The Food and Drug Administration has approved the Portico with FlexNav (Abbott) transcatheter aortic valve replacement (TAVR) system for patients with “symptomatic, severe aortic stenosis who are at high or extreme risk for open-heart surgery,” the company has announced.

Olivier Le Moal/Getty Images

The approval indication is in line with the entry criteria of PORTICO IDE, the investigational device exemption trial from which the FDA largely made its decision.

With the self-expanding Portico valve, Abbott joins two other companies with TAVR valves on the U.S. market: Medtronic with the self-expanding Corevalve Evolut (Medtronic) line, and Edwards Lifesciences with its Sapien (Edwards Lifesciences) valves, both of which can be used in patients at low surgical risk.

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

The Food and Drug Administration has approved the Portico with FlexNav (Abbott) transcatheter aortic valve replacement (TAVR) system for patients with “symptomatic, severe aortic stenosis who are at high or extreme risk for open-heart surgery,” the company has announced.

Olivier Le Moal/Getty Images

The approval indication is in line with the entry criteria of PORTICO IDE, the investigational device exemption trial from which the FDA largely made its decision.

With the self-expanding Portico valve, Abbott joins two other companies with TAVR valves on the U.S. market: Medtronic with the self-expanding Corevalve Evolut (Medtronic) line, and Edwards Lifesciences with its Sapien (Edwards Lifesciences) valves, both of which can be used in patients at low surgical risk.

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

The Food and Drug Administration has approved the Portico with FlexNav (Abbott) transcatheter aortic valve replacement (TAVR) system for patients with “symptomatic, severe aortic stenosis who are at high or extreme risk for open-heart surgery,” the company has announced.

Olivier Le Moal/Getty Images

The approval indication is in line with the entry criteria of PORTICO IDE, the investigational device exemption trial from which the FDA largely made its decision.

With the self-expanding Portico valve, Abbott joins two other companies with TAVR valves on the U.S. market: Medtronic with the self-expanding Corevalve Evolut (Medtronic) line, and Edwards Lifesciences with its Sapien (Edwards Lifesciences) valves, both of which can be used in patients at low surgical risk.

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

ILLUSTRATIVE CASE

A 50-year-old woman presents to your office for a well-woman exam. Her past medical history includes a 22-pack-year smoking history (she quit 5 years ago), well-controlled hypertension, and mild obesity. She has no family history of cancer, but she does have a family history of type 2 diabetes and heart disease. Besides age- and risk-appropriate laboratory tests, cervical cancer screening, breast cancer screening, and initial colon cancer screening, are there any other preventive services you would offer her?

Lung cancer is the second most common cancer in both men and women, and it is the leading cause of cancer death in the United States—regardless of gender. The American Cancer Society estimates that 235,760 people will be diagnosed with lung cancer and 131,880 people will die of the disease in 2021.²

In the 2015 National Cancer Institute report on the economic costs of cancer, direct and indirect costs of lung cancer totaled $21.1 billion annually. Lost productivity from lung cancer added another $36.1 billion in annual costs.³ The economic costs increased to $23.8 billion in 2020, with no data on lost productivity.⁴

Smoking tobacco is by far the primary risk factor for lung cancer, and it is estimated to account for 90% of all lung cancer cases. Compared with nonsmokers, the relative risk of lung cancer is approximately 20 times higher for smokers.^5,6

Because the median age of lung cancer diagnosis is 70 years, increasing age is also considered a risk factor for lung cancer.^2,7

Although lung cancer has a relatively poor prognosis—with an average 5-year survival rate of 20.5%—early-stage lung cancer is more amenable to treatment and has a better prognosis (as is true with many cancers).¹

LDCT has a high sensitivity, as well as a reasonable specificity, for lung cancer detection. There is demonstrated benefit in screening patients who are at high risk for lung cancer.^8-11 In 2013, the USPSTF recommended annual lung cancer screening (B recommendation) with LDCT in adults 55 to 80 years of age who have a 30-pack-year smoking history, and who currently smoke or quit within the past 15 years.¹

Continue to: STUDY SUMMARY

Broader eligibility for screening supports mortality benefit

This is an update to the 2013 clinical practice guideline on lung cancer screening. The USPSTF used 2 methods to provide the best possible evidence for the recommendations. The first method was a systematic review of the accuracy of screening for lung cancer with LDCT, evaluating both the benefits and harms of lung cancer screening. The systematic review examined various subgroups, the number and/or frequency of LDCT scans, and various approaches to reducing false-positive results. In addition to the systematic review, they used collaborative modeling studies to determine the optimal age for beginning and ending screening, the optimal screening interval, and the relative benefits and harms of various screening strategies. These modeling studies complemented the evidence review.

This updated guideline nearly doubles eligibility for lung cancer screening using low-dose CT scanning.

The review included 7 randomized controlled trials (RCTs), plus the modeling studies. Only the National Lung Screening Trial (NLST; N = 53,454) and the Nederlands-Leuvens Longkanker Screenings Onderzoek (NELSON) trial (N = 15,792) had adequate power to detect a mortality benefit from screening (NLST: relative risk reduction = 16%; 95% CI, 5%-25%; NELSON: incidence rate ratio = 0.75; 95% CI, 0.61-0.90) compared with no screening.

Screening intervals, from the NLST and NELSON trials as well as the modeling studies, revealed the greatest benefit from annual screening (statistics not shared). Evidence also showed that screening those with lighter smoking histories (< 30 pack-years) and at an earlier age (age 50) provided increased mortality benefit. No evidence was found for a benefit of screening past 80 years of age. The modeling studies concluded that the 2013 USPSTF screening program, using a starting age of 55 and a 30-pack-year smoking history, would reduce mortality by 9.8%, but by changing to a starting age of 50, a 20-pack-year smoking history, and annual screening, the mortality benefit was increased to 13%.^1,11

Comparison with computer-based risk prediction models from the Cancer Intervention and Surveillance Modeling Network (CISNET) revealed insufficient evidence at this time to show that prediction model–based screening offered any benefit beyond that of the age and smoking history risk factor model.

The incidence of false-positive results was > 25% in the NLST at baseline and at 1 year. Use of a classification system such as the Lung Imaging Reporting and Data System (Lung-RADS) could reduce that from 26.6% to 12.8%.² Another potential harm from LDCT screening is radiation exposure. Evidence from several RCTs and cohort studies showed the exposure from 1 LDCT scan to be 0.65 to 2.36 mSv, whereas the annual background radiation in the United States is 2.4 mSv. The modeling studies estimated that there would be 1 death caused by LDCT for every 18.5 cancer deaths avoided.^1,11

Continue to: WHAT'S NEW

Expanded age range, reduced pack-year history

Annual lung cancer screening is now recommended to begin for patients at age 50 years with a 20-pack-year history instead of age 55 years with a 30-pack-year history. This would nearly double (87% overall) the number of people eligible for screening, and it would include more Black patients and women, who tend to smoke fewer cigarettes than their White male counterparts. The American College of Radiology estimates that the expanded screening criteria could save between 30,000 and 60,000 lives per year.¹²

CAVEATS

Screening criteria for upper age limit, years since smoking remain unchanged

For those patients who quit smoking, the guidelines apply only to those who have stopped smoking within the past 15 years. Furthermore, the benefit does not extend beyond age 80 or where other conditions reduce life expectancy. And, as noted earlier, modeling studies estimate that there would be 1 death caused by LDCT for every 18.5 cancer deaths avoided.^1,11

CHALLENGES TO IMPLEMENTATION

Concerns about false-positives, ­radiation exposure may limit acceptance

Challenges would be based mostly on the need for greater, more detailed dialogue between physicians and patients at higher risk for lung cancer in a time-constrained environment. Also, LDCT may not be available in some areas, and patients and physicians may have concerns regarding repeated CT exposure. In addition, false-positive results increase patient stress and may adversely affect both patient and physician acceptance.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 50-year-old woman presents to your office for a well-woman exam. Her past medical history includes a 22-pack-year smoking history (she quit 5 years ago), well-controlled hypertension, and mild obesity. She has no family history of cancer, but she does have a family history of type 2 diabetes and heart disease. Besides age- and risk-appropriate laboratory tests, cervical cancer screening, breast cancer screening, and initial colon cancer screening, are there any other preventive services you would offer her?

Lung cancer is the second most common cancer in both men and women, and it is the leading cause of cancer death in the United States—regardless of gender. The American Cancer Society estimates that 235,760 people will be diagnosed with lung cancer and 131,880 people will die of the disease in 2021.²

In the 2015 National Cancer Institute report on the economic costs of cancer, direct and indirect costs of lung cancer totaled $21.1 billion annually. Lost productivity from lung cancer added another $36.1 billion in annual costs.³ The economic costs increased to $23.8 billion in 2020, with no data on lost productivity.⁴

Smoking tobacco is by far the primary risk factor for lung cancer, and it is estimated to account for 90% of all lung cancer cases. Compared with nonsmokers, the relative risk of lung cancer is approximately 20 times higher for smokers.^5,6

Because the median age of lung cancer diagnosis is 70 years, increasing age is also considered a risk factor for lung cancer.^2,7

Although lung cancer has a relatively poor prognosis—with an average 5-year survival rate of 20.5%—early-stage lung cancer is more amenable to treatment and has a better prognosis (as is true with many cancers).¹

LDCT has a high sensitivity, as well as a reasonable specificity, for lung cancer detection. There is demonstrated benefit in screening patients who are at high risk for lung cancer.^8-11 In 2013, the USPSTF recommended annual lung cancer screening (B recommendation) with LDCT in adults 55 to 80 years of age who have a 30-pack-year smoking history, and who currently smoke or quit within the past 15 years.¹

Continue to: STUDY SUMMARY

Broader eligibility for screening supports mortality benefit

This is an update to the 2013 clinical practice guideline on lung cancer screening. The USPSTF used 2 methods to provide the best possible evidence for the recommendations. The first method was a systematic review of the accuracy of screening for lung cancer with LDCT, evaluating both the benefits and harms of lung cancer screening. The systematic review examined various subgroups, the number and/or frequency of LDCT scans, and various approaches to reducing false-positive results. In addition to the systematic review, they used collaborative modeling studies to determine the optimal age for beginning and ending screening, the optimal screening interval, and the relative benefits and harms of various screening strategies. These modeling studies complemented the evidence review.

This updated guideline nearly doubles eligibility for lung cancer screening using low-dose CT scanning.

The review included 7 randomized controlled trials (RCTs), plus the modeling studies. Only the National Lung Screening Trial (NLST; N = 53,454) and the Nederlands-Leuvens Longkanker Screenings Onderzoek (NELSON) trial (N = 15,792) had adequate power to detect a mortality benefit from screening (NLST: relative risk reduction = 16%; 95% CI, 5%-25%; NELSON: incidence rate ratio = 0.75; 95% CI, 0.61-0.90) compared with no screening.

Screening intervals, from the NLST and NELSON trials as well as the modeling studies, revealed the greatest benefit from annual screening (statistics not shared). Evidence also showed that screening those with lighter smoking histories (< 30 pack-years) and at an earlier age (age 50) provided increased mortality benefit. No evidence was found for a benefit of screening past 80 years of age. The modeling studies concluded that the 2013 USPSTF screening program, using a starting age of 55 and a 30-pack-year smoking history, would reduce mortality by 9.8%, but by changing to a starting age of 50, a 20-pack-year smoking history, and annual screening, the mortality benefit was increased to 13%.^1,11

Comparison with computer-based risk prediction models from the Cancer Intervention and Surveillance Modeling Network (CISNET) revealed insufficient evidence at this time to show that prediction model–based screening offered any benefit beyond that of the age and smoking history risk factor model.

The incidence of false-positive results was > 25% in the NLST at baseline and at 1 year. Use of a classification system such as the Lung Imaging Reporting and Data System (Lung-RADS) could reduce that from 26.6% to 12.8%.² Another potential harm from LDCT screening is radiation exposure. Evidence from several RCTs and cohort studies showed the exposure from 1 LDCT scan to be 0.65 to 2.36 mSv, whereas the annual background radiation in the United States is 2.4 mSv. The modeling studies estimated that there would be 1 death caused by LDCT for every 18.5 cancer deaths avoided.^1,11

Continue to: WHAT'S NEW

Expanded age range, reduced pack-year history

Annual lung cancer screening is now recommended to begin for patients at age 50 years with a 20-pack-year history instead of age 55 years with a 30-pack-year history. This would nearly double (87% overall) the number of people eligible for screening, and it would include more Black patients and women, who tend to smoke fewer cigarettes than their White male counterparts. The American College of Radiology estimates that the expanded screening criteria could save between 30,000 and 60,000 lives per year.¹²

CAVEATS

Screening criteria for upper age limit, years since smoking remain unchanged

For those patients who quit smoking, the guidelines apply only to those who have stopped smoking within the past 15 years. Furthermore, the benefit does not extend beyond age 80 or where other conditions reduce life expectancy. And, as noted earlier, modeling studies estimate that there would be 1 death caused by LDCT for every 18.5 cancer deaths avoided.^1,11

CHALLENGES TO IMPLEMENTATION

Concerns about false-positives, ­radiation exposure may limit acceptance

Challenges would be based mostly on the need for greater, more detailed dialogue between physicians and patients at higher risk for lung cancer in a time-constrained environment. Also, LDCT may not be available in some areas, and patients and physicians may have concerns regarding repeated CT exposure. In addition, false-positive results increase patient stress and may adversely affect both patient and physician acceptance.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 50-year-old woman presents to your office for a well-woman exam. Her past medical history includes a 22-pack-year smoking history (she quit 5 years ago), well-controlled hypertension, and mild obesity. She has no family history of cancer, but she does have a family history of type 2 diabetes and heart disease. Besides age- and risk-appropriate laboratory tests, cervical cancer screening, breast cancer screening, and initial colon cancer screening, are there any other preventive services you would offer her?

Lung cancer is the second most common cancer in both men and women, and it is the leading cause of cancer death in the United States—regardless of gender. The American Cancer Society estimates that 235,760 people will be diagnosed with lung cancer and 131,880 people will die of the disease in 2021.²

In the 2015 National Cancer Institute report on the economic costs of cancer, direct and indirect costs of lung cancer totaled $21.1 billion annually. Lost productivity from lung cancer added another $36.1 billion in annual costs.³ The economic costs increased to $23.8 billion in 2020, with no data on lost productivity.⁴

Smoking tobacco is by far the primary risk factor for lung cancer, and it is estimated to account for 90% of all lung cancer cases. Compared with nonsmokers, the relative risk of lung cancer is approximately 20 times higher for smokers.^5,6

Because the median age of lung cancer diagnosis is 70 years, increasing age is also considered a risk factor for lung cancer.^2,7

Although lung cancer has a relatively poor prognosis—with an average 5-year survival rate of 20.5%—early-stage lung cancer is more amenable to treatment and has a better prognosis (as is true with many cancers).¹

LDCT has a high sensitivity, as well as a reasonable specificity, for lung cancer detection. There is demonstrated benefit in screening patients who are at high risk for lung cancer.^8-11 In 2013, the USPSTF recommended annual lung cancer screening (B recommendation) with LDCT in adults 55 to 80 years of age who have a 30-pack-year smoking history, and who currently smoke or quit within the past 15 years.¹

Continue to: STUDY SUMMARY

Broader eligibility for screening supports mortality benefit

This is an update to the 2013 clinical practice guideline on lung cancer screening. The USPSTF used 2 methods to provide the best possible evidence for the recommendations. The first method was a systematic review of the accuracy of screening for lung cancer with LDCT, evaluating both the benefits and harms of lung cancer screening. The systematic review examined various subgroups, the number and/or frequency of LDCT scans, and various approaches to reducing false-positive results. In addition to the systematic review, they used collaborative modeling studies to determine the optimal age for beginning and ending screening, the optimal screening interval, and the relative benefits and harms of various screening strategies. These modeling studies complemented the evidence review.

This updated guideline nearly doubles eligibility for lung cancer screening using low-dose CT scanning.

The review included 7 randomized controlled trials (RCTs), plus the modeling studies. Only the National Lung Screening Trial (NLST; N = 53,454) and the Nederlands-Leuvens Longkanker Screenings Onderzoek (NELSON) trial (N = 15,792) had adequate power to detect a mortality benefit from screening (NLST: relative risk reduction = 16%; 95% CI, 5%-25%; NELSON: incidence rate ratio = 0.75; 95% CI, 0.61-0.90) compared with no screening.

Screening intervals, from the NLST and NELSON trials as well as the modeling studies, revealed the greatest benefit from annual screening (statistics not shared). Evidence also showed that screening those with lighter smoking histories (< 30 pack-years) and at an earlier age (age 50) provided increased mortality benefit. No evidence was found for a benefit of screening past 80 years of age. The modeling studies concluded that the 2013 USPSTF screening program, using a starting age of 55 and a 30-pack-year smoking history, would reduce mortality by 9.8%, but by changing to a starting age of 50, a 20-pack-year smoking history, and annual screening, the mortality benefit was increased to 13%.^1,11

Comparison with computer-based risk prediction models from the Cancer Intervention and Surveillance Modeling Network (CISNET) revealed insufficient evidence at this time to show that prediction model–based screening offered any benefit beyond that of the age and smoking history risk factor model.

The incidence of false-positive results was > 25% in the NLST at baseline and at 1 year. Use of a classification system such as the Lung Imaging Reporting and Data System (Lung-RADS) could reduce that from 26.6% to 12.8%.² Another potential harm from LDCT screening is radiation exposure. Evidence from several RCTs and cohort studies showed the exposure from 1 LDCT scan to be 0.65 to 2.36 mSv, whereas the annual background radiation in the United States is 2.4 mSv. The modeling studies estimated that there would be 1 death caused by LDCT for every 18.5 cancer deaths avoided.^1,11

Continue to: WHAT'S NEW

Expanded age range, reduced pack-year history

Annual lung cancer screening is now recommended to begin for patients at age 50 years with a 20-pack-year history instead of age 55 years with a 30-pack-year history. This would nearly double (87% overall) the number of people eligible for screening, and it would include more Black patients and women, who tend to smoke fewer cigarettes than their White male counterparts. The American College of Radiology estimates that the expanded screening criteria could save between 30,000 and 60,000 lives per year.¹²

CAVEATS

Screening criteria for upper age limit, years since smoking remain unchanged

For those patients who quit smoking, the guidelines apply only to those who have stopped smoking within the past 15 years. Furthermore, the benefit does not extend beyond age 80 or where other conditions reduce life expectancy. And, as noted earlier, modeling studies estimate that there would be 1 death caused by LDCT for every 18.5 cancer deaths avoided.^1,11

CHALLENGES TO IMPLEMENTATION

Concerns about false-positives, ­radiation exposure may limit acceptance

Challenges would be based mostly on the need for greater, more detailed dialogue between physicians and patients at higher risk for lung cancer in a time-constrained environment. Also, LDCT may not be available in some areas, and patients and physicians may have concerns regarding repeated CT exposure. In addition, false-positive results increase patient stress and may adversely affect both patient and physician acceptance.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

Details of what works, and what doesn’t, in triple-negative breast cancer (TNBC) come from long-term follow-up of the phase 3 randomized BrighTNess trial.

The initial improvement that was seen in pathologic complete response (pCR) rates with the addition of carboplatin to paclitaxel and standard neoadjuvant chemotherapy translated into improved event-free survival (EFS) rates in patients with resectable TNBC more than 4 years after surgery.

The benefits of adding carboplatin to paclitaxel, followed by four cycles of AC (doxorubicin and cyclophosphamide) chemotherapy, were seen both in patients with germline BRCA mutations and those with wildtype BRCA.

The trial results also demonstrated, however, that there were no short- or long-term benefits to adding veliparib (ABT-888), a poly (ADP-ribose) polymerase (PARP) inhibitor, to the mix.

Although pCR and EFS rates were significantly improved with the combination of paclitaxel and carboplatin compared with paclitaxel alone, there were no significant differences when veliparib was added in either pCR, EFS, or overall survival (OS).

“These findings overall support the inclusion of carboplatin into neoadjuvant chemotherapy for stage 2 and 3 triple-negative breast cancer patients, regardless of germline BRCA status,” concluded lead author Sibylle Loibl, MD, PhD, chief executive officer and chair of the German Breast Group.

She presented the new data during an oral session at the virtual European Society for Medical Oncology (ESMO) Congress 2021.

The BrighTNess results show that “neoadjuvant carboplatin plus paclitaxel is superior to paclitaxel alone, with high pCR rates and benefit of event-free survival rates with manageable toxicity and no safety signals,” commented invited discussant Monica Arnedos, MD, PhD, head of the breast cancer research program at the Institut Bergonié in Bordeaux, France.

The findings also put to rest the notion that patients with germline BRCA mutations would not benefit from carboplatin treatment because of extreme sensitivity to standard neoadjuvant chemotherapy.

“The BrighTNess study says otherwise,” Dr. Arnedos said. “Today we’ve seen that the pCR improved event-free survival regardless of the germline BRCA mutated status, so BRCA-mutated germline patients require neoadjuvant carboplatin.”

The new data may lead to changes in breast cancer guidelines, she suggested.

Prior to these results, the evidence was that “platinum salts as neoadjuvant chemotherapy increased pCR rates in triple-negative breast cancer patients, but this was associated with more toxicity, and with higher rates of treatment discontinuation and dose reduction, without strong evidence of long-term benefit. This led to a lack of consensus to recommend platinum salts in this setting between the different breast cancer guidelines.”

The new BrighTNess data showed that the improved pCR rates translated into an EFS benefit in both platinum-containing groups of the trial, a finding that is consistent with the KEYNOTE-522 trial, which showed that adding pembrolizumab (Keytruda) to chemotherapy improved pCR in patients with early TNBC.

The BrighTNess results suggest that patients with high- or moderate-risk TNBC could be treated in the neoadjuvant setting with paclitaxel and carboplatin followed by standard chemotherapy concurrently with pembrolizumab, followed by surgery, and adjuvant therapy with pembrolizumab plus olaparib (Lynparza) for patients with germline BRCA mutations, or capecitabine for patients without mutations, Dr. Arnedos proposed.
 

BrighTNess study details

The BrighTNess trial involved 634 patients with previously untreated histologically or cytologically confirmed stage 2-3 TNBC who were candidates for potentially curative surgery and had a good performance status. They were randomly assigned to receive either paclitaxel plus carboplatin and veliparib, paclitaxel plus carboplatin only, or paclitaxel alone prior to four cycles of chemotherapy with doxorubicin and cyclophosphamide (AC).

Initial results, published in 2018 in The Lancet Oncology, showed that the addition of veliparib to carboplatin and paclitaxel improved pCR rates compared with paclitaxel alone but not paclitaxel plus carboplatin. The trial data supported the addition of carboplatin to standard neoadjuvant chemotherapy but not veliparib, the investigators stated at the time.

Now at the ESMO meeting, Dr. Loibl presented longer follow-up results.

After a median follow-up of 4.5 years, the hazard ratio (HR) for event-free survival with the paclitaxel/carboplatin/veliparib combination compared with paclitaxel alone was 0.63 (P = .016). In a post-hoc analysis, the adjusted HR was 0.57 (P = .018).

In a subgroup of 309 patients who had initial pCRs, the HR for EFS compared with patients without a pCR was 0.26 (P < .0001). Among patients with germline BRCA mutation, the HR for EFS for those who had a pCR was 0.14 (P = .0004), and among those with germline wildtype BRCA and a pCR the HR was 0.29 (P < .0001).

However, there were no significant differences in OS a median of 4.5 years after surgery.

An analysis of the frequency of myelodysplastic syndrome, acute myeloid leukemia, or other second primary malignancies also showed no significant differences between the groups, Dr. Loibl noted.

Although there were higher rates of hematologic malignancies with the addition of carboplatin, with or without veliparib, these adverse events did not compromise either treatment delivery of the benefits of carboplatin on the primary pCR endpoint, she added.

The BrighTNess trial was supported by AbbVie. Dr. Loibl has reported receiving grants and honoraria from AbbVie and others, including Medscape. Dr. Arnedos has reported receiving honoraria, travel grants, and/or research grants from AstraZeneca, Novartis, Pfizer, and Roche.

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

Details of what works, and what doesn’t, in triple-negative breast cancer (TNBC) come from long-term follow-up of the phase 3 randomized BrighTNess trial.

The initial improvement that was seen in pathologic complete response (pCR) rates with the addition of carboplatin to paclitaxel and standard neoadjuvant chemotherapy translated into improved event-free survival (EFS) rates in patients with resectable TNBC more than 4 years after surgery.

The benefits of adding carboplatin to paclitaxel, followed by four cycles of AC (doxorubicin and cyclophosphamide) chemotherapy, were seen both in patients with germline BRCA mutations and those with wildtype BRCA.

The trial results also demonstrated, however, that there were no short- or long-term benefits to adding veliparib (ABT-888), a poly (ADP-ribose) polymerase (PARP) inhibitor, to the mix.

Although pCR and EFS rates were significantly improved with the combination of paclitaxel and carboplatin compared with paclitaxel alone, there were no significant differences when veliparib was added in either pCR, EFS, or overall survival (OS).

“These findings overall support the inclusion of carboplatin into neoadjuvant chemotherapy for stage 2 and 3 triple-negative breast cancer patients, regardless of germline BRCA status,” concluded lead author Sibylle Loibl, MD, PhD, chief executive officer and chair of the German Breast Group.

She presented the new data during an oral session at the virtual European Society for Medical Oncology (ESMO) Congress 2021.

The BrighTNess results show that “neoadjuvant carboplatin plus paclitaxel is superior to paclitaxel alone, with high pCR rates and benefit of event-free survival rates with manageable toxicity and no safety signals,” commented invited discussant Monica Arnedos, MD, PhD, head of the breast cancer research program at the Institut Bergonié in Bordeaux, France.

The findings also put to rest the notion that patients with germline BRCA mutations would not benefit from carboplatin treatment because of extreme sensitivity to standard neoadjuvant chemotherapy.

“The BrighTNess study says otherwise,” Dr. Arnedos said. “Today we’ve seen that the pCR improved event-free survival regardless of the germline BRCA mutated status, so BRCA-mutated germline patients require neoadjuvant carboplatin.”

The new data may lead to changes in breast cancer guidelines, she suggested.

Prior to these results, the evidence was that “platinum salts as neoadjuvant chemotherapy increased pCR rates in triple-negative breast cancer patients, but this was associated with more toxicity, and with higher rates of treatment discontinuation and dose reduction, without strong evidence of long-term benefit. This led to a lack of consensus to recommend platinum salts in this setting between the different breast cancer guidelines.”

The new BrighTNess data showed that the improved pCR rates translated into an EFS benefit in both platinum-containing groups of the trial, a finding that is consistent with the KEYNOTE-522 trial, which showed that adding pembrolizumab (Keytruda) to chemotherapy improved pCR in patients with early TNBC.

The BrighTNess results suggest that patients with high- or moderate-risk TNBC could be treated in the neoadjuvant setting with paclitaxel and carboplatin followed by standard chemotherapy concurrently with pembrolizumab, followed by surgery, and adjuvant therapy with pembrolizumab plus olaparib (Lynparza) for patients with germline BRCA mutations, or capecitabine for patients without mutations, Dr. Arnedos proposed.
 

BrighTNess study details

The BrighTNess trial involved 634 patients with previously untreated histologically or cytologically confirmed stage 2-3 TNBC who were candidates for potentially curative surgery and had a good performance status. They were randomly assigned to receive either paclitaxel plus carboplatin and veliparib, paclitaxel plus carboplatin only, or paclitaxel alone prior to four cycles of chemotherapy with doxorubicin and cyclophosphamide (AC).

Initial results, published in 2018 in The Lancet Oncology, showed that the addition of veliparib to carboplatin and paclitaxel improved pCR rates compared with paclitaxel alone but not paclitaxel plus carboplatin. The trial data supported the addition of carboplatin to standard neoadjuvant chemotherapy but not veliparib, the investigators stated at the time.

Now at the ESMO meeting, Dr. Loibl presented longer follow-up results.

After a median follow-up of 4.5 years, the hazard ratio (HR) for event-free survival with the paclitaxel/carboplatin/veliparib combination compared with paclitaxel alone was 0.63 (P = .016). In a post-hoc analysis, the adjusted HR was 0.57 (P = .018).

In a subgroup of 309 patients who had initial pCRs, the HR for EFS compared with patients without a pCR was 0.26 (P < .0001). Among patients with germline BRCA mutation, the HR for EFS for those who had a pCR was 0.14 (P = .0004), and among those with germline wildtype BRCA and a pCR the HR was 0.29 (P < .0001).

However, there were no significant differences in OS a median of 4.5 years after surgery.

An analysis of the frequency of myelodysplastic syndrome, acute myeloid leukemia, or other second primary malignancies also showed no significant differences between the groups, Dr. Loibl noted.

Although there were higher rates of hematologic malignancies with the addition of carboplatin, with or without veliparib, these adverse events did not compromise either treatment delivery of the benefits of carboplatin on the primary pCR endpoint, she added.

The BrighTNess trial was supported by AbbVie. Dr. Loibl has reported receiving grants and honoraria from AbbVie and others, including Medscape. Dr. Arnedos has reported receiving honoraria, travel grants, and/or research grants from AstraZeneca, Novartis, Pfizer, and Roche.

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

Details of what works, and what doesn’t, in triple-negative breast cancer (TNBC) come from long-term follow-up of the phase 3 randomized BrighTNess trial.

The initial improvement that was seen in pathologic complete response (pCR) rates with the addition of carboplatin to paclitaxel and standard neoadjuvant chemotherapy translated into improved event-free survival (EFS) rates in patients with resectable TNBC more than 4 years after surgery.

The benefits of adding carboplatin to paclitaxel, followed by four cycles of AC (doxorubicin and cyclophosphamide) chemotherapy, were seen both in patients with germline BRCA mutations and those with wildtype BRCA.

The trial results also demonstrated, however, that there were no short- or long-term benefits to adding veliparib (ABT-888), a poly (ADP-ribose) polymerase (PARP) inhibitor, to the mix.

Although pCR and EFS rates were significantly improved with the combination of paclitaxel and carboplatin compared with paclitaxel alone, there were no significant differences when veliparib was added in either pCR, EFS, or overall survival (OS).

“These findings overall support the inclusion of carboplatin into neoadjuvant chemotherapy for stage 2 and 3 triple-negative breast cancer patients, regardless of germline BRCA status,” concluded lead author Sibylle Loibl, MD, PhD, chief executive officer and chair of the German Breast Group.

She presented the new data during an oral session at the virtual European Society for Medical Oncology (ESMO) Congress 2021.

The BrighTNess results show that “neoadjuvant carboplatin plus paclitaxel is superior to paclitaxel alone, with high pCR rates and benefit of event-free survival rates with manageable toxicity and no safety signals,” commented invited discussant Monica Arnedos, MD, PhD, head of the breast cancer research program at the Institut Bergonié in Bordeaux, France.

The findings also put to rest the notion that patients with germline BRCA mutations would not benefit from carboplatin treatment because of extreme sensitivity to standard neoadjuvant chemotherapy.

“The BrighTNess study says otherwise,” Dr. Arnedos said. “Today we’ve seen that the pCR improved event-free survival regardless of the germline BRCA mutated status, so BRCA-mutated germline patients require neoadjuvant carboplatin.”

The new data may lead to changes in breast cancer guidelines, she suggested.

Prior to these results, the evidence was that “platinum salts as neoadjuvant chemotherapy increased pCR rates in triple-negative breast cancer patients, but this was associated with more toxicity, and with higher rates of treatment discontinuation and dose reduction, without strong evidence of long-term benefit. This led to a lack of consensus to recommend platinum salts in this setting between the different breast cancer guidelines.”

The new BrighTNess data showed that the improved pCR rates translated into an EFS benefit in both platinum-containing groups of the trial, a finding that is consistent with the KEYNOTE-522 trial, which showed that adding pembrolizumab (Keytruda) to chemotherapy improved pCR in patients with early TNBC.

The BrighTNess results suggest that patients with high- or moderate-risk TNBC could be treated in the neoadjuvant setting with paclitaxel and carboplatin followed by standard chemotherapy concurrently with pembrolizumab, followed by surgery, and adjuvant therapy with pembrolizumab plus olaparib (Lynparza) for patients with germline BRCA mutations, or capecitabine for patients without mutations, Dr. Arnedos proposed.
 

BrighTNess study details

The BrighTNess trial involved 634 patients with previously untreated histologically or cytologically confirmed stage 2-3 TNBC who were candidates for potentially curative surgery and had a good performance status. They were randomly assigned to receive either paclitaxel plus carboplatin and veliparib, paclitaxel plus carboplatin only, or paclitaxel alone prior to four cycles of chemotherapy with doxorubicin and cyclophosphamide (AC).

Initial results, published in 2018 in The Lancet Oncology, showed that the addition of veliparib to carboplatin and paclitaxel improved pCR rates compared with paclitaxel alone but not paclitaxel plus carboplatin. The trial data supported the addition of carboplatin to standard neoadjuvant chemotherapy but not veliparib, the investigators stated at the time.

Now at the ESMO meeting, Dr. Loibl presented longer follow-up results.

After a median follow-up of 4.5 years, the hazard ratio (HR) for event-free survival with the paclitaxel/carboplatin/veliparib combination compared with paclitaxel alone was 0.63 (P = .016). In a post-hoc analysis, the adjusted HR was 0.57 (P = .018).

In a subgroup of 309 patients who had initial pCRs, the HR for EFS compared with patients without a pCR was 0.26 (P < .0001). Among patients with germline BRCA mutation, the HR for EFS for those who had a pCR was 0.14 (P = .0004), and among those with germline wildtype BRCA and a pCR the HR was 0.29 (P < .0001).

However, there were no significant differences in OS a median of 4.5 years after surgery.

An analysis of the frequency of myelodysplastic syndrome, acute myeloid leukemia, or other second primary malignancies also showed no significant differences between the groups, Dr. Loibl noted.

Although there were higher rates of hematologic malignancies with the addition of carboplatin, with or without veliparib, these adverse events did not compromise either treatment delivery of the benefits of carboplatin on the primary pCR endpoint, she added.

The BrighTNess trial was supported by AbbVie. Dr. Loibl has reported receiving grants and honoraria from AbbVie and others, including Medscape. Dr. Arnedos has reported receiving honoraria, travel grants, and/or research grants from AstraZeneca, Novartis, Pfizer, and Roche.

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

THE CASE

Joe, an 18-year-old, has been your patient for many years and has an uncomplicated medical history. He presents for his preparticipation sports examination for the upcoming high school baseball season. Joe’s mother, who arrives at the office with him, tells you she’s worried because she found an e-cigarette in his backpack last week. Joe says that many of the kids at his school vape and he tried it a while back and now vapes “a lot.”

After talking further with Joe, you realize that he is vaping every day, using a 5% nicotine pod. Based on previous consults with the behavioral health counselor in your clinic, you know that this level of vaping is about the same as smoking 1 pack of cigarettes per day in terms of nicotine exposure. Joe states that he often vapes in the bathroom at school because he cannot concentrate in class if he doesn’t vape. He also reports that he had previously used 1 pod per week but had recently started vaping more to help with his cravings.

You assess his withdrawal symptoms and learn that he feels on edge when he is not able to vape and that he vapes heavily before going into school because he knows he will not be able to vape again until his third passing period.

● How would you proceed with this patient?

Electronic cigarettes (e-cigarettes; also called “vapes”) are electronic nicotine delivery systems that heat and aerosolize e-liquid or “e-juice” that is inhaled by the user. The e-liquid is made up primarily of propylene glycol, vegetable glycerin, and flavorings, and often includes nicotine. Nicotine levels in e-cigarettes can range from 0 mg/mL to 60 mg/mL (regular cigarettes contain ~12 mg of nicotine). The nicotine level of the pod available from e-cigarette company JUUL (50 mg/mL e-liquid) is equivalent to about 1 pack of cigarettes.¹ E-cigarette devices are relatively affordable; popular brands cost $10 to $20, while the replacement pods or e-liquid are typically about $4 each.

The e-cigarette market is quickly evolving and diversifying. Originally, e-cigarettes looked similar to cigarettes (cig-a-likes) but did not efficiently deliver nicotine to the user.² E-cigarettes have evolved and some now deliver cigarette-like levels of nicotine to the user.^3,4 Youth and young adults primarily use pod-mod e-cigarettes, which have a sleek design and produce less vapor than older e-cigarettes, making them easier to conceal. They can look like a USB flash-drive or have a teardrop shape. Pod-mod e-cigarettes dominate the current market, led by companies such as JUUL, NJOY, and Vuse.⁵

E-cigarette use is proliferating in the United States, particularly among young people and facilitated by the introduction of pod-based e-cigarettes in appealing flavors.^6,7 While rates of current e-cigarette use by US adults is around 5.5%,⁸ recent data show that 32.7% of US high school students say they’ve used an e-cigarette in the past 30 days.⁹

Continue to: A double-edged sword

A double-edged sword. E-cigarettes are less harmful than traditional cigarettes in the short term and likely benefit adult smokers who completely substitute e-cigarettes for their tobacco cigarettes.¹⁰ In randomized trials of adult smokers, e-cigarette use resulted in moderate combustible-cigarette cessation rates that rival or exceed rates achieved with traditional nicotine replacement therapy (NRT).^11-13 However, most e-cigarettes contain addictive nicotine, can facilitate transitions to more harmful forms of tobacco use,^10,14,15 and have unknown long-term health effects. Therefore, youth, young adults, and those who are otherwise tobacco naïve should not initiate e-cigarette use.

Moreover, cases of e-cigarette or vaping product use–associated lung injury (EVALI)—a disease linked to vaping that causes cough, fever, shortness of breath, and death—were first identified in August 2019 and peaked in September 2019 before new cases decreased dramatically through January 2020.¹⁶ Since the initial cases of EVALI arose, product testing has shown that tetrahydrocannabinol (THC) and vitamin E acetate are the main ingredients linked to EVALI cases.¹⁷ For this reason, the Centers for Disease Control and Prevention and others strongly recommend against use of THC-containing e-cigarettes.¹⁸

Data show that 32.7% of US high school students say they’ve used an e-cigarette in the past 30 days.

Given the high rates of e-cigarette use among youth and young adults and its potential health harms, it is critical to inquire about e-cigarette use at primary care visits, and, as appropriate, to assess frequency and quantity of use. Patients who require intervention will be more likely to succeed in quitting if they are connected with behavioral health counseling and prescribed medication. This article offers evidence-based guidance to assess and advise teens and young adults regarding the potential health impact of e-cigarettes.

A NEW ICD-10-CM CODE AND A BRIEF ASSESSMENT TOOL

According to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5)¹⁹ and the International Classification of Diseases, 10th Revision (ICD-10-CM),²⁰ a tobacco use disorder is a problematic pattern of use leading to clinically significant impairment or distress. Associated features and behavioral markers of frequency and quantity include use within 30 minutes of waking, daily use, and increasing use. However, with youth, consider intervention for use of any nicotine or tobacco product, including e-cigarettes, regardless of whether it meets the threshold for diagnosis.²¹

The new code. Interestingly, prior to the April 2020 modification to ICD-10-CM codes, there was no code for e-cigarette use–related problems. However, the newly released code (U07.0) allows for billing for these services and serves to recognize the importance of screening, diagnosis, and treatment of e-cigarette use.

Continue to: As with other tobacco use...

As with other tobacco use, assess e-­cigarette use patterns by asking questions about the frequency, duration, and quantity of use. Additionally, determine the level of nicotine in the e-liquid (discussed earlier) and evaluate whether the individual displays signs of physiologic dependence (eg, failed attempts to reduce or quit e-cigarette use, increased use, nicotine withdrawal symptoms).

A useful assessment tool. While e-cigarette use is not often included on current substance use screening measures, the above questions can be added to the end of measures such as the CRAFFT (Car-Relax-Alone-Forget-Family and Friends-Trouble) test.²² Additionally, if an adolescent reports vaping, the American Academy of Pediatrics (AAP) recommends using a brief screening tool such as the Hooked on Nicotine Checklist (HONC) to establish his or her level of dependence (TABLE 1).²³

The HONC is ideal for a primary care setting because it is brief and has a high level of sensitivity, minimizing false-negative reports²⁴; a patient’s acknowledgement of any item indicates a loss of autonomy over nicotine. Establishing the level of nicotine dependence is particularly pertinent when making decisions regarding the course of treatment and whether to prescribe NRT (eg, nicotine patch, gum, lozenge). Alternatively, you can quickly assess level of dependence by determining the time to first e-cigarette use in the morning. Tobacco guidelines suggest that if time to first use is > 30 minutes, the individual is “moderately dependent”; if time to first use is < 30 minutes after waking, the individual is “severely dependent.”²⁵

COMBINATION TREATMENT IS MOST SUCCESSFUL

Studies have shown that the most effective treatment for tobacco cessation is pairing behavioral treatment with combination NRT (eg, nicotine gum + patch).^25,26 The literature on e-cigarette cessation remains in its infancy, but techniques from traditional smoking cessation can be applied because the behaviors differ only in their mode of nicotine delivery.

Behavioral treatment. There are several options for behavioral treatment for tobacco cessation—and thus, e-cigarette cessation. The first step will depend on the patient’s level of motivation. If the patient is not yet ready to quit, consider using brief motivational interviewing. Once the patient is willing to engage in treatment, options include setting a mutually agreed upon quit date or planning for a reduction in the frequency and duration of vaping.

Continue to: Referrals to the Quitline...

Referrals to the Quitline (800-QUIT-NOW) have long been standard practice and can be used to extend primary care treatment.²⁵ Studies show that it is more effective to connect patients directly to the Quitline at their primary care appointment²⁷ than asking them to call after the visit.^28,29 We suggest providing direct assistance in the office to patients as they initiate treatment with the Quitline.

Finally, if the level of dependence is severe or the patient is not motivated to quit, connect them with a behavioral health provider in your clinic or with an outside therapist skilled in cognitive behavioral techniques related to tobacco cessation. Discuss with the patient that quitting nicotine use is difficult for many people and that the best option for success is the combination of counseling and medication.²⁵

Nicotine replacement therapy for e-cigarette use. While over-the-counter NRT (nicotine gum, patches, lozenges) is approved by the US Food and Drug Administration only for sale to adults ≥ 18 years, the AAP issued guidance on prescribing NRT for those < 18 years who use e-cigarettes.³⁰ While the AAP does not suggest a lower age limit for prescribing NRT, national data show that < 6% of middle schoolers report e-cigarette use and that e-cigarette use does not become common (~20% current use) until high school.³¹ It is therefore unlikely that a child < 14 years would require pharmacotherapy. On their fact sheet, the AAP includes the following guidance:

“Patients who are motivated to quit should use as much safe, FDA-approved NRT as needed to avoid smoking or vaping. When assessing a patient’s current level of nicotine use, it may be helpful to understand that using one JUUL pod per day is equivalent to one pack of cigarettes per day …. Pediatricians and other healthcare providers should work with each patient to determine a starting dosage of NRT that is most likely to help them quit successfully. Dosing is based on the patient’s level of nicotine dependence, which can be measured using a screening tool” (TABLE 1²³).³²

The AAP NRT dosing guidelines can be found at downloads.aap.org/RCE/NRT_and_Adolescents_Pediatrician_Guidance_factsheet.pdf.³² Of note, the dosing guidelines for adolescents are the same as those for adults and are based on level of use and dependence. Moreover, the clinician and patient should work together to choose the initial dose and the plan for weaning NRT over time.

Continue to: THE CASE

Based on your conversation with Joe, you administer the HONC screening tool. He scores 9 out of 10, indicating significant loss of autonomy over nicotine. You consult with a behavioral health counselor, who believes that Joe would benefit from counseling and NRT. You discuss this treatment plan with Joe, who says he is ready to quit because he does not like feeling as if he depends on vaping. Your shared decision is to start the 21-mg patch and 4-mg gum with plans to step down from there.

Studies show it is more effective to connect patients directly to the Quitline at the office visit than asking them to call after the visit.

Joe agrees to set a quit date in the following week. The behavioral health counselor then meets with Joe and they develop a quit plan, which is shared with you so you can follow up at the next visit. Joe also agrees to talk with his parents, who are unaware of his level of use and dependence. Everyone agrees on the quit plan, and a follow-up visit is scheduled.

At the follow-up visit 1 month later, Joe and his parents report that he has quit vaping but is still using the patch and gum. You instruct Joe to reduce his NRT use to the 14-mg patch and 2-mg gum and to stop using them over the next 2 to 3 weeks. Everyone is in agreement with the treatment plan. You also re-administer the HONC screening tool and see that Joe’s score has reduced by 7 points to just 2 out of 10. You recommend that Joe continue to see the behavioral health counselor and follow up as needed. (A noted benefit of having a behavioral health counselor in your clinic is the opportunity for informal briefings on patient progress.^33,34)

Following each visit with Joe, you make sure to complete documentation on (1) tobacco/e-cigarette use assessment, (2) diagnoses, (3) discussion of benefits of quitting,(4) assessment of readiness to quit, (5) creation and support of a quit plan, and (6) connection with a behavioral health counselor and planned follow-up. (See TABLE 2³⁵ for details onbilling codes.) 

CORRESPONDENCE
Eleanor L. S. Leavens, PhD, 3901 Rainbow Boulevard, Mail Stop 1008, Kansas City, KS 66160; [email protected]

THE CASE

Joe, an 18-year-old, has been your patient for many years and has an uncomplicated medical history. He presents for his preparticipation sports examination for the upcoming high school baseball season. Joe’s mother, who arrives at the office with him, tells you she’s worried because she found an e-cigarette in his backpack last week. Joe says that many of the kids at his school vape and he tried it a while back and now vapes “a lot.”

After talking further with Joe, you realize that he is vaping every day, using a 5% nicotine pod. Based on previous consults with the behavioral health counselor in your clinic, you know that this level of vaping is about the same as smoking 1 pack of cigarettes per day in terms of nicotine exposure. Joe states that he often vapes in the bathroom at school because he cannot concentrate in class if he doesn’t vape. He also reports that he had previously used 1 pod per week but had recently started vaping more to help with his cravings.

You assess his withdrawal symptoms and learn that he feels on edge when he is not able to vape and that he vapes heavily before going into school because he knows he will not be able to vape again until his third passing period.

● How would you proceed with this patient?

Electronic cigarettes (e-cigarettes; also called “vapes”) are electronic nicotine delivery systems that heat and aerosolize e-liquid or “e-juice” that is inhaled by the user. The e-liquid is made up primarily of propylene glycol, vegetable glycerin, and flavorings, and often includes nicotine. Nicotine levels in e-cigarettes can range from 0 mg/mL to 60 mg/mL (regular cigarettes contain ~12 mg of nicotine). The nicotine level of the pod available from e-cigarette company JUUL (50 mg/mL e-liquid) is equivalent to about 1 pack of cigarettes.¹ E-cigarette devices are relatively affordable; popular brands cost $10 to $20, while the replacement pods or e-liquid are typically about $4 each.

The e-cigarette market is quickly evolving and diversifying. Originally, e-cigarettes looked similar to cigarettes (cig-a-likes) but did not efficiently deliver nicotine to the user.² E-cigarettes have evolved and some now deliver cigarette-like levels of nicotine to the user.^3,4 Youth and young adults primarily use pod-mod e-cigarettes, which have a sleek design and produce less vapor than older e-cigarettes, making them easier to conceal. They can look like a USB flash-drive or have a teardrop shape. Pod-mod e-cigarettes dominate the current market, led by companies such as JUUL, NJOY, and Vuse.⁵

E-cigarette use is proliferating in the United States, particularly among young people and facilitated by the introduction of pod-based e-cigarettes in appealing flavors.^6,7 While rates of current e-cigarette use by US adults is around 5.5%,⁸ recent data show that 32.7% of US high school students say they’ve used an e-cigarette in the past 30 days.⁹

Continue to: A double-edged sword

A double-edged sword. E-cigarettes are less harmful than traditional cigarettes in the short term and likely benefit adult smokers who completely substitute e-cigarettes for their tobacco cigarettes.¹⁰ In randomized trials of adult smokers, e-cigarette use resulted in moderate combustible-cigarette cessation rates that rival or exceed rates achieved with traditional nicotine replacement therapy (NRT).^11-13 However, most e-cigarettes contain addictive nicotine, can facilitate transitions to more harmful forms of tobacco use,^10,14,15 and have unknown long-term health effects. Therefore, youth, young adults, and those who are otherwise tobacco naïve should not initiate e-cigarette use.

Moreover, cases of e-cigarette or vaping product use–associated lung injury (EVALI)—a disease linked to vaping that causes cough, fever, shortness of breath, and death—were first identified in August 2019 and peaked in September 2019 before new cases decreased dramatically through January 2020.¹⁶ Since the initial cases of EVALI arose, product testing has shown that tetrahydrocannabinol (THC) and vitamin E acetate are the main ingredients linked to EVALI cases.¹⁷ For this reason, the Centers for Disease Control and Prevention and others strongly recommend against use of THC-containing e-cigarettes.¹⁸

Data show that 32.7% of US high school students say they’ve used an e-cigarette in the past 30 days.

Given the high rates of e-cigarette use among youth and young adults and its potential health harms, it is critical to inquire about e-cigarette use at primary care visits, and, as appropriate, to assess frequency and quantity of use. Patients who require intervention will be more likely to succeed in quitting if they are connected with behavioral health counseling and prescribed medication. This article offers evidence-based guidance to assess and advise teens and young adults regarding the potential health impact of e-cigarettes.

A NEW ICD-10-CM CODE AND A BRIEF ASSESSMENT TOOL

According to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5)¹⁹ and the International Classification of Diseases, 10th Revision (ICD-10-CM),²⁰ a tobacco use disorder is a problematic pattern of use leading to clinically significant impairment or distress. Associated features and behavioral markers of frequency and quantity include use within 30 minutes of waking, daily use, and increasing use. However, with youth, consider intervention for use of any nicotine or tobacco product, including e-cigarettes, regardless of whether it meets the threshold for diagnosis.²¹

The new code. Interestingly, prior to the April 2020 modification to ICD-10-CM codes, there was no code for e-cigarette use–related problems. However, the newly released code (U07.0) allows for billing for these services and serves to recognize the importance of screening, diagnosis, and treatment of e-cigarette use.

Continue to: As with other tobacco use...

As with other tobacco use, assess e-­cigarette use patterns by asking questions about the frequency, duration, and quantity of use. Additionally, determine the level of nicotine in the e-liquid (discussed earlier) and evaluate whether the individual displays signs of physiologic dependence (eg, failed attempts to reduce or quit e-cigarette use, increased use, nicotine withdrawal symptoms).

A useful assessment tool. While e-cigarette use is not often included on current substance use screening measures, the above questions can be added to the end of measures such as the CRAFFT (Car-Relax-Alone-Forget-Family and Friends-Trouble) test.²² Additionally, if an adolescent reports vaping, the American Academy of Pediatrics (AAP) recommends using a brief screening tool such as the Hooked on Nicotine Checklist (HONC) to establish his or her level of dependence (TABLE 1).²³

The HONC is ideal for a primary care setting because it is brief and has a high level of sensitivity, minimizing false-negative reports²⁴; a patient’s acknowledgement of any item indicates a loss of autonomy over nicotine. Establishing the level of nicotine dependence is particularly pertinent when making decisions regarding the course of treatment and whether to prescribe NRT (eg, nicotine patch, gum, lozenge). Alternatively, you can quickly assess level of dependence by determining the time to first e-cigarette use in the morning. Tobacco guidelines suggest that if time to first use is > 30 minutes, the individual is “moderately dependent”; if time to first use is < 30 minutes after waking, the individual is “severely dependent.”²⁵

COMBINATION TREATMENT IS MOST SUCCESSFUL

Studies have shown that the most effective treatment for tobacco cessation is pairing behavioral treatment with combination NRT (eg, nicotine gum + patch).^25,26 The literature on e-cigarette cessation remains in its infancy, but techniques from traditional smoking cessation can be applied because the behaviors differ only in their mode of nicotine delivery.

Behavioral treatment. There are several options for behavioral treatment for tobacco cessation—and thus, e-cigarette cessation. The first step will depend on the patient’s level of motivation. If the patient is not yet ready to quit, consider using brief motivational interviewing. Once the patient is willing to engage in treatment, options include setting a mutually agreed upon quit date or planning for a reduction in the frequency and duration of vaping.

Continue to: Referrals to the Quitline...

Referrals to the Quitline (800-QUIT-NOW) have long been standard practice and can be used to extend primary care treatment.²⁵ Studies show that it is more effective to connect patients directly to the Quitline at their primary care appointment²⁷ than asking them to call after the visit.^28,29 We suggest providing direct assistance in the office to patients as they initiate treatment with the Quitline.

Finally, if the level of dependence is severe or the patient is not motivated to quit, connect them with a behavioral health provider in your clinic or with an outside therapist skilled in cognitive behavioral techniques related to tobacco cessation. Discuss with the patient that quitting nicotine use is difficult for many people and that the best option for success is the combination of counseling and medication.²⁵

Nicotine replacement therapy for e-cigarette use. While over-the-counter NRT (nicotine gum, patches, lozenges) is approved by the US Food and Drug Administration only for sale to adults ≥ 18 years, the AAP issued guidance on prescribing NRT for those < 18 years who use e-cigarettes.³⁰ While the AAP does not suggest a lower age limit for prescribing NRT, national data show that < 6% of middle schoolers report e-cigarette use and that e-cigarette use does not become common (~20% current use) until high school.³¹ It is therefore unlikely that a child < 14 years would require pharmacotherapy. On their fact sheet, the AAP includes the following guidance:

“Patients who are motivated to quit should use as much safe, FDA-approved NRT as needed to avoid smoking or vaping. When assessing a patient’s current level of nicotine use, it may be helpful to understand that using one JUUL pod per day is equivalent to one pack of cigarettes per day …. Pediatricians and other healthcare providers should work with each patient to determine a starting dosage of NRT that is most likely to help them quit successfully. Dosing is based on the patient’s level of nicotine dependence, which can be measured using a screening tool” (TABLE 1²³).³²

The AAP NRT dosing guidelines can be found at downloads.aap.org/RCE/NRT_and_Adolescents_Pediatrician_Guidance_factsheet.pdf.³² Of note, the dosing guidelines for adolescents are the same as those for adults and are based on level of use and dependence. Moreover, the clinician and patient should work together to choose the initial dose and the plan for weaning NRT over time.

Continue to: THE CASE

Based on your conversation with Joe, you administer the HONC screening tool. He scores 9 out of 10, indicating significant loss of autonomy over nicotine. You consult with a behavioral health counselor, who believes that Joe would benefit from counseling and NRT. You discuss this treatment plan with Joe, who says he is ready to quit because he does not like feeling as if he depends on vaping. Your shared decision is to start the 21-mg patch and 4-mg gum with plans to step down from there.

Studies show it is more effective to connect patients directly to the Quitline at the office visit than asking them to call after the visit.

Joe agrees to set a quit date in the following week. The behavioral health counselor then meets with Joe and they develop a quit plan, which is shared with you so you can follow up at the next visit. Joe also agrees to talk with his parents, who are unaware of his level of use and dependence. Everyone agrees on the quit plan, and a follow-up visit is scheduled.

At the follow-up visit 1 month later, Joe and his parents report that he has quit vaping but is still using the patch and gum. You instruct Joe to reduce his NRT use to the 14-mg patch and 2-mg gum and to stop using them over the next 2 to 3 weeks. Everyone is in agreement with the treatment plan. You also re-administer the HONC screening tool and see that Joe’s score has reduced by 7 points to just 2 out of 10. You recommend that Joe continue to see the behavioral health counselor and follow up as needed. (A noted benefit of having a behavioral health counselor in your clinic is the opportunity for informal briefings on patient progress.^33,34)

Following each visit with Joe, you make sure to complete documentation on (1) tobacco/e-cigarette use assessment, (2) diagnoses, (3) discussion of benefits of quitting,(4) assessment of readiness to quit, (5) creation and support of a quit plan, and (6) connection with a behavioral health counselor and planned follow-up. (See TABLE 2³⁵ for details onbilling codes.) 

CORRESPONDENCE
Eleanor L. S. Leavens, PhD, 3901 Rainbow Boulevard, Mail Stop 1008, Kansas City, KS 66160; [email protected]

THE CASE

Joe, an 18-year-old, has been your patient for many years and has an uncomplicated medical history. He presents for his preparticipation sports examination for the upcoming high school baseball season. Joe’s mother, who arrives at the office with him, tells you she’s worried because she found an e-cigarette in his backpack last week. Joe says that many of the kids at his school vape and he tried it a while back and now vapes “a lot.”

After talking further with Joe, you realize that he is vaping every day, using a 5% nicotine pod. Based on previous consults with the behavioral health counselor in your clinic, you know that this level of vaping is about the same as smoking 1 pack of cigarettes per day in terms of nicotine exposure. Joe states that he often vapes in the bathroom at school because he cannot concentrate in class if he doesn’t vape. He also reports that he had previously used 1 pod per week but had recently started vaping more to help with his cravings.

You assess his withdrawal symptoms and learn that he feels on edge when he is not able to vape and that he vapes heavily before going into school because he knows he will not be able to vape again until his third passing period.

● How would you proceed with this patient?

Electronic cigarettes (e-cigarettes; also called “vapes”) are electronic nicotine delivery systems that heat and aerosolize e-liquid or “e-juice” that is inhaled by the user. The e-liquid is made up primarily of propylene glycol, vegetable glycerin, and flavorings, and often includes nicotine. Nicotine levels in e-cigarettes can range from 0 mg/mL to 60 mg/mL (regular cigarettes contain ~12 mg of nicotine). The nicotine level of the pod available from e-cigarette company JUUL (50 mg/mL e-liquid) is equivalent to about 1 pack of cigarettes.¹ E-cigarette devices are relatively affordable; popular brands cost $10 to $20, while the replacement pods or e-liquid are typically about $4 each.

The e-cigarette market is quickly evolving and diversifying. Originally, e-cigarettes looked similar to cigarettes (cig-a-likes) but did not efficiently deliver nicotine to the user.² E-cigarettes have evolved and some now deliver cigarette-like levels of nicotine to the user.^3,4 Youth and young adults primarily use pod-mod e-cigarettes, which have a sleek design and produce less vapor than older e-cigarettes, making them easier to conceal. They can look like a USB flash-drive or have a teardrop shape. Pod-mod e-cigarettes dominate the current market, led by companies such as JUUL, NJOY, and Vuse.⁵

E-cigarette use is proliferating in the United States, particularly among young people and facilitated by the introduction of pod-based e-cigarettes in appealing flavors.^6,7 While rates of current e-cigarette use by US adults is around 5.5%,⁸ recent data show that 32.7% of US high school students say they’ve used an e-cigarette in the past 30 days.⁹

Continue to: A double-edged sword

A double-edged sword. E-cigarettes are less harmful than traditional cigarettes in the short term and likely benefit adult smokers who completely substitute e-cigarettes for their tobacco cigarettes.¹⁰ In randomized trials of adult smokers, e-cigarette use resulted in moderate combustible-cigarette cessation rates that rival or exceed rates achieved with traditional nicotine replacement therapy (NRT).^11-13 However, most e-cigarettes contain addictive nicotine, can facilitate transitions to more harmful forms of tobacco use,^10,14,15 and have unknown long-term health effects. Therefore, youth, young adults, and those who are otherwise tobacco naïve should not initiate e-cigarette use.

Moreover, cases of e-cigarette or vaping product use–associated lung injury (EVALI)—a disease linked to vaping that causes cough, fever, shortness of breath, and death—were first identified in August 2019 and peaked in September 2019 before new cases decreased dramatically through January 2020.¹⁶ Since the initial cases of EVALI arose, product testing has shown that tetrahydrocannabinol (THC) and vitamin E acetate are the main ingredients linked to EVALI cases.¹⁷ For this reason, the Centers for Disease Control and Prevention and others strongly recommend against use of THC-containing e-cigarettes.¹⁸

Data show that 32.7% of US high school students say they’ve used an e-cigarette in the past 30 days.

Given the high rates of e-cigarette use among youth and young adults and its potential health harms, it is critical to inquire about e-cigarette use at primary care visits, and, as appropriate, to assess frequency and quantity of use. Patients who require intervention will be more likely to succeed in quitting if they are connected with behavioral health counseling and prescribed medication. This article offers evidence-based guidance to assess and advise teens and young adults regarding the potential health impact of e-cigarettes.

A NEW ICD-10-CM CODE AND A BRIEF ASSESSMENT TOOL

According to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5)¹⁹ and the International Classification of Diseases, 10th Revision (ICD-10-CM),²⁰ a tobacco use disorder is a problematic pattern of use leading to clinically significant impairment or distress. Associated features and behavioral markers of frequency and quantity include use within 30 minutes of waking, daily use, and increasing use. However, with youth, consider intervention for use of any nicotine or tobacco product, including e-cigarettes, regardless of whether it meets the threshold for diagnosis.²¹

The new code. Interestingly, prior to the April 2020 modification to ICD-10-CM codes, there was no code for e-cigarette use–related problems. However, the newly released code (U07.0) allows for billing for these services and serves to recognize the importance of screening, diagnosis, and treatment of e-cigarette use.

Continue to: As with other tobacco use...

As with other tobacco use, assess e-­cigarette use patterns by asking questions about the frequency, duration, and quantity of use. Additionally, determine the level of nicotine in the e-liquid (discussed earlier) and evaluate whether the individual displays signs of physiologic dependence (eg, failed attempts to reduce or quit e-cigarette use, increased use, nicotine withdrawal symptoms).

A useful assessment tool. While e-cigarette use is not often included on current substance use screening measures, the above questions can be added to the end of measures such as the CRAFFT (Car-Relax-Alone-Forget-Family and Friends-Trouble) test.²² Additionally, if an adolescent reports vaping, the American Academy of Pediatrics (AAP) recommends using a brief screening tool such as the Hooked on Nicotine Checklist (HONC) to establish his or her level of dependence (TABLE 1).²³

The HONC is ideal for a primary care setting because it is brief and has a high level of sensitivity, minimizing false-negative reports²⁴; a patient’s acknowledgement of any item indicates a loss of autonomy over nicotine. Establishing the level of nicotine dependence is particularly pertinent when making decisions regarding the course of treatment and whether to prescribe NRT (eg, nicotine patch, gum, lozenge). Alternatively, you can quickly assess level of dependence by determining the time to first e-cigarette use in the morning. Tobacco guidelines suggest that if time to first use is > 30 minutes, the individual is “moderately dependent”; if time to first use is < 30 minutes after waking, the individual is “severely dependent.”²⁵

COMBINATION TREATMENT IS MOST SUCCESSFUL

Studies have shown that the most effective treatment for tobacco cessation is pairing behavioral treatment with combination NRT (eg, nicotine gum + patch).^25,26 The literature on e-cigarette cessation remains in its infancy, but techniques from traditional smoking cessation can be applied because the behaviors differ only in their mode of nicotine delivery.

Behavioral treatment. There are several options for behavioral treatment for tobacco cessation—and thus, e-cigarette cessation. The first step will depend on the patient’s level of motivation. If the patient is not yet ready to quit, consider using brief motivational interviewing. Once the patient is willing to engage in treatment, options include setting a mutually agreed upon quit date or planning for a reduction in the frequency and duration of vaping.

Continue to: Referrals to the Quitline...

Referrals to the Quitline (800-QUIT-NOW) have long been standard practice and can be used to extend primary care treatment.²⁵ Studies show that it is more effective to connect patients directly to the Quitline at their primary care appointment²⁷ than asking them to call after the visit.^28,29 We suggest providing direct assistance in the office to patients as they initiate treatment with the Quitline.

Finally, if the level of dependence is severe or the patient is not motivated to quit, connect them with a behavioral health provider in your clinic or with an outside therapist skilled in cognitive behavioral techniques related to tobacco cessation. Discuss with the patient that quitting nicotine use is difficult for many people and that the best option for success is the combination of counseling and medication.²⁵

Nicotine replacement therapy for e-cigarette use. While over-the-counter NRT (nicotine gum, patches, lozenges) is approved by the US Food and Drug Administration only for sale to adults ≥ 18 years, the AAP issued guidance on prescribing NRT for those < 18 years who use e-cigarettes.³⁰ While the AAP does not suggest a lower age limit for prescribing NRT, national data show that < 6% of middle schoolers report e-cigarette use and that e-cigarette use does not become common (~20% current use) until high school.³¹ It is therefore unlikely that a child < 14 years would require pharmacotherapy. On their fact sheet, the AAP includes the following guidance:

“Patients who are motivated to quit should use as much safe, FDA-approved NRT as needed to avoid smoking or vaping. When assessing a patient’s current level of nicotine use, it may be helpful to understand that using one JUUL pod per day is equivalent to one pack of cigarettes per day …. Pediatricians and other healthcare providers should work with each patient to determine a starting dosage of NRT that is most likely to help them quit successfully. Dosing is based on the patient’s level of nicotine dependence, which can be measured using a screening tool” (TABLE 1²³).³²

The AAP NRT dosing guidelines can be found at downloads.aap.org/RCE/NRT_and_Adolescents_Pediatrician_Guidance_factsheet.pdf.³² Of note, the dosing guidelines for adolescents are the same as those for adults and are based on level of use and dependence. Moreover, the clinician and patient should work together to choose the initial dose and the plan for weaning NRT over time.

Continue to: THE CASE

Based on your conversation with Joe, you administer the HONC screening tool. He scores 9 out of 10, indicating significant loss of autonomy over nicotine. You consult with a behavioral health counselor, who believes that Joe would benefit from counseling and NRT. You discuss this treatment plan with Joe, who says he is ready to quit because he does not like feeling as if he depends on vaping. Your shared decision is to start the 21-mg patch and 4-mg gum with plans to step down from there.

Studies show it is more effective to connect patients directly to the Quitline at the office visit than asking them to call after the visit.

Joe agrees to set a quit date in the following week. The behavioral health counselor then meets with Joe and they develop a quit plan, which is shared with you so you can follow up at the next visit. Joe also agrees to talk with his parents, who are unaware of his level of use and dependence. Everyone agrees on the quit plan, and a follow-up visit is scheduled.

At the follow-up visit 1 month later, Joe and his parents report that he has quit vaping but is still using the patch and gum. You instruct Joe to reduce his NRT use to the 14-mg patch and 2-mg gum and to stop using them over the next 2 to 3 weeks. Everyone is in agreement with the treatment plan. You also re-administer the HONC screening tool and see that Joe’s score has reduced by 7 points to just 2 out of 10. You recommend that Joe continue to see the behavioral health counselor and follow up as needed. (A noted benefit of having a behavioral health counselor in your clinic is the opportunity for informal briefings on patient progress.^33,34)

Following each visit with Joe, you make sure to complete documentation on (1) tobacco/e-cigarette use assessment, (2) diagnoses, (3) discussion of benefits of quitting,(4) assessment of readiness to quit, (5) creation and support of a quit plan, and (6) connection with a behavioral health counselor and planned follow-up. (See TABLE 2³⁵ for details onbilling codes.) 

CORRESPONDENCE
Eleanor L. S. Leavens, PhD, 3901 Rainbow Boulevard, Mail Stop 1008, Kansas City, KS 66160; [email protected]

The immunotherapy combination of nivolumab (Opdivo) and ipilimumab (Yervoy) offers a durable, long-term survival benefit over chemotherapy for patients with unresectable malignant pleural mesothelioma (MPM), confirms a 3-year updated analysis of the CheckMate 743 trial.

After 3 years, 23% of patients who received combination immunotherapy were still alive, in comparison with 15% of patients in the chemotherapy arm.

Combination immunotherapy continued to provide a “durable and long-term benefit” compared with chemotherapy, commented Solange Peters, MD, from the Oncology Department, Center Hospitalier Universitaire Vaudois, Lausanne, Switzerland.

The new data from the additional 12 months of follow-up “confirm nivolumab plus ipilimumab as a standard of care for unresectable MPM, regardless of histology,” she commented.

She presented the update on September 17 at the annual meeting of the European Society of Medical Oncology (ESMO). She is the current president of the organization.

Previously, 2-year data from this study showed that the combination yielded a median overall survival of 18.1 months, compared to 14.1 months with standard-of-care chemotherapy.

As reported by this news organization, this translated into a 26% improvement in overall survival; 41% of patients in the immunotherapy arm were still alive at 2 years, versus 27% in the chemotherapy group.

On the basis of these data, the combination was subsequently approved in the United States, the European Union, and elsewhere for the first-line treatment of adults with unresectable MPM.

The new data come from a 3-year update, as well as an exploratory biomarker analysis. The new data show significantly improved overall survival with the combination immunotherapy. Among those who responded to immunotherapy, response was ongoing for 28% of patients at 3 years.

Benefit was seen even for patients who discontinued the treatment because of treatment-related adverse events, indicating that discontinuance does not appear to have a negative impact on the long-term benefits, Dr. Peters commented.

In addition, the new analysis suggested that patients with a high score on a four-gene inflammatory signature did particularly well with nivolumab plus ipilimumab, whereas chemotherapy patients did worse if they had nonepithelioid disease, a finding not seen with immunotherapy.

The discussant for this abstract, Pilar Garrido, MD, PhD, associate professor of medicine at the Universidad de Alcalá, Madrid, said that despite the impressive findings, there is a “critical need” to establish predictive biomarkers in MPM.

This is particularly pressing in cases involving early progression, inasmuch as median progression-free survival (PFS) in CheckMate 743 was similar overall, and chemotherapy performed better than immunotherapy in the first 8 months.

There is also a need to be able to identify patients who will have an ongoing response at 3 years, as well as to clarify the impact of toxicity, given that the median duration of response was 20 months following discontinuation of treatment after just 4 months.

Dr. Garrido cautioned that the exploratory analyses were of “limited value,” because RNA data for the gene signature analysis were available for only 54% of patients, and the study was not powered to detect differences on the basis of programmed cell death–ligand-1 (PD-L1) expression.

Summarizing, Dr. Garrido said that although the current results showed that combination immunotherapy “continued to provide” a survival benefit in “a subgroup of patients,” the “better characterization of predictive biomarkers” will be “crucial” to improving these results.
 

Study details

Dr. Peters reminded the audience that the CheckMate 743 trial involved patients with unresectable MPM who had not previously received any systemic therapy and who had a good performance status.

A total of 605 patients were enrolled. They were randomly assigned in a 1:1 ratio to receive either nivolumab plus ipilimumab for up to 2 years or six cycles of pemetrexed plus cisplatin or carboplatin.

The median age of the patients was 69 years, and 77% were men. The baseline characteristics were well balanced between the two treatment groups; 75% to 76% had epithelioid disease, and for 74% to 80% of patients, baseline PD-L1 expression was greater than or equal to 1%.

Subgroup analysis indicated that combination immunotherapy was beneficial regardless of patient age, sex, performance status, and smoking status.

However, the new analysis suggested that the improvement in overall survival depended on PD-L1 expression, at a hazard ratio for combination immunotherapy versus chemotherapy of 0.71 in patients with expression of greater than or equal to 1%, compared with 0.99 for patients with expression of less than 1%.

Dr. Peters explained that the performance of nivolumab plus ipilimumab was identical in both PD-L1 expression groups, but it was the chemotherapy arm that performed markedly better for patients with expression of less than 1%.

An inverse finding was observed when patients were stratified by tumor histology.

In those with epithelioid disease, the median overall survival with combination immunotherapy was 18.2 months, versus 16.7 with chemotherapy, at a hazard ratio of 0.85.

At 36 months, 24% of immunotherapy patients were still alive, as were 19% of those given standard-of-care chemotherapy.

Among patients with nonepithelioid disease, however, median overall survival was 18.1 months with nivolumab plus ipilimumab, versus just 8.8 months with chemotherapy, at a hazard ratio of 0.48. At 3 years, 22% of patients who received combination immunotherapy were still alive, compared with 4% of those who received chemotherapy.

Other results showed that PFS was only slightly longer with combination immunotherapy, at 6.8 months versus 7.2 months, for a hazard ratio of 0.92.

Yet at 36 months, 14% of patients who received nivolumab plus ipilimumab had not experienced disease progression, versus just 1% of those in the chemotherapy arm.

This difference was even more pronounced when the researchers assessed objective response rates: 28% of patients who received combination immunotherapy were still responding at 36 months, versus 0% among patients given chemotherapy.

This translated into a median duration of response of 11.6 months for nivolumab plus ipilimumab, versus 6.7 months with chemotherapy.

The safety assessment showed that rates of treatment-related adverse events of any grade and of grade 3-4 were similar between the combination immunotherapy and chemotherapy arms.

However, rates of treatment-related adverse events that led to discontinuation of all components of the regimen were higher with immunotherapy, at 17% for events of any grade and 13% for events of grade 3-4, compared with 8% and 5%, respectively, with chemotherapy.

Serious treatment-related adverse events were more common with nivolumab plus ipilimumab. Events of grade 3-4 occurred in 13% of patients with nivolumab plus ipilimumab, versus 5% with chemotherapy.

Dr. Peters showed that this did not severely affect overall survival, however. Among patients who discontinued combination immunotherapy, the median duration of response was 20.0 months.

Median overall survival in these patients was 25.4 months, and the 3-year overall survival rate was 37%.

The study was funded by Bristol-Myers Squibb. Dr. Peters and Dr. Garrido reported relationships with numerous sources in industry.

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

The immunotherapy combination of nivolumab (Opdivo) and ipilimumab (Yervoy) offers a durable, long-term survival benefit over chemotherapy for patients with unresectable malignant pleural mesothelioma (MPM), confirms a 3-year updated analysis of the CheckMate 743 trial.

After 3 years, 23% of patients who received combination immunotherapy were still alive, in comparison with 15% of patients in the chemotherapy arm.

Combination immunotherapy continued to provide a “durable and long-term benefit” compared with chemotherapy, commented Solange Peters, MD, from the Oncology Department, Center Hospitalier Universitaire Vaudois, Lausanne, Switzerland.

The new data from the additional 12 months of follow-up “confirm nivolumab plus ipilimumab as a standard of care for unresectable MPM, regardless of histology,” she commented.

She presented the update on September 17 at the annual meeting of the European Society of Medical Oncology (ESMO). She is the current president of the organization.

Previously, 2-year data from this study showed that the combination yielded a median overall survival of 18.1 months, compared to 14.1 months with standard-of-care chemotherapy.

As reported by this news organization, this translated into a 26% improvement in overall survival; 41% of patients in the immunotherapy arm were still alive at 2 years, versus 27% in the chemotherapy group.

On the basis of these data, the combination was subsequently approved in the United States, the European Union, and elsewhere for the first-line treatment of adults with unresectable MPM.

The new data come from a 3-year update, as well as an exploratory biomarker analysis. The new data show significantly improved overall survival with the combination immunotherapy. Among those who responded to immunotherapy, response was ongoing for 28% of patients at 3 years.

Benefit was seen even for patients who discontinued the treatment because of treatment-related adverse events, indicating that discontinuance does not appear to have a negative impact on the long-term benefits, Dr. Peters commented.

In addition, the new analysis suggested that patients with a high score on a four-gene inflammatory signature did particularly well with nivolumab plus ipilimumab, whereas chemotherapy patients did worse if they had nonepithelioid disease, a finding not seen with immunotherapy.

The discussant for this abstract, Pilar Garrido, MD, PhD, associate professor of medicine at the Universidad de Alcalá, Madrid, said that despite the impressive findings, there is a “critical need” to establish predictive biomarkers in MPM.

This is particularly pressing in cases involving early progression, inasmuch as median progression-free survival (PFS) in CheckMate 743 was similar overall, and chemotherapy performed better than immunotherapy in the first 8 months.

There is also a need to be able to identify patients who will have an ongoing response at 3 years, as well as to clarify the impact of toxicity, given that the median duration of response was 20 months following discontinuation of treatment after just 4 months.

Dr. Garrido cautioned that the exploratory analyses were of “limited value,” because RNA data for the gene signature analysis were available for only 54% of patients, and the study was not powered to detect differences on the basis of programmed cell death–ligand-1 (PD-L1) expression.

Summarizing, Dr. Garrido said that although the current results showed that combination immunotherapy “continued to provide” a survival benefit in “a subgroup of patients,” the “better characterization of predictive biomarkers” will be “crucial” to improving these results.
 

Study details

Dr. Peters reminded the audience that the CheckMate 743 trial involved patients with unresectable MPM who had not previously received any systemic therapy and who had a good performance status.

A total of 605 patients were enrolled. They were randomly assigned in a 1:1 ratio to receive either nivolumab plus ipilimumab for up to 2 years or six cycles of pemetrexed plus cisplatin or carboplatin.

The median age of the patients was 69 years, and 77% were men. The baseline characteristics were well balanced between the two treatment groups; 75% to 76% had epithelioid disease, and for 74% to 80% of patients, baseline PD-L1 expression was greater than or equal to 1%.

Subgroup analysis indicated that combination immunotherapy was beneficial regardless of patient age, sex, performance status, and smoking status.

However, the new analysis suggested that the improvement in overall survival depended on PD-L1 expression, at a hazard ratio for combination immunotherapy versus chemotherapy of 0.71 in patients with expression of greater than or equal to 1%, compared with 0.99 for patients with expression of less than 1%.

Dr. Peters explained that the performance of nivolumab plus ipilimumab was identical in both PD-L1 expression groups, but it was the chemotherapy arm that performed markedly better for patients with expression of less than 1%.

An inverse finding was observed when patients were stratified by tumor histology.

In those with epithelioid disease, the median overall survival with combination immunotherapy was 18.2 months, versus 16.7 with chemotherapy, at a hazard ratio of 0.85.

At 36 months, 24% of immunotherapy patients were still alive, as were 19% of those given standard-of-care chemotherapy.

Among patients with nonepithelioid disease, however, median overall survival was 18.1 months with nivolumab plus ipilimumab, versus just 8.8 months with chemotherapy, at a hazard ratio of 0.48. At 3 years, 22% of patients who received combination immunotherapy were still alive, compared with 4% of those who received chemotherapy.

Other results showed that PFS was only slightly longer with combination immunotherapy, at 6.8 months versus 7.2 months, for a hazard ratio of 0.92.

Yet at 36 months, 14% of patients who received nivolumab plus ipilimumab had not experienced disease progression, versus just 1% of those in the chemotherapy arm.

This difference was even more pronounced when the researchers assessed objective response rates: 28% of patients who received combination immunotherapy were still responding at 36 months, versus 0% among patients given chemotherapy.

This translated into a median duration of response of 11.6 months for nivolumab plus ipilimumab, versus 6.7 months with chemotherapy.

The safety assessment showed that rates of treatment-related adverse events of any grade and of grade 3-4 were similar between the combination immunotherapy and chemotherapy arms.

However, rates of treatment-related adverse events that led to discontinuation of all components of the regimen were higher with immunotherapy, at 17% for events of any grade and 13% for events of grade 3-4, compared with 8% and 5%, respectively, with chemotherapy.

Serious treatment-related adverse events were more common with nivolumab plus ipilimumab. Events of grade 3-4 occurred in 13% of patients with nivolumab plus ipilimumab, versus 5% with chemotherapy.

Dr. Peters showed that this did not severely affect overall survival, however. Among patients who discontinued combination immunotherapy, the median duration of response was 20.0 months.

Median overall survival in these patients was 25.4 months, and the 3-year overall survival rate was 37%.

The study was funded by Bristol-Myers Squibb. Dr. Peters and Dr. Garrido reported relationships with numerous sources in industry.

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

The immunotherapy combination of nivolumab (Opdivo) and ipilimumab (Yervoy) offers a durable, long-term survival benefit over chemotherapy for patients with unresectable malignant pleural mesothelioma (MPM), confirms a 3-year updated analysis of the CheckMate 743 trial.

After 3 years, 23% of patients who received combination immunotherapy were still alive, in comparison with 15% of patients in the chemotherapy arm.

Combination immunotherapy continued to provide a “durable and long-term benefit” compared with chemotherapy, commented Solange Peters, MD, from the Oncology Department, Center Hospitalier Universitaire Vaudois, Lausanne, Switzerland.

The new data from the additional 12 months of follow-up “confirm nivolumab plus ipilimumab as a standard of care for unresectable MPM, regardless of histology,” she commented.

She presented the update on September 17 at the annual meeting of the European Society of Medical Oncology (ESMO). She is the current president of the organization.

Previously, 2-year data from this study showed that the combination yielded a median overall survival of 18.1 months, compared to 14.1 months with standard-of-care chemotherapy.

As reported by this news organization, this translated into a 26% improvement in overall survival; 41% of patients in the immunotherapy arm were still alive at 2 years, versus 27% in the chemotherapy group.

On the basis of these data, the combination was subsequently approved in the United States, the European Union, and elsewhere for the first-line treatment of adults with unresectable MPM.

The new data come from a 3-year update, as well as an exploratory biomarker analysis. The new data show significantly improved overall survival with the combination immunotherapy. Among those who responded to immunotherapy, response was ongoing for 28% of patients at 3 years.

Benefit was seen even for patients who discontinued the treatment because of treatment-related adverse events, indicating that discontinuance does not appear to have a negative impact on the long-term benefits, Dr. Peters commented.

In addition, the new analysis suggested that patients with a high score on a four-gene inflammatory signature did particularly well with nivolumab plus ipilimumab, whereas chemotherapy patients did worse if they had nonepithelioid disease, a finding not seen with immunotherapy.

The discussant for this abstract, Pilar Garrido, MD, PhD, associate professor of medicine at the Universidad de Alcalá, Madrid, said that despite the impressive findings, there is a “critical need” to establish predictive biomarkers in MPM.

This is particularly pressing in cases involving early progression, inasmuch as median progression-free survival (PFS) in CheckMate 743 was similar overall, and chemotherapy performed better than immunotherapy in the first 8 months.

There is also a need to be able to identify patients who will have an ongoing response at 3 years, as well as to clarify the impact of toxicity, given that the median duration of response was 20 months following discontinuation of treatment after just 4 months.

Dr. Garrido cautioned that the exploratory analyses were of “limited value,” because RNA data for the gene signature analysis were available for only 54% of patients, and the study was not powered to detect differences on the basis of programmed cell death–ligand-1 (PD-L1) expression.

Summarizing, Dr. Garrido said that although the current results showed that combination immunotherapy “continued to provide” a survival benefit in “a subgroup of patients,” the “better characterization of predictive biomarkers” will be “crucial” to improving these results.
 

Study details

Dr. Peters reminded the audience that the CheckMate 743 trial involved patients with unresectable MPM who had not previously received any systemic therapy and who had a good performance status.

A total of 605 patients were enrolled. They were randomly assigned in a 1:1 ratio to receive either nivolumab plus ipilimumab for up to 2 years or six cycles of pemetrexed plus cisplatin or carboplatin.

The median age of the patients was 69 years, and 77% were men. The baseline characteristics were well balanced between the two treatment groups; 75% to 76% had epithelioid disease, and for 74% to 80% of patients, baseline PD-L1 expression was greater than or equal to 1%.

Subgroup analysis indicated that combination immunotherapy was beneficial regardless of patient age, sex, performance status, and smoking status.

However, the new analysis suggested that the improvement in overall survival depended on PD-L1 expression, at a hazard ratio for combination immunotherapy versus chemotherapy of 0.71 in patients with expression of greater than or equal to 1%, compared with 0.99 for patients with expression of less than 1%.

Dr. Peters explained that the performance of nivolumab plus ipilimumab was identical in both PD-L1 expression groups, but it was the chemotherapy arm that performed markedly better for patients with expression of less than 1%.

An inverse finding was observed when patients were stratified by tumor histology.

In those with epithelioid disease, the median overall survival with combination immunotherapy was 18.2 months, versus 16.7 with chemotherapy, at a hazard ratio of 0.85.

At 36 months, 24% of immunotherapy patients were still alive, as were 19% of those given standard-of-care chemotherapy.

Among patients with nonepithelioid disease, however, median overall survival was 18.1 months with nivolumab plus ipilimumab, versus just 8.8 months with chemotherapy, at a hazard ratio of 0.48. At 3 years, 22% of patients who received combination immunotherapy were still alive, compared with 4% of those who received chemotherapy.

Other results showed that PFS was only slightly longer with combination immunotherapy, at 6.8 months versus 7.2 months, for a hazard ratio of 0.92.

Yet at 36 months, 14% of patients who received nivolumab plus ipilimumab had not experienced disease progression, versus just 1% of those in the chemotherapy arm.

This difference was even more pronounced when the researchers assessed objective response rates: 28% of patients who received combination immunotherapy were still responding at 36 months, versus 0% among patients given chemotherapy.

This translated into a median duration of response of 11.6 months for nivolumab plus ipilimumab, versus 6.7 months with chemotherapy.

The safety assessment showed that rates of treatment-related adverse events of any grade and of grade 3-4 were similar between the combination immunotherapy and chemotherapy arms.

However, rates of treatment-related adverse events that led to discontinuation of all components of the regimen were higher with immunotherapy, at 17% for events of any grade and 13% for events of grade 3-4, compared with 8% and 5%, respectively, with chemotherapy.

Serious treatment-related adverse events were more common with nivolumab plus ipilimumab. Events of grade 3-4 occurred in 13% of patients with nivolumab plus ipilimumab, versus 5% with chemotherapy.

Dr. Peters showed that this did not severely affect overall survival, however. Among patients who discontinued combination immunotherapy, the median duration of response was 20.0 months.

Median overall survival in these patients was 25.4 months, and the 3-year overall survival rate was 37%.

The study was funded by Bristol-Myers Squibb. Dr. Peters and Dr. Garrido reported relationships with numerous sources in industry.

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

The gut microbiome, previously shown to have an association with rheumatoid arthritis, may also provide signals of a patient’s disease prognosis, researchers at the Mayo Clinic have reported.

“We found that the gut microbiome is linked to whether patients with RA improve in their clinical symptoms or not,” cosenior author Jaeyun Sung, PhD, said in an interview. “We found features of the gut microbiome that linked to improvement, and we also put those features in a machine-learning model that can actually predict improvement at a follow-up visit.” Dr. Sung is a computational biologist with Mayo Clinic’s Center for Individualized Medicine in Rochester, Minn.

The retrospective, observational cohort study included 32 patients diagnosed with RA between 1988 and 2014. The researchers performed meta-genome shotgun sequencing on 64 stool samples kept in a biobank and collected at two separate visits 6-12 months apart. Dr. Sung and colleagues observed significantly different microbiome traits between patients who eventually showed minimally clinically important improvement and those who didn’t.

KATERYNA KON/Science SourceSource

The study also provided a proof of concept for using machine-learning technology to analyze the gut microbiome to predict the course of the disease, Dr. Sung said.

Cosenior author John M. Davis III, MD, a clinical rheumatologist and rheumatology research chair of the Mayo Clinic, noted that their own previous study had confirmed dysbiosis in people with RA when compared with controls. “We had some preliminary insight that it may be linked to some extent to the disease state and maybe treatments,” Dr. Davis said. “So that led us to hypothesize that there may be an association between the gut microbiome and response to treatment or disease activity over time.”

The study found that age was the dominant factor in determining variations in the gut microbiome composition, but the next prevailing factor was minimum clinically important improvement status, which 12 of the 32 study participants achieved at their follow-up visits. At baseline, all patients were on some type of treatment – either biologic or conventional disease-modifying antirheumatic drugs (DMARDs, 46.9% and 87.5%, respectively), or prednisone (46.9%).
 

Gut microbiome composition

The patients who achieved minimum clinically important improvement had an average decline in Clinical Disease Activity Index of 16.7 units (standard deviation, 12.8) versus a gain of 5.7 (SD, 8.9) in the remaining patients. The study found higher species-level alpha diversity and richness and higher beta diversity in the group that achieved minimum clinically important improvement, compared with those who did not.

They identified six microbial taxa as higher in abundance in the improved patients: Negativicutes (class); Selenomonadales (order); Prevotellaceae (family); Coprococcus (genus); Bacteroides sp. 3_1_19 (species); and Bilophila sp. 4_1_30 (species). In the patients who showed no improvement, Eubacterium sp. 3_1_31 (species) was found to be higher (P < .05). They also found 15 metabolic pathways that were differently abundant between the two groups at baseline.

Two things make this study different from other studies of the gut microbiome in RA, Dr. Sung said: It didn’t have a control group, only RA patients, and it didn’t evaluate a specific drug in RA patients.

“We’re thinking beyond just drug or treatment, independent of prior treatment, independent of prior clinical measurements, independent of age, sex, and other factors, can we predict RA response just using the gut microbiome alone?” Dr. Sung said. “Is there an association between clinical improvement and the gut microbiome?”

The study also showed that the microbiome may be a modifiable target for RA, Dr. Davis said.

“This research is attractive because it may complement medical treatment for RA if we can identify dietary modifications,” he said. “Still, there’s the question if probiotics or prebiotics can influence the gut. Can we modify the gut microbiome to further ameliorate the disease state? That’s something I think is an open question that’s specifically called out in our paper.”

This study included patients with long-term disease, but the group’s ongoing research is focusing on patients with earlier-stage RA, Dr. Davis said. “The next steps have to be in validating [the findings] in additional and external populations and looking at patients with very early disease where a lot of the decision-making is very active and happening in real time.”

James T. Rosenbaum, MD, an ophthalmologist and rheumatologist at Oregon Health & Science University, Portland, acknowledged that this is the first study in RA to find an effect on the gut microbiome using the minimum clinically important improvement endpoint.

“It also raises a ‘chicken-egg’ dilemma,” Dr. Rosenbaum said in an interview. “Did the patients improve and then their microbiome changed, or was the microbiome the first change that led to the clinical improvement? If the latter is correct, we potentially could alter the microbiome, for example, by diet, to treat rheumatic disease.”

He noted that studies with fecal transplants for ulcerative colitis support the therapeutic potential of microbiome modification. “But,” he added, “we are still a long way from putting this in practice.”

“The outcome is promising,” Claudia Mauri, PhD, a professor of immunology at University College London, said of the study. “Obviously, if this can be repeated in a very large cohort of patients, it would give us the possibility to be able to, based on the composition of the microbiota, to predict who is going to respond to treatment or not.”

She noted that, while RA has a broader array of available treatments than other autoimmune diseases, some RA patients don’t respond their first biologic treatment. “If from the outset we would be able to see who may not respond based on the microbiota, we may prepare physicians to better target these patients by, for example, offering them an alternative second biologic agent,” Dr. Mauri said.

Dr. Davis reported receiving research grants from Pfizer. Dr. Sung and other study coauthors have no financial relationships to disclose. Dr. Rosenbaum reported that the National Institutes of Health supports his research. Dr. Mauri has no financial relationships to disclose.

The gut microbiome, previously shown to have an association with rheumatoid arthritis, may also provide signals of a patient’s disease prognosis, researchers at the Mayo Clinic have reported.

“We found that the gut microbiome is linked to whether patients with RA improve in their clinical symptoms or not,” cosenior author Jaeyun Sung, PhD, said in an interview. “We found features of the gut microbiome that linked to improvement, and we also put those features in a machine-learning model that can actually predict improvement at a follow-up visit.” Dr. Sung is a computational biologist with Mayo Clinic’s Center for Individualized Medicine in Rochester, Minn.

The retrospective, observational cohort study included 32 patients diagnosed with RA between 1988 and 2014. The researchers performed meta-genome shotgun sequencing on 64 stool samples kept in a biobank and collected at two separate visits 6-12 months apart. Dr. Sung and colleagues observed significantly different microbiome traits between patients who eventually showed minimally clinically important improvement and those who didn’t.

KATERYNA KON/Science SourceSource

The study also provided a proof of concept for using machine-learning technology to analyze the gut microbiome to predict the course of the disease, Dr. Sung said.

Cosenior author John M. Davis III, MD, a clinical rheumatologist and rheumatology research chair of the Mayo Clinic, noted that their own previous study had confirmed dysbiosis in people with RA when compared with controls. “We had some preliminary insight that it may be linked to some extent to the disease state and maybe treatments,” Dr. Davis said. “So that led us to hypothesize that there may be an association between the gut microbiome and response to treatment or disease activity over time.”

The study found that age was the dominant factor in determining variations in the gut microbiome composition, but the next prevailing factor was minimum clinically important improvement status, which 12 of the 32 study participants achieved at their follow-up visits. At baseline, all patients were on some type of treatment – either biologic or conventional disease-modifying antirheumatic drugs (DMARDs, 46.9% and 87.5%, respectively), or prednisone (46.9%).
 

Gut microbiome composition

The patients who achieved minimum clinically important improvement had an average decline in Clinical Disease Activity Index of 16.7 units (standard deviation, 12.8) versus a gain of 5.7 (SD, 8.9) in the remaining patients. The study found higher species-level alpha diversity and richness and higher beta diversity in the group that achieved minimum clinically important improvement, compared with those who did not.

They identified six microbial taxa as higher in abundance in the improved patients: Negativicutes (class); Selenomonadales (order); Prevotellaceae (family); Coprococcus (genus); Bacteroides sp. 3_1_19 (species); and Bilophila sp. 4_1_30 (species). In the patients who showed no improvement, Eubacterium sp. 3_1_31 (species) was found to be higher (P < .05). They also found 15 metabolic pathways that were differently abundant between the two groups at baseline.

Two things make this study different from other studies of the gut microbiome in RA, Dr. Sung said: It didn’t have a control group, only RA patients, and it didn’t evaluate a specific drug in RA patients.

“We’re thinking beyond just drug or treatment, independent of prior treatment, independent of prior clinical measurements, independent of age, sex, and other factors, can we predict RA response just using the gut microbiome alone?” Dr. Sung said. “Is there an association between clinical improvement and the gut microbiome?”

The study also showed that the microbiome may be a modifiable target for RA, Dr. Davis said.

“This research is attractive because it may complement medical treatment for RA if we can identify dietary modifications,” he said. “Still, there’s the question if probiotics or prebiotics can influence the gut. Can we modify the gut microbiome to further ameliorate the disease state? That’s something I think is an open question that’s specifically called out in our paper.”

This study included patients with long-term disease, but the group’s ongoing research is focusing on patients with earlier-stage RA, Dr. Davis said. “The next steps have to be in validating [the findings] in additional and external populations and looking at patients with very early disease where a lot of the decision-making is very active and happening in real time.”

James T. Rosenbaum, MD, an ophthalmologist and rheumatologist at Oregon Health & Science University, Portland, acknowledged that this is the first study in RA to find an effect on the gut microbiome using the minimum clinically important improvement endpoint.

“It also raises a ‘chicken-egg’ dilemma,” Dr. Rosenbaum said in an interview. “Did the patients improve and then their microbiome changed, or was the microbiome the first change that led to the clinical improvement? If the latter is correct, we potentially could alter the microbiome, for example, by diet, to treat rheumatic disease.”

He noted that studies with fecal transplants for ulcerative colitis support the therapeutic potential of microbiome modification. “But,” he added, “we are still a long way from putting this in practice.”

“The outcome is promising,” Claudia Mauri, PhD, a professor of immunology at University College London, said of the study. “Obviously, if this can be repeated in a very large cohort of patients, it would give us the possibility to be able to, based on the composition of the microbiota, to predict who is going to respond to treatment or not.”

She noted that, while RA has a broader array of available treatments than other autoimmune diseases, some RA patients don’t respond their first biologic treatment. “If from the outset we would be able to see who may not respond based on the microbiota, we may prepare physicians to better target these patients by, for example, offering them an alternative second biologic agent,” Dr. Mauri said.

Dr. Davis reported receiving research grants from Pfizer. Dr. Sung and other study coauthors have no financial relationships to disclose. Dr. Rosenbaum reported that the National Institutes of Health supports his research. Dr. Mauri has no financial relationships to disclose.

The gut microbiome, previously shown to have an association with rheumatoid arthritis, may also provide signals of a patient’s disease prognosis, researchers at the Mayo Clinic have reported.

“We found that the gut microbiome is linked to whether patients with RA improve in their clinical symptoms or not,” cosenior author Jaeyun Sung, PhD, said in an interview. “We found features of the gut microbiome that linked to improvement, and we also put those features in a machine-learning model that can actually predict improvement at a follow-up visit.” Dr. Sung is a computational biologist with Mayo Clinic’s Center for Individualized Medicine in Rochester, Minn.

The retrospective, observational cohort study included 32 patients diagnosed with RA between 1988 and 2014. The researchers performed meta-genome shotgun sequencing on 64 stool samples kept in a biobank and collected at two separate visits 6-12 months apart. Dr. Sung and colleagues observed significantly different microbiome traits between patients who eventually showed minimally clinically important improvement and those who didn’t.

KATERYNA KON/Science SourceSource

The study also provided a proof of concept for using machine-learning technology to analyze the gut microbiome to predict the course of the disease, Dr. Sung said.

Cosenior author John M. Davis III, MD, a clinical rheumatologist and rheumatology research chair of the Mayo Clinic, noted that their own previous study had confirmed dysbiosis in people with RA when compared with controls. “We had some preliminary insight that it may be linked to some extent to the disease state and maybe treatments,” Dr. Davis said. “So that led us to hypothesize that there may be an association between the gut microbiome and response to treatment or disease activity over time.”

The study found that age was the dominant factor in determining variations in the gut microbiome composition, but the next prevailing factor was minimum clinically important improvement status, which 12 of the 32 study participants achieved at their follow-up visits. At baseline, all patients were on some type of treatment – either biologic or conventional disease-modifying antirheumatic drugs (DMARDs, 46.9% and 87.5%, respectively), or prednisone (46.9%).
 

Gut microbiome composition

The patients who achieved minimum clinically important improvement had an average decline in Clinical Disease Activity Index of 16.7 units (standard deviation, 12.8) versus a gain of 5.7 (SD, 8.9) in the remaining patients. The study found higher species-level alpha diversity and richness and higher beta diversity in the group that achieved minimum clinically important improvement, compared with those who did not.

They identified six microbial taxa as higher in abundance in the improved patients: Negativicutes (class); Selenomonadales (order); Prevotellaceae (family); Coprococcus (genus); Bacteroides sp. 3_1_19 (species); and Bilophila sp. 4_1_30 (species). In the patients who showed no improvement, Eubacterium sp. 3_1_31 (species) was found to be higher (P < .05). They also found 15 metabolic pathways that were differently abundant between the two groups at baseline.

Two things make this study different from other studies of the gut microbiome in RA, Dr. Sung said: It didn’t have a control group, only RA patients, and it didn’t evaluate a specific drug in RA patients.

“We’re thinking beyond just drug or treatment, independent of prior treatment, independent of prior clinical measurements, independent of age, sex, and other factors, can we predict RA response just using the gut microbiome alone?” Dr. Sung said. “Is there an association between clinical improvement and the gut microbiome?”

The study also showed that the microbiome may be a modifiable target for RA, Dr. Davis said.

“This research is attractive because it may complement medical treatment for RA if we can identify dietary modifications,” he said. “Still, there’s the question if probiotics or prebiotics can influence the gut. Can we modify the gut microbiome to further ameliorate the disease state? That’s something I think is an open question that’s specifically called out in our paper.”

This study included patients with long-term disease, but the group’s ongoing research is focusing on patients with earlier-stage RA, Dr. Davis said. “The next steps have to be in validating [the findings] in additional and external populations and looking at patients with very early disease where a lot of the decision-making is very active and happening in real time.”

James T. Rosenbaum, MD, an ophthalmologist and rheumatologist at Oregon Health & Science University, Portland, acknowledged that this is the first study in RA to find an effect on the gut microbiome using the minimum clinically important improvement endpoint.

“It also raises a ‘chicken-egg’ dilemma,” Dr. Rosenbaum said in an interview. “Did the patients improve and then their microbiome changed, or was the microbiome the first change that led to the clinical improvement? If the latter is correct, we potentially could alter the microbiome, for example, by diet, to treat rheumatic disease.”

He noted that studies with fecal transplants for ulcerative colitis support the therapeutic potential of microbiome modification. “But,” he added, “we are still a long way from putting this in practice.”

“The outcome is promising,” Claudia Mauri, PhD, a professor of immunology at University College London, said of the study. “Obviously, if this can be repeated in a very large cohort of patients, it would give us the possibility to be able to, based on the composition of the microbiota, to predict who is going to respond to treatment or not.”

She noted that, while RA has a broader array of available treatments than other autoimmune diseases, some RA patients don’t respond their first biologic treatment. “If from the outset we would be able to see who may not respond based on the microbiota, we may prepare physicians to better target these patients by, for example, offering them an alternative second biologic agent,” Dr. Mauri said.

Dr. Davis reported receiving research grants from Pfizer. Dr. Sung and other study coauthors have no financial relationships to disclose. Dr. Rosenbaum reported that the National Institutes of Health supports his research. Dr. Mauri has no financial relationships to disclose.

CASE

A 55-year-old right-hand-dominant woman presented to the clinic with a chief complaint of right ring finger pain and stiffness. There was no history of trauma or prior surgery. She had no tingling or numbness. She had a history of type 2 diabetes that was well controlled. She worked as a clerk for a government office for many years, and her painful, limited finger motion interfered with keyboarding and picking up items. Physical examination revealed tenderness to palpation over the palmar aspect of the metacarpophalangeal joint (MCPJ) of the ring finger with no other joint tenderness or swelling. When she made a fist, her ring finger MCPJ, proximal interphalangeal joint (PIPJ), and distal interphalangeal joint (DIPJ) locked in a flexed position that required manipulation to extend the finger. A firm mass was palpated in the palm with finger flexion that moved into the finger with extension.

Stenosing tenosynovitis, also known as trigger finger (TF), is an inflammatory condition that causes pain in the distal palm and proximal digit with associated limited motion. The most commonly affected digits are the middle and ring fingers of the dominant hand.¹ The disorder is particularly noticeable when it inhibits day-to-day functioning.

TF affects 2% to 3% of the general population and up to 20% of patients with diabetes.^2,3 Patient age and duration of diabetes are commonly cited as contributing factors, although the effect of well-controlled blood glucose and A1C on the frequency and cure rate of TF has not been established.^3,4 TF is most commonly seen in individuals ages 40 to 60 years, with a 6 times’ greater frequency in females than males.⁵

In the United States, there are an estimated 200,000 cases of TF each year, with initial presentation typically being to a primary care physician.⁶ For this reason, it is essential for primary care physicians to recognize this common pathology and treat symptoms early to prevent progression and the need for surgical intervention.

An impaired gliding motion of the flexor tendons

In each finger, a tendon sheath, consisting of 5 annular pulleys and 3 cruciate pulleys, forms a tunnel around the flexor digitorum profundus (FDP) and flexor digitorum superficialis (FDS). The tendon sheath allows for maximum force by eliminating bowstringing of the tendons when the digit is flexed. Deep to the tendons and surrounding the tendons is a synovial membrane that provides nutrition and reduces friction between the tendons and the tendon sheath.⁷

Trigger finger affects 2% to 3% of the general population and up to 20% of patients with diabetes.

The FDP is longer and assists in flexion of the MCPJ and the PIPJ. It is the sole flexor of the DIPJ. The shorter FDS assists in flexion of the MCPJ and is the primary flexor of the PIPJ. The bifurcation of the shorter FDS tendon allows the longer FDP tendon to pass through to continue to its insertion on the distal phalanx.

In the thumb, the flexor pollicis longus (FPL) is the only flexor within its tendon sheath. The FPL assists in flexion of the MCPJ and flexes the thumb interphalangeal joint (IPJ). The intrinsic muscles (lumbricals and interossei) do not extend into the tendon sheath and do not contribute to TF.

Continue to: TF occurs when

TF occurs when the tendon sheath, most commonly at the first annular pulley (A1), or the flexor tendons thicken due to fibrocartilaginous metaplasia. This results in impaired gliding motion of the flexor tendons.⁸ The stenosed A1 pulley can lead to pinching of the flexor tendons and cause the formation of a nodule on the FDS tendon at its bifurcation.⁹ The nodule of the FDS bifurcation moves proximal to the A1 pulley when the finger is flexed. Upon extension, the tendon nodule may get caught on the A1 pulley. This prevents smooth extension and is the source of pain and triggering (FIGURE 1). In a similar manner, thumb triggering is the result of a stenosed A1 pulley creating a nodule on the FPL tendon, which prevents smooth gliding of the FPL.

What you’ll see

TF is characterized by locking, popping, or clicking at the base of the finger or thumb.^7,10 A small nodule may be palpated on the palmar aspect of the MCPJ when the finger is flexed. This nodule will then move distally when the finger is extended. Patients will present with the affected digit in a flexed position and will have difficulty extending the digit. In some cases, the patient may have to use the other hand to straighten the affected digit. In more severe cases, the digit may be fixed in a position of flexion or extension. The severity of triggering is commonly graded by the Green’s classification system (see TABLE¹¹).

Is it Dupuytren contracture, trigger finger, or something else?

The differential diagnosis for TF includes Dupuytren contracture, MCPJ sprain, calcific peritendinitis, flexor tenosynovitis, diabetic cheiroarthropathy (DCA), rheumatoid arthritis (RA), osteoarthritis (OA), and crystalline arthropathy (gout).⁵

Dupuytren contracture is usually nonpainful and manifests with a palpable cord in the palm and a fixed flexion contracture that has progressed over time, with no history of catching.

MCPJ sprain is diagnosed with tenderness of the MCPJ and a history of trauma.

Continue to: Calcific peritendinitis

Calcific peritendinitis is characterized by pain, tenderness, and edema near a joint with calcified deposits seen on radiographs.

Flexor tenosynovitis manifests with fusiform swelling of the digit, tenderness over the flexor tendon sheath, and pain with passive extension of the digit; it is more commonly associated with RA.

DCA, RA, OA, and gout usually affect more than 1 digit. DCA is associated with both type 1 and type 2 diabetes and is characterized by thickened, waxy skin and painless, limited extension of the digits. RA and OA are diagnosed by medical history, lab work, and radiographs. Gout is diagnosed with lab work and aspiration of joint fluid.

Trigger finger occurs when the tendon sheath or the flexor tendons thicken due to fibrocartilaginous metaplasia.

A thorough history, physical exam, and review of radiographs must be performed to rule out these other disorders. Once the diagnosis of TF is made, available treatment options should be pursued.

Treatment: A conservative or surgical approach?

Current treatment options include both nonsurgical (conservative) and surgical interventions. Nonsurgical interventions include activity modification, splinting, and corticosteroid injections. While nonsteroidal anti-inflammatory drugs are commonly recommended to resolve the local inflammation secondary to triggering, there is no scientific evidence to support their use at this time.⁷ Surgical interventions, utilized in more severe cases or after conservative treatment has failed, include percutaneous and open release of the tendon sheath.^2,7

Continue to: Conservative treatments

Splinting is only an option for digits that retain flexibility (Green’s classification grades I, II, and III). The goal of splinting is to keep the affected digit in extension to avoid repeated friction between the tendon and the tendon sheath.¹² This ideally allows any cartilaginous metaplasia or inflammation to resolve, subsequently alleviating symptoms. The recommended length of treatment with splinting ranges from 3 to 12 weeks, with an average of 6 weeks.¹

Multiple studies have shown long-term alleviation of symptoms with the use of orthotic devices. A retrospective analysis found that 87% of patients who wore their PIPJ orthotic device both day and night for a minimum of 6 weeks required no further treatment at 1-year follow-up.¹³ In contrast, MCPJ splinting only at night has been shown to resolve symptoms in just 55% of patients after 6 weeks.¹⁴ From a practical standpoint, however, patients are more likely to be compliant with night-only splinting, making it a reasonable option. Splinting does remain efficacious for patients even after 6 months of symptomatology.¹⁵

Day and night splinting for approximately 8 weeks using a PIPJ orthotic could be considered as an effective first-line intervention.¹⁶ Notably, PIPJ splinting is more functional, as it allows motion of the MCPJ and DIPJ. There are several options available for PIPJ splints, including a stiff cushioned sleeve, a prefabricated plastic splint, and a large adhesive bandage.

An adjunct treatment to splinting is tendon-gliding exercises, including passive IPJ flexion, full finger flexion and extension, and hooking.¹³ Patients may remove the orthotic device to perform these exercises 3 times a day for 5 repetitions, as well as for activities that are not conducive to splinting.¹³

Corticosteroid injections. Injections of a corticosteroid and 1% lidocaine in a 1:1 mixture for a total volume of 1 cc can be inserted into the tendon sheath, A1 pulley, or adjacent tissue.¹⁷ Steroid injections help to decrease inflammation and pain in the affected area, giving symptom relief lasting a few months in as many as 57% to 87% of patients.¹⁸

Continue to: While the location of the injection...

While the location of the injection has been debated, recent literature suggests that symptoms can be effectively alleviated regardless of the specific anatomic injection site, such as intra-sheath or extra-sheath (FIGURE 2).¹⁹ This allows flexibility for the clinician, as the injection does not have to be placed within the tendon sheath. Corticosteroids should not be injected into the tendon itself, and the needle tip should be slightly withdrawn if there is resistance while injecting. Patients who are averse to injections have been shown to benefit from needle-free jet lidocaine (J-tip) administration prior to the actual steroid injection.²⁰

A randomized controlled trial comparing dexamethasone to triamcinolone injections found no difference in outcome at the 3-month follow-up (n = 84).¹⁷ This may suggest that the choice of corticosteroid is at the clinician’s discretion. In terms of long-term efficacy of steroid injections, it has been shown that 70% of trigger digits had complete resolution of symptoms at a mean follow-up of 8 years after just 1 injection (n = 43).²¹

Some patients, though, may require additional corticosteroid injections to maintain symptom control. If multiple injections are performed, they should not be given in intervals shorter than 4 months between treatments.⁵ Furthermore, steroids can be administered safely up to 3 times in the same digit before surgery is recommended.²²

A patient’s options should be reconsidered if efficacy is not demonstrated with prior injections. Notably, a lower success rate has been shown in patients with type 2 diabetes (66%) compared to those without diabetes (90%).^4,23 This difference in success rates is not well understood, as there is no causal relationship between well-controlled diabetes and TF.⁴ Complications of corticosteroid injections include local pain, fat atrophy, and hypopigmentation at the site of the injection, as well as short-term elevations in blood glucose levels in patients with diabetes.^5,24

Surgical correction (to be discussed) remains superior to steroid injections in terms of cure rate and resolution of symptoms. A randomized controlled trial (n = 165) found that an injection-only group reported 86% and 49% success at 3-month and 12-month follow-up, respectively, compared to 99% success at both 3- and 12-month follow-up for the surgical group. Further, at 12-month follow-up, the median pain scores were significantly higher in the injection group (3; range, 1-9) than in the surgery group (1; range, 1-7).²⁵ If conservative treatment modalities lead to unresolved symptoms or recurrence, referral to a hand specialist for surgery is recommended.

Continue to: Surgical treatments in an office setting

Surgical treatments in an office setting

Procedures for TF can be safely performed under conscious sedation or local anesthesia, with or without a tourniquet.²⁶ Wide-awake procedures with local anesthesia and no tourniquet (WALANT) can be performed in an office-based procedure room rather than the operating room. This increases efficiency for the surgeon, reduces the amount of preparation and recovery time for the patient, and helps to keep costs down.

Percutaneous release involves the insertion of a 16-gauge hypodermic needle into the affected A1 pulley. The needle is used to fray and disrupt the pulley by moving the needle tip over the fibrotic A1 pulley.

While NSAIDs are commonly recommended to resolve the local inflammation secondary to triggering, there is no scientific evidence to support their use.

However, it is not without possible complications.²⁷ Inadvertent A2 pulley damage is particularly troublesome, as it leads to “bowstringing” or protrusion of the flexor tendon into the palm upon flexion. This can cause pain and failure to fully extend or flex the finger.¹⁰ Because the anatomy is not well visualized during the percutaneous approach, incomplete release, neurovascular injury, and iatrogenic injury to the A2 pulley or deep tendon may occur.²⁸ Ultrasound-guided percutaneous release techniques have shown effective clinical outcomes with minimal complications compared to nonguided percutaneous release techniques.^29,30

Open release is the gold standard surgical treatment for trigger finger (FIGURE 3). A small incision (1-2 cm) is made directly over or proximal to the A1 pulley in the distal palmar crease at the base of the affected digit. After blunt dissection through the subcutaneous tissue, the A1 pulley is sharply incised. An open approach has the clear benefit of avoiding the digital neurovascular bundles, as well as visualizing the resolution of triggering upon flexion and extension prior to closure. The WALANT procedure has the advantage of allowing the awake patient to actively flex and extend the digit to determine if the A1 release has been successful prior to closure of the incision.

Outcomes and complications of surgery. A recent systematic review and meta-analysis has shown percutaneous techniques to be successful in 94% of cases.²⁷ The success rate of open surgery has been reported at 99% to 100% at varying follow-up intervals up to 1 year.^25,30,31 The complication rate for percutaneous release (guided and nonguided) was calculated at 2.2% (n = 2114).²⁷ In another study, the overall complication rate of open releases was calculated at 1% (n = 999).³² When comparing percutaneous release (guided and nonguided) and open release, a meta-analysis found no significant difference in complication rate (RR = 0.84) or failure rate (RR = 0.94).³²

Continue to: Several risk factors...

Several risk factors have been associated with postoperative surgical infection, including recent steroid injection (< 80 d), smoking status, increasing age, and pre-operative use of lidocaine with epinephrine.³³ Open release has been shown to be an effective and safe treatment modality for patients with and without diabetes alike.³⁴ Overall, definitive surgical correction has been demonstrated to be superior to conservative measures due to a significantly lower rate of recurrence.³⁵

CASE

Given the patient’s presentation with triggering of the digit, tenderness over the A1 pulley, and lack of trauma history, we diagnosed trigger finger in this patient. Potential treatments included splinting, corticosteroid injections, and surgery. After discussion of the risks and benefits of each treatment option, the patient elected to undergo a corticosteroid injection. She was also given a neoprene finger sleeve to wear every night, and in the daytime when possible.

At 12-week follow-up, she noted early improvement in her triggering, which had since recurred. Due to her history of diabetes, the patient was then referred for surgery. She had an open release under local anesthesia. The surgery was uncomplicated, and the abnormality was corrected. At the patient’s 1-year postoperative follow-up visit, there was no evidence of recurrence, and she had regained full active and passive range of motion of her finger.

Acknowledgements
The authors wish to thank Jose Borrero, MD, for contributing his time and creative talents to produce the illustrations in this article.

CORRESPONDENCE
Evan P. Johnson, MD; 506 South Greer Street, Memphis, TN 38111; [email protected]

CASE

A 55-year-old right-hand-dominant woman presented to the clinic with a chief complaint of right ring finger pain and stiffness. There was no history of trauma or prior surgery. She had no tingling or numbness. She had a history of type 2 diabetes that was well controlled. She worked as a clerk for a government office for many years, and her painful, limited finger motion interfered with keyboarding and picking up items. Physical examination revealed tenderness to palpation over the palmar aspect of the metacarpophalangeal joint (MCPJ) of the ring finger with no other joint tenderness or swelling. When she made a fist, her ring finger MCPJ, proximal interphalangeal joint (PIPJ), and distal interphalangeal joint (DIPJ) locked in a flexed position that required manipulation to extend the finger. A firm mass was palpated in the palm with finger flexion that moved into the finger with extension.

Stenosing tenosynovitis, also known as trigger finger (TF), is an inflammatory condition that causes pain in the distal palm and proximal digit with associated limited motion. The most commonly affected digits are the middle and ring fingers of the dominant hand.¹ The disorder is particularly noticeable when it inhibits day-to-day functioning.

TF affects 2% to 3% of the general population and up to 20% of patients with diabetes.^2,3 Patient age and duration of diabetes are commonly cited as contributing factors, although the effect of well-controlled blood glucose and A1C on the frequency and cure rate of TF has not been established.^3,4 TF is most commonly seen in individuals ages 40 to 60 years, with a 6 times’ greater frequency in females than males.⁵

In the United States, there are an estimated 200,000 cases of TF each year, with initial presentation typically being to a primary care physician.⁶ For this reason, it is essential for primary care physicians to recognize this common pathology and treat symptoms early to prevent progression and the need for surgical intervention.

An impaired gliding motion of the flexor tendons

In each finger, a tendon sheath, consisting of 5 annular pulleys and 3 cruciate pulleys, forms a tunnel around the flexor digitorum profundus (FDP) and flexor digitorum superficialis (FDS). The tendon sheath allows for maximum force by eliminating bowstringing of the tendons when the digit is flexed. Deep to the tendons and surrounding the tendons is a synovial membrane that provides nutrition and reduces friction between the tendons and the tendon sheath.⁷

Trigger finger affects 2% to 3% of the general population and up to 20% of patients with diabetes.

The FDP is longer and assists in flexion of the MCPJ and the PIPJ. It is the sole flexor of the DIPJ. The shorter FDS assists in flexion of the MCPJ and is the primary flexor of the PIPJ. The bifurcation of the shorter FDS tendon allows the longer FDP tendon to pass through to continue to its insertion on the distal phalanx.

In the thumb, the flexor pollicis longus (FPL) is the only flexor within its tendon sheath. The FPL assists in flexion of the MCPJ and flexes the thumb interphalangeal joint (IPJ). The intrinsic muscles (lumbricals and interossei) do not extend into the tendon sheath and do not contribute to TF.

Continue to: TF occurs when

TF occurs when the tendon sheath, most commonly at the first annular pulley (A1), or the flexor tendons thicken due to fibrocartilaginous metaplasia. This results in impaired gliding motion of the flexor tendons.⁸ The stenosed A1 pulley can lead to pinching of the flexor tendons and cause the formation of a nodule on the FDS tendon at its bifurcation.⁹ The nodule of the FDS bifurcation moves proximal to the A1 pulley when the finger is flexed. Upon extension, the tendon nodule may get caught on the A1 pulley. This prevents smooth extension and is the source of pain and triggering (FIGURE 1). In a similar manner, thumb triggering is the result of a stenosed A1 pulley creating a nodule on the FPL tendon, which prevents smooth gliding of the FPL.

What you’ll see

TF is characterized by locking, popping, or clicking at the base of the finger or thumb.^7,10 A small nodule may be palpated on the palmar aspect of the MCPJ when the finger is flexed. This nodule will then move distally when the finger is extended. Patients will present with the affected digit in a flexed position and will have difficulty extending the digit. In some cases, the patient may have to use the other hand to straighten the affected digit. In more severe cases, the digit may be fixed in a position of flexion or extension. The severity of triggering is commonly graded by the Green’s classification system (see TABLE¹¹).

Is it Dupuytren contracture, trigger finger, or something else?

The differential diagnosis for TF includes Dupuytren contracture, MCPJ sprain, calcific peritendinitis, flexor tenosynovitis, diabetic cheiroarthropathy (DCA), rheumatoid arthritis (RA), osteoarthritis (OA), and crystalline arthropathy (gout).⁵

Dupuytren contracture is usually nonpainful and manifests with a palpable cord in the palm and a fixed flexion contracture that has progressed over time, with no history of catching.

MCPJ sprain is diagnosed with tenderness of the MCPJ and a history of trauma.

Continue to: Calcific peritendinitis

Calcific peritendinitis is characterized by pain, tenderness, and edema near a joint with calcified deposits seen on radiographs.

Flexor tenosynovitis manifests with fusiform swelling of the digit, tenderness over the flexor tendon sheath, and pain with passive extension of the digit; it is more commonly associated with RA.

DCA, RA, OA, and gout usually affect more than 1 digit. DCA is associated with both type 1 and type 2 diabetes and is characterized by thickened, waxy skin and painless, limited extension of the digits. RA and OA are diagnosed by medical history, lab work, and radiographs. Gout is diagnosed with lab work and aspiration of joint fluid.

Trigger finger occurs when the tendon sheath or the flexor tendons thicken due to fibrocartilaginous metaplasia.

A thorough history, physical exam, and review of radiographs must be performed to rule out these other disorders. Once the diagnosis of TF is made, available treatment options should be pursued.

Treatment: A conservative or surgical approach?

Current treatment options include both nonsurgical (conservative) and surgical interventions. Nonsurgical interventions include activity modification, splinting, and corticosteroid injections. While nonsteroidal anti-inflammatory drugs are commonly recommended to resolve the local inflammation secondary to triggering, there is no scientific evidence to support their use at this time.⁷ Surgical interventions, utilized in more severe cases or after conservative treatment has failed, include percutaneous and open release of the tendon sheath.^2,7

Continue to: Conservative treatments

Splinting is only an option for digits that retain flexibility (Green’s classification grades I, II, and III). The goal of splinting is to keep the affected digit in extension to avoid repeated friction between the tendon and the tendon sheath.¹² This ideally allows any cartilaginous metaplasia or inflammation to resolve, subsequently alleviating symptoms. The recommended length of treatment with splinting ranges from 3 to 12 weeks, with an average of 6 weeks.¹

Multiple studies have shown long-term alleviation of symptoms with the use of orthotic devices. A retrospective analysis found that 87% of patients who wore their PIPJ orthotic device both day and night for a minimum of 6 weeks required no further treatment at 1-year follow-up.¹³ In contrast, MCPJ splinting only at night has been shown to resolve symptoms in just 55% of patients after 6 weeks.¹⁴ From a practical standpoint, however, patients are more likely to be compliant with night-only splinting, making it a reasonable option. Splinting does remain efficacious for patients even after 6 months of symptomatology.¹⁵

Day and night splinting for approximately 8 weeks using a PIPJ orthotic could be considered as an effective first-line intervention.¹⁶ Notably, PIPJ splinting is more functional, as it allows motion of the MCPJ and DIPJ. There are several options available for PIPJ splints, including a stiff cushioned sleeve, a prefabricated plastic splint, and a large adhesive bandage.

An adjunct treatment to splinting is tendon-gliding exercises, including passive IPJ flexion, full finger flexion and extension, and hooking.¹³ Patients may remove the orthotic device to perform these exercises 3 times a day for 5 repetitions, as well as for activities that are not conducive to splinting.¹³

Corticosteroid injections. Injections of a corticosteroid and 1% lidocaine in a 1:1 mixture for a total volume of 1 cc can be inserted into the tendon sheath, A1 pulley, or adjacent tissue.¹⁷ Steroid injections help to decrease inflammation and pain in the affected area, giving symptom relief lasting a few months in as many as 57% to 87% of patients.¹⁸

Continue to: While the location of the injection...

While the location of the injection has been debated, recent literature suggests that symptoms can be effectively alleviated regardless of the specific anatomic injection site, such as intra-sheath or extra-sheath (FIGURE 2).¹⁹ This allows flexibility for the clinician, as the injection does not have to be placed within the tendon sheath. Corticosteroids should not be injected into the tendon itself, and the needle tip should be slightly withdrawn if there is resistance while injecting. Patients who are averse to injections have been shown to benefit from needle-free jet lidocaine (J-tip) administration prior to the actual steroid injection.²⁰

A randomized controlled trial comparing dexamethasone to triamcinolone injections found no difference in outcome at the 3-month follow-up (n = 84).¹⁷ This may suggest that the choice of corticosteroid is at the clinician’s discretion. In terms of long-term efficacy of steroid injections, it has been shown that 70% of trigger digits had complete resolution of symptoms at a mean follow-up of 8 years after just 1 injection (n = 43).²¹

Some patients, though, may require additional corticosteroid injections to maintain symptom control. If multiple injections are performed, they should not be given in intervals shorter than 4 months between treatments.⁵ Furthermore, steroids can be administered safely up to 3 times in the same digit before surgery is recommended.²²

A patient’s options should be reconsidered if efficacy is not demonstrated with prior injections. Notably, a lower success rate has been shown in patients with type 2 diabetes (66%) compared to those without diabetes (90%).^4,23 This difference in success rates is not well understood, as there is no causal relationship between well-controlled diabetes and TF.⁴ Complications of corticosteroid injections include local pain, fat atrophy, and hypopigmentation at the site of the injection, as well as short-term elevations in blood glucose levels in patients with diabetes.^5,24

Surgical correction (to be discussed) remains superior to steroid injections in terms of cure rate and resolution of symptoms. A randomized controlled trial (n = 165) found that an injection-only group reported 86% and 49% success at 3-month and 12-month follow-up, respectively, compared to 99% success at both 3- and 12-month follow-up for the surgical group. Further, at 12-month follow-up, the median pain scores were significantly higher in the injection group (3; range, 1-9) than in the surgery group (1; range, 1-7).²⁵ If conservative treatment modalities lead to unresolved symptoms or recurrence, referral to a hand specialist for surgery is recommended.

Continue to: Surgical treatments in an office setting

Surgical treatments in an office setting

Procedures for TF can be safely performed under conscious sedation or local anesthesia, with or without a tourniquet.²⁶ Wide-awake procedures with local anesthesia and no tourniquet (WALANT) can be performed in an office-based procedure room rather than the operating room. This increases efficiency for the surgeon, reduces the amount of preparation and recovery time for the patient, and helps to keep costs down.

Percutaneous release involves the insertion of a 16-gauge hypodermic needle into the affected A1 pulley. The needle is used to fray and disrupt the pulley by moving the needle tip over the fibrotic A1 pulley.

While NSAIDs are commonly recommended to resolve the local inflammation secondary to triggering, there is no scientific evidence to support their use.

However, it is not without possible complications.²⁷ Inadvertent A2 pulley damage is particularly troublesome, as it leads to “bowstringing” or protrusion of the flexor tendon into the palm upon flexion. This can cause pain and failure to fully extend or flex the finger.¹⁰ Because the anatomy is not well visualized during the percutaneous approach, incomplete release, neurovascular injury, and iatrogenic injury to the A2 pulley or deep tendon may occur.²⁸ Ultrasound-guided percutaneous release techniques have shown effective clinical outcomes with minimal complications compared to nonguided percutaneous release techniques.^29,30

Open release is the gold standard surgical treatment for trigger finger (FIGURE 3). A small incision (1-2 cm) is made directly over or proximal to the A1 pulley in the distal palmar crease at the base of the affected digit. After blunt dissection through the subcutaneous tissue, the A1 pulley is sharply incised. An open approach has the clear benefit of avoiding the digital neurovascular bundles, as well as visualizing the resolution of triggering upon flexion and extension prior to closure. The WALANT procedure has the advantage of allowing the awake patient to actively flex and extend the digit to determine if the A1 release has been successful prior to closure of the incision.

Outcomes and complications of surgery. A recent systematic review and meta-analysis has shown percutaneous techniques to be successful in 94% of cases.²⁷ The success rate of open surgery has been reported at 99% to 100% at varying follow-up intervals up to 1 year.^25,30,31 The complication rate for percutaneous release (guided and nonguided) was calculated at 2.2% (n = 2114).²⁷ In another study, the overall complication rate of open releases was calculated at 1% (n = 999).³² When comparing percutaneous release (guided and nonguided) and open release, a meta-analysis found no significant difference in complication rate (RR = 0.84) or failure rate (RR = 0.94).³²

Continue to: Several risk factors...

Several risk factors have been associated with postoperative surgical infection, including recent steroid injection (< 80 d), smoking status, increasing age, and pre-operative use of lidocaine with epinephrine.³³ Open release has been shown to be an effective and safe treatment modality for patients with and without diabetes alike.³⁴ Overall, definitive surgical correction has been demonstrated to be superior to conservative measures due to a significantly lower rate of recurrence.³⁵

CASE

Given the patient’s presentation with triggering of the digit, tenderness over the A1 pulley, and lack of trauma history, we diagnosed trigger finger in this patient. Potential treatments included splinting, corticosteroid injections, and surgery. After discussion of the risks and benefits of each treatment option, the patient elected to undergo a corticosteroid injection. She was also given a neoprene finger sleeve to wear every night, and in the daytime when possible.

At 12-week follow-up, she noted early improvement in her triggering, which had since recurred. Due to her history of diabetes, the patient was then referred for surgery. She had an open release under local anesthesia. The surgery was uncomplicated, and the abnormality was corrected. At the patient’s 1-year postoperative follow-up visit, there was no evidence of recurrence, and she had regained full active and passive range of motion of her finger.

Acknowledgements
The authors wish to thank Jose Borrero, MD, for contributing his time and creative talents to produce the illustrations in this article.

CORRESPONDENCE
Evan P. Johnson, MD; 506 South Greer Street, Memphis, TN 38111; [email protected]

CASE

A 55-year-old right-hand-dominant woman presented to the clinic with a chief complaint of right ring finger pain and stiffness. There was no history of trauma or prior surgery. She had no tingling or numbness. She had a history of type 2 diabetes that was well controlled. She worked as a clerk for a government office for many years, and her painful, limited finger motion interfered with keyboarding and picking up items. Physical examination revealed tenderness to palpation over the palmar aspect of the metacarpophalangeal joint (MCPJ) of the ring finger with no other joint tenderness or swelling. When she made a fist, her ring finger MCPJ, proximal interphalangeal joint (PIPJ), and distal interphalangeal joint (DIPJ) locked in a flexed position that required manipulation to extend the finger. A firm mass was palpated in the palm with finger flexion that moved into the finger with extension.

Stenosing tenosynovitis, also known as trigger finger (TF), is an inflammatory condition that causes pain in the distal palm and proximal digit with associated limited motion. The most commonly affected digits are the middle and ring fingers of the dominant hand.¹ The disorder is particularly noticeable when it inhibits day-to-day functioning.

TF affects 2% to 3% of the general population and up to 20% of patients with diabetes.^2,3 Patient age and duration of diabetes are commonly cited as contributing factors, although the effect of well-controlled blood glucose and A1C on the frequency and cure rate of TF has not been established.^3,4 TF is most commonly seen in individuals ages 40 to 60 years, with a 6 times’ greater frequency in females than males.⁵

In the United States, there are an estimated 200,000 cases of TF each year, with initial presentation typically being to a primary care physician.⁶ For this reason, it is essential for primary care physicians to recognize this common pathology and treat symptoms early to prevent progression and the need for surgical intervention.

An impaired gliding motion of the flexor tendons

In each finger, a tendon sheath, consisting of 5 annular pulleys and 3 cruciate pulleys, forms a tunnel around the flexor digitorum profundus (FDP) and flexor digitorum superficialis (FDS). The tendon sheath allows for maximum force by eliminating bowstringing of the tendons when the digit is flexed. Deep to the tendons and surrounding the tendons is a synovial membrane that provides nutrition and reduces friction between the tendons and the tendon sheath.⁷

Trigger finger affects 2% to 3% of the general population and up to 20% of patients with diabetes.

The FDP is longer and assists in flexion of the MCPJ and the PIPJ. It is the sole flexor of the DIPJ. The shorter FDS assists in flexion of the MCPJ and is the primary flexor of the PIPJ. The bifurcation of the shorter FDS tendon allows the longer FDP tendon to pass through to continue to its insertion on the distal phalanx.

In the thumb, the flexor pollicis longus (FPL) is the only flexor within its tendon sheath. The FPL assists in flexion of the MCPJ and flexes the thumb interphalangeal joint (IPJ). The intrinsic muscles (lumbricals and interossei) do not extend into the tendon sheath and do not contribute to TF.

Continue to: TF occurs when

TF occurs when the tendon sheath, most commonly at the first annular pulley (A1), or the flexor tendons thicken due to fibrocartilaginous metaplasia. This results in impaired gliding motion of the flexor tendons.⁸ The stenosed A1 pulley can lead to pinching of the flexor tendons and cause the formation of a nodule on the FDS tendon at its bifurcation.⁹ The nodule of the FDS bifurcation moves proximal to the A1 pulley when the finger is flexed. Upon extension, the tendon nodule may get caught on the A1 pulley. This prevents smooth extension and is the source of pain and triggering (FIGURE 1). In a similar manner, thumb triggering is the result of a stenosed A1 pulley creating a nodule on the FPL tendon, which prevents smooth gliding of the FPL.

What you’ll see

TF is characterized by locking, popping, or clicking at the base of the finger or thumb.^7,10 A small nodule may be palpated on the palmar aspect of the MCPJ when the finger is flexed. This nodule will then move distally when the finger is extended. Patients will present with the affected digit in a flexed position and will have difficulty extending the digit. In some cases, the patient may have to use the other hand to straighten the affected digit. In more severe cases, the digit may be fixed in a position of flexion or extension. The severity of triggering is commonly graded by the Green’s classification system (see TABLE¹¹).

Is it Dupuytren contracture, trigger finger, or something else?

The differential diagnosis for TF includes Dupuytren contracture, MCPJ sprain, calcific peritendinitis, flexor tenosynovitis, diabetic cheiroarthropathy (DCA), rheumatoid arthritis (RA), osteoarthritis (OA), and crystalline arthropathy (gout).⁵

Dupuytren contracture is usually nonpainful and manifests with a palpable cord in the palm and a fixed flexion contracture that has progressed over time, with no history of catching.

MCPJ sprain is diagnosed with tenderness of the MCPJ and a history of trauma.

Continue to: Calcific peritendinitis

Calcific peritendinitis is characterized by pain, tenderness, and edema near a joint with calcified deposits seen on radiographs.

Flexor tenosynovitis manifests with fusiform swelling of the digit, tenderness over the flexor tendon sheath, and pain with passive extension of the digit; it is more commonly associated with RA.

DCA, RA, OA, and gout usually affect more than 1 digit. DCA is associated with both type 1 and type 2 diabetes and is characterized by thickened, waxy skin and painless, limited extension of the digits. RA and OA are diagnosed by medical history, lab work, and radiographs. Gout is diagnosed with lab work and aspiration of joint fluid.

Trigger finger occurs when the tendon sheath or the flexor tendons thicken due to fibrocartilaginous metaplasia.

A thorough history, physical exam, and review of radiographs must be performed to rule out these other disorders. Once the diagnosis of TF is made, available treatment options should be pursued.

Treatment: A conservative or surgical approach?

Current treatment options include both nonsurgical (conservative) and surgical interventions. Nonsurgical interventions include activity modification, splinting, and corticosteroid injections. While nonsteroidal anti-inflammatory drugs are commonly recommended to resolve the local inflammation secondary to triggering, there is no scientific evidence to support their use at this time.⁷ Surgical interventions, utilized in more severe cases or after conservative treatment has failed, include percutaneous and open release of the tendon sheath.^2,7

Continue to: Conservative treatments

Splinting is only an option for digits that retain flexibility (Green’s classification grades I, II, and III). The goal of splinting is to keep the affected digit in extension to avoid repeated friction between the tendon and the tendon sheath.¹² This ideally allows any cartilaginous metaplasia or inflammation to resolve, subsequently alleviating symptoms. The recommended length of treatment with splinting ranges from 3 to 12 weeks, with an average of 6 weeks.¹

Multiple studies have shown long-term alleviation of symptoms with the use of orthotic devices. A retrospective analysis found that 87% of patients who wore their PIPJ orthotic device both day and night for a minimum of 6 weeks required no further treatment at 1-year follow-up.¹³ In contrast, MCPJ splinting only at night has been shown to resolve symptoms in just 55% of patients after 6 weeks.¹⁴ From a practical standpoint, however, patients are more likely to be compliant with night-only splinting, making it a reasonable option. Splinting does remain efficacious for patients even after 6 months of symptomatology.¹⁵

Day and night splinting for approximately 8 weeks using a PIPJ orthotic could be considered as an effective first-line intervention.¹⁶ Notably, PIPJ splinting is more functional, as it allows motion of the MCPJ and DIPJ. There are several options available for PIPJ splints, including a stiff cushioned sleeve, a prefabricated plastic splint, and a large adhesive bandage.

An adjunct treatment to splinting is tendon-gliding exercises, including passive IPJ flexion, full finger flexion and extension, and hooking.¹³ Patients may remove the orthotic device to perform these exercises 3 times a day for 5 repetitions, as well as for activities that are not conducive to splinting.¹³

Corticosteroid injections. Injections of a corticosteroid and 1% lidocaine in a 1:1 mixture for a total volume of 1 cc can be inserted into the tendon sheath, A1 pulley, or adjacent tissue.¹⁷ Steroid injections help to decrease inflammation and pain in the affected area, giving symptom relief lasting a few months in as many as 57% to 87% of patients.¹⁸

Continue to: While the location of the injection...

While the location of the injection has been debated, recent literature suggests that symptoms can be effectively alleviated regardless of the specific anatomic injection site, such as intra-sheath or extra-sheath (FIGURE 2).¹⁹ This allows flexibility for the clinician, as the injection does not have to be placed within the tendon sheath. Corticosteroids should not be injected into the tendon itself, and the needle tip should be slightly withdrawn if there is resistance while injecting. Patients who are averse to injections have been shown to benefit from needle-free jet lidocaine (J-tip) administration prior to the actual steroid injection.²⁰

A randomized controlled trial comparing dexamethasone to triamcinolone injections found no difference in outcome at the 3-month follow-up (n = 84).¹⁷ This may suggest that the choice of corticosteroid is at the clinician’s discretion. In terms of long-term efficacy of steroid injections, it has been shown that 70% of trigger digits had complete resolution of symptoms at a mean follow-up of 8 years after just 1 injection (n = 43).²¹

Some patients, though, may require additional corticosteroid injections to maintain symptom control. If multiple injections are performed, they should not be given in intervals shorter than 4 months between treatments.⁵ Furthermore, steroids can be administered safely up to 3 times in the same digit before surgery is recommended.²²

A patient’s options should be reconsidered if efficacy is not demonstrated with prior injections. Notably, a lower success rate has been shown in patients with type 2 diabetes (66%) compared to those without diabetes (90%).^4,23 This difference in success rates is not well understood, as there is no causal relationship between well-controlled diabetes and TF.⁴ Complications of corticosteroid injections include local pain, fat atrophy, and hypopigmentation at the site of the injection, as well as short-term elevations in blood glucose levels in patients with diabetes.^5,24

Surgical correction (to be discussed) remains superior to steroid injections in terms of cure rate and resolution of symptoms. A randomized controlled trial (n = 165) found that an injection-only group reported 86% and 49% success at 3-month and 12-month follow-up, respectively, compared to 99% success at both 3- and 12-month follow-up for the surgical group. Further, at 12-month follow-up, the median pain scores were significantly higher in the injection group (3; range, 1-9) than in the surgery group (1; range, 1-7).²⁵ If conservative treatment modalities lead to unresolved symptoms or recurrence, referral to a hand specialist for surgery is recommended.

Continue to: Surgical treatments in an office setting

Surgical treatments in an office setting

Procedures for TF can be safely performed under conscious sedation or local anesthesia, with or without a tourniquet.²⁶ Wide-awake procedures with local anesthesia and no tourniquet (WALANT) can be performed in an office-based procedure room rather than the operating room. This increases efficiency for the surgeon, reduces the amount of preparation and recovery time for the patient, and helps to keep costs down.

Percutaneous release involves the insertion of a 16-gauge hypodermic needle into the affected A1 pulley. The needle is used to fray and disrupt the pulley by moving the needle tip over the fibrotic A1 pulley.

While NSAIDs are commonly recommended to resolve the local inflammation secondary to triggering, there is no scientific evidence to support their use.

However, it is not without possible complications.²⁷ Inadvertent A2 pulley damage is particularly troublesome, as it leads to “bowstringing” or protrusion of the flexor tendon into the palm upon flexion. This can cause pain and failure to fully extend or flex the finger.¹⁰ Because the anatomy is not well visualized during the percutaneous approach, incomplete release, neurovascular injury, and iatrogenic injury to the A2 pulley or deep tendon may occur.²⁸ Ultrasound-guided percutaneous release techniques have shown effective clinical outcomes with minimal complications compared to nonguided percutaneous release techniques.^29,30

Open release is the gold standard surgical treatment for trigger finger (FIGURE 3). A small incision (1-2 cm) is made directly over or proximal to the A1 pulley in the distal palmar crease at the base of the affected digit. After blunt dissection through the subcutaneous tissue, the A1 pulley is sharply incised. An open approach has the clear benefit of avoiding the digital neurovascular bundles, as well as visualizing the resolution of triggering upon flexion and extension prior to closure. The WALANT procedure has the advantage of allowing the awake patient to actively flex and extend the digit to determine if the A1 release has been successful prior to closure of the incision.

Outcomes and complications of surgery. A recent systematic review and meta-analysis has shown percutaneous techniques to be successful in 94% of cases.²⁷ The success rate of open surgery has been reported at 99% to 100% at varying follow-up intervals up to 1 year.^25,30,31 The complication rate for percutaneous release (guided and nonguided) was calculated at 2.2% (n = 2114).²⁷ In another study, the overall complication rate of open releases was calculated at 1% (n = 999).³² When comparing percutaneous release (guided and nonguided) and open release, a meta-analysis found no significant difference in complication rate (RR = 0.84) or failure rate (RR = 0.94).³²

Continue to: Several risk factors...

Several risk factors have been associated with postoperative surgical infection, including recent steroid injection (< 80 d), smoking status, increasing age, and pre-operative use of lidocaine with epinephrine.³³ Open release has been shown to be an effective and safe treatment modality for patients with and without diabetes alike.³⁴ Overall, definitive surgical correction has been demonstrated to be superior to conservative measures due to a significantly lower rate of recurrence.³⁵

CASE

Given the patient’s presentation with triggering of the digit, tenderness over the A1 pulley, and lack of trauma history, we diagnosed trigger finger in this patient. Potential treatments included splinting, corticosteroid injections, and surgery. After discussion of the risks and benefits of each treatment option, the patient elected to undergo a corticosteroid injection. She was also given a neoprene finger sleeve to wear every night, and in the daytime when possible.

At 12-week follow-up, she noted early improvement in her triggering, which had since recurred. Due to her history of diabetes, the patient was then referred for surgery. She had an open release under local anesthesia. The surgery was uncomplicated, and the abnormality was corrected. At the patient’s 1-year postoperative follow-up visit, there was no evidence of recurrence, and she had regained full active and passive range of motion of her finger.

Acknowledgements
The authors wish to thank Jose Borrero, MD, for contributing his time and creative talents to produce the illustrations in this article.

CORRESPONDENCE
Evan P. Johnson, MD; 506 South Greer Street, Memphis, TN 38111; [email protected]

EVIDENCE SUMMARY

Mixed results, quality issues do not support screening asymptomatic patients

A meta-analysis (12 observational studies; n = 1002) compared the diagnostic accuracy of panoramic radiography (PR) to Doppler ultrasonography (11 studies) or angiography (1 study) in detecting calcified carotid artery atheroma (CCAA).¹ The studies, conducted in 8 countries, were published after 2006. Patients were 29 to 71 years old without history of stroke, endarterectomy, angioplasty, or renal disease. In a pooled analysis, the sensitivity of PR to detect CCAA was 73% (range, 31%-95%; 95% CI, 69%-77%), and the specificity was 72% (range, 19%-99%; 95% CI, 68%-76%). The pooled positive predictive value was 70% (range, 37%-95%; 95% CI, 66%-74%), and negative predictive value was 75% (range, 43%-93%; 95% CI, 71%-79%). Pooled positive likelihood ratio was 2.32 (95% CI, 1.49-3.60) and negative likelihood ratio was 0.40 (95% CI, 0.25-0.63). Seven studies had high risk of patient selection bias, and most had methodologic limitations.

In a retrospective cohort study (n = 778) from the United States, researchers identified carotid artery calcifications on routine dental radiographs in patients ≥ 55 years old and prospectively performed duplex ultrasound (DUS) to assess for significant carotid stenosis (≥ 50%).² Twenty-seven patients (3.5%) had carotid artery calcifications on radiographs, and 20 of those patients underwent DUS of bilateral carotid arteries (40 sides). Of 26 sides with calcifications on radiograph, 13 (50%) had stenosis confirmed with DUS. Of the 14 sides without calcification on radiograph, 3 (21%) had stenosis on DUS. The positive predictive value for calcification on PR predicting significant carotid stenosis was between 40% and 80%.

In a cross-sectional study from Sweden, investigators sought surgical candidates for asymptomatic carotid endarterectomy and performed PRs of 1182 patients.³ Calcifications were found in 176 people; 117 of them were eligible for asymptomatic carotid endarterectomy (ages 18-74; no cancer or other serious comorbidity; and no prior stroke or transient ischemic attack) and underwent ultrasound to assess for significant carotid stenosis (≥ 50%). Of the 117 participants who underwent ultrasound, 8 (6.8%; 95% CI, 2.2%-11.5%), all men, were found to have significant carotid stenosis. Compared to a sex- and age-matched reference group (n = 119) with no calcifications on PR, the prevalence of carotid stenosis was significantly higher in men (12.5%; 95% CI, 4.2%-20.8%) and in patients who were current smokers (19%; 95% CI, 0.7%-37.4%), were taking cholesterol medications (13.1%; 95% CI 4.4%-21.8%), and had a cardiovascular event history (15.9%; 95% CI, 7%-27.2%).

Recommendations from others

The US Preventive Services Task Force ­(USPSTF) and the American Academy of Family Physicians do not mention carotid screening with radiographs but recommend against screening for carotid artery stenosis in asymptomatic adults because the risks of screening outweigh the potential benefits (USPSTF grade D; the harms outweigh the benefits).^4,5

Editor’s takeaway

If you see calcification of the carotid artery on an x-ray of an asymptomatic patient, ignore it. The positive and negative predictive values for carotid stenosis are poor, and you should not pursue further testing.

EVIDENCE SUMMARY

Mixed results, quality issues do not support screening asymptomatic patients

A meta-analysis (12 observational studies; n = 1002) compared the diagnostic accuracy of panoramic radiography (PR) to Doppler ultrasonography (11 studies) or angiography (1 study) in detecting calcified carotid artery atheroma (CCAA).¹ The studies, conducted in 8 countries, were published after 2006. Patients were 29 to 71 years old without history of stroke, endarterectomy, angioplasty, or renal disease. In a pooled analysis, the sensitivity of PR to detect CCAA was 73% (range, 31%-95%; 95% CI, 69%-77%), and the specificity was 72% (range, 19%-99%; 95% CI, 68%-76%). The pooled positive predictive value was 70% (range, 37%-95%; 95% CI, 66%-74%), and negative predictive value was 75% (range, 43%-93%; 95% CI, 71%-79%). Pooled positive likelihood ratio was 2.32 (95% CI, 1.49-3.60) and negative likelihood ratio was 0.40 (95% CI, 0.25-0.63). Seven studies had high risk of patient selection bias, and most had methodologic limitations.

In a retrospective cohort study (n = 778) from the United States, researchers identified carotid artery calcifications on routine dental radiographs in patients ≥ 55 years old and prospectively performed duplex ultrasound (DUS) to assess for significant carotid stenosis (≥ 50%).² Twenty-seven patients (3.5%) had carotid artery calcifications on radiographs, and 20 of those patients underwent DUS of bilateral carotid arteries (40 sides). Of 26 sides with calcifications on radiograph, 13 (50%) had stenosis confirmed with DUS. Of the 14 sides without calcification on radiograph, 3 (21%) had stenosis on DUS. The positive predictive value for calcification on PR predicting significant carotid stenosis was between 40% and 80%.

In a cross-sectional study from Sweden, investigators sought surgical candidates for asymptomatic carotid endarterectomy and performed PRs of 1182 patients.³ Calcifications were found in 176 people; 117 of them were eligible for asymptomatic carotid endarterectomy (ages 18-74; no cancer or other serious comorbidity; and no prior stroke or transient ischemic attack) and underwent ultrasound to assess for significant carotid stenosis (≥ 50%). Of the 117 participants who underwent ultrasound, 8 (6.8%; 95% CI, 2.2%-11.5%), all men, were found to have significant carotid stenosis. Compared to a sex- and age-matched reference group (n = 119) with no calcifications on PR, the prevalence of carotid stenosis was significantly higher in men (12.5%; 95% CI, 4.2%-20.8%) and in patients who were current smokers (19%; 95% CI, 0.7%-37.4%), were taking cholesterol medications (13.1%; 95% CI 4.4%-21.8%), and had a cardiovascular event history (15.9%; 95% CI, 7%-27.2%).

Recommendations from others

The US Preventive Services Task Force ­(USPSTF) and the American Academy of Family Physicians do not mention carotid screening with radiographs but recommend against screening for carotid artery stenosis in asymptomatic adults because the risks of screening outweigh the potential benefits (USPSTF grade D; the harms outweigh the benefits).^4,5

Editor’s takeaway

If you see calcification of the carotid artery on an x-ray of an asymptomatic patient, ignore it. The positive and negative predictive values for carotid stenosis are poor, and you should not pursue further testing.

EVIDENCE SUMMARY

Mixed results, quality issues do not support screening asymptomatic patients

A meta-analysis (12 observational studies; n = 1002) compared the diagnostic accuracy of panoramic radiography (PR) to Doppler ultrasonography (11 studies) or angiography (1 study) in detecting calcified carotid artery atheroma (CCAA).¹ The studies, conducted in 8 countries, were published after 2006. Patients were 29 to 71 years old without history of stroke, endarterectomy, angioplasty, or renal disease. In a pooled analysis, the sensitivity of PR to detect CCAA was 73% (range, 31%-95%; 95% CI, 69%-77%), and the specificity was 72% (range, 19%-99%; 95% CI, 68%-76%). The pooled positive predictive value was 70% (range, 37%-95%; 95% CI, 66%-74%), and negative predictive value was 75% (range, 43%-93%; 95% CI, 71%-79%). Pooled positive likelihood ratio was 2.32 (95% CI, 1.49-3.60) and negative likelihood ratio was 0.40 (95% CI, 0.25-0.63). Seven studies had high risk of patient selection bias, and most had methodologic limitations.

In a retrospective cohort study (n = 778) from the United States, researchers identified carotid artery calcifications on routine dental radiographs in patients ≥ 55 years old and prospectively performed duplex ultrasound (DUS) to assess for significant carotid stenosis (≥ 50%).² Twenty-seven patients (3.5%) had carotid artery calcifications on radiographs, and 20 of those patients underwent DUS of bilateral carotid arteries (40 sides). Of 26 sides with calcifications on radiograph, 13 (50%) had stenosis confirmed with DUS. Of the 14 sides without calcification on radiograph, 3 (21%) had stenosis on DUS. The positive predictive value for calcification on PR predicting significant carotid stenosis was between 40% and 80%.

In a cross-sectional study from Sweden, investigators sought surgical candidates for asymptomatic carotid endarterectomy and performed PRs of 1182 patients.³ Calcifications were found in 176 people; 117 of them were eligible for asymptomatic carotid endarterectomy (ages 18-74; no cancer or other serious comorbidity; and no prior stroke or transient ischemic attack) and underwent ultrasound to assess for significant carotid stenosis (≥ 50%). Of the 117 participants who underwent ultrasound, 8 (6.8%; 95% CI, 2.2%-11.5%), all men, were found to have significant carotid stenosis. Compared to a sex- and age-matched reference group (n = 119) with no calcifications on PR, the prevalence of carotid stenosis was significantly higher in men (12.5%; 95% CI, 4.2%-20.8%) and in patients who were current smokers (19%; 95% CI, 0.7%-37.4%), were taking cholesterol medications (13.1%; 95% CI 4.4%-21.8%), and had a cardiovascular event history (15.9%; 95% CI, 7%-27.2%).

Recommendations from others

The US Preventive Services Task Force ­(USPSTF) and the American Academy of Family Physicians do not mention carotid screening with radiographs but recommend against screening for carotid artery stenosis in asymptomatic adults because the risks of screening outweigh the potential benefits (USPSTF grade D; the harms outweigh the benefits).^4,5

Editor’s takeaway

If you see calcification of the carotid artery on an x-ray of an asymptomatic patient, ignore it. The positive and negative predictive values for carotid stenosis are poor, and you should not pursue further testing.

The Food and Drug Administration today gave the nod to topical ruxolitinib cream for the treatment of non-immunocompromised patients with mild to moderate atopic dermatitis ages 12 years and older, making it the first topical JAK inhibitor approved for AD – and the first JAK inhibitor approved for this indication – in the United States.

The approval is limited to patients whose AD is not adequately controlled with topical prescription therapies, or when those therapies are not advisable.

“Approval of topical ruxolitinib fills a major gap in the treatment of atopic dermatitis: a safe, effective, and tolerable non-steroidal topical therapy,” Eric L. Simpson, MD, professor of dermatology and director of the Oregon Health & Science University Dermatology Clinical Research Center, Portland, told this news organization. “This approval will allow for long-term treatment without the concern of steroid side effects. From earlier studies, ruxolitinib cream appears to be as effective as a medium-potency topical steroid. These efficacy levels and low incidence of burning will be a welcome addition to our current nonsteroidal therapies.”

The drug’s approval was based on results from two phase 3, randomized studies of identical design involving 1,249 patients aged 12 years and older with AD: TRuE-AD1 and TRuE-AD2. In these studies, ruxolitinib cream demonstrated anti-inflammatory activity, with rapid and sustained antipruritic action, compared with vehicle. In the trials, patients with an Investigator’s Global Assessment (IGA) score of 2 or 3 and 3%-20% of affected body surface area (BSA) were randomized (2:2:1) to twice-daily 0.75% ruxolitinib cream, 1.5% ruxolitinib cream, or vehicle cream for 8 continuous weeks. The 1.5% concentration was approved by the FDA.

A study first published in May of 2021 found that significantly more patients in TRuE-AD1 and TRuE-AD2 achieved IGA treatment success with 0.75% (50% vs. 39%, respectively) and 1.5% ruxolitinib cream (53.8% vs. 51.3%), compared with vehicle (15.1% vs. 7.6%; P < .0001) at week 8. In addition, significant reductions in itch, compared with vehicle, were reported within 12 hours of first applying 1.5% ruxolitinib cream (P < .05).

More key findings from TRuE-AD1 and TRuE-AD2 are scheduled to be presented during the upcoming European Academy of Dermatology and Venereology meeting Sept. 29-Oct. 2, but during the Revolutionizing Atopic Dermatitis Symposium on June 13, Kim Papp, MD, PhD, presented long-term safety data of ruxolitinib cream in patients who were followed for an additional 44 weeks. Dr. Papp, a dermatologist and founder of Probity Medical Research, Waterloo, Ont., reported that 543 patients from TRuE-AD1 and 530 from TRuE-AD2 entered the long-term analysis and that about 78% of these patients completed the study. From weeks 12 to 52, the proportion of patients with an IGA score of 0 or 1 with 0.75% and 1.5% ruxolitinib cream ranged from 62%-77% and 67%-77%, respectively, in TRuE-AD1, to 60%-77% and 72%-80% in TRuE-AD2.

The measured mean total affected BSA was less than 3% throughout the follow-up period in the 1.5% ruxolitinib cream arm in TRuE-AD1 and TRuE-AD2 and was less than 3% in the 0.75% ruxolitinib cream arm during most of the study period.

In a pooled safety analysis, treatment-emergent adverse events (TEAEs) were reported in 60% and 54% of patients who applied 0.75% and 1.5% ruxolitinib cream, respectively, over 44 weeks. The frequency of application-site reactions remained low. Specifically, treatment-related adverse events were reported in 5% of patients who applied 0.75% ruxolitinib cream and in 3% of patients who applied 1.5% ruxolitinib cream; none were serious. TEAEs led to discontinuation in 2% of patients in the 0.75% ruxolitinib cream group, and no patients in the 1.5% ruxolitinib cream group.

Dr. Papp and his colleagues observed that the most common treatment adverse events were upper respiratory tract infections and nasopharyngitis. According to Incyte’s press release, the most common treatment-emergent adverse reactions in patients treated with ruxolitinib during clinical trials were nasopharyngitis, diarrhea, bronchitis, ear infection, eosinophil count increases, urticaria, folliculitis, tonsillitis, and rhinorrhea. The labeling includes boxed warnings for serious infections, mortality, malignancy, major adverse cardiovascular events, and thrombosis, seen with oral JAK inhibitors for inflammatory conditions.

Incyte will market ruxolitinib under the trade name Opzelura.

Dr. Simpson disclosed that he is a consultant to and/or an investigator for several pharmaceutical companies, including Incyte, Regeneron/Sanofi, Eli Lilly and Company, AbbVie, and Pfizer.

Dr. Papp disclosed that he has received honoraria or clinical research grants as a consultant, speaker, scientific officer, advisory board member, and/or steering committee member for several pharmaceutical companies, including Incyte.

Commentary by Robert Sidbury, MD, MPH

Another nonsteroidal topical medication approved for atopic dermatitis (AD)? Thank goodness. Topical ruxolitinib 1.5% cream twice daily for mild to moderate AD demonstrated excellent efficacy vs. placebo in duplicative trials (53.8/51.3% vs. 15.1%/7.6%; P < .001), with a reassuring safety profile. Application site reactions were uncommon, though past experience with other new nonsteroidal agents suggests judgment be reserved on that score. More compelling was the fact that no patients discontinued therapy in the 1.5% arm, and adverse events were mild and self-limited such as nasopharyngitis and diarrhea. This stands in contradistinction to the boxed warning attached to JAK inhibitors (topical and systemic) against a daunting list of destructive possibilities: malignancy, infection, cardiovascular disease, and blood clots. None of these things was seen in these topical ruxolitinib trials.

Dr. Sidbury is chief of dermatology at Seattle Children's Hospital and professor, department of pediatrics, University of Washington, Seattle. He is a site principal investigator for dupilumab trials, for which the hospital has a contract with Regeneron.

This article was updated 6/16/22.

The Food and Drug Administration today gave the nod to topical ruxolitinib cream for the treatment of non-immunocompromised patients with mild to moderate atopic dermatitis ages 12 years and older, making it the first topical JAK inhibitor approved for AD – and the first JAK inhibitor approved for this indication – in the United States.

The approval is limited to patients whose AD is not adequately controlled with topical prescription therapies, or when those therapies are not advisable.

“Approval of topical ruxolitinib fills a major gap in the treatment of atopic dermatitis: a safe, effective, and tolerable non-steroidal topical therapy,” Eric L. Simpson, MD, professor of dermatology and director of the Oregon Health & Science University Dermatology Clinical Research Center, Portland, told this news organization. “This approval will allow for long-term treatment without the concern of steroid side effects. From earlier studies, ruxolitinib cream appears to be as effective as a medium-potency topical steroid. These efficacy levels and low incidence of burning will be a welcome addition to our current nonsteroidal therapies.”

The drug’s approval was based on results from two phase 3, randomized studies of identical design involving 1,249 patients aged 12 years and older with AD: TRuE-AD1 and TRuE-AD2. In these studies, ruxolitinib cream demonstrated anti-inflammatory activity, with rapid and sustained antipruritic action, compared with vehicle. In the trials, patients with an Investigator’s Global Assessment (IGA) score of 2 or 3 and 3%-20% of affected body surface area (BSA) were randomized (2:2:1) to twice-daily 0.75% ruxolitinib cream, 1.5% ruxolitinib cream, or vehicle cream for 8 continuous weeks. The 1.5% concentration was approved by the FDA.

A study first published in May of 2021 found that significantly more patients in TRuE-AD1 and TRuE-AD2 achieved IGA treatment success with 0.75% (50% vs. 39%, respectively) and 1.5% ruxolitinib cream (53.8% vs. 51.3%), compared with vehicle (15.1% vs. 7.6%; P < .0001) at week 8. In addition, significant reductions in itch, compared with vehicle, were reported within 12 hours of first applying 1.5% ruxolitinib cream (P < .05).

More key findings from TRuE-AD1 and TRuE-AD2 are scheduled to be presented during the upcoming European Academy of Dermatology and Venereology meeting Sept. 29-Oct. 2, but during the Revolutionizing Atopic Dermatitis Symposium on June 13, Kim Papp, MD, PhD, presented long-term safety data of ruxolitinib cream in patients who were followed for an additional 44 weeks. Dr. Papp, a dermatologist and founder of Probity Medical Research, Waterloo, Ont., reported that 543 patients from TRuE-AD1 and 530 from TRuE-AD2 entered the long-term analysis and that about 78% of these patients completed the study. From weeks 12 to 52, the proportion of patients with an IGA score of 0 or 1 with 0.75% and 1.5% ruxolitinib cream ranged from 62%-77% and 67%-77%, respectively, in TRuE-AD1, to 60%-77% and 72%-80% in TRuE-AD2.

The measured mean total affected BSA was less than 3% throughout the follow-up period in the 1.5% ruxolitinib cream arm in TRuE-AD1 and TRuE-AD2 and was less than 3% in the 0.75% ruxolitinib cream arm during most of the study period.

In a pooled safety analysis, treatment-emergent adverse events (TEAEs) were reported in 60% and 54% of patients who applied 0.75% and 1.5% ruxolitinib cream, respectively, over 44 weeks. The frequency of application-site reactions remained low. Specifically, treatment-related adverse events were reported in 5% of patients who applied 0.75% ruxolitinib cream and in 3% of patients who applied 1.5% ruxolitinib cream; none were serious. TEAEs led to discontinuation in 2% of patients in the 0.75% ruxolitinib cream group, and no patients in the 1.5% ruxolitinib cream group.

Dr. Papp and his colleagues observed that the most common treatment adverse events were upper respiratory tract infections and nasopharyngitis. According to Incyte’s press release, the most common treatment-emergent adverse reactions in patients treated with ruxolitinib during clinical trials were nasopharyngitis, diarrhea, bronchitis, ear infection, eosinophil count increases, urticaria, folliculitis, tonsillitis, and rhinorrhea. The labeling includes boxed warnings for serious infections, mortality, malignancy, major adverse cardiovascular events, and thrombosis, seen with oral JAK inhibitors for inflammatory conditions.

Incyte will market ruxolitinib under the trade name Opzelura.

Dr. Simpson disclosed that he is a consultant to and/or an investigator for several pharmaceutical companies, including Incyte, Regeneron/Sanofi, Eli Lilly and Company, AbbVie, and Pfizer.

Dr. Papp disclosed that he has received honoraria or clinical research grants as a consultant, speaker, scientific officer, advisory board member, and/or steering committee member for several pharmaceutical companies, including Incyte.

Commentary by Robert Sidbury, MD, MPH

Another nonsteroidal topical medication approved for atopic dermatitis (AD)? Thank goodness. Topical ruxolitinib 1.5% cream twice daily for mild to moderate AD demonstrated excellent efficacy vs. placebo in duplicative trials (53.8/51.3% vs. 15.1%/7.6%; P < .001), with a reassuring safety profile. Application site reactions were uncommon, though past experience with other new nonsteroidal agents suggests judgment be reserved on that score. More compelling was the fact that no patients discontinued therapy in the 1.5% arm, and adverse events were mild and self-limited such as nasopharyngitis and diarrhea. This stands in contradistinction to the boxed warning attached to JAK inhibitors (topical and systemic) against a daunting list of destructive possibilities: malignancy, infection, cardiovascular disease, and blood clots. None of these things was seen in these topical ruxolitinib trials.

Dr. Sidbury is chief of dermatology at Seattle Children's Hospital and professor, department of pediatrics, University of Washington, Seattle. He is a site principal investigator for dupilumab trials, for which the hospital has a contract with Regeneron.

This article was updated 6/16/22.

The Food and Drug Administration today gave the nod to topical ruxolitinib cream for the treatment of non-immunocompromised patients with mild to moderate atopic dermatitis ages 12 years and older, making it the first topical JAK inhibitor approved for AD – and the first JAK inhibitor approved for this indication – in the United States.

The approval is limited to patients whose AD is not adequately controlled with topical prescription therapies, or when those therapies are not advisable.

“Approval of topical ruxolitinib fills a major gap in the treatment of atopic dermatitis: a safe, effective, and tolerable non-steroidal topical therapy,” Eric L. Simpson, MD, professor of dermatology and director of the Oregon Health & Science University Dermatology Clinical Research Center, Portland, told this news organization. “This approval will allow for long-term treatment without the concern of steroid side effects. From earlier studies, ruxolitinib cream appears to be as effective as a medium-potency topical steroid. These efficacy levels and low incidence of burning will be a welcome addition to our current nonsteroidal therapies.”

The drug’s approval was based on results from two phase 3, randomized studies of identical design involving 1,249 patients aged 12 years and older with AD: TRuE-AD1 and TRuE-AD2. In these studies, ruxolitinib cream demonstrated anti-inflammatory activity, with rapid and sustained antipruritic action, compared with vehicle. In the trials, patients with an Investigator’s Global Assessment (IGA) score of 2 or 3 and 3%-20% of affected body surface area (BSA) were randomized (2:2:1) to twice-daily 0.75% ruxolitinib cream, 1.5% ruxolitinib cream, or vehicle cream for 8 continuous weeks. The 1.5% concentration was approved by the FDA.

A study first published in May of 2021 found that significantly more patients in TRuE-AD1 and TRuE-AD2 achieved IGA treatment success with 0.75% (50% vs. 39%, respectively) and 1.5% ruxolitinib cream (53.8% vs. 51.3%), compared with vehicle (15.1% vs. 7.6%; P < .0001) at week 8. In addition, significant reductions in itch, compared with vehicle, were reported within 12 hours of first applying 1.5% ruxolitinib cream (P < .05).

More key findings from TRuE-AD1 and TRuE-AD2 are scheduled to be presented during the upcoming European Academy of Dermatology and Venereology meeting Sept. 29-Oct. 2, but during the Revolutionizing Atopic Dermatitis Symposium on June 13, Kim Papp, MD, PhD, presented long-term safety data of ruxolitinib cream in patients who were followed for an additional 44 weeks. Dr. Papp, a dermatologist and founder of Probity Medical Research, Waterloo, Ont., reported that 543 patients from TRuE-AD1 and 530 from TRuE-AD2 entered the long-term analysis and that about 78% of these patients completed the study. From weeks 12 to 52, the proportion of patients with an IGA score of 0 or 1 with 0.75% and 1.5% ruxolitinib cream ranged from 62%-77% and 67%-77%, respectively, in TRuE-AD1, to 60%-77% and 72%-80% in TRuE-AD2.

The measured mean total affected BSA was less than 3% throughout the follow-up period in the 1.5% ruxolitinib cream arm in TRuE-AD1 and TRuE-AD2 and was less than 3% in the 0.75% ruxolitinib cream arm during most of the study period.

In a pooled safety analysis, treatment-emergent adverse events (TEAEs) were reported in 60% and 54% of patients who applied 0.75% and 1.5% ruxolitinib cream, respectively, over 44 weeks. The frequency of application-site reactions remained low. Specifically, treatment-related adverse events were reported in 5% of patients who applied 0.75% ruxolitinib cream and in 3% of patients who applied 1.5% ruxolitinib cream; none were serious. TEAEs led to discontinuation in 2% of patients in the 0.75% ruxolitinib cream group, and no patients in the 1.5% ruxolitinib cream group.

Dr. Papp and his colleagues observed that the most common treatment adverse events were upper respiratory tract infections and nasopharyngitis. According to Incyte’s press release, the most common treatment-emergent adverse reactions in patients treated with ruxolitinib during clinical trials were nasopharyngitis, diarrhea, bronchitis, ear infection, eosinophil count increases, urticaria, folliculitis, tonsillitis, and rhinorrhea. The labeling includes boxed warnings for serious infections, mortality, malignancy, major adverse cardiovascular events, and thrombosis, seen with oral JAK inhibitors for inflammatory conditions.

Incyte will market ruxolitinib under the trade name Opzelura.

Dr. Simpson disclosed that he is a consultant to and/or an investigator for several pharmaceutical companies, including Incyte, Regeneron/Sanofi, Eli Lilly and Company, AbbVie, and Pfizer.

Dr. Papp disclosed that he has received honoraria or clinical research grants as a consultant, speaker, scientific officer, advisory board member, and/or steering committee member for several pharmaceutical companies, including Incyte.

Commentary by Robert Sidbury, MD, MPH

Another nonsteroidal topical medication approved for atopic dermatitis (AD)? Thank goodness. Topical ruxolitinib 1.5% cream twice daily for mild to moderate AD demonstrated excellent efficacy vs. placebo in duplicative trials (53.8/51.3% vs. 15.1%/7.6%; P < .001), with a reassuring safety profile. Application site reactions were uncommon, though past experience with other new nonsteroidal agents suggests judgment be reserved on that score. More compelling was the fact that no patients discontinued therapy in the 1.5% arm, and adverse events were mild and self-limited such as nasopharyngitis and diarrhea. This stands in contradistinction to the boxed warning attached to JAK inhibitors (topical and systemic) against a daunting list of destructive possibilities: malignancy, infection, cardiovascular disease, and blood clots. None of these things was seen in these topical ruxolitinib trials.

Dr. Sidbury is chief of dermatology at Seattle Children's Hospital and professor, department of pediatrics, University of Washington, Seattle. He is a site principal investigator for dupilumab trials, for which the hospital has a contract with Regeneron.

This article was updated 6/16/22.

The Supreme Court will hear arguments in a major Mississippi abortion case on Dec. 1, which could challenge the landmark Roe v. Wade decision that guarantees a woman’s right to an abortion.

On Sept. 20, the court issued its calendar for arguments that will be heard in late November and early December, The Associated Press reported.

The Mississippi case, Dobbs v. Jackson Women’s Health Organization, is seeking to overturn Roe v. Wade by asking the Supreme Court to uphold a ban on most abortions after the 15th week of pregnancy. The state also said the court should overrule the 1992 decision in Planned Parenthood v. Casey that prevents states from banning abortion before viability, which is around 24 weeks of pregnancy.

Earlier in September, the Supreme Court allowed a Texas law to take effect that bans abortions after cardiac activity can be detected, which is around 6 weeks of pregnancy and often before many women know they’re pregnant. The court, which was split 5-4, didn’t rule on the constitutional nature of the law, instead declining to block its enforcement.

Hundreds of legal briefs have been filed on both sides of the case, the AP reported. On Sept. 20, more than 500 women athletes, including members of the Women’s National Basketball Players Association, the National Women’s Soccer League Players Association, and Olympic medalists, filed a brief that said an abortion ban would be devastating for female athletes.

The Mississippi law was enacted in 2018 but was blocked after a challenge at the federal court level. The state’s only abortion clinic, Jackson Women’s Health Organization, remains open and offers abortions up to 16 weeks of pregnancy, the AP reported. About 100 abortions a year are completed after 15 weeks, the organization said.

More than 90% of abortions in the United States occur in the first 13 weeks of pregnancy, the AP said.

The Supreme Court justices will return to the courtroom in October to hear arguments now that all of them have been vaccinated, the AP reported. The justices had been hearing cases by phone during the pandemic.

The public won’t be able to attend sessions, but the court will allow live audio of the session. 

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

The Supreme Court will hear arguments in a major Mississippi abortion case on Dec. 1, which could challenge the landmark Roe v. Wade decision that guarantees a woman’s right to an abortion.

On Sept. 20, the court issued its calendar for arguments that will be heard in late November and early December, The Associated Press reported.

The Mississippi case, Dobbs v. Jackson Women’s Health Organization, is seeking to overturn Roe v. Wade by asking the Supreme Court to uphold a ban on most abortions after the 15th week of pregnancy. The state also said the court should overrule the 1992 decision in Planned Parenthood v. Casey that prevents states from banning abortion before viability, which is around 24 weeks of pregnancy.

Earlier in September, the Supreme Court allowed a Texas law to take effect that bans abortions after cardiac activity can be detected, which is around 6 weeks of pregnancy and often before many women know they’re pregnant. The court, which was split 5-4, didn’t rule on the constitutional nature of the law, instead declining to block its enforcement.

Hundreds of legal briefs have been filed on both sides of the case, the AP reported. On Sept. 20, more than 500 women athletes, including members of the Women’s National Basketball Players Association, the National Women’s Soccer League Players Association, and Olympic medalists, filed a brief that said an abortion ban would be devastating for female athletes.

The Mississippi law was enacted in 2018 but was blocked after a challenge at the federal court level. The state’s only abortion clinic, Jackson Women’s Health Organization, remains open and offers abortions up to 16 weeks of pregnancy, the AP reported. About 100 abortions a year are completed after 15 weeks, the organization said.

More than 90% of abortions in the United States occur in the first 13 weeks of pregnancy, the AP said.

The Supreme Court justices will return to the courtroom in October to hear arguments now that all of them have been vaccinated, the AP reported. The justices had been hearing cases by phone during the pandemic.

The public won’t be able to attend sessions, but the court will allow live audio of the session. 

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

The Supreme Court will hear arguments in a major Mississippi abortion case on Dec. 1, which could challenge the landmark Roe v. Wade decision that guarantees a woman’s right to an abortion.

On Sept. 20, the court issued its calendar for arguments that will be heard in late November and early December, The Associated Press reported.

The Mississippi case, Dobbs v. Jackson Women’s Health Organization, is seeking to overturn Roe v. Wade by asking the Supreme Court to uphold a ban on most abortions after the 15th week of pregnancy. The state also said the court should overrule the 1992 decision in Planned Parenthood v. Casey that prevents states from banning abortion before viability, which is around 24 weeks of pregnancy.

Earlier in September, the Supreme Court allowed a Texas law to take effect that bans abortions after cardiac activity can be detected, which is around 6 weeks of pregnancy and often before many women know they’re pregnant. The court, which was split 5-4, didn’t rule on the constitutional nature of the law, instead declining to block its enforcement.

Hundreds of legal briefs have been filed on both sides of the case, the AP reported. On Sept. 20, more than 500 women athletes, including members of the Women’s National Basketball Players Association, the National Women’s Soccer League Players Association, and Olympic medalists, filed a brief that said an abortion ban would be devastating for female athletes.

The Mississippi law was enacted in 2018 but was blocked after a challenge at the federal court level. The state’s only abortion clinic, Jackson Women’s Health Organization, remains open and offers abortions up to 16 weeks of pregnancy, the AP reported. About 100 abortions a year are completed after 15 weeks, the organization said.

More than 90% of abortions in the United States occur in the first 13 weeks of pregnancy, the AP said.

The Supreme Court justices will return to the courtroom in October to hear arguments now that all of them have been vaccinated, the AP reported. The justices had been hearing cases by phone during the pandemic.

The public won’t be able to attend sessions, but the court will allow live audio of the session. 

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