Neil Osterweil

SAN DIEGO — A lifestyle intervention focused on diet and exercise can improve cardiac function and the quality of life for patients with pulmonary arterial hypertension (PAH), results of a randomized clinical trial show.

At 12 weeks of follow-up, patients with PAH who were randomized to undergo a diet and cardiovascular exercise program had improved right ventricular function, better exercise capacity, and improved quality of life compared with patients randomized to the standard of care.

In addition, for those participants in the diet and exercise group who lost weight, right ventricular glucose uptake improved, reported Gustavo A. Heresi, MD, MS of the division of pulmonary medicine at the Cleveland Clinic.

Neil Osterweil/MDedge News

The intervention did not, however, have an effect on insulin sensitivity, suggesting that insulin resistance is not a significant pathological mechanism in PAH, he said in an oral abstract session at the American Thoracic Society’s international conference.

“With these data, in the context of prior studies showing the benefits of exercise interventions, we believe that diet and exercise should be incorporated and thought of as part of the treatment armamentarium for pulmonary arterial hypertension,” he said.

Despite the availability of 14 FDA-approved medications for PAH, the disease is incurable. It is marked by progressive pulmonary vasoconstriction, pulmonary vascular remodeling, fibrosis and inflammation, in situ thrombosis, and right ventricular failure.

Because abnormalities in both glucose and insulin metabolism are prevalent and associated with decreased survival in patients with PAH, Dr. Heresi and colleagues designed a randomized trial to test the hypothesis that a diet and exercise intervention could improve insulin sensitivity and right ventricular function.
 

PHINE details

In the study, dubbed Pulmonary Arterial Hypertension Improvement with Nutrition and Exercise (PHINE), the investigators enrolled adults with group 1 PAH who were stable on PAH medications for at least 2 months. Patients with portopulmonary hypertension, New York Heart Association (NYHA) class IV heart failure, syncope, or on supplemental oxygen greater than 4 liters per minute were excluded.

The patients were screened with a graded exercise test, intravenous glucose tolerance test, and other measures at baseline, and after stratification by NYHA class and tricuspid annular plane systolic excursion (TAPSE) score were randomized to the intervention arm (16 patients) or standard of care control arm (14 patients).

The intervention consisted of supervised exercise training for 50-60 minutes on a treadmill at 80%-85% of the patient’s maximum heart rate 5 days per week, plus weekly counseling on a combination low glycemic index/Mediterranean dietary pattern. The diet portion included olive oil as the primary fat source, three 1-ounce servings of nuts and peanuts weekly, fish and legumes at a minimum of 3 servings weekly, and no sugar-sweetened beverage, commercial bakery products, pastries, white breads, white rice, or white potatoes.
 

Results

At the conclusion of the study at 12 weeks there were no statistically significant differences between the groups in either insulin sensitivity or right ventricular strain.

However, patients in the intervention arm had significant improvements compared with controls in mean RV function as measured by TAPSE, improved exercise capacity as measured by peak oxygen uptake and 6-minute walking distance, quality of life as measured by EmPHasis-10 health-related quality of life score, and NYHA functional class.

As noted, right ventricular glucose uptake was improved among those patients in the intervention group who lost weight over the study period.
 

Worth trying

Ravi Kalhan, MD, MS, of Northwestern University Feinberg School of Medicine in Chicago, who co-moderated the session but was not involved in the study, said in an interview that the study results show promise.

“We’re so centered on what’s the next big pharmacotherapy you can give to fix the disease, but sometimes maybe we should be pushing lifestyle interventions that are impactful, and they have biologic mechanisms — it’s not just that you got in better shape, but right ventricular function also improves. I’m pretty drawn to that sort of thing,” he said.

“That’s a pretty major effect over a 3-month intervention,” agreed co-moderator Nuala J. Meyer, MD, MS, ATSF, of the Hospital of the University of Pennsylvania.

The PHINE trial was supported by National Institute of Health grants. Dr. Heresi, Dr. Kalhan, and Dr. Meyer reported no conflicts of interest.

SAN DIEGO — A lifestyle intervention focused on diet and exercise can improve cardiac function and the quality of life for patients with pulmonary arterial hypertension (PAH), results of a randomized clinical trial show.

At 12 weeks of follow-up, patients with PAH who were randomized to undergo a diet and cardiovascular exercise program had improved right ventricular function, better exercise capacity, and improved quality of life compared with patients randomized to the standard of care.

In addition, for those participants in the diet and exercise group who lost weight, right ventricular glucose uptake improved, reported Gustavo A. Heresi, MD, MS of the division of pulmonary medicine at the Cleveland Clinic.

Neil Osterweil/MDedge News

The intervention did not, however, have an effect on insulin sensitivity, suggesting that insulin resistance is not a significant pathological mechanism in PAH, he said in an oral abstract session at the American Thoracic Society’s international conference.

“With these data, in the context of prior studies showing the benefits of exercise interventions, we believe that diet and exercise should be incorporated and thought of as part of the treatment armamentarium for pulmonary arterial hypertension,” he said.

Despite the availability of 14 FDA-approved medications for PAH, the disease is incurable. It is marked by progressive pulmonary vasoconstriction, pulmonary vascular remodeling, fibrosis and inflammation, in situ thrombosis, and right ventricular failure.

Because abnormalities in both glucose and insulin metabolism are prevalent and associated with decreased survival in patients with PAH, Dr. Heresi and colleagues designed a randomized trial to test the hypothesis that a diet and exercise intervention could improve insulin sensitivity and right ventricular function.
 

PHINE details

In the study, dubbed Pulmonary Arterial Hypertension Improvement with Nutrition and Exercise (PHINE), the investigators enrolled adults with group 1 PAH who were stable on PAH medications for at least 2 months. Patients with portopulmonary hypertension, New York Heart Association (NYHA) class IV heart failure, syncope, or on supplemental oxygen greater than 4 liters per minute were excluded.

The patients were screened with a graded exercise test, intravenous glucose tolerance test, and other measures at baseline, and after stratification by NYHA class and tricuspid annular plane systolic excursion (TAPSE) score were randomized to the intervention arm (16 patients) or standard of care control arm (14 patients).

The intervention consisted of supervised exercise training for 50-60 minutes on a treadmill at 80%-85% of the patient’s maximum heart rate 5 days per week, plus weekly counseling on a combination low glycemic index/Mediterranean dietary pattern. The diet portion included olive oil as the primary fat source, three 1-ounce servings of nuts and peanuts weekly, fish and legumes at a minimum of 3 servings weekly, and no sugar-sweetened beverage, commercial bakery products, pastries, white breads, white rice, or white potatoes.
 

Results

At the conclusion of the study at 12 weeks there were no statistically significant differences between the groups in either insulin sensitivity or right ventricular strain.

However, patients in the intervention arm had significant improvements compared with controls in mean RV function as measured by TAPSE, improved exercise capacity as measured by peak oxygen uptake and 6-minute walking distance, quality of life as measured by EmPHasis-10 health-related quality of life score, and NYHA functional class.

As noted, right ventricular glucose uptake was improved among those patients in the intervention group who lost weight over the study period.
 

Worth trying

Ravi Kalhan, MD, MS, of Northwestern University Feinberg School of Medicine in Chicago, who co-moderated the session but was not involved in the study, said in an interview that the study results show promise.

“We’re so centered on what’s the next big pharmacotherapy you can give to fix the disease, but sometimes maybe we should be pushing lifestyle interventions that are impactful, and they have biologic mechanisms — it’s not just that you got in better shape, but right ventricular function also improves. I’m pretty drawn to that sort of thing,” he said.

“That’s a pretty major effect over a 3-month intervention,” agreed co-moderator Nuala J. Meyer, MD, MS, ATSF, of the Hospital of the University of Pennsylvania.

The PHINE trial was supported by National Institute of Health grants. Dr. Heresi, Dr. Kalhan, and Dr. Meyer reported no conflicts of interest.

SAN DIEGO — A lifestyle intervention focused on diet and exercise can improve cardiac function and the quality of life for patients with pulmonary arterial hypertension (PAH), results of a randomized clinical trial show.

At 12 weeks of follow-up, patients with PAH who were randomized to undergo a diet and cardiovascular exercise program had improved right ventricular function, better exercise capacity, and improved quality of life compared with patients randomized to the standard of care.

In addition, for those participants in the diet and exercise group who lost weight, right ventricular glucose uptake improved, reported Gustavo A. Heresi, MD, MS of the division of pulmonary medicine at the Cleveland Clinic.

Neil Osterweil/MDedge News

The intervention did not, however, have an effect on insulin sensitivity, suggesting that insulin resistance is not a significant pathological mechanism in PAH, he said in an oral abstract session at the American Thoracic Society’s international conference.

“With these data, in the context of prior studies showing the benefits of exercise interventions, we believe that diet and exercise should be incorporated and thought of as part of the treatment armamentarium for pulmonary arterial hypertension,” he said.

Despite the availability of 14 FDA-approved medications for PAH, the disease is incurable. It is marked by progressive pulmonary vasoconstriction, pulmonary vascular remodeling, fibrosis and inflammation, in situ thrombosis, and right ventricular failure.

Because abnormalities in both glucose and insulin metabolism are prevalent and associated with decreased survival in patients with PAH, Dr. Heresi and colleagues designed a randomized trial to test the hypothesis that a diet and exercise intervention could improve insulin sensitivity and right ventricular function.
 

PHINE details

In the study, dubbed Pulmonary Arterial Hypertension Improvement with Nutrition and Exercise (PHINE), the investigators enrolled adults with group 1 PAH who were stable on PAH medications for at least 2 months. Patients with portopulmonary hypertension, New York Heart Association (NYHA) class IV heart failure, syncope, or on supplemental oxygen greater than 4 liters per minute were excluded.

The patients were screened with a graded exercise test, intravenous glucose tolerance test, and other measures at baseline, and after stratification by NYHA class and tricuspid annular plane systolic excursion (TAPSE) score were randomized to the intervention arm (16 patients) or standard of care control arm (14 patients).

The intervention consisted of supervised exercise training for 50-60 minutes on a treadmill at 80%-85% of the patient’s maximum heart rate 5 days per week, plus weekly counseling on a combination low glycemic index/Mediterranean dietary pattern. The diet portion included olive oil as the primary fat source, three 1-ounce servings of nuts and peanuts weekly, fish and legumes at a minimum of 3 servings weekly, and no sugar-sweetened beverage, commercial bakery products, pastries, white breads, white rice, or white potatoes.
 

Results

At the conclusion of the study at 12 weeks there were no statistically significant differences between the groups in either insulin sensitivity or right ventricular strain.

However, patients in the intervention arm had significant improvements compared with controls in mean RV function as measured by TAPSE, improved exercise capacity as measured by peak oxygen uptake and 6-minute walking distance, quality of life as measured by EmPHasis-10 health-related quality of life score, and NYHA functional class.

As noted, right ventricular glucose uptake was improved among those patients in the intervention group who lost weight over the study period.
 

Worth trying

Ravi Kalhan, MD, MS, of Northwestern University Feinberg School of Medicine in Chicago, who co-moderated the session but was not involved in the study, said in an interview that the study results show promise.

“We’re so centered on what’s the next big pharmacotherapy you can give to fix the disease, but sometimes maybe we should be pushing lifestyle interventions that are impactful, and they have biologic mechanisms — it’s not just that you got in better shape, but right ventricular function also improves. I’m pretty drawn to that sort of thing,” he said.

“That’s a pretty major effect over a 3-month intervention,” agreed co-moderator Nuala J. Meyer, MD, MS, ATSF, of the Hospital of the University of Pennsylvania.

The PHINE trial was supported by National Institute of Health grants. Dr. Heresi, Dr. Kalhan, and Dr. Meyer reported no conflicts of interest.

SAN DIEGO — Avoiding the use of antianaerobic antibiotics for empiric treatment of patients with sepsis can prevent depletion of beneficial bacteria in the gut microbiome and reduce both organ dysfunction and in-hospital mortality, a critical care specialists contends.

“You may not be personally moved by a 2- to 5-percent absolute difference in mortality, but sepsis is so common and so lethal that even small differences in outcomes can actually translate into enormous public health implications,” said Robert P. Dickson, MD a pulmonary and critical care specialist at the University of Michigan in Ann Arbor.

Neil Osterweil/MDedge News

If instead of prescribing piperacillin-tazobactam (Zosyn; pip-tazo) for sepsis critical care specialists were to switch to cefepime “even if you make very conservative assumptions like a modest effect size, you’re still talking about [saving] thousands of lives a year,” he said in a scientific symposium at the American Thoracic Society’s international conference.

“This is why I say this isn’t really over the horizon; this is microbiome modulation that’s happening all the time,” he said.

Most patients with sepsis in a medical ICU with respiratory, urinary or bloodstream sources of infection do not have indications for antianaerobic antibiotics, and there are no head-to-head clinical trials demonstrating a benefit for one anti-sepsis antibiotic strategy over another he said.

“In contrast, every observational study between antianaerobic and non-antianaerobic shows benefits to the anaerobe-sparing [drugs], and it’s been shown with animal models too. So to my mind, it’s already practice changing. I need to be talked into giving antianaerobic antibiotics for septic patients” he said.
 

Targeting gut microbiota

There are three basic approaches to focusing on the gut microbiome as a therapeutic target. The hardest is attempting to engineer an ecosystem — a fiendishly complex task with unpredictable results that has never been shown to work in either the gut or in the ICU, Dr. Dickson said.

A second approach, the use of probiotics to repopulate the gut with beneficial bacteria, is largely futile in the ICU, as the large majority of patients are on antibiotics and can’t be safely weaned off of them while in critical care. In this situation, giving probiotics would be akin to try to repopulate a forest while a forest fire is raging, he said.

The third and easiest approach is to minimize dysbiosis — imbalance of organisms in the gut — in the first place.

Anaerobic bacteria in the gut have been shown in several different disease states and animals models to be protective against pneumonia, organ failure, and death.

To see whether antianaerobic antibiotics could increase risk for adverse outcomes in the ICU, Dr. Dickson and colleagues previously conducted a retrospective study of 3032 mechanically ventilated patients in their center who received antibiotics either with or without anaerobic coverage in the first 72 hours.

They found that patients treated with early antianaerobic antibiotics had decreased ventilator-associated pneumonia-free survival (hazard ratio [HR] 1.24), infection-free survival (HR 1.22), and overall survival (HR 1.14) compared with patients who received antibiotics without anaerobic cover (all comparisons statistically significant by confidence intervals).

In a subcohort of 116 patients for whom gut microbiota data compositions were available, those who received antianaerobic antibiotics had decreased initial gut bacterial density (P = .00038), increased microbiome expansion during hospitalization (P = .011), and domination of the microbiome by Enterobacteriaceae species (P = .045). They also found that Enterobacteriaceae were enriched among respiratory pathogens in antianaerobic treated patients, and that in murine models, treatment with antianaerobic antibiotics increased susceptibility to Enterobacteriaceae pneumonia and increased the risk of death from non-infectious injuries.
 

Pip-tazo vs. cefepime

In the ACORN (Antibiotic Choice on Renal Outcomes) trial, results of which were reported by this news organization in November 2023, there were no differences in the highest stage of acute kidney injury or death in the first 14 days between piperacillin-tazobactam and cefepime. Remarking on the results, lead investigator Edward T. Qian, MD, MSc from Vanderbilt University in Nashville, Tennessee, said “I think the big takeaway is that you should feel comfortable starting or using pip-tazo for your patients who are coming into the hospital and receiving empiric antibiotics for acute infection.”

But as Dr. Dickson’s group reported more recently in JAMA Internal Medicine, a 15-month pip-tazo shortage allowed the investigators to conduct a natural experiment comparing 90-day outcomes among 7569 patients with sepsis who received vancomycin plus either pip-tazo or cefepime.

They found in an instrumental variable analysis that piperacillin-tazobactam was associated with an absolute increase in mortality at 90 days of 5.0%, and that patients who received this antianaerobic antibiotic had 2.1 fewer organ failure–free days, 1.1 fewer ventilator-free days, and 1.5 fewer vasopressor-free days.

“Our study reveals the potential risks associated with empirical piperacillin-tazobactam in patients with sepsis without a specific indication for antianaerobic therapy. These findings should prompt reconsideration and further study of the widespread use of empirical antianaerobic antibiotics in sepsis,” the investigators concluded.
 

Who gets what?

In the question-and-answer at the end of the session, comoderator Christina Sarah Thornton, MD, PhD, FRCPC from the University of Calgary, Alberta, asked Dr. Dickson whether the question of antianaerobic overuse in the ICU “is a function that we aren’t able yet from a diagnostic perspective to identify the group that may need antianaerobes? Because we often don’t get culture data back in time for a critically ill patient. Do you think there could maybe be a more rapid diagnostic for these patients?”

He replied that “a lot of our problems would be solved if we had really good, reliable rapid diagnostics for infection,” but noted that most of the patients in the study mentioned above did not have indications for antianaerobics.

Asked by this reporter whether Dr. Dickson’s presentation changed her mind about the use of piperacillin-tazobactam in her patients, Dr. Thornton replied “Yes! It did for me.”

She noted that although in Canada respirologists don’t work in intensive care units, “it makes me wonder about just giving pip-tazo to patients that are really sick. It definitely changed my mind.”

The work of Dr. Dickson and colleagues is supported by National Institute of Health and Agency for Healthcare Research and Quality grants. He reported no other relevant disclosures. Dr. Thornton had no relevant disclosures.

SAN DIEGO — Avoiding the use of antianaerobic antibiotics for empiric treatment of patients with sepsis can prevent depletion of beneficial bacteria in the gut microbiome and reduce both organ dysfunction and in-hospital mortality, a critical care specialists contends.

“You may not be personally moved by a 2- to 5-percent absolute difference in mortality, but sepsis is so common and so lethal that even small differences in outcomes can actually translate into enormous public health implications,” said Robert P. Dickson, MD a pulmonary and critical care specialist at the University of Michigan in Ann Arbor.

Neil Osterweil/MDedge News

If instead of prescribing piperacillin-tazobactam (Zosyn; pip-tazo) for sepsis critical care specialists were to switch to cefepime “even if you make very conservative assumptions like a modest effect size, you’re still talking about [saving] thousands of lives a year,” he said in a scientific symposium at the American Thoracic Society’s international conference.

“This is why I say this isn’t really over the horizon; this is microbiome modulation that’s happening all the time,” he said.

Most patients with sepsis in a medical ICU with respiratory, urinary or bloodstream sources of infection do not have indications for antianaerobic antibiotics, and there are no head-to-head clinical trials demonstrating a benefit for one anti-sepsis antibiotic strategy over another he said.

“In contrast, every observational study between antianaerobic and non-antianaerobic shows benefits to the anaerobe-sparing [drugs], and it’s been shown with animal models too. So to my mind, it’s already practice changing. I need to be talked into giving antianaerobic antibiotics for septic patients” he said.
 

Targeting gut microbiota

There are three basic approaches to focusing on the gut microbiome as a therapeutic target. The hardest is attempting to engineer an ecosystem — a fiendishly complex task with unpredictable results that has never been shown to work in either the gut or in the ICU, Dr. Dickson said.

A second approach, the use of probiotics to repopulate the gut with beneficial bacteria, is largely futile in the ICU, as the large majority of patients are on antibiotics and can’t be safely weaned off of them while in critical care. In this situation, giving probiotics would be akin to try to repopulate a forest while a forest fire is raging, he said.

The third and easiest approach is to minimize dysbiosis — imbalance of organisms in the gut — in the first place.

Anaerobic bacteria in the gut have been shown in several different disease states and animals models to be protective against pneumonia, organ failure, and death.

To see whether antianaerobic antibiotics could increase risk for adverse outcomes in the ICU, Dr. Dickson and colleagues previously conducted a retrospective study of 3032 mechanically ventilated patients in their center who received antibiotics either with or without anaerobic coverage in the first 72 hours.

They found that patients treated with early antianaerobic antibiotics had decreased ventilator-associated pneumonia-free survival (hazard ratio [HR] 1.24), infection-free survival (HR 1.22), and overall survival (HR 1.14) compared with patients who received antibiotics without anaerobic cover (all comparisons statistically significant by confidence intervals).

In a subcohort of 116 patients for whom gut microbiota data compositions were available, those who received antianaerobic antibiotics had decreased initial gut bacterial density (P = .00038), increased microbiome expansion during hospitalization (P = .011), and domination of the microbiome by Enterobacteriaceae species (P = .045). They also found that Enterobacteriaceae were enriched among respiratory pathogens in antianaerobic treated patients, and that in murine models, treatment with antianaerobic antibiotics increased susceptibility to Enterobacteriaceae pneumonia and increased the risk of death from non-infectious injuries.
 

Pip-tazo vs. cefepime

In the ACORN (Antibiotic Choice on Renal Outcomes) trial, results of which were reported by this news organization in November 2023, there were no differences in the highest stage of acute kidney injury or death in the first 14 days between piperacillin-tazobactam and cefepime. Remarking on the results, lead investigator Edward T. Qian, MD, MSc from Vanderbilt University in Nashville, Tennessee, said “I think the big takeaway is that you should feel comfortable starting or using pip-tazo for your patients who are coming into the hospital and receiving empiric antibiotics for acute infection.”

But as Dr. Dickson’s group reported more recently in JAMA Internal Medicine, a 15-month pip-tazo shortage allowed the investigators to conduct a natural experiment comparing 90-day outcomes among 7569 patients with sepsis who received vancomycin plus either pip-tazo or cefepime.

They found in an instrumental variable analysis that piperacillin-tazobactam was associated with an absolute increase in mortality at 90 days of 5.0%, and that patients who received this antianaerobic antibiotic had 2.1 fewer organ failure–free days, 1.1 fewer ventilator-free days, and 1.5 fewer vasopressor-free days.

“Our study reveals the potential risks associated with empirical piperacillin-tazobactam in patients with sepsis without a specific indication for antianaerobic therapy. These findings should prompt reconsideration and further study of the widespread use of empirical antianaerobic antibiotics in sepsis,” the investigators concluded.
 

Who gets what?

In the question-and-answer at the end of the session, comoderator Christina Sarah Thornton, MD, PhD, FRCPC from the University of Calgary, Alberta, asked Dr. Dickson whether the question of antianaerobic overuse in the ICU “is a function that we aren’t able yet from a diagnostic perspective to identify the group that may need antianaerobes? Because we often don’t get culture data back in time for a critically ill patient. Do you think there could maybe be a more rapid diagnostic for these patients?”

He replied that “a lot of our problems would be solved if we had really good, reliable rapid diagnostics for infection,” but noted that most of the patients in the study mentioned above did not have indications for antianaerobics.

Asked by this reporter whether Dr. Dickson’s presentation changed her mind about the use of piperacillin-tazobactam in her patients, Dr. Thornton replied “Yes! It did for me.”

She noted that although in Canada respirologists don’t work in intensive care units, “it makes me wonder about just giving pip-tazo to patients that are really sick. It definitely changed my mind.”

The work of Dr. Dickson and colleagues is supported by National Institute of Health and Agency for Healthcare Research and Quality grants. He reported no other relevant disclosures. Dr. Thornton had no relevant disclosures.

SAN DIEGO — Avoiding the use of antianaerobic antibiotics for empiric treatment of patients with sepsis can prevent depletion of beneficial bacteria in the gut microbiome and reduce both organ dysfunction and in-hospital mortality, a critical care specialists contends.

“You may not be personally moved by a 2- to 5-percent absolute difference in mortality, but sepsis is so common and so lethal that even small differences in outcomes can actually translate into enormous public health implications,” said Robert P. Dickson, MD a pulmonary and critical care specialist at the University of Michigan in Ann Arbor.

Neil Osterweil/MDedge News

If instead of prescribing piperacillin-tazobactam (Zosyn; pip-tazo) for sepsis critical care specialists were to switch to cefepime “even if you make very conservative assumptions like a modest effect size, you’re still talking about [saving] thousands of lives a year,” he said in a scientific symposium at the American Thoracic Society’s international conference.

“This is why I say this isn’t really over the horizon; this is microbiome modulation that’s happening all the time,” he said.

Most patients with sepsis in a medical ICU with respiratory, urinary or bloodstream sources of infection do not have indications for antianaerobic antibiotics, and there are no head-to-head clinical trials demonstrating a benefit for one anti-sepsis antibiotic strategy over another he said.

“In contrast, every observational study between antianaerobic and non-antianaerobic shows benefits to the anaerobe-sparing [drugs], and it’s been shown with animal models too. So to my mind, it’s already practice changing. I need to be talked into giving antianaerobic antibiotics for septic patients” he said.
 

Targeting gut microbiota

There are three basic approaches to focusing on the gut microbiome as a therapeutic target. The hardest is attempting to engineer an ecosystem — a fiendishly complex task with unpredictable results that has never been shown to work in either the gut or in the ICU, Dr. Dickson said.

A second approach, the use of probiotics to repopulate the gut with beneficial bacteria, is largely futile in the ICU, as the large majority of patients are on antibiotics and can’t be safely weaned off of them while in critical care. In this situation, giving probiotics would be akin to try to repopulate a forest while a forest fire is raging, he said.

The third and easiest approach is to minimize dysbiosis — imbalance of organisms in the gut — in the first place.

Anaerobic bacteria in the gut have been shown in several different disease states and animals models to be protective against pneumonia, organ failure, and death.

To see whether antianaerobic antibiotics could increase risk for adverse outcomes in the ICU, Dr. Dickson and colleagues previously conducted a retrospective study of 3032 mechanically ventilated patients in their center who received antibiotics either with or without anaerobic coverage in the first 72 hours.

They found that patients treated with early antianaerobic antibiotics had decreased ventilator-associated pneumonia-free survival (hazard ratio [HR] 1.24), infection-free survival (HR 1.22), and overall survival (HR 1.14) compared with patients who received antibiotics without anaerobic cover (all comparisons statistically significant by confidence intervals).

In a subcohort of 116 patients for whom gut microbiota data compositions were available, those who received antianaerobic antibiotics had decreased initial gut bacterial density (P = .00038), increased microbiome expansion during hospitalization (P = .011), and domination of the microbiome by Enterobacteriaceae species (P = .045). They also found that Enterobacteriaceae were enriched among respiratory pathogens in antianaerobic treated patients, and that in murine models, treatment with antianaerobic antibiotics increased susceptibility to Enterobacteriaceae pneumonia and increased the risk of death from non-infectious injuries.
 

Pip-tazo vs. cefepime

In the ACORN (Antibiotic Choice on Renal Outcomes) trial, results of which were reported by this news organization in November 2023, there were no differences in the highest stage of acute kidney injury or death in the first 14 days between piperacillin-tazobactam and cefepime. Remarking on the results, lead investigator Edward T. Qian, MD, MSc from Vanderbilt University in Nashville, Tennessee, said “I think the big takeaway is that you should feel comfortable starting or using pip-tazo for your patients who are coming into the hospital and receiving empiric antibiotics for acute infection.”

But as Dr. Dickson’s group reported more recently in JAMA Internal Medicine, a 15-month pip-tazo shortage allowed the investigators to conduct a natural experiment comparing 90-day outcomes among 7569 patients with sepsis who received vancomycin plus either pip-tazo or cefepime.

They found in an instrumental variable analysis that piperacillin-tazobactam was associated with an absolute increase in mortality at 90 days of 5.0%, and that patients who received this antianaerobic antibiotic had 2.1 fewer organ failure–free days, 1.1 fewer ventilator-free days, and 1.5 fewer vasopressor-free days.

“Our study reveals the potential risks associated with empirical piperacillin-tazobactam in patients with sepsis without a specific indication for antianaerobic therapy. These findings should prompt reconsideration and further study of the widespread use of empirical antianaerobic antibiotics in sepsis,” the investigators concluded.
 

Who gets what?

In the question-and-answer at the end of the session, comoderator Christina Sarah Thornton, MD, PhD, FRCPC from the University of Calgary, Alberta, asked Dr. Dickson whether the question of antianaerobic overuse in the ICU “is a function that we aren’t able yet from a diagnostic perspective to identify the group that may need antianaerobes? Because we often don’t get culture data back in time for a critically ill patient. Do you think there could maybe be a more rapid diagnostic for these patients?”

He replied that “a lot of our problems would be solved if we had really good, reliable rapid diagnostics for infection,” but noted that most of the patients in the study mentioned above did not have indications for antianaerobics.

Asked by this reporter whether Dr. Dickson’s presentation changed her mind about the use of piperacillin-tazobactam in her patients, Dr. Thornton replied “Yes! It did for me.”

She noted that although in Canada respirologists don’t work in intensive care units, “it makes me wonder about just giving pip-tazo to patients that are really sick. It definitely changed my mind.”

The work of Dr. Dickson and colleagues is supported by National Institute of Health and Agency for Healthcare Research and Quality grants. He reported no other relevant disclosures. Dr. Thornton had no relevant disclosures.

SAN DIEGO – No matter where on earth you live, there’s likely to be an eye in the sky hovering overhead, and that’s a good thing, at least when it comes to satellite monitoring of air quality, said scientists from the National Aeronautics and Space Administration (NASA).

In a special symposium held at the American Thoracic Society’s international conference, NASA health and air quality specialists described the use of space-based systems and earth science applications to improve understanding of respiratory health risks worldwide, and to help enrich pulmonary research with galaxies of data.

“Every day we download over 25 terabytes of data,” said John Haynes, MS, program manager for Health and Air Quality Applications in the Earth Action Program of the NASA Earth Science Division in Washington.

Neil Osterweil/MDedge News

“Many of the observation data sets are critical for healthy air quality applications: observation of land surface temperature, sea surface temperature, precipitation, fires and thermal anomalies, aerosols, just to name a few, and the really awesome news is this offering from our constellation of satellites is free and open access, available to everyone across the globe,” he said.

The mission of NASA’s Earth Action Program is “to enable people and organizations to apply insights from Earth science to benefit the economy, health, quality of life, and environment.”

Program staff work with both industry and nonprofit environmental advocacy and health groups to help inform their decisions and actions with Earth science information.

NASA supports the use of Earth observations to help monitor and manage infectious diseases and environmental health, toxins and pathogens that affect health, air quality standards, and to assess the effects of climate change on air quality and public health.

Mr. Haynes noted that worldwide, six major cities have incorporated NASA data on fine particulate matter smaller than 2.5 microns (PM2.5) into their climate action plans. These cities include Accra, Ghana; Addis Ababa, Ethiopia; Buenos Aires, Argentina; Guadalajara, Mexico; Lima, Peru; and Johannesburg, South Africa.
 

Monitoring pollution with TEMPO

There are more than 30 Earth-monitoring systems currently in orbit or soon to be launched, including NASA’s Tropospheric Emissions: Monitoring of Pollution (TEMPO), launched in April 2023, with first operations in August 2023. The instrument is in a geostationary orbit about 22,236 miles above the equator at longitudes that allow it to survey virtually all of North America — from coast to coast, and from southern Mexico, Cuba, Puerto Rico, and the Bahamas to Northern Canada.

TEMPO is part of a geostationary air quality satellite “constellation” or group that provides daylight observation over the entire Northern Hemisphere, explained Aaron Naeger, PhD, MS, mission applications lead for TEMPO at the NASA Marshall Space Flight Center in Huntsville, Alabama.

Until TEMPO, space-based instruments had relatively low spatial resolution and could only capture one image each day. In contrast, TEMPO can scan east-west each daylight hour across its entire coverage area (known as the Field of Regard), and even more frequently during early morning and late afternoon. This allows researchers to measure volumes of pollution, sources, and how these pollution levels vary over time. The system measures ozone levels, nitrogen dioxide (NO₂,) formaldehyde, and aerosols.

More than 100 federal, state, local and tribal air quality agencies use the data captured by TEMPO to inform public health efforts.

Dr. Naeger gave examples of how the system can help identify public health hazards, including scans that showed high NO₂ levels from cities, traffic corridors, power plants, oil and gas fields, and fires.

Similarly, the system detected unhealthy ozone and PM2.5 levels during prescribed burns in April 2024, as well as notable differences between weekdays and weekends in NO₂ concentrations across California and the Front Range in Colorado. These showed higher levels along traffic corridors during weekdays related to increased traffic volumes and tailpipe emissions.
 

Fire and heat

Other NASA health and air quality initiatives include the FireAQ project, based at the University of Iowa in Iowa City, which provides free online weekly briefings on fire-related air quality concerns using data from TEMPO and other NASA satellite systems. The FireAQ project was described by Jun Wang, PhD, from the University of Iowa in Iowa City.

NASA also fosters collaborations to reduce health disparities in air quality and respiratory health in urban heat islands and other areas affected by extreme temperatures due to climate change, as discussed by Christopher K. Uejio, PhD, from Florida State University in Tallahassee.

Air pollution expert George D. Thurston, ScD, professor of medicine and population health at the NYU Grossman School of Medicine, who attended the session, said that the PM2.5 standard includes nontoxic particulate matter, such as soil, and misses sub-micron sized particles, and asked Mr. Haynes whether smaller particles were being measured in the studies he described.

Mr. Haynes replied that the systems do not directly measure PM2.5 but instead rely on aerosol optical depth, a measure of the extent to which atmospheric particles absorb or scatter sunlight.

Dr. Thurston, who in 1987 was coauthor of groundbreaking study showing the link between PM2.5 levels and mortality, is now an advocate for a tougher standard of measuring ambient ultrafine particles with an aerodynamic diameter less than .1 microns in size (PM1).

NASA health and climate data are available at https://www.earthdata.nasa.gov/.

Mr. Haynes and Dr. Naeger are NASA employees. Dr. Thurston had no relevant disclosures.

SAN DIEGO – No matter where on earth you live, there’s likely to be an eye in the sky hovering overhead, and that’s a good thing, at least when it comes to satellite monitoring of air quality, said scientists from the National Aeronautics and Space Administration (NASA).

In a special symposium held at the American Thoracic Society’s international conference, NASA health and air quality specialists described the use of space-based systems and earth science applications to improve understanding of respiratory health risks worldwide, and to help enrich pulmonary research with galaxies of data.

“Every day we download over 25 terabytes of data,” said John Haynes, MS, program manager for Health and Air Quality Applications in the Earth Action Program of the NASA Earth Science Division in Washington.

Neil Osterweil/MDedge News

“Many of the observation data sets are critical for healthy air quality applications: observation of land surface temperature, sea surface temperature, precipitation, fires and thermal anomalies, aerosols, just to name a few, and the really awesome news is this offering from our constellation of satellites is free and open access, available to everyone across the globe,” he said.

The mission of NASA’s Earth Action Program is “to enable people and organizations to apply insights from Earth science to benefit the economy, health, quality of life, and environment.”

Program staff work with both industry and nonprofit environmental advocacy and health groups to help inform their decisions and actions with Earth science information.

NASA supports the use of Earth observations to help monitor and manage infectious diseases and environmental health, toxins and pathogens that affect health, air quality standards, and to assess the effects of climate change on air quality and public health.

Mr. Haynes noted that worldwide, six major cities have incorporated NASA data on fine particulate matter smaller than 2.5 microns (PM2.5) into their climate action plans. These cities include Accra, Ghana; Addis Ababa, Ethiopia; Buenos Aires, Argentina; Guadalajara, Mexico; Lima, Peru; and Johannesburg, South Africa.
 

Monitoring pollution with TEMPO

There are more than 30 Earth-monitoring systems currently in orbit or soon to be launched, including NASA’s Tropospheric Emissions: Monitoring of Pollution (TEMPO), launched in April 2023, with first operations in August 2023. The instrument is in a geostationary orbit about 22,236 miles above the equator at longitudes that allow it to survey virtually all of North America — from coast to coast, and from southern Mexico, Cuba, Puerto Rico, and the Bahamas to Northern Canada.

TEMPO is part of a geostationary air quality satellite “constellation” or group that provides daylight observation over the entire Northern Hemisphere, explained Aaron Naeger, PhD, MS, mission applications lead for TEMPO at the NASA Marshall Space Flight Center in Huntsville, Alabama.

Until TEMPO, space-based instruments had relatively low spatial resolution and could only capture one image each day. In contrast, TEMPO can scan east-west each daylight hour across its entire coverage area (known as the Field of Regard), and even more frequently during early morning and late afternoon. This allows researchers to measure volumes of pollution, sources, and how these pollution levels vary over time. The system measures ozone levels, nitrogen dioxide (NO₂,) formaldehyde, and aerosols.

More than 100 federal, state, local and tribal air quality agencies use the data captured by TEMPO to inform public health efforts.

Dr. Naeger gave examples of how the system can help identify public health hazards, including scans that showed high NO₂ levels from cities, traffic corridors, power plants, oil and gas fields, and fires.

Similarly, the system detected unhealthy ozone and PM2.5 levels during prescribed burns in April 2024, as well as notable differences between weekdays and weekends in NO₂ concentrations across California and the Front Range in Colorado. These showed higher levels along traffic corridors during weekdays related to increased traffic volumes and tailpipe emissions.
 

Fire and heat

Other NASA health and air quality initiatives include the FireAQ project, based at the University of Iowa in Iowa City, which provides free online weekly briefings on fire-related air quality concerns using data from TEMPO and other NASA satellite systems. The FireAQ project was described by Jun Wang, PhD, from the University of Iowa in Iowa City.

NASA also fosters collaborations to reduce health disparities in air quality and respiratory health in urban heat islands and other areas affected by extreme temperatures due to climate change, as discussed by Christopher K. Uejio, PhD, from Florida State University in Tallahassee.

Air pollution expert George D. Thurston, ScD, professor of medicine and population health at the NYU Grossman School of Medicine, who attended the session, said that the PM2.5 standard includes nontoxic particulate matter, such as soil, and misses sub-micron sized particles, and asked Mr. Haynes whether smaller particles were being measured in the studies he described.

Mr. Haynes replied that the systems do not directly measure PM2.5 but instead rely on aerosol optical depth, a measure of the extent to which atmospheric particles absorb or scatter sunlight.

Dr. Thurston, who in 1987 was coauthor of groundbreaking study showing the link between PM2.5 levels and mortality, is now an advocate for a tougher standard of measuring ambient ultrafine particles with an aerodynamic diameter less than .1 microns in size (PM1).

NASA health and climate data are available at https://www.earthdata.nasa.gov/.

Mr. Haynes and Dr. Naeger are NASA employees. Dr. Thurston had no relevant disclosures.

SAN DIEGO – No matter where on earth you live, there’s likely to be an eye in the sky hovering overhead, and that’s a good thing, at least when it comes to satellite monitoring of air quality, said scientists from the National Aeronautics and Space Administration (NASA).

In a special symposium held at the American Thoracic Society’s international conference, NASA health and air quality specialists described the use of space-based systems and earth science applications to improve understanding of respiratory health risks worldwide, and to help enrich pulmonary research with galaxies of data.

“Every day we download over 25 terabytes of data,” said John Haynes, MS, program manager for Health and Air Quality Applications in the Earth Action Program of the NASA Earth Science Division in Washington.

Neil Osterweil/MDedge News

“Many of the observation data sets are critical for healthy air quality applications: observation of land surface temperature, sea surface temperature, precipitation, fires and thermal anomalies, aerosols, just to name a few, and the really awesome news is this offering from our constellation of satellites is free and open access, available to everyone across the globe,” he said.

The mission of NASA’s Earth Action Program is “to enable people and organizations to apply insights from Earth science to benefit the economy, health, quality of life, and environment.”

Program staff work with both industry and nonprofit environmental advocacy and health groups to help inform their decisions and actions with Earth science information.

NASA supports the use of Earth observations to help monitor and manage infectious diseases and environmental health, toxins and pathogens that affect health, air quality standards, and to assess the effects of climate change on air quality and public health.

Mr. Haynes noted that worldwide, six major cities have incorporated NASA data on fine particulate matter smaller than 2.5 microns (PM2.5) into their climate action plans. These cities include Accra, Ghana; Addis Ababa, Ethiopia; Buenos Aires, Argentina; Guadalajara, Mexico; Lima, Peru; and Johannesburg, South Africa.
 

Monitoring pollution with TEMPO

There are more than 30 Earth-monitoring systems currently in orbit or soon to be launched, including NASA’s Tropospheric Emissions: Monitoring of Pollution (TEMPO), launched in April 2023, with first operations in August 2023. The instrument is in a geostationary orbit about 22,236 miles above the equator at longitudes that allow it to survey virtually all of North America — from coast to coast, and from southern Mexico, Cuba, Puerto Rico, and the Bahamas to Northern Canada.

TEMPO is part of a geostationary air quality satellite “constellation” or group that provides daylight observation over the entire Northern Hemisphere, explained Aaron Naeger, PhD, MS, mission applications lead for TEMPO at the NASA Marshall Space Flight Center in Huntsville, Alabama.

Until TEMPO, space-based instruments had relatively low spatial resolution and could only capture one image each day. In contrast, TEMPO can scan east-west each daylight hour across its entire coverage area (known as the Field of Regard), and even more frequently during early morning and late afternoon. This allows researchers to measure volumes of pollution, sources, and how these pollution levels vary over time. The system measures ozone levels, nitrogen dioxide (NO₂,) formaldehyde, and aerosols.

More than 100 federal, state, local and tribal air quality agencies use the data captured by TEMPO to inform public health efforts.

Dr. Naeger gave examples of how the system can help identify public health hazards, including scans that showed high NO₂ levels from cities, traffic corridors, power plants, oil and gas fields, and fires.

Similarly, the system detected unhealthy ozone and PM2.5 levels during prescribed burns in April 2024, as well as notable differences between weekdays and weekends in NO₂ concentrations across California and the Front Range in Colorado. These showed higher levels along traffic corridors during weekdays related to increased traffic volumes and tailpipe emissions.
 

Fire and heat

Other NASA health and air quality initiatives include the FireAQ project, based at the University of Iowa in Iowa City, which provides free online weekly briefings on fire-related air quality concerns using data from TEMPO and other NASA satellite systems. The FireAQ project was described by Jun Wang, PhD, from the University of Iowa in Iowa City.

NASA also fosters collaborations to reduce health disparities in air quality and respiratory health in urban heat islands and other areas affected by extreme temperatures due to climate change, as discussed by Christopher K. Uejio, PhD, from Florida State University in Tallahassee.

Air pollution expert George D. Thurston, ScD, professor of medicine and population health at the NYU Grossman School of Medicine, who attended the session, said that the PM2.5 standard includes nontoxic particulate matter, such as soil, and misses sub-micron sized particles, and asked Mr. Haynes whether smaller particles were being measured in the studies he described.

Mr. Haynes replied that the systems do not directly measure PM2.5 but instead rely on aerosol optical depth, a measure of the extent to which atmospheric particles absorb or scatter sunlight.

Dr. Thurston, who in 1987 was coauthor of groundbreaking study showing the link between PM2.5 levels and mortality, is now an advocate for a tougher standard of measuring ambient ultrafine particles with an aerodynamic diameter less than .1 microns in size (PM1).

NASA health and climate data are available at https://www.earthdata.nasa.gov/.

Mr. Haynes and Dr. Naeger are NASA employees. Dr. Thurston had no relevant disclosures.

SAN DIEGO — While there is currently no smoking gun definitively showing that indoor nitrogen dioxide (NO₂) concentrations from gas appliances are a cause of pulmonary diseases, the circumstantial evidence of the baleful effects of gas stoves on lung function is pretty compelling, said participants in a pro-con debate.

In what the moderator called “one of the most agreeable debates yet,” experts presented their views on the risks that cooking with natural gas pose on pulmonary health, and discussed ways for mitigating that harm. The debate was held at the American Thoracic Society’s international conference.
 

PRO: Gas stoves cause lung disease

Arguing for the “pro” side, John R. Balmes, MD of the University of California, San Francisco, and a physician member of the California Air Resources Board, began by admitting that “I would never have said gas stoves cause lung disease, but that’s what they assigned me.”

Gamely proceeding anyway, Dr. Balmes noted that natural gas — methane — is a potent greenhouse gas, and that cooking with natural gas leads to generation of NO₂ with high peak concentrations in the home, especially in the kitchen, but in other rooms as well.

Neil Osterweil/MDedge News

Con: More evidence needed

Arguing for the “con” side of the question, Meredith C. McCormack, MD, MHS, professor of medicine in the pulmonary and critical care division at Johns Hopkins University in Baltimore, said that “more definitive evidence is needed to define whether gas stoves cause lung disease.”

But Dr. McCormack didn’t let the natural gas industry off the hook, noting that a systematic review and meta-analysis of cooking with gas in high-, middle-, and low-income countries showed that domestic use of gas fuels vs. electric was associated with increased risk of asthma (1.11 overall), COPD (1.15), and pneumonia (1.26).

Neil Osterweil/MDedge News

On common ground

Environmental interventions that can benefit all members of a household — not just those with obstructive pulmonary disease — include smoking cessation, charcoal filter-equipped air cleaners, stove hoods that vent outdoors, integrated pest management, hypoallergenic pillow and mattress covers, high efficiency particulate air (HEPA) vacuums, and mold and radon abatement.

Both Dr. Balmes and Dr. McCormack agreed in the end that gas stoves contribute to respiratory morbidity, and that both state and national policy changes are needed to support transition to cleaner indoor air, with financial incentives available for households with more modest incomes.

“For everyone, there is a climate-change mitigation imperative to transition away from gas appliances if we want to tackle the climate emergency,” Dr. Balmes said.
 

End indoor combustion

George D. Thurston, ScD, professor of medicine and population health at the NYU Grossman School of Medicine, who attended the debate, told Chest Physician that the participants talked about NO₂ but didn’t touch on particulate pollution generated by gas stoves.

Burning natural gas produces particles that are very similar in composition to those produced by burning coal, oil, or diesel fuel, Dr. Thurston said, and he pointed out that interventions such as range hoods work only if they actually vent outdoors, and aren’t simply fans that recirculate the air within the home. And even when ventilation works as it should to move air out of the house, it only pumps it back into the atmosphere, where it contributes to climate change.

“We need combustion-free homes. That’s the unifying principle. We have to keep our eyes on that prize,” he said.

Dr. Balmes, Dr. McCormack, and Dr. Thurston all reported having no relevant disclosures.

SAN DIEGO — While there is currently no smoking gun definitively showing that indoor nitrogen dioxide (NO₂) concentrations from gas appliances are a cause of pulmonary diseases, the circumstantial evidence of the baleful effects of gas stoves on lung function is pretty compelling, said participants in a pro-con debate.

In what the moderator called “one of the most agreeable debates yet,” experts presented their views on the risks that cooking with natural gas pose on pulmonary health, and discussed ways for mitigating that harm. The debate was held at the American Thoracic Society’s international conference.
 

PRO: Gas stoves cause lung disease

Arguing for the “pro” side, John R. Balmes, MD of the University of California, San Francisco, and a physician member of the California Air Resources Board, began by admitting that “I would never have said gas stoves cause lung disease, but that’s what they assigned me.”

Gamely proceeding anyway, Dr. Balmes noted that natural gas — methane — is a potent greenhouse gas, and that cooking with natural gas leads to generation of NO₂ with high peak concentrations in the home, especially in the kitchen, but in other rooms as well.

Neil Osterweil/MDedge News

Con: More evidence needed

Arguing for the “con” side of the question, Meredith C. McCormack, MD, MHS, professor of medicine in the pulmonary and critical care division at Johns Hopkins University in Baltimore, said that “more definitive evidence is needed to define whether gas stoves cause lung disease.”

But Dr. McCormack didn’t let the natural gas industry off the hook, noting that a systematic review and meta-analysis of cooking with gas in high-, middle-, and low-income countries showed that domestic use of gas fuels vs. electric was associated with increased risk of asthma (1.11 overall), COPD (1.15), and pneumonia (1.26).

Neil Osterweil/MDedge News

On common ground

Environmental interventions that can benefit all members of a household — not just those with obstructive pulmonary disease — include smoking cessation, charcoal filter-equipped air cleaners, stove hoods that vent outdoors, integrated pest management, hypoallergenic pillow and mattress covers, high efficiency particulate air (HEPA) vacuums, and mold and radon abatement.

Both Dr. Balmes and Dr. McCormack agreed in the end that gas stoves contribute to respiratory morbidity, and that both state and national policy changes are needed to support transition to cleaner indoor air, with financial incentives available for households with more modest incomes.

“For everyone, there is a climate-change mitigation imperative to transition away from gas appliances if we want to tackle the climate emergency,” Dr. Balmes said.
 

End indoor combustion

George D. Thurston, ScD, professor of medicine and population health at the NYU Grossman School of Medicine, who attended the debate, told Chest Physician that the participants talked about NO₂ but didn’t touch on particulate pollution generated by gas stoves.

Burning natural gas produces particles that are very similar in composition to those produced by burning coal, oil, or diesel fuel, Dr. Thurston said, and he pointed out that interventions such as range hoods work only if they actually vent outdoors, and aren’t simply fans that recirculate the air within the home. And even when ventilation works as it should to move air out of the house, it only pumps it back into the atmosphere, where it contributes to climate change.

“We need combustion-free homes. That’s the unifying principle. We have to keep our eyes on that prize,” he said.

Dr. Balmes, Dr. McCormack, and Dr. Thurston all reported having no relevant disclosures.

SAN DIEGO — While there is currently no smoking gun definitively showing that indoor nitrogen dioxide (NO₂) concentrations from gas appliances are a cause of pulmonary diseases, the circumstantial evidence of the baleful effects of gas stoves on lung function is pretty compelling, said participants in a pro-con debate.

In what the moderator called “one of the most agreeable debates yet,” experts presented their views on the risks that cooking with natural gas pose on pulmonary health, and discussed ways for mitigating that harm. The debate was held at the American Thoracic Society’s international conference.
 

PRO: Gas stoves cause lung disease

Arguing for the “pro” side, John R. Balmes, MD of the University of California, San Francisco, and a physician member of the California Air Resources Board, began by admitting that “I would never have said gas stoves cause lung disease, but that’s what they assigned me.”

Gamely proceeding anyway, Dr. Balmes noted that natural gas — methane — is a potent greenhouse gas, and that cooking with natural gas leads to generation of NO₂ with high peak concentrations in the home, especially in the kitchen, but in other rooms as well.

Neil Osterweil/MDedge News

Con: More evidence needed

Arguing for the “con” side of the question, Meredith C. McCormack, MD, MHS, professor of medicine in the pulmonary and critical care division at Johns Hopkins University in Baltimore, said that “more definitive evidence is needed to define whether gas stoves cause lung disease.”

But Dr. McCormack didn’t let the natural gas industry off the hook, noting that a systematic review and meta-analysis of cooking with gas in high-, middle-, and low-income countries showed that domestic use of gas fuels vs. electric was associated with increased risk of asthma (1.11 overall), COPD (1.15), and pneumonia (1.26).

Neil Osterweil/MDedge News

On common ground

Environmental interventions that can benefit all members of a household — not just those with obstructive pulmonary disease — include smoking cessation, charcoal filter-equipped air cleaners, stove hoods that vent outdoors, integrated pest management, hypoallergenic pillow and mattress covers, high efficiency particulate air (HEPA) vacuums, and mold and radon abatement.

Both Dr. Balmes and Dr. McCormack agreed in the end that gas stoves contribute to respiratory morbidity, and that both state and national policy changes are needed to support transition to cleaner indoor air, with financial incentives available for households with more modest incomes.

“For everyone, there is a climate-change mitigation imperative to transition away from gas appliances if we want to tackle the climate emergency,” Dr. Balmes said.
 

End indoor combustion

George D. Thurston, ScD, professor of medicine and population health at the NYU Grossman School of Medicine, who attended the debate, told Chest Physician that the participants talked about NO₂ but didn’t touch on particulate pollution generated by gas stoves.

Burning natural gas produces particles that are very similar in composition to those produced by burning coal, oil, or diesel fuel, Dr. Thurston said, and he pointed out that interventions such as range hoods work only if they actually vent outdoors, and aren’t simply fans that recirculate the air within the home. And even when ventilation works as it should to move air out of the house, it only pumps it back into the atmosphere, where it contributes to climate change.

“We need combustion-free homes. That’s the unifying principle. We have to keep our eyes on that prize,” he said.

Dr. Balmes, Dr. McCormack, and Dr. Thurston all reported having no relevant disclosures.

SAN DIEGO — Patients with idiopathic pulmonary fibrosis (IPF) had significant improvements in lung function and reversal of lung fibrosis measures after 12 weeks of therapy with an investigational inhibitor of the Hedgehog signaling pathway.

Early efficacy data from a phase 2a safety trial suggest that the novel oral agent, dubbed ENV-101, is associated with improvements in forced vital capacity (FVC) and other measures of lung function, and may be a disease-modifying therapy for IPF, according to Toby M. Maher, MD, PhD, director of the interstitial lung disease program at Keck School of Medicine, University of Southern California, Los Angeles. Dr. Maher presented the results at the American Thoracic Society’s international conference.

“Historically we’ve not been seeing improvements in FVC, which is what we’ve been seeing [with ENV-101], and I think it’s conceivable that you can get remodeling of early areas of fibrosis in the lung,” Dr. Maher said in an interview with Chest Physician.

“We know from histology studies that if you look at IPF lungs you’ll see areas of end-stage fibrosis, but even in advanced disease you’ll see areas where the lung is relatively well preserved and there’s early fibrosis, so I think it’s conceivable that there is remodeling of some of those early areas of fibrosis,” he said.
 

Vital pathway

The Hedgehog pathway is highly conserved in evolution. The cell-signaling pathway is active embryogenesis, tissue proliferation, and organ development. There is also evidence to suggest that in adult the pathway becomes reactivated following tissue injury, as can occur in lung epithelia, Dr. Maher explained.

Although as the word “idiopathic” in IPF indicates the etiology of the disease is unknown, investigators have found that in IPF repetitive epithelial injury to lung tissue leads to activation of the Hedgehog pathway. Hedgehog signaling in turn induces formation and activation of myofibroblasts that lay down fibrotic matrix and contract lung tissue, leading to significant impairments in gas exchange, Dr. Maher said.

ENV-101 blocks Hedgehog from binding to the PTCH1 receptor, preventing release of the zinc-finger protein GLI1 from the kinase complex into the cell cytoplasm. With signaling blocked, myofibroblasts undergo apoptosis instead of initiating wound repair as they normally would, thereby eliminating an evident mechanism of IPF pathology, he explained.
 

Study details

In the phase 2a trial, investigators enrolled patients with IPF who were not taking antifibrotic agents and who had a percent predicted FVC greater than 50%, percent predicted diffusing capacity for carbon monoxide (DLCO) of at least 35%, and life expectancy of more than 1 year.

The patients were randomized to receive 200 mg oral ENV-101 daily (18 patients) or placebo (15 patients) for 12 weeks.

The primary endpoint of the trial was safety of the experimental agent. A previous phase 1b study of a different Hedgehog inhibitor — vismodegib (Erivedge), in combination with the antifibrotic agent pirfenidone (Pirespa) — in patients with IPF was discontinued because of poor tolerability.

In the current study, the most common treatment-related adverse events were dysgeusia in 57% of patients who received the drug, alopecia in 52%, and muscle spasms in 43%. The spasms were generally less severe than those seen in the vismodegib/pirfenidone trial mentioned above.

Seven patients (33%) had treatment-emergent events leading to dose interruption. Five patients discontinued treatment: one who withdrew because of taste alterations, one who was lost to follow-up after an IPF exacerbation, and three who withdrew consent.

There were no treatment-related deaths, and no clinically significant findings on labs, vital signs, electrocardiograms, or physical exam.
 

Efficacy endpoints

An analysis of the secondary efficacy endpoints showed a 1.9% mean improvement in FVC from baseline among patients assigned to ENV-101, compared with a mean decline of 1.3% of patients assigned to placebo (P = .035).

Patients on the active drug also had a 200-mL mean increase in total lung capacity, compared with a mean decline of 56 mL for patients on placebo (P = .005).

In addition, high-resolution CR studies showed a 9.4% absolute decrease from baseline in quantitative interstitial lung disease with ENV-101, vs. a 1.1% increase among controls, a 2% absolute decline from baseline in quantitative lung fibrosis compared with a 0.87% increase with placebo, and a 4.6% absolute decrease from baseline in quantitative ground glass, compared with an increase of 0.29% with placebo.
 

Bad taste a good sign?

Reinoud Gosens PhD, University of Groningen, the Netherlands, who co-moderated the session but was not involved in the study, questioned whether the dysgeusia seen in patients who received ENV-101 might be related to the dysgeusia seen in clinical trials of P2X3 receptor antagonists for cough.

“I was wondering if there would be a mechanistic overlap between Hedgehog inhibition and cough, which would be quite relevant for IPF,” he said in an interview.

The increase in FVC seen with ENV-101 and with the investigational agent buloxibutid, a novel angiotensin II type 2 receptor agonist described in a separate presentation by Dr. Maher, suggests that these drugs may have the ability to help remodel damaged lungs, Dr. Gosens said.

Investigators are currently planning a phase 2 dose-ranging trial (WHISTLE-PF) in patients with IPF or progressive pulmonary fibrosis.

The phase 2a trial was supported by Endeavor BioMedicines. Dr. Maher disclosed consultancy or speaker fees from Endeavor and others. Dr. Gosens had no relevant disclosures.

SAN DIEGO — Patients with idiopathic pulmonary fibrosis (IPF) had significant improvements in lung function and reversal of lung fibrosis measures after 12 weeks of therapy with an investigational inhibitor of the Hedgehog signaling pathway.

Early efficacy data from a phase 2a safety trial suggest that the novel oral agent, dubbed ENV-101, is associated with improvements in forced vital capacity (FVC) and other measures of lung function, and may be a disease-modifying therapy for IPF, according to Toby M. Maher, MD, PhD, director of the interstitial lung disease program at Keck School of Medicine, University of Southern California, Los Angeles. Dr. Maher presented the results at the American Thoracic Society’s international conference.

“Historically we’ve not been seeing improvements in FVC, which is what we’ve been seeing [with ENV-101], and I think it’s conceivable that you can get remodeling of early areas of fibrosis in the lung,” Dr. Maher said in an interview with Chest Physician.

“We know from histology studies that if you look at IPF lungs you’ll see areas of end-stage fibrosis, but even in advanced disease you’ll see areas where the lung is relatively well preserved and there’s early fibrosis, so I think it’s conceivable that there is remodeling of some of those early areas of fibrosis,” he said.
 

Vital pathway

The Hedgehog pathway is highly conserved in evolution. The cell-signaling pathway is active embryogenesis, tissue proliferation, and organ development. There is also evidence to suggest that in adult the pathway becomes reactivated following tissue injury, as can occur in lung epithelia, Dr. Maher explained.

Although as the word “idiopathic” in IPF indicates the etiology of the disease is unknown, investigators have found that in IPF repetitive epithelial injury to lung tissue leads to activation of the Hedgehog pathway. Hedgehog signaling in turn induces formation and activation of myofibroblasts that lay down fibrotic matrix and contract lung tissue, leading to significant impairments in gas exchange, Dr. Maher said.

ENV-101 blocks Hedgehog from binding to the PTCH1 receptor, preventing release of the zinc-finger protein GLI1 from the kinase complex into the cell cytoplasm. With signaling blocked, myofibroblasts undergo apoptosis instead of initiating wound repair as they normally would, thereby eliminating an evident mechanism of IPF pathology, he explained.
 

Study details

In the phase 2a trial, investigators enrolled patients with IPF who were not taking antifibrotic agents and who had a percent predicted FVC greater than 50%, percent predicted diffusing capacity for carbon monoxide (DLCO) of at least 35%, and life expectancy of more than 1 year.

The patients were randomized to receive 200 mg oral ENV-101 daily (18 patients) or placebo (15 patients) for 12 weeks.

The primary endpoint of the trial was safety of the experimental agent. A previous phase 1b study of a different Hedgehog inhibitor — vismodegib (Erivedge), in combination with the antifibrotic agent pirfenidone (Pirespa) — in patients with IPF was discontinued because of poor tolerability.

In the current study, the most common treatment-related adverse events were dysgeusia in 57% of patients who received the drug, alopecia in 52%, and muscle spasms in 43%. The spasms were generally less severe than those seen in the vismodegib/pirfenidone trial mentioned above.

Seven patients (33%) had treatment-emergent events leading to dose interruption. Five patients discontinued treatment: one who withdrew because of taste alterations, one who was lost to follow-up after an IPF exacerbation, and three who withdrew consent.

There were no treatment-related deaths, and no clinically significant findings on labs, vital signs, electrocardiograms, or physical exam.
 

Efficacy endpoints

An analysis of the secondary efficacy endpoints showed a 1.9% mean improvement in FVC from baseline among patients assigned to ENV-101, compared with a mean decline of 1.3% of patients assigned to placebo (P = .035).

Patients on the active drug also had a 200-mL mean increase in total lung capacity, compared with a mean decline of 56 mL for patients on placebo (P = .005).

In addition, high-resolution CR studies showed a 9.4% absolute decrease from baseline in quantitative interstitial lung disease with ENV-101, vs. a 1.1% increase among controls, a 2% absolute decline from baseline in quantitative lung fibrosis compared with a 0.87% increase with placebo, and a 4.6% absolute decrease from baseline in quantitative ground glass, compared with an increase of 0.29% with placebo.
 

Bad taste a good sign?

Reinoud Gosens PhD, University of Groningen, the Netherlands, who co-moderated the session but was not involved in the study, questioned whether the dysgeusia seen in patients who received ENV-101 might be related to the dysgeusia seen in clinical trials of P2X3 receptor antagonists for cough.

“I was wondering if there would be a mechanistic overlap between Hedgehog inhibition and cough, which would be quite relevant for IPF,” he said in an interview.

The increase in FVC seen with ENV-101 and with the investigational agent buloxibutid, a novel angiotensin II type 2 receptor agonist described in a separate presentation by Dr. Maher, suggests that these drugs may have the ability to help remodel damaged lungs, Dr. Gosens said.

Investigators are currently planning a phase 2 dose-ranging trial (WHISTLE-PF) in patients with IPF or progressive pulmonary fibrosis.

The phase 2a trial was supported by Endeavor BioMedicines. Dr. Maher disclosed consultancy or speaker fees from Endeavor and others. Dr. Gosens had no relevant disclosures.

SAN DIEGO — Patients with idiopathic pulmonary fibrosis (IPF) had significant improvements in lung function and reversal of lung fibrosis measures after 12 weeks of therapy with an investigational inhibitor of the Hedgehog signaling pathway.

Early efficacy data from a phase 2a safety trial suggest that the novel oral agent, dubbed ENV-101, is associated with improvements in forced vital capacity (FVC) and other measures of lung function, and may be a disease-modifying therapy for IPF, according to Toby M. Maher, MD, PhD, director of the interstitial lung disease program at Keck School of Medicine, University of Southern California, Los Angeles. Dr. Maher presented the results at the American Thoracic Society’s international conference.

“Historically we’ve not been seeing improvements in FVC, which is what we’ve been seeing [with ENV-101], and I think it’s conceivable that you can get remodeling of early areas of fibrosis in the lung,” Dr. Maher said in an interview with Chest Physician.

“We know from histology studies that if you look at IPF lungs you’ll see areas of end-stage fibrosis, but even in advanced disease you’ll see areas where the lung is relatively well preserved and there’s early fibrosis, so I think it’s conceivable that there is remodeling of some of those early areas of fibrosis,” he said.
 

Vital pathway

The Hedgehog pathway is highly conserved in evolution. The cell-signaling pathway is active embryogenesis, tissue proliferation, and organ development. There is also evidence to suggest that in adult the pathway becomes reactivated following tissue injury, as can occur in lung epithelia, Dr. Maher explained.

Although as the word “idiopathic” in IPF indicates the etiology of the disease is unknown, investigators have found that in IPF repetitive epithelial injury to lung tissue leads to activation of the Hedgehog pathway. Hedgehog signaling in turn induces formation and activation of myofibroblasts that lay down fibrotic matrix and contract lung tissue, leading to significant impairments in gas exchange, Dr. Maher said.

ENV-101 blocks Hedgehog from binding to the PTCH1 receptor, preventing release of the zinc-finger protein GLI1 from the kinase complex into the cell cytoplasm. With signaling blocked, myofibroblasts undergo apoptosis instead of initiating wound repair as they normally would, thereby eliminating an evident mechanism of IPF pathology, he explained.
 

Study details

In the phase 2a trial, investigators enrolled patients with IPF who were not taking antifibrotic agents and who had a percent predicted FVC greater than 50%, percent predicted diffusing capacity for carbon monoxide (DLCO) of at least 35%, and life expectancy of more than 1 year.

The patients were randomized to receive 200 mg oral ENV-101 daily (18 patients) or placebo (15 patients) for 12 weeks.

The primary endpoint of the trial was safety of the experimental agent. A previous phase 1b study of a different Hedgehog inhibitor — vismodegib (Erivedge), in combination with the antifibrotic agent pirfenidone (Pirespa) — in patients with IPF was discontinued because of poor tolerability.

In the current study, the most common treatment-related adverse events were dysgeusia in 57% of patients who received the drug, alopecia in 52%, and muscle spasms in 43%. The spasms were generally less severe than those seen in the vismodegib/pirfenidone trial mentioned above.

Seven patients (33%) had treatment-emergent events leading to dose interruption. Five patients discontinued treatment: one who withdrew because of taste alterations, one who was lost to follow-up after an IPF exacerbation, and three who withdrew consent.

There were no treatment-related deaths, and no clinically significant findings on labs, vital signs, electrocardiograms, or physical exam.
 

Efficacy endpoints

An analysis of the secondary efficacy endpoints showed a 1.9% mean improvement in FVC from baseline among patients assigned to ENV-101, compared with a mean decline of 1.3% of patients assigned to placebo (P = .035).

Patients on the active drug also had a 200-mL mean increase in total lung capacity, compared with a mean decline of 56 mL for patients on placebo (P = .005).

In addition, high-resolution CR studies showed a 9.4% absolute decrease from baseline in quantitative interstitial lung disease with ENV-101, vs. a 1.1% increase among controls, a 2% absolute decline from baseline in quantitative lung fibrosis compared with a 0.87% increase with placebo, and a 4.6% absolute decrease from baseline in quantitative ground glass, compared with an increase of 0.29% with placebo.
 

Bad taste a good sign?

Reinoud Gosens PhD, University of Groningen, the Netherlands, who co-moderated the session but was not involved in the study, questioned whether the dysgeusia seen in patients who received ENV-101 might be related to the dysgeusia seen in clinical trials of P2X3 receptor antagonists for cough.

“I was wondering if there would be a mechanistic overlap between Hedgehog inhibition and cough, which would be quite relevant for IPF,” he said in an interview.

The increase in FVC seen with ENV-101 and with the investigational agent buloxibutid, a novel angiotensin II type 2 receptor agonist described in a separate presentation by Dr. Maher, suggests that these drugs may have the ability to help remodel damaged lungs, Dr. Gosens said.

Investigators are currently planning a phase 2 dose-ranging trial (WHISTLE-PF) in patients with IPF or progressive pulmonary fibrosis.

The phase 2a trial was supported by Endeavor BioMedicines. Dr. Maher disclosed consultancy or speaker fees from Endeavor and others. Dr. Gosens had no relevant disclosures.

Only about 3% to 5% of patients with metastatic colorectal cancer have tumors that are positive for human epidermal growth factor receptor 2 (HER2), and until recently there was no treatment approved by the US Food and Drug Administration (FDA) for this subset of patients.

That all changed, in January of 2023. At that time, the FDA granted accelerated approval to tucatinib (Tukysa) in combination with trastuzumab for RAS wild-type HER2-positive unresectable or metastatic colorectal cancer that has progressed following fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.

The combination was the first FDA-approved treatment for this patient population.

The only other FDA-approved therapy for metastatic HER2-positive CRC is the antibody-drug conjugate trastuzumab deruxtecan (Enhertu). That drug received accelerated approval from the FDA for metastatic HER2-positive CRC for which no other suitable therapeutic option exists, on April 5, 2024. This FDA action represented an expansion of the drug’s earlier approvals for treating several cancer types, including certain patients with unresectable or metastatic HER2-positive breast cancer and adults with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who had received a prior trastuzumab-based regimen.

More than a year after tucatinib-trastuzumab’s approval, the dual HER2 blockade is bringing substantial clinical benefits to a population with few therapeutic options.
 

Drug Combo’s Use With Capecitabine in Breast Cancer

Tucatinib is a potent oral tyrosine kinase inhibitor (TKI) that has been shown to be highly selective for HER2. Prior to approval of the colorectal cancer indication, tucatinib had received FDA approval (in April 2020) in combination with trastuzumab and capecitabine for the treatment of patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who had received one or more prior anti-HER2-based regimens in the metastatic setting.

In these patients the combination was associated with significant improvements in both progression-free survival (PFS) and overall survival compared with trastuzumab and capecitabine.

Approval for the colorectal cancer indication was based on results of the phase 2 MOUNTAINEER trial, which were published in The Lancet Oncology.
 

Real-World Setting

Clinical experience with the combination in a real-world setting is still limited due to the relatively uncommon RAS wild-type HER2-positive CRC subtype, so most of what’s known about the efficacy and safety of tucatinib plus trastuzumab comes from clinical trials. But oncologists interviewed for this article emphasized that the tucatinib-trastuzumab combination nonetheless represents a major breakthrough.

“The population of RAS wild-type HER2-positive is small in colorectal cancer, but the benefit of this treatment is really remarkable. With this combination therapy there was a 38% response rate, and there was a very respectable duration of response. So the population is small, but the benefit of the treatment is by no means small,” said Afsaneh Barzi, MD, PhD, a medical oncologist specializing in gastrointestinal cancers at City of Hope in Duarte, California.

Another medical oncologist interviewed for this piece, who treats patients with HER2-positive metastatic CRC, said that the performance of tucatinib in the real-world setting is in keeping with the efficacy seen in clinical trials.

“There is a group of patients who have a very good response to HER2 [targeted] therapy. Often these are patients who have higher degrees of HER2 amplification, and they do not have concomitant other mutations that activate the pathway, such as RAS mutations,” said Kanwal PS Raghav, MD, MBBS, from the University of Texas MD Anderson Cancer Center in Houston.
 

Why It Works

In an interview, MOUNTAINEER coinvestigator Tanios S. Bekaii-Saab, MD, from the Mayo Clinic Comprehensive Cancer Center in Phoenix, Arizona, explained why dual HER2 blockade with tucatinib and trastuzumab is an important breakthrough for this population.

“HER2 as a target was already well established in breast cancer and in gastric cancer. In colon cancer we had signals [of anti-HER2 efficacy] but these signals were primarily with dual targeted therapy,” he said.

“What’s unique about tucatinib versus neratinib [Nerlynx], lapatinib [Tykerb] and some of the others is that this is a highly selective tyrosine kinase inhibitor, meaning it is potent just against HER2 and has limited activity against other receptors, classically EGFR, which also goes by the name of HER1,” said MOUNTAINEER trial chair John H. Strickler, MD, of Duke Cancer Center in Durham, North Carolina.

“The reason why that’s valuable is that when you inhibit other receptors like HER1 or EGFR, you can cause significant skin rash and other symptoms that can limit tolerability, which limits your ability to give the full dose. With tucatinib you can more completely inhibit HER2 with fewer side effects,” Dr. Strickler said in an interview.

Dr. Raghav noted that the primary adverse events of therapy with tucatinib have been diarrhea and fatigue, and other common side effects include abdominal pain, fever, nausea, rash, and infusion reactions.
 

Barriers to Treatment

Dr. Barzi pointed out that in the day-to-day practice setting there are two potential barriers to treatment with tucatinib and trastuzumab for patients with HER2-positive colorectal cancer, hurdles that they would not encounter if they were enrolled in clinical trials.

The first barrier is the requirement for HER2 testing, either through immunohistochemistry or fluorescence in situ hybridization.

“The adoption of HER2 testing in colorectal cancer lags behind other molecular testing, such as testing for KRAS or BRAF, so the provider needs to be aware that HER2 positivity is a possibility,” she said.

The second and more difficult-to-surmount barrier is imposed by the healthcare system. Although the combination is included in National Comprehensive Cancer Network guidelines and, therefore, should not be subject to restrictions or denials by insurers, “the challenge is that this is an oral and IV drug combination,” Dr. Barzi said.

While patients in real-world settings receive intravenous drugs such as trastuzumab in treatment centers, the oral drug component, tucatinib, is dispensed by pharmacies, and patients are often required to shell out high copays for such agents.

Dr. Barzi cited as an example the case of one of her patients who was receiving an oral agent — not tucatinib — for treatment of a different type of colorectal cancer.

“He has very good insurance, and after insurance his out-of-pocket cost on a monthly basis to obtain the drug is $275,” she said.
 

What’s Next

In colorectal cancer the combination of tucatinib and trastuzumab is approved only in the metastatic setting, but it is also being explored as a first-line therapy in combination with the mFOLFOX6 regimen (5-Fluorouracil, leucovorin, and oxaliplatin) in the MOUNTAINEER-03 trial, which is currently recruiting.

MOUNTAINEER was sponsored by Seagen and Merck. Dr. Strickler reported support from Seagen for the Lancet Oncology manuscript; institutional grants, consulting fees, and travel support from Seagen, and similar relationships with other companies. Dr. Bekaii-Saab reported institutional research and consulting fees from various companies, including Merck, personal consulting fees from various companies, and independent monitoring board/scientific advisory board activities. Dr. Raghav disclosed honoraria and an advisory/consulting role for Seagen and others. Dr. Barzi reported no relevant conflicts of interest.

Only about 3% to 5% of patients with metastatic colorectal cancer have tumors that are positive for human epidermal growth factor receptor 2 (HER2), and until recently there was no treatment approved by the US Food and Drug Administration (FDA) for this subset of patients.

That all changed, in January of 2023. At that time, the FDA granted accelerated approval to tucatinib (Tukysa) in combination with trastuzumab for RAS wild-type HER2-positive unresectable or metastatic colorectal cancer that has progressed following fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.

The combination was the first FDA-approved treatment for this patient population.

The only other FDA-approved therapy for metastatic HER2-positive CRC is the antibody-drug conjugate trastuzumab deruxtecan (Enhertu). That drug received accelerated approval from the FDA for metastatic HER2-positive CRC for which no other suitable therapeutic option exists, on April 5, 2024. This FDA action represented an expansion of the drug’s earlier approvals for treating several cancer types, including certain patients with unresectable or metastatic HER2-positive breast cancer and adults with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who had received a prior trastuzumab-based regimen.

More than a year after tucatinib-trastuzumab’s approval, the dual HER2 blockade is bringing substantial clinical benefits to a population with few therapeutic options.
 

Drug Combo’s Use With Capecitabine in Breast Cancer

Tucatinib is a potent oral tyrosine kinase inhibitor (TKI) that has been shown to be highly selective for HER2. Prior to approval of the colorectal cancer indication, tucatinib had received FDA approval (in April 2020) in combination with trastuzumab and capecitabine for the treatment of patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who had received one or more prior anti-HER2-based regimens in the metastatic setting.

In these patients the combination was associated with significant improvements in both progression-free survival (PFS) and overall survival compared with trastuzumab and capecitabine.

Approval for the colorectal cancer indication was based on results of the phase 2 MOUNTAINEER trial, which were published in The Lancet Oncology.
 

Real-World Setting

Clinical experience with the combination in a real-world setting is still limited due to the relatively uncommon RAS wild-type HER2-positive CRC subtype, so most of what’s known about the efficacy and safety of tucatinib plus trastuzumab comes from clinical trials. But oncologists interviewed for this article emphasized that the tucatinib-trastuzumab combination nonetheless represents a major breakthrough.

“The population of RAS wild-type HER2-positive is small in colorectal cancer, but the benefit of this treatment is really remarkable. With this combination therapy there was a 38% response rate, and there was a very respectable duration of response. So the population is small, but the benefit of the treatment is by no means small,” said Afsaneh Barzi, MD, PhD, a medical oncologist specializing in gastrointestinal cancers at City of Hope in Duarte, California.

Another medical oncologist interviewed for this piece, who treats patients with HER2-positive metastatic CRC, said that the performance of tucatinib in the real-world setting is in keeping with the efficacy seen in clinical trials.

“There is a group of patients who have a very good response to HER2 [targeted] therapy. Often these are patients who have higher degrees of HER2 amplification, and they do not have concomitant other mutations that activate the pathway, such as RAS mutations,” said Kanwal PS Raghav, MD, MBBS, from the University of Texas MD Anderson Cancer Center in Houston.
 

Why It Works

In an interview, MOUNTAINEER coinvestigator Tanios S. Bekaii-Saab, MD, from the Mayo Clinic Comprehensive Cancer Center in Phoenix, Arizona, explained why dual HER2 blockade with tucatinib and trastuzumab is an important breakthrough for this population.

“HER2 as a target was already well established in breast cancer and in gastric cancer. In colon cancer we had signals [of anti-HER2 efficacy] but these signals were primarily with dual targeted therapy,” he said.

“What’s unique about tucatinib versus neratinib [Nerlynx], lapatinib [Tykerb] and some of the others is that this is a highly selective tyrosine kinase inhibitor, meaning it is potent just against HER2 and has limited activity against other receptors, classically EGFR, which also goes by the name of HER1,” said MOUNTAINEER trial chair John H. Strickler, MD, of Duke Cancer Center in Durham, North Carolina.

“The reason why that’s valuable is that when you inhibit other receptors like HER1 or EGFR, you can cause significant skin rash and other symptoms that can limit tolerability, which limits your ability to give the full dose. With tucatinib you can more completely inhibit HER2 with fewer side effects,” Dr. Strickler said in an interview.

Dr. Raghav noted that the primary adverse events of therapy with tucatinib have been diarrhea and fatigue, and other common side effects include abdominal pain, fever, nausea, rash, and infusion reactions.
 

Barriers to Treatment

Dr. Barzi pointed out that in the day-to-day practice setting there are two potential barriers to treatment with tucatinib and trastuzumab for patients with HER2-positive colorectal cancer, hurdles that they would not encounter if they were enrolled in clinical trials.

The first barrier is the requirement for HER2 testing, either through immunohistochemistry or fluorescence in situ hybridization.

“The adoption of HER2 testing in colorectal cancer lags behind other molecular testing, such as testing for KRAS or BRAF, so the provider needs to be aware that HER2 positivity is a possibility,” she said.

The second and more difficult-to-surmount barrier is imposed by the healthcare system. Although the combination is included in National Comprehensive Cancer Network guidelines and, therefore, should not be subject to restrictions or denials by insurers, “the challenge is that this is an oral and IV drug combination,” Dr. Barzi said.

While patients in real-world settings receive intravenous drugs such as trastuzumab in treatment centers, the oral drug component, tucatinib, is dispensed by pharmacies, and patients are often required to shell out high copays for such agents.

Dr. Barzi cited as an example the case of one of her patients who was receiving an oral agent — not tucatinib — for treatment of a different type of colorectal cancer.

“He has very good insurance, and after insurance his out-of-pocket cost on a monthly basis to obtain the drug is $275,” she said.
 

What’s Next

In colorectal cancer the combination of tucatinib and trastuzumab is approved only in the metastatic setting, but it is also being explored as a first-line therapy in combination with the mFOLFOX6 regimen (5-Fluorouracil, leucovorin, and oxaliplatin) in the MOUNTAINEER-03 trial, which is currently recruiting.

MOUNTAINEER was sponsored by Seagen and Merck. Dr. Strickler reported support from Seagen for the Lancet Oncology manuscript; institutional grants, consulting fees, and travel support from Seagen, and similar relationships with other companies. Dr. Bekaii-Saab reported institutional research and consulting fees from various companies, including Merck, personal consulting fees from various companies, and independent monitoring board/scientific advisory board activities. Dr. Raghav disclosed honoraria and an advisory/consulting role for Seagen and others. Dr. Barzi reported no relevant conflicts of interest.

Only about 3% to 5% of patients with metastatic colorectal cancer have tumors that are positive for human epidermal growth factor receptor 2 (HER2), and until recently there was no treatment approved by the US Food and Drug Administration (FDA) for this subset of patients.

That all changed, in January of 2023. At that time, the FDA granted accelerated approval to tucatinib (Tukysa) in combination with trastuzumab for RAS wild-type HER2-positive unresectable or metastatic colorectal cancer that has progressed following fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.

The combination was the first FDA-approved treatment for this patient population.

The only other FDA-approved therapy for metastatic HER2-positive CRC is the antibody-drug conjugate trastuzumab deruxtecan (Enhertu). That drug received accelerated approval from the FDA for metastatic HER2-positive CRC for which no other suitable therapeutic option exists, on April 5, 2024. This FDA action represented an expansion of the drug’s earlier approvals for treating several cancer types, including certain patients with unresectable or metastatic HER2-positive breast cancer and adults with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who had received a prior trastuzumab-based regimen.

More than a year after tucatinib-trastuzumab’s approval, the dual HER2 blockade is bringing substantial clinical benefits to a population with few therapeutic options.
 

Drug Combo’s Use With Capecitabine in Breast Cancer

Tucatinib is a potent oral tyrosine kinase inhibitor (TKI) that has been shown to be highly selective for HER2. Prior to approval of the colorectal cancer indication, tucatinib had received FDA approval (in April 2020) in combination with trastuzumab and capecitabine for the treatment of patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who had received one or more prior anti-HER2-based regimens in the metastatic setting.

In these patients the combination was associated with significant improvements in both progression-free survival (PFS) and overall survival compared with trastuzumab and capecitabine.

Approval for the colorectal cancer indication was based on results of the phase 2 MOUNTAINEER trial, which were published in The Lancet Oncology.
 

Real-World Setting

Clinical experience with the combination in a real-world setting is still limited due to the relatively uncommon RAS wild-type HER2-positive CRC subtype, so most of what’s known about the efficacy and safety of tucatinib plus trastuzumab comes from clinical trials. But oncologists interviewed for this article emphasized that the tucatinib-trastuzumab combination nonetheless represents a major breakthrough.

“The population of RAS wild-type HER2-positive is small in colorectal cancer, but the benefit of this treatment is really remarkable. With this combination therapy there was a 38% response rate, and there was a very respectable duration of response. So the population is small, but the benefit of the treatment is by no means small,” said Afsaneh Barzi, MD, PhD, a medical oncologist specializing in gastrointestinal cancers at City of Hope in Duarte, California.

Another medical oncologist interviewed for this piece, who treats patients with HER2-positive metastatic CRC, said that the performance of tucatinib in the real-world setting is in keeping with the efficacy seen in clinical trials.

“There is a group of patients who have a very good response to HER2 [targeted] therapy. Often these are patients who have higher degrees of HER2 amplification, and they do not have concomitant other mutations that activate the pathway, such as RAS mutations,” said Kanwal PS Raghav, MD, MBBS, from the University of Texas MD Anderson Cancer Center in Houston.
 

Why It Works

In an interview, MOUNTAINEER coinvestigator Tanios S. Bekaii-Saab, MD, from the Mayo Clinic Comprehensive Cancer Center in Phoenix, Arizona, explained why dual HER2 blockade with tucatinib and trastuzumab is an important breakthrough for this population.

“HER2 as a target was already well established in breast cancer and in gastric cancer. In colon cancer we had signals [of anti-HER2 efficacy] but these signals were primarily with dual targeted therapy,” he said.

“What’s unique about tucatinib versus neratinib [Nerlynx], lapatinib [Tykerb] and some of the others is that this is a highly selective tyrosine kinase inhibitor, meaning it is potent just against HER2 and has limited activity against other receptors, classically EGFR, which also goes by the name of HER1,” said MOUNTAINEER trial chair John H. Strickler, MD, of Duke Cancer Center in Durham, North Carolina.

“The reason why that’s valuable is that when you inhibit other receptors like HER1 or EGFR, you can cause significant skin rash and other symptoms that can limit tolerability, which limits your ability to give the full dose. With tucatinib you can more completely inhibit HER2 with fewer side effects,” Dr. Strickler said in an interview.

Dr. Raghav noted that the primary adverse events of therapy with tucatinib have been diarrhea and fatigue, and other common side effects include abdominal pain, fever, nausea, rash, and infusion reactions.
 

Barriers to Treatment

Dr. Barzi pointed out that in the day-to-day practice setting there are two potential barriers to treatment with tucatinib and trastuzumab for patients with HER2-positive colorectal cancer, hurdles that they would not encounter if they were enrolled in clinical trials.

The first barrier is the requirement for HER2 testing, either through immunohistochemistry or fluorescence in situ hybridization.

“The adoption of HER2 testing in colorectal cancer lags behind other molecular testing, such as testing for KRAS or BRAF, so the provider needs to be aware that HER2 positivity is a possibility,” she said.

The second and more difficult-to-surmount barrier is imposed by the healthcare system. Although the combination is included in National Comprehensive Cancer Network guidelines and, therefore, should not be subject to restrictions or denials by insurers, “the challenge is that this is an oral and IV drug combination,” Dr. Barzi said.

While patients in real-world settings receive intravenous drugs such as trastuzumab in treatment centers, the oral drug component, tucatinib, is dispensed by pharmacies, and patients are often required to shell out high copays for such agents.

Dr. Barzi cited as an example the case of one of her patients who was receiving an oral agent — not tucatinib — for treatment of a different type of colorectal cancer.

“He has very good insurance, and after insurance his out-of-pocket cost on a monthly basis to obtain the drug is $275,” she said.
 

What’s Next

In colorectal cancer the combination of tucatinib and trastuzumab is approved only in the metastatic setting, but it is also being explored as a first-line therapy in combination with the mFOLFOX6 regimen (5-Fluorouracil, leucovorin, and oxaliplatin) in the MOUNTAINEER-03 trial, which is currently recruiting.

MOUNTAINEER was sponsored by Seagen and Merck. Dr. Strickler reported support from Seagen for the Lancet Oncology manuscript; institutional grants, consulting fees, and travel support from Seagen, and similar relationships with other companies. Dr. Bekaii-Saab reported institutional research and consulting fees from various companies, including Merck, personal consulting fees from various companies, and independent monitoring board/scientific advisory board activities. Dr. Raghav disclosed honoraria and an advisory/consulting role for Seagen and others. Dr. Barzi reported no relevant conflicts of interest.

Patient-reported outcomes (PROs) in rheumatology are not just personal lists of physical complaints or so-called “organ recitals.” In fact, PROs can both guide treatment decisions in daily practice and serve as key endpoints for clinical trials.

That’s the informed opinion of Clifton O. Bingham III, MD, director of the Johns Arthritis Center in Baltimore, Maryland, who discussed clinical and research applications of PROs at the 2024 Rheumatoid Arthritis Research Summit presented by the Arthritis Foundation and the Hospital for Special Surgery in New York City.

Johns Hopkins Medicine, Johns Hopkins Division of Rheumatology

“Integrating PROs into practice settings can enhance the clinician’s ability to understand their patients and monitor disease impact, and they are increasingly available for clinical care and are being qualified for outcome measures for clinical trials,” Dr. Bingham said.

“I posit to you that some of this ability to better characterize things like anxiety and depression levels of patients more precisely may help us to identify those patients who are less likely to respond to therapy and may require different interventions than disease-modifying therapies for their disease,” he told the audience.
 

PRO Examples

The term PRO encompasses a broad range of measures that may include health-related quality of life measures, symptoms and their affects, patient satisfaction, and the patient’s experience with care.

PROs are important for rheumatology care and research because “we now have the capacity to make what we used to think were the subjective experiences of disease more objective. We now have ways that we can put numbers and measurements to the experiences that patients have about their illness and use that information as a way to understand more about the patients who are in front of us and also how their disease changes over time,” Dr. Bingham said.

Patients are the best — or in some cases, the only — judges of many aspects of their health, and they are best suited to report on certain events and outcomes, he said.

PROs that are currently included in core outcome measures used to guide care and in clinical trials in pain scores as reported by visual analog scales; functioning, as measured by the Health Assessment Questionnaire-Disability Index (HAQ-DI); and patient global assessment.

In international qualitative studies in which patients with rheumatoid arthritis (RA) were asked what was most important to them, the usual suspects of pain, function, and fatigue were routinely cited across the studies. But patients in studies from these groups (RAPP-PI, RAID, and OMERACT) also said that other factors important to their well-being included good sleep, enjoyment of life, independence, ability to participate in valued activities, and freedom from emotional distress, Dr. Bingham noted.
 

The Promise of PROMIS

The science of clinical measurement has advanced dramatically during his career, as Dr. Bingham said.

“There have been significant changes in the science behind how you develop and validate outcomes measures. The fields of clinimetrics and psychometrics have evolved substantially. These are now grounded in what we call ‘modern measurement’ approaches, which focus on item-response theory, constructing interval scales of measurement in things that are very precise in their ability to detect change over time,” he said.

One such measurement instrument is the Patient-Reported Outcome Measurement Information System (PROMIS®), developed at the National Institutes of Health using advanced measurement science.

The system, administered through either computer or paper questionnaires, is designed to improve precision of health-related quality of life assessments in multiple domains, including most domains identified by patients with RA. It uses a T-score metric standardized to the US population.

“You can use this in a disease like rheumatoid arthritis, and you can find out how patients are doing in reference to the normative United States populations,” he said.

Dr. Bingham noted that his team has “very good data” to show that PROMIS system significantly outperforms existing instruments such as the HAQ.
 

How It Works

The system uses item banks, each with multiple items. For example, there are approximately 150 items for the physical function assessment portion. All the items are scored along a continuum, “from people who are completely disabled to those who can run marathons,” Dr. Bingham said.

Each item on the scale has a question and response component, ranging from “are you able to get in and out of bed?” to “are you able to walk from one room to another?” to “are you able to run 5 miles?”

To evaluate the PROMIS scale, Dr. Bingham and colleagues looked at the distribution of PROMIS T-scores for 1029 patients with RA at their center. The scales showed that patients with RA have higher levels of pain, fatigue, and sleep disturbances, as well as worse physical function, than population norms.

Dr. Bingham and colleagues also evaluated the performance of the system in patients with active RA who were starting on or switching to a different disease-modifying antirheumatic drug (DMARD). As they reported in 2019, among 106 participants who completed the 12-week study, all PROMIS scores improved after DMARD initiation (P ≤ .05). In addition, except for the depression domain, changes in all assessed PROMIS measures correlated with changes in Clinical Disease Activity Index scores.

To see whether integrating PROs into routine clinics could have an effect on care, Dr. Bingham and colleagues conducted a prospective cohort study, which showed that with the additional patient-reported data, clinicians changed or adjusted RA treatment in 16%-19% of visits, identified new symptoms in 27%-38%, and suggested nonpharmacologic interventions in 4%-11%.

“This is information that’s being used, and it’s going into changing medical decision making,” he said.

Summarizing his work, Dr. Bingham told the audience “I hope that I have convinced you that patients with RA prioritize domains that are impacted by their disease. PROMIS measures are really state-of-the-science methods to evaluate multiple aspects of health-related quality of life, and what I’ll note to you is that these have been translated into multiple languages internationally. There are Spanish-language versions, there are Chinese language versions, there are versions for every country in the [European Union] that have been validated and can be used.”
 

It’s a Start

In the Q & A following the presentation, Daniel H. Solomon, MD, MPH, from Brigham and Women’s Hospital in Boston, commented that “the measurement issues and automating measurements seems like it’s a fundamental practice issue — how to manage the system and how to manage patients better, and I feel like we’re kind of scratching the surface.”

He said that artificial intelligence and PROs in clinic offer some promise for improving care but added that “we can do better than this. We can figure out better systems for measuring PROs: Having patients measure PROs, having patients tell us about their PROs so they don’t have to come in, or coming in only when they need to come in, when they’re really flaring. There are lots of innovative ways of thinking about these tools, and it feels like we’re kind of on the cusp of really taking advantage.”

Dr. Bingham’s work is supported by the Patient-Centered Outcomes Research Institute, National Institutes of Health, Ira T. Fine Discovery Fund, Johns Hopkins Arthritis Center Discovery Fund, Camille J. Morgan Arthritis Research and Education Fund, and Scheer Family Foundation and Joanne and John Rogers. He disclosed consulting for AbbVie, Janssen, Lilly, and Sanofi and serving as a board member of the PROMIS health organization, co-chair of the Omeract Technical Advisory Group, and member of the C-PATH RA PRO working group. Dr. Solomon had no relevant disclosures.

A version of this article appeared on Medscape.com.

Patient-reported outcomes (PROs) in rheumatology are not just personal lists of physical complaints or so-called “organ recitals.” In fact, PROs can both guide treatment decisions in daily practice and serve as key endpoints for clinical trials.

That’s the informed opinion of Clifton O. Bingham III, MD, director of the Johns Arthritis Center in Baltimore, Maryland, who discussed clinical and research applications of PROs at the 2024 Rheumatoid Arthritis Research Summit presented by the Arthritis Foundation and the Hospital for Special Surgery in New York City.

Johns Hopkins Medicine, Johns Hopkins Division of Rheumatology

“Integrating PROs into practice settings can enhance the clinician’s ability to understand their patients and monitor disease impact, and they are increasingly available for clinical care and are being qualified for outcome measures for clinical trials,” Dr. Bingham said.

“I posit to you that some of this ability to better characterize things like anxiety and depression levels of patients more precisely may help us to identify those patients who are less likely to respond to therapy and may require different interventions than disease-modifying therapies for their disease,” he told the audience.
 

PRO Examples

The term PRO encompasses a broad range of measures that may include health-related quality of life measures, symptoms and their affects, patient satisfaction, and the patient’s experience with care.

PROs are important for rheumatology care and research because “we now have the capacity to make what we used to think were the subjective experiences of disease more objective. We now have ways that we can put numbers and measurements to the experiences that patients have about their illness and use that information as a way to understand more about the patients who are in front of us and also how their disease changes over time,” Dr. Bingham said.

Patients are the best — or in some cases, the only — judges of many aspects of their health, and they are best suited to report on certain events and outcomes, he said.

PROs that are currently included in core outcome measures used to guide care and in clinical trials in pain scores as reported by visual analog scales; functioning, as measured by the Health Assessment Questionnaire-Disability Index (HAQ-DI); and patient global assessment.

In international qualitative studies in which patients with rheumatoid arthritis (RA) were asked what was most important to them, the usual suspects of pain, function, and fatigue were routinely cited across the studies. But patients in studies from these groups (RAPP-PI, RAID, and OMERACT) also said that other factors important to their well-being included good sleep, enjoyment of life, independence, ability to participate in valued activities, and freedom from emotional distress, Dr. Bingham noted.
 

The Promise of PROMIS

The science of clinical measurement has advanced dramatically during his career, as Dr. Bingham said.

“There have been significant changes in the science behind how you develop and validate outcomes measures. The fields of clinimetrics and psychometrics have evolved substantially. These are now grounded in what we call ‘modern measurement’ approaches, which focus on item-response theory, constructing interval scales of measurement in things that are very precise in their ability to detect change over time,” he said.

One such measurement instrument is the Patient-Reported Outcome Measurement Information System (PROMIS®), developed at the National Institutes of Health using advanced measurement science.

The system, administered through either computer or paper questionnaires, is designed to improve precision of health-related quality of life assessments in multiple domains, including most domains identified by patients with RA. It uses a T-score metric standardized to the US population.

“You can use this in a disease like rheumatoid arthritis, and you can find out how patients are doing in reference to the normative United States populations,” he said.

Dr. Bingham noted that his team has “very good data” to show that PROMIS system significantly outperforms existing instruments such as the HAQ.
 

How It Works

The system uses item banks, each with multiple items. For example, there are approximately 150 items for the physical function assessment portion. All the items are scored along a continuum, “from people who are completely disabled to those who can run marathons,” Dr. Bingham said.

Each item on the scale has a question and response component, ranging from “are you able to get in and out of bed?” to “are you able to walk from one room to another?” to “are you able to run 5 miles?”

To evaluate the PROMIS scale, Dr. Bingham and colleagues looked at the distribution of PROMIS T-scores for 1029 patients with RA at their center. The scales showed that patients with RA have higher levels of pain, fatigue, and sleep disturbances, as well as worse physical function, than population norms.

Dr. Bingham and colleagues also evaluated the performance of the system in patients with active RA who were starting on or switching to a different disease-modifying antirheumatic drug (DMARD). As they reported in 2019, among 106 participants who completed the 12-week study, all PROMIS scores improved after DMARD initiation (P ≤ .05). In addition, except for the depression domain, changes in all assessed PROMIS measures correlated with changes in Clinical Disease Activity Index scores.

To see whether integrating PROs into routine clinics could have an effect on care, Dr. Bingham and colleagues conducted a prospective cohort study, which showed that with the additional patient-reported data, clinicians changed or adjusted RA treatment in 16%-19% of visits, identified new symptoms in 27%-38%, and suggested nonpharmacologic interventions in 4%-11%.

“This is information that’s being used, and it’s going into changing medical decision making,” he said.

Summarizing his work, Dr. Bingham told the audience “I hope that I have convinced you that patients with RA prioritize domains that are impacted by their disease. PROMIS measures are really state-of-the-science methods to evaluate multiple aspects of health-related quality of life, and what I’ll note to you is that these have been translated into multiple languages internationally. There are Spanish-language versions, there are Chinese language versions, there are versions for every country in the [European Union] that have been validated and can be used.”
 

It’s a Start

In the Q & A following the presentation, Daniel H. Solomon, MD, MPH, from Brigham and Women’s Hospital in Boston, commented that “the measurement issues and automating measurements seems like it’s a fundamental practice issue — how to manage the system and how to manage patients better, and I feel like we’re kind of scratching the surface.”

He said that artificial intelligence and PROs in clinic offer some promise for improving care but added that “we can do better than this. We can figure out better systems for measuring PROs: Having patients measure PROs, having patients tell us about their PROs so they don’t have to come in, or coming in only when they need to come in, when they’re really flaring. There are lots of innovative ways of thinking about these tools, and it feels like we’re kind of on the cusp of really taking advantage.”

Dr. Bingham’s work is supported by the Patient-Centered Outcomes Research Institute, National Institutes of Health, Ira T. Fine Discovery Fund, Johns Hopkins Arthritis Center Discovery Fund, Camille J. Morgan Arthritis Research and Education Fund, and Scheer Family Foundation and Joanne and John Rogers. He disclosed consulting for AbbVie, Janssen, Lilly, and Sanofi and serving as a board member of the PROMIS health organization, co-chair of the Omeract Technical Advisory Group, and member of the C-PATH RA PRO working group. Dr. Solomon had no relevant disclosures.

A version of this article appeared on Medscape.com.

Patient-reported outcomes (PROs) in rheumatology are not just personal lists of physical complaints or so-called “organ recitals.” In fact, PROs can both guide treatment decisions in daily practice and serve as key endpoints for clinical trials.

That’s the informed opinion of Clifton O. Bingham III, MD, director of the Johns Arthritis Center in Baltimore, Maryland, who discussed clinical and research applications of PROs at the 2024 Rheumatoid Arthritis Research Summit presented by the Arthritis Foundation and the Hospital for Special Surgery in New York City.

Johns Hopkins Medicine, Johns Hopkins Division of Rheumatology

“Integrating PROs into practice settings can enhance the clinician’s ability to understand their patients and monitor disease impact, and they are increasingly available for clinical care and are being qualified for outcome measures for clinical trials,” Dr. Bingham said.

“I posit to you that some of this ability to better characterize things like anxiety and depression levels of patients more precisely may help us to identify those patients who are less likely to respond to therapy and may require different interventions than disease-modifying therapies for their disease,” he told the audience.
 

PRO Examples

The term PRO encompasses a broad range of measures that may include health-related quality of life measures, symptoms and their affects, patient satisfaction, and the patient’s experience with care.

PROs are important for rheumatology care and research because “we now have the capacity to make what we used to think were the subjective experiences of disease more objective. We now have ways that we can put numbers and measurements to the experiences that patients have about their illness and use that information as a way to understand more about the patients who are in front of us and also how their disease changes over time,” Dr. Bingham said.

Patients are the best — or in some cases, the only — judges of many aspects of their health, and they are best suited to report on certain events and outcomes, he said.

PROs that are currently included in core outcome measures used to guide care and in clinical trials in pain scores as reported by visual analog scales; functioning, as measured by the Health Assessment Questionnaire-Disability Index (HAQ-DI); and patient global assessment.

In international qualitative studies in which patients with rheumatoid arthritis (RA) were asked what was most important to them, the usual suspects of pain, function, and fatigue were routinely cited across the studies. But patients in studies from these groups (RAPP-PI, RAID, and OMERACT) also said that other factors important to their well-being included good sleep, enjoyment of life, independence, ability to participate in valued activities, and freedom from emotional distress, Dr. Bingham noted.
 

The Promise of PROMIS

The science of clinical measurement has advanced dramatically during his career, as Dr. Bingham said.

“There have been significant changes in the science behind how you develop and validate outcomes measures. The fields of clinimetrics and psychometrics have evolved substantially. These are now grounded in what we call ‘modern measurement’ approaches, which focus on item-response theory, constructing interval scales of measurement in things that are very precise in their ability to detect change over time,” he said.

One such measurement instrument is the Patient-Reported Outcome Measurement Information System (PROMIS®), developed at the National Institutes of Health using advanced measurement science.

The system, administered through either computer or paper questionnaires, is designed to improve precision of health-related quality of life assessments in multiple domains, including most domains identified by patients with RA. It uses a T-score metric standardized to the US population.

“You can use this in a disease like rheumatoid arthritis, and you can find out how patients are doing in reference to the normative United States populations,” he said.

Dr. Bingham noted that his team has “very good data” to show that PROMIS system significantly outperforms existing instruments such as the HAQ.
 

How It Works

The system uses item banks, each with multiple items. For example, there are approximately 150 items for the physical function assessment portion. All the items are scored along a continuum, “from people who are completely disabled to those who can run marathons,” Dr. Bingham said.

Each item on the scale has a question and response component, ranging from “are you able to get in and out of bed?” to “are you able to walk from one room to another?” to “are you able to run 5 miles?”

To evaluate the PROMIS scale, Dr. Bingham and colleagues looked at the distribution of PROMIS T-scores for 1029 patients with RA at their center. The scales showed that patients with RA have higher levels of pain, fatigue, and sleep disturbances, as well as worse physical function, than population norms.

Dr. Bingham and colleagues also evaluated the performance of the system in patients with active RA who were starting on or switching to a different disease-modifying antirheumatic drug (DMARD). As they reported in 2019, among 106 participants who completed the 12-week study, all PROMIS scores improved after DMARD initiation (P ≤ .05). In addition, except for the depression domain, changes in all assessed PROMIS measures correlated with changes in Clinical Disease Activity Index scores.

To see whether integrating PROs into routine clinics could have an effect on care, Dr. Bingham and colleagues conducted a prospective cohort study, which showed that with the additional patient-reported data, clinicians changed or adjusted RA treatment in 16%-19% of visits, identified new symptoms in 27%-38%, and suggested nonpharmacologic interventions in 4%-11%.

“This is information that’s being used, and it’s going into changing medical decision making,” he said.

Summarizing his work, Dr. Bingham told the audience “I hope that I have convinced you that patients with RA prioritize domains that are impacted by their disease. PROMIS measures are really state-of-the-science methods to evaluate multiple aspects of health-related quality of life, and what I’ll note to you is that these have been translated into multiple languages internationally. There are Spanish-language versions, there are Chinese language versions, there are versions for every country in the [European Union] that have been validated and can be used.”
 

It’s a Start

In the Q & A following the presentation, Daniel H. Solomon, MD, MPH, from Brigham and Women’s Hospital in Boston, commented that “the measurement issues and automating measurements seems like it’s a fundamental practice issue — how to manage the system and how to manage patients better, and I feel like we’re kind of scratching the surface.”

He said that artificial intelligence and PROs in clinic offer some promise for improving care but added that “we can do better than this. We can figure out better systems for measuring PROs: Having patients measure PROs, having patients tell us about their PROs so they don’t have to come in, or coming in only when they need to come in, when they’re really flaring. There are lots of innovative ways of thinking about these tools, and it feels like we’re kind of on the cusp of really taking advantage.”

Dr. Bingham’s work is supported by the Patient-Centered Outcomes Research Institute, National Institutes of Health, Ira T. Fine Discovery Fund, Johns Hopkins Arthritis Center Discovery Fund, Camille J. Morgan Arthritis Research and Education Fund, and Scheer Family Foundation and Joanne and John Rogers. He disclosed consulting for AbbVie, Janssen, Lilly, and Sanofi and serving as a board member of the PROMIS health organization, co-chair of the Omeract Technical Advisory Group, and member of the C-PATH RA PRO working group. Dr. Solomon had no relevant disclosures.

A version of this article appeared on Medscape.com.

Rheumatologists and their staff have been dutifully recording disease activity and patient-reported outcomes for decades, and now, all that drudgery is beginning to pay off with the introduction of artificial intelligence (AI) and natural language processing systems that can mine electronic health records (EHRs) for nuggets of research gold and accurately predict short-term rheumatoid arthritis (RA) outcomes.

“I think we have learned from our very early experiments that longitudinal deep learning models can forecast rheumatoid arthritis [RA] outcomes with actually surprising efficiency, with fewer patients than we assumed would be needed,” said Jinoos Yazdany, MD, MPH, chief of rheumatology at Zuckerberg San Francisco General Hospital and Trauma Center, and codirector of the University of California San Francisco (UCSF) Quality and Informatics Lab.

At the 2024 Rheumatoid Arthritis Research Summit (RA Summit 2024), presented by the Arthritis Foundation and the Hospital for Special Surgery in New York City, Dr. Yazdany discussed why rheumatologists are well positioned to take advantage of predictive analytics and how natural language processing systems can be used to extract previously hard-to-find data from EHRs, which can then be applied to RA prognostics and research.
 

Data Galore

EHR data can be particularly useful for RA research because of the large volume of information, clinical data such as notes and imaging, less selection bias compared with other data sources such as cohorts or randomized controlled trials, real-time access, and the fact that many records contain longitudinal data (follow-ups, etc.).

However, EHR data may have gaps or inaccurate coding, and data such as text and images may require significant data processing and scrubbing before it can be used to advance research. In addition, EHR data are subject to patient privacy and security concerns, can be plagued by incompatibility across different systems, and may not represent patients who have less access to care, Dr. Yazdany said.

She noted that most rheumatologists record some measure of RA disease activity and patient physical function, and that patient-reported outcomes have been routinely incorporated into clinical records, especially since the 1980 introduction of the Health Assessment Questionnaire.

“In rheumatology, by achieving consensus and building a national quality measurement program, we have a cohesive national RA outcome measure selection strategy. RA outcomes are available for a majority of patients seen by rheumatologists, and that’s a critical strength of EHR data,” she said.
 

Spinning Text Into Analytics

The challenge for investigators who want to use this treasure trove of RA data is that more than 80% of the data are in the form of text, which raises questions about how to best extract outcomes data and drug dosing information from the written record.

As described in an article published online in Arthritis Care & Research February 14, 2023, Dr. Yazdany and colleagues at UCSF and Stanford University developed a natural language processing “pipeline” designed to extract RA outcomes from clinical notes on all patients included in the American College of Rheumatology’s Rheumatology Informatics System for Effectiveness (RISE) registry.

The model used expert-curated terms and a text processing tool to identify patterns and numerical scores linked to outcome measures in the records.

“This was an enormously difficult and ambitious project because we had many, many sites, the data was very messy, we had very complicated [independent review board] procedures, and we actually had to go through de-identification procedures because we were using this data for research, so we learned a lot,” Dr. Yazdany said.

The model processed 34 million notes on 854,628 patients across 158 practices and 24 different EHR systems.

In internal validation studies, the models had 95% sensitivity, 87% positive predictive value (PPV), and an F1 score (a measure of predictive performance) of 91%. Applying the model to an EHR from a large, non-RISE health system for external validation, the natural language processing pipeline had a 92% sensitivity, 69% PPV, and an F1 score of 79%.

The investigators also looked at the use of OpenAI large language models, including GPT 3.5 and 4 to interpret complex prescription orders and found that after training with 100 examples, GPT 4 was able to correctly interpret 95.6% of orders. But this experiment came at a high computational and financial cost, with one experiment running north of $3000, Dr. Yazdany cautioned.
 

Predicting Outcomes

Experiments to see whether an AI system can forecast RA disease activity at the next clinic visit are in their early stages.

Dr. Yazdany and colleagues used EHR data from UCSF and Zuckerberg San Francisco General Hospital on patients with two RA diagnostic codes at 30 days apart, who had at least one disease-modifying antirheumatic drug prescription and two Clinical Disease Activity Index (CDAI) scores 30 days apart.

One model, designed to predict CDAI at the next visit by “playing the odds” based on clinical experience, showed that about 60% of patients at UCSF achieved treat-to-target goals, while the remaining 40% did not.

This model performed barely better than pure chance, with an area under the receiver operating characteristic curve (AUC) of 0.54.

A second model that included the patient’s last CDAI score also fared little better than a roll of the dice, with an AUC of 0.55.

However, a neural network or “deep learning” model designed to process data akin to the way that the human brain works performed much better at predicting outcomes at the second visit, with an AUC of 0.91.

Applying the UCSF-trained neural network model to the Zuckerberg San Francisco General Hospital population, with different patient characteristics from those of UCSF, the AUC was 0.74. Although this result was not as good as that seen when applied to UCSF patients, it demonstrated that the model retains some predictive capability across different hospital systems, Dr. Yazdany said.

The next steps, she said, are to build more robust models based on vast and varied patient data pools that will allow the predictive models to be generalized across various healthcare settings.
 

The Here and Now

In the Q & A following the presentation, an audience member said that the study was “very cool stuff.”

“Is there a way to sort of get ahead and think of the technology that we’re starting to pilot? Hospitals are already using AI scribes, for example, to collect the data that is going to make it much easier to feed it to the predictive analytics that we’re going to use,” she said.

Dr. Yazdany replied that “over the last couple of years, one of the projects that we’ve worked on is to interview rheumatologists who are participating in the RISE registry about the ways that they are collecting [patient-reported outcomes], and it has been fascinating: A vast majority of people are still using paper forms.”

“The challenge is that our patient populations are very diverse. Technology, and especially filling out forms via online platforms, doesn’t work for everybody, and in some ways, filling out the paper forms when you go to the doctor’s office is a great equalizer. So, I think that we have some real challenges, and the solutions have to be embedded in the real world,” she added.

Dr. Yazdany’s research was supported by grants from the Agency for Healthcare Research & Quality and the National Institutes of Health. She disclosed consulting fees and/or research support from AstraZeneca, Aurinia, Bristol Myers Squibb, Gilead, and Pfizer.

A version of this article appeared on Medscape.com.

Rheumatologists and their staff have been dutifully recording disease activity and patient-reported outcomes for decades, and now, all that drudgery is beginning to pay off with the introduction of artificial intelligence (AI) and natural language processing systems that can mine electronic health records (EHRs) for nuggets of research gold and accurately predict short-term rheumatoid arthritis (RA) outcomes.

“I think we have learned from our very early experiments that longitudinal deep learning models can forecast rheumatoid arthritis [RA] outcomes with actually surprising efficiency, with fewer patients than we assumed would be needed,” said Jinoos Yazdany, MD, MPH, chief of rheumatology at Zuckerberg San Francisco General Hospital and Trauma Center, and codirector of the University of California San Francisco (UCSF) Quality and Informatics Lab.

At the 2024 Rheumatoid Arthritis Research Summit (RA Summit 2024), presented by the Arthritis Foundation and the Hospital for Special Surgery in New York City, Dr. Yazdany discussed why rheumatologists are well positioned to take advantage of predictive analytics and how natural language processing systems can be used to extract previously hard-to-find data from EHRs, which can then be applied to RA prognostics and research.
 

Data Galore

EHR data can be particularly useful for RA research because of the large volume of information, clinical data such as notes and imaging, less selection bias compared with other data sources such as cohorts or randomized controlled trials, real-time access, and the fact that many records contain longitudinal data (follow-ups, etc.).

However, EHR data may have gaps or inaccurate coding, and data such as text and images may require significant data processing and scrubbing before it can be used to advance research. In addition, EHR data are subject to patient privacy and security concerns, can be plagued by incompatibility across different systems, and may not represent patients who have less access to care, Dr. Yazdany said.

She noted that most rheumatologists record some measure of RA disease activity and patient physical function, and that patient-reported outcomes have been routinely incorporated into clinical records, especially since the 1980 introduction of the Health Assessment Questionnaire.

“In rheumatology, by achieving consensus and building a national quality measurement program, we have a cohesive national RA outcome measure selection strategy. RA outcomes are available for a majority of patients seen by rheumatologists, and that’s a critical strength of EHR data,” she said.
 

Spinning Text Into Analytics

The challenge for investigators who want to use this treasure trove of RA data is that more than 80% of the data are in the form of text, which raises questions about how to best extract outcomes data and drug dosing information from the written record.

As described in an article published online in Arthritis Care & Research February 14, 2023, Dr. Yazdany and colleagues at UCSF and Stanford University developed a natural language processing “pipeline” designed to extract RA outcomes from clinical notes on all patients included in the American College of Rheumatology’s Rheumatology Informatics System for Effectiveness (RISE) registry.

The model used expert-curated terms and a text processing tool to identify patterns and numerical scores linked to outcome measures in the records.

“This was an enormously difficult and ambitious project because we had many, many sites, the data was very messy, we had very complicated [independent review board] procedures, and we actually had to go through de-identification procedures because we were using this data for research, so we learned a lot,” Dr. Yazdany said.

The model processed 34 million notes on 854,628 patients across 158 practices and 24 different EHR systems.

In internal validation studies, the models had 95% sensitivity, 87% positive predictive value (PPV), and an F1 score (a measure of predictive performance) of 91%. Applying the model to an EHR from a large, non-RISE health system for external validation, the natural language processing pipeline had a 92% sensitivity, 69% PPV, and an F1 score of 79%.

The investigators also looked at the use of OpenAI large language models, including GPT 3.5 and 4 to interpret complex prescription orders and found that after training with 100 examples, GPT 4 was able to correctly interpret 95.6% of orders. But this experiment came at a high computational and financial cost, with one experiment running north of $3000, Dr. Yazdany cautioned.
 

Predicting Outcomes

Experiments to see whether an AI system can forecast RA disease activity at the next clinic visit are in their early stages.

Dr. Yazdany and colleagues used EHR data from UCSF and Zuckerberg San Francisco General Hospital on patients with two RA diagnostic codes at 30 days apart, who had at least one disease-modifying antirheumatic drug prescription and two Clinical Disease Activity Index (CDAI) scores 30 days apart.

One model, designed to predict CDAI at the next visit by “playing the odds” based on clinical experience, showed that about 60% of patients at UCSF achieved treat-to-target goals, while the remaining 40% did not.

This model performed barely better than pure chance, with an area under the receiver operating characteristic curve (AUC) of 0.54.

A second model that included the patient’s last CDAI score also fared little better than a roll of the dice, with an AUC of 0.55.

However, a neural network or “deep learning” model designed to process data akin to the way that the human brain works performed much better at predicting outcomes at the second visit, with an AUC of 0.91.

Applying the UCSF-trained neural network model to the Zuckerberg San Francisco General Hospital population, with different patient characteristics from those of UCSF, the AUC was 0.74. Although this result was not as good as that seen when applied to UCSF patients, it demonstrated that the model retains some predictive capability across different hospital systems, Dr. Yazdany said.

The next steps, she said, are to build more robust models based on vast and varied patient data pools that will allow the predictive models to be generalized across various healthcare settings.
 

The Here and Now

In the Q & A following the presentation, an audience member said that the study was “very cool stuff.”

“Is there a way to sort of get ahead and think of the technology that we’re starting to pilot? Hospitals are already using AI scribes, for example, to collect the data that is going to make it much easier to feed it to the predictive analytics that we’re going to use,” she said.

Dr. Yazdany replied that “over the last couple of years, one of the projects that we’ve worked on is to interview rheumatologists who are participating in the RISE registry about the ways that they are collecting [patient-reported outcomes], and it has been fascinating: A vast majority of people are still using paper forms.”

“The challenge is that our patient populations are very diverse. Technology, and especially filling out forms via online platforms, doesn’t work for everybody, and in some ways, filling out the paper forms when you go to the doctor’s office is a great equalizer. So, I think that we have some real challenges, and the solutions have to be embedded in the real world,” she added.

Dr. Yazdany’s research was supported by grants from the Agency for Healthcare Research & Quality and the National Institutes of Health. She disclosed consulting fees and/or research support from AstraZeneca, Aurinia, Bristol Myers Squibb, Gilead, and Pfizer.

A version of this article appeared on Medscape.com.

Rheumatologists and their staff have been dutifully recording disease activity and patient-reported outcomes for decades, and now, all that drudgery is beginning to pay off with the introduction of artificial intelligence (AI) and natural language processing systems that can mine electronic health records (EHRs) for nuggets of research gold and accurately predict short-term rheumatoid arthritis (RA) outcomes.

“I think we have learned from our very early experiments that longitudinal deep learning models can forecast rheumatoid arthritis [RA] outcomes with actually surprising efficiency, with fewer patients than we assumed would be needed,” said Jinoos Yazdany, MD, MPH, chief of rheumatology at Zuckerberg San Francisco General Hospital and Trauma Center, and codirector of the University of California San Francisco (UCSF) Quality and Informatics Lab.

At the 2024 Rheumatoid Arthritis Research Summit (RA Summit 2024), presented by the Arthritis Foundation and the Hospital for Special Surgery in New York City, Dr. Yazdany discussed why rheumatologists are well positioned to take advantage of predictive analytics and how natural language processing systems can be used to extract previously hard-to-find data from EHRs, which can then be applied to RA prognostics and research.
 

Data Galore

EHR data can be particularly useful for RA research because of the large volume of information, clinical data such as notes and imaging, less selection bias compared with other data sources such as cohorts or randomized controlled trials, real-time access, and the fact that many records contain longitudinal data (follow-ups, etc.).

However, EHR data may have gaps or inaccurate coding, and data such as text and images may require significant data processing and scrubbing before it can be used to advance research. In addition, EHR data are subject to patient privacy and security concerns, can be plagued by incompatibility across different systems, and may not represent patients who have less access to care, Dr. Yazdany said.

She noted that most rheumatologists record some measure of RA disease activity and patient physical function, and that patient-reported outcomes have been routinely incorporated into clinical records, especially since the 1980 introduction of the Health Assessment Questionnaire.

“In rheumatology, by achieving consensus and building a national quality measurement program, we have a cohesive national RA outcome measure selection strategy. RA outcomes are available for a majority of patients seen by rheumatologists, and that’s a critical strength of EHR data,” she said.
 

Spinning Text Into Analytics

The challenge for investigators who want to use this treasure trove of RA data is that more than 80% of the data are in the form of text, which raises questions about how to best extract outcomes data and drug dosing information from the written record.

As described in an article published online in Arthritis Care & Research February 14, 2023, Dr. Yazdany and colleagues at UCSF and Stanford University developed a natural language processing “pipeline” designed to extract RA outcomes from clinical notes on all patients included in the American College of Rheumatology’s Rheumatology Informatics System for Effectiveness (RISE) registry.

The model used expert-curated terms and a text processing tool to identify patterns and numerical scores linked to outcome measures in the records.

“This was an enormously difficult and ambitious project because we had many, many sites, the data was very messy, we had very complicated [independent review board] procedures, and we actually had to go through de-identification procedures because we were using this data for research, so we learned a lot,” Dr. Yazdany said.

The model processed 34 million notes on 854,628 patients across 158 practices and 24 different EHR systems.

In internal validation studies, the models had 95% sensitivity, 87% positive predictive value (PPV), and an F1 score (a measure of predictive performance) of 91%. Applying the model to an EHR from a large, non-RISE health system for external validation, the natural language processing pipeline had a 92% sensitivity, 69% PPV, and an F1 score of 79%.

The investigators also looked at the use of OpenAI large language models, including GPT 3.5 and 4 to interpret complex prescription orders and found that after training with 100 examples, GPT 4 was able to correctly interpret 95.6% of orders. But this experiment came at a high computational and financial cost, with one experiment running north of $3000, Dr. Yazdany cautioned.
 

Predicting Outcomes

Experiments to see whether an AI system can forecast RA disease activity at the next clinic visit are in their early stages.

Dr. Yazdany and colleagues used EHR data from UCSF and Zuckerberg San Francisco General Hospital on patients with two RA diagnostic codes at 30 days apart, who had at least one disease-modifying antirheumatic drug prescription and two Clinical Disease Activity Index (CDAI) scores 30 days apart.

One model, designed to predict CDAI at the next visit by “playing the odds” based on clinical experience, showed that about 60% of patients at UCSF achieved treat-to-target goals, while the remaining 40% did not.

This model performed barely better than pure chance, with an area under the receiver operating characteristic curve (AUC) of 0.54.

A second model that included the patient’s last CDAI score also fared little better than a roll of the dice, with an AUC of 0.55.

However, a neural network or “deep learning” model designed to process data akin to the way that the human brain works performed much better at predicting outcomes at the second visit, with an AUC of 0.91.

Applying the UCSF-trained neural network model to the Zuckerberg San Francisco General Hospital population, with different patient characteristics from those of UCSF, the AUC was 0.74. Although this result was not as good as that seen when applied to UCSF patients, it demonstrated that the model retains some predictive capability across different hospital systems, Dr. Yazdany said.

The next steps, she said, are to build more robust models based on vast and varied patient data pools that will allow the predictive models to be generalized across various healthcare settings.
 

The Here and Now

In the Q & A following the presentation, an audience member said that the study was “very cool stuff.”

“Is there a way to sort of get ahead and think of the technology that we’re starting to pilot? Hospitals are already using AI scribes, for example, to collect the data that is going to make it much easier to feed it to the predictive analytics that we’re going to use,” she said.

Dr. Yazdany replied that “over the last couple of years, one of the projects that we’ve worked on is to interview rheumatologists who are participating in the RISE registry about the ways that they are collecting [patient-reported outcomes], and it has been fascinating: A vast majority of people are still using paper forms.”

“The challenge is that our patient populations are very diverse. Technology, and especially filling out forms via online platforms, doesn’t work for everybody, and in some ways, filling out the paper forms when you go to the doctor’s office is a great equalizer. So, I think that we have some real challenges, and the solutions have to be embedded in the real world,” she added.

Dr. Yazdany’s research was supported by grants from the Agency for Healthcare Research & Quality and the National Institutes of Health. She disclosed consulting fees and/or research support from AstraZeneca, Aurinia, Bristol Myers Squibb, Gilead, and Pfizer.

A version of this article appeared on Medscape.com.

Even in large urban areas there aren’t enough rheumatologists to go around, and as a 2015 American College of Rheumatology workforce study projected, the number of rheumatology providers is expected to drop by 25% by the year 2030, while the demand for patient care in rheumatology is expected to increase by more than 100%.

The shortage of rheumatology care is even more acute in rural areas, but as a pilot project supported by the Arthritis Foundation shows, linking rheumatologists to health centers in remote and underserved locations via telehealth can help community providers improve care for patients with rheumatic diseases.

The novel collaborative model was described by Alfredo Rivadeneira, MD, professor of medicine in the division of rheumatology, allergy, and immunology at the University of North Carolina (UNC) School of Medicine in Chapel Hill, North Carolina.

UNC School of Medicine

“We found that this pilot, a unique partnership in North Carolina, improves access to rheumatology care to a rural population with high satisfaction scores. It underlines the importance of seeking collaboration with community providers when implementing these programs. It also allows timely specialty care and alleviates the barriers relating to transportation, insurance coverage, and telecommunication challenges,” he said at the 2024 Rheumatoid Arthritis Research Summit presented by the Arthritis Foundation and the Hospital for Special Surgery in New York City. 
 

Too Many Patients, Too Few Rheumatologists

Access to health is challenging for people from traditionally underserved racial and ethnic backgrounds, especially in states such as North Carolina, where 40% of the population lives in rural counties, which have higher age-adjusted mortality than more densely populated areas of the state, Dr. Rivadeneira said. 

In addition, 42% of the North Carolina residents seen at the state’s 42 Federally Qualified Health Centers (FQHCs) don’t have health insurance, which is higher than the average of 23% uninsured seen at FQHCs in other states.

There are currently approximately 250 rheumatology providers in North Carolina, the majority of whom work in the states’ three academic medical centers. Currently, North Carolina has an estimated population of 10 million people, which is projected to increase to 11.7 million by 2030. And by 2030, 20% of North Carolinians will be aged ≥ 65 years, Dr. Rivadeneira said, highlighting the need for expanded rheumatology care. 

Although telehealth services could be an option for expanding services to underserved communities, only 14 of the 42 FQHCs in the state use telehealth and only on a limited basis because it is not sufficiently reimbursed. 

Rivadeneira pointed to a 2022 study that showed how patients with rheumatic and musculoskeletal disease patients in North Carolina were less likely to use online patient portals if they lived in rural areas; came from racial or ethnic minority backgrounds; were older, men, had lower economic status (Medicaid enrollment or uninsured); or spoke a language other than English as their primary tongue. 
 

Pilot Project

To help smooth out some of the above-mentioned disparities, Dr. Rivadeneira and colleagues, in collaboration with the Arthritis Foundation, started a pilot project in 2022 designed to enhance access to rheumatology specialty care for rural residents through a shared telehealth model between the UNC rheumatology clinic and two separate Piedmont Health Services clinics in rural areas.

The project includes tailored educational sessions designed to empower Piedmont Health Services providers for evaluating and managing patients with rheumatic diseases.

Patients with prior diagnoses of rheumatologic diseases who were lost to rheumatology specialty care follow-up and those with new rheumatic symptoms who had transportation and/or financial barriers to receiving specialty care are triaged to the shared telemedicine visits.

Providers conduct monthly clinic sessions via shared visits between the on-site Piedmont Health Services provider and patients, with off-site UNC rheumatology fellows and attending physicians connected virtually. 

The educational component of the project includes monthly didactic sessions offered to all Piedmont Health Services providers across 12 locations. 

The topics that were chosen cover the most common rheumatologic conditions seen by community providers, including evaluating pain from a rheumatology perspective; using antinuclear antibodies and other serologies; evaluating and managing rheumatoid arthritis, lupus, gout, giant cell arteritis, polymyalgia rheumatica, and osteoarthritis; and methotrexate management and complications. 

“One of the aspects of this pilot that I want to emphasize is the importance of having the generalists with the patient, relaying the objective data, especially the physical exam, and that’s one of the great features of this model. It also provides a stable platform for telehealth to the individual patients, as many of these patients don’t have access to health technology,” Dr. Rivadeneira said. 
 

Thumbs Up

Both patients and general practitioners in the Piedmont Health system expressed high degrees of satisfaction with the shared telehealth program. Patients especially liked the time they saved not having to travel to see a specialist, and a large majority agreed that the visits were “as good as” in-person visits, felt that their concerns were addressed appropriately during the virtual visit, expressed overall satisfaction, and said they would like to continue virtual visits.

Physicians expressed a high degree of satisfaction with the rheumatology didactic sessions and said that the sessions enhanced their knowledge of evaluating and managing or co-managing rheumatologic diseases, as well as helping them to feel comfortable about applying this knowledge to patient care.

Dr. Rivadeneira noted that the pilot study was limited by low levels of Piedmont Health Services physician participation (two out of 45 total participated in shared visits), and only three or four providers typically took part in each didactic session. 
 

How to Improve?

In a follow-up study, the investigators asked Piedmont Health Services providers about barriers to rheumatology care, the most common and challenging diseases they encountered, how to improve the didactic components, and their perspectives on the pilot and how it may have affected referral patterns to rheumatology care.

The providers identified the cost of diagnostic evaluations and medications, transportation, long wait times, and language as the main barriers to patient access of rheumatology care.

“Additionally, over a third of them encountered patients on a weekly basis that were overdue for a visit with a rheumatologist,” Dr. Rivadeneira said. 

“Direct participation in the physical exam by the primary care provider enhances greatly, in my opinion, these telehealth visits. Focused didactic sessions, electronic handouts and/or quick access guides could empower more rural community providers to manage rheumatic diseases,” he concluded.

In the Q&A following the presentation, Laura Cappelli, MD, MHS, MS, associate professor of medicine in the division of rheumatology at Johns Hopkins School of Medicine in Baltimore, asked Dr. Rivadeneira how rheumatologists involved felt about the program and whether his team did any surveying or qualitative work with them.

“Just so you know, the rheumatologist was me,” he replied.

“I’m very picky about telemedicine,” he continued. “I don’t like it, I prefer, as most of us do, to have the patient there. But having the provider there, doing the exam, and you guiding them — I can ask, ‘Did you check their joints? Did you check their strength?’ — makes a huge difference and makes me feel comfortable with the sessions.”

Dr. Rivadeneira added that if a particular case was too complex or too vague to adequately assess via telehealth, he would arrange to see the patient in person.

The project was supported by the Arthritis Foundation. Dr. Rivadeneira and Dr. Cappelli reported no conflicts of interest.
 

A version of this article appeared on Medscape.com.

Even in large urban areas there aren’t enough rheumatologists to go around, and as a 2015 American College of Rheumatology workforce study projected, the number of rheumatology providers is expected to drop by 25% by the year 2030, while the demand for patient care in rheumatology is expected to increase by more than 100%.

The shortage of rheumatology care is even more acute in rural areas, but as a pilot project supported by the Arthritis Foundation shows, linking rheumatologists to health centers in remote and underserved locations via telehealth can help community providers improve care for patients with rheumatic diseases.

The novel collaborative model was described by Alfredo Rivadeneira, MD, professor of medicine in the division of rheumatology, allergy, and immunology at the University of North Carolina (UNC) School of Medicine in Chapel Hill, North Carolina.

UNC School of Medicine

“We found that this pilot, a unique partnership in North Carolina, improves access to rheumatology care to a rural population with high satisfaction scores. It underlines the importance of seeking collaboration with community providers when implementing these programs. It also allows timely specialty care and alleviates the barriers relating to transportation, insurance coverage, and telecommunication challenges,” he said at the 2024 Rheumatoid Arthritis Research Summit presented by the Arthritis Foundation and the Hospital for Special Surgery in New York City. 
 

Too Many Patients, Too Few Rheumatologists

Access to health is challenging for people from traditionally underserved racial and ethnic backgrounds, especially in states such as North Carolina, where 40% of the population lives in rural counties, which have higher age-adjusted mortality than more densely populated areas of the state, Dr. Rivadeneira said. 

In addition, 42% of the North Carolina residents seen at the state’s 42 Federally Qualified Health Centers (FQHCs) don’t have health insurance, which is higher than the average of 23% uninsured seen at FQHCs in other states.

There are currently approximately 250 rheumatology providers in North Carolina, the majority of whom work in the states’ three academic medical centers. Currently, North Carolina has an estimated population of 10 million people, which is projected to increase to 11.7 million by 2030. And by 2030, 20% of North Carolinians will be aged ≥ 65 years, Dr. Rivadeneira said, highlighting the need for expanded rheumatology care. 

Although telehealth services could be an option for expanding services to underserved communities, only 14 of the 42 FQHCs in the state use telehealth and only on a limited basis because it is not sufficiently reimbursed. 

Rivadeneira pointed to a 2022 study that showed how patients with rheumatic and musculoskeletal disease patients in North Carolina were less likely to use online patient portals if they lived in rural areas; came from racial or ethnic minority backgrounds; were older, men, had lower economic status (Medicaid enrollment or uninsured); or spoke a language other than English as their primary tongue. 
 

Pilot Project

To help smooth out some of the above-mentioned disparities, Dr. Rivadeneira and colleagues, in collaboration with the Arthritis Foundation, started a pilot project in 2022 designed to enhance access to rheumatology specialty care for rural residents through a shared telehealth model between the UNC rheumatology clinic and two separate Piedmont Health Services clinics in rural areas.

The project includes tailored educational sessions designed to empower Piedmont Health Services providers for evaluating and managing patients with rheumatic diseases.

Patients with prior diagnoses of rheumatologic diseases who were lost to rheumatology specialty care follow-up and those with new rheumatic symptoms who had transportation and/or financial barriers to receiving specialty care are triaged to the shared telemedicine visits.

Providers conduct monthly clinic sessions via shared visits between the on-site Piedmont Health Services provider and patients, with off-site UNC rheumatology fellows and attending physicians connected virtually. 

The educational component of the project includes monthly didactic sessions offered to all Piedmont Health Services providers across 12 locations. 

The topics that were chosen cover the most common rheumatologic conditions seen by community providers, including evaluating pain from a rheumatology perspective; using antinuclear antibodies and other serologies; evaluating and managing rheumatoid arthritis, lupus, gout, giant cell arteritis, polymyalgia rheumatica, and osteoarthritis; and methotrexate management and complications. 

“One of the aspects of this pilot that I want to emphasize is the importance of having the generalists with the patient, relaying the objective data, especially the physical exam, and that’s one of the great features of this model. It also provides a stable platform for telehealth to the individual patients, as many of these patients don’t have access to health technology,” Dr. Rivadeneira said. 
 

Thumbs Up

Both patients and general practitioners in the Piedmont Health system expressed high degrees of satisfaction with the shared telehealth program. Patients especially liked the time they saved not having to travel to see a specialist, and a large majority agreed that the visits were “as good as” in-person visits, felt that their concerns were addressed appropriately during the virtual visit, expressed overall satisfaction, and said they would like to continue virtual visits.

Physicians expressed a high degree of satisfaction with the rheumatology didactic sessions and said that the sessions enhanced their knowledge of evaluating and managing or co-managing rheumatologic diseases, as well as helping them to feel comfortable about applying this knowledge to patient care.

Dr. Rivadeneira noted that the pilot study was limited by low levels of Piedmont Health Services physician participation (two out of 45 total participated in shared visits), and only three or four providers typically took part in each didactic session. 
 

How to Improve?

In a follow-up study, the investigators asked Piedmont Health Services providers about barriers to rheumatology care, the most common and challenging diseases they encountered, how to improve the didactic components, and their perspectives on the pilot and how it may have affected referral patterns to rheumatology care.

The providers identified the cost of diagnostic evaluations and medications, transportation, long wait times, and language as the main barriers to patient access of rheumatology care.

“Additionally, over a third of them encountered patients on a weekly basis that were overdue for a visit with a rheumatologist,” Dr. Rivadeneira said. 

“Direct participation in the physical exam by the primary care provider enhances greatly, in my opinion, these telehealth visits. Focused didactic sessions, electronic handouts and/or quick access guides could empower more rural community providers to manage rheumatic diseases,” he concluded.

In the Q&A following the presentation, Laura Cappelli, MD, MHS, MS, associate professor of medicine in the division of rheumatology at Johns Hopkins School of Medicine in Baltimore, asked Dr. Rivadeneira how rheumatologists involved felt about the program and whether his team did any surveying or qualitative work with them.

“Just so you know, the rheumatologist was me,” he replied.

“I’m very picky about telemedicine,” he continued. “I don’t like it, I prefer, as most of us do, to have the patient there. But having the provider there, doing the exam, and you guiding them — I can ask, ‘Did you check their joints? Did you check their strength?’ — makes a huge difference and makes me feel comfortable with the sessions.”

Dr. Rivadeneira added that if a particular case was too complex or too vague to adequately assess via telehealth, he would arrange to see the patient in person.

The project was supported by the Arthritis Foundation. Dr. Rivadeneira and Dr. Cappelli reported no conflicts of interest.
 

A version of this article appeared on Medscape.com.

Even in large urban areas there aren’t enough rheumatologists to go around, and as a 2015 American College of Rheumatology workforce study projected, the number of rheumatology providers is expected to drop by 25% by the year 2030, while the demand for patient care in rheumatology is expected to increase by more than 100%.

The shortage of rheumatology care is even more acute in rural areas, but as a pilot project supported by the Arthritis Foundation shows, linking rheumatologists to health centers in remote and underserved locations via telehealth can help community providers improve care for patients with rheumatic diseases.

The novel collaborative model was described by Alfredo Rivadeneira, MD, professor of medicine in the division of rheumatology, allergy, and immunology at the University of North Carolina (UNC) School of Medicine in Chapel Hill, North Carolina.

UNC School of Medicine

“We found that this pilot, a unique partnership in North Carolina, improves access to rheumatology care to a rural population with high satisfaction scores. It underlines the importance of seeking collaboration with community providers when implementing these programs. It also allows timely specialty care and alleviates the barriers relating to transportation, insurance coverage, and telecommunication challenges,” he said at the 2024 Rheumatoid Arthritis Research Summit presented by the Arthritis Foundation and the Hospital for Special Surgery in New York City. 
 

Too Many Patients, Too Few Rheumatologists

Access to health is challenging for people from traditionally underserved racial and ethnic backgrounds, especially in states such as North Carolina, where 40% of the population lives in rural counties, which have higher age-adjusted mortality than more densely populated areas of the state, Dr. Rivadeneira said. 

In addition, 42% of the North Carolina residents seen at the state’s 42 Federally Qualified Health Centers (FQHCs) don’t have health insurance, which is higher than the average of 23% uninsured seen at FQHCs in other states.

There are currently approximately 250 rheumatology providers in North Carolina, the majority of whom work in the states’ three academic medical centers. Currently, North Carolina has an estimated population of 10 million people, which is projected to increase to 11.7 million by 2030. And by 2030, 20% of North Carolinians will be aged ≥ 65 years, Dr. Rivadeneira said, highlighting the need for expanded rheumatology care. 

Although telehealth services could be an option for expanding services to underserved communities, only 14 of the 42 FQHCs in the state use telehealth and only on a limited basis because it is not sufficiently reimbursed. 

Rivadeneira pointed to a 2022 study that showed how patients with rheumatic and musculoskeletal disease patients in North Carolina were less likely to use online patient portals if they lived in rural areas; came from racial or ethnic minority backgrounds; were older, men, had lower economic status (Medicaid enrollment or uninsured); or spoke a language other than English as their primary tongue. 
 

Pilot Project

To help smooth out some of the above-mentioned disparities, Dr. Rivadeneira and colleagues, in collaboration with the Arthritis Foundation, started a pilot project in 2022 designed to enhance access to rheumatology specialty care for rural residents through a shared telehealth model between the UNC rheumatology clinic and two separate Piedmont Health Services clinics in rural areas.

The project includes tailored educational sessions designed to empower Piedmont Health Services providers for evaluating and managing patients with rheumatic diseases.

Patients with prior diagnoses of rheumatologic diseases who were lost to rheumatology specialty care follow-up and those with new rheumatic symptoms who had transportation and/or financial barriers to receiving specialty care are triaged to the shared telemedicine visits.

Providers conduct monthly clinic sessions via shared visits between the on-site Piedmont Health Services provider and patients, with off-site UNC rheumatology fellows and attending physicians connected virtually. 

The educational component of the project includes monthly didactic sessions offered to all Piedmont Health Services providers across 12 locations. 

The topics that were chosen cover the most common rheumatologic conditions seen by community providers, including evaluating pain from a rheumatology perspective; using antinuclear antibodies and other serologies; evaluating and managing rheumatoid arthritis, lupus, gout, giant cell arteritis, polymyalgia rheumatica, and osteoarthritis; and methotrexate management and complications. 

“One of the aspects of this pilot that I want to emphasize is the importance of having the generalists with the patient, relaying the objective data, especially the physical exam, and that’s one of the great features of this model. It also provides a stable platform for telehealth to the individual patients, as many of these patients don’t have access to health technology,” Dr. Rivadeneira said. 
 

Thumbs Up

Both patients and general practitioners in the Piedmont Health system expressed high degrees of satisfaction with the shared telehealth program. Patients especially liked the time they saved not having to travel to see a specialist, and a large majority agreed that the visits were “as good as” in-person visits, felt that their concerns were addressed appropriately during the virtual visit, expressed overall satisfaction, and said they would like to continue virtual visits.

Physicians expressed a high degree of satisfaction with the rheumatology didactic sessions and said that the sessions enhanced their knowledge of evaluating and managing or co-managing rheumatologic diseases, as well as helping them to feel comfortable about applying this knowledge to patient care.

Dr. Rivadeneira noted that the pilot study was limited by low levels of Piedmont Health Services physician participation (two out of 45 total participated in shared visits), and only three or four providers typically took part in each didactic session. 
 

How to Improve?

In a follow-up study, the investigators asked Piedmont Health Services providers about barriers to rheumatology care, the most common and challenging diseases they encountered, how to improve the didactic components, and their perspectives on the pilot and how it may have affected referral patterns to rheumatology care.

The providers identified the cost of diagnostic evaluations and medications, transportation, long wait times, and language as the main barriers to patient access of rheumatology care.

“Additionally, over a third of them encountered patients on a weekly basis that were overdue for a visit with a rheumatologist,” Dr. Rivadeneira said. 

“Direct participation in the physical exam by the primary care provider enhances greatly, in my opinion, these telehealth visits. Focused didactic sessions, electronic handouts and/or quick access guides could empower more rural community providers to manage rheumatic diseases,” he concluded.

In the Q&A following the presentation, Laura Cappelli, MD, MHS, MS, associate professor of medicine in the division of rheumatology at Johns Hopkins School of Medicine in Baltimore, asked Dr. Rivadeneira how rheumatologists involved felt about the program and whether his team did any surveying or qualitative work with them.

“Just so you know, the rheumatologist was me,” he replied.

“I’m very picky about telemedicine,” he continued. “I don’t like it, I prefer, as most of us do, to have the patient there. But having the provider there, doing the exam, and you guiding them — I can ask, ‘Did you check their joints? Did you check their strength?’ — makes a huge difference and makes me feel comfortable with the sessions.”

Dr. Rivadeneira added that if a particular case was too complex or too vague to adequately assess via telehealth, he would arrange to see the patient in person.

The project was supported by the Arthritis Foundation. Dr. Rivadeneira and Dr. Cappelli reported no conflicts of interest.
 

A version of this article appeared on Medscape.com.

If your gut is telling you that your disease-modifying antirheumatic drugs (DMARDs) aren’t working as well as they should, listen to it.

That’s the advice of Rebecca B. Blank, MD, PhD, a rheumatologist at NYU Langone Health in New York City, who studies methods for modulating the gut microbiome to enhance DMARD efficacy for patients with rheumatoid arthritis (RA).

“The baseline gut microbiome can predict patient responsiveness to methotrexate,” said Dr. Blank at the 2024 Rheumatoid Arthritis Research Summit, presented by the Arthritis Foundation and the Hospital for Special Surgery in New York City.

Dr. Blank and colleagues are investigating how the intestinal microbiome may influence drug metabolism and the therapeutic potential of short-chain fatty acids for improving the efficacy of methotrexate in patients with RA.
 

Mucosal Barrier Disruption

There are myriad factors contributing to the development and progression of RA, including dysbiosis, or disruption, of the mucosal barrier, Dr. Blank explained.

“Dysbiosis can be detected in at-risk individuals before clinical signs of rheumatoid arthritis even occur,” she said.

Dr. Blank cited a 2021 study of the gut-joint axis in RA,which indicated that subclinical inflammation in the oral, gut, and/or lung mucosa may lead to inflammatory arthritis.

“When there’s a break in the mucosal barrier, either bacteria or their bacterial products can translocate into the lamina propria and then lead to an inflammatory T-cell response, and in addition, bacteria or their products can induce auto-antibody formation, which can then lead to joint inflammation,” she said.

Dr. Blank and colleagues, as well as other research groups, showed that gut bacterial colonization by Prevotella copri can induce an inflammatory response in gut lamina propria, and that people with RA have increased abundance of P copri relative to people without RA.
 

DMARD Resistance

To see whether microbial dysbiosis might play a role in DMARD-resistant RA, Dr. Blank and her team looked at patients with new-onset RA who were scheduled for treatment with methotrexate as their first-line medication. They classified responders as those patients with a change in Disease Activity Score in 28 joints (DAS28) of at least 1.8 points.

They then conducted 16S rRNA sequencing and shotgun sequencing on patient fecal samples taken at baseline to determine whether baseline microbiome differences might contribute to responses to methotrexate.

“And so indeed, we were able to find a human gut microbial signature that predicted methotrexate responsiveness in these baseline microbiome samples,” Dr. Blank said.

They identified 462 differences in gene orthologs (ie, genes preserved during evolution and speciation) that differed between responders and nonresponders, narrowed the list down to the top 38, and then developed a predictive model for response to methotrexate with an area under the receiver operating characteristic curve of 0.84.

The investigators then cultured fecal baseline samples with methotrexate to see how levels of the drug would be affected over time and found that samples from nonresponders metabolized methotrexate at a faster rate than samples from patients who had clinical responses to the drug.

Their work was further supported by colleagues at the University of California San Francisco, who found evidence in mouse models to suggest that microbial metabolism plays a role in methotrexate levels in plasma.
 

Modulating the Gut

“Our next question was: Can we modulate the gut microbiome to improve methotrexate efficacy?” Dr. Blank said.

They considered probiotics and prebiotics as possible means for modulating gut microbiota, but evidence of efficacy for these agents has been decidedly mixed, she noted.

Instead, the investigators focused on short-chain fatty acids, gut microbial fermentation byproducts of indigestible carbohydrates, which have been demonstrated to help improve gut mucosal barrier integrity and promote a more tolerant immune response.

One such short-chain fatty acid, butyrate, is produced through microbial fermentation of dietary fiber in the colon; it is available in various foods and in supplement form.

Butyrate has been shown to ameliorate inflammatory arthritis in a collagen-induced arthritis model, and in this model, methotrexate efficacy was increased with the addition of butyrate or butyrate-producing bacterial species.

Dr. Blank and colleagues compared patients with new-onset RA treated with methotrexate alone or methotrexate plus butyrate for 4 months and looked at up to 2 months of methotrexate plus butyrate treatment in patients who had suboptimal response to methotrexate alone.

In preliminary analyses, they found that at baseline, fecal butyrate was significantly elevated in methotrexate responders compared with in nonresponders. In addition, in the new-onset RA cohort, they saw that the 4-month responsiveness rate was 52.6% for those treated with methotrexate compared with 64.7% for those treated with methotrexate plus butyrate.

“Although this difference was not statistically significant, it’s exciting to think we may have an impact. What’s more, we were really excited to find that oral butyrate can lead to increased microbial diversity,” she said.
 

What Are You Measuring?

In the Q & A following the presentation, Clifton O. Bingham III, MD, director of the Johns Hopkins Arthritis Center in Baltimore, Maryland, commented that “the definitions of response and nonresponse are quite variable, depending on the studies that you use, and I think this is potentially a real problem for this entire line of investigation.”

Johns Hopkins Medicine, Johns Hopkins Division of Rheumatology

He noted that the DAS28, as used by Dr. Blank and colleagues, was developed in 1993, and that American College of Rheumatology response criteria, employed by other investigators who also presented during the session, were developed in 1990.

“It was a very different world when those criteria and those response indices were developed for patients with a very different disease from what we know as RA today,” he said.

He added that “I see a tremendous need for the rheumatology community to reevaluate what we define as responders and nonresponders, so that in all of these studies that are being done around the world, there is one definition that we understand [for] someone who is doing better, responding, or not responding.”

Dr. Blank’s work is supported by NYU, the Arthritis Foundation, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. She reported having no conflicts of interest to disclose. Dr. Bingham had no relevant conflicts of interest to disclose.

A version of this article appeared on Medscape.com.

If your gut is telling you that your disease-modifying antirheumatic drugs (DMARDs) aren’t working as well as they should, listen to it.

That’s the advice of Rebecca B. Blank, MD, PhD, a rheumatologist at NYU Langone Health in New York City, who studies methods for modulating the gut microbiome to enhance DMARD efficacy for patients with rheumatoid arthritis (RA).

“The baseline gut microbiome can predict patient responsiveness to methotrexate,” said Dr. Blank at the 2024 Rheumatoid Arthritis Research Summit, presented by the Arthritis Foundation and the Hospital for Special Surgery in New York City.

Dr. Blank and colleagues are investigating how the intestinal microbiome may influence drug metabolism and the therapeutic potential of short-chain fatty acids for improving the efficacy of methotrexate in patients with RA.
 

Mucosal Barrier Disruption

There are myriad factors contributing to the development and progression of RA, including dysbiosis, or disruption, of the mucosal barrier, Dr. Blank explained.

“Dysbiosis can be detected in at-risk individuals before clinical signs of rheumatoid arthritis even occur,” she said.

Dr. Blank cited a 2021 study of the gut-joint axis in RA,which indicated that subclinical inflammation in the oral, gut, and/or lung mucosa may lead to inflammatory arthritis.

“When there’s a break in the mucosal barrier, either bacteria or their bacterial products can translocate into the lamina propria and then lead to an inflammatory T-cell response, and in addition, bacteria or their products can induce auto-antibody formation, which can then lead to joint inflammation,” she said.

Dr. Blank and colleagues, as well as other research groups, showed that gut bacterial colonization by Prevotella copri can induce an inflammatory response in gut lamina propria, and that people with RA have increased abundance of P copri relative to people without RA.
 

DMARD Resistance

To see whether microbial dysbiosis might play a role in DMARD-resistant RA, Dr. Blank and her team looked at patients with new-onset RA who were scheduled for treatment with methotrexate as their first-line medication. They classified responders as those patients with a change in Disease Activity Score in 28 joints (DAS28) of at least 1.8 points.

They then conducted 16S rRNA sequencing and shotgun sequencing on patient fecal samples taken at baseline to determine whether baseline microbiome differences might contribute to responses to methotrexate.

“And so indeed, we were able to find a human gut microbial signature that predicted methotrexate responsiveness in these baseline microbiome samples,” Dr. Blank said.

They identified 462 differences in gene orthologs (ie, genes preserved during evolution and speciation) that differed between responders and nonresponders, narrowed the list down to the top 38, and then developed a predictive model for response to methotrexate with an area under the receiver operating characteristic curve of 0.84.

The investigators then cultured fecal baseline samples with methotrexate to see how levels of the drug would be affected over time and found that samples from nonresponders metabolized methotrexate at a faster rate than samples from patients who had clinical responses to the drug.

Their work was further supported by colleagues at the University of California San Francisco, who found evidence in mouse models to suggest that microbial metabolism plays a role in methotrexate levels in plasma.
 

Modulating the Gut

“Our next question was: Can we modulate the gut microbiome to improve methotrexate efficacy?” Dr. Blank said.

They considered probiotics and prebiotics as possible means for modulating gut microbiota, but evidence of efficacy for these agents has been decidedly mixed, she noted.

Instead, the investigators focused on short-chain fatty acids, gut microbial fermentation byproducts of indigestible carbohydrates, which have been demonstrated to help improve gut mucosal barrier integrity and promote a more tolerant immune response.

One such short-chain fatty acid, butyrate, is produced through microbial fermentation of dietary fiber in the colon; it is available in various foods and in supplement form.

Butyrate has been shown to ameliorate inflammatory arthritis in a collagen-induced arthritis model, and in this model, methotrexate efficacy was increased with the addition of butyrate or butyrate-producing bacterial species.

Dr. Blank and colleagues compared patients with new-onset RA treated with methotrexate alone or methotrexate plus butyrate for 4 months and looked at up to 2 months of methotrexate plus butyrate treatment in patients who had suboptimal response to methotrexate alone.

In preliminary analyses, they found that at baseline, fecal butyrate was significantly elevated in methotrexate responders compared with in nonresponders. In addition, in the new-onset RA cohort, they saw that the 4-month responsiveness rate was 52.6% for those treated with methotrexate compared with 64.7% for those treated with methotrexate plus butyrate.

“Although this difference was not statistically significant, it’s exciting to think we may have an impact. What’s more, we were really excited to find that oral butyrate can lead to increased microbial diversity,” she said.
 

What Are You Measuring?

In the Q & A following the presentation, Clifton O. Bingham III, MD, director of the Johns Hopkins Arthritis Center in Baltimore, Maryland, commented that “the definitions of response and nonresponse are quite variable, depending on the studies that you use, and I think this is potentially a real problem for this entire line of investigation.”

Johns Hopkins Medicine, Johns Hopkins Division of Rheumatology

He noted that the DAS28, as used by Dr. Blank and colleagues, was developed in 1993, and that American College of Rheumatology response criteria, employed by other investigators who also presented during the session, were developed in 1990.

“It was a very different world when those criteria and those response indices were developed for patients with a very different disease from what we know as RA today,” he said.

He added that “I see a tremendous need for the rheumatology community to reevaluate what we define as responders and nonresponders, so that in all of these studies that are being done around the world, there is one definition that we understand [for] someone who is doing better, responding, or not responding.”

Dr. Blank’s work is supported by NYU, the Arthritis Foundation, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. She reported having no conflicts of interest to disclose. Dr. Bingham had no relevant conflicts of interest to disclose.

A version of this article appeared on Medscape.com.

If your gut is telling you that your disease-modifying antirheumatic drugs (DMARDs) aren’t working as well as they should, listen to it.

That’s the advice of Rebecca B. Blank, MD, PhD, a rheumatologist at NYU Langone Health in New York City, who studies methods for modulating the gut microbiome to enhance DMARD efficacy for patients with rheumatoid arthritis (RA).

“The baseline gut microbiome can predict patient responsiveness to methotrexate,” said Dr. Blank at the 2024 Rheumatoid Arthritis Research Summit, presented by the Arthritis Foundation and the Hospital for Special Surgery in New York City.

Dr. Blank and colleagues are investigating how the intestinal microbiome may influence drug metabolism and the therapeutic potential of short-chain fatty acids for improving the efficacy of methotrexate in patients with RA.
 

Mucosal Barrier Disruption

There are myriad factors contributing to the development and progression of RA, including dysbiosis, or disruption, of the mucosal barrier, Dr. Blank explained.

“Dysbiosis can be detected in at-risk individuals before clinical signs of rheumatoid arthritis even occur,” she said.

Dr. Blank cited a 2021 study of the gut-joint axis in RA,which indicated that subclinical inflammation in the oral, gut, and/or lung mucosa may lead to inflammatory arthritis.

“When there’s a break in the mucosal barrier, either bacteria or their bacterial products can translocate into the lamina propria and then lead to an inflammatory T-cell response, and in addition, bacteria or their products can induce auto-antibody formation, which can then lead to joint inflammation,” she said.

Dr. Blank and colleagues, as well as other research groups, showed that gut bacterial colonization by Prevotella copri can induce an inflammatory response in gut lamina propria, and that people with RA have increased abundance of P copri relative to people without RA.
 

DMARD Resistance

To see whether microbial dysbiosis might play a role in DMARD-resistant RA, Dr. Blank and her team looked at patients with new-onset RA who were scheduled for treatment with methotrexate as their first-line medication. They classified responders as those patients with a change in Disease Activity Score in 28 joints (DAS28) of at least 1.8 points.

They then conducted 16S rRNA sequencing and shotgun sequencing on patient fecal samples taken at baseline to determine whether baseline microbiome differences might contribute to responses to methotrexate.

“And so indeed, we were able to find a human gut microbial signature that predicted methotrexate responsiveness in these baseline microbiome samples,” Dr. Blank said.

They identified 462 differences in gene orthologs (ie, genes preserved during evolution and speciation) that differed between responders and nonresponders, narrowed the list down to the top 38, and then developed a predictive model for response to methotrexate with an area under the receiver operating characteristic curve of 0.84.

The investigators then cultured fecal baseline samples with methotrexate to see how levels of the drug would be affected over time and found that samples from nonresponders metabolized methotrexate at a faster rate than samples from patients who had clinical responses to the drug.

Their work was further supported by colleagues at the University of California San Francisco, who found evidence in mouse models to suggest that microbial metabolism plays a role in methotrexate levels in plasma.
 

Modulating the Gut

“Our next question was: Can we modulate the gut microbiome to improve methotrexate efficacy?” Dr. Blank said.

They considered probiotics and prebiotics as possible means for modulating gut microbiota, but evidence of efficacy for these agents has been decidedly mixed, she noted.

Instead, the investigators focused on short-chain fatty acids, gut microbial fermentation byproducts of indigestible carbohydrates, which have been demonstrated to help improve gut mucosal barrier integrity and promote a more tolerant immune response.

One such short-chain fatty acid, butyrate, is produced through microbial fermentation of dietary fiber in the colon; it is available in various foods and in supplement form.

Butyrate has been shown to ameliorate inflammatory arthritis in a collagen-induced arthritis model, and in this model, methotrexate efficacy was increased with the addition of butyrate or butyrate-producing bacterial species.

Dr. Blank and colleagues compared patients with new-onset RA treated with methotrexate alone or methotrexate plus butyrate for 4 months and looked at up to 2 months of methotrexate plus butyrate treatment in patients who had suboptimal response to methotrexate alone.

In preliminary analyses, they found that at baseline, fecal butyrate was significantly elevated in methotrexate responders compared with in nonresponders. In addition, in the new-onset RA cohort, they saw that the 4-month responsiveness rate was 52.6% for those treated with methotrexate compared with 64.7% for those treated with methotrexate plus butyrate.

“Although this difference was not statistically significant, it’s exciting to think we may have an impact. What’s more, we were really excited to find that oral butyrate can lead to increased microbial diversity,” she said.
 

What Are You Measuring?

In the Q & A following the presentation, Clifton O. Bingham III, MD, director of the Johns Hopkins Arthritis Center in Baltimore, Maryland, commented that “the definitions of response and nonresponse are quite variable, depending on the studies that you use, and I think this is potentially a real problem for this entire line of investigation.”

Johns Hopkins Medicine, Johns Hopkins Division of Rheumatology

He noted that the DAS28, as used by Dr. Blank and colleagues, was developed in 1993, and that American College of Rheumatology response criteria, employed by other investigators who also presented during the session, were developed in 1990.

“It was a very different world when those criteria and those response indices were developed for patients with a very different disease from what we know as RA today,” he said.

He added that “I see a tremendous need for the rheumatology community to reevaluate what we define as responders and nonresponders, so that in all of these studies that are being done around the world, there is one definition that we understand [for] someone who is doing better, responding, or not responding.”

Dr. Blank’s work is supported by NYU, the Arthritis Foundation, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. She reported having no conflicts of interest to disclose. Dr. Bingham had no relevant conflicts of interest to disclose.

A version of this article appeared on Medscape.com.