacy, but also undoubtedly contributed to the high diarrhea rate of 43% (Arthritis Rheum. 2010;62:1060-8).
Christopher M. Burns, MD, is a rheumatologist at Dartmouth-Hitchcock Medical Center, Lebanon, N.H. He has no relevant disclosures.
It’s not surprising that a relatively high dose of an NSAID like naproxen worked well for acute gout in the CONTACT study. That has been shown for multiple NSAIDs, although the quality of that evidence has been questioned (Cochrane Database Syst Rev. 2014 Sep 16;[9]:CD010120). What’s surprising is that colchicine did so well. It would have been informative to include the percentage of patients that responded to each treatment based on a predefined criterion, such as a 50% or greater reduction in pain scores at a given time point. The total colchicine dose used is on the high end of the “low dose” protocols, at 6.0 mg over 4 days, identical to the maximum low-dose over 4 days using current U.S. guidelines (Arthritis Care Res. 2012;64:1447-61). The higher dose may account for its efficacy, but also undoubtedly contributed to the high diarrhea rate of 43% (Arthritis Rheum. 2010;62:1060-8).
Christopher M. Burns, MD, is a rheumatologist at Dartmouth-Hitchcock Medical Center, Lebanon, N.H. He has no relevant disclosures.
BIRMINGHAM, ENGLAND – Naproxen may be considered the first-choice treatment for patients with acute gout in primary care, based on the results of the CONTACT (Colchicine or Naproxen Treatment for Acute Gout) trial.
“Our findings suggest that both naproxen and low-dose colchicine are effective treatments for acute gout,” Edward Roddy, MD, said at the British Society for Rheumatology annual conference.
The trial results showed, however, that there might be “a small, early treatment difference” favoring naproxen, and that the nonsteroidal anti-inflammatory drug “appeared to be associated with fewer side effects and less use of rescue analgesia for gout than low-dose colchicine,” said Dr. Roddy, a rheumatologist at Keele University, Staffordshire, England.
CONTACT was a multicenter, randomized, open-label trial involving 399 patients recruited at 100 primary care practices. Participants were mostly men (87%) and had a mean age of 59 years.
“The eligibility criteria were designed to reflect the pragmatic nature of the trial, but also to enable us to recruit the sorts of patients in whom either treatment option would be appropriate in routine practice,” Dr. Roddy explained.
Patients were eligible for inclusion if they had consulted a general practitioner for gout in the preceding 2 years and had a recent attack of acute gout that had been clinically assessed. Patients with medical or other contraindications to using either drug were excluded.
After giving their informed consent and completing a baseline questionnaire, patients were randomized to receive either naproxen as a single 750-mg dose, then as 250 mg three times a day for a maximum of 7 days, which is the licensed dose for gout in the United Kingdom, or 500 mcg of colchicine three times a day for 4 days. Patients completed a daily diary for 1 week, noting any pain, side effects, and analgesic drug use and then completed a follow-up questionnaire 4 weeks later.
The primary outcome was the worst pain intensity experienced in the preceding 24 hours, assessed on days 1-7 with a 10-point numeric rating scale (where 10 was the worst pain experienced).
The results showed that pain was reduced to a similar extent in both groups, with a mean difference in pain score between the treatments of 0.20 (95% confidence interval, –0.60 to 0.20) at 7 days and 0.08 (95% CI, –0.54 to 0.39) at 4 weeks’ follow-up, after adjustment for patients’ age, sex, and individual pain scores at baseline.
Greater mean improvement in pain intensity was seen with naproxen than colchicine on the second day of treatment, with a mean difference in pain scores between the groups of 0.48 (95% CI, –0.86 to –0.09) but not on any other day.
During the first 7 days of the study, diarrhea was the most commonly reported side effect occurring in the low-dose colchicine arm, reported by 43.2% of patients vs. 18.0% of those treated with naproxen (adjusted odds ratio, 3.04; 95% CI, 1.75-5.27). Conversely, constipation was a less frequently reported side effect occurring in 4.8% and 18.7% of patients, respectively (OR, 0.20; 95% CI, 0.08-0.49).
Patients treated with low-dose colchicine were also more likely than those treated with naproxen to report headache during the first 7 days (20.5% vs. 10.7%; OR, 1.90; 95% CI, 1.01-3.58).
There were no deaths in the study, and the three serious adverse events that occurred were thought to be unrelated to the study treatment. One NSAID-treated patient developed hospital-acquired pneumonia after elective heart valve surgery, and another NSAID-treated patient had noncardiac chest pain needing hospital treatment. One patient in the colchicine arm developed osteomyelitis that required hospitalization, but it was later thought that the patient might not have had gout to start with.
Between days 1 and 7 of the study, patients treated with low-dose colchicine were more likely to use other analgesic medications than were those treated with naproxen. This included the use of acetaminophen (23.6% vs. 13.4%; adjusted OR, 2.04; 95% CI, 1.10-3.78) and codeine (14.6% vs. 4.7%; aOR, 3.38; 95% CI, 1.45-7.91).
Patients in the low-dose colchicine group were also more likely to use an NSAID other than naproxen at week 4 than were those in the naproxen arm (24.0% vs. 13.4%; aOR, 1.93; 95% CI, 1.05-3.55).
Other secondary endpoints assessed showed no significant difference between the treatments, including changes in global assessment of response, acute gout recurrence, number of health care consultations, and ability to work.
The study was funded by the National Institute for Health Research School for Primary Care Research. Dr. Roddy had no conflicts of interest.
BIRMINGHAM, ENGLAND – Naproxen may be considered the first-choice treatment for patients with acute gout in primary care, based on the results of the CONTACT (Colchicine or Naproxen Treatment for Acute Gout) trial.
“Our findings suggest that both naproxen and low-dose colchicine are effective treatments for acute gout,” Edward Roddy, MD, said at the British Society for Rheumatology annual conference.
The trial results showed, however, that there might be “a small, early treatment difference” favoring naproxen, and that the nonsteroidal anti-inflammatory drug “appeared to be associated with fewer side effects and less use of rescue analgesia for gout than low-dose colchicine,” said Dr. Roddy, a rheumatologist at Keele University, Staffordshire, England.
CONTACT was a multicenter, randomized, open-label trial involving 399 patients recruited at 100 primary care practices. Participants were mostly men (87%) and had a mean age of 59 years.
“The eligibility criteria were designed to reflect the pragmatic nature of the trial, but also to enable us to recruit the sorts of patients in whom either treatment option would be appropriate in routine practice,” Dr. Roddy explained.
Patients were eligible for inclusion if they had consulted a general practitioner for gout in the preceding 2 years and had a recent attack of acute gout that had been clinically assessed. Patients with medical or other contraindications to using either drug were excluded.
After giving their informed consent and completing a baseline questionnaire, patients were randomized to receive either naproxen as a single 750-mg dose, then as 250 mg three times a day for a maximum of 7 days, which is the licensed dose for gout in the United Kingdom, or 500 mcg of colchicine three times a day for 4 days. Patients completed a daily diary for 1 week, noting any pain, side effects, and analgesic drug use and then completed a follow-up questionnaire 4 weeks later.
The primary outcome was the worst pain intensity experienced in the preceding 24 hours, assessed on days 1-7 with a 10-point numeric rating scale (where 10 was the worst pain experienced).
The results showed that pain was reduced to a similar extent in both groups, with a mean difference in pain score between the treatments of 0.20 (95% confidence interval, –0.60 to 0.20) at 7 days and 0.08 (95% CI, –0.54 to 0.39) at 4 weeks’ follow-up, after adjustment for patients’ age, sex, and individual pain scores at baseline.
Greater mean improvement in pain intensity was seen with naproxen than colchicine on the second day of treatment, with a mean difference in pain scores between the groups of 0.48 (95% CI, –0.86 to –0.09) but not on any other day.
During the first 7 days of the study, diarrhea was the most commonly reported side effect occurring in the low-dose colchicine arm, reported by 43.2% of patients vs. 18.0% of those treated with naproxen (adjusted odds ratio, 3.04; 95% CI, 1.75-5.27). Conversely, constipation was a less frequently reported side effect occurring in 4.8% and 18.7% of patients, respectively (OR, 0.20; 95% CI, 0.08-0.49).
Patients treated with low-dose colchicine were also more likely than those treated with naproxen to report headache during the first 7 days (20.5% vs. 10.7%; OR, 1.90; 95% CI, 1.01-3.58).
There were no deaths in the study, and the three serious adverse events that occurred were thought to be unrelated to the study treatment. One NSAID-treated patient developed hospital-acquired pneumonia after elective heart valve surgery, and another NSAID-treated patient had noncardiac chest pain needing hospital treatment. One patient in the colchicine arm developed osteomyelitis that required hospitalization, but it was later thought that the patient might not have had gout to start with.
Between days 1 and 7 of the study, patients treated with low-dose colchicine were more likely to use other analgesic medications than were those treated with naproxen. This included the use of acetaminophen (23.6% vs. 13.4%; adjusted OR, 2.04; 95% CI, 1.10-3.78) and codeine (14.6% vs. 4.7%; aOR, 3.38; 95% CI, 1.45-7.91).
Patients in the low-dose colchicine group were also more likely to use an NSAID other than naproxen at week 4 than were those in the naproxen arm (24.0% vs. 13.4%; aOR, 1.93; 95% CI, 1.05-3.55).
Other secondary endpoints assessed showed no significant difference between the treatments, including changes in global assessment of response, acute gout recurrence, number of health care consultations, and ability to work.
The study was funded by the National Institute for Health Research School for Primary Care Research. Dr. Roddy had no conflicts of interest.
Key clinical point:
Major finding: The mean difference in pain score between the treatments was 0.20 (95% CI, –0.60 to 0.20) at 7 days, but there was greater mean improvement in pain intensity on day 2 with naproxen.
Data source: The Colchicine or Naproxen Treatment for Acute Gout trial, a randomized, multicenter, open-label trial involving 399 patients with acute gout.
Disclosures: The study was funded by the National Institute for Health Research School for Primary Care Research. Dr. Roddy had no conflicts of interest.
ASCO updates NSCLC guidelines for adjuvant therapy
Adjuvant cisplatin-based chemotherapy is recommended for routine use in non–small cell lung cancer patients with stage IIA, IIB, or IIIA disease who have undergone complete surgical resections, according to updated guidelines from the American Society of Clinical Oncology.
In patients with stage IA disease, the guidelines recommend against cisplatin-based chemotherapy. The new guidelines are based on a systematic review current to January 2016 and an American Society for Radiation Oncology guideline and systematic review, which ASCO had already endorsed, which formed the basis for recommendations on adjuvant radiation therapy, Mark G. Kris, MD, and panel authors said (J Clin Oncol. 2017 April 26. doi: 10.1200/JCO.2017.72.4401).
The guidelines, available online, also recommend against routine cisplatin-based chemotherapy in patients with stage IB disease, but they suggest an evaluation of these patients to explore the pros and cons of adjuvant chemotherapy.
With respect to radiation, the authors recommend against it for patients with resected stage I or stage II disease, and they recommend against it for routine use in patients with stage IIIA. However, in patients with IIIA N2 disease, patients should be evaluated postoperatively, in consultation with a medical oncologist, for the potential risks and benefits of adjuvant radiation.
The authors also provide some recommendations for communicating with patients regarding treatment decisions. There are few studies examining this question, so the recommendations are based on low-quality evidence.
Non–small cell lung cancer patients may have complex social, psychological, and medical issues, and discussions should be carried out with this in mind. Pain, impaired breathing, and fatigue are common after surgery, and smoking cessation can lead to short-term stress as a result of nicotine withdrawal. Older patients may have a range of comorbidities.
Studies show that patients are most satisfied if they feel that physicians allow them to share in the decision making, and if they are given sufficient time to choose. To that end, the authors recommend a session dedicated to discussion of adjuvant therapy.
Communicating risk of death is challenging for many reasons. Patients should be asked how they would like to hear about their risks: some prefer general terms, while others may opt for numbers, charts, or graphs. The guidelines include a risk chart that can help patients understand the potential benefits and risks of chemotherapy.
The study authors report financial relationships with numerous pharmaceutical companies.
Adjuvant cisplatin-based chemotherapy is recommended for routine use in non–small cell lung cancer patients with stage IIA, IIB, or IIIA disease who have undergone complete surgical resections, according to updated guidelines from the American Society of Clinical Oncology.
In patients with stage IA disease, the guidelines recommend against cisplatin-based chemotherapy. The new guidelines are based on a systematic review current to January 2016 and an American Society for Radiation Oncology guideline and systematic review, which ASCO had already endorsed, which formed the basis for recommendations on adjuvant radiation therapy, Mark G. Kris, MD, and panel authors said (J Clin Oncol. 2017 April 26. doi: 10.1200/JCO.2017.72.4401).
The guidelines, available online, also recommend against routine cisplatin-based chemotherapy in patients with stage IB disease, but they suggest an evaluation of these patients to explore the pros and cons of adjuvant chemotherapy.
With respect to radiation, the authors recommend against it for patients with resected stage I or stage II disease, and they recommend against it for routine use in patients with stage IIIA. However, in patients with IIIA N2 disease, patients should be evaluated postoperatively, in consultation with a medical oncologist, for the potential risks and benefits of adjuvant radiation.
The authors also provide some recommendations for communicating with patients regarding treatment decisions. There are few studies examining this question, so the recommendations are based on low-quality evidence.
Non–small cell lung cancer patients may have complex social, psychological, and medical issues, and discussions should be carried out with this in mind. Pain, impaired breathing, and fatigue are common after surgery, and smoking cessation can lead to short-term stress as a result of nicotine withdrawal. Older patients may have a range of comorbidities.
Studies show that patients are most satisfied if they feel that physicians allow them to share in the decision making, and if they are given sufficient time to choose. To that end, the authors recommend a session dedicated to discussion of adjuvant therapy.
Communicating risk of death is challenging for many reasons. Patients should be asked how they would like to hear about their risks: some prefer general terms, while others may opt for numbers, charts, or graphs. The guidelines include a risk chart that can help patients understand the potential benefits and risks of chemotherapy.
The study authors report financial relationships with numerous pharmaceutical companies.
Adjuvant cisplatin-based chemotherapy is recommended for routine use in non–small cell lung cancer patients with stage IIA, IIB, or IIIA disease who have undergone complete surgical resections, according to updated guidelines from the American Society of Clinical Oncology.
In patients with stage IA disease, the guidelines recommend against cisplatin-based chemotherapy. The new guidelines are based on a systematic review current to January 2016 and an American Society for Radiation Oncology guideline and systematic review, which ASCO had already endorsed, which formed the basis for recommendations on adjuvant radiation therapy, Mark G. Kris, MD, and panel authors said (J Clin Oncol. 2017 April 26. doi: 10.1200/JCO.2017.72.4401).
The guidelines, available online, also recommend against routine cisplatin-based chemotherapy in patients with stage IB disease, but they suggest an evaluation of these patients to explore the pros and cons of adjuvant chemotherapy.
With respect to radiation, the authors recommend against it for patients with resected stage I or stage II disease, and they recommend against it for routine use in patients with stage IIIA. However, in patients with IIIA N2 disease, patients should be evaluated postoperatively, in consultation with a medical oncologist, for the potential risks and benefits of adjuvant radiation.
The authors also provide some recommendations for communicating with patients regarding treatment decisions. There are few studies examining this question, so the recommendations are based on low-quality evidence.
Non–small cell lung cancer patients may have complex social, psychological, and medical issues, and discussions should be carried out with this in mind. Pain, impaired breathing, and fatigue are common after surgery, and smoking cessation can lead to short-term stress as a result of nicotine withdrawal. Older patients may have a range of comorbidities.
Studies show that patients are most satisfied if they feel that physicians allow them to share in the decision making, and if they are given sufficient time to choose. To that end, the authors recommend a session dedicated to discussion of adjuvant therapy.
Communicating risk of death is challenging for many reasons. Patients should be asked how they would like to hear about their risks: some prefer general terms, while others may opt for numbers, charts, or graphs. The guidelines include a risk chart that can help patients understand the potential benefits and risks of chemotherapy.
The study authors report financial relationships with numerous pharmaceutical companies.
TNFSF13B variant linked to MS and SLE
A variant in the TNFSF13B gene has been linked to susceptibility to both multiple sclerosis and systemic lupus erythematosus, according to a report published online April 26 in the New England Journal of Medicine.
This gene encodes the cytokine B-cell activating factor (BAFF), which is essential for B-cell activation, differentiation, and survival. BAFF is targeted by agents such as belimumab that are used in the treatment of autoimmune disorders, and is primarily produced by monocytes and neutrophils, said Maristella Steri, PhD, of Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche Monserrato (Italy), and her associates.
The researchers have named this TNFSF13B variation “BAFF-var.”
Previous genome-wide association studies have identified more than 110 independent signals for MS and 43 for SLE but have not yet delineated the effector mechanisms for most of these associations. To explore these mechanisms in greater detail, Dr. Steri and her associates studied the population in Sardinia, Italy, which has the highest prevalences of MS and SLE in the world. 
They performed genome-wide association studies and other genetic investigations in case-control sets of 2,934 patients with MS, 411 with SLE, and 3,392 control subjects, analyzing roughly 12.2 million single-nucleotide polymorphisms (SNPs). They ruled out rs1287404 as a likely variant driving the association and identified BAFF-var as the variant most strongly associated with MS (odds ratio, 1.27).
The investigators then replicated their findings in a series of genetic studies in case-control sets from mainland Italy (2,292 patients with MS, 503 with SLE, and 2,563 controls), Sweden (4,548 patients with MS and 3,481 controls), the United Kingdom (3,176 patients with MS and 2,958 controls), and the Iberian peninsula (1,120 patients with SLE and 1,300 controls). BAFF-var was most common across Sardinia, with a frequency of 26.5%, and became progressively less common moving northward (5.7% in Italy, 4.9% in Spain, 1.8% in the United Kingdom and Sweden).
Taken together, “these findings pinpoint BAFF-var as the variant in TNFSF13B that is most strongly associated with MS,” wrote Dr. Steri and her associates (N Engl J Med. 2017 Apr 27. doi: 10.1056/NEJMoa1610528).
BAFF-var also proved to be associated with SLE in case-control sets from Sardinia (OR, 1.38), mainland Italy (OR, 1.49), and the Iberian peninsula (OR, 1.55). This indicates that “the effect of BAFF-var is not restricted to MS alone,” they noted.
Further analyses showed that BAFF-var “dramatically” increased levels of soluble BAFF and circulating B cells, especially CD24+CD27+ cells, as well as total IgG, IgA, IgM, and monocytes. In one notable analysis, preclinical blood samples taken from Sardinians participating in a longitudinal study showed elevated levels of soluble BAFF in people who did not go on to develop MS until years later.
“We infer [from this] that BAFF-var is the causal variant driving an increase in soluble BAFF and a cascade of immune effects leading to increased autoimmunity risk,” Dr. Steri and her associates said.
Further study suggested that positive selection specifically favoring BAFF-var, not random genetic drift, accounted for the high frequency of this mutation in Sardinia and its progressively lower frequency moving northward. The most likely possibility is that BAFF-var was positively selected because it provided resistance to malaria, which was “strikingly prevalent” in Sardinia until it was eradicated in the 1950s. In mouse models, BAFF overexpression confers protection against lethal malaria.
“In addition, as shown here, BAFF-var increases antibody production, and classic findings showed that antibody transfer from adults with immunity to malaria to acutely infected children reduced blood-stage parasitemia and disease severity,” the investigators said.
“The evolutionary scenario we propose is that BAFF-var was selected as an adaptive response to malaria infection, resulting in an increased present-day risk of autoimmunity,” they said.
The Italian Foundation for Multiple Sclerosis, the National Institute on Aging, the Italian Ministry of Economy and Finance, the European Union, the National Human Genome Research Institute, and other organizations supported the study. Dr. Steri reported having no relevant disclosures; some of her associates reported ties to numerous industry sources.
Perhaps the next challenge is the clinical application of the findings from Steri et al. is to determine whether BAFF-var status can be used to stratify patients for a specific therapy.
These data clearly point in that direction, but the discriminatory power of this single variant may not be sufficient for clinical decision making.
In contrast, it does seem reasonable to examine whether stratifying patients according to their BAFF-var status would be useful in clinical trials assessing B-cell–directed therapies.
Thomas Korn, MD, of the Technical University of Munich and the Munich Cluster for Systems Neurology, reported ties to Biogen, Novartis, Merck Serono, and Bayer. Mohamed Oukka, PhD, of the University of Washington, Seattle, and the Center for Immunity and Immunotherapies at Seattle Children’s Research Institute, reported having no relevant disclosures. They made these remarks in an editorial accompanying Dr. Steri’s report (N Engl J Med. 2017 Apr 27. doi: 10.1056/NEJMe1700720).
Perhaps the next challenge is the clinical application of the findings from Steri et al. is to determine whether BAFF-var status can be used to stratify patients for a specific therapy.
These data clearly point in that direction, but the discriminatory power of this single variant may not be sufficient for clinical decision making.
In contrast, it does seem reasonable to examine whether stratifying patients according to their BAFF-var status would be useful in clinical trials assessing B-cell–directed therapies.
Thomas Korn, MD, of the Technical University of Munich and the Munich Cluster for Systems Neurology, reported ties to Biogen, Novartis, Merck Serono, and Bayer. Mohamed Oukka, PhD, of the University of Washington, Seattle, and the Center for Immunity and Immunotherapies at Seattle Children’s Research Institute, reported having no relevant disclosures. They made these remarks in an editorial accompanying Dr. Steri’s report (N Engl J Med. 2017 Apr 27. doi: 10.1056/NEJMe1700720).
Perhaps the next challenge is the clinical application of the findings from Steri et al. is to determine whether BAFF-var status can be used to stratify patients for a specific therapy.
These data clearly point in that direction, but the discriminatory power of this single variant may not be sufficient for clinical decision making.
In contrast, it does seem reasonable to examine whether stratifying patients according to their BAFF-var status would be useful in clinical trials assessing B-cell–directed therapies.
Thomas Korn, MD, of the Technical University of Munich and the Munich Cluster for Systems Neurology, reported ties to Biogen, Novartis, Merck Serono, and Bayer. Mohamed Oukka, PhD, of the University of Washington, Seattle, and the Center for Immunity and Immunotherapies at Seattle Children’s Research Institute, reported having no relevant disclosures. They made these remarks in an editorial accompanying Dr. Steri’s report (N Engl J Med. 2017 Apr 27. doi: 10.1056/NEJMe1700720).
A variant in the TNFSF13B gene has been linked to susceptibility to both multiple sclerosis and systemic lupus erythematosus, according to a report published online April 26 in the New England Journal of Medicine.
This gene encodes the cytokine B-cell activating factor (BAFF), which is essential for B-cell activation, differentiation, and survival. BAFF is targeted by agents such as belimumab that are used in the treatment of autoimmune disorders, and is primarily produced by monocytes and neutrophils, said Maristella Steri, PhD, of Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche Monserrato (Italy), and her associates.
The researchers have named this TNFSF13B variation “BAFF-var.”
Previous genome-wide association studies have identified more than 110 independent signals for MS and 43 for SLE but have not yet delineated the effector mechanisms for most of these associations. To explore these mechanisms in greater detail, Dr. Steri and her associates studied the population in Sardinia, Italy, which has the highest prevalences of MS and SLE in the world.
They performed genome-wide association studies and other genetic investigations in case-control sets of 2,934 patients with MS, 411 with SLE, and 3,392 control subjects, analyzing roughly 12.2 million single-nucleotide polymorphisms (SNPs). They ruled out rs1287404 as a likely variant driving the association and identified BAFF-var as the variant most strongly associated with MS (odds ratio, 1.27).
The investigators then replicated their findings in a series of genetic studies in case-control sets from mainland Italy (2,292 patients with MS, 503 with SLE, and 2,563 controls), Sweden (4,548 patients with MS and 3,481 controls), the United Kingdom (3,176 patients with MS and 2,958 controls), and the Iberian peninsula (1,120 patients with SLE and 1,300 controls). BAFF-var was most common across Sardinia, with a frequency of 26.5%, and became progressively less common moving northward (5.7% in Italy, 4.9% in Spain, 1.8% in the United Kingdom and Sweden).
Taken together, “these findings pinpoint BAFF-var as the variant in TNFSF13B that is most strongly associated with MS,” wrote Dr. Steri and her associates (N Engl J Med. 2017 Apr 27. doi: 10.1056/NEJMoa1610528).
BAFF-var also proved to be associated with SLE in case-control sets from Sardinia (OR, 1.38), mainland Italy (OR, 1.49), and the Iberian peninsula (OR, 1.55). This indicates that “the effect of BAFF-var is not restricted to MS alone,” they noted.
Further analyses showed that BAFF-var “dramatically” increased levels of soluble BAFF and circulating B cells, especially CD24+CD27+ cells, as well as total IgG, IgA, IgM, and monocytes. In one notable analysis, preclinical blood samples taken from Sardinians participating in a longitudinal study showed elevated levels of soluble BAFF in people who did not go on to develop MS until years later.
“We infer [from this] that BAFF-var is the causal variant driving an increase in soluble BAFF and a cascade of immune effects leading to increased autoimmunity risk,” Dr. Steri and her associates said.
Further study suggested that positive selection specifically favoring BAFF-var, not random genetic drift, accounted for the high frequency of this mutation in Sardinia and its progressively lower frequency moving northward. The most likely possibility is that BAFF-var was positively selected because it provided resistance to malaria, which was “strikingly prevalent” in Sardinia until it was eradicated in the 1950s. In mouse models, BAFF overexpression confers protection against lethal malaria.
“In addition, as shown here, BAFF-var increases antibody production, and classic findings showed that antibody transfer from adults with immunity to malaria to acutely infected children reduced blood-stage parasitemia and disease severity,” the investigators said.
“The evolutionary scenario we propose is that BAFF-var was selected as an adaptive response to malaria infection, resulting in an increased present-day risk of autoimmunity,” they said.
The Italian Foundation for Multiple Sclerosis, the National Institute on Aging, the Italian Ministry of Economy and Finance, the European Union, the National Human Genome Research Institute, and other organizations supported the study. Dr. Steri reported having no relevant disclosures; some of her associates reported ties to numerous industry sources.
A variant in the TNFSF13B gene has been linked to susceptibility to both multiple sclerosis and systemic lupus erythematosus, according to a report published online April 26 in the New England Journal of Medicine.
This gene encodes the cytokine B-cell activating factor (BAFF), which is essential for B-cell activation, differentiation, and survival. BAFF is targeted by agents such as belimumab that are used in the treatment of autoimmune disorders, and is primarily produced by monocytes and neutrophils, said Maristella Steri, PhD, of Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche Monserrato (Italy), and her associates.
The researchers have named this TNFSF13B variation “BAFF-var.”
Previous genome-wide association studies have identified more than 110 independent signals for MS and 43 for SLE but have not yet delineated the effector mechanisms for most of these associations. To explore these mechanisms in greater detail, Dr. Steri and her associates studied the population in Sardinia, Italy, which has the highest prevalences of MS and SLE in the world.
They performed genome-wide association studies and other genetic investigations in case-control sets of 2,934 patients with MS, 411 with SLE, and 3,392 control subjects, analyzing roughly 12.2 million single-nucleotide polymorphisms (SNPs). They ruled out rs1287404 as a likely variant driving the association and identified BAFF-var as the variant most strongly associated with MS (odds ratio, 1.27).
The investigators then replicated their findings in a series of genetic studies in case-control sets from mainland Italy (2,292 patients with MS, 503 with SLE, and 2,563 controls), Sweden (4,548 patients with MS and 3,481 controls), the United Kingdom (3,176 patients with MS and 2,958 controls), and the Iberian peninsula (1,120 patients with SLE and 1,300 controls). BAFF-var was most common across Sardinia, with a frequency of 26.5%, and became progressively less common moving northward (5.7% in Italy, 4.9% in Spain, 1.8% in the United Kingdom and Sweden).
Taken together, “these findings pinpoint BAFF-var as the variant in TNFSF13B that is most strongly associated with MS,” wrote Dr. Steri and her associates (N Engl J Med. 2017 Apr 27. doi: 10.1056/NEJMoa1610528).
BAFF-var also proved to be associated with SLE in case-control sets from Sardinia (OR, 1.38), mainland Italy (OR, 1.49), and the Iberian peninsula (OR, 1.55). This indicates that “the effect of BAFF-var is not restricted to MS alone,” they noted.
Further analyses showed that BAFF-var “dramatically” increased levels of soluble BAFF and circulating B cells, especially CD24+CD27+ cells, as well as total IgG, IgA, IgM, and monocytes. In one notable analysis, preclinical blood samples taken from Sardinians participating in a longitudinal study showed elevated levels of soluble BAFF in people who did not go on to develop MS until years later.
“We infer [from this] that BAFF-var is the causal variant driving an increase in soluble BAFF and a cascade of immune effects leading to increased autoimmunity risk,” Dr. Steri and her associates said.
Further study suggested that positive selection specifically favoring BAFF-var, not random genetic drift, accounted for the high frequency of this mutation in Sardinia and its progressively lower frequency moving northward. The most likely possibility is that BAFF-var was positively selected because it provided resistance to malaria, which was “strikingly prevalent” in Sardinia until it was eradicated in the 1950s. In mouse models, BAFF overexpression confers protection against lethal malaria.
“In addition, as shown here, BAFF-var increases antibody production, and classic findings showed that antibody transfer from adults with immunity to malaria to acutely infected children reduced blood-stage parasitemia and disease severity,” the investigators said.
“The evolutionary scenario we propose is that BAFF-var was selected as an adaptive response to malaria infection, resulting in an increased present-day risk of autoimmunity,” they said.
The Italian Foundation for Multiple Sclerosis, the National Institute on Aging, the Italian Ministry of Economy and Finance, the European Union, the National Human Genome Research Institute, and other organizations supported the study. Dr. Steri reported having no relevant disclosures; some of her associates reported ties to numerous industry sources.
Key clinical point: A variant in the TNFSF13B gene has been linked to susceptibility to both multiple sclerosis and systemic lupus erythematosus.
Major finding: BAFF-var was the TNFSF13B variant most strongly associated with MS in Sardinia (OR, 1.27), and was also associated with SLE in Sardinia (OR, 1.38), mainland Italy (OR, 1.49), and the Iberian peninsula (OR, 1.55).
Data source: A series of genome-wide association studies and other genetic studies involving thousands of patients with MS or SLE in Sardinia and confirmed in thousands of patients across Italy, Spain, Sweden, and the United Kingdom.
Disclosures: The Italian Foundation for Multiple Sclerosis, the National Institute on Aging, the Italian Ministry of Economy and Finance, the European Union, the National Human Genome Research Institute, and other organizations supported the study. Dr. Steri reported having no relevant disclosures; some of her associates reported ties to numerous industry sources.