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A toll-like receptor 9 (TLR9) antagonist may eventually be used to combat brain edema in acute liver failure, according to investigators.

This prediction is based on results of a recent study involving mouse models, which showed that ODN2088, a TLR9 antagonist, could stop ammonia-induced colocalization of DNA with TLR9 in innate immune cells, thereby blocking cytokine production and ensuant brain edema, reported lead author Godhev Kumar Manakkat Vijay of King’s College London and colleagues.

“Ammonia plays a pivotal role in the development of hepatic encephalopathy and brain edema in acute liver failure,” the investigators explained in Cellular and Molecular Gastroenterology and Hepatology. “A robust systemic inflammatory response and susceptibility to developing infection are common in acute liver failure, exacerbate the development of ammonia-induced brain edema and are major prognosticators. Experimental models have unequivocally associated ammonia exposure with astrocyte swelling and brain edema, potentiated by proinflammatory cytokines.”

The investigators added that, “although the evidence base supporting the relationship between ammonia, inflammation, and brain edema is robust in acute liver failure, there is a paucity of data characterizing the specific pathogenic mechanisms entailed.” Previous research suggested that TLR9 plays a key role in acetaminophen-induced liver inflammation, they noted, and that ammonia, in combination with DNA, triggers TLR9 expression in neutrophils, which brought TLR9 into focus for the present study.

Along with wild-type mice, the investigators relied upon two knockout models: TLR9–/– mice, in which TLR9 is entirely absent, and LysM-Cre TLR9fl/fl mice, in which TLR9 is absent from lysozyme-expressing cells (predominantly neutrophils and macrophages). Comparing against controls, the investigators assessed cytokine production and brain edema in each type of mouse when intraperitoneally injected with ammonium acetate (4 mmol/kg). Specifically, 6 hours after injection, they measured intracellular cytokines in splenic macrophages, CD8+ T cells, and CD4+ T cells. In addition, they recorded total plasma DNA and brain water, a measure of brain edema.

Following ammonium acetate injection, wild-type mice developed brain edema and liver enlargement, while TLR9–/– mice and control-injected mice did not. After injection, total plasma DNA levels rose by comparable magnitudes in both wild-type mice and TLR9–/– mice, but did not change in control-injected mice, suggesting that ammonium-acetate injection was causing a release of DNA, which was binding with TLR9, resulting in activation of the innate immune system.

This hypothesis was supported by measurements of cytokines in T cells and splenic macrophages, which showed that wild-type mice had elevations of cytokines, whereas knockout mice did not. Further experiments showed that LysM-Cre TLR9fl/fl mice had similar outcomes as TLR9–/– mice, highlighting that macrophages and neutrophils are the key immune cells linking TLR9 activation with cytokine release, and therefore brain edema.

To ensure that brain edema was not directly caused by the acetate component of ammonium acetate, or acetate’s potential to increase pH, a different set of wild-type mice were injected with sodium acetate adjusted to the same pH as ammonium acetate. This had no impact on cytokine production, brain-water content, or liver-to-body weight ratio, confirming that acetate was not responsible for brain edema while providing further support for the role of TLR9.

Finally, the investigators treated wild-type mice immediately after ammonium acetate injection with the TLR9 antagonist ODN2088 (50 mcg/mouse). This treatment halted cytokine production, inflammation, and brain edema, strongly supporting the link between these ammonia-induced processes and TLR9 activation.

“These data are well supported by the findings of Imaeda et al. (J Clin Invest. 2009 Feb 2. doi: 10.1172/JCI35958), who in an acetaminophen-induced hepatotoxicity model established that inhibition of TLR9 using ODN2088 and IRS954, a TLR7/9 antagonist, down-regulated proinflammatory cytokine release and reduced mortality,” the investigators wrote. “The amelioration of brain edema and cytokine production by ODN2088 supports exploration of TLR9 antagonism as a therapeutic modality in early acute liver failure to prevent the development of brain edema and intracranial hypertension.”

The study was funded by the U.K. Institute of Liver Studies Charitable Fund and the National Institutes of Health. The investigators reported no conflicts of interest.

SOURCE: Vijay GKM et al. Cell Mol Gastroenterol Hepatol. 2019 Aug 8. doi: 10.1016/j.jcmgh.2019.08.002.

A toll-like receptor 9 (TLR9) antagonist may eventually be used to combat brain edema in acute liver failure, according to investigators.

This prediction is based on results of a recent study involving mouse models, which showed that ODN2088, a TLR9 antagonist, could stop ammonia-induced colocalization of DNA with TLR9 in innate immune cells, thereby blocking cytokine production and ensuant brain edema, reported lead author Godhev Kumar Manakkat Vijay of King’s College London and colleagues.

“Ammonia plays a pivotal role in the development of hepatic encephalopathy and brain edema in acute liver failure,” the investigators explained in Cellular and Molecular Gastroenterology and Hepatology. “A robust systemic inflammatory response and susceptibility to developing infection are common in acute liver failure, exacerbate the development of ammonia-induced brain edema and are major prognosticators. Experimental models have unequivocally associated ammonia exposure with astrocyte swelling and brain edema, potentiated by proinflammatory cytokines.”

The investigators added that, “although the evidence base supporting the relationship between ammonia, inflammation, and brain edema is robust in acute liver failure, there is a paucity of data characterizing the specific pathogenic mechanisms entailed.” Previous research suggested that TLR9 plays a key role in acetaminophen-induced liver inflammation, they noted, and that ammonia, in combination with DNA, triggers TLR9 expression in neutrophils, which brought TLR9 into focus for the present study.

Along with wild-type mice, the investigators relied upon two knockout models: TLR9–/– mice, in which TLR9 is entirely absent, and LysM-Cre TLR9fl/fl mice, in which TLR9 is absent from lysozyme-expressing cells (predominantly neutrophils and macrophages). Comparing against controls, the investigators assessed cytokine production and brain edema in each type of mouse when intraperitoneally injected with ammonium acetate (4 mmol/kg). Specifically, 6 hours after injection, they measured intracellular cytokines in splenic macrophages, CD8+ T cells, and CD4+ T cells. In addition, they recorded total plasma DNA and brain water, a measure of brain edema.

Following ammonium acetate injection, wild-type mice developed brain edema and liver enlargement, while TLR9–/– mice and control-injected mice did not. After injection, total plasma DNA levels rose by comparable magnitudes in both wild-type mice and TLR9–/– mice, but did not change in control-injected mice, suggesting that ammonium-acetate injection was causing a release of DNA, which was binding with TLR9, resulting in activation of the innate immune system.

This hypothesis was supported by measurements of cytokines in T cells and splenic macrophages, which showed that wild-type mice had elevations of cytokines, whereas knockout mice did not. Further experiments showed that LysM-Cre TLR9fl/fl mice had similar outcomes as TLR9–/– mice, highlighting that macrophages and neutrophils are the key immune cells linking TLR9 activation with cytokine release, and therefore brain edema.

To ensure that brain edema was not directly caused by the acetate component of ammonium acetate, or acetate’s potential to increase pH, a different set of wild-type mice were injected with sodium acetate adjusted to the same pH as ammonium acetate. This had no impact on cytokine production, brain-water content, or liver-to-body weight ratio, confirming that acetate was not responsible for brain edema while providing further support for the role of TLR9.

Finally, the investigators treated wild-type mice immediately after ammonium acetate injection with the TLR9 antagonist ODN2088 (50 mcg/mouse). This treatment halted cytokine production, inflammation, and brain edema, strongly supporting the link between these ammonia-induced processes and TLR9 activation.

“These data are well supported by the findings of Imaeda et al. (J Clin Invest. 2009 Feb 2. doi: 10.1172/JCI35958), who in an acetaminophen-induced hepatotoxicity model established that inhibition of TLR9 using ODN2088 and IRS954, a TLR7/9 antagonist, down-regulated proinflammatory cytokine release and reduced mortality,” the investigators wrote. “The amelioration of brain edema and cytokine production by ODN2088 supports exploration of TLR9 antagonism as a therapeutic modality in early acute liver failure to prevent the development of brain edema and intracranial hypertension.”

The study was funded by the U.K. Institute of Liver Studies Charitable Fund and the National Institutes of Health. The investigators reported no conflicts of interest.

SOURCE: Vijay GKM et al. Cell Mol Gastroenterol Hepatol. 2019 Aug 8. doi: 10.1016/j.jcmgh.2019.08.002.

A toll-like receptor 9 (TLR9) antagonist may eventually be used to combat brain edema in acute liver failure, according to investigators.

This prediction is based on results of a recent study involving mouse models, which showed that ODN2088, a TLR9 antagonist, could stop ammonia-induced colocalization of DNA with TLR9 in innate immune cells, thereby blocking cytokine production and ensuant brain edema, reported lead author Godhev Kumar Manakkat Vijay of King’s College London and colleagues.

“Ammonia plays a pivotal role in the development of hepatic encephalopathy and brain edema in acute liver failure,” the investigators explained in Cellular and Molecular Gastroenterology and Hepatology. “A robust systemic inflammatory response and susceptibility to developing infection are common in acute liver failure, exacerbate the development of ammonia-induced brain edema and are major prognosticators. Experimental models have unequivocally associated ammonia exposure with astrocyte swelling and brain edema, potentiated by proinflammatory cytokines.”

The investigators added that, “although the evidence base supporting the relationship between ammonia, inflammation, and brain edema is robust in acute liver failure, there is a paucity of data characterizing the specific pathogenic mechanisms entailed.” Previous research suggested that TLR9 plays a key role in acetaminophen-induced liver inflammation, they noted, and that ammonia, in combination with DNA, triggers TLR9 expression in neutrophils, which brought TLR9 into focus for the present study.

Along with wild-type mice, the investigators relied upon two knockout models: TLR9–/– mice, in which TLR9 is entirely absent, and LysM-Cre TLR9fl/fl mice, in which TLR9 is absent from lysozyme-expressing cells (predominantly neutrophils and macrophages). Comparing against controls, the investigators assessed cytokine production and brain edema in each type of mouse when intraperitoneally injected with ammonium acetate (4 mmol/kg). Specifically, 6 hours after injection, they measured intracellular cytokines in splenic macrophages, CD8+ T cells, and CD4+ T cells. In addition, they recorded total plasma DNA and brain water, a measure of brain edema.

Following ammonium acetate injection, wild-type mice developed brain edema and liver enlargement, while TLR9–/– mice and control-injected mice did not. After injection, total plasma DNA levels rose by comparable magnitudes in both wild-type mice and TLR9–/– mice, but did not change in control-injected mice, suggesting that ammonium-acetate injection was causing a release of DNA, which was binding with TLR9, resulting in activation of the innate immune system.

This hypothesis was supported by measurements of cytokines in T cells and splenic macrophages, which showed that wild-type mice had elevations of cytokines, whereas knockout mice did not. Further experiments showed that LysM-Cre TLR9fl/fl mice had similar outcomes as TLR9–/– mice, highlighting that macrophages and neutrophils are the key immune cells linking TLR9 activation with cytokine release, and therefore brain edema.

To ensure that brain edema was not directly caused by the acetate component of ammonium acetate, or acetate’s potential to increase pH, a different set of wild-type mice were injected with sodium acetate adjusted to the same pH as ammonium acetate. This had no impact on cytokine production, brain-water content, or liver-to-body weight ratio, confirming that acetate was not responsible for brain edema while providing further support for the role of TLR9.

Finally, the investigators treated wild-type mice immediately after ammonium acetate injection with the TLR9 antagonist ODN2088 (50 mcg/mouse). This treatment halted cytokine production, inflammation, and brain edema, strongly supporting the link between these ammonia-induced processes and TLR9 activation.

“These data are well supported by the findings of Imaeda et al. (J Clin Invest. 2009 Feb 2. doi: 10.1172/JCI35958), who in an acetaminophen-induced hepatotoxicity model established that inhibition of TLR9 using ODN2088 and IRS954, a TLR7/9 antagonist, down-regulated proinflammatory cytokine release and reduced mortality,” the investigators wrote. “The amelioration of brain edema and cytokine production by ODN2088 supports exploration of TLR9 antagonism as a therapeutic modality in early acute liver failure to prevent the development of brain edema and intracranial hypertension.”

The study was funded by the U.K. Institute of Liver Studies Charitable Fund and the National Institutes of Health. The investigators reported no conflicts of interest.

SOURCE: Vijay GKM et al. Cell Mol Gastroenterol Hepatol. 2019 Aug 8. doi: 10.1016/j.jcmgh.2019.08.002.

For patients with epidermal growth factor receptor–mutated non–small cell lung cancer (NSCLC), adding the vascular endothelial growth factor receptor 2 (VEGFR-2) inhibitor ramucirumab to standard erlotinib therapy may extend progression-free survival, based on results from the phase 3 RELAY trial.

Considering the acceptable safety profile, this dual regimen should be considered for first-line treatment of epidermal growth factor receptor (EGFR)–mutated disease, according to lead author Kazuhiko Nakagawa, MD, PhD, of the Kindai University faculty of medicine in Osaka, Japan, and colleagues.

Dual blockade of the EGFR and VEGF pathways is supported by previous studies which pointed to efficacy among EGFR-mutated subgroups, the investigators explained in Lancet Oncology, noting that ramucirumab appeared to be the best candidate for VEGF pathway inhibition. “Ramucirumab, a human monoclonal IgG1 antibody, selectively targets VEGFR-2, thereby blocking signaling mediated by VEGF-A, VEGF-C, and VEGF-D in NSCLC,” the investigators wrote. “Therefore, ramucirumab has the potential for broader antitumor activity than inhibitors of VEGF-A.”

The trial involved 449 patients with stage IV NSCLC and an EGFR exon 21 substitution or exon 19 deletion. Patients were randomized in a 1:1 ratio to receive either erlotinib (150 mg/day) plus placebo, or erlotinib plus ramucirumab (10 mg/kg every 2 weeks). The primary endpoint was progression-free survival. Secondary endpoints included safety and toxicity, overall survival, and various measures of response.

After a median follow-up of 20.7 months, the addition of ramucirumab was associated with a significantly better median progression-free survival, at 19.4 months, compared with 12.4 months among patients who received erlotinib alone, which translates to a hazard ratio of 0.59 (P less than .0001). In each cohort, 1% of patients achieved a complete response. Partial responses were also highly similar at 75% for ramucirumab versus 74% for placebo.

Turning to safety, ramucirumab was associated with more safety concerns, including a higher rate of grade 3-4 treatment-emergent adverse events (72% vs. 54%), most often hypertension. Serious adverse events were also more frequent with ramucirumab at a rate of 29%, compared with 21% among those who received erlotinib alone.

Despite these differences, the investigators concluded that the dual regimen still offers acceptable tolerability. “Safety was consistent with the established safety profiles of the individual compounds and a metastatic NSCLC population,” they wrote. “The RELAY regimen is therefore a viable new treatment option for the initial treatment of patients with metastatic EGFR-mutated NSCLC.”

The RELAY trial was funded by Eli Lilly. The investigators reported additional relationships with AstraZeneca, Bristol-Myers Squibb, Novartis, and others.

SOURCE: Nakagawa K et al. Lancet Oncol. 2019 Oct 4. doi: 10.1016/S1470-2045(19)30634-5.

For patients with epidermal growth factor receptor–mutated non–small cell lung cancer (NSCLC), adding the vascular endothelial growth factor receptor 2 (VEGFR-2) inhibitor ramucirumab to standard erlotinib therapy may extend progression-free survival, based on results from the phase 3 RELAY trial.

Considering the acceptable safety profile, this dual regimen should be considered for first-line treatment of epidermal growth factor receptor (EGFR)–mutated disease, according to lead author Kazuhiko Nakagawa, MD, PhD, of the Kindai University faculty of medicine in Osaka, Japan, and colleagues.

Dual blockade of the EGFR and VEGF pathways is supported by previous studies which pointed to efficacy among EGFR-mutated subgroups, the investigators explained in Lancet Oncology, noting that ramucirumab appeared to be the best candidate for VEGF pathway inhibition. “Ramucirumab, a human monoclonal IgG1 antibody, selectively targets VEGFR-2, thereby blocking signaling mediated by VEGF-A, VEGF-C, and VEGF-D in NSCLC,” the investigators wrote. “Therefore, ramucirumab has the potential for broader antitumor activity than inhibitors of VEGF-A.”

The trial involved 449 patients with stage IV NSCLC and an EGFR exon 21 substitution or exon 19 deletion. Patients were randomized in a 1:1 ratio to receive either erlotinib (150 mg/day) plus placebo, or erlotinib plus ramucirumab (10 mg/kg every 2 weeks). The primary endpoint was progression-free survival. Secondary endpoints included safety and toxicity, overall survival, and various measures of response.

After a median follow-up of 20.7 months, the addition of ramucirumab was associated with a significantly better median progression-free survival, at 19.4 months, compared with 12.4 months among patients who received erlotinib alone, which translates to a hazard ratio of 0.59 (P less than .0001). In each cohort, 1% of patients achieved a complete response. Partial responses were also highly similar at 75% for ramucirumab versus 74% for placebo.

Turning to safety, ramucirumab was associated with more safety concerns, including a higher rate of grade 3-4 treatment-emergent adverse events (72% vs. 54%), most often hypertension. Serious adverse events were also more frequent with ramucirumab at a rate of 29%, compared with 21% among those who received erlotinib alone.

Despite these differences, the investigators concluded that the dual regimen still offers acceptable tolerability. “Safety was consistent with the established safety profiles of the individual compounds and a metastatic NSCLC population,” they wrote. “The RELAY regimen is therefore a viable new treatment option for the initial treatment of patients with metastatic EGFR-mutated NSCLC.”

The RELAY trial was funded by Eli Lilly. The investigators reported additional relationships with AstraZeneca, Bristol-Myers Squibb, Novartis, and others.

SOURCE: Nakagawa K et al. Lancet Oncol. 2019 Oct 4. doi: 10.1016/S1470-2045(19)30634-5.

For patients with epidermal growth factor receptor–mutated non–small cell lung cancer (NSCLC), adding the vascular endothelial growth factor receptor 2 (VEGFR-2) inhibitor ramucirumab to standard erlotinib therapy may extend progression-free survival, based on results from the phase 3 RELAY trial.

Considering the acceptable safety profile, this dual regimen should be considered for first-line treatment of epidermal growth factor receptor (EGFR)–mutated disease, according to lead author Kazuhiko Nakagawa, MD, PhD, of the Kindai University faculty of medicine in Osaka, Japan, and colleagues.

Dual blockade of the EGFR and VEGF pathways is supported by previous studies which pointed to efficacy among EGFR-mutated subgroups, the investigators explained in Lancet Oncology, noting that ramucirumab appeared to be the best candidate for VEGF pathway inhibition. “Ramucirumab, a human monoclonal IgG1 antibody, selectively targets VEGFR-2, thereby blocking signaling mediated by VEGF-A, VEGF-C, and VEGF-D in NSCLC,” the investigators wrote. “Therefore, ramucirumab has the potential for broader antitumor activity than inhibitors of VEGF-A.”

The trial involved 449 patients with stage IV NSCLC and an EGFR exon 21 substitution or exon 19 deletion. Patients were randomized in a 1:1 ratio to receive either erlotinib (150 mg/day) plus placebo, or erlotinib plus ramucirumab (10 mg/kg every 2 weeks). The primary endpoint was progression-free survival. Secondary endpoints included safety and toxicity, overall survival, and various measures of response.

After a median follow-up of 20.7 months, the addition of ramucirumab was associated with a significantly better median progression-free survival, at 19.4 months, compared with 12.4 months among patients who received erlotinib alone, which translates to a hazard ratio of 0.59 (P less than .0001). In each cohort, 1% of patients achieved a complete response. Partial responses were also highly similar at 75% for ramucirumab versus 74% for placebo.

Turning to safety, ramucirumab was associated with more safety concerns, including a higher rate of grade 3-4 treatment-emergent adverse events (72% vs. 54%), most often hypertension. Serious adverse events were also more frequent with ramucirumab at a rate of 29%, compared with 21% among those who received erlotinib alone.

Despite these differences, the investigators concluded that the dual regimen still offers acceptable tolerability. “Safety was consistent with the established safety profiles of the individual compounds and a metastatic NSCLC population,” they wrote. “The RELAY regimen is therefore a viable new treatment option for the initial treatment of patients with metastatic EGFR-mutated NSCLC.”

The RELAY trial was funded by Eli Lilly. The investigators reported additional relationships with AstraZeneca, Bristol-Myers Squibb, Novartis, and others.

SOURCE: Nakagawa K et al. Lancet Oncol. 2019 Oct 4. doi: 10.1016/S1470-2045(19)30634-5.

A new point-of-care assay designed with machine learning offers improved accuracy for rapid identification of active tuberculosis (TB) infection, according to investigators.

Martynasfoto/ThinkStock

The blood-based triage test, which relies upon four host proteins and one TB antigen, is another step closer toward diagnostic accuracy standards proposed by the World Health Organization, reported lead author Rushdy Ahmad, PhD, of the Broad Institute of MIT and Harvard in Cambridge, Mass., and colleagues. When fully developed, such a test could improve interventions for the most vulnerable patients, such as those with HIV, among whom TB often goes undiagnosed.

“Rapid and accurate diagnosis of active TB with current sputum-based diagnostic tools remains challenging in high-burden, resource-limited settings,” the investigators wrote. Their report is in Science Translational Medicine.

They went on to explain the gap that currently exists between microscopy, which is operator dependent and insensitive, and newer technologies, such as nucleic acid amplification, which are more sensitive but heavily resource dependent. “Furthermore, two of the most vulnerable and highly affected groups – young children and adults with HIV infection – are unlikely to be diagnosed using sputum because of difficulty obtaining sputum and low bacillary loads in the sample.”

To look for a more practical option, the investigators drew blood from 406 patients with chronic cough. Then, using a bead-based immunoassay with machine learning, the investigators identified four blood proteins associated with active TB infection: interleukin-6 (IL-6), IL-8, IL-18, and vascular endothelial growth factor (VEGF). Blind validation of 317 samples from patients with chronic cough in Asia, Africa, and South America showed that the four biomarkers offered a sensitivity of 80% and a specificity of 65%. By adding a fifth biomarker, an antibody against TB antigen Ag85B, the investigators were able to raise accuracy figures to 86% sensitivity and 69% specificity.

Adding even more biomarkers could theoretically raise accuracy even further, according to the investigators. The WHO minimal performance thresholds are 90% sensitivity and 70% specificity, with optimal targets slightly higher, at 95% sensitivity and 80% specificity. Although these standards have not yet been met, the investigators plan on testing the existing assay in real-world scenarios while simultaneously aiming to make it better.

“A near-term goal is ... to incrementally improve the marker panel up to an anticipated 6- to 10-plex assay,” the investigators wrote. “However, given the urgency of the problem, the possibility of incremental improvements will not delay platform refinement and field testing.”

The Bill and Melinda Gates Foundation funded the study. The investigators reported additional relationships with Quanterix Corporation and FIND.

SOURCE: Ahmad et al. Sci Transl Med. 2019 Oct 23. doi: 10.1126/scitranslmed.aaw8287.

A new point-of-care assay designed with machine learning offers improved accuracy for rapid identification of active tuberculosis (TB) infection, according to investigators.

Martynasfoto/ThinkStock

The blood-based triage test, which relies upon four host proteins and one TB antigen, is another step closer toward diagnostic accuracy standards proposed by the World Health Organization, reported lead author Rushdy Ahmad, PhD, of the Broad Institute of MIT and Harvard in Cambridge, Mass., and colleagues. When fully developed, such a test could improve interventions for the most vulnerable patients, such as those with HIV, among whom TB often goes undiagnosed.

“Rapid and accurate diagnosis of active TB with current sputum-based diagnostic tools remains challenging in high-burden, resource-limited settings,” the investigators wrote. Their report is in Science Translational Medicine.

They went on to explain the gap that currently exists between microscopy, which is operator dependent and insensitive, and newer technologies, such as nucleic acid amplification, which are more sensitive but heavily resource dependent. “Furthermore, two of the most vulnerable and highly affected groups – young children and adults with HIV infection – are unlikely to be diagnosed using sputum because of difficulty obtaining sputum and low bacillary loads in the sample.”

To look for a more practical option, the investigators drew blood from 406 patients with chronic cough. Then, using a bead-based immunoassay with machine learning, the investigators identified four blood proteins associated with active TB infection: interleukin-6 (IL-6), IL-8, IL-18, and vascular endothelial growth factor (VEGF). Blind validation of 317 samples from patients with chronic cough in Asia, Africa, and South America showed that the four biomarkers offered a sensitivity of 80% and a specificity of 65%. By adding a fifth biomarker, an antibody against TB antigen Ag85B, the investigators were able to raise accuracy figures to 86% sensitivity and 69% specificity.

Adding even more biomarkers could theoretically raise accuracy even further, according to the investigators. The WHO minimal performance thresholds are 90% sensitivity and 70% specificity, with optimal targets slightly higher, at 95% sensitivity and 80% specificity. Although these standards have not yet been met, the investigators plan on testing the existing assay in real-world scenarios while simultaneously aiming to make it better.

“A near-term goal is ... to incrementally improve the marker panel up to an anticipated 6- to 10-plex assay,” the investigators wrote. “However, given the urgency of the problem, the possibility of incremental improvements will not delay platform refinement and field testing.”

The Bill and Melinda Gates Foundation funded the study. The investigators reported additional relationships with Quanterix Corporation and FIND.

SOURCE: Ahmad et al. Sci Transl Med. 2019 Oct 23. doi: 10.1126/scitranslmed.aaw8287.

A new point-of-care assay designed with machine learning offers improved accuracy for rapid identification of active tuberculosis (TB) infection, according to investigators.

Martynasfoto/ThinkStock

The blood-based triage test, which relies upon four host proteins and one TB antigen, is another step closer toward diagnostic accuracy standards proposed by the World Health Organization, reported lead author Rushdy Ahmad, PhD, of the Broad Institute of MIT and Harvard in Cambridge, Mass., and colleagues. When fully developed, such a test could improve interventions for the most vulnerable patients, such as those with HIV, among whom TB often goes undiagnosed.

“Rapid and accurate diagnosis of active TB with current sputum-based diagnostic tools remains challenging in high-burden, resource-limited settings,” the investigators wrote. Their report is in Science Translational Medicine.

They went on to explain the gap that currently exists between microscopy, which is operator dependent and insensitive, and newer technologies, such as nucleic acid amplification, which are more sensitive but heavily resource dependent. “Furthermore, two of the most vulnerable and highly affected groups – young children and adults with HIV infection – are unlikely to be diagnosed using sputum because of difficulty obtaining sputum and low bacillary loads in the sample.”

To look for a more practical option, the investigators drew blood from 406 patients with chronic cough. Then, using a bead-based immunoassay with machine learning, the investigators identified four blood proteins associated with active TB infection: interleukin-6 (IL-6), IL-8, IL-18, and vascular endothelial growth factor (VEGF). Blind validation of 317 samples from patients with chronic cough in Asia, Africa, and South America showed that the four biomarkers offered a sensitivity of 80% and a specificity of 65%. By adding a fifth biomarker, an antibody against TB antigen Ag85B, the investigators were able to raise accuracy figures to 86% sensitivity and 69% specificity.

Adding even more biomarkers could theoretically raise accuracy even further, according to the investigators. The WHO minimal performance thresholds are 90% sensitivity and 70% specificity, with optimal targets slightly higher, at 95% sensitivity and 80% specificity. Although these standards have not yet been met, the investigators plan on testing the existing assay in real-world scenarios while simultaneously aiming to make it better.

“A near-term goal is ... to incrementally improve the marker panel up to an anticipated 6- to 10-plex assay,” the investigators wrote. “However, given the urgency of the problem, the possibility of incremental improvements will not delay platform refinement and field testing.”

The Bill and Melinda Gates Foundation funded the study. The investigators reported additional relationships with Quanterix Corporation and FIND.

SOURCE: Ahmad et al. Sci Transl Med. 2019 Oct 23. doi: 10.1126/scitranslmed.aaw8287.

Among patients with human epidermal growth factor receptor 2–positive (HER2+) breast cancer, adding trastuzumab to adjuvant chemotherapy reduces risk of recurrence for at least 10 years, according to investigators.

The benefit of trastuzumab was greater among patients with hormone receptor–positive (HR+) disease than those with HR– disease until the 5-year timepoint, after which HR status had no significant impact on recurrence rates, reported lead author Saranya Chumsri, MD, of the Mayo Clinic in Jacksonville, Fla., and colleagues. This finding echoes a pattern similar to that of HER2– breast cancer, in which patients with HR+ disease have relatively consistent risk of recurrence over time, whereas patients with HR– disease have an early risk of recurrence that decreases after 5 years.

“To the best of our knowledge, this analysis is the first to address the risk of late relapses in subsets of HER2+ breast cancer patients who were treated with adjuvant trastuzumab,” the investigators wrote. Their report is in Journal of Clinical Oncology.

They drew data from 3,177 patients with HER2+ breast cancer who were involved in two phase 3 studies: the North Central Cancer Treatment Group N9831 and National Surgical Adjuvant Breast and Bowel Project B-31 trials. Patients involved in the analysis received either standard adjuvant chemotherapy with cyclophosphamide and doxorubicin followed by weekly paclitaxel or the same chemotherapy regimen plus concurrent trastuzumab. The primary outcome was recurrence-free survival, which was defined as time from randomization until local, regional, or distant recurrence of breast cancer or breast cancer–related death. Kaplan-Meier estimates were performed to determine recurrence-free survival, while Cox proportional hazards regression models were used to determine factors that predicted relapse.

Including a median follow-up of 8 years across all patients, the analysis showed that those with HR+ breast cancer had a significantly higher estimated rate of recurrence-free survival than that of those with HR– disease after 5 years (81.49% vs. 74.65%) and 10 years (73.84% vs. 69.22%). Overall, a comparable level of benefit was derived from adding trastuzumab regardless of HR status (interaction P = .87). However, during the first 5 years, HR positivity predicted greater benefit from adding trastuzumab, as patients with HR+ disease had a 40% lower risk of relapse than that of those with HR– disease (hazard ratio, 0.60; P less than .001). Between years 5 and 10, the statistical significance of HR status faded (P = .12), suggesting that HR status is not a predictor of long-term recurrence.

“Given concerning adverse effects and potentially smaller benefit of extended adjuvant endocrine therapy, particularly in patients with N0 or N1 disease, our findings highlight the need to develop better risk prediction models and biomarkers to identify which patients have sufficient risk for late relapse to warrant the use of extended endocrine therapy in HER2+ breast cancer,” the investigators concluded.

The study was funded by the National Institutes of Health, the Breast Cancer Research Foundation, Bankhead-Coley Research Program, the DONNA Foundation, and Genentech. Dr. Chumsri disclosed a financial relationship with Merck. Coauthors disclosed ties with Merck, Novartis, Genentech, and NanoString Technologies.

SOURCE: Chumsri et al. J Clin Oncol. 2019 Oct 17. doi: 10.1200/JCO.19.00443.

Among patients with human epidermal growth factor receptor 2–positive (HER2+) breast cancer, adding trastuzumab to adjuvant chemotherapy reduces risk of recurrence for at least 10 years, according to investigators.

The benefit of trastuzumab was greater among patients with hormone receptor–positive (HR+) disease than those with HR– disease until the 5-year timepoint, after which HR status had no significant impact on recurrence rates, reported lead author Saranya Chumsri, MD, of the Mayo Clinic in Jacksonville, Fla., and colleagues. This finding echoes a pattern similar to that of HER2– breast cancer, in which patients with HR+ disease have relatively consistent risk of recurrence over time, whereas patients with HR– disease have an early risk of recurrence that decreases after 5 years.

“To the best of our knowledge, this analysis is the first to address the risk of late relapses in subsets of HER2+ breast cancer patients who were treated with adjuvant trastuzumab,” the investigators wrote. Their report is in Journal of Clinical Oncology.

They drew data from 3,177 patients with HER2+ breast cancer who were involved in two phase 3 studies: the North Central Cancer Treatment Group N9831 and National Surgical Adjuvant Breast and Bowel Project B-31 trials. Patients involved in the analysis received either standard adjuvant chemotherapy with cyclophosphamide and doxorubicin followed by weekly paclitaxel or the same chemotherapy regimen plus concurrent trastuzumab. The primary outcome was recurrence-free survival, which was defined as time from randomization until local, regional, or distant recurrence of breast cancer or breast cancer–related death. Kaplan-Meier estimates were performed to determine recurrence-free survival, while Cox proportional hazards regression models were used to determine factors that predicted relapse.

Including a median follow-up of 8 years across all patients, the analysis showed that those with HR+ breast cancer had a significantly higher estimated rate of recurrence-free survival than that of those with HR– disease after 5 years (81.49% vs. 74.65%) and 10 years (73.84% vs. 69.22%). Overall, a comparable level of benefit was derived from adding trastuzumab regardless of HR status (interaction P = .87). However, during the first 5 years, HR positivity predicted greater benefit from adding trastuzumab, as patients with HR+ disease had a 40% lower risk of relapse than that of those with HR– disease (hazard ratio, 0.60; P less than .001). Between years 5 and 10, the statistical significance of HR status faded (P = .12), suggesting that HR status is not a predictor of long-term recurrence.

“Given concerning adverse effects and potentially smaller benefit of extended adjuvant endocrine therapy, particularly in patients with N0 or N1 disease, our findings highlight the need to develop better risk prediction models and biomarkers to identify which patients have sufficient risk for late relapse to warrant the use of extended endocrine therapy in HER2+ breast cancer,” the investigators concluded.

The study was funded by the National Institutes of Health, the Breast Cancer Research Foundation, Bankhead-Coley Research Program, the DONNA Foundation, and Genentech. Dr. Chumsri disclosed a financial relationship with Merck. Coauthors disclosed ties with Merck, Novartis, Genentech, and NanoString Technologies.

SOURCE: Chumsri et al. J Clin Oncol. 2019 Oct 17. doi: 10.1200/JCO.19.00443.

Among patients with human epidermal growth factor receptor 2–positive (HER2+) breast cancer, adding trastuzumab to adjuvant chemotherapy reduces risk of recurrence for at least 10 years, according to investigators.

The benefit of trastuzumab was greater among patients with hormone receptor–positive (HR+) disease than those with HR– disease until the 5-year timepoint, after which HR status had no significant impact on recurrence rates, reported lead author Saranya Chumsri, MD, of the Mayo Clinic in Jacksonville, Fla., and colleagues. This finding echoes a pattern similar to that of HER2– breast cancer, in which patients with HR+ disease have relatively consistent risk of recurrence over time, whereas patients with HR– disease have an early risk of recurrence that decreases after 5 years.

“To the best of our knowledge, this analysis is the first to address the risk of late relapses in subsets of HER2+ breast cancer patients who were treated with adjuvant trastuzumab,” the investigators wrote. Their report is in Journal of Clinical Oncology.

They drew data from 3,177 patients with HER2+ breast cancer who were involved in two phase 3 studies: the North Central Cancer Treatment Group N9831 and National Surgical Adjuvant Breast and Bowel Project B-31 trials. Patients involved in the analysis received either standard adjuvant chemotherapy with cyclophosphamide and doxorubicin followed by weekly paclitaxel or the same chemotherapy regimen plus concurrent trastuzumab. The primary outcome was recurrence-free survival, which was defined as time from randomization until local, regional, or distant recurrence of breast cancer or breast cancer–related death. Kaplan-Meier estimates were performed to determine recurrence-free survival, while Cox proportional hazards regression models were used to determine factors that predicted relapse.

Including a median follow-up of 8 years across all patients, the analysis showed that those with HR+ breast cancer had a significantly higher estimated rate of recurrence-free survival than that of those with HR– disease after 5 years (81.49% vs. 74.65%) and 10 years (73.84% vs. 69.22%). Overall, a comparable level of benefit was derived from adding trastuzumab regardless of HR status (interaction P = .87). However, during the first 5 years, HR positivity predicted greater benefit from adding trastuzumab, as patients with HR+ disease had a 40% lower risk of relapse than that of those with HR– disease (hazard ratio, 0.60; P less than .001). Between years 5 and 10, the statistical significance of HR status faded (P = .12), suggesting that HR status is not a predictor of long-term recurrence.

“Given concerning adverse effects and potentially smaller benefit of extended adjuvant endocrine therapy, particularly in patients with N0 or N1 disease, our findings highlight the need to develop better risk prediction models and biomarkers to identify which patients have sufficient risk for late relapse to warrant the use of extended endocrine therapy in HER2+ breast cancer,” the investigators concluded.

The study was funded by the National Institutes of Health, the Breast Cancer Research Foundation, Bankhead-Coley Research Program, the DONNA Foundation, and Genentech. Dr. Chumsri disclosed a financial relationship with Merck. Coauthors disclosed ties with Merck, Novartis, Genentech, and NanoString Technologies.

SOURCE: Chumsri et al. J Clin Oncol. 2019 Oct 17. doi: 10.1200/JCO.19.00443.

A new draft guideline for the diagnosis and management of thrombocytopenic purpura (TTP) was recently released by the International Society on Thrombosis and Hemostasis (ISTH).

Svisio/Thinkstock

According to the panel of experts involved, the ISTH guideline takes into account the latest TTP findings, offering a more up-to-date resource for clinicians than the two previously published guidelines in 2012 from the British Committee for Standards in Haematology and in 2017 from the TTP group of Japan’s Blood Coagulation Abnormalities Research Team.

“Since the publication of these guidelines, there have been significant developments in the diagnosis and treatment of TTP, and an increase in published data on how management strategies affect objective health outcomes,” the panel members wrote in the guideline, which is available at ISTH.org.

Despite these advancements, TTP remains a challenging condition for both clinicians and patients for a variety of reasons, the panel noted, which was led by clinical cochair X. Long Zheng, MD, PhD, of the University of Alabama in Birmingham and method cochair Sara K. Vesely, PhD, of the University of Oklahoma, Oklahoma City.

The ISTH guideline provides recommendations for adult patients with either immune or hereditary TTP, from acute events through remission, including diagnostic steps to determine if a case of thrombotic microangiopathy is in fact TTP.

Nearly all the recommendations are based on very-low-certainty evidence. Some of the key treatment recommendations include the following:

• For patients with immune TTP experiencing a first acute event, add corticosteroids to therapeutic plasma exchange (TPE), rather than treating with TPE alone. This is a strong recommendation.
• For patients with immune TTP experiencing a first acute event, add rituximab to corticosteroids and TPE, rather than corticosteroids and TPE alone. This is a conditional recommendation.
• For patients with immune TTP experiencing a relapse, add corticosteroids to TPE, rather than TPE alone. This is a strong recommendation.
• For patients with immune TTP experiencing a relapse, add rituximab to corticosteroids and TPE, rather than steroids and TPE alone. This is a conditional recommendation.
• For patients with immune TTP experiencing an acute event – either a first event or a relapse – use caplacizumab. This is a conditional recommendation based on moderate-certainty evidence.
• For patients with immune TTP who are in remission and have low plasma ADAMTS13 activity but no other symptoms of TMA, use rituximab for prophylaxis. This is a conditional recommendation.
• For patients with hereditary TTP who are in remission, plasma infusion or a watch-and-wait strategy is recommended. This is a conditional recommendation.
• For patients with hereditary TTP who are in remission, do not use factor VIII concentrate infusions. A watch-and-wait strategy is advised. This is a conditional recommendation.
• For patients with immune TTP who are pregnant and have decreased plasma ADAMTS13 activity but no symptoms of TMA, use prophylactic treatment. This is a strong recommendation.
• For patients with hereditary TTP who are pregnant, use prophylactic treatment. This is a strong recommendation. The panel further recommended treatment with plasma infusion rather than factor VIII products, which was a conditional recommendation.

The multidisciplinary expert panel included hematologists and pathologists with expertise in TTP, neurologists, nephrologists, intensive care specialists, and patient representatives. The panel followed the GRADE approach and the Population, Intervention, Comparison, Outcome (PICO) framework, and adhered to standards set forth by the Health and Medicine Division (HMD) of the National Academies of Sciences, Engineering, and Medicine and the GIN-McMaster Guideline Development Checklist.

Even with an experienced group of physicians and a structured plan, however, the creation of guidelines for rare diseases like TTP presents a unique set of obstacles, according to the panel members. Challenges include a small body of relevant evidence that is often inconsistent and lacking in high certainty and studies that do not address outcomes important to patients. These shortcomings can make it difficult for guideline developers to issue strong recommendations.

“However, well-developed clinical practice guidelines are vital in rare diseases; these conditions are, by their nature, encountered very infrequently by individual clinicians, who may feel unprepared to address their diagnosis and treatment,” the panelists wrote. “Well-synthesized evidence and clear recommendations play an important role in supporting clinical decision making. Systematically created guidelines can also highlight areas where evidence is uncertain, clinical judgement is required, and future research in the area is warranted.”

The guideline was supported by ISTH. Fifty percent of the panel members had no or minimal conflict of interest; those with conflicts of interest abstained from voting on recommendations relevant to their conflicts.

A new draft guideline for the diagnosis and management of thrombocytopenic purpura (TTP) was recently released by the International Society on Thrombosis and Hemostasis (ISTH).

Svisio/Thinkstock

According to the panel of experts involved, the ISTH guideline takes into account the latest TTP findings, offering a more up-to-date resource for clinicians than the two previously published guidelines in 2012 from the British Committee for Standards in Haematology and in 2017 from the TTP group of Japan’s Blood Coagulation Abnormalities Research Team.

“Since the publication of these guidelines, there have been significant developments in the diagnosis and treatment of TTP, and an increase in published data on how management strategies affect objective health outcomes,” the panel members wrote in the guideline, which is available at ISTH.org.

Despite these advancements, TTP remains a challenging condition for both clinicians and patients for a variety of reasons, the panel noted, which was led by clinical cochair X. Long Zheng, MD, PhD, of the University of Alabama in Birmingham and method cochair Sara K. Vesely, PhD, of the University of Oklahoma, Oklahoma City.

The ISTH guideline provides recommendations for adult patients with either immune or hereditary TTP, from acute events through remission, including diagnostic steps to determine if a case of thrombotic microangiopathy is in fact TTP.

Nearly all the recommendations are based on very-low-certainty evidence. Some of the key treatment recommendations include the following:

• For patients with immune TTP experiencing a first acute event, add corticosteroids to therapeutic plasma exchange (TPE), rather than treating with TPE alone. This is a strong recommendation.
• For patients with immune TTP experiencing a first acute event, add rituximab to corticosteroids and TPE, rather than corticosteroids and TPE alone. This is a conditional recommendation.
• For patients with immune TTP experiencing a relapse, add corticosteroids to TPE, rather than TPE alone. This is a strong recommendation.
• For patients with immune TTP experiencing a relapse, add rituximab to corticosteroids and TPE, rather than steroids and TPE alone. This is a conditional recommendation.
• For patients with immune TTP experiencing an acute event – either a first event or a relapse – use caplacizumab. This is a conditional recommendation based on moderate-certainty evidence.
• For patients with immune TTP who are in remission and have low plasma ADAMTS13 activity but no other symptoms of TMA, use rituximab for prophylaxis. This is a conditional recommendation.
• For patients with hereditary TTP who are in remission, plasma infusion or a watch-and-wait strategy is recommended. This is a conditional recommendation.
• For patients with hereditary TTP who are in remission, do not use factor VIII concentrate infusions. A watch-and-wait strategy is advised. This is a conditional recommendation.
• For patients with immune TTP who are pregnant and have decreased plasma ADAMTS13 activity but no symptoms of TMA, use prophylactic treatment. This is a strong recommendation.
• For patients with hereditary TTP who are pregnant, use prophylactic treatment. This is a strong recommendation. The panel further recommended treatment with plasma infusion rather than factor VIII products, which was a conditional recommendation.

The multidisciplinary expert panel included hematologists and pathologists with expertise in TTP, neurologists, nephrologists, intensive care specialists, and patient representatives. The panel followed the GRADE approach and the Population, Intervention, Comparison, Outcome (PICO) framework, and adhered to standards set forth by the Health and Medicine Division (HMD) of the National Academies of Sciences, Engineering, and Medicine and the GIN-McMaster Guideline Development Checklist.

Even with an experienced group of physicians and a structured plan, however, the creation of guidelines for rare diseases like TTP presents a unique set of obstacles, according to the panel members. Challenges include a small body of relevant evidence that is often inconsistent and lacking in high certainty and studies that do not address outcomes important to patients. These shortcomings can make it difficult for guideline developers to issue strong recommendations.

“However, well-developed clinical practice guidelines are vital in rare diseases; these conditions are, by their nature, encountered very infrequently by individual clinicians, who may feel unprepared to address their diagnosis and treatment,” the panelists wrote. “Well-synthesized evidence and clear recommendations play an important role in supporting clinical decision making. Systematically created guidelines can also highlight areas where evidence is uncertain, clinical judgement is required, and future research in the area is warranted.”

The guideline was supported by ISTH. Fifty percent of the panel members had no or minimal conflict of interest; those with conflicts of interest abstained from voting on recommendations relevant to their conflicts.

A new draft guideline for the diagnosis and management of thrombocytopenic purpura (TTP) was recently released by the International Society on Thrombosis and Hemostasis (ISTH).

Svisio/Thinkstock

According to the panel of experts involved, the ISTH guideline takes into account the latest TTP findings, offering a more up-to-date resource for clinicians than the two previously published guidelines in 2012 from the British Committee for Standards in Haematology and in 2017 from the TTP group of Japan’s Blood Coagulation Abnormalities Research Team.

“Since the publication of these guidelines, there have been significant developments in the diagnosis and treatment of TTP, and an increase in published data on how management strategies affect objective health outcomes,” the panel members wrote in the guideline, which is available at ISTH.org.

Despite these advancements, TTP remains a challenging condition for both clinicians and patients for a variety of reasons, the panel noted, which was led by clinical cochair X. Long Zheng, MD, PhD, of the University of Alabama in Birmingham and method cochair Sara K. Vesely, PhD, of the University of Oklahoma, Oklahoma City.

The ISTH guideline provides recommendations for adult patients with either immune or hereditary TTP, from acute events through remission, including diagnostic steps to determine if a case of thrombotic microangiopathy is in fact TTP.

Nearly all the recommendations are based on very-low-certainty evidence. Some of the key treatment recommendations include the following:

• For patients with immune TTP experiencing a first acute event, add corticosteroids to therapeutic plasma exchange (TPE), rather than treating with TPE alone. This is a strong recommendation.
• For patients with immune TTP experiencing a first acute event, add rituximab to corticosteroids and TPE, rather than corticosteroids and TPE alone. This is a conditional recommendation.
• For patients with immune TTP experiencing a relapse, add corticosteroids to TPE, rather than TPE alone. This is a strong recommendation.
• For patients with immune TTP experiencing a relapse, add rituximab to corticosteroids and TPE, rather than steroids and TPE alone. This is a conditional recommendation.
• For patients with immune TTP experiencing an acute event – either a first event or a relapse – use caplacizumab. This is a conditional recommendation based on moderate-certainty evidence.
• For patients with immune TTP who are in remission and have low plasma ADAMTS13 activity but no other symptoms of TMA, use rituximab for prophylaxis. This is a conditional recommendation.
• For patients with hereditary TTP who are in remission, plasma infusion or a watch-and-wait strategy is recommended. This is a conditional recommendation.
• For patients with hereditary TTP who are in remission, do not use factor VIII concentrate infusions. A watch-and-wait strategy is advised. This is a conditional recommendation.
• For patients with immune TTP who are pregnant and have decreased plasma ADAMTS13 activity but no symptoms of TMA, use prophylactic treatment. This is a strong recommendation.
• For patients with hereditary TTP who are pregnant, use prophylactic treatment. This is a strong recommendation. The panel further recommended treatment with plasma infusion rather than factor VIII products, which was a conditional recommendation.

The multidisciplinary expert panel included hematologists and pathologists with expertise in TTP, neurologists, nephrologists, intensive care specialists, and patient representatives. The panel followed the GRADE approach and the Population, Intervention, Comparison, Outcome (PICO) framework, and adhered to standards set forth by the Health and Medicine Division (HMD) of the National Academies of Sciences, Engineering, and Medicine and the GIN-McMaster Guideline Development Checklist.

Even with an experienced group of physicians and a structured plan, however, the creation of guidelines for rare diseases like TTP presents a unique set of obstacles, according to the panel members. Challenges include a small body of relevant evidence that is often inconsistent and lacking in high certainty and studies that do not address outcomes important to patients. These shortcomings can make it difficult for guideline developers to issue strong recommendations.

“However, well-developed clinical practice guidelines are vital in rare diseases; these conditions are, by their nature, encountered very infrequently by individual clinicians, who may feel unprepared to address their diagnosis and treatment,” the panelists wrote. “Well-synthesized evidence and clear recommendations play an important role in supporting clinical decision making. Systematically created guidelines can also highlight areas where evidence is uncertain, clinical judgement is required, and future research in the area is warranted.”

The guideline was supported by ISTH. Fifty percent of the panel members had no or minimal conflict of interest; those with conflicts of interest abstained from voting on recommendations relevant to their conflicts.

Nearly two-thirds of countries worldwide have an insufficient supply of blood for transfusion, according to findings from a recent modeling study including 195 countries and territories.

Tomasz Gierygowski/Thinkstock

Low- and middle-income countries are most often affected, reported lead author Nicholas Roberts of the University of Washington in Seattle and colleagues. Among all countries in Oceania, south Asia, and eastern, central, and western sub-Saharan Africa, not one had enough blood to meet estimated needs, they noted.

Shortages are attributable to a variety of challenges, including resource constraints, insufficient component production, and a high prevalence of infectious diseases, according to investigators. And existing guidelines, which call for 10-20 donations per 1,000 people in the population, may need to be revised, investigators suggested.

“These estimates are important, as they can be used to guide further investments in blood transfusion services, for analysis of current transfusion practices, and to highlight need for alternatives to transfusions such as antifibrinolytics, blood saving devices, and implementation of blood management systems,” the investigators wrote in Lancet Haematology.

Blood availability was calculated using the 2016 WHO Global Status Report on Blood Safety and Availability, in which 92% of countries participated. Blood needs were calculated using multiple databases, including the (U.S.) National Inpatient Sample datasets from 2000-2014, the State Inpatient Databases from 2003-2007, and the Global Burden of Disease 2017 study.

The global blood need was almost 305 million blood product units, while the supply totaled approximately 272 million units. These shortages, however, were not distributed equally across the globe. Out of 195 countries, 119 (61%) had an insufficient supply of blood to meet anticipated demand. Within this group, the shortage equated to about 102 million blood product units.

Denmark had the greatest supply of blood products (red blood cell products, platelets, and plasma), at 14,704 units per 100,000 population, compared with South Sudan, the least prepared to meet transfusion needs, with just 46 blood product units available per 100,000 population. This pattern was echoed across the globe; high-income countries were usually better stocked than those with low or middle income.

To meet demands, some of the most affected countries would need to raise their collection goals from single-digit figures to as high as 40 donations per 1,000 population, the investigators advised.

“Many countries face critical undersupply of transfusions, which will become more pronounced as access to care improves,” the investigators wrote.

The study was funded by the National Institutes of Health. The investigators reported having no other financial disclosures.

SOURCE: Roberts N et al. Lancet Haematol. 2019 Oct 17. doi: 10.1016/ S2352-3026(19)30200-5.

Nearly two-thirds of countries worldwide have an insufficient supply of blood for transfusion, according to findings from a recent modeling study including 195 countries and territories.

Tomasz Gierygowski/Thinkstock

Low- and middle-income countries are most often affected, reported lead author Nicholas Roberts of the University of Washington in Seattle and colleagues. Among all countries in Oceania, south Asia, and eastern, central, and western sub-Saharan Africa, not one had enough blood to meet estimated needs, they noted.

Shortages are attributable to a variety of challenges, including resource constraints, insufficient component production, and a high prevalence of infectious diseases, according to investigators. And existing guidelines, which call for 10-20 donations per 1,000 people in the population, may need to be revised, investigators suggested.

“These estimates are important, as they can be used to guide further investments in blood transfusion services, for analysis of current transfusion practices, and to highlight need for alternatives to transfusions such as antifibrinolytics, blood saving devices, and implementation of blood management systems,” the investigators wrote in Lancet Haematology.

Blood availability was calculated using the 2016 WHO Global Status Report on Blood Safety and Availability, in which 92% of countries participated. Blood needs were calculated using multiple databases, including the (U.S.) National Inpatient Sample datasets from 2000-2014, the State Inpatient Databases from 2003-2007, and the Global Burden of Disease 2017 study.

The global blood need was almost 305 million blood product units, while the supply totaled approximately 272 million units. These shortages, however, were not distributed equally across the globe. Out of 195 countries, 119 (61%) had an insufficient supply of blood to meet anticipated demand. Within this group, the shortage equated to about 102 million blood product units.

Denmark had the greatest supply of blood products (red blood cell products, platelets, and plasma), at 14,704 units per 100,000 population, compared with South Sudan, the least prepared to meet transfusion needs, with just 46 blood product units available per 100,000 population. This pattern was echoed across the globe; high-income countries were usually better stocked than those with low or middle income.

To meet demands, some of the most affected countries would need to raise their collection goals from single-digit figures to as high as 40 donations per 1,000 population, the investigators advised.

“Many countries face critical undersupply of transfusions, which will become more pronounced as access to care improves,” the investigators wrote.

The study was funded by the National Institutes of Health. The investigators reported having no other financial disclosures.

SOURCE: Roberts N et al. Lancet Haematol. 2019 Oct 17. doi: 10.1016/ S2352-3026(19)30200-5.

Nearly two-thirds of countries worldwide have an insufficient supply of blood for transfusion, according to findings from a recent modeling study including 195 countries and territories.

Tomasz Gierygowski/Thinkstock

Low- and middle-income countries are most often affected, reported lead author Nicholas Roberts of the University of Washington in Seattle and colleagues. Among all countries in Oceania, south Asia, and eastern, central, and western sub-Saharan Africa, not one had enough blood to meet estimated needs, they noted.

Shortages are attributable to a variety of challenges, including resource constraints, insufficient component production, and a high prevalence of infectious diseases, according to investigators. And existing guidelines, which call for 10-20 donations per 1,000 people in the population, may need to be revised, investigators suggested.

“These estimates are important, as they can be used to guide further investments in blood transfusion services, for analysis of current transfusion practices, and to highlight need for alternatives to transfusions such as antifibrinolytics, blood saving devices, and implementation of blood management systems,” the investigators wrote in Lancet Haematology.

Blood availability was calculated using the 2016 WHO Global Status Report on Blood Safety and Availability, in which 92% of countries participated. Blood needs were calculated using multiple databases, including the (U.S.) National Inpatient Sample datasets from 2000-2014, the State Inpatient Databases from 2003-2007, and the Global Burden of Disease 2017 study.

The global blood need was almost 305 million blood product units, while the supply totaled approximately 272 million units. These shortages, however, were not distributed equally across the globe. Out of 195 countries, 119 (61%) had an insufficient supply of blood to meet anticipated demand. Within this group, the shortage equated to about 102 million blood product units.

Denmark had the greatest supply of blood products (red blood cell products, platelets, and plasma), at 14,704 units per 100,000 population, compared with South Sudan, the least prepared to meet transfusion needs, with just 46 blood product units available per 100,000 population. This pattern was echoed across the globe; high-income countries were usually better stocked than those with low or middle income.

To meet demands, some of the most affected countries would need to raise their collection goals from single-digit figures to as high as 40 donations per 1,000 population, the investigators advised.

“Many countries face critical undersupply of transfusions, which will become more pronounced as access to care improves,” the investigators wrote.

The study was funded by the National Institutes of Health. The investigators reported having no other financial disclosures.

SOURCE: Roberts N et al. Lancet Haematol. 2019 Oct 17. doi: 10.1016/ S2352-3026(19)30200-5.

Patients with thrombotic antiphospholipid syndrome (APS) may have a greater risk of recurrent thrombosis when taking rivaroxaban instead of a vitamin K antagonist, suggests a recent trial conducted in Spain.

Stroke was also more common among those taking rivaroxaban, while major bleeding was slightly less common, reported lead author Josep Ordi-Ros, MD, PhD, of Vall d’Hebrón University Hospital Research Institute in Barcelona, and colleagues in Annals of Internal Medicine.

“Two randomized, controlled trials comparing rivaroxaban with warfarin suggested that rivaroxaban may be efficacious in patients with previous venous thromboembolism who are receiving standard-intensity anticoagulation but showed an increased thrombotic risk in those with triple-positive antiphospholipid antibodies,” the investigators wrote. However, they also noted that these findings required a cautious interpretation because of study limitations, such as premature termination caused by an excess of study events and the use of a laboratory surrogate marker as a primary outcome.

To learn more, the investigators performed an open-label, phase 3 trial involving 190 patients with thrombotic APS. Patients were randomized in a 1:1 ratio to receive either rivaroxaban (20 mg per day, or 15 mg per day for patients with a creatinine clearance of 30-49 mL/min per 1.73 m²) or an adjusted dosage of vitamin K antagonists (target international normalized ratio of 2.0-3.0, or 3.1-4.0 for those with a history of recurrent thrombosis).

Patients underwent evaluations every month for the first 3 months and then every 3 months thereafter, each of which involved a variety of laboratory diagnostics such as checks for antinuclear antibodies and lupus anticoagulant, among others. Statistical analyses aimed to determine if rivaroxaban was noninferior to therapy with vitamin K antagonists based on parameters drawn from previous meta-analyses, as no studies had compared the two types of treatment when the present study was designed.

After 3 years of follow-up, almost twice as many patients in the rivaroxaban group had experienced recurrent thrombosis (11.6% vs. 6.3%), although this finding lacked statistical significance for both noninferiority of rivaroxaban (P = .29) and superiority of vitamin K antagonists (P = .20). Still, supporting a similar trend toward differences in efficacy, stroke was more common in the rivaroxaban group, in which nine events occurred, compared with none in the vitamin K antagonist group. In contrast, major bleeding was slightly less common with rivaroxaban than vitamin K antagonists (6.3% vs. 7.4%).

“In conclusion, rivaroxaban did not demonstrate noninferiority to dose-adjusted vitamin K antagonists for secondary thromboprophylaxis in patients with thrombotic APS,” the investigators wrote. “Instead, our results indicate a recurrent thrombotic rate that is nearly double, albeit without statistical significance.”

The study was funded by Bayer Hispania. One coauthor reported additional relationships with Pfizer, Lilly, Janssen, and others.

SOURCE: Ordi-Ros J et al. Ann Intern Med. 2019 Oct 15. doi: 10.7326/M19-0291.

Patients with thrombotic antiphospholipid syndrome (APS) may have a greater risk of recurrent thrombosis when taking rivaroxaban instead of a vitamin K antagonist, suggests a recent trial conducted in Spain.

Stroke was also more common among those taking rivaroxaban, while major bleeding was slightly less common, reported lead author Josep Ordi-Ros, MD, PhD, of Vall d’Hebrón University Hospital Research Institute in Barcelona, and colleagues in Annals of Internal Medicine.

“Two randomized, controlled trials comparing rivaroxaban with warfarin suggested that rivaroxaban may be efficacious in patients with previous venous thromboembolism who are receiving standard-intensity anticoagulation but showed an increased thrombotic risk in those with triple-positive antiphospholipid antibodies,” the investigators wrote. However, they also noted that these findings required a cautious interpretation because of study limitations, such as premature termination caused by an excess of study events and the use of a laboratory surrogate marker as a primary outcome.

To learn more, the investigators performed an open-label, phase 3 trial involving 190 patients with thrombotic APS. Patients were randomized in a 1:1 ratio to receive either rivaroxaban (20 mg per day, or 15 mg per day for patients with a creatinine clearance of 30-49 mL/min per 1.73 m²) or an adjusted dosage of vitamin K antagonists (target international normalized ratio of 2.0-3.0, or 3.1-4.0 for those with a history of recurrent thrombosis).

Patients underwent evaluations every month for the first 3 months and then every 3 months thereafter, each of which involved a variety of laboratory diagnostics such as checks for antinuclear antibodies and lupus anticoagulant, among others. Statistical analyses aimed to determine if rivaroxaban was noninferior to therapy with vitamin K antagonists based on parameters drawn from previous meta-analyses, as no studies had compared the two types of treatment when the present study was designed.

After 3 years of follow-up, almost twice as many patients in the rivaroxaban group had experienced recurrent thrombosis (11.6% vs. 6.3%), although this finding lacked statistical significance for both noninferiority of rivaroxaban (P = .29) and superiority of vitamin K antagonists (P = .20). Still, supporting a similar trend toward differences in efficacy, stroke was more common in the rivaroxaban group, in which nine events occurred, compared with none in the vitamin K antagonist group. In contrast, major bleeding was slightly less common with rivaroxaban than vitamin K antagonists (6.3% vs. 7.4%).

“In conclusion, rivaroxaban did not demonstrate noninferiority to dose-adjusted vitamin K antagonists for secondary thromboprophylaxis in patients with thrombotic APS,” the investigators wrote. “Instead, our results indicate a recurrent thrombotic rate that is nearly double, albeit without statistical significance.”

The study was funded by Bayer Hispania. One coauthor reported additional relationships with Pfizer, Lilly, Janssen, and others.

SOURCE: Ordi-Ros J et al. Ann Intern Med. 2019 Oct 15. doi: 10.7326/M19-0291.

Patients with thrombotic antiphospholipid syndrome (APS) may have a greater risk of recurrent thrombosis when taking rivaroxaban instead of a vitamin K antagonist, suggests a recent trial conducted in Spain.

Stroke was also more common among those taking rivaroxaban, while major bleeding was slightly less common, reported lead author Josep Ordi-Ros, MD, PhD, of Vall d’Hebrón University Hospital Research Institute in Barcelona, and colleagues in Annals of Internal Medicine.

“Two randomized, controlled trials comparing rivaroxaban with warfarin suggested that rivaroxaban may be efficacious in patients with previous venous thromboembolism who are receiving standard-intensity anticoagulation but showed an increased thrombotic risk in those with triple-positive antiphospholipid antibodies,” the investigators wrote. However, they also noted that these findings required a cautious interpretation because of study limitations, such as premature termination caused by an excess of study events and the use of a laboratory surrogate marker as a primary outcome.

To learn more, the investigators performed an open-label, phase 3 trial involving 190 patients with thrombotic APS. Patients were randomized in a 1:1 ratio to receive either rivaroxaban (20 mg per day, or 15 mg per day for patients with a creatinine clearance of 30-49 mL/min per 1.73 m²) or an adjusted dosage of vitamin K antagonists (target international normalized ratio of 2.0-3.0, or 3.1-4.0 for those with a history of recurrent thrombosis).

Patients underwent evaluations every month for the first 3 months and then every 3 months thereafter, each of which involved a variety of laboratory diagnostics such as checks for antinuclear antibodies and lupus anticoagulant, among others. Statistical analyses aimed to determine if rivaroxaban was noninferior to therapy with vitamin K antagonists based on parameters drawn from previous meta-analyses, as no studies had compared the two types of treatment when the present study was designed.

After 3 years of follow-up, almost twice as many patients in the rivaroxaban group had experienced recurrent thrombosis (11.6% vs. 6.3%), although this finding lacked statistical significance for both noninferiority of rivaroxaban (P = .29) and superiority of vitamin K antagonists (P = .20). Still, supporting a similar trend toward differences in efficacy, stroke was more common in the rivaroxaban group, in which nine events occurred, compared with none in the vitamin K antagonist group. In contrast, major bleeding was slightly less common with rivaroxaban than vitamin K antagonists (6.3% vs. 7.4%).

“In conclusion, rivaroxaban did not demonstrate noninferiority to dose-adjusted vitamin K antagonists for secondary thromboprophylaxis in patients with thrombotic APS,” the investigators wrote. “Instead, our results indicate a recurrent thrombotic rate that is nearly double, albeit without statistical significance.”

The study was funded by Bayer Hispania. One coauthor reported additional relationships with Pfizer, Lilly, Janssen, and others.

SOURCE: Ordi-Ros J et al. Ann Intern Med. 2019 Oct 15. doi: 10.7326/M19-0291.

The number of people with hemophilia worldwide is higher than previously estimated, and patients still face a shortened life expectancy, according to an international meta-analysis of registry data.

©designer491/Thinkstock

Approximately 1.125 million people have hemophilia worldwide, compared with the previous estimate of 400,000, reported lead author Alfonso Iorio, MD, PhD, of McMaster University, Hamilton, Ont., and colleagues.

The previous estimate, from the early 2000s, was based on prevalence in the United States and the global population at the time, the investigators explained. Their report is in Annals of Internal Medicine.

They noted a lack of clarity in prior estimates concerning type and severity of hemophilia, and aimed to correct this knowledge gap with the present meta-analysis.

Prevalence was estimated using data from registries in Australia, Canada, Italy, France, the United Kingdom, and New Zealand, which are all high-income countries. Prevalence at birth was estimated using the Canadian, French, and British registries, as these are the most established databases, according to the investigators. The World Federation of Hemophilia Annual Global survey was used to estimate the total global number of patients with hemophilia, while national statistics databases were used to determine the number of males and live male births.

Of the 1.125 million cases of hemophilia worldwide, the investigators estimated that 418,000 are likely severe. Proportionally, 17.1 out of 100,000 males have hemophilia A, with 6.0 out of 100,000 males exhibiting severe hemophilia A. Hemophilia B is less common, occurring in 3.8 out of 100,000 males, with a 1.1 out of 100,000 classified as severe.

Turning to prevalence at birth, the investigators estimated that there are 24.6 cases of hemophilia A per 100,000 male births and 5.0 cases of hemophilia B per 100,000 male births.

The associated life expectancy disadvantage in high-income countries is highest for severe hemophilia A (37%), followed by all severities of hemophilia A (30%), severe hemophilia B (27%), and all severities of hemophilia B (24%).

“Having 1,125,000 persons with hemophilia worldwide, of whom about 418,000 have severe and mostly undiagnosed disease, constitutes a formidable challenge and burden for researchers and health care systems, especially because only 196,706 patients have been identified and reported globally,” the investigators wrote. “More efficient diagnostic approaches are needed in less wealthy countries to take advantage of current and future treatment modalities, including gene therapy. Increased demand for care should drive new policy planning and spur renewed effort toward the development and manufacture of new drugs.”

The updated prevalence figures will serve as a valuable roadmap for the future, according to J. Michael Soucie, PhD, of the Centers for Disease Control and Prevention, Atlanta.

“Although the magnitude of the global gaps in care for persons with hemophilia is daunting, country specific data generated by application of the prevalence estimates reported by Iorio and colleagues are an important step toward prioritizing efforts to address these gaps,” Dr. Soucie wrote in an accompanying editorial. “Having more accurate prevalence data might also allow identification of ways in which regional efforts to improve care access could generate considerable benefits for patients and cost savings for countries. Armed with these data for action, we can hope to make substantial progress toward the goal of improving the lives of persons with hemophilia wherever they live.”

The study received no financial support. The investigators reported relationships with Pfizer, Roche, Novo Nordisk, and others. Dr. Soucie reported having no conflicts of interest.

SOURCE: Iorio A et al. Ann Intern Med. 2019 Sept 10. doi: 10.7326/M19-1208.

The number of people with hemophilia worldwide is higher than previously estimated, and patients still face a shortened life expectancy, according to an international meta-analysis of registry data.

©designer491/Thinkstock

Approximately 1.125 million people have hemophilia worldwide, compared with the previous estimate of 400,000, reported lead author Alfonso Iorio, MD, PhD, of McMaster University, Hamilton, Ont., and colleagues.

The previous estimate, from the early 2000s, was based on prevalence in the United States and the global population at the time, the investigators explained. Their report is in Annals of Internal Medicine.

They noted a lack of clarity in prior estimates concerning type and severity of hemophilia, and aimed to correct this knowledge gap with the present meta-analysis.

Prevalence was estimated using data from registries in Australia, Canada, Italy, France, the United Kingdom, and New Zealand, which are all high-income countries. Prevalence at birth was estimated using the Canadian, French, and British registries, as these are the most established databases, according to the investigators. The World Federation of Hemophilia Annual Global survey was used to estimate the total global number of patients with hemophilia, while national statistics databases were used to determine the number of males and live male births.

Of the 1.125 million cases of hemophilia worldwide, the investigators estimated that 418,000 are likely severe. Proportionally, 17.1 out of 100,000 males have hemophilia A, with 6.0 out of 100,000 males exhibiting severe hemophilia A. Hemophilia B is less common, occurring in 3.8 out of 100,000 males, with a 1.1 out of 100,000 classified as severe.

Turning to prevalence at birth, the investigators estimated that there are 24.6 cases of hemophilia A per 100,000 male births and 5.0 cases of hemophilia B per 100,000 male births.

The associated life expectancy disadvantage in high-income countries is highest for severe hemophilia A (37%), followed by all severities of hemophilia A (30%), severe hemophilia B (27%), and all severities of hemophilia B (24%).

“Having 1,125,000 persons with hemophilia worldwide, of whom about 418,000 have severe and mostly undiagnosed disease, constitutes a formidable challenge and burden for researchers and health care systems, especially because only 196,706 patients have been identified and reported globally,” the investigators wrote. “More efficient diagnostic approaches are needed in less wealthy countries to take advantage of current and future treatment modalities, including gene therapy. Increased demand for care should drive new policy planning and spur renewed effort toward the development and manufacture of new drugs.”

The updated prevalence figures will serve as a valuable roadmap for the future, according to J. Michael Soucie, PhD, of the Centers for Disease Control and Prevention, Atlanta.

“Although the magnitude of the global gaps in care for persons with hemophilia is daunting, country specific data generated by application of the prevalence estimates reported by Iorio and colleagues are an important step toward prioritizing efforts to address these gaps,” Dr. Soucie wrote in an accompanying editorial. “Having more accurate prevalence data might also allow identification of ways in which regional efforts to improve care access could generate considerable benefits for patients and cost savings for countries. Armed with these data for action, we can hope to make substantial progress toward the goal of improving the lives of persons with hemophilia wherever they live.”

The study received no financial support. The investigators reported relationships with Pfizer, Roche, Novo Nordisk, and others. Dr. Soucie reported having no conflicts of interest.

SOURCE: Iorio A et al. Ann Intern Med. 2019 Sept 10. doi: 10.7326/M19-1208.

The number of people with hemophilia worldwide is higher than previously estimated, and patients still face a shortened life expectancy, according to an international meta-analysis of registry data.

©designer491/Thinkstock

Approximately 1.125 million people have hemophilia worldwide, compared with the previous estimate of 400,000, reported lead author Alfonso Iorio, MD, PhD, of McMaster University, Hamilton, Ont., and colleagues.

The previous estimate, from the early 2000s, was based on prevalence in the United States and the global population at the time, the investigators explained. Their report is in Annals of Internal Medicine.

They noted a lack of clarity in prior estimates concerning type and severity of hemophilia, and aimed to correct this knowledge gap with the present meta-analysis.

Prevalence was estimated using data from registries in Australia, Canada, Italy, France, the United Kingdom, and New Zealand, which are all high-income countries. Prevalence at birth was estimated using the Canadian, French, and British registries, as these are the most established databases, according to the investigators. The World Federation of Hemophilia Annual Global survey was used to estimate the total global number of patients with hemophilia, while national statistics databases were used to determine the number of males and live male births.

Of the 1.125 million cases of hemophilia worldwide, the investigators estimated that 418,000 are likely severe. Proportionally, 17.1 out of 100,000 males have hemophilia A, with 6.0 out of 100,000 males exhibiting severe hemophilia A. Hemophilia B is less common, occurring in 3.8 out of 100,000 males, with a 1.1 out of 100,000 classified as severe.

Turning to prevalence at birth, the investigators estimated that there are 24.6 cases of hemophilia A per 100,000 male births and 5.0 cases of hemophilia B per 100,000 male births.

The associated life expectancy disadvantage in high-income countries is highest for severe hemophilia A (37%), followed by all severities of hemophilia A (30%), severe hemophilia B (27%), and all severities of hemophilia B (24%).

“Having 1,125,000 persons with hemophilia worldwide, of whom about 418,000 have severe and mostly undiagnosed disease, constitutes a formidable challenge and burden for researchers and health care systems, especially because only 196,706 patients have been identified and reported globally,” the investigators wrote. “More efficient diagnostic approaches are needed in less wealthy countries to take advantage of current and future treatment modalities, including gene therapy. Increased demand for care should drive new policy planning and spur renewed effort toward the development and manufacture of new drugs.”

The updated prevalence figures will serve as a valuable roadmap for the future, according to J. Michael Soucie, PhD, of the Centers for Disease Control and Prevention, Atlanta.

“Although the magnitude of the global gaps in care for persons with hemophilia is daunting, country specific data generated by application of the prevalence estimates reported by Iorio and colleagues are an important step toward prioritizing efforts to address these gaps,” Dr. Soucie wrote in an accompanying editorial. “Having more accurate prevalence data might also allow identification of ways in which regional efforts to improve care access could generate considerable benefits for patients and cost savings for countries. Armed with these data for action, we can hope to make substantial progress toward the goal of improving the lives of persons with hemophilia wherever they live.”

The study received no financial support. The investigators reported relationships with Pfizer, Roche, Novo Nordisk, and others. Dr. Soucie reported having no conflicts of interest.

SOURCE: Iorio A et al. Ann Intern Med. 2019 Sept 10. doi: 10.7326/M19-1208.

Continuous use of NSAIDs could increase the risk of incident hypertension among patients with ankylosing spondylitis (AS), according to findings from a recent prospective study.

dolgachov/Thinkstock

Against expectations, data also suggested that tumor necrosis factor inhibitor (TNFi) therapy could increase blood pressure, although this finding was not significant across all methods of analysis, reported lead author Jean W. Liew, MD, of the University of Washington, Seattle, and colleagues.

The investigators noted that patients with AS already have a greater risk of cardiovascular disease than that of the general population, making any added risks that much more concerning.

“[T]he evidence for increased cardiovascular disease burden and cardiovascular risk in patients with inflammatory rheumatic diseases is well recognized,” the investigators wrote in Arthritis Care & Research. “Multiple population-based studies have demonstrated increased cardiovascular events and cardiovascular-related mortality in AS. There is a high prevalence of cardiovascular risk factors among individuals with AS, particularly hypertension.”

Exacerbation of this risk by NSAIDs has been previously studied with mixed results, according to the investigators. Meta-analyses have suggested that NSAIDs increase blood pressure in normotensive and hypertensive individuals, but some data point to a cardioprotective effect among those with AS, possibly as a consequence of dampened inflammation, and/or improved physical activity, which could lead to a secondary CV benefit. Still, the relationship between NSAIDs and CV risk was unclear, prompting the current study.

The investigators enrolled 1,282 patients with AS at five centers in the United States and Australia. Using a combination of clinical evaluations and self-reporting, enrollees were monitored at regular intervals. Disease activity was tracked with the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), while the Bath Ankylosing Spondylitis Functional Index (BASFI) was used for functional impairments. Patients were also checked for a variety of comorbidities such as hypertension, coronary artery disease, mental health conditions, and renal disorders. Medication data included type, dosage, frequency, duration, and number of missed doses.

Including only baseline normotensive patients with at least 1 year of follow-up, 628 participants were eligible for analysis, of whom 200 used NSAIDs continuously. After a median of 7 years follow-up, 129 out of 628 patients developed hypertension. This translated to a hazard ratio (HR) for incident hypertension of 1.12 (95% confidence interval, 1.04-1.20), compared with nonusers or those who took NSAIDs intermittently. This relationship did not differ across subgroups defined by age, disease activity, body mass index, or TNFi use. Multiple sensitivity analyses added support to the association between continuous NSAID use and hypertension.

“The association of NSAIDs and incident hypertension remains particularly concerning, as the early development of hypertension may portend a higher risk of premature CV events due to cumulative exposure,” the investigators wrote.

In contrast with NSAIDs, TNFi therapy was not associated with hypertension across all models; however, against expectations, two models of analysis pointed to an 8% increased risk.

“Although TNFi use did not reach statistical significance in the main model, the direction of association was opposite that hypothesized based on prior data, specifically that TNFi use reduces CV risk by suppressing chronic inflammation,” the investigators wrote.

Considering the present findings, and previous studies, which have reported conflicting associations between TNFi use and hypertension, the investigators suggested that more research is needed, and offered specific methods to approach the topic.

“The association of TNFi use and incident hypertension requires further clarification in future studies,” they wrote, “which may be done by applying a marginal structural modeling (MSM) framework and inverse probability of treatment weighting (IPTW) statistical analyses to account for the relationships between TNFi use, disease activity, and NSAID use.”

In their concluding remarks, the investigators further emphasized the current knowledge gap in this area.

“There is an unmet need to clarify how treatment choices, particularly the use of NSAIDs and TNFi, impact CV risk factors and CV events in AS,” they wrote. “Further studies are needed to focus on precision medicine and predicting risk and benefit for patients in whom continuous NSAIDs are being considered. These further studies can inform the revision of guidelines to address the management of CV risk factors and CV disease in AS and axial spondyloarthritis more broadly.”

The investigators reported funding from the National Institutes of Health, the Assessment of Spondyloarthritis International Society, the Spondylitis Association of America, and the Russel Engleman Rheumatology Research Center at the University of California, San Francisco. Some authors reported ties with Eli Lilly, Novartis, and other pharmaceutical companies..

SOURCE: Liew et al. Arthritis Care Res. 2019 Sep 17. doi: 10.1002/acr.24070.

Continuous use of NSAIDs could increase the risk of incident hypertension among patients with ankylosing spondylitis (AS), according to findings from a recent prospective study.

dolgachov/Thinkstock

Against expectations, data also suggested that tumor necrosis factor inhibitor (TNFi) therapy could increase blood pressure, although this finding was not significant across all methods of analysis, reported lead author Jean W. Liew, MD, of the University of Washington, Seattle, and colleagues.

The investigators noted that patients with AS already have a greater risk of cardiovascular disease than that of the general population, making any added risks that much more concerning.

“[T]he evidence for increased cardiovascular disease burden and cardiovascular risk in patients with inflammatory rheumatic diseases is well recognized,” the investigators wrote in Arthritis Care & Research. “Multiple population-based studies have demonstrated increased cardiovascular events and cardiovascular-related mortality in AS. There is a high prevalence of cardiovascular risk factors among individuals with AS, particularly hypertension.”

Exacerbation of this risk by NSAIDs has been previously studied with mixed results, according to the investigators. Meta-analyses have suggested that NSAIDs increase blood pressure in normotensive and hypertensive individuals, but some data point to a cardioprotective effect among those with AS, possibly as a consequence of dampened inflammation, and/or improved physical activity, which could lead to a secondary CV benefit. Still, the relationship between NSAIDs and CV risk was unclear, prompting the current study.

The investigators enrolled 1,282 patients with AS at five centers in the United States and Australia. Using a combination of clinical evaluations and self-reporting, enrollees were monitored at regular intervals. Disease activity was tracked with the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), while the Bath Ankylosing Spondylitis Functional Index (BASFI) was used for functional impairments. Patients were also checked for a variety of comorbidities such as hypertension, coronary artery disease, mental health conditions, and renal disorders. Medication data included type, dosage, frequency, duration, and number of missed doses.

Including only baseline normotensive patients with at least 1 year of follow-up, 628 participants were eligible for analysis, of whom 200 used NSAIDs continuously. After a median of 7 years follow-up, 129 out of 628 patients developed hypertension. This translated to a hazard ratio (HR) for incident hypertension of 1.12 (95% confidence interval, 1.04-1.20), compared with nonusers or those who took NSAIDs intermittently. This relationship did not differ across subgroups defined by age, disease activity, body mass index, or TNFi use. Multiple sensitivity analyses added support to the association between continuous NSAID use and hypertension.

“The association of NSAIDs and incident hypertension remains particularly concerning, as the early development of hypertension may portend a higher risk of premature CV events due to cumulative exposure,” the investigators wrote.

In contrast with NSAIDs, TNFi therapy was not associated with hypertension across all models; however, against expectations, two models of analysis pointed to an 8% increased risk.

“Although TNFi use did not reach statistical significance in the main model, the direction of association was opposite that hypothesized based on prior data, specifically that TNFi use reduces CV risk by suppressing chronic inflammation,” the investigators wrote.

Considering the present findings, and previous studies, which have reported conflicting associations between TNFi use and hypertension, the investigators suggested that more research is needed, and offered specific methods to approach the topic.

“The association of TNFi use and incident hypertension requires further clarification in future studies,” they wrote, “which may be done by applying a marginal structural modeling (MSM) framework and inverse probability of treatment weighting (IPTW) statistical analyses to account for the relationships between TNFi use, disease activity, and NSAID use.”

In their concluding remarks, the investigators further emphasized the current knowledge gap in this area.

“There is an unmet need to clarify how treatment choices, particularly the use of NSAIDs and TNFi, impact CV risk factors and CV events in AS,” they wrote. “Further studies are needed to focus on precision medicine and predicting risk and benefit for patients in whom continuous NSAIDs are being considered. These further studies can inform the revision of guidelines to address the management of CV risk factors and CV disease in AS and axial spondyloarthritis more broadly.”

The investigators reported funding from the National Institutes of Health, the Assessment of Spondyloarthritis International Society, the Spondylitis Association of America, and the Russel Engleman Rheumatology Research Center at the University of California, San Francisco. Some authors reported ties with Eli Lilly, Novartis, and other pharmaceutical companies..

SOURCE: Liew et al. Arthritis Care Res. 2019 Sep 17. doi: 10.1002/acr.24070.

Continuous use of NSAIDs could increase the risk of incident hypertension among patients with ankylosing spondylitis (AS), according to findings from a recent prospective study.

dolgachov/Thinkstock

Against expectations, data also suggested that tumor necrosis factor inhibitor (TNFi) therapy could increase blood pressure, although this finding was not significant across all methods of analysis, reported lead author Jean W. Liew, MD, of the University of Washington, Seattle, and colleagues.

The investigators noted that patients with AS already have a greater risk of cardiovascular disease than that of the general population, making any added risks that much more concerning.

“[T]he evidence for increased cardiovascular disease burden and cardiovascular risk in patients with inflammatory rheumatic diseases is well recognized,” the investigators wrote in Arthritis Care & Research. “Multiple population-based studies have demonstrated increased cardiovascular events and cardiovascular-related mortality in AS. There is a high prevalence of cardiovascular risk factors among individuals with AS, particularly hypertension.”

Exacerbation of this risk by NSAIDs has been previously studied with mixed results, according to the investigators. Meta-analyses have suggested that NSAIDs increase blood pressure in normotensive and hypertensive individuals, but some data point to a cardioprotective effect among those with AS, possibly as a consequence of dampened inflammation, and/or improved physical activity, which could lead to a secondary CV benefit. Still, the relationship between NSAIDs and CV risk was unclear, prompting the current study.

The investigators enrolled 1,282 patients with AS at five centers in the United States and Australia. Using a combination of clinical evaluations and self-reporting, enrollees were monitored at regular intervals. Disease activity was tracked with the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), while the Bath Ankylosing Spondylitis Functional Index (BASFI) was used for functional impairments. Patients were also checked for a variety of comorbidities such as hypertension, coronary artery disease, mental health conditions, and renal disorders. Medication data included type, dosage, frequency, duration, and number of missed doses.

Including only baseline normotensive patients with at least 1 year of follow-up, 628 participants were eligible for analysis, of whom 200 used NSAIDs continuously. After a median of 7 years follow-up, 129 out of 628 patients developed hypertension. This translated to a hazard ratio (HR) for incident hypertension of 1.12 (95% confidence interval, 1.04-1.20), compared with nonusers or those who took NSAIDs intermittently. This relationship did not differ across subgroups defined by age, disease activity, body mass index, or TNFi use. Multiple sensitivity analyses added support to the association between continuous NSAID use and hypertension.

“The association of NSAIDs and incident hypertension remains particularly concerning, as the early development of hypertension may portend a higher risk of premature CV events due to cumulative exposure,” the investigators wrote.

In contrast with NSAIDs, TNFi therapy was not associated with hypertension across all models; however, against expectations, two models of analysis pointed to an 8% increased risk.

“Although TNFi use did not reach statistical significance in the main model, the direction of association was opposite that hypothesized based on prior data, specifically that TNFi use reduces CV risk by suppressing chronic inflammation,” the investigators wrote.

Considering the present findings, and previous studies, which have reported conflicting associations between TNFi use and hypertension, the investigators suggested that more research is needed, and offered specific methods to approach the topic.

“The association of TNFi use and incident hypertension requires further clarification in future studies,” they wrote, “which may be done by applying a marginal structural modeling (MSM) framework and inverse probability of treatment weighting (IPTW) statistical analyses to account for the relationships between TNFi use, disease activity, and NSAID use.”

In their concluding remarks, the investigators further emphasized the current knowledge gap in this area.

“There is an unmet need to clarify how treatment choices, particularly the use of NSAIDs and TNFi, impact CV risk factors and CV events in AS,” they wrote. “Further studies are needed to focus on precision medicine and predicting risk and benefit for patients in whom continuous NSAIDs are being considered. These further studies can inform the revision of guidelines to address the management of CV risk factors and CV disease in AS and axial spondyloarthritis more broadly.”

The investigators reported funding from the National Institutes of Health, the Assessment of Spondyloarthritis International Society, the Spondylitis Association of America, and the Russel Engleman Rheumatology Research Center at the University of California, San Francisco. Some authors reported ties with Eli Lilly, Novartis, and other pharmaceutical companies..

SOURCE: Liew et al. Arthritis Care Res. 2019 Sep 17. doi: 10.1002/acr.24070.

High-risk multigene testing for all patients with breast cancer may be a cost-effective way to reduce rates of breast cancer and ovarian cancer, according to investigators.

A microsimulation modeling study suggested that moving from standard BRCA testing based on clinical criteria or family history to widespread adoption of multigene testing could potentially save more than 2,400 lives per year in the United States, reported lead author Li Sun, MSc, of the London School of Hygiene & Tropical Medicine, and colleagues.

“Moving toward unselected BC testing may give an impetus for prevention in unaffected family members along with clinical implications for the patient with BC. Pathogenic variant carriers with newly diagnosed BC can opt for bilateral mastectomy rather than breast conservation at initial BC surgery,” the investigators wrote in JAMA Oncology. They noted that, presently, only 20%-30% of eligible patients are actually tested. “Testing all patients with breast cancer at diagnosis can increase testing access and uptake and identify many more pathogenic variant carriers for screening and prevention.”

To see if such a broad roll-out would be economically and medically feasible and beneficial, the investigators performed a modeling study involving 11,836 women with breast cancer, with data drawn from four large databases in the United Kingdom, the United States, and Australia.

The model compared annual costs, number of detected cases of breast cancer and ovarian cancer, and related rates of mortality between standard BRCA testing based on clinical criteria or family history versus high-risk multigene testing (BRCA1/BRCA2/PALB2) for all patients with breast cancer.

Resultant incremental cost-effectiveness ratios (ICERs) showed that in both the United Kingdom and the United States, multigene testing would cost, on average, significantly less than minimum willingness-to-pay thresholds of £30,000 per quality-adjusted life-year (QALY) and $100,000/QALY, respectively. In the United Kingdom, the estimated cost of multigene testing was £10,464/QALY from a payer’s perspective and £7,216/QALY from a societal perspective, the latter of which incorporates economic costs beyond the health care system. In the United States, these values rose to $65,661/QALY (payer perspective) and $61,618/QALY (societal perspective). Probabilistic sensitivity analysis suggested that multigene testing would be cost-effective for almost all health system simulations in the United Kingdom (98%-99%) and approximately two-thirds of those in the United States (64%-68%).

Epidemiologically, in the United Kingdom, multigene testing could potentially prevent 2,101 cases of breast cancer and ovarian cancer and 633 deaths per year, while in the United States, 9,733 cases might be prevented, with 2,406 lives saved.

“Our analysis suggests that an unselected testing strategy is extremely cost-effective for U.K. and U.S. health systems and provides a basis for change in current guidelines and policy to implement this strategy,” the investigators said.

The study was funded by the National Cancer Institute, the State of Washington, the Fred Hutchinson Cancer Research Center, and others. The investigators reported additional relationships with AstraZeneca, the Manchester National Institute for Health Research Biomedical Research Centre, Cancer Research UK, an others.

SOURCE: Sun et al. JAMA Oncol. 2019 Oct 3. doi: 10.1001/jamaoncol.2019.3323.

High-risk multigene testing for all patients with breast cancer may be a cost-effective way to reduce rates of breast cancer and ovarian cancer, according to investigators.

A microsimulation modeling study suggested that moving from standard BRCA testing based on clinical criteria or family history to widespread adoption of multigene testing could potentially save more than 2,400 lives per year in the United States, reported lead author Li Sun, MSc, of the London School of Hygiene & Tropical Medicine, and colleagues.

“Moving toward unselected BC testing may give an impetus for prevention in unaffected family members along with clinical implications for the patient with BC. Pathogenic variant carriers with newly diagnosed BC can opt for bilateral mastectomy rather than breast conservation at initial BC surgery,” the investigators wrote in JAMA Oncology. They noted that, presently, only 20%-30% of eligible patients are actually tested. “Testing all patients with breast cancer at diagnosis can increase testing access and uptake and identify many more pathogenic variant carriers for screening and prevention.”

To see if such a broad roll-out would be economically and medically feasible and beneficial, the investigators performed a modeling study involving 11,836 women with breast cancer, with data drawn from four large databases in the United Kingdom, the United States, and Australia.

The model compared annual costs, number of detected cases of breast cancer and ovarian cancer, and related rates of mortality between standard BRCA testing based on clinical criteria or family history versus high-risk multigene testing (BRCA1/BRCA2/PALB2) for all patients with breast cancer.

Resultant incremental cost-effectiveness ratios (ICERs) showed that in both the United Kingdom and the United States, multigene testing would cost, on average, significantly less than minimum willingness-to-pay thresholds of £30,000 per quality-adjusted life-year (QALY) and $100,000/QALY, respectively. In the United Kingdom, the estimated cost of multigene testing was £10,464/QALY from a payer’s perspective and £7,216/QALY from a societal perspective, the latter of which incorporates economic costs beyond the health care system. In the United States, these values rose to $65,661/QALY (payer perspective) and $61,618/QALY (societal perspective). Probabilistic sensitivity analysis suggested that multigene testing would be cost-effective for almost all health system simulations in the United Kingdom (98%-99%) and approximately two-thirds of those in the United States (64%-68%).

Epidemiologically, in the United Kingdom, multigene testing could potentially prevent 2,101 cases of breast cancer and ovarian cancer and 633 deaths per year, while in the United States, 9,733 cases might be prevented, with 2,406 lives saved.

“Our analysis suggests that an unselected testing strategy is extremely cost-effective for U.K. and U.S. health systems and provides a basis for change in current guidelines and policy to implement this strategy,” the investigators said.

The study was funded by the National Cancer Institute, the State of Washington, the Fred Hutchinson Cancer Research Center, and others. The investigators reported additional relationships with AstraZeneca, the Manchester National Institute for Health Research Biomedical Research Centre, Cancer Research UK, an others.

SOURCE: Sun et al. JAMA Oncol. 2019 Oct 3. doi: 10.1001/jamaoncol.2019.3323.

High-risk multigene testing for all patients with breast cancer may be a cost-effective way to reduce rates of breast cancer and ovarian cancer, according to investigators.

A microsimulation modeling study suggested that moving from standard BRCA testing based on clinical criteria or family history to widespread adoption of multigene testing could potentially save more than 2,400 lives per year in the United States, reported lead author Li Sun, MSc, of the London School of Hygiene & Tropical Medicine, and colleagues.

“Moving toward unselected BC testing may give an impetus for prevention in unaffected family members along with clinical implications for the patient with BC. Pathogenic variant carriers with newly diagnosed BC can opt for bilateral mastectomy rather than breast conservation at initial BC surgery,” the investigators wrote in JAMA Oncology. They noted that, presently, only 20%-30% of eligible patients are actually tested. “Testing all patients with breast cancer at diagnosis can increase testing access and uptake and identify many more pathogenic variant carriers for screening and prevention.”

To see if such a broad roll-out would be economically and medically feasible and beneficial, the investigators performed a modeling study involving 11,836 women with breast cancer, with data drawn from four large databases in the United Kingdom, the United States, and Australia.

The model compared annual costs, number of detected cases of breast cancer and ovarian cancer, and related rates of mortality between standard BRCA testing based on clinical criteria or family history versus high-risk multigene testing (BRCA1/BRCA2/PALB2) for all patients with breast cancer.

Resultant incremental cost-effectiveness ratios (ICERs) showed that in both the United Kingdom and the United States, multigene testing would cost, on average, significantly less than minimum willingness-to-pay thresholds of £30,000 per quality-adjusted life-year (QALY) and $100,000/QALY, respectively. In the United Kingdom, the estimated cost of multigene testing was £10,464/QALY from a payer’s perspective and £7,216/QALY from a societal perspective, the latter of which incorporates economic costs beyond the health care system. In the United States, these values rose to $65,661/QALY (payer perspective) and $61,618/QALY (societal perspective). Probabilistic sensitivity analysis suggested that multigene testing would be cost-effective for almost all health system simulations in the United Kingdom (98%-99%) and approximately two-thirds of those in the United States (64%-68%).

Epidemiologically, in the United Kingdom, multigene testing could potentially prevent 2,101 cases of breast cancer and ovarian cancer and 633 deaths per year, while in the United States, 9,733 cases might be prevented, with 2,406 lives saved.

“Our analysis suggests that an unselected testing strategy is extremely cost-effective for U.K. and U.S. health systems and provides a basis for change in current guidelines and policy to implement this strategy,” the investigators said.

The study was funded by the National Cancer Institute, the State of Washington, the Fred Hutchinson Cancer Research Center, and others. The investigators reported additional relationships with AstraZeneca, the Manchester National Institute for Health Research Biomedical Research Centre, Cancer Research UK, an others.

SOURCE: Sun et al. JAMA Oncol. 2019 Oct 3. doi: 10.1001/jamaoncol.2019.3323.