Pulmonology

Use of pharmacomechanical catheter-directory thrombolysis significantly reduced the number of pulmonary artery branches with total or subtotal occlusions in patients with acute pulmonary embolism, based on data from more than 100 individuals.

Reduced distal vascular volume is a significant predictor of 30-day and 90-day mortality in acute pulmonary embolism (PE) patients, and pulmonary obstruction is often the cause, wrote Riyaz Bashir, MD, of Temple University, Philadelphia, Pennsylvania, and colleagues.

Some studies of catheter-based treatments have shown a reduction in pulmonary artery (PA) obstruction in PE patients, but the impact has been modest, the researchers said.

“The recently published RESCUE (Recombinant tPA by Endovascular Administration for the Treatment of Submassive PE Using CDT for the Reduction of Thrombus Burden) trial showed a 35.9% reduction in PA obstruction using the Refined Modified Miller Index (RMMI), the largest reduction of all published catheter studies with core lab measurement, with similar doses of tissue plasminogen activator (tPA),” the researchers wrote.

The Bashir endovascular catheter was designed to maximize thrombus reduction via a pharmacomechanical infusion. The catheter features an expandable basket of 6 nitinol-reinforced infusion limbs.

“There are three crucial goals that we want to accomplish in patients who have a severe pulmonary embolism,” Dr. Bashir said in an interview. “Those include, in the order of importance, survival, recovery of right ventricular function, and resolution of blocked pulmonary arteries; both segmental and proximal pulmonary arteries,” he said.

Most previous studies have focused on the first two goals, but they still need to evaluate the resolution of PA blockages carefully, said Dr. Bashir. “In our clinical practice, we have seen a large number of patients who develop debilitating shortness of breath from these blockages. We decided to carefully evaluate these blockages before and after pharmacomechanical catheter-directed thrombolysis with the Bashir endovascular catheter using the core lab data from the RESCUE study,” he said.

In the current study published in JACC: Advances), the researchers used baseline and 48-hour posttreatment contrast-enhanced chest computed tomography angiography of adult PE patients with right ventricular dilatation.

The study population included 107 adults with acute intermediate-risk PE who were treated with pharmacomechanical catheter-directory thrombolysis (PM-CDT) at 18 sites in the United States. Of these, 98 had intermediate high-risk PE with elevated troponin and/or brain-type natriuretic peptide (BNP) levels and 102 had bilateral PE.

The primary endpoint was the change in the number of segmental and proximal PA branches with total or subtotal occlusions (defined as > 65%) after 48 hours compared to baseline. Occlusions were assessed using McNemar’s test.

Patients with bilateral PE received two Bashir catheters; those with unilateral PE received one catheter each.

Each patient received a pulse spray of 2 mg of recombinant tPA (r-tPA) into each lung, followed by 5 mg of r-tPA over 5 hours; the total dose was 7 mg of r-tPA for patients with unilateral PEs and 14 mg for those with bilateral PEs, the researchers said. The median times for catheter placement and total procedure were 15 minutes and 54 minutes, respectively.

The number of segmental PA branches with total or subtotal occlusions decreased significantly, from 40.5% at baseline to 11.7% at 48 hours, and proximal PA branch total or subtotal occlusions decreased significantly, from 28.7% at baseline to 11.0% at 48 hours (P < 0.0001 for both).

The magnitude of the reductions in both total and subtotal occlusions of segmental arteries was significantly correlated with the extent of right ventricle recovery (measured by the reduction in right ventricular/left ventricular ratio) with a correlation coefficient of 0.287 (P = .0026); however, this correlation was not observed in the proximal PA arteries (correlation coefficient 0.132, P = .173).

One major bleeding event occurred within 72 hours in a patient who also experienced a device-related left common iliac vein thrombosis while not taking anticoagulation medication, and one death unrelated to PE occurred within 30 days.

“The two findings that surprised me include, first, a more than 70% reduction in total and subtotal occlusions in the segmental arteries with such a low dose of r-tPA and, second, the resolution of the blockages was seen not only in the arteries where the device was placed but also at remote sites away from the location of the catheter,” Dr. Bashir told this news organization.

The findings were limited by several factors including the lack of long-term clinical follow-up outcomes data and lack of comparison groups who underwent other treatments.

However, “This study implies that we now have a safe therapy for these patients that improves survival and right ventricular recovery in addition to dramatically improving blocked pulmonary arteries,” Dr. Bashir said.

As for additional research, “we need all the current and future prospective pulmonary embolism studies to include an assessment of pulmonary artery blockage resolution as an essential endpoint,” he said.
 

Catheter Expands Treatment Options

The current study, a subgroup analysis of the RESCUE trial, was one of the first to examine the impact of catheter-directed lysis on distal occlusions, study coauthor Parth M. Rali, MD, said in an interview.

To this point, literature has been limited to evaluation for proximal disease, said Dr. Rali, director of thoracic surgery and medicine and part of the Pulmonary Embolism Response Team at Temple University Hospital, Philadelphia.

Dr. Rali said he was encouraged to see confirmation that the BEC catheter, because of its design, works in patients with proximal or distal occlusive disease.

In clinical practice, “the catheter provides an additional option for care in patients with multiple distal occlusive disease when a systemic tissue plasminogen activator (tPA), may put patient at high bleeding risk,” Dr. Rali said.

Looking ahead, a prospective, observational multicenter study would be useful to validate the findings from the post hoc analysis of the current study, he noted.

The study was sponsored by the National Heart, Lung, and Blood Institute, Commonwealth of Pennsylvania, and Thrombolex Inc., a medical device company developing interventional catheter-based therapies for the rapid and effective treatment of acute venous thromboembolic disorders. Dr. Bashir is a cofounder and has an equity interest in Thrombolex Inc. Dr. Rali disclosed serving as a consultant for Thrombolex, Inari Medical, Viz AI, and ThinkSono.

Use of pharmacomechanical catheter-directory thrombolysis significantly reduced the number of pulmonary artery branches with total or subtotal occlusions in patients with acute pulmonary embolism, based on data from more than 100 individuals.

Reduced distal vascular volume is a significant predictor of 30-day and 90-day mortality in acute pulmonary embolism (PE) patients, and pulmonary obstruction is often the cause, wrote Riyaz Bashir, MD, of Temple University, Philadelphia, Pennsylvania, and colleagues.

Some studies of catheter-based treatments have shown a reduction in pulmonary artery (PA) obstruction in PE patients, but the impact has been modest, the researchers said.

“The recently published RESCUE (Recombinant tPA by Endovascular Administration for the Treatment of Submassive PE Using CDT for the Reduction of Thrombus Burden) trial showed a 35.9% reduction in PA obstruction using the Refined Modified Miller Index (RMMI), the largest reduction of all published catheter studies with core lab measurement, with similar doses of tissue plasminogen activator (tPA),” the researchers wrote.

The Bashir endovascular catheter was designed to maximize thrombus reduction via a pharmacomechanical infusion. The catheter features an expandable basket of 6 nitinol-reinforced infusion limbs.

“There are three crucial goals that we want to accomplish in patients who have a severe pulmonary embolism,” Dr. Bashir said in an interview. “Those include, in the order of importance, survival, recovery of right ventricular function, and resolution of blocked pulmonary arteries; both segmental and proximal pulmonary arteries,” he said.

Most previous studies have focused on the first two goals, but they still need to evaluate the resolution of PA blockages carefully, said Dr. Bashir. “In our clinical practice, we have seen a large number of patients who develop debilitating shortness of breath from these blockages. We decided to carefully evaluate these blockages before and after pharmacomechanical catheter-directed thrombolysis with the Bashir endovascular catheter using the core lab data from the RESCUE study,” he said.

In the current study published in JACC: Advances), the researchers used baseline and 48-hour posttreatment contrast-enhanced chest computed tomography angiography of adult PE patients with right ventricular dilatation.

The study population included 107 adults with acute intermediate-risk PE who were treated with pharmacomechanical catheter-directory thrombolysis (PM-CDT) at 18 sites in the United States. Of these, 98 had intermediate high-risk PE with elevated troponin and/or brain-type natriuretic peptide (BNP) levels and 102 had bilateral PE.

The primary endpoint was the change in the number of segmental and proximal PA branches with total or subtotal occlusions (defined as > 65%) after 48 hours compared to baseline. Occlusions were assessed using McNemar’s test.

Patients with bilateral PE received two Bashir catheters; those with unilateral PE received one catheter each.

Each patient received a pulse spray of 2 mg of recombinant tPA (r-tPA) into each lung, followed by 5 mg of r-tPA over 5 hours; the total dose was 7 mg of r-tPA for patients with unilateral PEs and 14 mg for those with bilateral PEs, the researchers said. The median times for catheter placement and total procedure were 15 minutes and 54 minutes, respectively.

The number of segmental PA branches with total or subtotal occlusions decreased significantly, from 40.5% at baseline to 11.7% at 48 hours, and proximal PA branch total or subtotal occlusions decreased significantly, from 28.7% at baseline to 11.0% at 48 hours (P < 0.0001 for both).

The magnitude of the reductions in both total and subtotal occlusions of segmental arteries was significantly correlated with the extent of right ventricle recovery (measured by the reduction in right ventricular/left ventricular ratio) with a correlation coefficient of 0.287 (P = .0026); however, this correlation was not observed in the proximal PA arteries (correlation coefficient 0.132, P = .173).

One major bleeding event occurred within 72 hours in a patient who also experienced a device-related left common iliac vein thrombosis while not taking anticoagulation medication, and one death unrelated to PE occurred within 30 days.

“The two findings that surprised me include, first, a more than 70% reduction in total and subtotal occlusions in the segmental arteries with such a low dose of r-tPA and, second, the resolution of the blockages was seen not only in the arteries where the device was placed but also at remote sites away from the location of the catheter,” Dr. Bashir told this news organization.

The findings were limited by several factors including the lack of long-term clinical follow-up outcomes data and lack of comparison groups who underwent other treatments.

However, “This study implies that we now have a safe therapy for these patients that improves survival and right ventricular recovery in addition to dramatically improving blocked pulmonary arteries,” Dr. Bashir said.

As for additional research, “we need all the current and future prospective pulmonary embolism studies to include an assessment of pulmonary artery blockage resolution as an essential endpoint,” he said.
 

Catheter Expands Treatment Options

The current study, a subgroup analysis of the RESCUE trial, was one of the first to examine the impact of catheter-directed lysis on distal occlusions, study coauthor Parth M. Rali, MD, said in an interview.

To this point, literature has been limited to evaluation for proximal disease, said Dr. Rali, director of thoracic surgery and medicine and part of the Pulmonary Embolism Response Team at Temple University Hospital, Philadelphia.

Dr. Rali said he was encouraged to see confirmation that the BEC catheter, because of its design, works in patients with proximal or distal occlusive disease.

In clinical practice, “the catheter provides an additional option for care in patients with multiple distal occlusive disease when a systemic tissue plasminogen activator (tPA), may put patient at high bleeding risk,” Dr. Rali said.

Looking ahead, a prospective, observational multicenter study would be useful to validate the findings from the post hoc analysis of the current study, he noted.

The study was sponsored by the National Heart, Lung, and Blood Institute, Commonwealth of Pennsylvania, and Thrombolex Inc., a medical device company developing interventional catheter-based therapies for the rapid and effective treatment of acute venous thromboembolic disorders. Dr. Bashir is a cofounder and has an equity interest in Thrombolex Inc. Dr. Rali disclosed serving as a consultant for Thrombolex, Inari Medical, Viz AI, and ThinkSono.

Use of pharmacomechanical catheter-directory thrombolysis significantly reduced the number of pulmonary artery branches with total or subtotal occlusions in patients with acute pulmonary embolism, based on data from more than 100 individuals.

Reduced distal vascular volume is a significant predictor of 30-day and 90-day mortality in acute pulmonary embolism (PE) patients, and pulmonary obstruction is often the cause, wrote Riyaz Bashir, MD, of Temple University, Philadelphia, Pennsylvania, and colleagues.

Some studies of catheter-based treatments have shown a reduction in pulmonary artery (PA) obstruction in PE patients, but the impact has been modest, the researchers said.

“The recently published RESCUE (Recombinant tPA by Endovascular Administration for the Treatment of Submassive PE Using CDT for the Reduction of Thrombus Burden) trial showed a 35.9% reduction in PA obstruction using the Refined Modified Miller Index (RMMI), the largest reduction of all published catheter studies with core lab measurement, with similar doses of tissue plasminogen activator (tPA),” the researchers wrote.

The Bashir endovascular catheter was designed to maximize thrombus reduction via a pharmacomechanical infusion. The catheter features an expandable basket of 6 nitinol-reinforced infusion limbs.

“There are three crucial goals that we want to accomplish in patients who have a severe pulmonary embolism,” Dr. Bashir said in an interview. “Those include, in the order of importance, survival, recovery of right ventricular function, and resolution of blocked pulmonary arteries; both segmental and proximal pulmonary arteries,” he said.

Most previous studies have focused on the first two goals, but they still need to evaluate the resolution of PA blockages carefully, said Dr. Bashir. “In our clinical practice, we have seen a large number of patients who develop debilitating shortness of breath from these blockages. We decided to carefully evaluate these blockages before and after pharmacomechanical catheter-directed thrombolysis with the Bashir endovascular catheter using the core lab data from the RESCUE study,” he said.

In the current study published in JACC: Advances), the researchers used baseline and 48-hour posttreatment contrast-enhanced chest computed tomography angiography of adult PE patients with right ventricular dilatation.

The study population included 107 adults with acute intermediate-risk PE who were treated with pharmacomechanical catheter-directory thrombolysis (PM-CDT) at 18 sites in the United States. Of these, 98 had intermediate high-risk PE with elevated troponin and/or brain-type natriuretic peptide (BNP) levels and 102 had bilateral PE.

The primary endpoint was the change in the number of segmental and proximal PA branches with total or subtotal occlusions (defined as > 65%) after 48 hours compared to baseline. Occlusions were assessed using McNemar’s test.

Patients with bilateral PE received two Bashir catheters; those with unilateral PE received one catheter each.

Each patient received a pulse spray of 2 mg of recombinant tPA (r-tPA) into each lung, followed by 5 mg of r-tPA over 5 hours; the total dose was 7 mg of r-tPA for patients with unilateral PEs and 14 mg for those with bilateral PEs, the researchers said. The median times for catheter placement and total procedure were 15 minutes and 54 minutes, respectively.

The number of segmental PA branches with total or subtotal occlusions decreased significantly, from 40.5% at baseline to 11.7% at 48 hours, and proximal PA branch total or subtotal occlusions decreased significantly, from 28.7% at baseline to 11.0% at 48 hours (P < 0.0001 for both).

The magnitude of the reductions in both total and subtotal occlusions of segmental arteries was significantly correlated with the extent of right ventricle recovery (measured by the reduction in right ventricular/left ventricular ratio) with a correlation coefficient of 0.287 (P = .0026); however, this correlation was not observed in the proximal PA arteries (correlation coefficient 0.132, P = .173).

One major bleeding event occurred within 72 hours in a patient who also experienced a device-related left common iliac vein thrombosis while not taking anticoagulation medication, and one death unrelated to PE occurred within 30 days.

“The two findings that surprised me include, first, a more than 70% reduction in total and subtotal occlusions in the segmental arteries with such a low dose of r-tPA and, second, the resolution of the blockages was seen not only in the arteries where the device was placed but also at remote sites away from the location of the catheter,” Dr. Bashir told this news organization.

The findings were limited by several factors including the lack of long-term clinical follow-up outcomes data and lack of comparison groups who underwent other treatments.

However, “This study implies that we now have a safe therapy for these patients that improves survival and right ventricular recovery in addition to dramatically improving blocked pulmonary arteries,” Dr. Bashir said.

As for additional research, “we need all the current and future prospective pulmonary embolism studies to include an assessment of pulmonary artery blockage resolution as an essential endpoint,” he said.
 

Catheter Expands Treatment Options

The current study, a subgroup analysis of the RESCUE trial, was one of the first to examine the impact of catheter-directed lysis on distal occlusions, study coauthor Parth M. Rali, MD, said in an interview.

To this point, literature has been limited to evaluation for proximal disease, said Dr. Rali, director of thoracic surgery and medicine and part of the Pulmonary Embolism Response Team at Temple University Hospital, Philadelphia.

Dr. Rali said he was encouraged to see confirmation that the BEC catheter, because of its design, works in patients with proximal or distal occlusive disease.

In clinical practice, “the catheter provides an additional option for care in patients with multiple distal occlusive disease when a systemic tissue plasminogen activator (tPA), may put patient at high bleeding risk,” Dr. Rali said.

Looking ahead, a prospective, observational multicenter study would be useful to validate the findings from the post hoc analysis of the current study, he noted.

The study was sponsored by the National Heart, Lung, and Blood Institute, Commonwealth of Pennsylvania, and Thrombolex Inc., a medical device company developing interventional catheter-based therapies for the rapid and effective treatment of acute venous thromboembolic disorders. Dr. Bashir is a cofounder and has an equity interest in Thrombolex Inc. Dr. Rali disclosed serving as a consultant for Thrombolex, Inari Medical, Viz AI, and ThinkSono.

Sabine Roman, MD, PhD, associate professor of gastroenterology and physiology at Lyon University Hospital in France, took the floor at the United European Gastroenterology Week to discuss the link between a chronic cough and gastroesophageal reflux disease (GERD). During a session on extraesophageal symptoms, Dr. Roman relayed two key messages: In patients with a chronic cough, reflux absolutely must be documented, and proton pump inhibitors (PPIs) must only be prescribed when a diagnosis of GERD has been made.
 

Overestimated Cause

Chronic cough is a widespread problem with a prevalence of between 9% and 33%, according to clinical studies. The root causes of this cough are varied; they’re mainly related to the respiratory system (eg, asthma, chronic obstructive pulmonary disease, respiratory infections, or smoking) and the ear, nose, and throat field (eg, postnasal drip). What’s more, taking certain medicines, notably angiotensin-converting enzyme inhibitors, can also be at the root of this condition.

GERD is also a possible cause of a chronic cough but one that is likely overestimated. A 2023 Spanish study provides evidence of this; GERD was suspected to be linked to cough in 46% of patients (compared with 32% for asthma and 15% for postnasal drip).

The treatments most commonly prescribed include PPIs (79.6%) and respiratory medicines (87.8%). Note that antibiotics are administered empirically to 28.6% of patients. For Roman, “the blame for a chronic cough is too often assigned to GERD, especially considering that in this study, only 43% of patients had seen a gastroenterologist, 27% had an endoscopy, and 24% had undergone esophageal pH monitoring.”

Added to this observation is the difficulty of establishing a causal link between a cough and GERD when the latter is present, even when the patient has had a diagnosis of GERD. Of course, a link between the two does not necessarily imply a cause–effect relationship, especially given that studies have shown that a cough itself can induce GERD. Studies using automatic cough detection to count cough events have shown that GERD certainly preceded a cough in 48% of patients, but in 56% of cases, it was the cough that came before the GERD. What’s more, both mechanisms were present in one third of patients.
 

Prescribing PPIs Effectively

PPIs are commonly prescribed as a test treatment. However, their efficacy is in no way proof of the existence of underlying GERD. In reality, all placebo-controlled studies have shown that in cases where no prior diagnosis of GERD has been made, PPIs have no superior efficacy.

If reflux has been proven, then the improvement provided by PPIs, compared with placebo, is between 12% and 35%. Therefore, it is essential that the presence of GERD be demonstrated, particularly if the patient has no characteristic symptoms of GERD, such as heartburn and acid reflux.

Response factors to PPIs were evaluated in 178 Italian patients with a chronic cough who presented with suspected GERD. Of those, 45% responded to treatment. It has been shown that typical symptoms, severe esophagitis (grade C/D), abnormal acid exposure, and low levels of nocturnal baseline impedance were independent factors of response to treatment.

In conclusion, patients with a chronic cough must be comprehensively tested for GERD before a long-term prescription of PPIs can be considered.
 

Cough Reflex Threshold

Various studies have also revealed that patients with GERD and presenting with a chronic cough have an increased sensitivity to the cough reflex. This hypersensitivity to the cough reflex has inspired several trials involving gabapentin and baclofen. A randomized controlled trial found the two treatments to be equally effective, achieving improvement of around 50%.

Lesogaberan, a new GABA(B) receptor agonist acting on the peripheral nervous system which is better tolerated than baclofen, a drug belonging to the same therapeutic class, showed a 26% benefit over placebo, but it was not statistically significant; lesogaberan has not been developed further.

Anti-reflux surgery is an option. A 2021 meta-analysis revealed that 84% of patients enrolled in these studies saw an improvement in their symptoms. However, these results must be regarded with caution because none of these studies were controlled, most of them were retrospective with very heterogeneous patient populations, and the data obtained on postoperative reflux control were often found to be lacking.

A retrospective study showed that among the factors for nonresponse or recurrence of symptoms after anti-reflux surgery, lack of response to medical treatment and extraesophageal symptoms such as a cough were significant factors. Consequently, potential candidates for surgery must be rigorously screened before being considered for such a procedure.

The recent recommendations for good practice published by the American Gastroenterological Association also insist that lack of response to medical treatment is a major factor for failure of surgical treatment.

In sum, patients with a chronic cough can be prescribed PPIs as first-line treatment if they have typical symptoms of GERD. In the event of treatment failure or isolated cough without typical symptoms, tests to confirm or rule out GERD are essential (such as endoscopy, esophageal pH monitoring, or impedance-pH monitoring).
 

This article was translated from the Medscape French edition. A version of this article appeared on Medscape.com.

Sabine Roman, MD, PhD, associate professor of gastroenterology and physiology at Lyon University Hospital in France, took the floor at the United European Gastroenterology Week to discuss the link between a chronic cough and gastroesophageal reflux disease (GERD). During a session on extraesophageal symptoms, Dr. Roman relayed two key messages: In patients with a chronic cough, reflux absolutely must be documented, and proton pump inhibitors (PPIs) must only be prescribed when a diagnosis of GERD has been made.
 

Overestimated Cause

Chronic cough is a widespread problem with a prevalence of between 9% and 33%, according to clinical studies. The root causes of this cough are varied; they’re mainly related to the respiratory system (eg, asthma, chronic obstructive pulmonary disease, respiratory infections, or smoking) and the ear, nose, and throat field (eg, postnasal drip). What’s more, taking certain medicines, notably angiotensin-converting enzyme inhibitors, can also be at the root of this condition.

GERD is also a possible cause of a chronic cough but one that is likely overestimated. A 2023 Spanish study provides evidence of this; GERD was suspected to be linked to cough in 46% of patients (compared with 32% for asthma and 15% for postnasal drip).

The treatments most commonly prescribed include PPIs (79.6%) and respiratory medicines (87.8%). Note that antibiotics are administered empirically to 28.6% of patients. For Roman, “the blame for a chronic cough is too often assigned to GERD, especially considering that in this study, only 43% of patients had seen a gastroenterologist, 27% had an endoscopy, and 24% had undergone esophageal pH monitoring.”

Added to this observation is the difficulty of establishing a causal link between a cough and GERD when the latter is present, even when the patient has had a diagnosis of GERD. Of course, a link between the two does not necessarily imply a cause–effect relationship, especially given that studies have shown that a cough itself can induce GERD. Studies using automatic cough detection to count cough events have shown that GERD certainly preceded a cough in 48% of patients, but in 56% of cases, it was the cough that came before the GERD. What’s more, both mechanisms were present in one third of patients.
 

Prescribing PPIs Effectively

PPIs are commonly prescribed as a test treatment. However, their efficacy is in no way proof of the existence of underlying GERD. In reality, all placebo-controlled studies have shown that in cases where no prior diagnosis of GERD has been made, PPIs have no superior efficacy.

If reflux has been proven, then the improvement provided by PPIs, compared with placebo, is between 12% and 35%. Therefore, it is essential that the presence of GERD be demonstrated, particularly if the patient has no characteristic symptoms of GERD, such as heartburn and acid reflux.

Response factors to PPIs were evaluated in 178 Italian patients with a chronic cough who presented with suspected GERD. Of those, 45% responded to treatment. It has been shown that typical symptoms, severe esophagitis (grade C/D), abnormal acid exposure, and low levels of nocturnal baseline impedance were independent factors of response to treatment.

In conclusion, patients with a chronic cough must be comprehensively tested for GERD before a long-term prescription of PPIs can be considered.
 

Cough Reflex Threshold

Various studies have also revealed that patients with GERD and presenting with a chronic cough have an increased sensitivity to the cough reflex. This hypersensitivity to the cough reflex has inspired several trials involving gabapentin and baclofen. A randomized controlled trial found the two treatments to be equally effective, achieving improvement of around 50%.

Lesogaberan, a new GABA(B) receptor agonist acting on the peripheral nervous system which is better tolerated than baclofen, a drug belonging to the same therapeutic class, showed a 26% benefit over placebo, but it was not statistically significant; lesogaberan has not been developed further.

Anti-reflux surgery is an option. A 2021 meta-analysis revealed that 84% of patients enrolled in these studies saw an improvement in their symptoms. However, these results must be regarded with caution because none of these studies were controlled, most of them were retrospective with very heterogeneous patient populations, and the data obtained on postoperative reflux control were often found to be lacking.

A retrospective study showed that among the factors for nonresponse or recurrence of symptoms after anti-reflux surgery, lack of response to medical treatment and extraesophageal symptoms such as a cough were significant factors. Consequently, potential candidates for surgery must be rigorously screened before being considered for such a procedure.

The recent recommendations for good practice published by the American Gastroenterological Association also insist that lack of response to medical treatment is a major factor for failure of surgical treatment.

In sum, patients with a chronic cough can be prescribed PPIs as first-line treatment if they have typical symptoms of GERD. In the event of treatment failure or isolated cough without typical symptoms, tests to confirm or rule out GERD are essential (such as endoscopy, esophageal pH monitoring, or impedance-pH monitoring).
 

This article was translated from the Medscape French edition. A version of this article appeared on Medscape.com.

Sabine Roman, MD, PhD, associate professor of gastroenterology and physiology at Lyon University Hospital in France, took the floor at the United European Gastroenterology Week to discuss the link between a chronic cough and gastroesophageal reflux disease (GERD). During a session on extraesophageal symptoms, Dr. Roman relayed two key messages: In patients with a chronic cough, reflux absolutely must be documented, and proton pump inhibitors (PPIs) must only be prescribed when a diagnosis of GERD has been made.
 

Overestimated Cause

Chronic cough is a widespread problem with a prevalence of between 9% and 33%, according to clinical studies. The root causes of this cough are varied; they’re mainly related to the respiratory system (eg, asthma, chronic obstructive pulmonary disease, respiratory infections, or smoking) and the ear, nose, and throat field (eg, postnasal drip). What’s more, taking certain medicines, notably angiotensin-converting enzyme inhibitors, can also be at the root of this condition.

GERD is also a possible cause of a chronic cough but one that is likely overestimated. A 2023 Spanish study provides evidence of this; GERD was suspected to be linked to cough in 46% of patients (compared with 32% for asthma and 15% for postnasal drip).

The treatments most commonly prescribed include PPIs (79.6%) and respiratory medicines (87.8%). Note that antibiotics are administered empirically to 28.6% of patients. For Roman, “the blame for a chronic cough is too often assigned to GERD, especially considering that in this study, only 43% of patients had seen a gastroenterologist, 27% had an endoscopy, and 24% had undergone esophageal pH monitoring.”

Added to this observation is the difficulty of establishing a causal link between a cough and GERD when the latter is present, even when the patient has had a diagnosis of GERD. Of course, a link between the two does not necessarily imply a cause–effect relationship, especially given that studies have shown that a cough itself can induce GERD. Studies using automatic cough detection to count cough events have shown that GERD certainly preceded a cough in 48% of patients, but in 56% of cases, it was the cough that came before the GERD. What’s more, both mechanisms were present in one third of patients.
 

Prescribing PPIs Effectively

PPIs are commonly prescribed as a test treatment. However, their efficacy is in no way proof of the existence of underlying GERD. In reality, all placebo-controlled studies have shown that in cases where no prior diagnosis of GERD has been made, PPIs have no superior efficacy.

If reflux has been proven, then the improvement provided by PPIs, compared with placebo, is between 12% and 35%. Therefore, it is essential that the presence of GERD be demonstrated, particularly if the patient has no characteristic symptoms of GERD, such as heartburn and acid reflux.

Response factors to PPIs were evaluated in 178 Italian patients with a chronic cough who presented with suspected GERD. Of those, 45% responded to treatment. It has been shown that typical symptoms, severe esophagitis (grade C/D), abnormal acid exposure, and low levels of nocturnal baseline impedance were independent factors of response to treatment.

In conclusion, patients with a chronic cough must be comprehensively tested for GERD before a long-term prescription of PPIs can be considered.
 

Cough Reflex Threshold

Various studies have also revealed that patients with GERD and presenting with a chronic cough have an increased sensitivity to the cough reflex. This hypersensitivity to the cough reflex has inspired several trials involving gabapentin and baclofen. A randomized controlled trial found the two treatments to be equally effective, achieving improvement of around 50%.

Lesogaberan, a new GABA(B) receptor agonist acting on the peripheral nervous system which is better tolerated than baclofen, a drug belonging to the same therapeutic class, showed a 26% benefit over placebo, but it was not statistically significant; lesogaberan has not been developed further.

Anti-reflux surgery is an option. A 2021 meta-analysis revealed that 84% of patients enrolled in these studies saw an improvement in their symptoms. However, these results must be regarded with caution because none of these studies were controlled, most of them were retrospective with very heterogeneous patient populations, and the data obtained on postoperative reflux control were often found to be lacking.

A retrospective study showed that among the factors for nonresponse or recurrence of symptoms after anti-reflux surgery, lack of response to medical treatment and extraesophageal symptoms such as a cough were significant factors. Consequently, potential candidates for surgery must be rigorously screened before being considered for such a procedure.

The recent recommendations for good practice published by the American Gastroenterological Association also insist that lack of response to medical treatment is a major factor for failure of surgical treatment.

In sum, patients with a chronic cough can be prescribed PPIs as first-line treatment if they have typical symptoms of GERD. In the event of treatment failure or isolated cough without typical symptoms, tests to confirm or rule out GERD are essential (such as endoscopy, esophageal pH monitoring, or impedance-pH monitoring).
 

This article was translated from the Medscape French edition. A version of this article appeared on Medscape.com.

TOPLINE:

Among adolescent pregnancies in the United States, the prevalence of e-cigarette use during the third trimester increased from 0.8% in 2016 to 4.1% in 2021, according to research published online on December 13 in JAMA Network Open. 

METHODOLOGY:

• Researchers analyzed data from the 2016-2021 Pregnancy Risk Assessment Monitoring System.
• They focused on 10,428 adolescents aged 10-19 years who had had a singleton birth and provided information about their use of e-cigarettes or cigarettes.

TAKEAWAY:

• Whereas the researchers found a roughly fivefold increase in the exclusive use of e-cigarettes, the percentage of patients using only cigarettes decreased from 9.2% in 2017 to 3.2% in 2021.
• The percentage of patients who both vaped and smoked fluctuated between 0.6% and 1.6%.
• The rate of small-for-gestational-age (SGA) births for adolescents who did not smoke or vape (12.9%) did not differ significantly from that among adolescents who exclusively used e-cigarettes (16.8%) or those who used both cigarettes and e-cigarettes (17.6%).
• The researchers found use of cigarettes only was associated with a significantly higher rate of SGA births: 24.6%.

IN PRACTICE:

“Exclusive e-cigarette use and dual use of cigarettes and e-cigarettes did not seem to be statistically significantly associated with SGA birth in our analysis, but this finding should be interpreted with caution given the low prevalence of use and the limited sample size,” the study authors wrote.

SOURCE:

Xiaozhong Wen, MD, PhD, with the Jacobs School of Medicine and Biomedical Sciences at the State University of New York at Buffalo, was the corresponding author of the study. 

LIMITATIONS:

Participants may have underreported their use of e-cigarettes and cigarettes because of fears of social stigma. The researchers lacked information about vaping in the first and second trimesters, exposure to secondhand smoke, cannabis use, and diet. 

DISCLOSURES:

The research was supported by the National Institute on Drug Abuse; the Food and Drug Administration Center for Tobacco Products; the National Heart, Lung, and Blood Institute; and the American Heart Association. A study coauthor has received grants from Pfizer and personal fees from Johnson & Johnson, the World Health Organization, and the Campaign for Tobacco-Free Kids.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Among adolescent pregnancies in the United States, the prevalence of e-cigarette use during the third trimester increased from 0.8% in 2016 to 4.1% in 2021, according to research published online on December 13 in JAMA Network Open. 

METHODOLOGY:

• Researchers analyzed data from the 2016-2021 Pregnancy Risk Assessment Monitoring System.
• They focused on 10,428 adolescents aged 10-19 years who had had a singleton birth and provided information about their use of e-cigarettes or cigarettes.

TAKEAWAY:

• Whereas the researchers found a roughly fivefold increase in the exclusive use of e-cigarettes, the percentage of patients using only cigarettes decreased from 9.2% in 2017 to 3.2% in 2021.
• The percentage of patients who both vaped and smoked fluctuated between 0.6% and 1.6%.
• The rate of small-for-gestational-age (SGA) births for adolescents who did not smoke or vape (12.9%) did not differ significantly from that among adolescents who exclusively used e-cigarettes (16.8%) or those who used both cigarettes and e-cigarettes (17.6%).
• The researchers found use of cigarettes only was associated with a significantly higher rate of SGA births: 24.6%.

IN PRACTICE:

“Exclusive e-cigarette use and dual use of cigarettes and e-cigarettes did not seem to be statistically significantly associated with SGA birth in our analysis, but this finding should be interpreted with caution given the low prevalence of use and the limited sample size,” the study authors wrote.

SOURCE:

Xiaozhong Wen, MD, PhD, with the Jacobs School of Medicine and Biomedical Sciences at the State University of New York at Buffalo, was the corresponding author of the study. 

LIMITATIONS:

Participants may have underreported their use of e-cigarettes and cigarettes because of fears of social stigma. The researchers lacked information about vaping in the first and second trimesters, exposure to secondhand smoke, cannabis use, and diet. 

DISCLOSURES:

The research was supported by the National Institute on Drug Abuse; the Food and Drug Administration Center for Tobacco Products; the National Heart, Lung, and Blood Institute; and the American Heart Association. A study coauthor has received grants from Pfizer and personal fees from Johnson & Johnson, the World Health Organization, and the Campaign for Tobacco-Free Kids.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Among adolescent pregnancies in the United States, the prevalence of e-cigarette use during the third trimester increased from 0.8% in 2016 to 4.1% in 2021, according to research published online on December 13 in JAMA Network Open. 

METHODOLOGY:

• Researchers analyzed data from the 2016-2021 Pregnancy Risk Assessment Monitoring System.
• They focused on 10,428 adolescents aged 10-19 years who had had a singleton birth and provided information about their use of e-cigarettes or cigarettes.

TAKEAWAY:

• Whereas the researchers found a roughly fivefold increase in the exclusive use of e-cigarettes, the percentage of patients using only cigarettes decreased from 9.2% in 2017 to 3.2% in 2021.
• The percentage of patients who both vaped and smoked fluctuated between 0.6% and 1.6%.
• The rate of small-for-gestational-age (SGA) births for adolescents who did not smoke or vape (12.9%) did not differ significantly from that among adolescents who exclusively used e-cigarettes (16.8%) or those who used both cigarettes and e-cigarettes (17.6%).
• The researchers found use of cigarettes only was associated with a significantly higher rate of SGA births: 24.6%.

IN PRACTICE:

“Exclusive e-cigarette use and dual use of cigarettes and e-cigarettes did not seem to be statistically significantly associated with SGA birth in our analysis, but this finding should be interpreted with caution given the low prevalence of use and the limited sample size,” the study authors wrote.

SOURCE:

Xiaozhong Wen, MD, PhD, with the Jacobs School of Medicine and Biomedical Sciences at the State University of New York at Buffalo, was the corresponding author of the study. 

LIMITATIONS:

Participants may have underreported their use of e-cigarettes and cigarettes because of fears of social stigma. The researchers lacked information about vaping in the first and second trimesters, exposure to secondhand smoke, cannabis use, and diet. 

DISCLOSURES:

The research was supported by the National Institute on Drug Abuse; the Food and Drug Administration Center for Tobacco Products; the National Heart, Lung, and Blood Institute; and the American Heart Association. A study coauthor has received grants from Pfizer and personal fees from Johnson & Johnson, the World Health Organization, and the Campaign for Tobacco-Free Kids.
 

A version of this article appeared on Medscape.com.

SAN DIEGO — Clinically significant interstitial lung disease (ILD) is believed to occur in 5%-10% of patients with rheumatoid arthritis (RA), but robust data are lacking on how to best predict which patients face the highest risk for RA-associated ILD. However, the results of several studies presented at the American College of Rheumatology annual meeting indicate that researchers are making strides in this field of rheumatologic care.

Adding Genetic Factors Improves ILD Risk Prediction

In the realm of risk stratification, Austin M. Wheeler, MD, a rheumatology fellow at the University of Nebraska Medical Center, Omaha, discussed the development and validation of a combined clinical and genetic risk score for ILD. “There is clear and well documented phenotypic and genetic overlap of ILD with idiopathic pulmonary fibrosis (IPF),” Dr. Wheeler said. “A number of clinical risk factors have been described for RA-ILD, including older age, male sex, smoking history, higher disease activity, and seropositivity. There are also well-documented genetic risk factors for RA-ILD. The MUC5B genetic variant is the strongest risk factor for IPF, and it’s been described in RA-ILD as well.”

Dr. Wheeler

A recently published study indicated that a genetic risk score without the MUC5B variant improved predictive ability for IPF and interstitial lung abnormalities better than using the MUC5B variant alone, “but no prior attempts have been made at developing a composite genetic risk score in RA-ILD” using both genetic and clinical risk factors, he said.

For the current study, Dr. Wheeler and colleagues drew from 2,386 participants in the Veterans Affairs Rheumatoid Arthritis (VARA) Registry, a multicenter, prospective cohort of US veterans with rheumatologist-diagnosed RA and who fulfilled the 1987 ACR classification criteria. The researchers validated ILD through a systematic review of medical records, including clinical diagnosis of ILD plus either imaging or lung biopsy findings, and collected whole genome data that included 12 single nucleotide polymorphisms (SNPs) previously identified to be associated with risk for RA-ILD. They then used a meta-analytic approach to create pooled associations for each of those respective SNPs using data from the VARA registry participants as well as participants from the past study where the SNPs were first identified. “Those pooled associations were what we used for our effects size within the genetic risk score,” which ended up using five of the SNPs, Dr. Wheeler explained. Next, he and his colleagues combined the genetic risk score with clinical risk factors including age, sex, smoking history, disease activity, and rheumatoid factor (RF) positivity to create their combined risk score.

The mean age of the cohort was 70 years, 89% were male, 78% had a smoking history, and 78% were anti–cyclic citrullinated peptide (CCP) antibody positive. Of the 2,386 participants, 224 (9.4%) had RA-ILD. The full composite risk score had the highest area under the receiver operating curve (AUC) of 0.67, compared with an AUC of 0.623 using the clinical factors alone, 0.651 using the clinical factors plus only the MUC5B variant, and 0.654 using the composite score minus only the MUC5B variant. These AUCs show that “the combined risk score performs better than clinical factors even without the inclusion of the MUC5B variant in the score, which is notable because it supports the importance of further investigation into polygenic risk scores in RA-ILD as there is clearly more at play in a patient’s overall genetic risk,” Dr. Wheeler said.

As an example of the composite score’s ability to discriminate between people with and without RA-ILD, a cutpoint of 0.05 gave a sensitivity of 90.2% and would have eliminated about 25% of the cohort from unnecessary high-resolution CT scans and pulmonary function tests, he said.

“This study demonstrates the potential utility of genetic risk scores in RA-ILD identification and supports further investigation into individual risk stratification and screening,” he concluded. “This isn’t ready for clinical applicability by any means, but I think it serves as a proof of concept of the idea of a genetic risk score in RA-ILD.”

Biomarker Score Investigated

In a separate abstract, Brent Luedders, MD, assistant professor of rheumatology and immunology at the University of Nebraska Medical Center, and colleagues set out to determine if a previously derived biomarker score is associated with prevalent and incident ILD in the same VARA Registry cohort. An abstract presented at the ACR 2022 annual meeting found that a panel derived from IPF peripheral biomarkers was significantly associated with RA-ILD, including matrix metalloproteinase (MMP)-2, -7, and -9, eotaxin, macrophage-derived chemokine (MDC), monocyte chemoattractant protein-1 (MCP-1), fms-like tyrosine kinase 3 ligand (Flt3L) and interleukin-8 (IL-8). For the current analysis, Dr. Luedders and colleagues measured the concentrations of seven biomarkers (MMP-7, MMP-9, eotaxin, MDC, MCP-1, Flt3L, IL-8) from serum/plasma samples collected from VARA’s participants at enrollment to develop a score based on the concentrations of each biomarker.

Dr. Luedders

Baseline characteristics were similar between the groups, although those with prevalent RA-ILD were slightly older than those without ILD, and those who developed incident ILD during follow-up had slightly higher RA disease activity at the time of enrollment. When the researchers examined the association of the biomarker score with prevalent RA-ILD as a continuous measure, they found an adjusted OR of 1.08 for prevalent RA-ILD for each 1-point increase in the biomarker score. “When this was divided into quartiles, we found that the highest quartile of the biomarker score was associated with an adjusted odds ratio of 2.31 for prevalent RA-ILD,” Dr. Luedders said. “We saw a significant P for trend of < .001, suggesting a dose-response relationship, in which higher scores had higher risk.” Similar associations were observed for incident RA-ILD, in which participants with the highest quartile had an adjusted hazard ratio of 2.26 for incident RA-ILD.

The AUC of 0.653 that was obtained with clinical factors did not significantly improve with inclusion of the biomarker score, rising to only 0.669. “In receiver operating characteristic analysis, the addition of the biomarker score to clinical variables (age, sex, race, smoking status, anti-CCP positivity, and RA disease activity by DAS28) did not lead to a significant increase in the area under the curve. Therefore, further work is needed to identify combinations of clinical, biomarker, and other factors to accurately predict which people with RA will develop ILD,” he said.

Dr. Luedders acknowledged certain limitations of the results, including the fact that MMP-2 was not measured in this cohort and thus not included in the score. “This was an observational study with usual care; therefore, the absence of systemic evaluation for ILD may miss early or mild RA-ILD cases,” he added. “Similarly, a male predominance may limit the generalizability, and we have limited information on the RA-ILD pattern.” He concluded that the study results “support the shared pathogenesis of IPF and RA-ILD. However, we found that this score has limited discriminative performance, compared to clinical risk factors alone.”
 

Drilling Down on ILD Subtypes

In a poster abstract presentation at the meeting, Gregory Campbell McDermott, MD, MPH, a rheumatologist at Brigham and Women’s Hospital, Boston, highlighted results from a study that investigated differences in demographic, serologic, and lifestyle factors for RA-ILD and the major subtypes of RA-ILD: usual interstitial pneumonia (UIP) and nonspecific interstitial pneumonia (NSIP). “Historically, RA-ILD has been studied as a single entity, even though we increasingly recognized that there are lots of different subtypes that fall under the umbrella of RA-ILD,” Dr. McDermott said in an interview. “We are also learning that the different subtypes probably have both prognostic and potentially therapeutic implications. For example, the UIP subtype, which is the most fibrotic subtype, has the worst prognosis but also may be a potential target for antifibrotic therapies. We’ve been trying to see if we can identify factors that are associated with specific subtypes, in particular the UIP subtype which has the worst prognosis.”

Dr. McDermott

He and his colleagues examined 208 patients with RA-ILD with a mean age of 51 years and 547 patients with RA but no ILD with a mean age of 49 years from two RA cohorts comprising 3,328 patients: the Mass General Brigham Biobank RA Cohort and the Brigham RA Sequential Study (BRASS). Of the 208 RA-ILD cases, nearly half (48%) were RA-UIP, 18% were RA-NSIP, 8% were organizing pneumonia, 3% were respiratory bronchiolitis-ILD, and 23% were other/indeterminate. After conducting multivariable adjusted analyses, the researchers found that RA-ILD was associated with male sex (OR, 1.58; 95% CI, 1.09-2.23), seropositivity for RF and/or anti-CCP (OR, 2.22; 95% CI, 1.51-3.24) and being an ever smoker (OR, 1.70; 95% CI, 1.13-2.54). Having all three of these risk factors was strongly associated with RA-ILD (OR, 6.04; 95% CI, 2.92-12.47) and with RA-UIP in particular (OR, 7.1). “We found that a lot of the traditional RA-ILD risk factors like male sex, history of smoking, and seropositive status were most strongly associated with a UIP pattern,” Dr. McDermott said. “We think this is a first step in trying to understand how these different ILD subtypes may have different risk factors, pathogenesis, and potentially different treatments, prevention, and screening strategies.”

While clinicians wait for guidelines on systemic autoimmune rheumatic disease-associated ILD that are expected to be published by the ACR in 2024, he added that “we probably shouldn’t screen every single person with RA for ILD, but we need to identify people who have symptoms or findings on clinical exam. This study wasn’t designed to look specifically at who is at high risk, but I think we are moving toward that question: Who is high risk, and who’s asymptomatic [but] may need more screening?”

He pointed out limitations of the study, including its retrospective design and the fact that imaging was done for clinical purposes, “so it’s probably a higher risk group to begin with than the whole RA population,” he said. “We also didn’t have data on RA disease activity or erosions, some of these other measures that we think are important for understanding the full RA disease phenotype in these patients.”

Dr. Wheeler reported having no disclosures. Dr. Luedders reported that his study was supported by the VA, the Rheumatology Research Foundation, and the University of Nebraska Medical Center Mentored Scholars Program. Dr. McDermott reported that his study was supported by the Rheumatology Research Foundation.

SAN DIEGO — Clinically significant interstitial lung disease (ILD) is believed to occur in 5%-10% of patients with rheumatoid arthritis (RA), but robust data are lacking on how to best predict which patients face the highest risk for RA-associated ILD. However, the results of several studies presented at the American College of Rheumatology annual meeting indicate that researchers are making strides in this field of rheumatologic care.

Adding Genetic Factors Improves ILD Risk Prediction

In the realm of risk stratification, Austin M. Wheeler, MD, a rheumatology fellow at the University of Nebraska Medical Center, Omaha, discussed the development and validation of a combined clinical and genetic risk score for ILD. “There is clear and well documented phenotypic and genetic overlap of ILD with idiopathic pulmonary fibrosis (IPF),” Dr. Wheeler said. “A number of clinical risk factors have been described for RA-ILD, including older age, male sex, smoking history, higher disease activity, and seropositivity. There are also well-documented genetic risk factors for RA-ILD. The MUC5B genetic variant is the strongest risk factor for IPF, and it’s been described in RA-ILD as well.”

Dr. Wheeler

A recently published study indicated that a genetic risk score without the MUC5B variant improved predictive ability for IPF and interstitial lung abnormalities better than using the MUC5B variant alone, “but no prior attempts have been made at developing a composite genetic risk score in RA-ILD” using both genetic and clinical risk factors, he said.

For the current study, Dr. Wheeler and colleagues drew from 2,386 participants in the Veterans Affairs Rheumatoid Arthritis (VARA) Registry, a multicenter, prospective cohort of US veterans with rheumatologist-diagnosed RA and who fulfilled the 1987 ACR classification criteria. The researchers validated ILD through a systematic review of medical records, including clinical diagnosis of ILD plus either imaging or lung biopsy findings, and collected whole genome data that included 12 single nucleotide polymorphisms (SNPs) previously identified to be associated with risk for RA-ILD. They then used a meta-analytic approach to create pooled associations for each of those respective SNPs using data from the VARA registry participants as well as participants from the past study where the SNPs were first identified. “Those pooled associations were what we used for our effects size within the genetic risk score,” which ended up using five of the SNPs, Dr. Wheeler explained. Next, he and his colleagues combined the genetic risk score with clinical risk factors including age, sex, smoking history, disease activity, and rheumatoid factor (RF) positivity to create their combined risk score.

The mean age of the cohort was 70 years, 89% were male, 78% had a smoking history, and 78% were anti–cyclic citrullinated peptide (CCP) antibody positive. Of the 2,386 participants, 224 (9.4%) had RA-ILD. The full composite risk score had the highest area under the receiver operating curve (AUC) of 0.67, compared with an AUC of 0.623 using the clinical factors alone, 0.651 using the clinical factors plus only the MUC5B variant, and 0.654 using the composite score minus only the MUC5B variant. These AUCs show that “the combined risk score performs better than clinical factors even without the inclusion of the MUC5B variant in the score, which is notable because it supports the importance of further investigation into polygenic risk scores in RA-ILD as there is clearly more at play in a patient’s overall genetic risk,” Dr. Wheeler said.

As an example of the composite score’s ability to discriminate between people with and without RA-ILD, a cutpoint of 0.05 gave a sensitivity of 90.2% and would have eliminated about 25% of the cohort from unnecessary high-resolution CT scans and pulmonary function tests, he said.

“This study demonstrates the potential utility of genetic risk scores in RA-ILD identification and supports further investigation into individual risk stratification and screening,” he concluded. “This isn’t ready for clinical applicability by any means, but I think it serves as a proof of concept of the idea of a genetic risk score in RA-ILD.”

Biomarker Score Investigated

In a separate abstract, Brent Luedders, MD, assistant professor of rheumatology and immunology at the University of Nebraska Medical Center, and colleagues set out to determine if a previously derived biomarker score is associated with prevalent and incident ILD in the same VARA Registry cohort. An abstract presented at the ACR 2022 annual meeting found that a panel derived from IPF peripheral biomarkers was significantly associated with RA-ILD, including matrix metalloproteinase (MMP)-2, -7, and -9, eotaxin, macrophage-derived chemokine (MDC), monocyte chemoattractant protein-1 (MCP-1), fms-like tyrosine kinase 3 ligand (Flt3L) and interleukin-8 (IL-8). For the current analysis, Dr. Luedders and colleagues measured the concentrations of seven biomarkers (MMP-7, MMP-9, eotaxin, MDC, MCP-1, Flt3L, IL-8) from serum/plasma samples collected from VARA’s participants at enrollment to develop a score based on the concentrations of each biomarker.

Dr. Luedders

Baseline characteristics were similar between the groups, although those with prevalent RA-ILD were slightly older than those without ILD, and those who developed incident ILD during follow-up had slightly higher RA disease activity at the time of enrollment. When the researchers examined the association of the biomarker score with prevalent RA-ILD as a continuous measure, they found an adjusted OR of 1.08 for prevalent RA-ILD for each 1-point increase in the biomarker score. “When this was divided into quartiles, we found that the highest quartile of the biomarker score was associated with an adjusted odds ratio of 2.31 for prevalent RA-ILD,” Dr. Luedders said. “We saw a significant P for trend of < .001, suggesting a dose-response relationship, in which higher scores had higher risk.” Similar associations were observed for incident RA-ILD, in which participants with the highest quartile had an adjusted hazard ratio of 2.26 for incident RA-ILD.

The AUC of 0.653 that was obtained with clinical factors did not significantly improve with inclusion of the biomarker score, rising to only 0.669. “In receiver operating characteristic analysis, the addition of the biomarker score to clinical variables (age, sex, race, smoking status, anti-CCP positivity, and RA disease activity by DAS28) did not lead to a significant increase in the area under the curve. Therefore, further work is needed to identify combinations of clinical, biomarker, and other factors to accurately predict which people with RA will develop ILD,” he said.

Dr. Luedders acknowledged certain limitations of the results, including the fact that MMP-2 was not measured in this cohort and thus not included in the score. “This was an observational study with usual care; therefore, the absence of systemic evaluation for ILD may miss early or mild RA-ILD cases,” he added. “Similarly, a male predominance may limit the generalizability, and we have limited information on the RA-ILD pattern.” He concluded that the study results “support the shared pathogenesis of IPF and RA-ILD. However, we found that this score has limited discriminative performance, compared to clinical risk factors alone.”
 

Drilling Down on ILD Subtypes

In a poster abstract presentation at the meeting, Gregory Campbell McDermott, MD, MPH, a rheumatologist at Brigham and Women’s Hospital, Boston, highlighted results from a study that investigated differences in demographic, serologic, and lifestyle factors for RA-ILD and the major subtypes of RA-ILD: usual interstitial pneumonia (UIP) and nonspecific interstitial pneumonia (NSIP). “Historically, RA-ILD has been studied as a single entity, even though we increasingly recognized that there are lots of different subtypes that fall under the umbrella of RA-ILD,” Dr. McDermott said in an interview. “We are also learning that the different subtypes probably have both prognostic and potentially therapeutic implications. For example, the UIP subtype, which is the most fibrotic subtype, has the worst prognosis but also may be a potential target for antifibrotic therapies. We’ve been trying to see if we can identify factors that are associated with specific subtypes, in particular the UIP subtype which has the worst prognosis.”

Dr. McDermott

He and his colleagues examined 208 patients with RA-ILD with a mean age of 51 years and 547 patients with RA but no ILD with a mean age of 49 years from two RA cohorts comprising 3,328 patients: the Mass General Brigham Biobank RA Cohort and the Brigham RA Sequential Study (BRASS). Of the 208 RA-ILD cases, nearly half (48%) were RA-UIP, 18% were RA-NSIP, 8% were organizing pneumonia, 3% were respiratory bronchiolitis-ILD, and 23% were other/indeterminate. After conducting multivariable adjusted analyses, the researchers found that RA-ILD was associated with male sex (OR, 1.58; 95% CI, 1.09-2.23), seropositivity for RF and/or anti-CCP (OR, 2.22; 95% CI, 1.51-3.24) and being an ever smoker (OR, 1.70; 95% CI, 1.13-2.54). Having all three of these risk factors was strongly associated with RA-ILD (OR, 6.04; 95% CI, 2.92-12.47) and with RA-UIP in particular (OR, 7.1). “We found that a lot of the traditional RA-ILD risk factors like male sex, history of smoking, and seropositive status were most strongly associated with a UIP pattern,” Dr. McDermott said. “We think this is a first step in trying to understand how these different ILD subtypes may have different risk factors, pathogenesis, and potentially different treatments, prevention, and screening strategies.”

While clinicians wait for guidelines on systemic autoimmune rheumatic disease-associated ILD that are expected to be published by the ACR in 2024, he added that “we probably shouldn’t screen every single person with RA for ILD, but we need to identify people who have symptoms or findings on clinical exam. This study wasn’t designed to look specifically at who is at high risk, but I think we are moving toward that question: Who is high risk, and who’s asymptomatic [but] may need more screening?”

He pointed out limitations of the study, including its retrospective design and the fact that imaging was done for clinical purposes, “so it’s probably a higher risk group to begin with than the whole RA population,” he said. “We also didn’t have data on RA disease activity or erosions, some of these other measures that we think are important for understanding the full RA disease phenotype in these patients.”

Dr. Wheeler reported having no disclosures. Dr. Luedders reported that his study was supported by the VA, the Rheumatology Research Foundation, and the University of Nebraska Medical Center Mentored Scholars Program. Dr. McDermott reported that his study was supported by the Rheumatology Research Foundation.

SAN DIEGO — Clinically significant interstitial lung disease (ILD) is believed to occur in 5%-10% of patients with rheumatoid arthritis (RA), but robust data are lacking on how to best predict which patients face the highest risk for RA-associated ILD. However, the results of several studies presented at the American College of Rheumatology annual meeting indicate that researchers are making strides in this field of rheumatologic care.

Adding Genetic Factors Improves ILD Risk Prediction

In the realm of risk stratification, Austin M. Wheeler, MD, a rheumatology fellow at the University of Nebraska Medical Center, Omaha, discussed the development and validation of a combined clinical and genetic risk score for ILD. “There is clear and well documented phenotypic and genetic overlap of ILD with idiopathic pulmonary fibrosis (IPF),” Dr. Wheeler said. “A number of clinical risk factors have been described for RA-ILD, including older age, male sex, smoking history, higher disease activity, and seropositivity. There are also well-documented genetic risk factors for RA-ILD. The MUC5B genetic variant is the strongest risk factor for IPF, and it’s been described in RA-ILD as well.”

Dr. Wheeler

A recently published study indicated that a genetic risk score without the MUC5B variant improved predictive ability for IPF and interstitial lung abnormalities better than using the MUC5B variant alone, “but no prior attempts have been made at developing a composite genetic risk score in RA-ILD” using both genetic and clinical risk factors, he said.

For the current study, Dr. Wheeler and colleagues drew from 2,386 participants in the Veterans Affairs Rheumatoid Arthritis (VARA) Registry, a multicenter, prospective cohort of US veterans with rheumatologist-diagnosed RA and who fulfilled the 1987 ACR classification criteria. The researchers validated ILD through a systematic review of medical records, including clinical diagnosis of ILD plus either imaging or lung biopsy findings, and collected whole genome data that included 12 single nucleotide polymorphisms (SNPs) previously identified to be associated with risk for RA-ILD. They then used a meta-analytic approach to create pooled associations for each of those respective SNPs using data from the VARA registry participants as well as participants from the past study where the SNPs were first identified. “Those pooled associations were what we used for our effects size within the genetic risk score,” which ended up using five of the SNPs, Dr. Wheeler explained. Next, he and his colleagues combined the genetic risk score with clinical risk factors including age, sex, smoking history, disease activity, and rheumatoid factor (RF) positivity to create their combined risk score.

The mean age of the cohort was 70 years, 89% were male, 78% had a smoking history, and 78% were anti–cyclic citrullinated peptide (CCP) antibody positive. Of the 2,386 participants, 224 (9.4%) had RA-ILD. The full composite risk score had the highest area under the receiver operating curve (AUC) of 0.67, compared with an AUC of 0.623 using the clinical factors alone, 0.651 using the clinical factors plus only the MUC5B variant, and 0.654 using the composite score minus only the MUC5B variant. These AUCs show that “the combined risk score performs better than clinical factors even without the inclusion of the MUC5B variant in the score, which is notable because it supports the importance of further investigation into polygenic risk scores in RA-ILD as there is clearly more at play in a patient’s overall genetic risk,” Dr. Wheeler said.

As an example of the composite score’s ability to discriminate between people with and without RA-ILD, a cutpoint of 0.05 gave a sensitivity of 90.2% and would have eliminated about 25% of the cohort from unnecessary high-resolution CT scans and pulmonary function tests, he said.

“This study demonstrates the potential utility of genetic risk scores in RA-ILD identification and supports further investigation into individual risk stratification and screening,” he concluded. “This isn’t ready for clinical applicability by any means, but I think it serves as a proof of concept of the idea of a genetic risk score in RA-ILD.”

Biomarker Score Investigated

In a separate abstract, Brent Luedders, MD, assistant professor of rheumatology and immunology at the University of Nebraska Medical Center, and colleagues set out to determine if a previously derived biomarker score is associated with prevalent and incident ILD in the same VARA Registry cohort. An abstract presented at the ACR 2022 annual meeting found that a panel derived from IPF peripheral biomarkers was significantly associated with RA-ILD, including matrix metalloproteinase (MMP)-2, -7, and -9, eotaxin, macrophage-derived chemokine (MDC), monocyte chemoattractant protein-1 (MCP-1), fms-like tyrosine kinase 3 ligand (Flt3L) and interleukin-8 (IL-8). For the current analysis, Dr. Luedders and colleagues measured the concentrations of seven biomarkers (MMP-7, MMP-9, eotaxin, MDC, MCP-1, Flt3L, IL-8) from serum/plasma samples collected from VARA’s participants at enrollment to develop a score based on the concentrations of each biomarker.

Dr. Luedders

Baseline characteristics were similar between the groups, although those with prevalent RA-ILD were slightly older than those without ILD, and those who developed incident ILD during follow-up had slightly higher RA disease activity at the time of enrollment. When the researchers examined the association of the biomarker score with prevalent RA-ILD as a continuous measure, they found an adjusted OR of 1.08 for prevalent RA-ILD for each 1-point increase in the biomarker score. “When this was divided into quartiles, we found that the highest quartile of the biomarker score was associated with an adjusted odds ratio of 2.31 for prevalent RA-ILD,” Dr. Luedders said. “We saw a significant P for trend of < .001, suggesting a dose-response relationship, in which higher scores had higher risk.” Similar associations were observed for incident RA-ILD, in which participants with the highest quartile had an adjusted hazard ratio of 2.26 for incident RA-ILD.

The AUC of 0.653 that was obtained with clinical factors did not significantly improve with inclusion of the biomarker score, rising to only 0.669. “In receiver operating characteristic analysis, the addition of the biomarker score to clinical variables (age, sex, race, smoking status, anti-CCP positivity, and RA disease activity by DAS28) did not lead to a significant increase in the area under the curve. Therefore, further work is needed to identify combinations of clinical, biomarker, and other factors to accurately predict which people with RA will develop ILD,” he said.

Dr. Luedders acknowledged certain limitations of the results, including the fact that MMP-2 was not measured in this cohort and thus not included in the score. “This was an observational study with usual care; therefore, the absence of systemic evaluation for ILD may miss early or mild RA-ILD cases,” he added. “Similarly, a male predominance may limit the generalizability, and we have limited information on the RA-ILD pattern.” He concluded that the study results “support the shared pathogenesis of IPF and RA-ILD. However, we found that this score has limited discriminative performance, compared to clinical risk factors alone.”
 

Drilling Down on ILD Subtypes

In a poster abstract presentation at the meeting, Gregory Campbell McDermott, MD, MPH, a rheumatologist at Brigham and Women’s Hospital, Boston, highlighted results from a study that investigated differences in demographic, serologic, and lifestyle factors for RA-ILD and the major subtypes of RA-ILD: usual interstitial pneumonia (UIP) and nonspecific interstitial pneumonia (NSIP). “Historically, RA-ILD has been studied as a single entity, even though we increasingly recognized that there are lots of different subtypes that fall under the umbrella of RA-ILD,” Dr. McDermott said in an interview. “We are also learning that the different subtypes probably have both prognostic and potentially therapeutic implications. For example, the UIP subtype, which is the most fibrotic subtype, has the worst prognosis but also may be a potential target for antifibrotic therapies. We’ve been trying to see if we can identify factors that are associated with specific subtypes, in particular the UIP subtype which has the worst prognosis.”

Dr. McDermott

He and his colleagues examined 208 patients with RA-ILD with a mean age of 51 years and 547 patients with RA but no ILD with a mean age of 49 years from two RA cohorts comprising 3,328 patients: the Mass General Brigham Biobank RA Cohort and the Brigham RA Sequential Study (BRASS). Of the 208 RA-ILD cases, nearly half (48%) were RA-UIP, 18% were RA-NSIP, 8% were organizing pneumonia, 3% were respiratory bronchiolitis-ILD, and 23% were other/indeterminate. After conducting multivariable adjusted analyses, the researchers found that RA-ILD was associated with male sex (OR, 1.58; 95% CI, 1.09-2.23), seropositivity for RF and/or anti-CCP (OR, 2.22; 95% CI, 1.51-3.24) and being an ever smoker (OR, 1.70; 95% CI, 1.13-2.54). Having all three of these risk factors was strongly associated with RA-ILD (OR, 6.04; 95% CI, 2.92-12.47) and with RA-UIP in particular (OR, 7.1). “We found that a lot of the traditional RA-ILD risk factors like male sex, history of smoking, and seropositive status were most strongly associated with a UIP pattern,” Dr. McDermott said. “We think this is a first step in trying to understand how these different ILD subtypes may have different risk factors, pathogenesis, and potentially different treatments, prevention, and screening strategies.”

While clinicians wait for guidelines on systemic autoimmune rheumatic disease-associated ILD that are expected to be published by the ACR in 2024, he added that “we probably shouldn’t screen every single person with RA for ILD, but we need to identify people who have symptoms or findings on clinical exam. This study wasn’t designed to look specifically at who is at high risk, but I think we are moving toward that question: Who is high risk, and who’s asymptomatic [but] may need more screening?”

He pointed out limitations of the study, including its retrospective design and the fact that imaging was done for clinical purposes, “so it’s probably a higher risk group to begin with than the whole RA population,” he said. “We also didn’t have data on RA disease activity or erosions, some of these other measures that we think are important for understanding the full RA disease phenotype in these patients.”

Dr. Wheeler reported having no disclosures. Dr. Luedders reported that his study was supported by the VA, the Rheumatology Research Foundation, and the University of Nebraska Medical Center Mentored Scholars Program. Dr. McDermott reported that his study was supported by the Rheumatology Research Foundation.

In a new report, the Midwest Institute for Clinical and Economic Review’s (ICER) Comparative Effectiveness Public Advisory Council concluded that the Merck drug sotatercept, currently under review by the US Food and Drug Administration (FDA), has a high certainty of at least a small net health benefit to patients with pulmonary arterial hypertension (PAH) when added to background therapy. The limited availability of evidence means that the benefit could range from minimal to substantial, according to the authors. 

Sotatercept, administered by injection every 3 weeks, is a first-in-class activin signaling inhibitor. It counters cell proliferation and decreases inflammation in vessel walls, which may lead to improved pulmonary blood flow. The US FDA is considering it for approval through a biologics license application, with a decision expected by March 26, 2024.

There remains a great deal of uncertainty surrounding the long-term benefits of sotatercept. It’s possible that the drug is disease-modifying, but there isn’t yet any proof, according to Greg Curfman, MD, who attended a virtual ICER public meeting on December 1 that summarized the report and accepted public comments. “I’m still wondering the extent to which disease-modifying issue here is more aspirational at this point than really documented,” said Dr. Curfman, who is an associated professor of medicine at Harvard Medical School and executive editor of the Journal of the American Medical Association.

Current PAH treatment consists of vasodilators, including phosphodiesterase-5 inhibitors (PDE5i), guanylate cyclase stimulators, endothelin receptor antagonists (ERA), prostacyclin analogues (prostanoids), and a prostacyclin receptor agonist. The 2022 European Society of Cardiology and the European Respiratory Society clinical practice guideline recommends that low- and intermediate-risk patients should be started on ERA/PDE5i combination therapy, while high-risk patients should also be given an intravenous or subcutaneous prostacyclin analogue, referred to as triple therapy.

Sotatercept’s regulatory approval hinges on the phase 3 STELLAR trial, which included 323 patients with World Health Organization functional class (WHO-FC) II and III PAH who were randomized to 0.75 mg/kg sotatercept in addition to background double or triple therapy, or background therapy alone. The mean age was 48 years, and the mean time since diagnosis was 8.8 years. About 40% received infused prostacyclin therapy at baseline. At 24 weeks, the median change in 6-min walking distance (6mWD) was 40.8 m longer in the sotatercept group. More patients in the sotatercept group experienced WHO-FC improvement (29.4% vs 13.8%). Those in the sotatercept group also experienced an 84% reduction in risk for clinical worsening or death. PAH-specific quality of life scales did not show a difference between the two groups. Open-label extension trials have shown that benefits are maintained for up to 2 years. Adverse events likely related to sotatercept included telangiectasias, increased hemoglobin levels, and bleeding events.

Along with its benefits, the report authors suggest that the subcutaneous delivery of sotatercept may be less burdensome to patients than some other PAH treatments, especially inhaled and intravenous prostanoids. “However, uncertainty remains about sotatercept’s efficacy in sicker populations and in those with connective tissue disease, and about the durability of effect,” the authors wrote.

A lack of long-term data leaves open the question of its effect on mortality and unknown adverse effects.

Using a de novo decision analytic model, the authors estimated that sotatercept treatment would lead to a longer time without symptoms at rest and more quality-adjusted life years, life years, and equal value life years. They determined the health benefit price benchmark for sotatercept to be between $18,700 and $36,200 per year. “The long-term conventional cost-effectiveness of sotatercept is largely dependent on the long-term effect of sotatercept on improving functional class and slowing the worsening in functional class; however, controlled trial evidence for sotatercept is limited to 24 weeks. Long-term data are necessary to reduce the uncertainty in sotatercept’s long-term effect on improving functional class and slowing the worsening in functional class,” the authors wrote. 

During the online meeting, Dr. Curfman took note of the fact that the STELLAR trial reported a median value of increase in 6mWD, rather than a mean, and the 40-m improvement is close to the value accepted as clinically meaningful. “So that tells us that half the patients had less than a clinically important improvement in the six-minute walk distance. We should be putting that in perspective,” said Dr. Curfman.

Another attendee pointed out that the open-label PULSAR extension trial showed that the proportion of patients in the sotatercept arm who were functional class I rose from 7.5% at the end of the trial to 20.6% at the end of the open-label period and wondered if that could be a sign of disease-modifying activity. “I think that’s a remarkable piece of data. I don’t recall seeing that in any other open label [trial of a PAH therapy] — that much of an improvement in getting to our best functional status,” said Marc Simon, MD, professor of medicine and director of the Pulmonary Hypertension Center at the University of California, San Francisco, who was a coauthor of the report.

Dr. Curfman has no relevant financial disclosures. Dr. Simon has consulted for Merck.

A version of this article appeared on Medscape.com.

In a new report, the Midwest Institute for Clinical and Economic Review’s (ICER) Comparative Effectiveness Public Advisory Council concluded that the Merck drug sotatercept, currently under review by the US Food and Drug Administration (FDA), has a high certainty of at least a small net health benefit to patients with pulmonary arterial hypertension (PAH) when added to background therapy. The limited availability of evidence means that the benefit could range from minimal to substantial, according to the authors. 

Sotatercept, administered by injection every 3 weeks, is a first-in-class activin signaling inhibitor. It counters cell proliferation and decreases inflammation in vessel walls, which may lead to improved pulmonary blood flow. The US FDA is considering it for approval through a biologics license application, with a decision expected by March 26, 2024.

There remains a great deal of uncertainty surrounding the long-term benefits of sotatercept. It’s possible that the drug is disease-modifying, but there isn’t yet any proof, according to Greg Curfman, MD, who attended a virtual ICER public meeting on December 1 that summarized the report and accepted public comments. “I’m still wondering the extent to which disease-modifying issue here is more aspirational at this point than really documented,” said Dr. Curfman, who is an associated professor of medicine at Harvard Medical School and executive editor of the Journal of the American Medical Association.

Current PAH treatment consists of vasodilators, including phosphodiesterase-5 inhibitors (PDE5i), guanylate cyclase stimulators, endothelin receptor antagonists (ERA), prostacyclin analogues (prostanoids), and a prostacyclin receptor agonist. The 2022 European Society of Cardiology and the European Respiratory Society clinical practice guideline recommends that low- and intermediate-risk patients should be started on ERA/PDE5i combination therapy, while high-risk patients should also be given an intravenous or subcutaneous prostacyclin analogue, referred to as triple therapy.

Sotatercept’s regulatory approval hinges on the phase 3 STELLAR trial, which included 323 patients with World Health Organization functional class (WHO-FC) II and III PAH who were randomized to 0.75 mg/kg sotatercept in addition to background double or triple therapy, or background therapy alone. The mean age was 48 years, and the mean time since diagnosis was 8.8 years. About 40% received infused prostacyclin therapy at baseline. At 24 weeks, the median change in 6-min walking distance (6mWD) was 40.8 m longer in the sotatercept group. More patients in the sotatercept group experienced WHO-FC improvement (29.4% vs 13.8%). Those in the sotatercept group also experienced an 84% reduction in risk for clinical worsening or death. PAH-specific quality of life scales did not show a difference between the two groups. Open-label extension trials have shown that benefits are maintained for up to 2 years. Adverse events likely related to sotatercept included telangiectasias, increased hemoglobin levels, and bleeding events.

Along with its benefits, the report authors suggest that the subcutaneous delivery of sotatercept may be less burdensome to patients than some other PAH treatments, especially inhaled and intravenous prostanoids. “However, uncertainty remains about sotatercept’s efficacy in sicker populations and in those with connective tissue disease, and about the durability of effect,” the authors wrote.

A lack of long-term data leaves open the question of its effect on mortality and unknown adverse effects.

Using a de novo decision analytic model, the authors estimated that sotatercept treatment would lead to a longer time without symptoms at rest and more quality-adjusted life years, life years, and equal value life years. They determined the health benefit price benchmark for sotatercept to be between $18,700 and $36,200 per year. “The long-term conventional cost-effectiveness of sotatercept is largely dependent on the long-term effect of sotatercept on improving functional class and slowing the worsening in functional class; however, controlled trial evidence for sotatercept is limited to 24 weeks. Long-term data are necessary to reduce the uncertainty in sotatercept’s long-term effect on improving functional class and slowing the worsening in functional class,” the authors wrote. 

During the online meeting, Dr. Curfman took note of the fact that the STELLAR trial reported a median value of increase in 6mWD, rather than a mean, and the 40-m improvement is close to the value accepted as clinically meaningful. “So that tells us that half the patients had less than a clinically important improvement in the six-minute walk distance. We should be putting that in perspective,” said Dr. Curfman.

Another attendee pointed out that the open-label PULSAR extension trial showed that the proportion of patients in the sotatercept arm who were functional class I rose from 7.5% at the end of the trial to 20.6% at the end of the open-label period and wondered if that could be a sign of disease-modifying activity. “I think that’s a remarkable piece of data. I don’t recall seeing that in any other open label [trial of a PAH therapy] — that much of an improvement in getting to our best functional status,” said Marc Simon, MD, professor of medicine and director of the Pulmonary Hypertension Center at the University of California, San Francisco, who was a coauthor of the report.

Dr. Curfman has no relevant financial disclosures. Dr. Simon has consulted for Merck.

A version of this article appeared on Medscape.com.

In a new report, the Midwest Institute for Clinical and Economic Review’s (ICER) Comparative Effectiveness Public Advisory Council concluded that the Merck drug sotatercept, currently under review by the US Food and Drug Administration (FDA), has a high certainty of at least a small net health benefit to patients with pulmonary arterial hypertension (PAH) when added to background therapy. The limited availability of evidence means that the benefit could range from minimal to substantial, according to the authors. 

Sotatercept, administered by injection every 3 weeks, is a first-in-class activin signaling inhibitor. It counters cell proliferation and decreases inflammation in vessel walls, which may lead to improved pulmonary blood flow. The US FDA is considering it for approval through a biologics license application, with a decision expected by March 26, 2024.

There remains a great deal of uncertainty surrounding the long-term benefits of sotatercept. It’s possible that the drug is disease-modifying, but there isn’t yet any proof, according to Greg Curfman, MD, who attended a virtual ICER public meeting on December 1 that summarized the report and accepted public comments. “I’m still wondering the extent to which disease-modifying issue here is more aspirational at this point than really documented,” said Dr. Curfman, who is an associated professor of medicine at Harvard Medical School and executive editor of the Journal of the American Medical Association.

Current PAH treatment consists of vasodilators, including phosphodiesterase-5 inhibitors (PDE5i), guanylate cyclase stimulators, endothelin receptor antagonists (ERA), prostacyclin analogues (prostanoids), and a prostacyclin receptor agonist. The 2022 European Society of Cardiology and the European Respiratory Society clinical practice guideline recommends that low- and intermediate-risk patients should be started on ERA/PDE5i combination therapy, while high-risk patients should also be given an intravenous or subcutaneous prostacyclin analogue, referred to as triple therapy.

Sotatercept’s regulatory approval hinges on the phase 3 STELLAR trial, which included 323 patients with World Health Organization functional class (WHO-FC) II and III PAH who were randomized to 0.75 mg/kg sotatercept in addition to background double or triple therapy, or background therapy alone. The mean age was 48 years, and the mean time since diagnosis was 8.8 years. About 40% received infused prostacyclin therapy at baseline. At 24 weeks, the median change in 6-min walking distance (6mWD) was 40.8 m longer in the sotatercept group. More patients in the sotatercept group experienced WHO-FC improvement (29.4% vs 13.8%). Those in the sotatercept group also experienced an 84% reduction in risk for clinical worsening or death. PAH-specific quality of life scales did not show a difference between the two groups. Open-label extension trials have shown that benefits are maintained for up to 2 years. Adverse events likely related to sotatercept included telangiectasias, increased hemoglobin levels, and bleeding events.

Along with its benefits, the report authors suggest that the subcutaneous delivery of sotatercept may be less burdensome to patients than some other PAH treatments, especially inhaled and intravenous prostanoids. “However, uncertainty remains about sotatercept’s efficacy in sicker populations and in those with connective tissue disease, and about the durability of effect,” the authors wrote.

A lack of long-term data leaves open the question of its effect on mortality and unknown adverse effects.

Using a de novo decision analytic model, the authors estimated that sotatercept treatment would lead to a longer time without symptoms at rest and more quality-adjusted life years, life years, and equal value life years. They determined the health benefit price benchmark for sotatercept to be between $18,700 and $36,200 per year. “The long-term conventional cost-effectiveness of sotatercept is largely dependent on the long-term effect of sotatercept on improving functional class and slowing the worsening in functional class; however, controlled trial evidence for sotatercept is limited to 24 weeks. Long-term data are necessary to reduce the uncertainty in sotatercept’s long-term effect on improving functional class and slowing the worsening in functional class,” the authors wrote. 

During the online meeting, Dr. Curfman took note of the fact that the STELLAR trial reported a median value of increase in 6mWD, rather than a mean, and the 40-m improvement is close to the value accepted as clinically meaningful. “So that tells us that half the patients had less than a clinically important improvement in the six-minute walk distance. We should be putting that in perspective,” said Dr. Curfman.

Another attendee pointed out that the open-label PULSAR extension trial showed that the proportion of patients in the sotatercept arm who were functional class I rose from 7.5% at the end of the trial to 20.6% at the end of the open-label period and wondered if that could be a sign of disease-modifying activity. “I think that’s a remarkable piece of data. I don’t recall seeing that in any other open label [trial of a PAH therapy] — that much of an improvement in getting to our best functional status,” said Marc Simon, MD, professor of medicine and director of the Pulmonary Hypertension Center at the University of California, San Francisco, who was a coauthor of the report.

Dr. Curfman has no relevant financial disclosures. Dr. Simon has consulted for Merck.

A version of this article appeared on Medscape.com.

No one planning holiday gatherings or travel wants to hear this, but the rise of a new COVID-19 variant, JN.1, is concerning experts, who say it may threaten those good times. 

The good news is recent research suggests the 2023-2024 COVID-19 vaccine appears to work against this newest variant. But so few people have gotten the latest vaccine — less than 16% of U.S. adults — that some experts suggest it’s time for the CDC to urge the public who haven’t it to do so now, so the antibodies can kick in before the festivities.

“A significant wave [of JN.1] has started here and could be blunted with a high booster rate and mitigation measures,” said Eric Topol, MD, professor and executive vice president of Scripps Research in La Jolla, CA, and editor-in-chief of Medscape, a sister site of this news organization.

COVID metrics, meanwhile, have started to climb again. Nearly 10,000 people were hospitalized for COVID in the U.S. for the week ending Nov. 25, the CDC said, a 10% increase over the previous week. 
 

Who’s Who in the Family Tree

JN.1, an Omicron subvariant, was first detected in the U.S. in September and is termed “a notable descendent lineage” of Omicron subvariant BA.2.86 by the World Health Organization. When BA.2.86, also known as Pirola, was first identified in August, it appeared very different from other variants, the CDC said. That triggered concerns it might be more infectious than previous ones, even for people with immunity from vaccination and previous infections. 

“JN.1 is Pirola’s kid,” said Rajendram Rajnarayanan, PhD, assistant dean of research and associate professor at the New York Institute of Technology at Arkansas State University, who maintains a COVID-19 variant database. The variant BA.2.86 and offspring are worrisome due to the mutations, he said.
 

How Widespread Is JN.1?

As of Nov. 27, the CDC says, BA.2.86 is projected to comprise 5%-15% of circulating variants in the U.S. “The expected public health risk of this variant, including its offshoot JN.1, is low,” the agency said.

Currently, JN.1 is reported more often in Europe, Dr. Rajnarayanan said, but some countries have better reporting data than others. “It has probably spread to every country tracking COVID,’’ he said, due to the mutations in the spike protein that make it easier for it to bind and infect.

Wastewater data suggest the variant’s rise is helping to fuel a wave, Dr. Topol said. 
 

Vaccine Effectiveness Against JN.1, Other New Variants 

The new XBB.1.5 monovalent vaccine, protects against XBB.1.5, another Omicron subvariant, but also JN.1 and other “emergent” viruses, a team of researchers reported Nov. 26 in a study on bioRxiv that has not yet been certified by peer review.

The updated vaccine, when given to uninfected people, boosted antibodies about 27-fold against XBB.1.5 and about 13- to 27-fold against JN.1 and other emergent viruses, the researchers reported.

While even primary doses of the COVID vaccine will likely help protect against the new JN.1 subvariant, “if you got the XBB.1.5 booster, it is going to be protecting you better against this new variant,” Dr. Rajnarayanan said.
 

2023-2024 Vaccine Uptake Low 

In November, the CDC posted the first detailed estimates of who did. As of Nov. 18, less than 16% of U.S. adults had, with nearly 15% saying they planned to get it.

Coverage among children is lower, with just 6.3% of children up to date on the newest vaccine and 19% of parents saying they planned to get the 2023-2024 vaccine for their children.
 

Predictions, Mitigation

While some experts say a peak due to JN.1 is expected in the weeks ahead, Dr. Topol said it’s impossible to predict exactly how JN.1 will play out.

“It’s not going to be a repeat of November 2021,” when Omicron surfaced, Dr. Rajnarayanan predicted. Within 4 weeks of the World Health Organization declaring Omicron as a virus of concern, it spread around the world.

Mitigation measures can help, Dr. Rajnarayanan said. He suggested:

Get the new vaccine, and especially encourage vulnerable family and friends to do so.

If you are gathering inside for holiday festivities, improve circulation in the house, if possible.

Wear masks in airports and on planes and other public transportation.

A version of this article appeared on WebMD.com.

No one planning holiday gatherings or travel wants to hear this, but the rise of a new COVID-19 variant, JN.1, is concerning experts, who say it may threaten those good times. 

The good news is recent research suggests the 2023-2024 COVID-19 vaccine appears to work against this newest variant. But so few people have gotten the latest vaccine — less than 16% of U.S. adults — that some experts suggest it’s time for the CDC to urge the public who haven’t it to do so now, so the antibodies can kick in before the festivities.

“A significant wave [of JN.1] has started here and could be blunted with a high booster rate and mitigation measures,” said Eric Topol, MD, professor and executive vice president of Scripps Research in La Jolla, CA, and editor-in-chief of Medscape, a sister site of this news organization.

COVID metrics, meanwhile, have started to climb again. Nearly 10,000 people were hospitalized for COVID in the U.S. for the week ending Nov. 25, the CDC said, a 10% increase over the previous week. 
 

Who’s Who in the Family Tree

JN.1, an Omicron subvariant, was first detected in the U.S. in September and is termed “a notable descendent lineage” of Omicron subvariant BA.2.86 by the World Health Organization. When BA.2.86, also known as Pirola, was first identified in August, it appeared very different from other variants, the CDC said. That triggered concerns it might be more infectious than previous ones, even for people with immunity from vaccination and previous infections. 

“JN.1 is Pirola’s kid,” said Rajendram Rajnarayanan, PhD, assistant dean of research and associate professor at the New York Institute of Technology at Arkansas State University, who maintains a COVID-19 variant database. The variant BA.2.86 and offspring are worrisome due to the mutations, he said.
 

How Widespread Is JN.1?

As of Nov. 27, the CDC says, BA.2.86 is projected to comprise 5%-15% of circulating variants in the U.S. “The expected public health risk of this variant, including its offshoot JN.1, is low,” the agency said.

Currently, JN.1 is reported more often in Europe, Dr. Rajnarayanan said, but some countries have better reporting data than others. “It has probably spread to every country tracking COVID,’’ he said, due to the mutations in the spike protein that make it easier for it to bind and infect.

Wastewater data suggest the variant’s rise is helping to fuel a wave, Dr. Topol said. 
 

Vaccine Effectiveness Against JN.1, Other New Variants 

The new XBB.1.5 monovalent vaccine, protects against XBB.1.5, another Omicron subvariant, but also JN.1 and other “emergent” viruses, a team of researchers reported Nov. 26 in a study on bioRxiv that has not yet been certified by peer review.

The updated vaccine, when given to uninfected people, boosted antibodies about 27-fold against XBB.1.5 and about 13- to 27-fold against JN.1 and other emergent viruses, the researchers reported.

While even primary doses of the COVID vaccine will likely help protect against the new JN.1 subvariant, “if you got the XBB.1.5 booster, it is going to be protecting you better against this new variant,” Dr. Rajnarayanan said.
 

2023-2024 Vaccine Uptake Low 

In November, the CDC posted the first detailed estimates of who did. As of Nov. 18, less than 16% of U.S. adults had, with nearly 15% saying they planned to get it.

Coverage among children is lower, with just 6.3% of children up to date on the newest vaccine and 19% of parents saying they planned to get the 2023-2024 vaccine for their children.
 

Predictions, Mitigation

While some experts say a peak due to JN.1 is expected in the weeks ahead, Dr. Topol said it’s impossible to predict exactly how JN.1 will play out.

“It’s not going to be a repeat of November 2021,” when Omicron surfaced, Dr. Rajnarayanan predicted. Within 4 weeks of the World Health Organization declaring Omicron as a virus of concern, it spread around the world.

Mitigation measures can help, Dr. Rajnarayanan said. He suggested:

Get the new vaccine, and especially encourage vulnerable family and friends to do so.

If you are gathering inside for holiday festivities, improve circulation in the house, if possible.

Wear masks in airports and on planes and other public transportation.

A version of this article appeared on WebMD.com.

No one planning holiday gatherings or travel wants to hear this, but the rise of a new COVID-19 variant, JN.1, is concerning experts, who say it may threaten those good times. 

The good news is recent research suggests the 2023-2024 COVID-19 vaccine appears to work against this newest variant. But so few people have gotten the latest vaccine — less than 16% of U.S. adults — that some experts suggest it’s time for the CDC to urge the public who haven’t it to do so now, so the antibodies can kick in before the festivities.

“A significant wave [of JN.1] has started here and could be blunted with a high booster rate and mitigation measures,” said Eric Topol, MD, professor and executive vice president of Scripps Research in La Jolla, CA, and editor-in-chief of Medscape, a sister site of this news organization.

COVID metrics, meanwhile, have started to climb again. Nearly 10,000 people were hospitalized for COVID in the U.S. for the week ending Nov. 25, the CDC said, a 10% increase over the previous week. 
 

Who’s Who in the Family Tree

JN.1, an Omicron subvariant, was first detected in the U.S. in September and is termed “a notable descendent lineage” of Omicron subvariant BA.2.86 by the World Health Organization. When BA.2.86, also known as Pirola, was first identified in August, it appeared very different from other variants, the CDC said. That triggered concerns it might be more infectious than previous ones, even for people with immunity from vaccination and previous infections. 

“JN.1 is Pirola’s kid,” said Rajendram Rajnarayanan, PhD, assistant dean of research and associate professor at the New York Institute of Technology at Arkansas State University, who maintains a COVID-19 variant database. The variant BA.2.86 and offspring are worrisome due to the mutations, he said.
 

How Widespread Is JN.1?

As of Nov. 27, the CDC says, BA.2.86 is projected to comprise 5%-15% of circulating variants in the U.S. “The expected public health risk of this variant, including its offshoot JN.1, is low,” the agency said.

Currently, JN.1 is reported more often in Europe, Dr. Rajnarayanan said, but some countries have better reporting data than others. “It has probably spread to every country tracking COVID,’’ he said, due to the mutations in the spike protein that make it easier for it to bind and infect.

Wastewater data suggest the variant’s rise is helping to fuel a wave, Dr. Topol said. 
 

Vaccine Effectiveness Against JN.1, Other New Variants 

The new XBB.1.5 monovalent vaccine, protects against XBB.1.5, another Omicron subvariant, but also JN.1 and other “emergent” viruses, a team of researchers reported Nov. 26 in a study on bioRxiv that has not yet been certified by peer review.

The updated vaccine, when given to uninfected people, boosted antibodies about 27-fold against XBB.1.5 and about 13- to 27-fold against JN.1 and other emergent viruses, the researchers reported.

While even primary doses of the COVID vaccine will likely help protect against the new JN.1 subvariant, “if you got the XBB.1.5 booster, it is going to be protecting you better against this new variant,” Dr. Rajnarayanan said.
 

2023-2024 Vaccine Uptake Low 

In November, the CDC posted the first detailed estimates of who did. As of Nov. 18, less than 16% of U.S. adults had, with nearly 15% saying they planned to get it.

Coverage among children is lower, with just 6.3% of children up to date on the newest vaccine and 19% of parents saying they planned to get the 2023-2024 vaccine for their children.
 

Predictions, Mitigation

While some experts say a peak due to JN.1 is expected in the weeks ahead, Dr. Topol said it’s impossible to predict exactly how JN.1 will play out.

“It’s not going to be a repeat of November 2021,” when Omicron surfaced, Dr. Rajnarayanan predicted. Within 4 weeks of the World Health Organization declaring Omicron as a virus of concern, it spread around the world.

Mitigation measures can help, Dr. Rajnarayanan said. He suggested:

Get the new vaccine, and especially encourage vulnerable family and friends to do so.

If you are gathering inside for holiday festivities, improve circulation in the house, if possible.

Wear masks in airports and on planes and other public transportation.

A version of this article appeared on WebMD.com.

PHILADELPHIA — Promise that the unmet need for more effective pulmonary artery hypertension treatments may soon be met was in strong evidence in research into three strategies presented at this year’s recent American Heart Association scientific sessions; one was based on an ancient Chinese herb epimedium (yin yang huo or horny goat weed) commonly used for treating sexual dysfunction and directly related to the phosphodiesterase inhibitors sildenafil, vardenafil, and tadalafil (sold as Viagra, Levitra, and Cialis). A second studied sotatercept, an investigational, potential first-in-class activin signaling inhibitor biologic, and a third evaluated physically ablating the baroreceptor nerves that stimulate vasoconstriction of the pulmonary artery via catheter-based techniques.

Until as recently as the late 1970s, a pulmonary arterial hypertension diagnosis was a uniformly fatal one.¹ While targeted therapies have since improved prognosis, pulmonary arterial hypertension remains a chronic and progressive disorder of the pulmonary vasculature with significant morbidity and mortality associated with pulmonary and right ventricle remodeling, and leads toward heart failure and death. The complex underlying pathogenesis was divided into six groups by the 6th World Symposium on Pulmonary Hypertension (WSPH) in 2018, and includes as its most common features pulmonary artery endothelial cell dysfunction, pulmonary artery smooth muscle cell proliferation and migration, and dysregulated fibroblast activity leading to dysregulated vasoconstriction, micro and in-situ vascular thrombosis, vascular fibrosis and pathogenic remodeling of pulmonary vessels.¹ The threshold mean arterial pressure (mPAP) for pulmonary arterial hypertension was defined by the 6th [WSPH] at mPAP ≥ 20 mm Hg, twice the upper limit of a normal mPAP of 14.0 ± 3.3 mm Hg as reported by Kovacs et al. in 2018.²

Pathways for current therapies

Current drugs for pulmonary arterial hypertension focus on three signaling pathways, including the endothelin receptor, prostacyclin and nitric oxide pathways, stated Zhi-Cheng Jing, MD, professor of medicine, head of the cardiology department at Peking Union Medical College Hospital, Peking, China. While the phosphodiesterase 5 inhibitors sildenafil and tadalafil, which target the nitric oxide pathway, came into wide use after Food and Drug Administration approval, the need for higher PDE5-selectivity remains, Dr. Jing said. Structurally modified from the active ingredient in epimedium, TPN171H is an investigational PDE5 inhibitor which has shown several favorable features: a greater PDE5 selectivity than both sildenafil and tadalafil in vitro, an ability to decrease right ventricular systolic pressure and alleviate arterial remodeling in animal studies, and safety and tolerability in healthy human subjects.

The current randomized, double-blind, placebo-and active-controlled phase IIa study assessed the hemodynamic impact of a single oral dose of TPN171H in 60 pulmonary arterial hypertension patients (mean age ~34 years, 83.3% female), all with negative vasodilation test results and in WHO class 2 or 3. Only patients aged 18-75 years with group 1 pulmonary arterial hypertension of idiopathic, connective tissue disorder, or repaired congenital heart defects etiology were included. Patients were divided into six groups: placebo, TPN171H at 2.5, 5, and 10 milligrams, and tadalafil at 20 and 40 milligrams.

For the primary endpoint of maximum decrease in pulmonary vascular resistance (PVR), significant reductions vs. placebo were found only for the TPN171H 5-mg group (–41.2% vs. –24.4%; P = .008) and for the 20-mg (–39.8%) and 40-mg (–37.6%) tadalafil groups (both P < .05). What was not seen in the tadalafil groups, but was evident in the TPN171H 5-mg group, was a significant reduction in the secondary endpoint of PVR/SVR (systolic vascular resistance) at 2, 3, and 5 hours (all P < .05). “As we know,” Dr. Jing said in an interview, “the PDE5 inhibitor functions as a vasodilator, having an impact on both pulmonary circulation and systemic circulation. So, to evaluate the  selectivity for pulmonary circulation is crucial when exploring a novel drug for pulmonary arterial hypertension. The change of PVR/SVR ratio from baseline is an indicator for selectivity for pulmonary circulation and implies that TPN171H has good PDE5 selectivity in the pulmonary vasculature,” Dr. Jing said.

TPN171H was well tolerated with no serious adverse effects (vomiting 10% and headache 10% were most common with no discontinuations).
 

TGF-signaling pathway

A meta-analysis of randomized controlled trials of sotatercept, an investigational fusion protein under priority FDA review that modulates the TGF-beta superfamily signaling pathway, looked at PVR, pulmonary arterial pressure (PAP), right arterial pressure (RAP) and N-terminal pro-brain natriuretic peptide (NT-proBNP). A literature search by corresponding author Vamsikalyan Borra, MD, Knapp Medical Center, Weslaco, Texas, and colleagues identified two trials (STELLAR and PULSAR) comprising 429 patients with pulmonary arterial hypertension. The experimental arms (sotatercept) had 237 patients (mean age ~49 years, ~82% female) and the placebo arm had 192 patients (mean age ~47 years, ~80% female).

A pooled analysis showed significant reductions with sotatercept in PVR (standardization mean difference [SMD] = –1.00, 95% confidence interval [CI] = –1.2, –.79, P < .001), PAP (SMD = –1.34, 95% CI = 1.6, –1.08, P < .001), RAP (SMD = –0.66, 95% CI = –0.93, –0.39, P < .001), and the levels of NT-proBNP (SMD = –0.64, 95% CI = –1.01, –0.27, P < .001) at 24 weeks from baseline. The sotatercept safety profile was favorable, with lower overall incidence of adverse events (84.8% vs. 87.5%) and fewer adverse events leading to death (0.4% vs. 3.1%) compared with placebo. Further investigation is needed, however, according to Dr. Borra, into the higher frequency of reported thrombocytopenia (71.7% vs. 20.8%) with sotatercept. “Our findings,” Dr. Borra said in a poster session, “suggest that sotatercept is an effective treatment option for pulmonary arterial hypertension, with the potential to improve both pulmonary and cardiac function.”
 

Denervation technique

Catheter-based ablation techniques, most commonly using thermal energy, target the afferent and efferent fibers of the baroreceptor reflex in the main pulmonary artery trunk and bifurcation involved in elevated pulmonary artery pressure. Mounica Vorla, MD, Carle Foundation Hospital, Urbana, Illinois, and colleagues conducted an updated systematic review and meta-analysis of the safety and efficacy of pulmonary artery denervation (PADN) for pulmonary arterial hypertension in seven clinical trials with 506 patients with moderate-severe pulmonary arterial hypertension conducted from 2013 to 2022.

Compared with placebo, PADN treatment was associated with a significant reduction in mean pulmonary artery pressure (weighted mean difference [WMD] = –6.9 mm Hg; 95% CI = –9.7, –4.1; P < .01; I2 = 61) and pulmonary vascular resistance (WMD = –3.2; 95% CI = –5.4, –0.9; P = .005). PADN improvements in cardiac output were also statistically significant (WMD = 0.3; 95% CI = 0.07, 0.6; P = .012), with numerical improvement in 6-minute walking distance (WMD = 67.7; 95% CI = –3.73, 139.2; P = .06) in the PADN group. Side effects were less common in the PADN group as compared with the placebo group, Dr. Vorla reported. She concluded, “This updated meta-analysis supports PADN as a safe and efficacious therapy for severe pulmonary arterial hypertension.” The authors noted limitations imposed by the small sample size, large data heterogeneity, and medium-quality literature. Larger randomized, controlled trials with clinical endpoints comparing PADN with optimal medical therapy are needed, they stated.
 

References

1. Shah AJ et al. New Drugs and Therapies in Pulmonary Arterial Hypertension. Int J Mol Sci. 2023 Mar 19;24(6):5850. doi: 10.3390/ijms24065850. PMID: 36982922; PMCID: PMC10058689.

2. Kovacs G et al. Pulmonary Vascular Involvement in Chronic Obstructive Pulmonary Disease. Is There a Pulmonary Vascular Phenotype? Am J Respir Crit Care Med. 2018 Oct 15;198(8):1000-11. doi: 10.1164/rccm.201801-0095PP. PMID: 29746142.

PHILADELPHIA — Promise that the unmet need for more effective pulmonary artery hypertension treatments may soon be met was in strong evidence in research into three strategies presented at this year’s recent American Heart Association scientific sessions; one was based on an ancient Chinese herb epimedium (yin yang huo or horny goat weed) commonly used for treating sexual dysfunction and directly related to the phosphodiesterase inhibitors sildenafil, vardenafil, and tadalafil (sold as Viagra, Levitra, and Cialis). A second studied sotatercept, an investigational, potential first-in-class activin signaling inhibitor biologic, and a third evaluated physically ablating the baroreceptor nerves that stimulate vasoconstriction of the pulmonary artery via catheter-based techniques.

Until as recently as the late 1970s, a pulmonary arterial hypertension diagnosis was a uniformly fatal one.¹ While targeted therapies have since improved prognosis, pulmonary arterial hypertension remains a chronic and progressive disorder of the pulmonary vasculature with significant morbidity and mortality associated with pulmonary and right ventricle remodeling, and leads toward heart failure and death. The complex underlying pathogenesis was divided into six groups by the 6th World Symposium on Pulmonary Hypertension (WSPH) in 2018, and includes as its most common features pulmonary artery endothelial cell dysfunction, pulmonary artery smooth muscle cell proliferation and migration, and dysregulated fibroblast activity leading to dysregulated vasoconstriction, micro and in-situ vascular thrombosis, vascular fibrosis and pathogenic remodeling of pulmonary vessels.¹ The threshold mean arterial pressure (mPAP) for pulmonary arterial hypertension was defined by the 6th [WSPH] at mPAP ≥ 20 mm Hg, twice the upper limit of a normal mPAP of 14.0 ± 3.3 mm Hg as reported by Kovacs et al. in 2018.²

Pathways for current therapies

Current drugs for pulmonary arterial hypertension focus on three signaling pathways, including the endothelin receptor, prostacyclin and nitric oxide pathways, stated Zhi-Cheng Jing, MD, professor of medicine, head of the cardiology department at Peking Union Medical College Hospital, Peking, China. While the phosphodiesterase 5 inhibitors sildenafil and tadalafil, which target the nitric oxide pathway, came into wide use after Food and Drug Administration approval, the need for higher PDE5-selectivity remains, Dr. Jing said. Structurally modified from the active ingredient in epimedium, TPN171H is an investigational PDE5 inhibitor which has shown several favorable features: a greater PDE5 selectivity than both sildenafil and tadalafil in vitro, an ability to decrease right ventricular systolic pressure and alleviate arterial remodeling in animal studies, and safety and tolerability in healthy human subjects.

The current randomized, double-blind, placebo-and active-controlled phase IIa study assessed the hemodynamic impact of a single oral dose of TPN171H in 60 pulmonary arterial hypertension patients (mean age ~34 years, 83.3% female), all with negative vasodilation test results and in WHO class 2 or 3. Only patients aged 18-75 years with group 1 pulmonary arterial hypertension of idiopathic, connective tissue disorder, or repaired congenital heart defects etiology were included. Patients were divided into six groups: placebo, TPN171H at 2.5, 5, and 10 milligrams, and tadalafil at 20 and 40 milligrams.

For the primary endpoint of maximum decrease in pulmonary vascular resistance (PVR), significant reductions vs. placebo were found only for the TPN171H 5-mg group (–41.2% vs. –24.4%; P = .008) and for the 20-mg (–39.8%) and 40-mg (–37.6%) tadalafil groups (both P < .05). What was not seen in the tadalafil groups, but was evident in the TPN171H 5-mg group, was a significant reduction in the secondary endpoint of PVR/SVR (systolic vascular resistance) at 2, 3, and 5 hours (all P < .05). “As we know,” Dr. Jing said in an interview, “the PDE5 inhibitor functions as a vasodilator, having an impact on both pulmonary circulation and systemic circulation. So, to evaluate the  selectivity for pulmonary circulation is crucial when exploring a novel drug for pulmonary arterial hypertension. The change of PVR/SVR ratio from baseline is an indicator for selectivity for pulmonary circulation and implies that TPN171H has good PDE5 selectivity in the pulmonary vasculature,” Dr. Jing said.

TPN171H was well tolerated with no serious adverse effects (vomiting 10% and headache 10% were most common with no discontinuations).
 

TGF-signaling pathway

A meta-analysis of randomized controlled trials of sotatercept, an investigational fusion protein under priority FDA review that modulates the TGF-beta superfamily signaling pathway, looked at PVR, pulmonary arterial pressure (PAP), right arterial pressure (RAP) and N-terminal pro-brain natriuretic peptide (NT-proBNP). A literature search by corresponding author Vamsikalyan Borra, MD, Knapp Medical Center, Weslaco, Texas, and colleagues identified two trials (STELLAR and PULSAR) comprising 429 patients with pulmonary arterial hypertension. The experimental arms (sotatercept) had 237 patients (mean age ~49 years, ~82% female) and the placebo arm had 192 patients (mean age ~47 years, ~80% female).

A pooled analysis showed significant reductions with sotatercept in PVR (standardization mean difference [SMD] = –1.00, 95% confidence interval [CI] = –1.2, –.79, P < .001), PAP (SMD = –1.34, 95% CI = 1.6, –1.08, P < .001), RAP (SMD = –0.66, 95% CI = –0.93, –0.39, P < .001), and the levels of NT-proBNP (SMD = –0.64, 95% CI = –1.01, –0.27, P < .001) at 24 weeks from baseline. The sotatercept safety profile was favorable, with lower overall incidence of adverse events (84.8% vs. 87.5%) and fewer adverse events leading to death (0.4% vs. 3.1%) compared with placebo. Further investigation is needed, however, according to Dr. Borra, into the higher frequency of reported thrombocytopenia (71.7% vs. 20.8%) with sotatercept. “Our findings,” Dr. Borra said in a poster session, “suggest that sotatercept is an effective treatment option for pulmonary arterial hypertension, with the potential to improve both pulmonary and cardiac function.”
 

Denervation technique

Catheter-based ablation techniques, most commonly using thermal energy, target the afferent and efferent fibers of the baroreceptor reflex in the main pulmonary artery trunk and bifurcation involved in elevated pulmonary artery pressure. Mounica Vorla, MD, Carle Foundation Hospital, Urbana, Illinois, and colleagues conducted an updated systematic review and meta-analysis of the safety and efficacy of pulmonary artery denervation (PADN) for pulmonary arterial hypertension in seven clinical trials with 506 patients with moderate-severe pulmonary arterial hypertension conducted from 2013 to 2022.

Compared with placebo, PADN treatment was associated with a significant reduction in mean pulmonary artery pressure (weighted mean difference [WMD] = –6.9 mm Hg; 95% CI = –9.7, –4.1; P < .01; I2 = 61) and pulmonary vascular resistance (WMD = –3.2; 95% CI = –5.4, –0.9; P = .005). PADN improvements in cardiac output were also statistically significant (WMD = 0.3; 95% CI = 0.07, 0.6; P = .012), with numerical improvement in 6-minute walking distance (WMD = 67.7; 95% CI = –3.73, 139.2; P = .06) in the PADN group. Side effects were less common in the PADN group as compared with the placebo group, Dr. Vorla reported. She concluded, “This updated meta-analysis supports PADN as a safe and efficacious therapy for severe pulmonary arterial hypertension.” The authors noted limitations imposed by the small sample size, large data heterogeneity, and medium-quality literature. Larger randomized, controlled trials with clinical endpoints comparing PADN with optimal medical therapy are needed, they stated.
 

References

1. Shah AJ et al. New Drugs and Therapies in Pulmonary Arterial Hypertension. Int J Mol Sci. 2023 Mar 19;24(6):5850. doi: 10.3390/ijms24065850. PMID: 36982922; PMCID: PMC10058689.

2. Kovacs G et al. Pulmonary Vascular Involvement in Chronic Obstructive Pulmonary Disease. Is There a Pulmonary Vascular Phenotype? Am J Respir Crit Care Med. 2018 Oct 15;198(8):1000-11. doi: 10.1164/rccm.201801-0095PP. PMID: 29746142.

PHILADELPHIA — Promise that the unmet need for more effective pulmonary artery hypertension treatments may soon be met was in strong evidence in research into three strategies presented at this year’s recent American Heart Association scientific sessions; one was based on an ancient Chinese herb epimedium (yin yang huo or horny goat weed) commonly used for treating sexual dysfunction and directly related to the phosphodiesterase inhibitors sildenafil, vardenafil, and tadalafil (sold as Viagra, Levitra, and Cialis). A second studied sotatercept, an investigational, potential first-in-class activin signaling inhibitor biologic, and a third evaluated physically ablating the baroreceptor nerves that stimulate vasoconstriction of the pulmonary artery via catheter-based techniques.

Until as recently as the late 1970s, a pulmonary arterial hypertension diagnosis was a uniformly fatal one.¹ While targeted therapies have since improved prognosis, pulmonary arterial hypertension remains a chronic and progressive disorder of the pulmonary vasculature with significant morbidity and mortality associated with pulmonary and right ventricle remodeling, and leads toward heart failure and death. The complex underlying pathogenesis was divided into six groups by the 6th World Symposium on Pulmonary Hypertension (WSPH) in 2018, and includes as its most common features pulmonary artery endothelial cell dysfunction, pulmonary artery smooth muscle cell proliferation and migration, and dysregulated fibroblast activity leading to dysregulated vasoconstriction, micro and in-situ vascular thrombosis, vascular fibrosis and pathogenic remodeling of pulmonary vessels.¹ The threshold mean arterial pressure (mPAP) for pulmonary arterial hypertension was defined by the 6th [WSPH] at mPAP ≥ 20 mm Hg, twice the upper limit of a normal mPAP of 14.0 ± 3.3 mm Hg as reported by Kovacs et al. in 2018.²

Pathways for current therapies

Current drugs for pulmonary arterial hypertension focus on three signaling pathways, including the endothelin receptor, prostacyclin and nitric oxide pathways, stated Zhi-Cheng Jing, MD, professor of medicine, head of the cardiology department at Peking Union Medical College Hospital, Peking, China. While the phosphodiesterase 5 inhibitors sildenafil and tadalafil, which target the nitric oxide pathway, came into wide use after Food and Drug Administration approval, the need for higher PDE5-selectivity remains, Dr. Jing said. Structurally modified from the active ingredient in epimedium, TPN171H is an investigational PDE5 inhibitor which has shown several favorable features: a greater PDE5 selectivity than both sildenafil and tadalafil in vitro, an ability to decrease right ventricular systolic pressure and alleviate arterial remodeling in animal studies, and safety and tolerability in healthy human subjects.

The current randomized, double-blind, placebo-and active-controlled phase IIa study assessed the hemodynamic impact of a single oral dose of TPN171H in 60 pulmonary arterial hypertension patients (mean age ~34 years, 83.3% female), all with negative vasodilation test results and in WHO class 2 or 3. Only patients aged 18-75 years with group 1 pulmonary arterial hypertension of idiopathic, connective tissue disorder, or repaired congenital heart defects etiology were included. Patients were divided into six groups: placebo, TPN171H at 2.5, 5, and 10 milligrams, and tadalafil at 20 and 40 milligrams.

For the primary endpoint of maximum decrease in pulmonary vascular resistance (PVR), significant reductions vs. placebo were found only for the TPN171H 5-mg group (–41.2% vs. –24.4%; P = .008) and for the 20-mg (–39.8%) and 40-mg (–37.6%) tadalafil groups (both P < .05). What was not seen in the tadalafil groups, but was evident in the TPN171H 5-mg group, was a significant reduction in the secondary endpoint of PVR/SVR (systolic vascular resistance) at 2, 3, and 5 hours (all P < .05). “As we know,” Dr. Jing said in an interview, “the PDE5 inhibitor functions as a vasodilator, having an impact on both pulmonary circulation and systemic circulation. So, to evaluate the  selectivity for pulmonary circulation is crucial when exploring a novel drug for pulmonary arterial hypertension. The change of PVR/SVR ratio from baseline is an indicator for selectivity for pulmonary circulation and implies that TPN171H has good PDE5 selectivity in the pulmonary vasculature,” Dr. Jing said.

TPN171H was well tolerated with no serious adverse effects (vomiting 10% and headache 10% were most common with no discontinuations).
 

TGF-signaling pathway

A meta-analysis of randomized controlled trials of sotatercept, an investigational fusion protein under priority FDA review that modulates the TGF-beta superfamily signaling pathway, looked at PVR, pulmonary arterial pressure (PAP), right arterial pressure (RAP) and N-terminal pro-brain natriuretic peptide (NT-proBNP). A literature search by corresponding author Vamsikalyan Borra, MD, Knapp Medical Center, Weslaco, Texas, and colleagues identified two trials (STELLAR and PULSAR) comprising 429 patients with pulmonary arterial hypertension. The experimental arms (sotatercept) had 237 patients (mean age ~49 years, ~82% female) and the placebo arm had 192 patients (mean age ~47 years, ~80% female).

A pooled analysis showed significant reductions with sotatercept in PVR (standardization mean difference [SMD] = –1.00, 95% confidence interval [CI] = –1.2, –.79, P < .001), PAP (SMD = –1.34, 95% CI = 1.6, –1.08, P < .001), RAP (SMD = –0.66, 95% CI = –0.93, –0.39, P < .001), and the levels of NT-proBNP (SMD = –0.64, 95% CI = –1.01, –0.27, P < .001) at 24 weeks from baseline. The sotatercept safety profile was favorable, with lower overall incidence of adverse events (84.8% vs. 87.5%) and fewer adverse events leading to death (0.4% vs. 3.1%) compared with placebo. Further investigation is needed, however, according to Dr. Borra, into the higher frequency of reported thrombocytopenia (71.7% vs. 20.8%) with sotatercept. “Our findings,” Dr. Borra said in a poster session, “suggest that sotatercept is an effective treatment option for pulmonary arterial hypertension, with the potential to improve both pulmonary and cardiac function.”
 

Denervation technique

Catheter-based ablation techniques, most commonly using thermal energy, target the afferent and efferent fibers of the baroreceptor reflex in the main pulmonary artery trunk and bifurcation involved in elevated pulmonary artery pressure. Mounica Vorla, MD, Carle Foundation Hospital, Urbana, Illinois, and colleagues conducted an updated systematic review and meta-analysis of the safety and efficacy of pulmonary artery denervation (PADN) for pulmonary arterial hypertension in seven clinical trials with 506 patients with moderate-severe pulmonary arterial hypertension conducted from 2013 to 2022.

Compared with placebo, PADN treatment was associated with a significant reduction in mean pulmonary artery pressure (weighted mean difference [WMD] = –6.9 mm Hg; 95% CI = –9.7, –4.1; P < .01; I2 = 61) and pulmonary vascular resistance (WMD = –3.2; 95% CI = –5.4, –0.9; P = .005). PADN improvements in cardiac output were also statistically significant (WMD = 0.3; 95% CI = 0.07, 0.6; P = .012), with numerical improvement in 6-minute walking distance (WMD = 67.7; 95% CI = –3.73, 139.2; P = .06) in the PADN group. Side effects were less common in the PADN group as compared with the placebo group, Dr. Vorla reported. She concluded, “This updated meta-analysis supports PADN as a safe and efficacious therapy for severe pulmonary arterial hypertension.” The authors noted limitations imposed by the small sample size, large data heterogeneity, and medium-quality literature. Larger randomized, controlled trials with clinical endpoints comparing PADN with optimal medical therapy are needed, they stated.
 

References

1. Shah AJ et al. New Drugs and Therapies in Pulmonary Arterial Hypertension. Int J Mol Sci. 2023 Mar 19;24(6):5850. doi: 10.3390/ijms24065850. PMID: 36982922; PMCID: PMC10058689.

2. Kovacs G et al. Pulmonary Vascular Involvement in Chronic Obstructive Pulmonary Disease. Is There a Pulmonary Vascular Phenotype? Am J Respir Crit Care Med. 2018 Oct 15;198(8):1000-11. doi: 10.1164/rccm.201801-0095PP. PMID: 29746142.

TOPLINE:

Salivary microbiota changes caused by cigarette smoking may affect metabolic pathways and increase disease risk.

METHODOLOGY:

The researchers analyzed health information and data on the composition of salivary microbiota from 1601 adult participants in the Cooperative Health Research in South Tyrol (CHRIS) microbiome study (CHRISMB); CHRIS is an ongoing study in Italy.

The average age of the study population was 45 years; 53% were female, and 45% were current or former smokers.

The researchers hypothesized that changes in salivary microbial composition would be associated with smoking, with more nitrate-reducing bacteria present, and that nitrate reduction pathways would be reduced in smokers.

TAKEAWAY:

The researchers identified 44 genera that differed in the salivary microbiota of current smokers and nonsmokers. In smokers, seven genera in the phylum Proteobacteria were decreased and six in the phylum Actinobacteria were increased compared with nonsmokers; these phyla contain primarily aerobic and anaerobic taxa, respectively.

Some microbiota changes were significantly associated with daily smoking intensity; genera from the classes Betaproteobacteria (Lautropia or Neisseria), Gammaproteobacteria (Cardiobacterium), and Flavobacteriia (Capnocytophaga) decreased significantly with increased grams of tobacco smoked per day, measured in 5-g increments.

Smoking was associated with changes in the salivary microbiota; the nitrate reduction pathway was significantly lower in smokers compared with nonsmokers, and these decreases were consistent with previous studies of decreased cardiovascular events in former smokers.

However, the salivary microbiota of smokers who had quit for at least 5 years resembled that of individuals who had never smoked.

IN PRACTICE:

“Decreased microbial nitrate reduction pathway abundance in smokers may provide an additional explanation for the effect of smoking on cardiovascular and periodontal diseases risk, a hypothesis which should be tested in future studies,” the researchers wrote.

SOURCE:

The lead author of the study was Giacomo Antonello, MD, of Eurac Research, Affiliated Institute of the University of Lübeck, Bolzano, Italy. The study was published online in Scientific Reports (a Nature journal) on November 2, 2023.

LIMITATIONS:

The cross-sectional design and lack of professional assessment of tooth and gum health were limiting factors, as were potential confounding factors including medication use, diet, and alcohol intake.

DISCLOSURES:

The study was supported by the Department of Innovation, Research and University of the Autonomous Province of Bolzano-South Tyrol and by the European Regional Development Fund. The CHRISMB microbiota data generation was funded by the National Institute of Dental and Craniofacial Research. The researchers had no financial conflicts to disclose.

A version of this article first appeared on Medscape.com.

TOPLINE:

Salivary microbiota changes caused by cigarette smoking may affect metabolic pathways and increase disease risk.

METHODOLOGY:

The researchers analyzed health information and data on the composition of salivary microbiota from 1601 adult participants in the Cooperative Health Research in South Tyrol (CHRIS) microbiome study (CHRISMB); CHRIS is an ongoing study in Italy.

The average age of the study population was 45 years; 53% were female, and 45% were current or former smokers.

The researchers hypothesized that changes in salivary microbial composition would be associated with smoking, with more nitrate-reducing bacteria present, and that nitrate reduction pathways would be reduced in smokers.

TAKEAWAY:

The researchers identified 44 genera that differed in the salivary microbiota of current smokers and nonsmokers. In smokers, seven genera in the phylum Proteobacteria were decreased and six in the phylum Actinobacteria were increased compared with nonsmokers; these phyla contain primarily aerobic and anaerobic taxa, respectively.

Some microbiota changes were significantly associated with daily smoking intensity; genera from the classes Betaproteobacteria (Lautropia or Neisseria), Gammaproteobacteria (Cardiobacterium), and Flavobacteriia (Capnocytophaga) decreased significantly with increased grams of tobacco smoked per day, measured in 5-g increments.

Smoking was associated with changes in the salivary microbiota; the nitrate reduction pathway was significantly lower in smokers compared with nonsmokers, and these decreases were consistent with previous studies of decreased cardiovascular events in former smokers.

However, the salivary microbiota of smokers who had quit for at least 5 years resembled that of individuals who had never smoked.

IN PRACTICE:

“Decreased microbial nitrate reduction pathway abundance in smokers may provide an additional explanation for the effect of smoking on cardiovascular and periodontal diseases risk, a hypothesis which should be tested in future studies,” the researchers wrote.

SOURCE:

The lead author of the study was Giacomo Antonello, MD, of Eurac Research, Affiliated Institute of the University of Lübeck, Bolzano, Italy. The study was published online in Scientific Reports (a Nature journal) on November 2, 2023.

LIMITATIONS:

The cross-sectional design and lack of professional assessment of tooth and gum health were limiting factors, as were potential confounding factors including medication use, diet, and alcohol intake.

DISCLOSURES:

The study was supported by the Department of Innovation, Research and University of the Autonomous Province of Bolzano-South Tyrol and by the European Regional Development Fund. The CHRISMB microbiota data generation was funded by the National Institute of Dental and Craniofacial Research. The researchers had no financial conflicts to disclose.

A version of this article first appeared on Medscape.com.

TOPLINE:

Salivary microbiota changes caused by cigarette smoking may affect metabolic pathways and increase disease risk.

METHODOLOGY:

The researchers analyzed health information and data on the composition of salivary microbiota from 1601 adult participants in the Cooperative Health Research in South Tyrol (CHRIS) microbiome study (CHRISMB); CHRIS is an ongoing study in Italy.

The average age of the study population was 45 years; 53% were female, and 45% were current or former smokers.

The researchers hypothesized that changes in salivary microbial composition would be associated with smoking, with more nitrate-reducing bacteria present, and that nitrate reduction pathways would be reduced in smokers.

TAKEAWAY:

The researchers identified 44 genera that differed in the salivary microbiota of current smokers and nonsmokers. In smokers, seven genera in the phylum Proteobacteria were decreased and six in the phylum Actinobacteria were increased compared with nonsmokers; these phyla contain primarily aerobic and anaerobic taxa, respectively.

Some microbiota changes were significantly associated with daily smoking intensity; genera from the classes Betaproteobacteria (Lautropia or Neisseria), Gammaproteobacteria (Cardiobacterium), and Flavobacteriia (Capnocytophaga) decreased significantly with increased grams of tobacco smoked per day, measured in 5-g increments.

Smoking was associated with changes in the salivary microbiota; the nitrate reduction pathway was significantly lower in smokers compared with nonsmokers, and these decreases were consistent with previous studies of decreased cardiovascular events in former smokers.

However, the salivary microbiota of smokers who had quit for at least 5 years resembled that of individuals who had never smoked.

IN PRACTICE:

“Decreased microbial nitrate reduction pathway abundance in smokers may provide an additional explanation for the effect of smoking on cardiovascular and periodontal diseases risk, a hypothesis which should be tested in future studies,” the researchers wrote.

SOURCE:

The lead author of the study was Giacomo Antonello, MD, of Eurac Research, Affiliated Institute of the University of Lübeck, Bolzano, Italy. The study was published online in Scientific Reports (a Nature journal) on November 2, 2023.

LIMITATIONS:

The cross-sectional design and lack of professional assessment of tooth and gum health were limiting factors, as were potential confounding factors including medication use, diet, and alcohol intake.

DISCLOSURES:

The study was supported by the Department of Innovation, Research and University of the Autonomous Province of Bolzano-South Tyrol and by the European Regional Development Fund. The CHRISMB microbiota data generation was funded by the National Institute of Dental and Craniofacial Research. The researchers had no financial conflicts to disclose.

A version of this article first appeared on Medscape.com.

TOPLINE:

Heavy secondhand smoke (SHS) exposure is associated with severe headache or migraine in adults who have never smoked, with effects of exposure varying depending on body mass index (BMI) and level of physical activity, new research shows.

METHODOLOGY:

Investigators analyzed data on 4,560 participants (median age, 43 years; 60% female; 71.5% White) from the 1999-2004 National Health and Nutrition Examination Survey.

Participants were aged 20 years or older and had never smoked.

Migraine headache status was determined by asking whether participants experienced severe headaches or migraines during the previous 3 months.

SHS exposure was categorized as unexposed (serum cotinine levels <0.05 ng/mL and no smoker in the home), low (0.05 ng/mL ≤ serum cotinine level <1 ng/mL), or heavy (1 ng/mL ≤ serum cotinine level ≤ 10 ng/mL).

TAKEAWAY:

In all, 919 (20%) participants had severe headaches or migraines.

After adjustment for demographic and lifestyle factors (including medication use), heavy SHS exposure was positively associated with severe headache or migraine (adjusted odds ratio [aOR], 2.02; 95% CI, 1.19-3.43).

No significant association was found between low SHS exposure and severe headaches or migraine (aOR, 1.15; 95% CI, 0.91-1.47).

In participants who were sedentary (P=.016) and those with a BMI <25 (P=.001), significant associations between SHS and severe headache or migraine were observed.

IN PRACTICE:

Noting a linear dose-response relationship between cotinine and severe headaches or migraine, the investigators write, “These findings underscore the need for stronger regulation of tobacco exposure, particularly in homes and public places.”

SOURCE:

Junpeng Wu, MMc, and Haitang Wang, MD, of Southern Medical University in Guangzhou, China, and their colleagues conducted the study. It was published online in Headache.

LIMITATIONS:

The study could not establish causal relationships between SHS and migraine or severe headache. In addition, the half-life of serum cotinine is 15-40 hours and thus this measure can reflect only recent SHS exposure.

DISCLOSURES:

The study was not funded. The investigators reported no disclosures.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Heavy secondhand smoke (SHS) exposure is associated with severe headache or migraine in adults who have never smoked, with effects of exposure varying depending on body mass index (BMI) and level of physical activity, new research shows.

METHODOLOGY:

Investigators analyzed data on 4,560 participants (median age, 43 years; 60% female; 71.5% White) from the 1999-2004 National Health and Nutrition Examination Survey.

Participants were aged 20 years or older and had never smoked.

Migraine headache status was determined by asking whether participants experienced severe headaches or migraines during the previous 3 months.

SHS exposure was categorized as unexposed (serum cotinine levels <0.05 ng/mL and no smoker in the home), low (0.05 ng/mL ≤ serum cotinine level <1 ng/mL), or heavy (1 ng/mL ≤ serum cotinine level ≤ 10 ng/mL).

TAKEAWAY:

In all, 919 (20%) participants had severe headaches or migraines.

After adjustment for demographic and lifestyle factors (including medication use), heavy SHS exposure was positively associated with severe headache or migraine (adjusted odds ratio [aOR], 2.02; 95% CI, 1.19-3.43).

No significant association was found between low SHS exposure and severe headaches or migraine (aOR, 1.15; 95% CI, 0.91-1.47).

In participants who were sedentary (P=.016) and those with a BMI <25 (P=.001), significant associations between SHS and severe headache or migraine were observed.

IN PRACTICE:

Noting a linear dose-response relationship between cotinine and severe headaches or migraine, the investigators write, “These findings underscore the need for stronger regulation of tobacco exposure, particularly in homes and public places.”

SOURCE:

Junpeng Wu, MMc, and Haitang Wang, MD, of Southern Medical University in Guangzhou, China, and their colleagues conducted the study. It was published online in Headache.

LIMITATIONS:

The study could not establish causal relationships between SHS and migraine or severe headache. In addition, the half-life of serum cotinine is 15-40 hours and thus this measure can reflect only recent SHS exposure.

DISCLOSURES:

The study was not funded. The investigators reported no disclosures.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Heavy secondhand smoke (SHS) exposure is associated with severe headache or migraine in adults who have never smoked, with effects of exposure varying depending on body mass index (BMI) and level of physical activity, new research shows.

METHODOLOGY:

Investigators analyzed data on 4,560 participants (median age, 43 years; 60% female; 71.5% White) from the 1999-2004 National Health and Nutrition Examination Survey.

Participants were aged 20 years or older and had never smoked.

Migraine headache status was determined by asking whether participants experienced severe headaches or migraines during the previous 3 months.

SHS exposure was categorized as unexposed (serum cotinine levels <0.05 ng/mL and no smoker in the home), low (0.05 ng/mL ≤ serum cotinine level <1 ng/mL), or heavy (1 ng/mL ≤ serum cotinine level ≤ 10 ng/mL).

TAKEAWAY:

In all, 919 (20%) participants had severe headaches or migraines.

After adjustment for demographic and lifestyle factors (including medication use), heavy SHS exposure was positively associated with severe headache or migraine (adjusted odds ratio [aOR], 2.02; 95% CI, 1.19-3.43).

No significant association was found between low SHS exposure and severe headaches or migraine (aOR, 1.15; 95% CI, 0.91-1.47).

In participants who were sedentary (P=.016) and those with a BMI <25 (P=.001), significant associations between SHS and severe headache or migraine were observed.

IN PRACTICE:

Noting a linear dose-response relationship between cotinine and severe headaches or migraine, the investigators write, “These findings underscore the need for stronger regulation of tobacco exposure, particularly in homes and public places.”

SOURCE:

Junpeng Wu, MMc, and Haitang Wang, MD, of Southern Medical University in Guangzhou, China, and their colleagues conducted the study. It was published online in Headache.

LIMITATIONS:

The study could not establish causal relationships between SHS and migraine or severe headache. In addition, the half-life of serum cotinine is 15-40 hours and thus this measure can reflect only recent SHS exposure.

DISCLOSURES:

The study was not funded. The investigators reported no disclosures.
 

A version of this article appeared on Medscape.com.