CHICAGO – A smartphone app that delivers nutritional cognitive behavioral therapy (CBT) to people with type 2 diabetes produced an average 0.29 percentage point drop in hemoglobin A1c during 180 days of use compared with controls, and an average 0.37 percentage point reduction in A1c compared with baseline values in a randomized, pivotal trial with 669 adults.

Use of the app for 180 days also significantly linked with a reduced need for additional medications, reduced weight and blood pressure, and improved patient-reported outcomes, and it led to fewer adverse effects than seen in control subjects, Marc P. Bonaca, MD, reported at the American Heart Association scientific sessions.

Mitchel L. Zoler/MDedge News

The findings also showed a clear dose-response relationship: The more CBT lessons a person completed with the app, the greater the A1c reduction.

The results suggest that the app, called BT-001, “potentially provides a scalable treatment option for patients with type 2 diabetes,” concluded Dr. Bonaca.

On the basis of the results from this trial, also called BT-001, the company developing the app, Better Therapeutics, announced in September 2022 that it had filed a classification request with the Food and Drug Administration that would allow marketing authorization for the BT-001 app. Better Therapeutics envisions that once authorized by the FDA, the app would be available to people with type 2 diabetes by prescriptions written by health care providers and that the cost for the app would be covered by health insurance, explained a company spokesperson.
 

A ‘modest positive impact’

“CBT is an empirically supported psychotherapy for a variety of emotional disorders, and it has been adapted to target specific emotional distress in the context of chronic illness,” said Amit Shapira, PhD, a clinical psychologist at the Joslin Diabetes Center in Boston who has not been involved in the BT-001 studies. A CBT protocol designed for diabetes, CBT for Adherence and Depression, “has been shown to have a positive impact on depression symptoms and glycemic control in adults with type 2 diabetes,” Dr. Shapira said in an interview.

Based on published results, the BT-001 app “seems to have a modest positive impact on glycemic control, especially among people who completed more than 10 [lesson] modules.” The evidence appears to suggest that the app “might be a good supplement to working with a behavioral health counselor.”

The BT-001 trial enrolled 669 adults with type 2 diabetes for an average of 11 years and an A1c of 7%-10.9% with an average level of 8.2%. Participants had to be on a stable medication regimen for at least 3 months but not using insulin, and their treatment regimens could undergo adjustment during the trial. At baseline, each subject was on an average of 2.1 antidiabetes medications, including 90% on metformin and 42% on a sulfonylurea. The researchers also highlighted that the enrolled cohort of people with type 2 diabetes had a demographic profile that was “generally representative” of U.S. adults with type 2 diabetes.

The researchers told the 326 people who were randomized to the active intervention group to use the app but subjects were free to determine their frequency of use. The app introduced a new lesson module weekly that took 10-20 minutes to complete, and each weekly lesson came with associated exercises aimed at practicing skills related to behavioral beliefs.

The study’s primary efficacy endpoint was the average change from baseline in A1c compared with the 343 control participants after 90 days of app use, and 610 of the 669 enrolled participants (91%) had paired baseline and 90-day measurements. At 90 days, people in the app group had an average 0.28 percentage point decrease in their A1c compared with an average 0.11 percentage point increase among the controls, a between-group difference of 0.39 percentage points. Both the reduction from baseline with app use and the reduction relative to the controls were significant. These results appeared in an article published online in in Diabetes Care.

At the scientific sessions, Dr. Bonaca presented additional outcome data after 180 days of app use. He reported an average 0.37 percentage point reduction from baseline in A1c among app users and a 0.08 percentage point decrease from baseline among the controls, for a net 0.29 percentage point incremental decline with the app, a significant difference. At 180 days, 50% of the people in the app group had an A1c decline from baseline of at least 0.4 percentage points compared with 34% of the controls, a significant difference.


 

A dose-response relationship

Notably, app use showed a clear dose-response pattern. During 180 days of app availability, people who used the app fewer than 10 times had an average reduction from baseline in their A1c of less than 0.1 percentage points. Among those who used the app 10-20 times (a subgroup with roughly one-third of the people randomized to app use) average A1c reduction increased to about 0.4 percentage points, and among those who used the app more than 20 times, also one-third of the intervention group, the average A1c reduction from baseline was about 0.6 percentage points.

“It would be interesting to learn more about the adults who engaged with the app” and had a higher use rate “to provide more targeted care” with the app to people who match the profiles of those who were more likely to use the app during the trial, said Dr. Shapira.

Dr. Bonaca, a cardiologist and vascular medicine specialist and executive director of CPC Clinical Research and CPC Community Health, an academic research organization created by and affiliated with the University of Colorado Anschutz Medical Campus in Aurora, Colo., reported several other 180-day outcomes in the BT-001 trial:

• A 33% relative decrease in the percentage of subjects who needed during the study an additional antidiabetes medication or increased dosages of their baseline medications, which occurred at a rate of 21% among the controls and 14% among those who used the app.
• An average weight loss from baseline of 5.5 pounds using the app compared with an average 1.9 pound decrease among controls, a significant difference.
• A decline in average systolic blood pressure of 4.7 mm Hg with app use compared with a 1.8 mm Hg average decline among the controls, a significant difference.
• Significant incremental average improvements in a self-reported Short Form-12 physical component score with the app compared with controls, and increased average improvement in the PHQ9 self-reported measure of depression in app users compared with controls.
• Significantly fewer treatment-emergent adverse effects, and significantly fewer serious treatment-emergent adverse effects among the app users compared with the controls.

‘Ready for clinical use’

Based on these findings, “in my view the app is ready for [routine] clinical use,” declared Judith Hsia, MD, a cardiologist and professor of medicine at the University of Colorado in Aurora, and with Dr. Bonaca a co-lead investigator for the study.

The BT-001 app can serve as “an addition to the toolkit of diabetes treatments,” Dr. Hsia said in an interview. One key advantage of the app is that, once approved, it could be available to many more people with type 2 diabetes than would be able to receive CBT directly from a therapist. Another potential plus for the CBT app is that “the effects should be durable in contrast to medications,” which must be taken on an ongoing basis to maintain effectiveness. In addition, the safety profile “is favorable compared with drug therapies, which should appeal to health care providers,” said Dr. Hsia, chief science officer for CPC Clinical Research.

However, Dr. Shapira cited the issue that therapeutic apps “raise privacy and licensing liability concerns.”

The BT-001 trial was sponsored by Better Therapeutics, the company developing the app. CPC Clinical Research receives research and consulting funding from numerous companies. Dr. Bonaca has been a consultant to Audentes, and is a stockholder of Medtronic and Pfizer. Dr. Shapira had no disclosures. Dr. Hsia is a stockholder of AstraZeneca.

CHICAGO – A smartphone app that delivers nutritional cognitive behavioral therapy (CBT) to people with type 2 diabetes produced an average 0.29 percentage point drop in hemoglobin A1c during 180 days of use compared with controls, and an average 0.37 percentage point reduction in A1c compared with baseline values in a randomized, pivotal trial with 669 adults.

Use of the app for 180 days also significantly linked with a reduced need for additional medications, reduced weight and blood pressure, and improved patient-reported outcomes, and it led to fewer adverse effects than seen in control subjects, Marc P. Bonaca, MD, reported at the American Heart Association scientific sessions.

Mitchel L. Zoler/MDedge News

The findings also showed a clear dose-response relationship: The more CBT lessons a person completed with the app, the greater the A1c reduction.

The results suggest that the app, called BT-001, “potentially provides a scalable treatment option for patients with type 2 diabetes,” concluded Dr. Bonaca.

On the basis of the results from this trial, also called BT-001, the company developing the app, Better Therapeutics, announced in September 2022 that it had filed a classification request with the Food and Drug Administration that would allow marketing authorization for the BT-001 app. Better Therapeutics envisions that once authorized by the FDA, the app would be available to people with type 2 diabetes by prescriptions written by health care providers and that the cost for the app would be covered by health insurance, explained a company spokesperson.
 

A ‘modest positive impact’

“CBT is an empirically supported psychotherapy for a variety of emotional disorders, and it has been adapted to target specific emotional distress in the context of chronic illness,” said Amit Shapira, PhD, a clinical psychologist at the Joslin Diabetes Center in Boston who has not been involved in the BT-001 studies. A CBT protocol designed for diabetes, CBT for Adherence and Depression, “has been shown to have a positive impact on depression symptoms and glycemic control in adults with type 2 diabetes,” Dr. Shapira said in an interview.

Based on published results, the BT-001 app “seems to have a modest positive impact on glycemic control, especially among people who completed more than 10 [lesson] modules.” The evidence appears to suggest that the app “might be a good supplement to working with a behavioral health counselor.”

The BT-001 trial enrolled 669 adults with type 2 diabetes for an average of 11 years and an A1c of 7%-10.9% with an average level of 8.2%. Participants had to be on a stable medication regimen for at least 3 months but not using insulin, and their treatment regimens could undergo adjustment during the trial. At baseline, each subject was on an average of 2.1 antidiabetes medications, including 90% on metformin and 42% on a sulfonylurea. The researchers also highlighted that the enrolled cohort of people with type 2 diabetes had a demographic profile that was “generally representative” of U.S. adults with type 2 diabetes.

The researchers told the 326 people who were randomized to the active intervention group to use the app but subjects were free to determine their frequency of use. The app introduced a new lesson module weekly that took 10-20 minutes to complete, and each weekly lesson came with associated exercises aimed at practicing skills related to behavioral beliefs.

The study’s primary efficacy endpoint was the average change from baseline in A1c compared with the 343 control participants after 90 days of app use, and 610 of the 669 enrolled participants (91%) had paired baseline and 90-day measurements. At 90 days, people in the app group had an average 0.28 percentage point decrease in their A1c compared with an average 0.11 percentage point increase among the controls, a between-group difference of 0.39 percentage points. Both the reduction from baseline with app use and the reduction relative to the controls were significant. These results appeared in an article published online in in Diabetes Care.

At the scientific sessions, Dr. Bonaca presented additional outcome data after 180 days of app use. He reported an average 0.37 percentage point reduction from baseline in A1c among app users and a 0.08 percentage point decrease from baseline among the controls, for a net 0.29 percentage point incremental decline with the app, a significant difference. At 180 days, 50% of the people in the app group had an A1c decline from baseline of at least 0.4 percentage points compared with 34% of the controls, a significant difference.


 

A dose-response relationship

Notably, app use showed a clear dose-response pattern. During 180 days of app availability, people who used the app fewer than 10 times had an average reduction from baseline in their A1c of less than 0.1 percentage points. Among those who used the app 10-20 times (a subgroup with roughly one-third of the people randomized to app use) average A1c reduction increased to about 0.4 percentage points, and among those who used the app more than 20 times, also one-third of the intervention group, the average A1c reduction from baseline was about 0.6 percentage points.

“It would be interesting to learn more about the adults who engaged with the app” and had a higher use rate “to provide more targeted care” with the app to people who match the profiles of those who were more likely to use the app during the trial, said Dr. Shapira.

Dr. Bonaca, a cardiologist and vascular medicine specialist and executive director of CPC Clinical Research and CPC Community Health, an academic research organization created by and affiliated with the University of Colorado Anschutz Medical Campus in Aurora, Colo., reported several other 180-day outcomes in the BT-001 trial:

• A 33% relative decrease in the percentage of subjects who needed during the study an additional antidiabetes medication or increased dosages of their baseline medications, which occurred at a rate of 21% among the controls and 14% among those who used the app.
• An average weight loss from baseline of 5.5 pounds using the app compared with an average 1.9 pound decrease among controls, a significant difference.
• A decline in average systolic blood pressure of 4.7 mm Hg with app use compared with a 1.8 mm Hg average decline among the controls, a significant difference.
• Significant incremental average improvements in a self-reported Short Form-12 physical component score with the app compared with controls, and increased average improvement in the PHQ9 self-reported measure of depression in app users compared with controls.
• Significantly fewer treatment-emergent adverse effects, and significantly fewer serious treatment-emergent adverse effects among the app users compared with the controls.

‘Ready for clinical use’

Based on these findings, “in my view the app is ready for [routine] clinical use,” declared Judith Hsia, MD, a cardiologist and professor of medicine at the University of Colorado in Aurora, and with Dr. Bonaca a co-lead investigator for the study.

The BT-001 app can serve as “an addition to the toolkit of diabetes treatments,” Dr. Hsia said in an interview. One key advantage of the app is that, once approved, it could be available to many more people with type 2 diabetes than would be able to receive CBT directly from a therapist. Another potential plus for the CBT app is that “the effects should be durable in contrast to medications,” which must be taken on an ongoing basis to maintain effectiveness. In addition, the safety profile “is favorable compared with drug therapies, which should appeal to health care providers,” said Dr. Hsia, chief science officer for CPC Clinical Research.

However, Dr. Shapira cited the issue that therapeutic apps “raise privacy and licensing liability concerns.”

The BT-001 trial was sponsored by Better Therapeutics, the company developing the app. CPC Clinical Research receives research and consulting funding from numerous companies. Dr. Bonaca has been a consultant to Audentes, and is a stockholder of Medtronic and Pfizer. Dr. Shapira had no disclosures. Dr. Hsia is a stockholder of AstraZeneca.

CHICAGO – A smartphone app that delivers nutritional cognitive behavioral therapy (CBT) to people with type 2 diabetes produced an average 0.29 percentage point drop in hemoglobin A1c during 180 days of use compared with controls, and an average 0.37 percentage point reduction in A1c compared with baseline values in a randomized, pivotal trial with 669 adults.

Use of the app for 180 days also significantly linked with a reduced need for additional medications, reduced weight and blood pressure, and improved patient-reported outcomes, and it led to fewer adverse effects than seen in control subjects, Marc P. Bonaca, MD, reported at the American Heart Association scientific sessions.

Mitchel L. Zoler/MDedge News

The findings also showed a clear dose-response relationship: The more CBT lessons a person completed with the app, the greater the A1c reduction.

The results suggest that the app, called BT-001, “potentially provides a scalable treatment option for patients with type 2 diabetes,” concluded Dr. Bonaca.

On the basis of the results from this trial, also called BT-001, the company developing the app, Better Therapeutics, announced in September 2022 that it had filed a classification request with the Food and Drug Administration that would allow marketing authorization for the BT-001 app. Better Therapeutics envisions that once authorized by the FDA, the app would be available to people with type 2 diabetes by prescriptions written by health care providers and that the cost for the app would be covered by health insurance, explained a company spokesperson.
 

A ‘modest positive impact’

“CBT is an empirically supported psychotherapy for a variety of emotional disorders, and it has been adapted to target specific emotional distress in the context of chronic illness,” said Amit Shapira, PhD, a clinical psychologist at the Joslin Diabetes Center in Boston who has not been involved in the BT-001 studies. A CBT protocol designed for diabetes, CBT for Adherence and Depression, “has been shown to have a positive impact on depression symptoms and glycemic control in adults with type 2 diabetes,” Dr. Shapira said in an interview.

Based on published results, the BT-001 app “seems to have a modest positive impact on glycemic control, especially among people who completed more than 10 [lesson] modules.” The evidence appears to suggest that the app “might be a good supplement to working with a behavioral health counselor.”

The BT-001 trial enrolled 669 adults with type 2 diabetes for an average of 11 years and an A1c of 7%-10.9% with an average level of 8.2%. Participants had to be on a stable medication regimen for at least 3 months but not using insulin, and their treatment regimens could undergo adjustment during the trial. At baseline, each subject was on an average of 2.1 antidiabetes medications, including 90% on metformin and 42% on a sulfonylurea. The researchers also highlighted that the enrolled cohort of people with type 2 diabetes had a demographic profile that was “generally representative” of U.S. adults with type 2 diabetes.

The researchers told the 326 people who were randomized to the active intervention group to use the app but subjects were free to determine their frequency of use. The app introduced a new lesson module weekly that took 10-20 minutes to complete, and each weekly lesson came with associated exercises aimed at practicing skills related to behavioral beliefs.

The study’s primary efficacy endpoint was the average change from baseline in A1c compared with the 343 control participants after 90 days of app use, and 610 of the 669 enrolled participants (91%) had paired baseline and 90-day measurements. At 90 days, people in the app group had an average 0.28 percentage point decrease in their A1c compared with an average 0.11 percentage point increase among the controls, a between-group difference of 0.39 percentage points. Both the reduction from baseline with app use and the reduction relative to the controls were significant. These results appeared in an article published online in in Diabetes Care.

At the scientific sessions, Dr. Bonaca presented additional outcome data after 180 days of app use. He reported an average 0.37 percentage point reduction from baseline in A1c among app users and a 0.08 percentage point decrease from baseline among the controls, for a net 0.29 percentage point incremental decline with the app, a significant difference. At 180 days, 50% of the people in the app group had an A1c decline from baseline of at least 0.4 percentage points compared with 34% of the controls, a significant difference.


 

A dose-response relationship

Notably, app use showed a clear dose-response pattern. During 180 days of app availability, people who used the app fewer than 10 times had an average reduction from baseline in their A1c of less than 0.1 percentage points. Among those who used the app 10-20 times (a subgroup with roughly one-third of the people randomized to app use) average A1c reduction increased to about 0.4 percentage points, and among those who used the app more than 20 times, also one-third of the intervention group, the average A1c reduction from baseline was about 0.6 percentage points.

“It would be interesting to learn more about the adults who engaged with the app” and had a higher use rate “to provide more targeted care” with the app to people who match the profiles of those who were more likely to use the app during the trial, said Dr. Shapira.

Dr. Bonaca, a cardiologist and vascular medicine specialist and executive director of CPC Clinical Research and CPC Community Health, an academic research organization created by and affiliated with the University of Colorado Anschutz Medical Campus in Aurora, Colo., reported several other 180-day outcomes in the BT-001 trial:

• A 33% relative decrease in the percentage of subjects who needed during the study an additional antidiabetes medication or increased dosages of their baseline medications, which occurred at a rate of 21% among the controls and 14% among those who used the app.
• An average weight loss from baseline of 5.5 pounds using the app compared with an average 1.9 pound decrease among controls, a significant difference.
• A decline in average systolic blood pressure of 4.7 mm Hg with app use compared with a 1.8 mm Hg average decline among the controls, a significant difference.
• Significant incremental average improvements in a self-reported Short Form-12 physical component score with the app compared with controls, and increased average improvement in the PHQ9 self-reported measure of depression in app users compared with controls.
• Significantly fewer treatment-emergent adverse effects, and significantly fewer serious treatment-emergent adverse effects among the app users compared with the controls.

‘Ready for clinical use’

Based on these findings, “in my view the app is ready for [routine] clinical use,” declared Judith Hsia, MD, a cardiologist and professor of medicine at the University of Colorado in Aurora, and with Dr. Bonaca a co-lead investigator for the study.

The BT-001 app can serve as “an addition to the toolkit of diabetes treatments,” Dr. Hsia said in an interview. One key advantage of the app is that, once approved, it could be available to many more people with type 2 diabetes than would be able to receive CBT directly from a therapist. Another potential plus for the CBT app is that “the effects should be durable in contrast to medications,” which must be taken on an ongoing basis to maintain effectiveness. In addition, the safety profile “is favorable compared with drug therapies, which should appeal to health care providers,” said Dr. Hsia, chief science officer for CPC Clinical Research.

However, Dr. Shapira cited the issue that therapeutic apps “raise privacy and licensing liability concerns.”

The BT-001 trial was sponsored by Better Therapeutics, the company developing the app. CPC Clinical Research receives research and consulting funding from numerous companies. Dr. Bonaca has been a consultant to Audentes, and is a stockholder of Medtronic and Pfizer. Dr. Shapira had no disclosures. Dr. Hsia is a stockholder of AstraZeneca.

A new generation of treatments appears to have caused U.S. melanoma mortality rates to plunge between 2013 and 2017 for the first time in 4 decades, a new study finds, although the dip appeared to stabilize over the next 2 years.

“This data is very encouraging and represents the real-world effectiveness of these newer therapies, which include immunotherapies and targeted therapies,” hematologist/oncologist Navkirat Kahlon, MD, MPH, of Seacoast Cancer Center and Massachusetts General Brigham Wentworth-Douglass Hospital, Dover, N.H., one of the study authors, said in an interview. In clinical trials, these new treatments “have been very effective ... so the timing as well as magnitude of drop seen in melanoma-specific population mortality was not at all surprising. But it’s still very exciting.”

The report, published in JAMA Network Open, tracked mortality rates for the deadliest form of skin cancer from 1975 to 2019. The researchers launched the study to better understand outcomes in cutaneous melanoma following the rise of new therapies that now provide options in addition to chemotherapy. “With the use of novel therapies, the survival of these patients has increased from a few weeks or months to many years in clinical trials,” Dr. Kahlon said. “Given the magnitude of benefit compared to traditional chemotherapy in clinical trials, we decided to see if the real-world U.S. population is deriving the same benefit.”

New drugs introduced in recent years include immunotherapy agents such as ipilimumab and targeted therapies such as vemurafenib.

The researchers analyzed age-adjusted melanoma outcome data from the Surveillance, Epidemiology, and End Results (SEER) database. In 1975, the long-term melanoma mortality rate for melanoma was 2.07 per 100,000 people (95% confidence interval [CI], 2.00-2.13). It rose to 2.65 (95% CI, 2.58-2.65) in 1988 and 2.67 (95% CI, 2.61-2.72) in 2013, then fell to 2.09 (95% CI, 2.05-2.14) in 2017 and 2.01 (95% CI, 1.97-2.06) in 2019.

Per the analysis, the rate grew at an annual percentage change (APC) of 1.65% (95% CI, 1.30%-2.00%, P < .001) from 1975 to 1988 and remained stable from 1988 to 2013 (P = .85). Then it fell by an APC of 6.28% (95% CI, –8.52% to –3.97%, P < .001) from 2013 to 2017. There was no statistically significant difference between 2017 and 2019, although “the trend was downward,” the authors noted.

“Our study didn’t study the parameters that can answer the question about how many more years of life patients are getting or how many lives aren’t lost,” Dr. Kahlon said in the interview. “But looking at other studies and clinical trial data, the prognosis of these patients with a historical median overall survival of a few weeks to months has improved to many months to years.”

But why do melanoma mortality rates remain roughly about the same as they were in 1975? “The incidence of melanoma has continued to rise,” she said. “Also, over time, we have become better at collecting more accurate information, so the [rate] in 1975 could potentially be an underestimated rate.”

In an interview, dermatologist Adewole “Ade” Adamson, MD, MPP, of the University of Texas at Austin, noted that a 2020 study examined melanoma death rates in Whites – who are most affected by melanoma – and found similar trends from 2013 to 2016. “Nothing about these [new] findings surprises me as they have been shown before. However, these confirmatory findings are reassuring because they show the powerful effect of novel treatments at a population level.”

A new generation of treatments appears to have caused U.S. melanoma mortality rates to plunge between 2013 and 2017 for the first time in 4 decades, a new study finds, although the dip appeared to stabilize over the next 2 years.

“This data is very encouraging and represents the real-world effectiveness of these newer therapies, which include immunotherapies and targeted therapies,” hematologist/oncologist Navkirat Kahlon, MD, MPH, of Seacoast Cancer Center and Massachusetts General Brigham Wentworth-Douglass Hospital, Dover, N.H., one of the study authors, said in an interview. In clinical trials, these new treatments “have been very effective ... so the timing as well as magnitude of drop seen in melanoma-specific population mortality was not at all surprising. But it’s still very exciting.”

The report, published in JAMA Network Open, tracked mortality rates for the deadliest form of skin cancer from 1975 to 2019. The researchers launched the study to better understand outcomes in cutaneous melanoma following the rise of new therapies that now provide options in addition to chemotherapy. “With the use of novel therapies, the survival of these patients has increased from a few weeks or months to many years in clinical trials,” Dr. Kahlon said. “Given the magnitude of benefit compared to traditional chemotherapy in clinical trials, we decided to see if the real-world U.S. population is deriving the same benefit.”

New drugs introduced in recent years include immunotherapy agents such as ipilimumab and targeted therapies such as vemurafenib.

The researchers analyzed age-adjusted melanoma outcome data from the Surveillance, Epidemiology, and End Results (SEER) database. In 1975, the long-term melanoma mortality rate for melanoma was 2.07 per 100,000 people (95% confidence interval [CI], 2.00-2.13). It rose to 2.65 (95% CI, 2.58-2.65) in 1988 and 2.67 (95% CI, 2.61-2.72) in 2013, then fell to 2.09 (95% CI, 2.05-2.14) in 2017 and 2.01 (95% CI, 1.97-2.06) in 2019.

Per the analysis, the rate grew at an annual percentage change (APC) of 1.65% (95% CI, 1.30%-2.00%, P < .001) from 1975 to 1988 and remained stable from 1988 to 2013 (P = .85). Then it fell by an APC of 6.28% (95% CI, –8.52% to –3.97%, P < .001) from 2013 to 2017. There was no statistically significant difference between 2017 and 2019, although “the trend was downward,” the authors noted.

“Our study didn’t study the parameters that can answer the question about how many more years of life patients are getting or how many lives aren’t lost,” Dr. Kahlon said in the interview. “But looking at other studies and clinical trial data, the prognosis of these patients with a historical median overall survival of a few weeks to months has improved to many months to years.”

But why do melanoma mortality rates remain roughly about the same as they were in 1975? “The incidence of melanoma has continued to rise,” she said. “Also, over time, we have become better at collecting more accurate information, so the [rate] in 1975 could potentially be an underestimated rate.”

In an interview, dermatologist Adewole “Ade” Adamson, MD, MPP, of the University of Texas at Austin, noted that a 2020 study examined melanoma death rates in Whites – who are most affected by melanoma – and found similar trends from 2013 to 2016. “Nothing about these [new] findings surprises me as they have been shown before. However, these confirmatory findings are reassuring because they show the powerful effect of novel treatments at a population level.”

A new generation of treatments appears to have caused U.S. melanoma mortality rates to plunge between 2013 and 2017 for the first time in 4 decades, a new study finds, although the dip appeared to stabilize over the next 2 years.

“This data is very encouraging and represents the real-world effectiveness of these newer therapies, which include immunotherapies and targeted therapies,” hematologist/oncologist Navkirat Kahlon, MD, MPH, of Seacoast Cancer Center and Massachusetts General Brigham Wentworth-Douglass Hospital, Dover, N.H., one of the study authors, said in an interview. In clinical trials, these new treatments “have been very effective ... so the timing as well as magnitude of drop seen in melanoma-specific population mortality was not at all surprising. But it’s still very exciting.”

The report, published in JAMA Network Open, tracked mortality rates for the deadliest form of skin cancer from 1975 to 2019. The researchers launched the study to better understand outcomes in cutaneous melanoma following the rise of new therapies that now provide options in addition to chemotherapy. “With the use of novel therapies, the survival of these patients has increased from a few weeks or months to many years in clinical trials,” Dr. Kahlon said. “Given the magnitude of benefit compared to traditional chemotherapy in clinical trials, we decided to see if the real-world U.S. population is deriving the same benefit.”

New drugs introduced in recent years include immunotherapy agents such as ipilimumab and targeted therapies such as vemurafenib.

The researchers analyzed age-adjusted melanoma outcome data from the Surveillance, Epidemiology, and End Results (SEER) database. In 1975, the long-term melanoma mortality rate for melanoma was 2.07 per 100,000 people (95% confidence interval [CI], 2.00-2.13). It rose to 2.65 (95% CI, 2.58-2.65) in 1988 and 2.67 (95% CI, 2.61-2.72) in 2013, then fell to 2.09 (95% CI, 2.05-2.14) in 2017 and 2.01 (95% CI, 1.97-2.06) in 2019.

Per the analysis, the rate grew at an annual percentage change (APC) of 1.65% (95% CI, 1.30%-2.00%, P < .001) from 1975 to 1988 and remained stable from 1988 to 2013 (P = .85). Then it fell by an APC of 6.28% (95% CI, –8.52% to –3.97%, P < .001) from 2013 to 2017. There was no statistically significant difference between 2017 and 2019, although “the trend was downward,” the authors noted.

“Our study didn’t study the parameters that can answer the question about how many more years of life patients are getting or how many lives aren’t lost,” Dr. Kahlon said in the interview. “But looking at other studies and clinical trial data, the prognosis of these patients with a historical median overall survival of a few weeks to months has improved to many months to years.”

But why do melanoma mortality rates remain roughly about the same as they were in 1975? “The incidence of melanoma has continued to rise,” she said. “Also, over time, we have become better at collecting more accurate information, so the [rate] in 1975 could potentially be an underestimated rate.”

In an interview, dermatologist Adewole “Ade” Adamson, MD, MPP, of the University of Texas at Austin, noted that a 2020 study examined melanoma death rates in Whites – who are most affected by melanoma – and found similar trends from 2013 to 2016. “Nothing about these [new] findings surprises me as they have been shown before. However, these confirmatory findings are reassuring because they show the powerful effect of novel treatments at a population level.”

SAN Antonio – How do you shoot at an invisible target? It seems counterintuitive, but trastuzumab deruxtecan (T-DXd) (Enhertu), which combines an antibody targeted to HER2 with a toxic payload, showed promising preliminary activity against localized hormone receptor–positive breast cancers with only low levels of HER2 expression (HR+/HER2-low).

In the investigator-initiated TRIO-US B-12 TALENT study looking at neoadjuvant T-DXd either alone or in combination with the hormone therapy anastrazole, the objective response rate (ORR) with T-DXd alone was 68%, compared with 58% for T-DXd plus anastrazole, reported Aditya Bardia, MD, MPH, a medical oncologist with Massachusetts General Hospital Cancer Center in Boston. He recently presented the study findings at the 2022 San Antonio Breast Cancer Symposium.

“The study provides a rich platform for additional translational research to evaluate more sensitive methods of HER2 detection, develop predictive biomarkers, and understand mechanisms of resistance in residual disease which would guide subsequent therapeutic strategies, including combination therapy,” he said in an oral abstract session at the meeting.
 

Not-so-innocent bystander

In an interview, Dr. Bardia explained that the T-DXd may have efficacy in HER2-low cancers because of a bystander effect.

“With these antibody drug conjugates, if you have the antigen, the ADC binds to the antigen, gets internalized, and releases the payload, but the payload has a bystander effect ... it’s membrane permeable, so it can go outside and affect other cells that do not express the antigen. So for HER2-low tumors, even if there is HER2 heterogeneity or if there are some cells that do not express HER2, this would work because of the bystander effect,” he said.

Although neoadjuvant chemotherapy with an anthracycline and taxane is often used to treat patients with high-risk localized HR-positive breast cancer, the therapy is associated with low pathologic complete response (pCR) rates, radiological response rates of around 50%, and significant toxicities, including myelosuppression, neuropathy, cardiomyopathy, and leukemia risk, Dr. Bardia said.
 

At cross purposes

The trial included both a T-DXd monotherapy arm and a second arm containing the antibody drug conjugate (ADC) with endocrine therapy. The rationale for the latter is that there is documented “cross-talk” between the estrogen receptor (ER) and HER2.

“In tumors that become endocrine resistant, you see an increase in the HER2 pathway, and if you block ER, you see that HER2 goes up and vice versa. If you just block HER2 alone, the expression of ER can go up, and if you block the PI3 kinase alone, the expression of ER goes up,” he said.

Dual blockade can be effective with antibody-based therapy or with tyrosine kinase inhibitors, but with an ADC, the dual blockade strategy may be less effective, Dr. Bardia said, “because if you have an ADC, you need HER2, the ADC binds to HER2, then gives the payload to the cancer cells and essentially kills the cancer cells,” Dr. Bardia explained in a media briefing held prior to his presentation.

In fact, the T-DXd–anastrozole combination was associated with a lower overall response rate in the study than T-DXd alone, but Dr. Bardia cautioned about overinterpreting these results, as the study included only 39 patients.
 

Study details

The investigators enrolled 58 patients – 56 pre- and postmenopausal women and 2 men – with HR+/HER2-low tumors determined by local and/or central review, and operable stage II or III cancers.

After stratification by HER2 expression level and menopausal status, the patients were randomized to receive either T-DXd alone at a dose of 5.4 mg/kg, or with T-DXd at the same dose plus anastrozole, with men and premenopausal women also receiving a gonadotropin-releasing hormone analog.

The protocol originally called for six cycles of therapy, but was amended in February 2022 to increase the number to eight for newly enrolled participants and patients who were already on study treatment but had not yet had surgery.

The majority of patients in each arm had invasive ductal cancers, and most had HER2 expression on immunohistochemistry (IHC) of 1+, which is generally considered to be HER2-negative. However, there was only modest concordance between local and central review in determining HER2 expression levels, Dr. Bardia noted. Indeed, the entire question of HER2-low cancers, whether they compose a separate clinical entity from other cancers and how to standardize testing, was the subject of a special session at this year’s SABCS.
 

Results

Overall response rate, the primary endpoint, was 68% in the T-DXd arm and 58% in the T-DXd plus anastrazole arm.

Although the low response rate with the combination suggests that endocrine therapy may not be helpful in this patient population, it’s still too early to say so conclusively, Dr. Bardia said.

Looking at the change in HER2 expression by IHC from baseline to surgery, they found that 48.6% of patients had a change in HER2 IHC expression after T-DXd treatment, and that nearly 90% of these patients had a decrease in expression levels.

Among 42 patients with available data on residual cancer burden (RCB) at the time of data cutoff, one patient in the T-DXd alone arm with stage 3A disease had an RCB of 0, equivalent to a pathologic complete response (pCR). There were no other RCB 0 tumors after surgery in either study arm. The rate of combined RCB and RCB 1 (near pCR) was about 15% in each arm.

In all, 3 of the 58 patients in the study (5.2%) required dose reductions because of adverse events. There were no cases of grade 3 or greater pneumonitis, and no cases of either cardiomyopathy or neuropathy.
 

Way better than chemotherapy?

“It was very exciting when we got the DESTINY-Breast04 results showing this impressive activity of trastuzumab deruxtecan in this HER2-low entity, and now we know that hormone-positive [tumors], the majority of them are HER2-low. It was really encouraging, it was practice changing, but we were left wondering about this HER2-low entity, and can we act on it in the earlier setting,” commented Jason A. Mouabbi, MD, from the University of Texas MD Anderson Cancer Center in Houston.

“The beauty of the TRIO-US B-12 TALENT study is that it looked at the neoadjuvant setting where we know those patients who are hormone-positive usually do not respond well to chemotherapy,” he said in an interview.

He said that although the study didn’t compare T-DXd to chemotherapy, “it’s an excellent first start.”

An overall response rate near 70% “is something amazing. I’m really excited to see it against chemo. I think it’s going to do way better,” Dr. Mouabbi said.

The study was conducted by the Translational Research In Oncology (TRIO)-US network. Funding was provided by Daiichi Sankyo, the maker of trastuzumab deruxtecan (Enhertu). Dr. Bardia serves as a consultant or advisory board member for Pfizer, Novartis, Genentech, Merck, Radius Health, Immunomedics/Gilead Sciences, Sanofi, Daiichi Sankyo, AstraZeneca, and Eli Lilly, and has received research funding from Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health, Immunomedics/Gilead Sciences, Daiichi Sankyo, AstraZeneca, and Eli Lilly.

Dr. Mouabbi disclosed honoraria from BostonGene, Cardinal Health, Napo Pharmaceuticals, and Fresenius Kabi.

SAN Antonio – How do you shoot at an invisible target? It seems counterintuitive, but trastuzumab deruxtecan (T-DXd) (Enhertu), which combines an antibody targeted to HER2 with a toxic payload, showed promising preliminary activity against localized hormone receptor–positive breast cancers with only low levels of HER2 expression (HR+/HER2-low).

In the investigator-initiated TRIO-US B-12 TALENT study looking at neoadjuvant T-DXd either alone or in combination with the hormone therapy anastrazole, the objective response rate (ORR) with T-DXd alone was 68%, compared with 58% for T-DXd plus anastrazole, reported Aditya Bardia, MD, MPH, a medical oncologist with Massachusetts General Hospital Cancer Center in Boston. He recently presented the study findings at the 2022 San Antonio Breast Cancer Symposium.

“The study provides a rich platform for additional translational research to evaluate more sensitive methods of HER2 detection, develop predictive biomarkers, and understand mechanisms of resistance in residual disease which would guide subsequent therapeutic strategies, including combination therapy,” he said in an oral abstract session at the meeting.
 

Not-so-innocent bystander

In an interview, Dr. Bardia explained that the T-DXd may have efficacy in HER2-low cancers because of a bystander effect.

“With these antibody drug conjugates, if you have the antigen, the ADC binds to the antigen, gets internalized, and releases the payload, but the payload has a bystander effect ... it’s membrane permeable, so it can go outside and affect other cells that do not express the antigen. So for HER2-low tumors, even if there is HER2 heterogeneity or if there are some cells that do not express HER2, this would work because of the bystander effect,” he said.

Although neoadjuvant chemotherapy with an anthracycline and taxane is often used to treat patients with high-risk localized HR-positive breast cancer, the therapy is associated with low pathologic complete response (pCR) rates, radiological response rates of around 50%, and significant toxicities, including myelosuppression, neuropathy, cardiomyopathy, and leukemia risk, Dr. Bardia said.
 

At cross purposes

The trial included both a T-DXd monotherapy arm and a second arm containing the antibody drug conjugate (ADC) with endocrine therapy. The rationale for the latter is that there is documented “cross-talk” between the estrogen receptor (ER) and HER2.

“In tumors that become endocrine resistant, you see an increase in the HER2 pathway, and if you block ER, you see that HER2 goes up and vice versa. If you just block HER2 alone, the expression of ER can go up, and if you block the PI3 kinase alone, the expression of ER goes up,” he said.

Dual blockade can be effective with antibody-based therapy or with tyrosine kinase inhibitors, but with an ADC, the dual blockade strategy may be less effective, Dr. Bardia said, “because if you have an ADC, you need HER2, the ADC binds to HER2, then gives the payload to the cancer cells and essentially kills the cancer cells,” Dr. Bardia explained in a media briefing held prior to his presentation.

In fact, the T-DXd–anastrozole combination was associated with a lower overall response rate in the study than T-DXd alone, but Dr. Bardia cautioned about overinterpreting these results, as the study included only 39 patients.
 

Study details

The investigators enrolled 58 patients – 56 pre- and postmenopausal women and 2 men – with HR+/HER2-low tumors determined by local and/or central review, and operable stage II or III cancers.

After stratification by HER2 expression level and menopausal status, the patients were randomized to receive either T-DXd alone at a dose of 5.4 mg/kg, or with T-DXd at the same dose plus anastrozole, with men and premenopausal women also receiving a gonadotropin-releasing hormone analog.

The protocol originally called for six cycles of therapy, but was amended in February 2022 to increase the number to eight for newly enrolled participants and patients who were already on study treatment but had not yet had surgery.

The majority of patients in each arm had invasive ductal cancers, and most had HER2 expression on immunohistochemistry (IHC) of 1+, which is generally considered to be HER2-negative. However, there was only modest concordance between local and central review in determining HER2 expression levels, Dr. Bardia noted. Indeed, the entire question of HER2-low cancers, whether they compose a separate clinical entity from other cancers and how to standardize testing, was the subject of a special session at this year’s SABCS.
 

Results

Overall response rate, the primary endpoint, was 68% in the T-DXd arm and 58% in the T-DXd plus anastrazole arm.

Although the low response rate with the combination suggests that endocrine therapy may not be helpful in this patient population, it’s still too early to say so conclusively, Dr. Bardia said.

Looking at the change in HER2 expression by IHC from baseline to surgery, they found that 48.6% of patients had a change in HER2 IHC expression after T-DXd treatment, and that nearly 90% of these patients had a decrease in expression levels.

Among 42 patients with available data on residual cancer burden (RCB) at the time of data cutoff, one patient in the T-DXd alone arm with stage 3A disease had an RCB of 0, equivalent to a pathologic complete response (pCR). There were no other RCB 0 tumors after surgery in either study arm. The rate of combined RCB and RCB 1 (near pCR) was about 15% in each arm.

In all, 3 of the 58 patients in the study (5.2%) required dose reductions because of adverse events. There were no cases of grade 3 or greater pneumonitis, and no cases of either cardiomyopathy or neuropathy.
 

Way better than chemotherapy?

“It was very exciting when we got the DESTINY-Breast04 results showing this impressive activity of trastuzumab deruxtecan in this HER2-low entity, and now we know that hormone-positive [tumors], the majority of them are HER2-low. It was really encouraging, it was practice changing, but we were left wondering about this HER2-low entity, and can we act on it in the earlier setting,” commented Jason A. Mouabbi, MD, from the University of Texas MD Anderson Cancer Center in Houston.

“The beauty of the TRIO-US B-12 TALENT study is that it looked at the neoadjuvant setting where we know those patients who are hormone-positive usually do not respond well to chemotherapy,” he said in an interview.

He said that although the study didn’t compare T-DXd to chemotherapy, “it’s an excellent first start.”

An overall response rate near 70% “is something amazing. I’m really excited to see it against chemo. I think it’s going to do way better,” Dr. Mouabbi said.

The study was conducted by the Translational Research In Oncology (TRIO)-US network. Funding was provided by Daiichi Sankyo, the maker of trastuzumab deruxtecan (Enhertu). Dr. Bardia serves as a consultant or advisory board member for Pfizer, Novartis, Genentech, Merck, Radius Health, Immunomedics/Gilead Sciences, Sanofi, Daiichi Sankyo, AstraZeneca, and Eli Lilly, and has received research funding from Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health, Immunomedics/Gilead Sciences, Daiichi Sankyo, AstraZeneca, and Eli Lilly.

Dr. Mouabbi disclosed honoraria from BostonGene, Cardinal Health, Napo Pharmaceuticals, and Fresenius Kabi.

SAN Antonio – How do you shoot at an invisible target? It seems counterintuitive, but trastuzumab deruxtecan (T-DXd) (Enhertu), which combines an antibody targeted to HER2 with a toxic payload, showed promising preliminary activity against localized hormone receptor–positive breast cancers with only low levels of HER2 expression (HR+/HER2-low).

In the investigator-initiated TRIO-US B-12 TALENT study looking at neoadjuvant T-DXd either alone or in combination with the hormone therapy anastrazole, the objective response rate (ORR) with T-DXd alone was 68%, compared with 58% for T-DXd plus anastrazole, reported Aditya Bardia, MD, MPH, a medical oncologist with Massachusetts General Hospital Cancer Center in Boston. He recently presented the study findings at the 2022 San Antonio Breast Cancer Symposium.

“The study provides a rich platform for additional translational research to evaluate more sensitive methods of HER2 detection, develop predictive biomarkers, and understand mechanisms of resistance in residual disease which would guide subsequent therapeutic strategies, including combination therapy,” he said in an oral abstract session at the meeting.
 

Not-so-innocent bystander

In an interview, Dr. Bardia explained that the T-DXd may have efficacy in HER2-low cancers because of a bystander effect.

“With these antibody drug conjugates, if you have the antigen, the ADC binds to the antigen, gets internalized, and releases the payload, but the payload has a bystander effect ... it’s membrane permeable, so it can go outside and affect other cells that do not express the antigen. So for HER2-low tumors, even if there is HER2 heterogeneity or if there are some cells that do not express HER2, this would work because of the bystander effect,” he said.

Although neoadjuvant chemotherapy with an anthracycline and taxane is often used to treat patients with high-risk localized HR-positive breast cancer, the therapy is associated with low pathologic complete response (pCR) rates, radiological response rates of around 50%, and significant toxicities, including myelosuppression, neuropathy, cardiomyopathy, and leukemia risk, Dr. Bardia said.
 

At cross purposes

The trial included both a T-DXd monotherapy arm and a second arm containing the antibody drug conjugate (ADC) with endocrine therapy. The rationale for the latter is that there is documented “cross-talk” between the estrogen receptor (ER) and HER2.

“In tumors that become endocrine resistant, you see an increase in the HER2 pathway, and if you block ER, you see that HER2 goes up and vice versa. If you just block HER2 alone, the expression of ER can go up, and if you block the PI3 kinase alone, the expression of ER goes up,” he said.

Dual blockade can be effective with antibody-based therapy or with tyrosine kinase inhibitors, but with an ADC, the dual blockade strategy may be less effective, Dr. Bardia said, “because if you have an ADC, you need HER2, the ADC binds to HER2, then gives the payload to the cancer cells and essentially kills the cancer cells,” Dr. Bardia explained in a media briefing held prior to his presentation.

In fact, the T-DXd–anastrozole combination was associated with a lower overall response rate in the study than T-DXd alone, but Dr. Bardia cautioned about overinterpreting these results, as the study included only 39 patients.
 

Study details

The investigators enrolled 58 patients – 56 pre- and postmenopausal women and 2 men – with HR+/HER2-low tumors determined by local and/or central review, and operable stage II or III cancers.

After stratification by HER2 expression level and menopausal status, the patients were randomized to receive either T-DXd alone at a dose of 5.4 mg/kg, or with T-DXd at the same dose plus anastrozole, with men and premenopausal women also receiving a gonadotropin-releasing hormone analog.

The protocol originally called for six cycles of therapy, but was amended in February 2022 to increase the number to eight for newly enrolled participants and patients who were already on study treatment but had not yet had surgery.

The majority of patients in each arm had invasive ductal cancers, and most had HER2 expression on immunohistochemistry (IHC) of 1+, which is generally considered to be HER2-negative. However, there was only modest concordance between local and central review in determining HER2 expression levels, Dr. Bardia noted. Indeed, the entire question of HER2-low cancers, whether they compose a separate clinical entity from other cancers and how to standardize testing, was the subject of a special session at this year’s SABCS.
 

Results

Overall response rate, the primary endpoint, was 68% in the T-DXd arm and 58% in the T-DXd plus anastrazole arm.

Although the low response rate with the combination suggests that endocrine therapy may not be helpful in this patient population, it’s still too early to say so conclusively, Dr. Bardia said.

Looking at the change in HER2 expression by IHC from baseline to surgery, they found that 48.6% of patients had a change in HER2 IHC expression after T-DXd treatment, and that nearly 90% of these patients had a decrease in expression levels.

Among 42 patients with available data on residual cancer burden (RCB) at the time of data cutoff, one patient in the T-DXd alone arm with stage 3A disease had an RCB of 0, equivalent to a pathologic complete response (pCR). There were no other RCB 0 tumors after surgery in either study arm. The rate of combined RCB and RCB 1 (near pCR) was about 15% in each arm.

In all, 3 of the 58 patients in the study (5.2%) required dose reductions because of adverse events. There were no cases of grade 3 or greater pneumonitis, and no cases of either cardiomyopathy or neuropathy.
 

Way better than chemotherapy?

“It was very exciting when we got the DESTINY-Breast04 results showing this impressive activity of trastuzumab deruxtecan in this HER2-low entity, and now we know that hormone-positive [tumors], the majority of them are HER2-low. It was really encouraging, it was practice changing, but we were left wondering about this HER2-low entity, and can we act on it in the earlier setting,” commented Jason A. Mouabbi, MD, from the University of Texas MD Anderson Cancer Center in Houston.

“The beauty of the TRIO-US B-12 TALENT study is that it looked at the neoadjuvant setting where we know those patients who are hormone-positive usually do not respond well to chemotherapy,” he said in an interview.

He said that although the study didn’t compare T-DXd to chemotherapy, “it’s an excellent first start.”

An overall response rate near 70% “is something amazing. I’m really excited to see it against chemo. I think it’s going to do way better,” Dr. Mouabbi said.

The study was conducted by the Translational Research In Oncology (TRIO)-US network. Funding was provided by Daiichi Sankyo, the maker of trastuzumab deruxtecan (Enhertu). Dr. Bardia serves as a consultant or advisory board member for Pfizer, Novartis, Genentech, Merck, Radius Health, Immunomedics/Gilead Sciences, Sanofi, Daiichi Sankyo, AstraZeneca, and Eli Lilly, and has received research funding from Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health, Immunomedics/Gilead Sciences, Daiichi Sankyo, AstraZeneca, and Eli Lilly.

Dr. Mouabbi disclosed honoraria from BostonGene, Cardinal Health, Napo Pharmaceuticals, and Fresenius Kabi.

Hidradenitis suppurativa (HS), also known as acne inversa or Verneuil disease, is a chronic, recurrent, inflammatory occlusive disease affecting the terminal follicular epithelium in apocrine gland–bearing skin areas.¹ HS manifests as painful nodules, abscesses, fistulas, and scarring and often has a severe psychological impact on the affected patient.²

When HS was first identified in the 1800s, it was believed to result from a dysfunction of the sweat glands.³ In 1939, scientists identified the true cause: follicular occlusion.³

Due to its chronic nature, heterogeneity in presentation, and apparent low prevalence,⁴ HS is considered an orphan disease.⁵ Over the past 10 years, there has been a surge in HS research—particularly in medical management—which has provided a better understanding of this condition.^6,7

In this review, we discuss the most updated evidence regarding the diagnosis and treatment of HS to guide the family physician (FP)’s approach to managing this debilitating disease. But first, we offer a word about the etiology and pathophysiology of the condition.

3 events set the stage for hidradenitis suppurativa

Although the exact cause of HS is still unknown, some researchers have hypothesized that HS results from a combination of genetic predisposition and environmental and lifestyle factors.^8-12 The primary mechanism of HS is the obstruction of the terminal follicular epithelium by a keratin plug.^1,13,14 A systematic review of molecular inflammatory pathways involved in HS divides the pathogenesis of HS into 3 events: follicular occlusion followed by dilation, follicular rupture and inflammatory response, and chronic inflammatory state with sinus tracts.⁸

An underreported condition

HS is often underreported and misdiagnosed.^4,15 Globally, the prevalence of HS varies from < 1% to 4%.^15,16 A systematic review with meta-analysis showed a higher prevalence of HS in females compared to males in American and European populations.¹⁷ In the United States, the overall frequency of HS is 0.1%, or 98 per 100,000 persons.¹⁶ The prevalence of HS is highest among patients ages 30 to 39 years; there is decreased prevalence in patients ages 55 years and older.^16,18

Who is at heightened risk?

Recent research has shown a relationship between ethnicity and HS.^16,19,20 African American and biracial groups (defined as African American and White) have a 3-fold and 2-fold greater prevalence of HS, respectively, compared to White patients.¹⁶ However, the prevalence of HS in non-White ethnic groups may be underestimated in clinical trials due to a lack of representation and subgroup analyses based on ethnicity, which may affect generalizability in HS recommendations.²¹

Continue to: Genetic predisposition

Genetic predisposition. As many as 40% of patients with HS report having at least 1 affected family member. A positive family history of HS is associated with earlier onset, longer disease duration, and severe disease.²² HS is genetically heterogeneous, and several mutations (eg, gamma secretase, PSTPIP1, PSEN1 genes) have been identified in patients and in vitro as the cause of dysregulation of epidermal proliferation and differentiation, immune dysregulation, and promotion of amyloid formation.^8,23-25

Obesity and metabolic risk factors. There is a strong relationship between HS and obesity. As many as 70% of patients with HS are obese, and 9% to 40% have metabolic syndrome.^12,18,26-28 Obesity is associated with maceration and mechanical stress, increased fragility of the dermo-epidermal junction, changes in cutaneous blood flow, and subdermal fat inflammation—all of which favor the pathophysiology of HS.^29,30

Smoking. Tobacco smoking is associated with severe HS and a lower chance of remission.¹² Population-based studies have shown that as many as 90% of patients with HS have a history of smoking ≥ 20 packs of cigarettes per year.^{1,12,18,31,32} The nicotine and thousands of other chemicals present in cigarettes trigger keratinocytes and fibroblasts, resulting in epidermal hyperplasia, infundibular hyperkeratosis, excessive cornification, and dysbiosis.^8,23,24

Hormones. The exact role sex hormones play in the pathogenesis of HS remains unclear.^8,32 Most information is based primarily on small studies looking at antiandrogen treatments, HS activity during the menstrual cycle and pregnancy, HS exacerbation related to androgenic effects of hormonal contraception, and the association of HS with metabolic-endocrine disorders (eg, polycystic ovary syndrome [PCOS]).^8,33

A family history of hidradenitis suppurativa is associated with earlier onset, longer disease duration, and severe disease.

Androgens induce hyperkeratosis that may lead to follicular occlusion—the hallmark of HS pathology.³⁴ A systematic review looking at the role of androgen and estrogen in HS found that while some patients with HS have elevated androgen levels, most have androgen and estrogen levels within normal range.³⁵ Therefore, increased peripheral androgen receptor sensitivity has been hypothesized as the mechanism of action contributing to HS manifestation.³⁴

Continue to: Host-defense defects

Host-defense defects. HS shares a similar cytokine profile with other well-­established immune-mediated inflammatory diseases, including pyoderma gangrenosum (PG)^36,37 and Crohn disease.^38-40 HS is characterized by the expression of several immune mediators, including tumor necrosis factor-alpha (TNF-alpha), interleukin-1 ­alpha (IL-1 alpha), IL-1 beta, IL-8, IL-17, and the IL-23/T helper 17 pathway, all of which are upregulated in other inflammatory diseases and also result in an abnormal innate immune response.^8,24 The recently described clinical triad of PG, acne, and HS (PASH) and the tetrad of pyogenic arthritis, PG, acne, and HS (PAPASH) further support the role of immune dysregulation in the pathogenesis of HS.⁴⁰ Nonetheless, further studies are needed to determine the exact pathways of cytokine effect in HS.⁴¹

Use these criteria to make the diagnosis

The US and Canadian Hidradenitis Suppurativa Foundations (HSF) guidelines base the clinical diagnosis of HS on the following criteria²:

• Typical HS lesions: Erythematous skin lesions; inflamed, deep-seated painful nodules; “tombstone” double-ended comedones; sinus tracts; scarring; deformity. FIGURES 1A-1E show typical lesions seen in patients with HS.
• Typical locations: Intertriginous regions—apocrine gland–containing areas in axilla, groin, perineal region, buttocks, gluteal cleft, and mammary folds; beltline and waistband areas; areas of skin compression and friction.
• Recurrence and chronicity: Recurrent painful or suppurating lesions that appear more than twice in a 6-month period.^2,41-43

Patients with HS usually present with painful recurrent abscesses and scarring and often report multiple visits to the emergency department for drainage or failed antibiotic treatment for abscesses.^15,44

Ask patients these 2 questions. Vinding et al⁴⁵ developed a survey for the diagnosis of HS using 2 simple questions based on the 3 criteria established by the HSF:

1. “Have you had an outbreak of boils during the last 6 months?” and
2. “Where and how many boils have you had?” (This question includes a list of the typical HS locations—eg, axilla, groin, genitals, area under breast.)

In their questionnaire, Vinding et al⁴⁵ found that an affirmative answer to Question 1 and reports of > 2 boils in response to Question 2 correlated to a sensitivity of 90%, specificity of 97%, positive predictive value of 96%, and negative predictive value of 92% for the diagnosis of HS. The differential diagnosis of HS is summarized in TABLE 1.^42,45-52

Continue to: These tools can help you to stage hidradenitis suppurativa

Multiple tools are available to assess the severity of HS.⁵³ We will describe the Hurley staging system and the International Hidradenitis Suppurativa Severity Score System (IHS4). Other diagnostic tools, such as the Sartorius score and the Hidradenitis Suppurativa Physician’s Global Assessment Scale (HS-PGA), can be time-consuming and challenging to interpret, limiting their use in the clinical setting.^2,54

Hurley staging system (available at www.hsdiseasesource.com/hs-disease-­staging) considers the presence of nodules, abscesses, sinus tracts, and scarring affecting an entire anatomical area.^13,55 This system is most useful as a rapid classification tool for patients with HS in the clinical setting but should not be used to assess clinical response.^2,13,56

The IHS4 (available at https://online­ library.wiley.com/doi/10.1111/bjd.15748) is a validated and easy-to-use tool for assessing HS and guiding the therapeutic strategy in clinical practice.⁵⁴ With IHS4, the clinician must calculate the following:

• total number of nodules > 10 mm in diameter
• total number of abscesses multiplied by 2, and
• total number of draining tunnels (fistulae/sinuses) multiplied by 4.

Mild HS is defined as a score ≤ 3 points; moderate HS, 4 to 10 points; and severe HS, ≥ 11 points.⁵⁴

No diagnostic tests, but ultrasound may be helpful

There are currently no established biological markers or specific tests for diagnosing HS.¹⁵ Ultrasound is emerging as a tool to assess dermal thickness, hair follicle morphology, and number and extent of fluid collections. Two recent studies showed that pairing clinical assessment with ultrasound findings improves accuracy of scoring in 84% of cases.^57,58 For patients with severe HS, skin biopsy can be considered to rule out squamous cell carcinoma. Cultures, however, have limited utility except for suspected superimposed bacterial infection.²

Continue to: Screening for comorbidities

Screening for comorbidities

HSF recommends clinicians screen patients for comorbidities associated with HS (TABLE 2).² Overall, screening patients for active and past history of smoking is strongly recommended, as is screening for metabolic syndrome, hyperlipidemia, type 2 diabetes (1.5- to 3-fold greater risk of type 2 diabetes in HS patients), and PCOS (3-fold greater risk).^2,26,27,59 Screening patients for depression and anxiety is also routinely recommended.² However, the authors of this article strongly recommend screening all patients with HS for psychiatric comorbidities, as research has shown a 2-fold greater risk of depression and anxiety, social isolation, and low self-esteem that severely limits quality of life (QOL) in this patient population.^60,61

Management

Treat existing lesions, reduce formation of new ones

The main goals of treatment for patients with HS are to treat existing lesions and reduce associated symptoms, reduce the formation of new lesions, and minimize associated psychological morbidity.¹⁵ FPs play an important role in the early diagnosis, treatment, and comprehensive care of patients with HS. This includes monitoring patients, managing comorbidities, making appropriate referrals to dermatologists, and coordinating the multidisciplinary care that patients with HS require.

As many as 90% of patients with hidradenitis suppurativa have a history of smoking ≥ 20 packs of cigarettes per year.

A systematic review identified more than 50 interventions used to treat HS, most based on small observational studies and randomized controlled trials (RCTs) with a high risk of bias.⁶² FIGURE 2^2,62-69 provides an evidence-based treatment algorithm for HS, and TABLE 3^{2,63,64,70-75} summarizes the most commonly used treatments.

Biologic agents

Adalimumab (ADA) is a fully human immunoglobulin G1 monoclonal antibody that binds to TNF-alpha, neutralizes its bioactivity, and induces apoptosis of TNF-expressing mononuclear cells. It is the only medication approved by the US Food and Drug Administration for active refractory moderate and severe HS.^62,65 Several double-blinded RCTs, including PIONEER I and PIONEER II, studied the effectiveness of ADA for HS and found significant clinical responses at Week 12, 50% reduction in abscess and nodule counts, no increase in abscesses or draining fistulas at Week 12, and sustained improvement in lesion counts, pain, and QOL.^66,67,76

IL-1 and IL-23 inhibitors. The efficacy of etanercept and golimumab (anti-TNF), as well as anakinra (IL-1 inhibitor) and ustekinumab (IL-1/IL-23 inhibitor), continue to be investigated with variable results; they are considered second-line treatment for active refractory moderate and severe HS after ADA.^65,77-80 In­fliximab (IL-1 beta inhibitor) has shown no effect on reducing disease severity.⁷⁰Compared to other treatments, biologic therapy is associated with higher costs (TABLE 3),^{2,63,64,70-75} an increased risk for reactivation of latent infections (eg, tuberculosis, herpes simplex, and hepatitis C virus [HCV], and B [HBV]), and an attenuated response to vaccines.⁸¹ Prior to starting biologic therapy, FPs should screen patients with HS for tuberculosis and HBV, consider HIV and HCV screening in at-risk patients, and optimize the immunization status of the patient.^82,83 While inactivated vaccines can be administered without discontinuing biologic treatment, patients should avoid live-attenuated vaccines while taking biologics.⁸³

Continue to: Antibiotic therapy

Topical antibiotics are considered first-line treatment for mild and moderate uncomplicated HS.^63,64 Clindamycin 1%, the only topical antibiotic studied in a small double-blind RCT of patients with Hurley stage I and stage II HS, demonstrated significant clinical improvement after 12 weeks of treatment (twice- daily application), compared to placebo.⁸⁴ Topical clindamycin is also recommended to treat flares in patients with mild disease.^2,64

Oral antibiotics. Tetracycline (500 mg twice daily for 4 months) is considered a second-line treatment for patients with mild HS.^64,68 Doxycycline (200 mg/d for 3 months) may also be considered as a second-line treatment in patients with mild disease.⁸⁵

All patients with hidradenitis suppurativa should be screened for depression, anxiety, social isolation, and low self-esteem.

Combination oral clindamycin (300 mg) and rifampicin (300 mg) twice daily for 10 weeks is recommended as first-line treatment for patients with moderate HS.^2,64,69 Combination rifampin (300 mg twice daily), moxifloxacin (400 mg/d), and metronidazole (500 mg three times a day) is not routinely recommended due to increased risk of ­toxicity.²

Ertapenem (1 g intravenously daily for 6 weeks) is supported by lower-level evidence as a third-line rescue therapy option and as a bridge to surgery; however, limitations for home infusions, costs, and concerns for antibiotic resistance limit its use.^2,86

Corticosteroids and systemic immunomodulators

Intralesional triamcinolone (2-20 mg) may be beneficial in the early stages of HS, although its use is based on a small prospective open study of 33 patients.⁸⁷ A recent double-blind placebo-controlled RCT comparing varying concentrations of intralesional triamcinolone (10 mg/mL and 40 mg/mL) vs normal saline showed no statistically significant difference in inflammatory clearance, pain reduction, or patient satisfaction.⁸⁸

Continue to: Short-term systemic corticosteroid tapers...

Short-term systemic corticosteroid tapers (eg, prednisone, starting at 0.5-1 mg/kg) are recommended to treat flares. Long-term corticosteroids and cyclosporine are reserved for patients with severe refractory disease; however, due to safety concerns, their regular use is strongly discouraged.^63,64,85 There is limited evidence to support the use of methotrexate for severe refractory disease, and its use is not recommended.⁶³

Hormonal therapy

The use of hormonal therapy for HS is limited by the low-quality evidence (eg, anecdotal evidence, small retrospective analyses, uncontrolled trials).^33,63 The only exception is a small double-blind controlled crossover trial from 1986 showing that the antiandrogen effects of combination oral contraceptives (ethinyloestradiol 50 mcg/cyproterone acetate in a reverse sequential regimen and ethinyloestradiol 50 mcg/norgestrel 500 mcg) improved HS lesions.⁸⁹

Spironolactone, an antiandrogen diuretic, has been studied in small case report series with a high risk for bias. It is used mainly in female patients with mild or moderate disease, or in combination with other agents in patients with severe HS. Further research is needed to determine its utility in the treatment of HS.^63,90,91

Metformin, alone or in combination with other therapies (dapsone, finasteride, liraglutide), has been analyzed in small prospective studies of primarily female patients with different severities of HS, obesity, and PCOS. These studies have shown improvement in lesions, QOL, and reduction of workdays lost.^92,93

Finasteride. Studies have shown finasteride (1.25-5 mg/d) alone or in combination with other treatments (metformin, liraglutide, levonorgestrel-ethinyl estradiol, and dapsone) provided varying degrees of resolution or improvement in patients with severe and advanced HS. Finasteride has been used for 4 to 16 weeks with a good safety profile.^92,94-96

Continue to: Retinoids

Acitretin, alitretinoin, and isotretinoin have been studied in small retrospective studies to manage HS, with variable results.^97-99 Robust prospective studies are needed. Retinoids, in general, should be considered as a second- or third-line treatment for moderate to severe HS.⁶³

Surgical intervention

Surgical interventions, which should be considered in patients with widespread mild, moderate, or severe disease, are associated with improved daily activity and work productivity.¹⁰⁰ Incision and drainage should be avoided in patients with HS, as this technique does not remove the affected follicles and is associated with 100% recurrence.¹⁰¹

Wide excision is the preferred surgical technique for patients with Hurley stage II and stage III HS; it is associated with lower recurrence rates (13%) compared to local excision (22%) and deroofing (27%).¹⁰² Secondary intention healing is the most commonly chosen method, based on lower recurrence rates than primary closure.¹⁰²

STEEP and laser techniques. The skin-tissue-sparing excision with electrosurgical peeling (STEEP) procedure involves successive tangential excision of affected tissue until the epithelized bottom of the sinus tracts has been reached. This allows for the removal of fibrotic tissue and the sparing of the deep subcutaneous fat. STEEP is associated with 30% of relapses after 43 months.⁷¹

When considering biologic therapy, screen all patients with hidradenitis suppurativa for tuberculosis and hepatitis B, and confirm they are current with age-appropriate immunizations.

Laser surgery has also been studied in patients with Hurley stage II and stage III HS. The most commonly used lasers for HS are the 1064-nm neodymium-doped yttrium aluminum garnet (Nd: YAG) and the carbon dioxide laser; they have been shown to reduce disease severity in inguinal, axillary, and inflammatory sites.^72-74

Pain management: Start with lidocaine, NSAIDs

There are few studies about HS-associated pain management.¹⁰³ For acute episodes, short-acting nonopioid local treatment with lidocaine, topical or oral nonsteroidal anti-inflammatory drugs, and acetaminophen are preferred. Opioids should be reserved for moderate-to-severe pain that has not responded to other analgesics. Adjuvant therapy with pregabalin, gabapentin, selective serotonin reuptake inhibitors, or serotonin-norepinephrine reuptake inhibitors can also be considered for the comanagement of pain and depression.^62,104

Consider this tool to measure treatment response

The HS clinical response (HiSCR) tool is an outcome measure used to evaluate treatment outcomes. The tool uses an HS-specific binary score with the following criteria:

1. ≥ 50% reduction in the number of inflammatory nodules;
2. no increase in the number of abscesses; and
3. no increase in the number of draining fistulas.¹⁰⁵

The HiSCR was developed for the ­PIONEER studies^105,106 to assess the response to ADA treatment. It is the only HS scoring system to undergo an extensive validation process with a meaningful clinical endpoint for HS treatment evaluation that is easy to use. Compared to the HS-PGA score (clear, minimal, mild), HiSCR was more responsive to change in patients with HS.^105,106 

CORRESPONDENCE
Cristina Marti-Amarista, MD, 101 Nicolls Road, Stony Brook, NY, 11794-8228; [email protected]

Hidradenitis suppurativa (HS), also known as acne inversa or Verneuil disease, is a chronic, recurrent, inflammatory occlusive disease affecting the terminal follicular epithelium in apocrine gland–bearing skin areas.¹ HS manifests as painful nodules, abscesses, fistulas, and scarring and often has a severe psychological impact on the affected patient.²

When HS was first identified in the 1800s, it was believed to result from a dysfunction of the sweat glands.³ In 1939, scientists identified the true cause: follicular occlusion.³

Due to its chronic nature, heterogeneity in presentation, and apparent low prevalence,⁴ HS is considered an orphan disease.⁵ Over the past 10 years, there has been a surge in HS research—particularly in medical management—which has provided a better understanding of this condition.^6,7

In this review, we discuss the most updated evidence regarding the diagnosis and treatment of HS to guide the family physician (FP)’s approach to managing this debilitating disease. But first, we offer a word about the etiology and pathophysiology of the condition.

3 events set the stage for hidradenitis suppurativa

Although the exact cause of HS is still unknown, some researchers have hypothesized that HS results from a combination of genetic predisposition and environmental and lifestyle factors.^8-12 The primary mechanism of HS is the obstruction of the terminal follicular epithelium by a keratin plug.^1,13,14 A systematic review of molecular inflammatory pathways involved in HS divides the pathogenesis of HS into 3 events: follicular occlusion followed by dilation, follicular rupture and inflammatory response, and chronic inflammatory state with sinus tracts.⁸

An underreported condition

HS is often underreported and misdiagnosed.^4,15 Globally, the prevalence of HS varies from < 1% to 4%.^15,16 A systematic review with meta-analysis showed a higher prevalence of HS in females compared to males in American and European populations.¹⁷ In the United States, the overall frequency of HS is 0.1%, or 98 per 100,000 persons.¹⁶ The prevalence of HS is highest among patients ages 30 to 39 years; there is decreased prevalence in patients ages 55 years and older.^16,18

Who is at heightened risk?

Recent research has shown a relationship between ethnicity and HS.^16,19,20 African American and biracial groups (defined as African American and White) have a 3-fold and 2-fold greater prevalence of HS, respectively, compared to White patients.¹⁶ However, the prevalence of HS in non-White ethnic groups may be underestimated in clinical trials due to a lack of representation and subgroup analyses based on ethnicity, which may affect generalizability in HS recommendations.²¹

Continue to: Genetic predisposition

Genetic predisposition. As many as 40% of patients with HS report having at least 1 affected family member. A positive family history of HS is associated with earlier onset, longer disease duration, and severe disease.²² HS is genetically heterogeneous, and several mutations (eg, gamma secretase, PSTPIP1, PSEN1 genes) have been identified in patients and in vitro as the cause of dysregulation of epidermal proliferation and differentiation, immune dysregulation, and promotion of amyloid formation.^8,23-25

Obesity and metabolic risk factors. There is a strong relationship between HS and obesity. As many as 70% of patients with HS are obese, and 9% to 40% have metabolic syndrome.^12,18,26-28 Obesity is associated with maceration and mechanical stress, increased fragility of the dermo-epidermal junction, changes in cutaneous blood flow, and subdermal fat inflammation—all of which favor the pathophysiology of HS.^29,30

Smoking. Tobacco smoking is associated with severe HS and a lower chance of remission.¹² Population-based studies have shown that as many as 90% of patients with HS have a history of smoking ≥ 20 packs of cigarettes per year.^{1,12,18,31,32} The nicotine and thousands of other chemicals present in cigarettes trigger keratinocytes and fibroblasts, resulting in epidermal hyperplasia, infundibular hyperkeratosis, excessive cornification, and dysbiosis.^8,23,24

Hormones. The exact role sex hormones play in the pathogenesis of HS remains unclear.^8,32 Most information is based primarily on small studies looking at antiandrogen treatments, HS activity during the menstrual cycle and pregnancy, HS exacerbation related to androgenic effects of hormonal contraception, and the association of HS with metabolic-endocrine disorders (eg, polycystic ovary syndrome [PCOS]).^8,33

A family history of hidradenitis suppurativa is associated with earlier onset, longer disease duration, and severe disease.

Androgens induce hyperkeratosis that may lead to follicular occlusion—the hallmark of HS pathology.³⁴ A systematic review looking at the role of androgen and estrogen in HS found that while some patients with HS have elevated androgen levels, most have androgen and estrogen levels within normal range.³⁵ Therefore, increased peripheral androgen receptor sensitivity has been hypothesized as the mechanism of action contributing to HS manifestation.³⁴

Continue to: Host-defense defects

Host-defense defects. HS shares a similar cytokine profile with other well-­established immune-mediated inflammatory diseases, including pyoderma gangrenosum (PG)^36,37 and Crohn disease.^38-40 HS is characterized by the expression of several immune mediators, including tumor necrosis factor-alpha (TNF-alpha), interleukin-1 ­alpha (IL-1 alpha), IL-1 beta, IL-8, IL-17, and the IL-23/T helper 17 pathway, all of which are upregulated in other inflammatory diseases and also result in an abnormal innate immune response.^8,24 The recently described clinical triad of PG, acne, and HS (PASH) and the tetrad of pyogenic arthritis, PG, acne, and HS (PAPASH) further support the role of immune dysregulation in the pathogenesis of HS.⁴⁰ Nonetheless, further studies are needed to determine the exact pathways of cytokine effect in HS.⁴¹

Use these criteria to make the diagnosis

The US and Canadian Hidradenitis Suppurativa Foundations (HSF) guidelines base the clinical diagnosis of HS on the following criteria²:

• Typical HS lesions: Erythematous skin lesions; inflamed, deep-seated painful nodules; “tombstone” double-ended comedones; sinus tracts; scarring; deformity. FIGURES 1A-1E show typical lesions seen in patients with HS.
• Typical locations: Intertriginous regions—apocrine gland–containing areas in axilla, groin, perineal region, buttocks, gluteal cleft, and mammary folds; beltline and waistband areas; areas of skin compression and friction.
• Recurrence and chronicity: Recurrent painful or suppurating lesions that appear more than twice in a 6-month period.^2,41-43

Patients with HS usually present with painful recurrent abscesses and scarring and often report multiple visits to the emergency department for drainage or failed antibiotic treatment for abscesses.^15,44

Ask patients these 2 questions. Vinding et al⁴⁵ developed a survey for the diagnosis of HS using 2 simple questions based on the 3 criteria established by the HSF:

1. “Have you had an outbreak of boils during the last 6 months?” and
2. “Where and how many boils have you had?” (This question includes a list of the typical HS locations—eg, axilla, groin, genitals, area under breast.)

In their questionnaire, Vinding et al⁴⁵ found that an affirmative answer to Question 1 and reports of > 2 boils in response to Question 2 correlated to a sensitivity of 90%, specificity of 97%, positive predictive value of 96%, and negative predictive value of 92% for the diagnosis of HS. The differential diagnosis of HS is summarized in TABLE 1.^42,45-52

Continue to: These tools can help you to stage hidradenitis suppurativa

Multiple tools are available to assess the severity of HS.⁵³ We will describe the Hurley staging system and the International Hidradenitis Suppurativa Severity Score System (IHS4). Other diagnostic tools, such as the Sartorius score and the Hidradenitis Suppurativa Physician’s Global Assessment Scale (HS-PGA), can be time-consuming and challenging to interpret, limiting their use in the clinical setting.^2,54

Hurley staging system (available at www.hsdiseasesource.com/hs-disease-­staging) considers the presence of nodules, abscesses, sinus tracts, and scarring affecting an entire anatomical area.^13,55 This system is most useful as a rapid classification tool for patients with HS in the clinical setting but should not be used to assess clinical response.^2,13,56

The IHS4 (available at https://online­ library.wiley.com/doi/10.1111/bjd.15748) is a validated and easy-to-use tool for assessing HS and guiding the therapeutic strategy in clinical practice.⁵⁴ With IHS4, the clinician must calculate the following:

• total number of nodules > 10 mm in diameter
• total number of abscesses multiplied by 2, and
• total number of draining tunnels (fistulae/sinuses) multiplied by 4.

Mild HS is defined as a score ≤ 3 points; moderate HS, 4 to 10 points; and severe HS, ≥ 11 points.⁵⁴

No diagnostic tests, but ultrasound may be helpful

There are currently no established biological markers or specific tests for diagnosing HS.¹⁵ Ultrasound is emerging as a tool to assess dermal thickness, hair follicle morphology, and number and extent of fluid collections. Two recent studies showed that pairing clinical assessment with ultrasound findings improves accuracy of scoring in 84% of cases.^57,58 For patients with severe HS, skin biopsy can be considered to rule out squamous cell carcinoma. Cultures, however, have limited utility except for suspected superimposed bacterial infection.²

Continue to: Screening for comorbidities

Screening for comorbidities

HSF recommends clinicians screen patients for comorbidities associated with HS (TABLE 2).² Overall, screening patients for active and past history of smoking is strongly recommended, as is screening for metabolic syndrome, hyperlipidemia, type 2 diabetes (1.5- to 3-fold greater risk of type 2 diabetes in HS patients), and PCOS (3-fold greater risk).^2,26,27,59 Screening patients for depression and anxiety is also routinely recommended.² However, the authors of this article strongly recommend screening all patients with HS for psychiatric comorbidities, as research has shown a 2-fold greater risk of depression and anxiety, social isolation, and low self-esteem that severely limits quality of life (QOL) in this patient population.^60,61

Management

Treat existing lesions, reduce formation of new ones

The main goals of treatment for patients with HS are to treat existing lesions and reduce associated symptoms, reduce the formation of new lesions, and minimize associated psychological morbidity.¹⁵ FPs play an important role in the early diagnosis, treatment, and comprehensive care of patients with HS. This includes monitoring patients, managing comorbidities, making appropriate referrals to dermatologists, and coordinating the multidisciplinary care that patients with HS require.

As many as 90% of patients with hidradenitis suppurativa have a history of smoking ≥ 20 packs of cigarettes per year.

A systematic review identified more than 50 interventions used to treat HS, most based on small observational studies and randomized controlled trials (RCTs) with a high risk of bias.⁶² FIGURE 2^2,62-69 provides an evidence-based treatment algorithm for HS, and TABLE 3^{2,63,64,70-75} summarizes the most commonly used treatments.

Biologic agents

Adalimumab (ADA) is a fully human immunoglobulin G1 monoclonal antibody that binds to TNF-alpha, neutralizes its bioactivity, and induces apoptosis of TNF-expressing mononuclear cells. It is the only medication approved by the US Food and Drug Administration for active refractory moderate and severe HS.^62,65 Several double-blinded RCTs, including PIONEER I and PIONEER II, studied the effectiveness of ADA for HS and found significant clinical responses at Week 12, 50% reduction in abscess and nodule counts, no increase in abscesses or draining fistulas at Week 12, and sustained improvement in lesion counts, pain, and QOL.^66,67,76

IL-1 and IL-23 inhibitors. The efficacy of etanercept and golimumab (anti-TNF), as well as anakinra (IL-1 inhibitor) and ustekinumab (IL-1/IL-23 inhibitor), continue to be investigated with variable results; they are considered second-line treatment for active refractory moderate and severe HS after ADA.^65,77-80 In­fliximab (IL-1 beta inhibitor) has shown no effect on reducing disease severity.⁷⁰Compared to other treatments, biologic therapy is associated with higher costs (TABLE 3),^{2,63,64,70-75} an increased risk for reactivation of latent infections (eg, tuberculosis, herpes simplex, and hepatitis C virus [HCV], and B [HBV]), and an attenuated response to vaccines.⁸¹ Prior to starting biologic therapy, FPs should screen patients with HS for tuberculosis and HBV, consider HIV and HCV screening in at-risk patients, and optimize the immunization status of the patient.^82,83 While inactivated vaccines can be administered without discontinuing biologic treatment, patients should avoid live-attenuated vaccines while taking biologics.⁸³

Continue to: Antibiotic therapy

Topical antibiotics are considered first-line treatment for mild and moderate uncomplicated HS.^63,64 Clindamycin 1%, the only topical antibiotic studied in a small double-blind RCT of patients with Hurley stage I and stage II HS, demonstrated significant clinical improvement after 12 weeks of treatment (twice- daily application), compared to placebo.⁸⁴ Topical clindamycin is also recommended to treat flares in patients with mild disease.^2,64

Oral antibiotics. Tetracycline (500 mg twice daily for 4 months) is considered a second-line treatment for patients with mild HS.^64,68 Doxycycline (200 mg/d for 3 months) may also be considered as a second-line treatment in patients with mild disease.⁸⁵

All patients with hidradenitis suppurativa should be screened for depression, anxiety, social isolation, and low self-esteem.

Combination oral clindamycin (300 mg) and rifampicin (300 mg) twice daily for 10 weeks is recommended as first-line treatment for patients with moderate HS.^2,64,69 Combination rifampin (300 mg twice daily), moxifloxacin (400 mg/d), and metronidazole (500 mg three times a day) is not routinely recommended due to increased risk of ­toxicity.²

Ertapenem (1 g intravenously daily for 6 weeks) is supported by lower-level evidence as a third-line rescue therapy option and as a bridge to surgery; however, limitations for home infusions, costs, and concerns for antibiotic resistance limit its use.^2,86

Corticosteroids and systemic immunomodulators

Intralesional triamcinolone (2-20 mg) may be beneficial in the early stages of HS, although its use is based on a small prospective open study of 33 patients.⁸⁷ A recent double-blind placebo-controlled RCT comparing varying concentrations of intralesional triamcinolone (10 mg/mL and 40 mg/mL) vs normal saline showed no statistically significant difference in inflammatory clearance, pain reduction, or patient satisfaction.⁸⁸

Continue to: Short-term systemic corticosteroid tapers...

Short-term systemic corticosteroid tapers (eg, prednisone, starting at 0.5-1 mg/kg) are recommended to treat flares. Long-term corticosteroids and cyclosporine are reserved for patients with severe refractory disease; however, due to safety concerns, their regular use is strongly discouraged.^63,64,85 There is limited evidence to support the use of methotrexate for severe refractory disease, and its use is not recommended.⁶³

Hormonal therapy

The use of hormonal therapy for HS is limited by the low-quality evidence (eg, anecdotal evidence, small retrospective analyses, uncontrolled trials).^33,63 The only exception is a small double-blind controlled crossover trial from 1986 showing that the antiandrogen effects of combination oral contraceptives (ethinyloestradiol 50 mcg/cyproterone acetate in a reverse sequential regimen and ethinyloestradiol 50 mcg/norgestrel 500 mcg) improved HS lesions.⁸⁹

Spironolactone, an antiandrogen diuretic, has been studied in small case report series with a high risk for bias. It is used mainly in female patients with mild or moderate disease, or in combination with other agents in patients with severe HS. Further research is needed to determine its utility in the treatment of HS.^63,90,91

Metformin, alone or in combination with other therapies (dapsone, finasteride, liraglutide), has been analyzed in small prospective studies of primarily female patients with different severities of HS, obesity, and PCOS. These studies have shown improvement in lesions, QOL, and reduction of workdays lost.^92,93

Finasteride. Studies have shown finasteride (1.25-5 mg/d) alone or in combination with other treatments (metformin, liraglutide, levonorgestrel-ethinyl estradiol, and dapsone) provided varying degrees of resolution or improvement in patients with severe and advanced HS. Finasteride has been used for 4 to 16 weeks with a good safety profile.^92,94-96

Continue to: Retinoids

Acitretin, alitretinoin, and isotretinoin have been studied in small retrospective studies to manage HS, with variable results.^97-99 Robust prospective studies are needed. Retinoids, in general, should be considered as a second- or third-line treatment for moderate to severe HS.⁶³

Surgical intervention

Surgical interventions, which should be considered in patients with widespread mild, moderate, or severe disease, are associated with improved daily activity and work productivity.¹⁰⁰ Incision and drainage should be avoided in patients with HS, as this technique does not remove the affected follicles and is associated with 100% recurrence.¹⁰¹

Wide excision is the preferred surgical technique for patients with Hurley stage II and stage III HS; it is associated with lower recurrence rates (13%) compared to local excision (22%) and deroofing (27%).¹⁰² Secondary intention healing is the most commonly chosen method, based on lower recurrence rates than primary closure.¹⁰²

STEEP and laser techniques. The skin-tissue-sparing excision with electrosurgical peeling (STEEP) procedure involves successive tangential excision of affected tissue until the epithelized bottom of the sinus tracts has been reached. This allows for the removal of fibrotic tissue and the sparing of the deep subcutaneous fat. STEEP is associated with 30% of relapses after 43 months.⁷¹

When considering biologic therapy, screen all patients with hidradenitis suppurativa for tuberculosis and hepatitis B, and confirm they are current with age-appropriate immunizations.

Laser surgery has also been studied in patients with Hurley stage II and stage III HS. The most commonly used lasers for HS are the 1064-nm neodymium-doped yttrium aluminum garnet (Nd: YAG) and the carbon dioxide laser; they have been shown to reduce disease severity in inguinal, axillary, and inflammatory sites.^72-74

Pain management: Start with lidocaine, NSAIDs

There are few studies about HS-associated pain management.¹⁰³ For acute episodes, short-acting nonopioid local treatment with lidocaine, topical or oral nonsteroidal anti-inflammatory drugs, and acetaminophen are preferred. Opioids should be reserved for moderate-to-severe pain that has not responded to other analgesics. Adjuvant therapy with pregabalin, gabapentin, selective serotonin reuptake inhibitors, or serotonin-norepinephrine reuptake inhibitors can also be considered for the comanagement of pain and depression.^62,104

Consider this tool to measure treatment response

The HS clinical response (HiSCR) tool is an outcome measure used to evaluate treatment outcomes. The tool uses an HS-specific binary score with the following criteria:

1. ≥ 50% reduction in the number of inflammatory nodules;
2. no increase in the number of abscesses; and
3. no increase in the number of draining fistulas.¹⁰⁵

The HiSCR was developed for the ­PIONEER studies^105,106 to assess the response to ADA treatment. It is the only HS scoring system to undergo an extensive validation process with a meaningful clinical endpoint for HS treatment evaluation that is easy to use. Compared to the HS-PGA score (clear, minimal, mild), HiSCR was more responsive to change in patients with HS.^105,106 

CORRESPONDENCE
Cristina Marti-Amarista, MD, 101 Nicolls Road, Stony Brook, NY, 11794-8228; [email protected]

Hidradenitis suppurativa (HS), also known as acne inversa or Verneuil disease, is a chronic, recurrent, inflammatory occlusive disease affecting the terminal follicular epithelium in apocrine gland–bearing skin areas.¹ HS manifests as painful nodules, abscesses, fistulas, and scarring and often has a severe psychological impact on the affected patient.²

When HS was first identified in the 1800s, it was believed to result from a dysfunction of the sweat glands.³ In 1939, scientists identified the true cause: follicular occlusion.³

Due to its chronic nature, heterogeneity in presentation, and apparent low prevalence,⁴ HS is considered an orphan disease.⁵ Over the past 10 years, there has been a surge in HS research—particularly in medical management—which has provided a better understanding of this condition.^6,7

In this review, we discuss the most updated evidence regarding the diagnosis and treatment of HS to guide the family physician (FP)’s approach to managing this debilitating disease. But first, we offer a word about the etiology and pathophysiology of the condition.

3 events set the stage for hidradenitis suppurativa

Although the exact cause of HS is still unknown, some researchers have hypothesized that HS results from a combination of genetic predisposition and environmental and lifestyle factors.^8-12 The primary mechanism of HS is the obstruction of the terminal follicular epithelium by a keratin plug.^1,13,14 A systematic review of molecular inflammatory pathways involved in HS divides the pathogenesis of HS into 3 events: follicular occlusion followed by dilation, follicular rupture and inflammatory response, and chronic inflammatory state with sinus tracts.⁸

An underreported condition

HS is often underreported and misdiagnosed.^4,15 Globally, the prevalence of HS varies from < 1% to 4%.^15,16 A systematic review with meta-analysis showed a higher prevalence of HS in females compared to males in American and European populations.¹⁷ In the United States, the overall frequency of HS is 0.1%, or 98 per 100,000 persons.¹⁶ The prevalence of HS is highest among patients ages 30 to 39 years; there is decreased prevalence in patients ages 55 years and older.^16,18

Who is at heightened risk?

Recent research has shown a relationship between ethnicity and HS.^16,19,20 African American and biracial groups (defined as African American and White) have a 3-fold and 2-fold greater prevalence of HS, respectively, compared to White patients.¹⁶ However, the prevalence of HS in non-White ethnic groups may be underestimated in clinical trials due to a lack of representation and subgroup analyses based on ethnicity, which may affect generalizability in HS recommendations.²¹

Continue to: Genetic predisposition

Genetic predisposition. As many as 40% of patients with HS report having at least 1 affected family member. A positive family history of HS is associated with earlier onset, longer disease duration, and severe disease.²² HS is genetically heterogeneous, and several mutations (eg, gamma secretase, PSTPIP1, PSEN1 genes) have been identified in patients and in vitro as the cause of dysregulation of epidermal proliferation and differentiation, immune dysregulation, and promotion of amyloid formation.^8,23-25

Obesity and metabolic risk factors. There is a strong relationship between HS and obesity. As many as 70% of patients with HS are obese, and 9% to 40% have metabolic syndrome.^12,18,26-28 Obesity is associated with maceration and mechanical stress, increased fragility of the dermo-epidermal junction, changes in cutaneous blood flow, and subdermal fat inflammation—all of which favor the pathophysiology of HS.^29,30

Smoking. Tobacco smoking is associated with severe HS and a lower chance of remission.¹² Population-based studies have shown that as many as 90% of patients with HS have a history of smoking ≥ 20 packs of cigarettes per year.^{1,12,18,31,32} The nicotine and thousands of other chemicals present in cigarettes trigger keratinocytes and fibroblasts, resulting in epidermal hyperplasia, infundibular hyperkeratosis, excessive cornification, and dysbiosis.^8,23,24

Hormones. The exact role sex hormones play in the pathogenesis of HS remains unclear.^8,32 Most information is based primarily on small studies looking at antiandrogen treatments, HS activity during the menstrual cycle and pregnancy, HS exacerbation related to androgenic effects of hormonal contraception, and the association of HS with metabolic-endocrine disorders (eg, polycystic ovary syndrome [PCOS]).^8,33

A family history of hidradenitis suppurativa is associated with earlier onset, longer disease duration, and severe disease.

Androgens induce hyperkeratosis that may lead to follicular occlusion—the hallmark of HS pathology.³⁴ A systematic review looking at the role of androgen and estrogen in HS found that while some patients with HS have elevated androgen levels, most have androgen and estrogen levels within normal range.³⁵ Therefore, increased peripheral androgen receptor sensitivity has been hypothesized as the mechanism of action contributing to HS manifestation.³⁴

Continue to: Host-defense defects

Host-defense defects. HS shares a similar cytokine profile with other well-­established immune-mediated inflammatory diseases, including pyoderma gangrenosum (PG)^36,37 and Crohn disease.^38-40 HS is characterized by the expression of several immune mediators, including tumor necrosis factor-alpha (TNF-alpha), interleukin-1 ­alpha (IL-1 alpha), IL-1 beta, IL-8, IL-17, and the IL-23/T helper 17 pathway, all of which are upregulated in other inflammatory diseases and also result in an abnormal innate immune response.^8,24 The recently described clinical triad of PG, acne, and HS (PASH) and the tetrad of pyogenic arthritis, PG, acne, and HS (PAPASH) further support the role of immune dysregulation in the pathogenesis of HS.⁴⁰ Nonetheless, further studies are needed to determine the exact pathways of cytokine effect in HS.⁴¹

Use these criteria to make the diagnosis

The US and Canadian Hidradenitis Suppurativa Foundations (HSF) guidelines base the clinical diagnosis of HS on the following criteria²:

• Typical HS lesions: Erythematous skin lesions; inflamed, deep-seated painful nodules; “tombstone” double-ended comedones; sinus tracts; scarring; deformity. FIGURES 1A-1E show typical lesions seen in patients with HS.
• Typical locations: Intertriginous regions—apocrine gland–containing areas in axilla, groin, perineal region, buttocks, gluteal cleft, and mammary folds; beltline and waistband areas; areas of skin compression and friction.
• Recurrence and chronicity: Recurrent painful or suppurating lesions that appear more than twice in a 6-month period.^2,41-43

Patients with HS usually present with painful recurrent abscesses and scarring and often report multiple visits to the emergency department for drainage or failed antibiotic treatment for abscesses.^15,44

Ask patients these 2 questions. Vinding et al⁴⁵ developed a survey for the diagnosis of HS using 2 simple questions based on the 3 criteria established by the HSF:

1. “Have you had an outbreak of boils during the last 6 months?” and
2. “Where and how many boils have you had?” (This question includes a list of the typical HS locations—eg, axilla, groin, genitals, area under breast.)

In their questionnaire, Vinding et al⁴⁵ found that an affirmative answer to Question 1 and reports of > 2 boils in response to Question 2 correlated to a sensitivity of 90%, specificity of 97%, positive predictive value of 96%, and negative predictive value of 92% for the diagnosis of HS. The differential diagnosis of HS is summarized in TABLE 1.^42,45-52

Continue to: These tools can help you to stage hidradenitis suppurativa

Multiple tools are available to assess the severity of HS.⁵³ We will describe the Hurley staging system and the International Hidradenitis Suppurativa Severity Score System (IHS4). Other diagnostic tools, such as the Sartorius score and the Hidradenitis Suppurativa Physician’s Global Assessment Scale (HS-PGA), can be time-consuming and challenging to interpret, limiting their use in the clinical setting.^2,54

Hurley staging system (available at www.hsdiseasesource.com/hs-disease-­staging) considers the presence of nodules, abscesses, sinus tracts, and scarring affecting an entire anatomical area.^13,55 This system is most useful as a rapid classification tool for patients with HS in the clinical setting but should not be used to assess clinical response.^2,13,56

The IHS4 (available at https://online­ library.wiley.com/doi/10.1111/bjd.15748) is a validated and easy-to-use tool for assessing HS and guiding the therapeutic strategy in clinical practice.⁵⁴ With IHS4, the clinician must calculate the following:

• total number of nodules > 10 mm in diameter
• total number of abscesses multiplied by 2, and
• total number of draining tunnels (fistulae/sinuses) multiplied by 4.

Mild HS is defined as a score ≤ 3 points; moderate HS, 4 to 10 points; and severe HS, ≥ 11 points.⁵⁴

No diagnostic tests, but ultrasound may be helpful

There are currently no established biological markers or specific tests for diagnosing HS.¹⁵ Ultrasound is emerging as a tool to assess dermal thickness, hair follicle morphology, and number and extent of fluid collections. Two recent studies showed that pairing clinical assessment with ultrasound findings improves accuracy of scoring in 84% of cases.^57,58 For patients with severe HS, skin biopsy can be considered to rule out squamous cell carcinoma. Cultures, however, have limited utility except for suspected superimposed bacterial infection.²

Continue to: Screening for comorbidities

Screening for comorbidities

HSF recommends clinicians screen patients for comorbidities associated with HS (TABLE 2).² Overall, screening patients for active and past history of smoking is strongly recommended, as is screening for metabolic syndrome, hyperlipidemia, type 2 diabetes (1.5- to 3-fold greater risk of type 2 diabetes in HS patients), and PCOS (3-fold greater risk).^2,26,27,59 Screening patients for depression and anxiety is also routinely recommended.² However, the authors of this article strongly recommend screening all patients with HS for psychiatric comorbidities, as research has shown a 2-fold greater risk of depression and anxiety, social isolation, and low self-esteem that severely limits quality of life (QOL) in this patient population.^60,61

Management

Treat existing lesions, reduce formation of new ones

The main goals of treatment for patients with HS are to treat existing lesions and reduce associated symptoms, reduce the formation of new lesions, and minimize associated psychological morbidity.¹⁵ FPs play an important role in the early diagnosis, treatment, and comprehensive care of patients with HS. This includes monitoring patients, managing comorbidities, making appropriate referrals to dermatologists, and coordinating the multidisciplinary care that patients with HS require.

As many as 90% of patients with hidradenitis suppurativa have a history of smoking ≥ 20 packs of cigarettes per year.

A systematic review identified more than 50 interventions used to treat HS, most based on small observational studies and randomized controlled trials (RCTs) with a high risk of bias.⁶² FIGURE 2^2,62-69 provides an evidence-based treatment algorithm for HS, and TABLE 3^{2,63,64,70-75} summarizes the most commonly used treatments.

Biologic agents

Adalimumab (ADA) is a fully human immunoglobulin G1 monoclonal antibody that binds to TNF-alpha, neutralizes its bioactivity, and induces apoptosis of TNF-expressing mononuclear cells. It is the only medication approved by the US Food and Drug Administration for active refractory moderate and severe HS.^62,65 Several double-blinded RCTs, including PIONEER I and PIONEER II, studied the effectiveness of ADA for HS and found significant clinical responses at Week 12, 50% reduction in abscess and nodule counts, no increase in abscesses or draining fistulas at Week 12, and sustained improvement in lesion counts, pain, and QOL.^66,67,76

IL-1 and IL-23 inhibitors. The efficacy of etanercept and golimumab (anti-TNF), as well as anakinra (IL-1 inhibitor) and ustekinumab (IL-1/IL-23 inhibitor), continue to be investigated with variable results; they are considered second-line treatment for active refractory moderate and severe HS after ADA.^65,77-80 In­fliximab (IL-1 beta inhibitor) has shown no effect on reducing disease severity.⁷⁰Compared to other treatments, biologic therapy is associated with higher costs (TABLE 3),^{2,63,64,70-75} an increased risk for reactivation of latent infections (eg, tuberculosis, herpes simplex, and hepatitis C virus [HCV], and B [HBV]), and an attenuated response to vaccines.⁸¹ Prior to starting biologic therapy, FPs should screen patients with HS for tuberculosis and HBV, consider HIV and HCV screening in at-risk patients, and optimize the immunization status of the patient.^82,83 While inactivated vaccines can be administered without discontinuing biologic treatment, patients should avoid live-attenuated vaccines while taking biologics.⁸³

Continue to: Antibiotic therapy

Topical antibiotics are considered first-line treatment for mild and moderate uncomplicated HS.^63,64 Clindamycin 1%, the only topical antibiotic studied in a small double-blind RCT of patients with Hurley stage I and stage II HS, demonstrated significant clinical improvement after 12 weeks of treatment (twice- daily application), compared to placebo.⁸⁴ Topical clindamycin is also recommended to treat flares in patients with mild disease.^2,64

Oral antibiotics. Tetracycline (500 mg twice daily for 4 months) is considered a second-line treatment for patients with mild HS.^64,68 Doxycycline (200 mg/d for 3 months) may also be considered as a second-line treatment in patients with mild disease.⁸⁵

All patients with hidradenitis suppurativa should be screened for depression, anxiety, social isolation, and low self-esteem.

Combination oral clindamycin (300 mg) and rifampicin (300 mg) twice daily for 10 weeks is recommended as first-line treatment for patients with moderate HS.^2,64,69 Combination rifampin (300 mg twice daily), moxifloxacin (400 mg/d), and metronidazole (500 mg three times a day) is not routinely recommended due to increased risk of ­toxicity.²

Ertapenem (1 g intravenously daily for 6 weeks) is supported by lower-level evidence as a third-line rescue therapy option and as a bridge to surgery; however, limitations for home infusions, costs, and concerns for antibiotic resistance limit its use.^2,86

Corticosteroids and systemic immunomodulators

Intralesional triamcinolone (2-20 mg) may be beneficial in the early stages of HS, although its use is based on a small prospective open study of 33 patients.⁸⁷ A recent double-blind placebo-controlled RCT comparing varying concentrations of intralesional triamcinolone (10 mg/mL and 40 mg/mL) vs normal saline showed no statistically significant difference in inflammatory clearance, pain reduction, or patient satisfaction.⁸⁸

Continue to: Short-term systemic corticosteroid tapers...

Short-term systemic corticosteroid tapers (eg, prednisone, starting at 0.5-1 mg/kg) are recommended to treat flares. Long-term corticosteroids and cyclosporine are reserved for patients with severe refractory disease; however, due to safety concerns, their regular use is strongly discouraged.^63,64,85 There is limited evidence to support the use of methotrexate for severe refractory disease, and its use is not recommended.⁶³

Hormonal therapy

The use of hormonal therapy for HS is limited by the low-quality evidence (eg, anecdotal evidence, small retrospective analyses, uncontrolled trials).^33,63 The only exception is a small double-blind controlled crossover trial from 1986 showing that the antiandrogen effects of combination oral contraceptives (ethinyloestradiol 50 mcg/cyproterone acetate in a reverse sequential regimen and ethinyloestradiol 50 mcg/norgestrel 500 mcg) improved HS lesions.⁸⁹

Spironolactone, an antiandrogen diuretic, has been studied in small case report series with a high risk for bias. It is used mainly in female patients with mild or moderate disease, or in combination with other agents in patients with severe HS. Further research is needed to determine its utility in the treatment of HS.^63,90,91

Metformin, alone or in combination with other therapies (dapsone, finasteride, liraglutide), has been analyzed in small prospective studies of primarily female patients with different severities of HS, obesity, and PCOS. These studies have shown improvement in lesions, QOL, and reduction of workdays lost.^92,93

Finasteride. Studies have shown finasteride (1.25-5 mg/d) alone or in combination with other treatments (metformin, liraglutide, levonorgestrel-ethinyl estradiol, and dapsone) provided varying degrees of resolution or improvement in patients with severe and advanced HS. Finasteride has been used for 4 to 16 weeks with a good safety profile.^92,94-96

Continue to: Retinoids

Acitretin, alitretinoin, and isotretinoin have been studied in small retrospective studies to manage HS, with variable results.^97-99 Robust prospective studies are needed. Retinoids, in general, should be considered as a second- or third-line treatment for moderate to severe HS.⁶³

Surgical intervention

Surgical interventions, which should be considered in patients with widespread mild, moderate, or severe disease, are associated with improved daily activity and work productivity.¹⁰⁰ Incision and drainage should be avoided in patients with HS, as this technique does not remove the affected follicles and is associated with 100% recurrence.¹⁰¹

Wide excision is the preferred surgical technique for patients with Hurley stage II and stage III HS; it is associated with lower recurrence rates (13%) compared to local excision (22%) and deroofing (27%).¹⁰² Secondary intention healing is the most commonly chosen method, based on lower recurrence rates than primary closure.¹⁰²

STEEP and laser techniques. The skin-tissue-sparing excision with electrosurgical peeling (STEEP) procedure involves successive tangential excision of affected tissue until the epithelized bottom of the sinus tracts has been reached. This allows for the removal of fibrotic tissue and the sparing of the deep subcutaneous fat. STEEP is associated with 30% of relapses after 43 months.⁷¹

When considering biologic therapy, screen all patients with hidradenitis suppurativa for tuberculosis and hepatitis B, and confirm they are current with age-appropriate immunizations.

Laser surgery has also been studied in patients with Hurley stage II and stage III HS. The most commonly used lasers for HS are the 1064-nm neodymium-doped yttrium aluminum garnet (Nd: YAG) and the carbon dioxide laser; they have been shown to reduce disease severity in inguinal, axillary, and inflammatory sites.^72-74

Pain management: Start with lidocaine, NSAIDs

There are few studies about HS-associated pain management.¹⁰³ For acute episodes, short-acting nonopioid local treatment with lidocaine, topical or oral nonsteroidal anti-inflammatory drugs, and acetaminophen are preferred. Opioids should be reserved for moderate-to-severe pain that has not responded to other analgesics. Adjuvant therapy with pregabalin, gabapentin, selective serotonin reuptake inhibitors, or serotonin-norepinephrine reuptake inhibitors can also be considered for the comanagement of pain and depression.^62,104

Consider this tool to measure treatment response

The HS clinical response (HiSCR) tool is an outcome measure used to evaluate treatment outcomes. The tool uses an HS-specific binary score with the following criteria:

1. ≥ 50% reduction in the number of inflammatory nodules;
2. no increase in the number of abscesses; and
3. no increase in the number of draining fistulas.¹⁰⁵

The HiSCR was developed for the ­PIONEER studies^105,106 to assess the response to ADA treatment. It is the only HS scoring system to undergo an extensive validation process with a meaningful clinical endpoint for HS treatment evaluation that is easy to use. Compared to the HS-PGA score (clear, minimal, mild), HiSCR was more responsive to change in patients with HS.^105,106 

CORRESPONDENCE
Cristina Marti-Amarista, MD, 101 Nicolls Road, Stony Brook, NY, 11794-8228; [email protected]

A 48-YEAR-OLD WOMAN presented to Dermatology for evaluation of a 6-cm abdominal lesion that had been present for 5 weeks ­(FIGURE 1). The lesion was originally about the size of a quarter, but it started to enlarge after treatment of an asthma exacerbation with a 4-day course of prednisone. It continued to grow after another physician, likely presuming the lesion was a corticosteroid-responsive dermatosis (eg, nummular eczema, granuloma annulare, or erythema annulare centrifugum), prescribed a 2-week trial of clobetasol ointment. Physical examination revealed a mildly pruritic, 6-cm erythematous plaque with scaly, annular, concentric rings on the left lower abdomen. The patient had no travel history.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

The patient was given a diagnosis of tinea incognito, a form of tinea corporis that is exacerbated by the inappropriate use of corticosteroids in the management of a cutaneous fungal infection.¹ Furthermore, this patient’s case was consistent with tinea pseudoimbricata, a variant of tinea incognito. Tinea pseudoimbricata is characterized by striking concentric scaly rings that mimic tinea imbricata, a fungal infection caused by the dermatophyte Trichophyton concentricum, which is commonly found in tropical areas.²

A common infection is alteredby steroid use

Tinea corporis has a relatively high prevalence. Approximately 10% to 20% of the world population is affected by fungal skin infections.³ 

T rubrum is the most common cause of tinea corporis. Other causes include T tonsurans, T interdigitale, T ­violaceum, Microsporum canis, M gypseum, and M audouinii.

These steroid treatments caused the abdominal lesion to morph from the typical appearance of tinea corporis to an erythematous plaque with striking concentric scaly rings.

Tinea corporis can be acquired through direct contact with an infected person, animal, or fomite. It may also be acquired through autoinoculation from another area of the body containing a dermatophyte fungal infection. Tinea corporis lesions are usually pruritic, erythematous, annular plaques with overlying scale and central clearing.

How steroid use can change the picture. Treatment with corticosteroids is ineffective for fungal skin infections and causes immunosuppression, allowing the fungus to thrive. This patient had been treated with a topical steroid (clobetasol) for the abdominal lesion caused by tinea corporis, as well as an oral steroid (prednisone) for an asthma exacerbation. These steroid treatments caused the abdominal lesion to morph from the typical appearance of tinea corporis—classically an annular erythematous plaque with overlying scale and central clearing—to an erythematous plaque with striking concentric scaly rings.

Continue to: Clinical exam can provide clues; KOH examination can reveal the Dx

The differential diagnosis for an annular skin lesion includes not only tinea corporis, but also superficial erythema annulare centrifugum, pityriasis rosea, granuloma annulare, subacute cutaneous lupus erythematosus (SCLE), and nummular eczema.

Superficial erythema annulare centrifugum, like tinea corporis, has scale. But the location of the scale sets the 2 apart. Superficial erythema annulare centrifugum lesions have a central trailing scale, whereas tinea corporis lesions have a peripheral leading scale.⁴

Pityriasis rosea forms multiple lesions in a “Christmas tree” pattern on the trunk, sometimes beginning with a single herald patch. Our patient’s single lesion with concentric scaly rings was inconsistent with the distribution and quality of the lesions in pityriasis rosea.⁴

Granuloma annulare lesions are smooth, nonscaly plaques that are most often seen on the dorsal hands and feet. The scaly manifestation of our patient’s lesion was not consistent with this diagnosis.⁴

SCLE lesions are typically photodistributed on sun-exposed skin (eg, the neck, upper trunk, or arms), whereas our patient’s lesion involved a sun-protected site.⁴

Continue to: Nummular eczema

Nummular eczema can be differentiated from tinea corporis by potassium hydroxide (KOH) examination. Nummular eczema is characterized by a negative KOH exam and response to topical corticosteroids.⁴

Performing a KOH examination, using the skin scrapings from the active border of a plaque, is useful on any lesion with potential fungal etiology. If the cause is indeed a dermatophyte infection, segmented fungal hyphae will be seen under light microscopy (FIGURE 2).¹ If a KOH examination is not feasible, a skin scraping can be performed with a surgical scalpel blade and collected in a sterile urine cup for stain and culture at a qualified laboratory.

Topical and oral antifungal medications combat dermatophyte fungi

Treatments for cutaneous infections caused by dermatophyte fungi, such as tinea corporis, include topical and oral antifungals. The choice of agent depends on the extent of the disease.

Limited, localized disease can be treated topically with allylamines (terbinafine, naftifine) or imidazoles (clotrimazole). Other topical agents, such as butenafine, ciclopirox, and tolnaftate, also may be used.

Extensive disease, or tinea infection of vellus hairs, may require treatment with oral antifungal medications, such as the azoles (itraconazole, fluconazole), allylamines (terbinafine), or griseofulvin. Systemic therapy with oral antifungals has been associated with liver damage; therefore, oral therapy should not be used in patients with liver disease and liver enzymes should be monitored when appropriate.⁵ Nystatin is not effective in treating dermatophyte fungal infections.¹

One complication of the inappropriate use of steroids on a dermatophyte infection is an increased risk of the fungus extending from the superficial skin into the hair follicles in the dermis, resulting in a condition known as Majocchi granuloma. Follicular infection is more severe and requires oral antifungal medication, such as terbinafine, itraconazole, fluconazole, or griseofulvin.¹

Our patient was treated with terbinafine 250 mg/d for 4 weeks, due to the possibility of follicular infection. After the completion of 4 weeks of therapy, the patient’s cutaneous symptoms had resolved.

A 48-YEAR-OLD WOMAN presented to Dermatology for evaluation of a 6-cm abdominal lesion that had been present for 5 weeks ­(FIGURE 1). The lesion was originally about the size of a quarter, but it started to enlarge after treatment of an asthma exacerbation with a 4-day course of prednisone. It continued to grow after another physician, likely presuming the lesion was a corticosteroid-responsive dermatosis (eg, nummular eczema, granuloma annulare, or erythema annulare centrifugum), prescribed a 2-week trial of clobetasol ointment. Physical examination revealed a mildly pruritic, 6-cm erythematous plaque with scaly, annular, concentric rings on the left lower abdomen. The patient had no travel history.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

The patient was given a diagnosis of tinea incognito, a form of tinea corporis that is exacerbated by the inappropriate use of corticosteroids in the management of a cutaneous fungal infection.¹ Furthermore, this patient’s case was consistent with tinea pseudoimbricata, a variant of tinea incognito. Tinea pseudoimbricata is characterized by striking concentric scaly rings that mimic tinea imbricata, a fungal infection caused by the dermatophyte Trichophyton concentricum, which is commonly found in tropical areas.²

A common infection is alteredby steroid use

Tinea corporis has a relatively high prevalence. Approximately 10% to 20% of the world population is affected by fungal skin infections.³ 

T rubrum is the most common cause of tinea corporis. Other causes include T tonsurans, T interdigitale, T ­violaceum, Microsporum canis, M gypseum, and M audouinii.

These steroid treatments caused the abdominal lesion to morph from the typical appearance of tinea corporis to an erythematous plaque with striking concentric scaly rings.

Tinea corporis can be acquired through direct contact with an infected person, animal, or fomite. It may also be acquired through autoinoculation from another area of the body containing a dermatophyte fungal infection. Tinea corporis lesions are usually pruritic, erythematous, annular plaques with overlying scale and central clearing.

How steroid use can change the picture. Treatment with corticosteroids is ineffective for fungal skin infections and causes immunosuppression, allowing the fungus to thrive. This patient had been treated with a topical steroid (clobetasol) for the abdominal lesion caused by tinea corporis, as well as an oral steroid (prednisone) for an asthma exacerbation. These steroid treatments caused the abdominal lesion to morph from the typical appearance of tinea corporis—classically an annular erythematous plaque with overlying scale and central clearing—to an erythematous plaque with striking concentric scaly rings.

Continue to: Clinical exam can provide clues; KOH examination can reveal the Dx

The differential diagnosis for an annular skin lesion includes not only tinea corporis, but also superficial erythema annulare centrifugum, pityriasis rosea, granuloma annulare, subacute cutaneous lupus erythematosus (SCLE), and nummular eczema.

Superficial erythema annulare centrifugum, like tinea corporis, has scale. But the location of the scale sets the 2 apart. Superficial erythema annulare centrifugum lesions have a central trailing scale, whereas tinea corporis lesions have a peripheral leading scale.⁴

Pityriasis rosea forms multiple lesions in a “Christmas tree” pattern on the trunk, sometimes beginning with a single herald patch. Our patient’s single lesion with concentric scaly rings was inconsistent with the distribution and quality of the lesions in pityriasis rosea.⁴

Granuloma annulare lesions are smooth, nonscaly plaques that are most often seen on the dorsal hands and feet. The scaly manifestation of our patient’s lesion was not consistent with this diagnosis.⁴

SCLE lesions are typically photodistributed on sun-exposed skin (eg, the neck, upper trunk, or arms), whereas our patient’s lesion involved a sun-protected site.⁴

Continue to: Nummular eczema

Nummular eczema can be differentiated from tinea corporis by potassium hydroxide (KOH) examination. Nummular eczema is characterized by a negative KOH exam and response to topical corticosteroids.⁴

Performing a KOH examination, using the skin scrapings from the active border of a plaque, is useful on any lesion with potential fungal etiology. If the cause is indeed a dermatophyte infection, segmented fungal hyphae will be seen under light microscopy (FIGURE 2).¹ If a KOH examination is not feasible, a skin scraping can be performed with a surgical scalpel blade and collected in a sterile urine cup for stain and culture at a qualified laboratory.

Topical and oral antifungal medications combat dermatophyte fungi

Treatments for cutaneous infections caused by dermatophyte fungi, such as tinea corporis, include topical and oral antifungals. The choice of agent depends on the extent of the disease.

Limited, localized disease can be treated topically with allylamines (terbinafine, naftifine) or imidazoles (clotrimazole). Other topical agents, such as butenafine, ciclopirox, and tolnaftate, also may be used.

Extensive disease, or tinea infection of vellus hairs, may require treatment with oral antifungal medications, such as the azoles (itraconazole, fluconazole), allylamines (terbinafine), or griseofulvin. Systemic therapy with oral antifungals has been associated with liver damage; therefore, oral therapy should not be used in patients with liver disease and liver enzymes should be monitored when appropriate.⁵ Nystatin is not effective in treating dermatophyte fungal infections.¹

One complication of the inappropriate use of steroids on a dermatophyte infection is an increased risk of the fungus extending from the superficial skin into the hair follicles in the dermis, resulting in a condition known as Majocchi granuloma. Follicular infection is more severe and requires oral antifungal medication, such as terbinafine, itraconazole, fluconazole, or griseofulvin.¹

Our patient was treated with terbinafine 250 mg/d for 4 weeks, due to the possibility of follicular infection. After the completion of 4 weeks of therapy, the patient’s cutaneous symptoms had resolved.

A 48-YEAR-OLD WOMAN presented to Dermatology for evaluation of a 6-cm abdominal lesion that had been present for 5 weeks ­(FIGURE 1). The lesion was originally about the size of a quarter, but it started to enlarge after treatment of an asthma exacerbation with a 4-day course of prednisone. It continued to grow after another physician, likely presuming the lesion was a corticosteroid-responsive dermatosis (eg, nummular eczema, granuloma annulare, or erythema annulare centrifugum), prescribed a 2-week trial of clobetasol ointment. Physical examination revealed a mildly pruritic, 6-cm erythematous plaque with scaly, annular, concentric rings on the left lower abdomen. The patient had no travel history.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

The patient was given a diagnosis of tinea incognito, a form of tinea corporis that is exacerbated by the inappropriate use of corticosteroids in the management of a cutaneous fungal infection.¹ Furthermore, this patient’s case was consistent with tinea pseudoimbricata, a variant of tinea incognito. Tinea pseudoimbricata is characterized by striking concentric scaly rings that mimic tinea imbricata, a fungal infection caused by the dermatophyte Trichophyton concentricum, which is commonly found in tropical areas.²

A common infection is alteredby steroid use

Tinea corporis has a relatively high prevalence. Approximately 10% to 20% of the world population is affected by fungal skin infections.³ 

T rubrum is the most common cause of tinea corporis. Other causes include T tonsurans, T interdigitale, T ­violaceum, Microsporum canis, M gypseum, and M audouinii.

These steroid treatments caused the abdominal lesion to morph from the typical appearance of tinea corporis to an erythematous plaque with striking concentric scaly rings.

Tinea corporis can be acquired through direct contact with an infected person, animal, or fomite. It may also be acquired through autoinoculation from another area of the body containing a dermatophyte fungal infection. Tinea corporis lesions are usually pruritic, erythematous, annular plaques with overlying scale and central clearing.

How steroid use can change the picture. Treatment with corticosteroids is ineffective for fungal skin infections and causes immunosuppression, allowing the fungus to thrive. This patient had been treated with a topical steroid (clobetasol) for the abdominal lesion caused by tinea corporis, as well as an oral steroid (prednisone) for an asthma exacerbation. These steroid treatments caused the abdominal lesion to morph from the typical appearance of tinea corporis—classically an annular erythematous plaque with overlying scale and central clearing—to an erythematous plaque with striking concentric scaly rings.

Continue to: Clinical exam can provide clues; KOH examination can reveal the Dx

The differential diagnosis for an annular skin lesion includes not only tinea corporis, but also superficial erythema annulare centrifugum, pityriasis rosea, granuloma annulare, subacute cutaneous lupus erythematosus (SCLE), and nummular eczema.

Superficial erythema annulare centrifugum, like tinea corporis, has scale. But the location of the scale sets the 2 apart. Superficial erythema annulare centrifugum lesions have a central trailing scale, whereas tinea corporis lesions have a peripheral leading scale.⁴

Pityriasis rosea forms multiple lesions in a “Christmas tree” pattern on the trunk, sometimes beginning with a single herald patch. Our patient’s single lesion with concentric scaly rings was inconsistent with the distribution and quality of the lesions in pityriasis rosea.⁴

Granuloma annulare lesions are smooth, nonscaly plaques that are most often seen on the dorsal hands and feet. The scaly manifestation of our patient’s lesion was not consistent with this diagnosis.⁴

SCLE lesions are typically photodistributed on sun-exposed skin (eg, the neck, upper trunk, or arms), whereas our patient’s lesion involved a sun-protected site.⁴

Continue to: Nummular eczema

Nummular eczema can be differentiated from tinea corporis by potassium hydroxide (KOH) examination. Nummular eczema is characterized by a negative KOH exam and response to topical corticosteroids.⁴

Performing a KOH examination, using the skin scrapings from the active border of a plaque, is useful on any lesion with potential fungal etiology. If the cause is indeed a dermatophyte infection, segmented fungal hyphae will be seen under light microscopy (FIGURE 2).¹ If a KOH examination is not feasible, a skin scraping can be performed with a surgical scalpel blade and collected in a sterile urine cup for stain and culture at a qualified laboratory.

Topical and oral antifungal medications combat dermatophyte fungi

Treatments for cutaneous infections caused by dermatophyte fungi, such as tinea corporis, include topical and oral antifungals. The choice of agent depends on the extent of the disease.

Limited, localized disease can be treated topically with allylamines (terbinafine, naftifine) or imidazoles (clotrimazole). Other topical agents, such as butenafine, ciclopirox, and tolnaftate, also may be used.

Extensive disease, or tinea infection of vellus hairs, may require treatment with oral antifungal medications, such as the azoles (itraconazole, fluconazole), allylamines (terbinafine), or griseofulvin. Systemic therapy with oral antifungals has been associated with liver damage; therefore, oral therapy should not be used in patients with liver disease and liver enzymes should be monitored when appropriate.⁵ Nystatin is not effective in treating dermatophyte fungal infections.¹

One complication of the inappropriate use of steroids on a dermatophyte infection is an increased risk of the fungus extending from the superficial skin into the hair follicles in the dermis, resulting in a condition known as Majocchi granuloma. Follicular infection is more severe and requires oral antifungal medication, such as terbinafine, itraconazole, fluconazole, or griseofulvin.¹

Our patient was treated with terbinafine 250 mg/d for 4 weeks, due to the possibility of follicular infection. After the completion of 4 weeks of therapy, the patient’s cutaneous symptoms had resolved.

Several years into the pandemic, COVID-19 continues to deeply impact our society; at the time of publication of this review, 98.8 million cases in the United States have been reported to the Centers for Disease Control and Prevention (CDC).¹ Although many people recover well from infection, there is mounting concern regarding long-term sequelae of COVID-19. These long-term symptoms have been termed long COVID, among other names.

What exactly is long COVID?

The CDC and National Institutes of Health define long COVID as new or ongoing health problems experienced ≥ 4 weeks after initial infection.² Evidence suggests that even people who have mild initial COVID-19 symptoms are at risk for long COVID.

Available data about long COVID are imperfect, however; much about the condition remains poorly understood. For example, there is little evidence regarding the effect of vaccination and viral variants on the prevalence of long ­COVID. A recent study of more than 13 million people from the US Department of Veterans Affairs database did demonstrate that vaccination against SARS-CoV-2 lowered the risk for long ­COVID by only about 15%.³

Persistent symptoms associated with long COVID often lead to disability and decreased quality of life. Furthermore, long COVID is a challenge to treat because there is a paucity of evidence to guide COVID-19 treatment beyond initial infection.

The prevalence of long COVID symptoms appears to increase with age.

Because many patients who have ongoing COVID-19 symptoms will be seen in primary care, it is important to understand how to manage and support them. In this article, we discuss current understanding of long COVID epidemiology, symptoms that can persist 4 weeks after initial infection, and potential treatment options.

Prevalence and diagnosis

The prevalence of long COVID is not well defined because many epidemiologic studies rely on self-reporting. The CDC reports that 20% to 25% of COVID-19 survivors experience a new condition that might be attributable to their initial infection.⁴ Other studies variously cite 5% to 85% of people who have had a diagnosis of COVID-19 as experiencing long COVID, although that rate more consistently appears to be 10% to 30%.⁵

Copyright Brian Stauffer

A study of adult patients in France found that self-reported symptoms of long COVID, 10 to 12 months after the first wave of the pandemic (May through November 2020), were associated with the belief of having had COVID-19 but not necessarily with having tested positive for anti-SARS-CoV-2 antibodies,⁶ which indicates prior COVID-19. This complicates research on long COVID because, first, there is no specific test to confirm a diagnosis of long COVID and, second, studies often rely on self-reporting of earlier COVID-19.

Continue to: As such, long COVID...

As such, long COVID is diagnosed primarily through a medical history and physical examination. The medical history provides a guide as to whether additional testing is warranted to evaluate for known complications of COVID-19, such as deep vein thrombosis, pulmonary embolism, myocarditis, and pulmonary fibrosis. As of October 1, 2021, a new International Classification of Disease (10th Revision) code went into effect for post ­COVID condition, unspecified (U09.9).⁷

The prevalence of long COVID symptoms appears to increase with age. Among patients whose disease was diagnosed using code U09.9, most were 36 to 64 years of age; children and adults ages 22 years or younger constituted only 10.5% of diagnoses.⁷ Long COVID symptoms might also be more prevalent among women and in people with a preexisting chronic comorbidity.^2,7

Symptoms can be numerous, severe or mild, and lasting

Initially, there was no widely accepted definition of long COVID; follow-up in early studies ranged from 21 days to 2 years after initial infection (or from discharge, for hospitalized patients).⁸ Differences in descriptions that have been used on surveys to self-report symptoms make it a challenge to clearly summarize the frequency of each aspect of long COVID.

Long COVID can be mild or debilitating; severity can fluctuate. Common symptoms include fatigue, dyspnea or other breathing difficulties, headache, and cognitive dysfunction, but as many as 203 lasting symptoms have been reported.^2,8-12 From October 1, 2021, through January 31, 2022, the most common accompanying manifestations of long COVID were difficulty breathing, cough, and fatigue.⁷ Long COVID can affect multiple organ systems,^13,14 with symptoms varying by organ system affected. Regardless of the need for hospitalization initially, having had COVID-19 significantly increases the risk for subsequent death at 30 days and at 6 months after initial infection.¹⁵

The CDC reports that 20% to 25% of COVID-19 survivors experience a new condition that might be attributable to their initial infection.

Symptoms of long COVID have been reported as long as 2 years after initial infection.⁸ When Davis and colleagues studied the onset and progression of reported symptoms of long COVID,⁹ they determined that, among patients who reported recovery from COVID-19 in < 90 days, symptoms peaked at approximately Week 2 of infection. In comparison, patients who reported not having recovered in < 90 days had (1) symptoms that peaked later (2 months) and (2) on average, more symptoms (mean, 17 reported symptoms, compared to 11 in recovered ­patients).⁹

Continue to: Fatigue

Fatigue, including postexertion malaise and impaired daily function and mobility, is the most common symptom of long COVID,^8-10,14 reported in 28% to 98%¹⁴ of patients after initial COVID-19. This fatigue is more than simply being tired: Patients describe profound exhaustion, in which fatigue is out of proportion to exertion. Fatigue and myalgia are commonly reported among patients with impaired hepatic and pulmonary function as a consequence of long COVID.¹³ Patients often report that even minor activities result in decreased attention, focus, and energy, for many hours or days afterward. Fatigue has been reported to persist from 2.5 months to as long as 6 months after initial infection or hospitalization.^9,16

Postviral fatigue has been seen in other viral outbreaks and seems to share characteristics with myalgic encephalomyelitis/­chronic fatigue syndrome, or ME/CFS, which itself has historically been stigmatized and poorly understood.¹⁷ Long COVID fatigue might be more common among women and patients who have an existing diagnosis of depression and antidepressant use,^10,11,16,18 although the mechanism of this relationship is unclear. Potential mechanisms include damage from systemic inflammation to metabolism in the frontal lobe and cerebellum¹⁹ and direct infection by SARS-CoV-2 in skeletal muscle.²⁰ Townsend and colleagues¹⁶ found no relationship between long COVID fatigue and markers of inflammation (leukocyte, neutrophil, and lymphocyte counts; the neutrophil-to-lymphocyte ratio; lactate dehydrogenase; C-reactive protein; serum interleukin-6; and soluble CD25).

Neuropsychiatric symptoms are also common in long COVID and can have a significant impact on patients’ quality of life. Studies have reported poor sleep quality or insomnia (38% to 90%), headache (17% to 91.2%), speech and language problems (48% to 50%), confusion (20%), dementia (28.6%), difficulty concentrating (1.9% to 27%), and memory loss or cognitive impairment (5.4% to 73%).^9,10,14,15 For some patients, these symptoms persisted for ≥ 6 months, making it difficult for those affected to return to work.⁹

Isolation and loneliness, a common situation for patients with COVID-19, can have long-term effects on mental health.²¹ The COVID-19 pandemic itself has had a negative effect on behavioral health, including depression (4.3% to 25% of patients), anxiety (1.9% to 46%), obsessive compulsive disorder (4.9% to 20%), and posttraumatic stress disorder (29%).²² The persistence of symptoms of long COVID has resulted in a great deal of frustration, fear, and confusion for those affected—some of whom report a loss of trust in their community health care providers to address their ongoing struggles.²³ Such loss can be accompanied by a reported increase in feelings of anxiety and changes to perceptions of self (ie, “how I used to be” in contrast to “how I am now”).²³ These neuropsychiatric symptoms, including mental health conditions, appear to be more common among older adults.⁴

Other neurologic deficits found in long COVID include olfactory disorders (9% to 27% of patients), altered taste (5% to 18%), numbness or tingling sensations (6%), blurred vision (17.1%), and tinnitus (16.%).¹⁴ Dizziness (2.6% to 6%) and lightheadedness or presyncope (7%) have also been reported, although these symptoms appear to be less common than other neurocognitive effects.¹⁴

Continue to: The mechanism of action...

The mechanism of action of damage to the nervous system in long COVID is likely multifactorial. COVID-19 can directly infect the central nervous system through a hematogenous route, which can result in direct cytolytic damage to neurons. Infection can also affect the blood–brain barrier.²⁴ Additionally, COVID-19 can invade the central nervous system through peripheral nerves, including the olfactory and vagus nerves.²⁵ Many human respiratory viruses, including SARS-CoV-2, result in an increase in pro-inflammatory and anti-inflammatory cytokines; this so-called cytokine storm is an exaggerated response to infection and can trigger neurodegenerative and psychiatric syndromes.²⁶ It is unclear whether the cytokine storm is different for people with COVID-19, compared to other respiratory viruses.

Respiratory symptoms are very common after COVID-19¹⁵: In studies, as many as 87.1% of patients continued to have shortness of breath ≥ 140 days after initial symptom onset, including breathlessness (48% to 60%), wheezing (5.3%), cough (10.5% to 46%), and congestion (32%),^14,18 any of which can persist for as long as 6 months.⁹ Among a sample of previously hospitalized COVID-19 patients in Wuhan, China, 22% to 56% displayed a pulmonary diffusion abnormality 6 months later, with those who required supplemental oxygen during initial COVID-19 having a greater risk for these abnormalities at follow-up, compared to those who did not require supplemental oxygen (odds ratio = 2.42; 95% CI, 1.15-5.08).¹¹

Cardiovascular symptoms. New-onset autonomic dysfunction has been described in multiple case reports and in some larger cohort studies of patients post COVID-19.²⁷ Many common long COVID symptoms, including fatigue and orthostatic intolerance, are commonly seen in postural orthostatic tachycardia syndrome. Emerging evidence indicates that there are likely similar underlying mechanisms and a significant amount of overlap between long COVID and postural orthostatic tachycardia syndrome.²⁷

The high rate of cardiac complications post COVID-19 highlights the importance of a thorough evaluation and work-up of chest pain in patients who have had COVID-19.

A study of patients within the US Department of Veterans Affairs population found that, regardless of disease severity, patients who had a positive COVID-19 test had a higher rate of cardiac disease 30 days after diagnosis,²⁸ including stroke, transient ischemic attack, dysrhythmia, inflammatory heart disease, acute coronary disease, myocardial infarction, ischemic cardiopathy, angina, heart failure, nonischemic cardiomyopathy, and cardiac arrest. Patients with COVID-19 were at increased risk for major adverse cardiovascular events (myocardial infarction, stroke, and all-cause mortality).²⁸ Demographics of the VA population (ie, most are White men) might limit the generalizability of these data, but similar findings have been found elsewhere.^5,10,15Given that, in general, chest pain is common after the acute phase of an infection and the causes of chest pain are broad, the high rate of cardiac complications post COVID-19 nevertheless highlights the importance of a thorough evaluation and work-up of chest pain in patients who have had COVID-19.

Other symptoms. Body aches and generalized joint pain are another common symptom group of long COVID.⁹ These include body aches (20%), joint pain (78%), and muscle aches (87.7%).^14,18

Continue to: Commonly reported...

Commonly reported gastrointestinal symptoms include diarrhea, loss of appetite, nausea, and abdominal pain.^9,15

Other symptoms reported less commonly include dermatologic conditions, such as pruritus and rash; reproductive and endocrine symptoms, including extreme thirst, irregular menstruation, and sexual dysfunction; and new or exacerbated allergic response.⁹

Does severity of initial disease play a role?

Keep in mind that long COVID is not specific to patients who were hospitalized or had severe initial infection. In fact, 75% of patients who have a diagnosis of a post–COVID-19 condition were not hospitalized for their initial infection.⁷ However, the severity of initial COVID-19 infection might contribute to the presence or severity of long COVID symptoms²—although findings in current literature are mixed. For example:

• In reporting from Wuhan, China, higher position on a disease severity scale during a hospital stay for COVID-19 was associated with:
  • greater likelihood of reporting ≥ 1 symptoms at a 6-month ­follow-up
  • increased risk for pulmonary diffusion abnormalities, fatigue, and mood disorders.¹¹
• After 2 years’ follow-up of the same cohort, 55% of patients continued to report ≥ 1 symptoms of long COVID, and those who had been hospitalized with COVID-19 continued to report reduced health-related quality of life, compared to the control group.⁸
• Similarly, patients initially hospitalized with COVID-19 were more likely to experience impairment of ≥ 2 organs—in particular, the liver and pancreas—compared to nonhospitalized patients after a median 5 months post initial infection, among a sample in the United Kingdom.¹³
• In an international cohort, patients who reported a greater number of symptoms during initial COVID-19 were more likely to experience long COVID.¹²
• Last, long COVID fatigue did not vary by severity of initial COVID-19 infection among a sample of hospitalized and nonhospitalized participants in Dublin, Ireland.¹⁶

No specific treatments yet available

There are no specific treatments for long ­COVID; overall, the emphasis is on providing supportive care and managing preexisting chronic conditions.⁵ This is where expertise in primary care, relationships with patients and the community, and psychosocial knowledge can help patients recover from ongoing ­COVID-19 symptoms.

Long COVID–associated fatigue is more than simply being tired. Patients describe profound exhaustion, in which fatigue is out of proportion to exertion.

Clinicians should continue to perform a thorough physical assessment of patients with previous or ongoing COVID-19 to identify and monitor new or recurring symptoms after hospital discharge or initial resolution of symptoms.²⁹ This approach includes developing an individualized plan for care and rehabilitation that is specific to presenting symptoms, including psychological support. We encourage family physicians to familiarize themselves with the work of Vance and colleagues,³⁰ who have created a comprehensive table^a to guide treatment and referral for the gamut of long COVID symptoms, including cardiovascular issues (eg, palpitations, edema), chronic cough, headache, pain, and insomnia.

Continue to: This new clinical entity is a formidable challenge

Long COVID is a new condition that requires comprehensive evaluation to understand the full, often long-term, effects of COVID-19. Our review of this condition substantiated that symptoms of long COVID often affect a variety of organs^13,14 and have been observed to persist for ≥ 2 years.⁸

Some studies that have examined the long-term effects of COVID-19 included only participants who were not hospitalized; others include hospitalized patients exclusively. The literature is mixed in regard to including severity of initial infection as it relates to long COVID. Available research demonstrates that it is common for people with COVID-19 to experience persistent symptoms that can significantly impact daily life and well-being.

Likely, it will be several years before we even begin to understand the full extent of COVID-19. Until research elucidates the relationship between the disease and short- and long-term health outcomes, clinicians should:

• acknowledge and address the reality of long COVID when meeting with persistently symptomatic patients,
• provide support, therapeutic listening, and referral to rehabilitation as appropriate, and
• offer information on the potential for long-term effects of COVID-19 to vaccine-hesitant patients.

^a “Systems, symptoms, and treatments for post-COVID patients,” pages 1231-1234 in the source article (www.jabfm.org/content/jabfp/34/6/1229.full.pdf).³⁰

CORRESPONDENCE
Nicole Mayo, PhD, 46 Prince Street, Rochester, NY 14607; [email protected]

Several years into the pandemic, COVID-19 continues to deeply impact our society; at the time of publication of this review, 98.8 million cases in the United States have been reported to the Centers for Disease Control and Prevention (CDC).¹ Although many people recover well from infection, there is mounting concern regarding long-term sequelae of COVID-19. These long-term symptoms have been termed long COVID, among other names.

What exactly is long COVID?

The CDC and National Institutes of Health define long COVID as new or ongoing health problems experienced ≥ 4 weeks after initial infection.² Evidence suggests that even people who have mild initial COVID-19 symptoms are at risk for long COVID.

Available data about long COVID are imperfect, however; much about the condition remains poorly understood. For example, there is little evidence regarding the effect of vaccination and viral variants on the prevalence of long ­COVID. A recent study of more than 13 million people from the US Department of Veterans Affairs database did demonstrate that vaccination against SARS-CoV-2 lowered the risk for long ­COVID by only about 15%.³

Persistent symptoms associated with long COVID often lead to disability and decreased quality of life. Furthermore, long COVID is a challenge to treat because there is a paucity of evidence to guide COVID-19 treatment beyond initial infection.

The prevalence of long COVID symptoms appears to increase with age.

Because many patients who have ongoing COVID-19 symptoms will be seen in primary care, it is important to understand how to manage and support them. In this article, we discuss current understanding of long COVID epidemiology, symptoms that can persist 4 weeks after initial infection, and potential treatment options.

Prevalence and diagnosis

The prevalence of long COVID is not well defined because many epidemiologic studies rely on self-reporting. The CDC reports that 20% to 25% of COVID-19 survivors experience a new condition that might be attributable to their initial infection.⁴ Other studies variously cite 5% to 85% of people who have had a diagnosis of COVID-19 as experiencing long COVID, although that rate more consistently appears to be 10% to 30%.⁵

Copyright Brian Stauffer

A study of adult patients in France found that self-reported symptoms of long COVID, 10 to 12 months after the first wave of the pandemic (May through November 2020), were associated with the belief of having had COVID-19 but not necessarily with having tested positive for anti-SARS-CoV-2 antibodies,⁶ which indicates prior COVID-19. This complicates research on long COVID because, first, there is no specific test to confirm a diagnosis of long COVID and, second, studies often rely on self-reporting of earlier COVID-19.

Continue to: As such, long COVID...

As such, long COVID is diagnosed primarily through a medical history and physical examination. The medical history provides a guide as to whether additional testing is warranted to evaluate for known complications of COVID-19, such as deep vein thrombosis, pulmonary embolism, myocarditis, and pulmonary fibrosis. As of October 1, 2021, a new International Classification of Disease (10th Revision) code went into effect for post ­COVID condition, unspecified (U09.9).⁷

The prevalence of long COVID symptoms appears to increase with age. Among patients whose disease was diagnosed using code U09.9, most were 36 to 64 years of age; children and adults ages 22 years or younger constituted only 10.5% of diagnoses.⁷ Long COVID symptoms might also be more prevalent among women and in people with a preexisting chronic comorbidity.^2,7

Symptoms can be numerous, severe or mild, and lasting

Initially, there was no widely accepted definition of long COVID; follow-up in early studies ranged from 21 days to 2 years after initial infection (or from discharge, for hospitalized patients).⁸ Differences in descriptions that have been used on surveys to self-report symptoms make it a challenge to clearly summarize the frequency of each aspect of long COVID.

Long COVID can be mild or debilitating; severity can fluctuate. Common symptoms include fatigue, dyspnea or other breathing difficulties, headache, and cognitive dysfunction, but as many as 203 lasting symptoms have been reported.^2,8-12 From October 1, 2021, through January 31, 2022, the most common accompanying manifestations of long COVID were difficulty breathing, cough, and fatigue.⁷ Long COVID can affect multiple organ systems,^13,14 with symptoms varying by organ system affected. Regardless of the need for hospitalization initially, having had COVID-19 significantly increases the risk for subsequent death at 30 days and at 6 months after initial infection.¹⁵

The CDC reports that 20% to 25% of COVID-19 survivors experience a new condition that might be attributable to their initial infection.

Symptoms of long COVID have been reported as long as 2 years after initial infection.⁸ When Davis and colleagues studied the onset and progression of reported symptoms of long COVID,⁹ they determined that, among patients who reported recovery from COVID-19 in < 90 days, symptoms peaked at approximately Week 2 of infection. In comparison, patients who reported not having recovered in < 90 days had (1) symptoms that peaked later (2 months) and (2) on average, more symptoms (mean, 17 reported symptoms, compared to 11 in recovered ­patients).⁹

Continue to: Fatigue

Fatigue, including postexertion malaise and impaired daily function and mobility, is the most common symptom of long COVID,^8-10,14 reported in 28% to 98%¹⁴ of patients after initial COVID-19. This fatigue is more than simply being tired: Patients describe profound exhaustion, in which fatigue is out of proportion to exertion. Fatigue and myalgia are commonly reported among patients with impaired hepatic and pulmonary function as a consequence of long COVID.¹³ Patients often report that even minor activities result in decreased attention, focus, and energy, for many hours or days afterward. Fatigue has been reported to persist from 2.5 months to as long as 6 months after initial infection or hospitalization.^9,16

Postviral fatigue has been seen in other viral outbreaks and seems to share characteristics with myalgic encephalomyelitis/­chronic fatigue syndrome, or ME/CFS, which itself has historically been stigmatized and poorly understood.¹⁷ Long COVID fatigue might be more common among women and patients who have an existing diagnosis of depression and antidepressant use,^10,11,16,18 although the mechanism of this relationship is unclear. Potential mechanisms include damage from systemic inflammation to metabolism in the frontal lobe and cerebellum¹⁹ and direct infection by SARS-CoV-2 in skeletal muscle.²⁰ Townsend and colleagues¹⁶ found no relationship between long COVID fatigue and markers of inflammation (leukocyte, neutrophil, and lymphocyte counts; the neutrophil-to-lymphocyte ratio; lactate dehydrogenase; C-reactive protein; serum interleukin-6; and soluble CD25).

Neuropsychiatric symptoms are also common in long COVID and can have a significant impact on patients’ quality of life. Studies have reported poor sleep quality or insomnia (38% to 90%), headache (17% to 91.2%), speech and language problems (48% to 50%), confusion (20%), dementia (28.6%), difficulty concentrating (1.9% to 27%), and memory loss or cognitive impairment (5.4% to 73%).^9,10,14,15 For some patients, these symptoms persisted for ≥ 6 months, making it difficult for those affected to return to work.⁹

Isolation and loneliness, a common situation for patients with COVID-19, can have long-term effects on mental health.²¹ The COVID-19 pandemic itself has had a negative effect on behavioral health, including depression (4.3% to 25% of patients), anxiety (1.9% to 46%), obsessive compulsive disorder (4.9% to 20%), and posttraumatic stress disorder (29%).²² The persistence of symptoms of long COVID has resulted in a great deal of frustration, fear, and confusion for those affected—some of whom report a loss of trust in their community health care providers to address their ongoing struggles.²³ Such loss can be accompanied by a reported increase in feelings of anxiety and changes to perceptions of self (ie, “how I used to be” in contrast to “how I am now”).²³ These neuropsychiatric symptoms, including mental health conditions, appear to be more common among older adults.⁴

Other neurologic deficits found in long COVID include olfactory disorders (9% to 27% of patients), altered taste (5% to 18%), numbness or tingling sensations (6%), blurred vision (17.1%), and tinnitus (16.%).¹⁴ Dizziness (2.6% to 6%) and lightheadedness or presyncope (7%) have also been reported, although these symptoms appear to be less common than other neurocognitive effects.¹⁴

Continue to: The mechanism of action...

The mechanism of action of damage to the nervous system in long COVID is likely multifactorial. COVID-19 can directly infect the central nervous system through a hematogenous route, which can result in direct cytolytic damage to neurons. Infection can also affect the blood–brain barrier.²⁴ Additionally, COVID-19 can invade the central nervous system through peripheral nerves, including the olfactory and vagus nerves.²⁵ Many human respiratory viruses, including SARS-CoV-2, result in an increase in pro-inflammatory and anti-inflammatory cytokines; this so-called cytokine storm is an exaggerated response to infection and can trigger neurodegenerative and psychiatric syndromes.²⁶ It is unclear whether the cytokine storm is different for people with COVID-19, compared to other respiratory viruses.

Respiratory symptoms are very common after COVID-19¹⁵: In studies, as many as 87.1% of patients continued to have shortness of breath ≥ 140 days after initial symptom onset, including breathlessness (48% to 60%), wheezing (5.3%), cough (10.5% to 46%), and congestion (32%),^14,18 any of which can persist for as long as 6 months.⁹ Among a sample of previously hospitalized COVID-19 patients in Wuhan, China, 22% to 56% displayed a pulmonary diffusion abnormality 6 months later, with those who required supplemental oxygen during initial COVID-19 having a greater risk for these abnormalities at follow-up, compared to those who did not require supplemental oxygen (odds ratio = 2.42; 95% CI, 1.15-5.08).¹¹

Cardiovascular symptoms. New-onset autonomic dysfunction has been described in multiple case reports and in some larger cohort studies of patients post COVID-19.²⁷ Many common long COVID symptoms, including fatigue and orthostatic intolerance, are commonly seen in postural orthostatic tachycardia syndrome. Emerging evidence indicates that there are likely similar underlying mechanisms and a significant amount of overlap between long COVID and postural orthostatic tachycardia syndrome.²⁷

The high rate of cardiac complications post COVID-19 highlights the importance of a thorough evaluation and work-up of chest pain in patients who have had COVID-19.

A study of patients within the US Department of Veterans Affairs population found that, regardless of disease severity, patients who had a positive COVID-19 test had a higher rate of cardiac disease 30 days after diagnosis,²⁸ including stroke, transient ischemic attack, dysrhythmia, inflammatory heart disease, acute coronary disease, myocardial infarction, ischemic cardiopathy, angina, heart failure, nonischemic cardiomyopathy, and cardiac arrest. Patients with COVID-19 were at increased risk for major adverse cardiovascular events (myocardial infarction, stroke, and all-cause mortality).²⁸ Demographics of the VA population (ie, most are White men) might limit the generalizability of these data, but similar findings have been found elsewhere.^5,10,15Given that, in general, chest pain is common after the acute phase of an infection and the causes of chest pain are broad, the high rate of cardiac complications post COVID-19 nevertheless highlights the importance of a thorough evaluation and work-up of chest pain in patients who have had COVID-19.

Other symptoms. Body aches and generalized joint pain are another common symptom group of long COVID.⁹ These include body aches (20%), joint pain (78%), and muscle aches (87.7%).^14,18

Continue to: Commonly reported...

Commonly reported gastrointestinal symptoms include diarrhea, loss of appetite, nausea, and abdominal pain.^9,15

Other symptoms reported less commonly include dermatologic conditions, such as pruritus and rash; reproductive and endocrine symptoms, including extreme thirst, irregular menstruation, and sexual dysfunction; and new or exacerbated allergic response.⁹

Does severity of initial disease play a role?

Keep in mind that long COVID is not specific to patients who were hospitalized or had severe initial infection. In fact, 75% of patients who have a diagnosis of a post–COVID-19 condition were not hospitalized for their initial infection.⁷ However, the severity of initial COVID-19 infection might contribute to the presence or severity of long COVID symptoms²—although findings in current literature are mixed. For example:

• In reporting from Wuhan, China, higher position on a disease severity scale during a hospital stay for COVID-19 was associated with:
  • greater likelihood of reporting ≥ 1 symptoms at a 6-month ­follow-up
  • increased risk for pulmonary diffusion abnormalities, fatigue, and mood disorders.¹¹
• After 2 years’ follow-up of the same cohort, 55% of patients continued to report ≥ 1 symptoms of long COVID, and those who had been hospitalized with COVID-19 continued to report reduced health-related quality of life, compared to the control group.⁸
• Similarly, patients initially hospitalized with COVID-19 were more likely to experience impairment of ≥ 2 organs—in particular, the liver and pancreas—compared to nonhospitalized patients after a median 5 months post initial infection, among a sample in the United Kingdom.¹³
• In an international cohort, patients who reported a greater number of symptoms during initial COVID-19 were more likely to experience long COVID.¹²
• Last, long COVID fatigue did not vary by severity of initial COVID-19 infection among a sample of hospitalized and nonhospitalized participants in Dublin, Ireland.¹⁶

No specific treatments yet available

There are no specific treatments for long ­COVID; overall, the emphasis is on providing supportive care and managing preexisting chronic conditions.⁵ This is where expertise in primary care, relationships with patients and the community, and psychosocial knowledge can help patients recover from ongoing ­COVID-19 symptoms.

Long COVID–associated fatigue is more than simply being tired. Patients describe profound exhaustion, in which fatigue is out of proportion to exertion.

Clinicians should continue to perform a thorough physical assessment of patients with previous or ongoing COVID-19 to identify and monitor new or recurring symptoms after hospital discharge or initial resolution of symptoms.²⁹ This approach includes developing an individualized plan for care and rehabilitation that is specific to presenting symptoms, including psychological support. We encourage family physicians to familiarize themselves with the work of Vance and colleagues,³⁰ who have created a comprehensive table^a to guide treatment and referral for the gamut of long COVID symptoms, including cardiovascular issues (eg, palpitations, edema), chronic cough, headache, pain, and insomnia.

Continue to: This new clinical entity is a formidable challenge

Long COVID is a new condition that requires comprehensive evaluation to understand the full, often long-term, effects of COVID-19. Our review of this condition substantiated that symptoms of long COVID often affect a variety of organs^13,14 and have been observed to persist for ≥ 2 years.⁸

Some studies that have examined the long-term effects of COVID-19 included only participants who were not hospitalized; others include hospitalized patients exclusively. The literature is mixed in regard to including severity of initial infection as it relates to long COVID. Available research demonstrates that it is common for people with COVID-19 to experience persistent symptoms that can significantly impact daily life and well-being.

Likely, it will be several years before we even begin to understand the full extent of COVID-19. Until research elucidates the relationship between the disease and short- and long-term health outcomes, clinicians should:

• acknowledge and address the reality of long COVID when meeting with persistently symptomatic patients,
• provide support, therapeutic listening, and referral to rehabilitation as appropriate, and
• offer information on the potential for long-term effects of COVID-19 to vaccine-hesitant patients.

^a “Systems, symptoms, and treatments for post-COVID patients,” pages 1231-1234 in the source article (www.jabfm.org/content/jabfp/34/6/1229.full.pdf).³⁰

CORRESPONDENCE
Nicole Mayo, PhD, 46 Prince Street, Rochester, NY 14607; [email protected]

Several years into the pandemic, COVID-19 continues to deeply impact our society; at the time of publication of this review, 98.8 million cases in the United States have been reported to the Centers for Disease Control and Prevention (CDC).¹ Although many people recover well from infection, there is mounting concern regarding long-term sequelae of COVID-19. These long-term symptoms have been termed long COVID, among other names.

What exactly is long COVID?

The CDC and National Institutes of Health define long COVID as new or ongoing health problems experienced ≥ 4 weeks after initial infection.² Evidence suggests that even people who have mild initial COVID-19 symptoms are at risk for long COVID.

Available data about long COVID are imperfect, however; much about the condition remains poorly understood. For example, there is little evidence regarding the effect of vaccination and viral variants on the prevalence of long ­COVID. A recent study of more than 13 million people from the US Department of Veterans Affairs database did demonstrate that vaccination against SARS-CoV-2 lowered the risk for long ­COVID by only about 15%.³

Persistent symptoms associated with long COVID often lead to disability and decreased quality of life. Furthermore, long COVID is a challenge to treat because there is a paucity of evidence to guide COVID-19 treatment beyond initial infection.

The prevalence of long COVID symptoms appears to increase with age.

Because many patients who have ongoing COVID-19 symptoms will be seen in primary care, it is important to understand how to manage and support them. In this article, we discuss current understanding of long COVID epidemiology, symptoms that can persist 4 weeks after initial infection, and potential treatment options.

Prevalence and diagnosis

The prevalence of long COVID is not well defined because many epidemiologic studies rely on self-reporting. The CDC reports that 20% to 25% of COVID-19 survivors experience a new condition that might be attributable to their initial infection.⁴ Other studies variously cite 5% to 85% of people who have had a diagnosis of COVID-19 as experiencing long COVID, although that rate more consistently appears to be 10% to 30%.⁵

Copyright Brian Stauffer

A study of adult patients in France found that self-reported symptoms of long COVID, 10 to 12 months after the first wave of the pandemic (May through November 2020), were associated with the belief of having had COVID-19 but not necessarily with having tested positive for anti-SARS-CoV-2 antibodies,⁶ which indicates prior COVID-19. This complicates research on long COVID because, first, there is no specific test to confirm a diagnosis of long COVID and, second, studies often rely on self-reporting of earlier COVID-19.

Continue to: As such, long COVID...

As such, long COVID is diagnosed primarily through a medical history and physical examination. The medical history provides a guide as to whether additional testing is warranted to evaluate for known complications of COVID-19, such as deep vein thrombosis, pulmonary embolism, myocarditis, and pulmonary fibrosis. As of October 1, 2021, a new International Classification of Disease (10th Revision) code went into effect for post ­COVID condition, unspecified (U09.9).⁷

The prevalence of long COVID symptoms appears to increase with age. Among patients whose disease was diagnosed using code U09.9, most were 36 to 64 years of age; children and adults ages 22 years or younger constituted only 10.5% of diagnoses.⁷ Long COVID symptoms might also be more prevalent among women and in people with a preexisting chronic comorbidity.^2,7

Symptoms can be numerous, severe or mild, and lasting

Initially, there was no widely accepted definition of long COVID; follow-up in early studies ranged from 21 days to 2 years after initial infection (or from discharge, for hospitalized patients).⁸ Differences in descriptions that have been used on surveys to self-report symptoms make it a challenge to clearly summarize the frequency of each aspect of long COVID.

Long COVID can be mild or debilitating; severity can fluctuate. Common symptoms include fatigue, dyspnea or other breathing difficulties, headache, and cognitive dysfunction, but as many as 203 lasting symptoms have been reported.^2,8-12 From October 1, 2021, through January 31, 2022, the most common accompanying manifestations of long COVID were difficulty breathing, cough, and fatigue.⁷ Long COVID can affect multiple organ systems,^13,14 with symptoms varying by organ system affected. Regardless of the need for hospitalization initially, having had COVID-19 significantly increases the risk for subsequent death at 30 days and at 6 months after initial infection.¹⁵

The CDC reports that 20% to 25% of COVID-19 survivors experience a new condition that might be attributable to their initial infection.

Symptoms of long COVID have been reported as long as 2 years after initial infection.⁸ When Davis and colleagues studied the onset and progression of reported symptoms of long COVID,⁹ they determined that, among patients who reported recovery from COVID-19 in < 90 days, symptoms peaked at approximately Week 2 of infection. In comparison, patients who reported not having recovered in < 90 days had (1) symptoms that peaked later (2 months) and (2) on average, more symptoms (mean, 17 reported symptoms, compared to 11 in recovered ­patients).⁹

Continue to: Fatigue

Fatigue, including postexertion malaise and impaired daily function and mobility, is the most common symptom of long COVID,^8-10,14 reported in 28% to 98%¹⁴ of patients after initial COVID-19. This fatigue is more than simply being tired: Patients describe profound exhaustion, in which fatigue is out of proportion to exertion. Fatigue and myalgia are commonly reported among patients with impaired hepatic and pulmonary function as a consequence of long COVID.¹³ Patients often report that even minor activities result in decreased attention, focus, and energy, for many hours or days afterward. Fatigue has been reported to persist from 2.5 months to as long as 6 months after initial infection or hospitalization.^9,16

Postviral fatigue has been seen in other viral outbreaks and seems to share characteristics with myalgic encephalomyelitis/­chronic fatigue syndrome, or ME/CFS, which itself has historically been stigmatized and poorly understood.¹⁷ Long COVID fatigue might be more common among women and patients who have an existing diagnosis of depression and antidepressant use,^10,11,16,18 although the mechanism of this relationship is unclear. Potential mechanisms include damage from systemic inflammation to metabolism in the frontal lobe and cerebellum¹⁹ and direct infection by SARS-CoV-2 in skeletal muscle.²⁰ Townsend and colleagues¹⁶ found no relationship between long COVID fatigue and markers of inflammation (leukocyte, neutrophil, and lymphocyte counts; the neutrophil-to-lymphocyte ratio; lactate dehydrogenase; C-reactive protein; serum interleukin-6; and soluble CD25).

Neuropsychiatric symptoms are also common in long COVID and can have a significant impact on patients’ quality of life. Studies have reported poor sleep quality or insomnia (38% to 90%), headache (17% to 91.2%), speech and language problems (48% to 50%), confusion (20%), dementia (28.6%), difficulty concentrating (1.9% to 27%), and memory loss or cognitive impairment (5.4% to 73%).^9,10,14,15 For some patients, these symptoms persisted for ≥ 6 months, making it difficult for those affected to return to work.⁹

Isolation and loneliness, a common situation for patients with COVID-19, can have long-term effects on mental health.²¹ The COVID-19 pandemic itself has had a negative effect on behavioral health, including depression (4.3% to 25% of patients), anxiety (1.9% to 46%), obsessive compulsive disorder (4.9% to 20%), and posttraumatic stress disorder (29%).²² The persistence of symptoms of long COVID has resulted in a great deal of frustration, fear, and confusion for those affected—some of whom report a loss of trust in their community health care providers to address their ongoing struggles.²³ Such loss can be accompanied by a reported increase in feelings of anxiety and changes to perceptions of self (ie, “how I used to be” in contrast to “how I am now”).²³ These neuropsychiatric symptoms, including mental health conditions, appear to be more common among older adults.⁴

Other neurologic deficits found in long COVID include olfactory disorders (9% to 27% of patients), altered taste (5% to 18%), numbness or tingling sensations (6%), blurred vision (17.1%), and tinnitus (16.%).¹⁴ Dizziness (2.6% to 6%) and lightheadedness or presyncope (7%) have also been reported, although these symptoms appear to be less common than other neurocognitive effects.¹⁴

Continue to: The mechanism of action...

The mechanism of action of damage to the nervous system in long COVID is likely multifactorial. COVID-19 can directly infect the central nervous system through a hematogenous route, which can result in direct cytolytic damage to neurons. Infection can also affect the blood–brain barrier.²⁴ Additionally, COVID-19 can invade the central nervous system through peripheral nerves, including the olfactory and vagus nerves.²⁵ Many human respiratory viruses, including SARS-CoV-2, result in an increase in pro-inflammatory and anti-inflammatory cytokines; this so-called cytokine storm is an exaggerated response to infection and can trigger neurodegenerative and psychiatric syndromes.²⁶ It is unclear whether the cytokine storm is different for people with COVID-19, compared to other respiratory viruses.

Respiratory symptoms are very common after COVID-19¹⁵: In studies, as many as 87.1% of patients continued to have shortness of breath ≥ 140 days after initial symptom onset, including breathlessness (48% to 60%), wheezing (5.3%), cough (10.5% to 46%), and congestion (32%),^14,18 any of which can persist for as long as 6 months.⁹ Among a sample of previously hospitalized COVID-19 patients in Wuhan, China, 22% to 56% displayed a pulmonary diffusion abnormality 6 months later, with those who required supplemental oxygen during initial COVID-19 having a greater risk for these abnormalities at follow-up, compared to those who did not require supplemental oxygen (odds ratio = 2.42; 95% CI, 1.15-5.08).¹¹

Cardiovascular symptoms. New-onset autonomic dysfunction has been described in multiple case reports and in some larger cohort studies of patients post COVID-19.²⁷ Many common long COVID symptoms, including fatigue and orthostatic intolerance, are commonly seen in postural orthostatic tachycardia syndrome. Emerging evidence indicates that there are likely similar underlying mechanisms and a significant amount of overlap between long COVID and postural orthostatic tachycardia syndrome.²⁷

The high rate of cardiac complications post COVID-19 highlights the importance of a thorough evaluation and work-up of chest pain in patients who have had COVID-19.

A study of patients within the US Department of Veterans Affairs population found that, regardless of disease severity, patients who had a positive COVID-19 test had a higher rate of cardiac disease 30 days after diagnosis,²⁸ including stroke, transient ischemic attack, dysrhythmia, inflammatory heart disease, acute coronary disease, myocardial infarction, ischemic cardiopathy, angina, heart failure, nonischemic cardiomyopathy, and cardiac arrest. Patients with COVID-19 were at increased risk for major adverse cardiovascular events (myocardial infarction, stroke, and all-cause mortality).²⁸ Demographics of the VA population (ie, most are White men) might limit the generalizability of these data, but similar findings have been found elsewhere.^5,10,15Given that, in general, chest pain is common after the acute phase of an infection and the causes of chest pain are broad, the high rate of cardiac complications post COVID-19 nevertheless highlights the importance of a thorough evaluation and work-up of chest pain in patients who have had COVID-19.

Other symptoms. Body aches and generalized joint pain are another common symptom group of long COVID.⁹ These include body aches (20%), joint pain (78%), and muscle aches (87.7%).^14,18

Continue to: Commonly reported...

Commonly reported gastrointestinal symptoms include diarrhea, loss of appetite, nausea, and abdominal pain.^9,15

Other symptoms reported less commonly include dermatologic conditions, such as pruritus and rash; reproductive and endocrine symptoms, including extreme thirst, irregular menstruation, and sexual dysfunction; and new or exacerbated allergic response.⁹

Does severity of initial disease play a role?

Keep in mind that long COVID is not specific to patients who were hospitalized or had severe initial infection. In fact, 75% of patients who have a diagnosis of a post–COVID-19 condition were not hospitalized for their initial infection.⁷ However, the severity of initial COVID-19 infection might contribute to the presence or severity of long COVID symptoms²—although findings in current literature are mixed. For example:

• In reporting from Wuhan, China, higher position on a disease severity scale during a hospital stay for COVID-19 was associated with:
  • greater likelihood of reporting ≥ 1 symptoms at a 6-month ­follow-up
  • increased risk for pulmonary diffusion abnormalities, fatigue, and mood disorders.¹¹
• After 2 years’ follow-up of the same cohort, 55% of patients continued to report ≥ 1 symptoms of long COVID, and those who had been hospitalized with COVID-19 continued to report reduced health-related quality of life, compared to the control group.⁸
• Similarly, patients initially hospitalized with COVID-19 were more likely to experience impairment of ≥ 2 organs—in particular, the liver and pancreas—compared to nonhospitalized patients after a median 5 months post initial infection, among a sample in the United Kingdom.¹³
• In an international cohort, patients who reported a greater number of symptoms during initial COVID-19 were more likely to experience long COVID.¹²
• Last, long COVID fatigue did not vary by severity of initial COVID-19 infection among a sample of hospitalized and nonhospitalized participants in Dublin, Ireland.¹⁶

No specific treatments yet available

There are no specific treatments for long ­COVID; overall, the emphasis is on providing supportive care and managing preexisting chronic conditions.⁵ This is where expertise in primary care, relationships with patients and the community, and psychosocial knowledge can help patients recover from ongoing ­COVID-19 symptoms.

Long COVID–associated fatigue is more than simply being tired. Patients describe profound exhaustion, in which fatigue is out of proportion to exertion.

Clinicians should continue to perform a thorough physical assessment of patients with previous or ongoing COVID-19 to identify and monitor new or recurring symptoms after hospital discharge or initial resolution of symptoms.²⁹ This approach includes developing an individualized plan for care and rehabilitation that is specific to presenting symptoms, including psychological support. We encourage family physicians to familiarize themselves with the work of Vance and colleagues,³⁰ who have created a comprehensive table^a to guide treatment and referral for the gamut of long COVID symptoms, including cardiovascular issues (eg, palpitations, edema), chronic cough, headache, pain, and insomnia.

Continue to: This new clinical entity is a formidable challenge

Long COVID is a new condition that requires comprehensive evaluation to understand the full, often long-term, effects of COVID-19. Our review of this condition substantiated that symptoms of long COVID often affect a variety of organs^13,14 and have been observed to persist for ≥ 2 years.⁸

Some studies that have examined the long-term effects of COVID-19 included only participants who were not hospitalized; others include hospitalized patients exclusively. The literature is mixed in regard to including severity of initial infection as it relates to long COVID. Available research demonstrates that it is common for people with COVID-19 to experience persistent symptoms that can significantly impact daily life and well-being.

Likely, it will be several years before we even begin to understand the full extent of COVID-19. Until research elucidates the relationship between the disease and short- and long-term health outcomes, clinicians should:

• acknowledge and address the reality of long COVID when meeting with persistently symptomatic patients,
• provide support, therapeutic listening, and referral to rehabilitation as appropriate, and
• offer information on the potential for long-term effects of COVID-19 to vaccine-hesitant patients.

^a “Systems, symptoms, and treatments for post-COVID patients,” pages 1231-1234 in the source article (www.jabfm.org/content/jabfp/34/6/1229.full.pdf).³⁰

CORRESPONDENCE
Nicole Mayo, PhD, 46 Prince Street, Rochester, NY 14607; [email protected]

Allowing people with type 2 diabetes to try agents from three different classes of antidiabetes drugs showed they usually find a clear preference, often the drug that gives them the best glycemic control and least bothersome adverse effects, according to secondary findings from a randomized study of patients in the United Kingdom.

“This is the first study in which the same patient has tried three different types of glucose-lowering drug, enabling them to directly compare them and then choose which one is best for them,” Andrew Hattersley, BMBCh, DM, the study’s principal investigator, said in a written statement. “We’ve shown that going with the patients’ choice results in better glucose control and fewer side effects than any other approach. When it’s not clear which drug is best to use, then patients should try before they choose. Surprisingly, that approach has never been tried before.”

Mitchel L. Zoler/MDedge News

These secondary results from the TriMaster study were recently published in Nature Medicine and presented at the annual meeting of the European Association for the Study of Diabetes (EASD) in September, as reported by this news organization.

TriMaster enrolled adults aged 30-80 years with a clinical diagnosis of type 2 diabetes for at least 12 months. Their glycemia was inadequately controlled despite treatment with metformin alone or two classes of oral glucose-lowering therapy that did not include an agent from any of the three classes tested in the study: dipeptidyl peptidase–4 (DPP-4) inhibitors, sodium-glucose cotransporter 2 (SGLT2) inhibitors, and thiazolidinediones. The people taking two different drug classes at entry were most often taking metformin and a sulfonylurea.
 

Do BMI and renal function affect treatment response?

TriMaster tested two hypotheses. Firstly, would people with a body mass index of more than 30 kg/m² have greater glucose lowering with the thiazolidinedione pioglitazone (Actos) than with the DPP-4 inhibitor sitagliptin (Januvia), compared to people with a lower BMI?

Secondly, would people with an estimated glomerular filtration rate (eGFR) of 60-90 mL/min/1.73 m² have greater glucose lowering with sitagliptin than with the SGLT2 inhibitor canagliflozin (Invokana), compared with people with higher levels of renal function? The metric for both hypotheses was change in A1c levels from baseline.

The study included 525 adults with type 2 diabetes in a double-blind, three-way crossover trial that assigned each participant a random order of serial 16-week trials of treatment with sitagliptin 100 mg once daily, canagliflozin 100 mg once daily, and pioglitazone 30 mg once daily, with each agent added to the preexisting background regimen.

Analysis showed that for second- or third-line therapy in people with type 2 diabetes “simple predefined stratification using BMI and renal function can determine the choice of the drug most likely to be effective for glucose lowering,” the researchers concluded.

Among those with a BMI of more than 30 kg/m², patients achieved a lower A1c on pioglitazone, compared with sitagliptin, while those with a lower BMI had their best A1c response on sitagliptin. Patients with impaired renal function (eGFR 60-90 mL/min/1.73 m²) had better A1c lowering with sitagliptin, while those with a higher eGFR had better A1c lowering with canagliflozin.

These results appeared in a second article published in Nature Medicine, and the researchers also presented these findings at the EASD 2021 annual meeting, as reported by this news organization at the time.
 

Patients identified the agent they liked best

Dr. Hattersley and associates used the TriMaster study to also address the secondary question of which of the three tested agents patients preferred, focusing on the 457 patients who provided information on their treatment preference.

The results showed that patient preference varied: Twenty-four percent liked pioglitazone best, 33% preferred sitagliptin, and 37% said canagliflozin was their favorite, with 6% having no preference. These numbers barely budged when participants learned how well each agent worked for them in terms of reducing their A1c and lowering their BMI.

The findings also showed good correlation between patient preferences and their A1c and adverse-effect responses. The agents that patients identified as their favorites were also the drugs that lowered their A1c the most 53% of the time before they got any feedback on which one gave them their best glycemic control. Once they had this feedback, 70% preferred the most effective agent, with the results likely reflecting that patients feel better when they have improved glucose levels as well as the education patients received that lower A1c levels are better.

Patients also tended to understandably favor the agents that caused the fewest and mildest adverse effects: Sixty-eight percent of the patients who identified a favorite drug picked the one that gave them the best adverse-effect profile.

In an interview at the EASD 2022 annual meeting, Dr. Hattersley promoted the study’s design as a best-practice approach to deciding which drug to next give a person with type 2 diabetes who needs additional glycemic control.

“Whenever you’re not sure how to balance adverse effects and positive effects the best person to decide is the one who experiences the effects,” he said. “Patients had overwhelming positivity about being able to choose their drug. Do it when you’re not certain which drug to prescribe,” suggested Dr. Hattersley, a professor and diabetologist at the University of Exeter, England. “We can’t know which drug a patient might prefer.”

But he stressed cautioning patients to return for treatment adjustment sooner than 4 months if they can’t tolerate a new drug they’re trying.

TriMaster received no commercial funding. Dr. Hattersley has reported no relevant financial relationships.

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

Allowing people with type 2 diabetes to try agents from three different classes of antidiabetes drugs showed they usually find a clear preference, often the drug that gives them the best glycemic control and least bothersome adverse effects, according to secondary findings from a randomized study of patients in the United Kingdom.

“This is the first study in which the same patient has tried three different types of glucose-lowering drug, enabling them to directly compare them and then choose which one is best for them,” Andrew Hattersley, BMBCh, DM, the study’s principal investigator, said in a written statement. “We’ve shown that going with the patients’ choice results in better glucose control and fewer side effects than any other approach. When it’s not clear which drug is best to use, then patients should try before they choose. Surprisingly, that approach has never been tried before.”

Mitchel L. Zoler/MDedge News

These secondary results from the TriMaster study were recently published in Nature Medicine and presented at the annual meeting of the European Association for the Study of Diabetes (EASD) in September, as reported by this news organization.

TriMaster enrolled adults aged 30-80 years with a clinical diagnosis of type 2 diabetes for at least 12 months. Their glycemia was inadequately controlled despite treatment with metformin alone or two classes of oral glucose-lowering therapy that did not include an agent from any of the three classes tested in the study: dipeptidyl peptidase–4 (DPP-4) inhibitors, sodium-glucose cotransporter 2 (SGLT2) inhibitors, and thiazolidinediones. The people taking two different drug classes at entry were most often taking metformin and a sulfonylurea.
 

Do BMI and renal function affect treatment response?

TriMaster tested two hypotheses. Firstly, would people with a body mass index of more than 30 kg/m² have greater glucose lowering with the thiazolidinedione pioglitazone (Actos) than with the DPP-4 inhibitor sitagliptin (Januvia), compared to people with a lower BMI?

Secondly, would people with an estimated glomerular filtration rate (eGFR) of 60-90 mL/min/1.73 m² have greater glucose lowering with sitagliptin than with the SGLT2 inhibitor canagliflozin (Invokana), compared with people with higher levels of renal function? The metric for both hypotheses was change in A1c levels from baseline.

The study included 525 adults with type 2 diabetes in a double-blind, three-way crossover trial that assigned each participant a random order of serial 16-week trials of treatment with sitagliptin 100 mg once daily, canagliflozin 100 mg once daily, and pioglitazone 30 mg once daily, with each agent added to the preexisting background regimen.

Analysis showed that for second- or third-line therapy in people with type 2 diabetes “simple predefined stratification using BMI and renal function can determine the choice of the drug most likely to be effective for glucose lowering,” the researchers concluded.

Among those with a BMI of more than 30 kg/m², patients achieved a lower A1c on pioglitazone, compared with sitagliptin, while those with a lower BMI had their best A1c response on sitagliptin. Patients with impaired renal function (eGFR 60-90 mL/min/1.73 m²) had better A1c lowering with sitagliptin, while those with a higher eGFR had better A1c lowering with canagliflozin.

These results appeared in a second article published in Nature Medicine, and the researchers also presented these findings at the EASD 2021 annual meeting, as reported by this news organization at the time.
 

Patients identified the agent they liked best

Dr. Hattersley and associates used the TriMaster study to also address the secondary question of which of the three tested agents patients preferred, focusing on the 457 patients who provided information on their treatment preference.

The results showed that patient preference varied: Twenty-four percent liked pioglitazone best, 33% preferred sitagliptin, and 37% said canagliflozin was their favorite, with 6% having no preference. These numbers barely budged when participants learned how well each agent worked for them in terms of reducing their A1c and lowering their BMI.

The findings also showed good correlation between patient preferences and their A1c and adverse-effect responses. The agents that patients identified as their favorites were also the drugs that lowered their A1c the most 53% of the time before they got any feedback on which one gave them their best glycemic control. Once they had this feedback, 70% preferred the most effective agent, with the results likely reflecting that patients feel better when they have improved glucose levels as well as the education patients received that lower A1c levels are better.

Patients also tended to understandably favor the agents that caused the fewest and mildest adverse effects: Sixty-eight percent of the patients who identified a favorite drug picked the one that gave them the best adverse-effect profile.

In an interview at the EASD 2022 annual meeting, Dr. Hattersley promoted the study’s design as a best-practice approach to deciding which drug to next give a person with type 2 diabetes who needs additional glycemic control.

“Whenever you’re not sure how to balance adverse effects and positive effects the best person to decide is the one who experiences the effects,” he said. “Patients had overwhelming positivity about being able to choose their drug. Do it when you’re not certain which drug to prescribe,” suggested Dr. Hattersley, a professor and diabetologist at the University of Exeter, England. “We can’t know which drug a patient might prefer.”

But he stressed cautioning patients to return for treatment adjustment sooner than 4 months if they can’t tolerate a new drug they’re trying.

TriMaster received no commercial funding. Dr. Hattersley has reported no relevant financial relationships.

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

Allowing people with type 2 diabetes to try agents from three different classes of antidiabetes drugs showed they usually find a clear preference, often the drug that gives them the best glycemic control and least bothersome adverse effects, according to secondary findings from a randomized study of patients in the United Kingdom.

“This is the first study in which the same patient has tried three different types of glucose-lowering drug, enabling them to directly compare them and then choose which one is best for them,” Andrew Hattersley, BMBCh, DM, the study’s principal investigator, said in a written statement. “We’ve shown that going with the patients’ choice results in better glucose control and fewer side effects than any other approach. When it’s not clear which drug is best to use, then patients should try before they choose. Surprisingly, that approach has never been tried before.”

Mitchel L. Zoler/MDedge News

These secondary results from the TriMaster study were recently published in Nature Medicine and presented at the annual meeting of the European Association for the Study of Diabetes (EASD) in September, as reported by this news organization.

TriMaster enrolled adults aged 30-80 years with a clinical diagnosis of type 2 diabetes for at least 12 months. Their glycemia was inadequately controlled despite treatment with metformin alone or two classes of oral glucose-lowering therapy that did not include an agent from any of the three classes tested in the study: dipeptidyl peptidase–4 (DPP-4) inhibitors, sodium-glucose cotransporter 2 (SGLT2) inhibitors, and thiazolidinediones. The people taking two different drug classes at entry were most often taking metformin and a sulfonylurea.
 

Do BMI and renal function affect treatment response?

TriMaster tested two hypotheses. Firstly, would people with a body mass index of more than 30 kg/m² have greater glucose lowering with the thiazolidinedione pioglitazone (Actos) than with the DPP-4 inhibitor sitagliptin (Januvia), compared to people with a lower BMI?

Secondly, would people with an estimated glomerular filtration rate (eGFR) of 60-90 mL/min/1.73 m² have greater glucose lowering with sitagliptin than with the SGLT2 inhibitor canagliflozin (Invokana), compared with people with higher levels of renal function? The metric for both hypotheses was change in A1c levels from baseline.

The study included 525 adults with type 2 diabetes in a double-blind, three-way crossover trial that assigned each participant a random order of serial 16-week trials of treatment with sitagliptin 100 mg once daily, canagliflozin 100 mg once daily, and pioglitazone 30 mg once daily, with each agent added to the preexisting background regimen.

Analysis showed that for second- or third-line therapy in people with type 2 diabetes “simple predefined stratification using BMI and renal function can determine the choice of the drug most likely to be effective for glucose lowering,” the researchers concluded.

Among those with a BMI of more than 30 kg/m², patients achieved a lower A1c on pioglitazone, compared with sitagliptin, while those with a lower BMI had their best A1c response on sitagliptin. Patients with impaired renal function (eGFR 60-90 mL/min/1.73 m²) had better A1c lowering with sitagliptin, while those with a higher eGFR had better A1c lowering with canagliflozin.

These results appeared in a second article published in Nature Medicine, and the researchers also presented these findings at the EASD 2021 annual meeting, as reported by this news organization at the time.
 

Patients identified the agent they liked best

Dr. Hattersley and associates used the TriMaster study to also address the secondary question of which of the three tested agents patients preferred, focusing on the 457 patients who provided information on their treatment preference.

The results showed that patient preference varied: Twenty-four percent liked pioglitazone best, 33% preferred sitagliptin, and 37% said canagliflozin was their favorite, with 6% having no preference. These numbers barely budged when participants learned how well each agent worked for them in terms of reducing their A1c and lowering their BMI.

The findings also showed good correlation between patient preferences and their A1c and adverse-effect responses. The agents that patients identified as their favorites were also the drugs that lowered their A1c the most 53% of the time before they got any feedback on which one gave them their best glycemic control. Once they had this feedback, 70% preferred the most effective agent, with the results likely reflecting that patients feel better when they have improved glucose levels as well as the education patients received that lower A1c levels are better.

Patients also tended to understandably favor the agents that caused the fewest and mildest adverse effects: Sixty-eight percent of the patients who identified a favorite drug picked the one that gave them the best adverse-effect profile.

In an interview at the EASD 2022 annual meeting, Dr. Hattersley promoted the study’s design as a best-practice approach to deciding which drug to next give a person with type 2 diabetes who needs additional glycemic control.

“Whenever you’re not sure how to balance adverse effects and positive effects the best person to decide is the one who experiences the effects,” he said. “Patients had overwhelming positivity about being able to choose their drug. Do it when you’re not certain which drug to prescribe,” suggested Dr. Hattersley, a professor and diabetologist at the University of Exeter, England. “We can’t know which drug a patient might prefer.”

But he stressed cautioning patients to return for treatment adjustment sooner than 4 months if they can’t tolerate a new drug they’re trying.

TriMaster received no commercial funding. Dr. Hattersley has reported no relevant financial relationships.

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

There are some benefits and potentially serious risks associated with complementary and alternative medicines (CAM) patients with heart failure (HF) may use to manage symptoms, the American Heart Association noted in a new scientific statement on the topic.

For example, yoga and tai chi can be helpful for people with HF, and omega-3 polyunsaturated fatty acids may also have benefits. However, there are safety concerns with other commonly used over-the-counter CAM therapies, including vitamin D, blue cohosh, and Lily of the Valley, the writing group said.

It’s estimated that roughly one in three patients with HF use CAM. But often patients don’t report their CAM use to their clinicians and clinicians may not routinely ask about CAM use or have the resources to evaluate CAM therapies, writing group chair Sheryl L. Chow, PharmD, told this news organization.

“This represents a major public health problem given that consumers are frequently purchasing these potentially dangerous and minimally regulated products without the knowledge or advice from a health care professional,” said Dr. Chow, of Western University of Health Sciences, Pomona, Calif., and University of California, Irvine.

The 27-page statement was published online in Circulation.
 

CAM use common in HF

The statement defines CAM as medical practices, supplements, and approaches that do not conform to the standards of conventional, evidence-based practice guidelines. CAM products are available without prescriptions or medical guidance at pharmacies, health food stores, and online retailers.

“These agents are largely unregulated by the [Food and Drug Administration] and manufacturers do not need to demonstrate efficacy or safety. It is important that both health care professionals and consumers improve communication with respect to OTC therapies and are educated about potential efficacy and risk of harm so that shared and informed decision-making can occur,” Dr. Chow said.

The writing group reviewed research published before November 2021 on CAM among people with HF.

Omega-3 polyunsaturated fatty acids (PUFAs), such as fish oil, have the strongest evidence among CAM agents for clinical benefit in HF and may be used safely by patients in moderation and in consultation with their health care team, the writing group said.

Research has shown that omega-3 PUFAs are associated with a lower risk of developing HF as well as improvements in left ventricular systolic function in those with existing HF, they pointed out.

However, two clinical trials found a higher incidence of atrial fibrillation with high-dose omega-3 PUFA administration. “This risk appears to be dose-related and increased when exceeding 2 g/d of fish oil,” the writing group said.

Research suggests that yoga and tai chi, when added to standard HF treatment, may help improve exercise tolerance and quality of life and decrease blood pressure.
 

Inconclusive or potentially harmful CAM therapies

Other CAM therapies for HF have been shown as ineffective based on current data, have mixed findings, or appear to be harmful. The writers highlighted the following examples:

• Overall evidence regarding the value of vitamin D supplementation in patients with HF remains “inconclusive” and may be harmful when taken with HF medications such as digoxin, calcium channel blockers, and diuretics.
• Routine thiamine supplementation in patients with HF and without clinically significant thiamine deficiency may not be efficacious and should be avoided.
• Research on alcohol varies, with some data showing that drinking low-to-moderate amounts (one to two drinks per day) may help prevent HF, while habitual drinking or consuming higher amounts is known to contribute to HF.
• The literature is mixed on vitamin E. It may have some benefit in reducing the risk of HF with preserved ejection fraction but has also been associated with an increased risk of HF hospitalization.
• Coenzyme Q10 (Co-Q10), commonly taken as a dietary supplement, may help improve HF class, symptoms, and quality of life, but it also may interact with antihypertensive and anticoagulant medication. Co-Q10 remains of “uncertain” value in HF at this time. Large-scale randomized controlled trials are needed before any definitive conclusion can be reached.
• Hawthorn, a flowering shrub, has been shown in some studies to increase exercise tolerance and improve HF symptoms such as fatigue. Yet it also has the potential to worsen HF, and there is conflicting research about whether it interacts with digoxin.
• The herbal supplement blue cohosh, from the root of a flowering plant found in hardwood forests, could cause tachycardia, high blood pressure, chest pain, and increased blood glucose. It may also decrease the effect of medications taken to treat high blood pressure and type 2 diabetes, they noted.
• Lily of the Valley, the root, stems, and flower of which are used in supplements, has long been used in mild HF because it contains active chemicals similar to digoxin. But when taken with digoxin, it could lead to hypokalemia.

In an AHA news release, Dr. Chow said, “Overall, more quality research and well-powered randomized controlled trials are needed to better understand the risks and benefits” of CAM therapies for HF.

“This scientific statement provides critical information to health care professionals who treat people with heart failure and may be used as a resource for consumers about the potential benefit and harm associated with complementary and alternative medicine products,” Dr. Chow added.

The writing group encourages health care professionals to routinely ask their HF patients about their use of CAM therapies. They also say pharmacists should be included in the multidisciplinary health care team to provide consultations about the use of CAM therapies for HF patients.

The scientific statement does not include cannabis or traditional Chinese medicine, which have also been used in HF.

In 2020, the AHA published a separate scientific statement on the use of medical marijuana and recreational cannabis on cardiovascular health, as reported previously by this news organization.

The scientific statement on CAM for HF was prepared by the volunteer writing group on behalf of the AHA Clinical Pharmacology Committee and Heart Failure and Transplantation Committee of the Council on Clinical Cardiology; the Council on Epidemiology and Prevention; and the Council on Cardiovascular and Stroke Nursing.

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

There are some benefits and potentially serious risks associated with complementary and alternative medicines (CAM) patients with heart failure (HF) may use to manage symptoms, the American Heart Association noted in a new scientific statement on the topic.

For example, yoga and tai chi can be helpful for people with HF, and omega-3 polyunsaturated fatty acids may also have benefits. However, there are safety concerns with other commonly used over-the-counter CAM therapies, including vitamin D, blue cohosh, and Lily of the Valley, the writing group said.

It’s estimated that roughly one in three patients with HF use CAM. But often patients don’t report their CAM use to their clinicians and clinicians may not routinely ask about CAM use or have the resources to evaluate CAM therapies, writing group chair Sheryl L. Chow, PharmD, told this news organization.

“This represents a major public health problem given that consumers are frequently purchasing these potentially dangerous and minimally regulated products without the knowledge or advice from a health care professional,” said Dr. Chow, of Western University of Health Sciences, Pomona, Calif., and University of California, Irvine.

The 27-page statement was published online in Circulation.
 

CAM use common in HF

The statement defines CAM as medical practices, supplements, and approaches that do not conform to the standards of conventional, evidence-based practice guidelines. CAM products are available without prescriptions or medical guidance at pharmacies, health food stores, and online retailers.

“These agents are largely unregulated by the [Food and Drug Administration] and manufacturers do not need to demonstrate efficacy or safety. It is important that both health care professionals and consumers improve communication with respect to OTC therapies and are educated about potential efficacy and risk of harm so that shared and informed decision-making can occur,” Dr. Chow said.

The writing group reviewed research published before November 2021 on CAM among people with HF.

Omega-3 polyunsaturated fatty acids (PUFAs), such as fish oil, have the strongest evidence among CAM agents for clinical benefit in HF and may be used safely by patients in moderation and in consultation with their health care team, the writing group said.

Research has shown that omega-3 PUFAs are associated with a lower risk of developing HF as well as improvements in left ventricular systolic function in those with existing HF, they pointed out.

However, two clinical trials found a higher incidence of atrial fibrillation with high-dose omega-3 PUFA administration. “This risk appears to be dose-related and increased when exceeding 2 g/d of fish oil,” the writing group said.

Research suggests that yoga and tai chi, when added to standard HF treatment, may help improve exercise tolerance and quality of life and decrease blood pressure.
 

Inconclusive or potentially harmful CAM therapies

Other CAM therapies for HF have been shown as ineffective based on current data, have mixed findings, or appear to be harmful. The writers highlighted the following examples:

• Overall evidence regarding the value of vitamin D supplementation in patients with HF remains “inconclusive” and may be harmful when taken with HF medications such as digoxin, calcium channel blockers, and diuretics.
• Routine thiamine supplementation in patients with HF and without clinically significant thiamine deficiency may not be efficacious and should be avoided.
• Research on alcohol varies, with some data showing that drinking low-to-moderate amounts (one to two drinks per day) may help prevent HF, while habitual drinking or consuming higher amounts is known to contribute to HF.
• The literature is mixed on vitamin E. It may have some benefit in reducing the risk of HF with preserved ejection fraction but has also been associated with an increased risk of HF hospitalization.
• Coenzyme Q10 (Co-Q10), commonly taken as a dietary supplement, may help improve HF class, symptoms, and quality of life, but it also may interact with antihypertensive and anticoagulant medication. Co-Q10 remains of “uncertain” value in HF at this time. Large-scale randomized controlled trials are needed before any definitive conclusion can be reached.
• Hawthorn, a flowering shrub, has been shown in some studies to increase exercise tolerance and improve HF symptoms such as fatigue. Yet it also has the potential to worsen HF, and there is conflicting research about whether it interacts with digoxin.
• The herbal supplement blue cohosh, from the root of a flowering plant found in hardwood forests, could cause tachycardia, high blood pressure, chest pain, and increased blood glucose. It may also decrease the effect of medications taken to treat high blood pressure and type 2 diabetes, they noted.
• Lily of the Valley, the root, stems, and flower of which are used in supplements, has long been used in mild HF because it contains active chemicals similar to digoxin. But when taken with digoxin, it could lead to hypokalemia.

In an AHA news release, Dr. Chow said, “Overall, more quality research and well-powered randomized controlled trials are needed to better understand the risks and benefits” of CAM therapies for HF.

“This scientific statement provides critical information to health care professionals who treat people with heart failure and may be used as a resource for consumers about the potential benefit and harm associated with complementary and alternative medicine products,” Dr. Chow added.

The writing group encourages health care professionals to routinely ask their HF patients about their use of CAM therapies. They also say pharmacists should be included in the multidisciplinary health care team to provide consultations about the use of CAM therapies for HF patients.

The scientific statement does not include cannabis or traditional Chinese medicine, which have also been used in HF.

In 2020, the AHA published a separate scientific statement on the use of medical marijuana and recreational cannabis on cardiovascular health, as reported previously by this news organization.

The scientific statement on CAM for HF was prepared by the volunteer writing group on behalf of the AHA Clinical Pharmacology Committee and Heart Failure and Transplantation Committee of the Council on Clinical Cardiology; the Council on Epidemiology and Prevention; and the Council on Cardiovascular and Stroke Nursing.

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

There are some benefits and potentially serious risks associated with complementary and alternative medicines (CAM) patients with heart failure (HF) may use to manage symptoms, the American Heart Association noted in a new scientific statement on the topic.

For example, yoga and tai chi can be helpful for people with HF, and omega-3 polyunsaturated fatty acids may also have benefits. However, there are safety concerns with other commonly used over-the-counter CAM therapies, including vitamin D, blue cohosh, and Lily of the Valley, the writing group said.

It’s estimated that roughly one in three patients with HF use CAM. But often patients don’t report their CAM use to their clinicians and clinicians may not routinely ask about CAM use or have the resources to evaluate CAM therapies, writing group chair Sheryl L. Chow, PharmD, told this news organization.

“This represents a major public health problem given that consumers are frequently purchasing these potentially dangerous and minimally regulated products without the knowledge or advice from a health care professional,” said Dr. Chow, of Western University of Health Sciences, Pomona, Calif., and University of California, Irvine.

The 27-page statement was published online in Circulation.
 

CAM use common in HF

The statement defines CAM as medical practices, supplements, and approaches that do not conform to the standards of conventional, evidence-based practice guidelines. CAM products are available without prescriptions or medical guidance at pharmacies, health food stores, and online retailers.

“These agents are largely unregulated by the [Food and Drug Administration] and manufacturers do not need to demonstrate efficacy or safety. It is important that both health care professionals and consumers improve communication with respect to OTC therapies and are educated about potential efficacy and risk of harm so that shared and informed decision-making can occur,” Dr. Chow said.

The writing group reviewed research published before November 2021 on CAM among people with HF.

Omega-3 polyunsaturated fatty acids (PUFAs), such as fish oil, have the strongest evidence among CAM agents for clinical benefit in HF and may be used safely by patients in moderation and in consultation with their health care team, the writing group said.

Research has shown that omega-3 PUFAs are associated with a lower risk of developing HF as well as improvements in left ventricular systolic function in those with existing HF, they pointed out.

However, two clinical trials found a higher incidence of atrial fibrillation with high-dose omega-3 PUFA administration. “This risk appears to be dose-related and increased when exceeding 2 g/d of fish oil,” the writing group said.

Research suggests that yoga and tai chi, when added to standard HF treatment, may help improve exercise tolerance and quality of life and decrease blood pressure.
 

Inconclusive or potentially harmful CAM therapies

Other CAM therapies for HF have been shown as ineffective based on current data, have mixed findings, or appear to be harmful. The writers highlighted the following examples:

• Overall evidence regarding the value of vitamin D supplementation in patients with HF remains “inconclusive” and may be harmful when taken with HF medications such as digoxin, calcium channel blockers, and diuretics.
• Routine thiamine supplementation in patients with HF and without clinically significant thiamine deficiency may not be efficacious and should be avoided.
• Research on alcohol varies, with some data showing that drinking low-to-moderate amounts (one to two drinks per day) may help prevent HF, while habitual drinking or consuming higher amounts is known to contribute to HF.
• The literature is mixed on vitamin E. It may have some benefit in reducing the risk of HF with preserved ejection fraction but has also been associated with an increased risk of HF hospitalization.
• Coenzyme Q10 (Co-Q10), commonly taken as a dietary supplement, may help improve HF class, symptoms, and quality of life, but it also may interact with antihypertensive and anticoagulant medication. Co-Q10 remains of “uncertain” value in HF at this time. Large-scale randomized controlled trials are needed before any definitive conclusion can be reached.
• Hawthorn, a flowering shrub, has been shown in some studies to increase exercise tolerance and improve HF symptoms such as fatigue. Yet it also has the potential to worsen HF, and there is conflicting research about whether it interacts with digoxin.
• The herbal supplement blue cohosh, from the root of a flowering plant found in hardwood forests, could cause tachycardia, high blood pressure, chest pain, and increased blood glucose. It may also decrease the effect of medications taken to treat high blood pressure and type 2 diabetes, they noted.
• Lily of the Valley, the root, stems, and flower of which are used in supplements, has long been used in mild HF because it contains active chemicals similar to digoxin. But when taken with digoxin, it could lead to hypokalemia.

In an AHA news release, Dr. Chow said, “Overall, more quality research and well-powered randomized controlled trials are needed to better understand the risks and benefits” of CAM therapies for HF.

“This scientific statement provides critical information to health care professionals who treat people with heart failure and may be used as a resource for consumers about the potential benefit and harm associated with complementary and alternative medicine products,” Dr. Chow added.

The writing group encourages health care professionals to routinely ask their HF patients about their use of CAM therapies. They also say pharmacists should be included in the multidisciplinary health care team to provide consultations about the use of CAM therapies for HF patients.

The scientific statement does not include cannabis or traditional Chinese medicine, which have also been used in HF.

In 2020, the AHA published a separate scientific statement on the use of medical marijuana and recreational cannabis on cardiovascular health, as reported previously by this news organization.

The scientific statement on CAM for HF was prepared by the volunteer writing group on behalf of the AHA Clinical Pharmacology Committee and Heart Failure and Transplantation Committee of the Council on Clinical Cardiology; the Council on Epidemiology and Prevention; and the Council on Cardiovascular and Stroke Nursing.

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

The U.S. Food and Drug Administration has cleared the Dexcom G7 continuous glucose monitoring (CGM) system for people with all types of diabetes aged 2 years and older and for use during pregnancy.

Wikimedia Commons/FitzColinGerald/Creative Commons License

The G7 has several improvements over the current G6 model, including a 60% smaller size, a 30-minute warm-up period (compared with 2 hours), an all-in-one sensor and transmitter (as opposed to the two separate devices), a mean absolute relative difference (compared with a standard, an assessment of accuracy) of 8.2% (compared with 12.8%), a 12-hour grace period (in contrast to the G6’s hard shutoff), and a redesigned mobile app.

It is indicated for wear on the back of the upper arm for people aged 2 years and older or the upper buttocks for ages 2-17 years old.

As an “integrated” CGM, the G7 has the capacity to work as part of automated insulin delivery systems, but that will require further FDA action. “Dexcom is working closely with its insulin pump partners to integrate Dexcom G7 into current and future automated insulin delivery systems as quickly as possible,” the company said in a statement.

Like the G6, it requires no fingersticks, scanning, or calibration. It provides real-time glucose readings every 5 minutes to a compatible device, including Apple Watch and other digital health apps, and allows for remote monitoring of data by as many as 10 followers.

Dexcom expects to initiate a U.S. launch of Dexcom G7 in early 2023. To facilitate immediate access to G7 for as many users as possible, the company will have accessible cash pay options in place as the company transitions coverage with availability for G7, the statement says.

The Dexcom G7 was granted a CE Mark (Conformité Européenne) in March 2022, which means it is approved for use in people with diabetes aged 2 years and older, including pregnant women, in Europe.

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

The U.S. Food and Drug Administration has cleared the Dexcom G7 continuous glucose monitoring (CGM) system for people with all types of diabetes aged 2 years and older and for use during pregnancy.

Wikimedia Commons/FitzColinGerald/Creative Commons License

The G7 has several improvements over the current G6 model, including a 60% smaller size, a 30-minute warm-up period (compared with 2 hours), an all-in-one sensor and transmitter (as opposed to the two separate devices), a mean absolute relative difference (compared with a standard, an assessment of accuracy) of 8.2% (compared with 12.8%), a 12-hour grace period (in contrast to the G6’s hard shutoff), and a redesigned mobile app.

It is indicated for wear on the back of the upper arm for people aged 2 years and older or the upper buttocks for ages 2-17 years old.

As an “integrated” CGM, the G7 has the capacity to work as part of automated insulin delivery systems, but that will require further FDA action. “Dexcom is working closely with its insulin pump partners to integrate Dexcom G7 into current and future automated insulin delivery systems as quickly as possible,” the company said in a statement.

Like the G6, it requires no fingersticks, scanning, or calibration. It provides real-time glucose readings every 5 minutes to a compatible device, including Apple Watch and other digital health apps, and allows for remote monitoring of data by as many as 10 followers.

Dexcom expects to initiate a U.S. launch of Dexcom G7 in early 2023. To facilitate immediate access to G7 for as many users as possible, the company will have accessible cash pay options in place as the company transitions coverage with availability for G7, the statement says.

The Dexcom G7 was granted a CE Mark (Conformité Européenne) in March 2022, which means it is approved for use in people with diabetes aged 2 years and older, including pregnant women, in Europe.

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

The U.S. Food and Drug Administration has cleared the Dexcom G7 continuous glucose monitoring (CGM) system for people with all types of diabetes aged 2 years and older and for use during pregnancy.

Wikimedia Commons/FitzColinGerald/Creative Commons License

The G7 has several improvements over the current G6 model, including a 60% smaller size, a 30-minute warm-up period (compared with 2 hours), an all-in-one sensor and transmitter (as opposed to the two separate devices), a mean absolute relative difference (compared with a standard, an assessment of accuracy) of 8.2% (compared with 12.8%), a 12-hour grace period (in contrast to the G6’s hard shutoff), and a redesigned mobile app.

It is indicated for wear on the back of the upper arm for people aged 2 years and older or the upper buttocks for ages 2-17 years old.

As an “integrated” CGM, the G7 has the capacity to work as part of automated insulin delivery systems, but that will require further FDA action. “Dexcom is working closely with its insulin pump partners to integrate Dexcom G7 into current and future automated insulin delivery systems as quickly as possible,” the company said in a statement.

Like the G6, it requires no fingersticks, scanning, or calibration. It provides real-time glucose readings every 5 minutes to a compatible device, including Apple Watch and other digital health apps, and allows for remote monitoring of data by as many as 10 followers.

Dexcom expects to initiate a U.S. launch of Dexcom G7 in early 2023. To facilitate immediate access to G7 for as many users as possible, the company will have accessible cash pay options in place as the company transitions coverage with availability for G7, the statement says.

The Dexcom G7 was granted a CE Mark (Conformité Européenne) in March 2022, which means it is approved for use in people with diabetes aged 2 years and older, including pregnant women, in Europe.

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

A new study has provided further reassurance on questions about the risk of intracerebral hemorrhage (ICH) with statins.

The Danish case-control study, which compared statin use in 2,164 case patients with ICH and in 86,255 matched control persons, found that current statin use was associated with a lower risk of having a first ICH and that the risk was further reduced with longer duration of statin use.

The study also showed that statin use was linked to a lower risk of ICH in the more superficial lobar areas of the brain and in the deeper, nonlobar locations. There was no difference in the magnitude of risk reduction between the two locations.

“Although this study is observational, I feel these data are strong, and the results are reassuring. It certainly does not suggest any increased risk of ICH with statins,” senior author David Gaist, PhD, Odense University Hospital, Denmark, said in an interview.

“On the contrary, it indicates a lower risk, which seems to be independent of the location of the bleed.”

The study was published online in Neurology.

The authors note that statins effectively reduce the occurrence of cardiovascular events and ischemic stroke in high-risk populations, but early randomized trials raised concerns of an increased risk of ICH among statin users who have a history of stroke.

Subsequent observational studies, including four meta-analyses, included patients with and those without prior stroke. The results were inconsistent, although most found no increase in bleeding. More recent studies have found a lower risk of ICH among statin users; the risk was inversely associated with the duration and intensity of statin treatment.

However, the researchers point out that few studies have assessed the association between statin use and the location of ICH. Hemorrhages that occur in the lobar region of the brain and those that occur in the nonlobar areas can have different pathophysiologies. Arteriolosclerosis, which is strongly associated with hypertension, is a common histologic finding in patients with ICH, regardless of hemorrhage location, while cerebral amyloid angiopathy (CAA) is associated with lobar but not nonlobar ICH.

The current study was conducted to look more closely at the relationship between statin use and hematoma location as a reflection of differences in the underlying pathophysiologies of lobar versus nonlobar ICH.

The researchers used Danish registries to identify all first-ever cases of spontaneous ICH that occurred between 2009 and 2018 in persons older than 55 years in the Southern Denmark region. Patients with traumatic ICH or ICH related to vascular malformations and tumors were excluded.

These cases were verified through medical records. ICH diagnoses were classified as having a lobar or nonlobar location, and patients were matched for age, sex, and calendar year to general population control persons. The nationwide prescription registry was also analyzed to ascertain use of statins and other medications.

The study included 989 patients with lobar ICH who were matched to 39,500 control persons and 1,175 patients with nonlobar ICH who were matched to 46,755 control persons.

Results showed that current statin use was associated with a 16%-17% relative reduction in ICH risk. There was no difference with respect to ICH location.

For lobar ICH, statin use showed an adjusted odds ratio of 0.83 (95% confidence interval, 0.70-0.98); for nonlobar ICH, the adjusted odds ratio was 0.84 (95% CI, 0.72-0.98).

Longer duration of statin use was associated with a greater reduction in risk of ICH; use for more than 5 years was associated with a relative reduction of ICH of 33%-38%, again with no difference with regard to ICH location.

For lobar ICH, statin use for more than 5 years showed an adjusted odds ratio of 0.67 (95% CI, 0.51-0.87); and for nonlobar ICH, the adjusted odds ratio was 0.62 (95% CI, 0.48-0.80).

“We suspected that statins may have more of an effect in reducing nonlobar ICH, as this type is considered to be more associated with arteriosclerosis, compared with lobar ICH,” Dr. Gaist explained. “But we didn’t find that. We found that taking statins was associated with a similar reduction in risk of both lobar and nonlobar ICH.”

Although amyloid angiopathy can contribute to lobar ICH, arteriosclerosis is still involved in the majority of cases, he noted. He cited a recent population-based U.K. study that showed that while histologically verified CAA was present in 58% of patients with a lobar ICH, most also had evidence of arteriosclerosis, with only 13% having isolated CAA pathology.

“If statins exert their effect on reducing ICH by reducing arteriosclerosis, which is likely, then this observation of arteriosclerosis pathology being prevalent in both lobar and nonlobar ICH locations would explain our results,” Dr. Gaist commented.

“Strengths of our study include the large numbers involved and the fact that the patients are unselected. We tried to find everyone who had had a first ICH in a well-defined region of Denmark, so issues of selection are less of a concern than in some other studies,” he noted.

He also pointed out that all the ICH diagnoses were verified from medical records and that in a substudy, brain scans were evaluated, with investigators masked to clinical data to evaluate the location and characteristics of the hematoma. In addition, data on statin use were collected prospectively from a nationwide prescription registry.
 

Interaction with antihypertensives, anticoagulants?

Other results from the study suggest a possible interaction between statin use and antihypertensive and anticoagulant drugs.

Data showed that the lower ICH risk was restricted to patients who received statins and antihypertensive drugs concurrently. Conversely, only patients who were not concurrently taking anticoagulants had a lower risk of ICH in association with statin use.

Dr. Gaist suggested that the lack of a reduction in ICH with statins among patients taking anticoagulants could be because the increased risk of ICH with anticoagulants was stronger than the reduced risk with statins.

Regarding the fact that the reduced risk of ICH with statins was only observed among individuals who were also taking antihypertensive medication, Dr. Gaist noted that because hypertension is such an important risk factor for ICH, “it may be that to get the true benefit of statins, patients have to have their hypertension controlled.”

However, an alternative explanation could that the finding is a result of “healthy adherer” bias, in which people who take antihypertensive medication and follow a healthy lifestyle as advised would be more likely to take statins.

“The observational nature of our study does not allow us to determine the extent to which associations are causal,” the authors say.

Dr. Gaist also noted that an important caveat in this study is that they focused on individuals who had had a first ICH.

“This data does not inform us about those who have already had an ICH and are taking statins. But we are planning to look at this in our next study,” he said.

The study was funded by the Novo Nordisk Foundation. Dr. Gaist has received speaker honorarium from Bristol-Myers Squibb and Pfizer unrelated to this work.

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

A new study has provided further reassurance on questions about the risk of intracerebral hemorrhage (ICH) with statins.

The Danish case-control study, which compared statin use in 2,164 case patients with ICH and in 86,255 matched control persons, found that current statin use was associated with a lower risk of having a first ICH and that the risk was further reduced with longer duration of statin use.

The study also showed that statin use was linked to a lower risk of ICH in the more superficial lobar areas of the brain and in the deeper, nonlobar locations. There was no difference in the magnitude of risk reduction between the two locations.

“Although this study is observational, I feel these data are strong, and the results are reassuring. It certainly does not suggest any increased risk of ICH with statins,” senior author David Gaist, PhD, Odense University Hospital, Denmark, said in an interview.

“On the contrary, it indicates a lower risk, which seems to be independent of the location of the bleed.”

The study was published online in Neurology.

The authors note that statins effectively reduce the occurrence of cardiovascular events and ischemic stroke in high-risk populations, but early randomized trials raised concerns of an increased risk of ICH among statin users who have a history of stroke.

Subsequent observational studies, including four meta-analyses, included patients with and those without prior stroke. The results were inconsistent, although most found no increase in bleeding. More recent studies have found a lower risk of ICH among statin users; the risk was inversely associated with the duration and intensity of statin treatment.

However, the researchers point out that few studies have assessed the association between statin use and the location of ICH. Hemorrhages that occur in the lobar region of the brain and those that occur in the nonlobar areas can have different pathophysiologies. Arteriolosclerosis, which is strongly associated with hypertension, is a common histologic finding in patients with ICH, regardless of hemorrhage location, while cerebral amyloid angiopathy (CAA) is associated with lobar but not nonlobar ICH.

The current study was conducted to look more closely at the relationship between statin use and hematoma location as a reflection of differences in the underlying pathophysiologies of lobar versus nonlobar ICH.

The researchers used Danish registries to identify all first-ever cases of spontaneous ICH that occurred between 2009 and 2018 in persons older than 55 years in the Southern Denmark region. Patients with traumatic ICH or ICH related to vascular malformations and tumors were excluded.

These cases were verified through medical records. ICH diagnoses were classified as having a lobar or nonlobar location, and patients were matched for age, sex, and calendar year to general population control persons. The nationwide prescription registry was also analyzed to ascertain use of statins and other medications.

The study included 989 patients with lobar ICH who were matched to 39,500 control persons and 1,175 patients with nonlobar ICH who were matched to 46,755 control persons.

Results showed that current statin use was associated with a 16%-17% relative reduction in ICH risk. There was no difference with respect to ICH location.

For lobar ICH, statin use showed an adjusted odds ratio of 0.83 (95% confidence interval, 0.70-0.98); for nonlobar ICH, the adjusted odds ratio was 0.84 (95% CI, 0.72-0.98).

Longer duration of statin use was associated with a greater reduction in risk of ICH; use for more than 5 years was associated with a relative reduction of ICH of 33%-38%, again with no difference with regard to ICH location.

For lobar ICH, statin use for more than 5 years showed an adjusted odds ratio of 0.67 (95% CI, 0.51-0.87); and for nonlobar ICH, the adjusted odds ratio was 0.62 (95% CI, 0.48-0.80).

“We suspected that statins may have more of an effect in reducing nonlobar ICH, as this type is considered to be more associated with arteriosclerosis, compared with lobar ICH,” Dr. Gaist explained. “But we didn’t find that. We found that taking statins was associated with a similar reduction in risk of both lobar and nonlobar ICH.”

Although amyloid angiopathy can contribute to lobar ICH, arteriosclerosis is still involved in the majority of cases, he noted. He cited a recent population-based U.K. study that showed that while histologically verified CAA was present in 58% of patients with a lobar ICH, most also had evidence of arteriosclerosis, with only 13% having isolated CAA pathology.

“If statins exert their effect on reducing ICH by reducing arteriosclerosis, which is likely, then this observation of arteriosclerosis pathology being prevalent in both lobar and nonlobar ICH locations would explain our results,” Dr. Gaist commented.

“Strengths of our study include the large numbers involved and the fact that the patients are unselected. We tried to find everyone who had had a first ICH in a well-defined region of Denmark, so issues of selection are less of a concern than in some other studies,” he noted.

He also pointed out that all the ICH diagnoses were verified from medical records and that in a substudy, brain scans were evaluated, with investigators masked to clinical data to evaluate the location and characteristics of the hematoma. In addition, data on statin use were collected prospectively from a nationwide prescription registry.
 

Interaction with antihypertensives, anticoagulants?

Other results from the study suggest a possible interaction between statin use and antihypertensive and anticoagulant drugs.

Data showed that the lower ICH risk was restricted to patients who received statins and antihypertensive drugs concurrently. Conversely, only patients who were not concurrently taking anticoagulants had a lower risk of ICH in association with statin use.

Dr. Gaist suggested that the lack of a reduction in ICH with statins among patients taking anticoagulants could be because the increased risk of ICH with anticoagulants was stronger than the reduced risk with statins.

Regarding the fact that the reduced risk of ICH with statins was only observed among individuals who were also taking antihypertensive medication, Dr. Gaist noted that because hypertension is such an important risk factor for ICH, “it may be that to get the true benefit of statins, patients have to have their hypertension controlled.”

However, an alternative explanation could that the finding is a result of “healthy adherer” bias, in which people who take antihypertensive medication and follow a healthy lifestyle as advised would be more likely to take statins.

“The observational nature of our study does not allow us to determine the extent to which associations are causal,” the authors say.

Dr. Gaist also noted that an important caveat in this study is that they focused on individuals who had had a first ICH.

“This data does not inform us about those who have already had an ICH and are taking statins. But we are planning to look at this in our next study,” he said.

The study was funded by the Novo Nordisk Foundation. Dr. Gaist has received speaker honorarium from Bristol-Myers Squibb and Pfizer unrelated to this work.

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

A new study has provided further reassurance on questions about the risk of intracerebral hemorrhage (ICH) with statins.

The Danish case-control study, which compared statin use in 2,164 case patients with ICH and in 86,255 matched control persons, found that current statin use was associated with a lower risk of having a first ICH and that the risk was further reduced with longer duration of statin use.

The study also showed that statin use was linked to a lower risk of ICH in the more superficial lobar areas of the brain and in the deeper, nonlobar locations. There was no difference in the magnitude of risk reduction between the two locations.

“Although this study is observational, I feel these data are strong, and the results are reassuring. It certainly does not suggest any increased risk of ICH with statins,” senior author David Gaist, PhD, Odense University Hospital, Denmark, said in an interview.

“On the contrary, it indicates a lower risk, which seems to be independent of the location of the bleed.”

The study was published online in Neurology.

The authors note that statins effectively reduce the occurrence of cardiovascular events and ischemic stroke in high-risk populations, but early randomized trials raised concerns of an increased risk of ICH among statin users who have a history of stroke.

Subsequent observational studies, including four meta-analyses, included patients with and those without prior stroke. The results were inconsistent, although most found no increase in bleeding. More recent studies have found a lower risk of ICH among statin users; the risk was inversely associated with the duration and intensity of statin treatment.

However, the researchers point out that few studies have assessed the association between statin use and the location of ICH. Hemorrhages that occur in the lobar region of the brain and those that occur in the nonlobar areas can have different pathophysiologies. Arteriolosclerosis, which is strongly associated with hypertension, is a common histologic finding in patients with ICH, regardless of hemorrhage location, while cerebral amyloid angiopathy (CAA) is associated with lobar but not nonlobar ICH.

The current study was conducted to look more closely at the relationship between statin use and hematoma location as a reflection of differences in the underlying pathophysiologies of lobar versus nonlobar ICH.

The researchers used Danish registries to identify all first-ever cases of spontaneous ICH that occurred between 2009 and 2018 in persons older than 55 years in the Southern Denmark region. Patients with traumatic ICH or ICH related to vascular malformations and tumors were excluded.

These cases were verified through medical records. ICH diagnoses were classified as having a lobar or nonlobar location, and patients were matched for age, sex, and calendar year to general population control persons. The nationwide prescription registry was also analyzed to ascertain use of statins and other medications.

The study included 989 patients with lobar ICH who were matched to 39,500 control persons and 1,175 patients with nonlobar ICH who were matched to 46,755 control persons.

Results showed that current statin use was associated with a 16%-17% relative reduction in ICH risk. There was no difference with respect to ICH location.

For lobar ICH, statin use showed an adjusted odds ratio of 0.83 (95% confidence interval, 0.70-0.98); for nonlobar ICH, the adjusted odds ratio was 0.84 (95% CI, 0.72-0.98).

Longer duration of statin use was associated with a greater reduction in risk of ICH; use for more than 5 years was associated with a relative reduction of ICH of 33%-38%, again with no difference with regard to ICH location.

For lobar ICH, statin use for more than 5 years showed an adjusted odds ratio of 0.67 (95% CI, 0.51-0.87); and for nonlobar ICH, the adjusted odds ratio was 0.62 (95% CI, 0.48-0.80).

“We suspected that statins may have more of an effect in reducing nonlobar ICH, as this type is considered to be more associated with arteriosclerosis, compared with lobar ICH,” Dr. Gaist explained. “But we didn’t find that. We found that taking statins was associated with a similar reduction in risk of both lobar and nonlobar ICH.”

Although amyloid angiopathy can contribute to lobar ICH, arteriosclerosis is still involved in the majority of cases, he noted. He cited a recent population-based U.K. study that showed that while histologically verified CAA was present in 58% of patients with a lobar ICH, most also had evidence of arteriosclerosis, with only 13% having isolated CAA pathology.

“If statins exert their effect on reducing ICH by reducing arteriosclerosis, which is likely, then this observation of arteriosclerosis pathology being prevalent in both lobar and nonlobar ICH locations would explain our results,” Dr. Gaist commented.

“Strengths of our study include the large numbers involved and the fact that the patients are unselected. We tried to find everyone who had had a first ICH in a well-defined region of Denmark, so issues of selection are less of a concern than in some other studies,” he noted.

He also pointed out that all the ICH diagnoses were verified from medical records and that in a substudy, brain scans were evaluated, with investigators masked to clinical data to evaluate the location and characteristics of the hematoma. In addition, data on statin use were collected prospectively from a nationwide prescription registry.
 

Interaction with antihypertensives, anticoagulants?

Other results from the study suggest a possible interaction between statin use and antihypertensive and anticoagulant drugs.

Data showed that the lower ICH risk was restricted to patients who received statins and antihypertensive drugs concurrently. Conversely, only patients who were not concurrently taking anticoagulants had a lower risk of ICH in association with statin use.

Dr. Gaist suggested that the lack of a reduction in ICH with statins among patients taking anticoagulants could be because the increased risk of ICH with anticoagulants was stronger than the reduced risk with statins.

Regarding the fact that the reduced risk of ICH with statins was only observed among individuals who were also taking antihypertensive medication, Dr. Gaist noted that because hypertension is such an important risk factor for ICH, “it may be that to get the true benefit of statins, patients have to have their hypertension controlled.”

However, an alternative explanation could that the finding is a result of “healthy adherer” bias, in which people who take antihypertensive medication and follow a healthy lifestyle as advised would be more likely to take statins.

“The observational nature of our study does not allow us to determine the extent to which associations are causal,” the authors say.

Dr. Gaist also noted that an important caveat in this study is that they focused on individuals who had had a first ICH.

“This data does not inform us about those who have already had an ICH and are taking statins. But we are planning to look at this in our next study,” he said.

The study was funded by the Novo Nordisk Foundation. Dr. Gaist has received speaker honorarium from Bristol-Myers Squibb and Pfizer unrelated to this work.

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