Article

ILLUSTRATIVE CASE

A 24-year-old cisgender man with no significant past medical history comes to your office requesting PrEP after starting a new sexual relationship. His partner is a 26-year-old cisgender man with known HIV. The patient reports that balancing graduate school and work has made him very forgetful, and he worries that he won’t remember to take a daily pill. Are there any other PrEP methods you can offer?

The efficacy of PrEP to reduce HIV acquisition has been established across varying populations at high risk for transmission.¹ PrEP has been found to reduce the risk for sexual acquisition of HIV by nearly 99%.²

Although the use of PrEP in the United States has increased steadily since 2012, adherence to an oral formulation remains a significant issue. One study of > 13,000 people found that daily oral PrEP was discontinued by 52% of participants, only 60% of whom reinitiated the therapy after discontinuation.² Although the federal government has required Medicaid and other insurance providers to cover PrEP in an effort to increase access to the medication, this does not necessarily increase adherence to a daily medication in an often otherwise healthy population.

Long-acting injectable forms of PrEP, which have a reduced dosing frequency that may support adherence, have been studied to potentially replace daily oral pills. This latest study compared cabotegravir (CAB-LA), a long-acting IM injection given every 8 weeks, to daily oral PrEP with tenofovir disoproxil fumarate–emtricitabine (TDF-FTC).¹

STUDY SUMMARY

Decreased seroconversion without daily pills

This randomized, double-blind, double-dummy, noninferiority trial compared long-acting injectable vs daily oral PrEP formulations for the prevention of HIV across an international population. Patients were randomized to receive either CAB-LA 600 mg IM every 8 weeks or TDF-FTC 300/200 mg orally daily. The double-dummy methodology meant that those patients receiving active CAB-LA also received a daily oral placebo, while those patients receiving active TDF-FTC also received a placebo injection every 8 weeks.

Study participants were cisgender MSM or transgender women who have sex with men; ages 18 years and older; and in good health but considered to be at high risk for HIV infection. To be included, participants had to have a negative HIV serologic test at enrollment, undetectable blood HIV RNA viral load within 14 days of enrollment, and creatinine clearance ≥ 60 mL/min. Exclusion criteria included intravenous (IV) drug use within 90 days of enrollment, coagulopathy, buttock implants or fillers, a seizure disorder, or a QTc interval > 500 ms.¹

HIV seroconversion occurred in 0.57% of patients receiving long-acting injectable PrEP vs 1.7% of patients receiving daily oral PrEP.

The intention-to-treat population included 4566 patients: 2282 in the CAB-LA group and 2284 in the TDF-FTC group. Demographic characteristics—including age, race, geographic region, and cohort (MSM vs transgender women)—were not significantly different between groups at baseline. The study lasted 153 weeks, and > 86% of patients were retained at 1 year (median follow-up, 1.4 years; interquartile range, 0.8-1.9).

Continue to: The primary efficacy and safety...

The primary efficacy and safety outcomes of interest were HIV infection and occurrence of a grade ≥ 2 adverse drug reaction, respectively. HIV seroconversion occurred in 13 of 2282 (0.57%) patients in the CAB-LA group and 39 of 2284 (1.7%) patients in the TDF-FTC group (hazard ratio = 0.34; 95% CI, 0.18-0.62). The rate of severe adverse drug reactions was similar between groups. The study was stopped early due to the superiority of CAB-LA.

WHAT’S NEW

Demonstrated superiority of injectable vs oral PrEP

The results of this study could have a monumental impact on the spread of HIV. Since adherence is a known limitation of daily oral PrEP, a long-acting injectable is an intriguing option. The 8-week period between injections offers convenience, allowing primary care physicians (PCPs) to schedule their patients in advance. And because every injection is administered in the office, this option would help PCPs track adherence. Witnessed adherence to the medication, and its demonstrated superiority, could have a significant effect on HIV prevention.

The limited serious adverse effects reported by both groups may ease some PCPs’ hesitation to prescribe CAB-LA.

CAVEATS

More injection-site reactions (but little impact on adherence)

Notably, 81.4% of patients in the CAB-LA group had injection-site reactions vs 31.3% in the TDF-FTC group. However, only 2.4% of patients in the CAB-LA group opted to stop receiving the injections because of these reactions.

Standard PrEP reduces the risk for HIV acquisition from IV drug use by 74%.² However, because IV drug use was an exclusion criterion in this study, future research will need to assess CAB-LA’s effectiveness in that population.

CHALLENGES TO IMPLEMENTATION

Price and storage requirementsof CAB-LA may create issues

CAB-LA is expensive, costing more than $25,000 per year—significantly outpricing TDF-FTC, which costs approximately $8300 per year.³ Insurance coverage for PrEP, including CAB-LA, varies widely. Given the superiority reflected in this study, more efforts should be made to lower the cost of the medication.

Another hurdle for CAB-LA is that it requires refrigeration for storage. Although likely not an issue in most of the United States, it will make adoption of this method difficult in other parts of the world.

ILLUSTRATIVE CASE

A 24-year-old cisgender man with no significant past medical history comes to your office requesting PrEP after starting a new sexual relationship. His partner is a 26-year-old cisgender man with known HIV. The patient reports that balancing graduate school and work has made him very forgetful, and he worries that he won’t remember to take a daily pill. Are there any other PrEP methods you can offer?

The efficacy of PrEP to reduce HIV acquisition has been established across varying populations at high risk for transmission.¹ PrEP has been found to reduce the risk for sexual acquisition of HIV by nearly 99%.²

Although the use of PrEP in the United States has increased steadily since 2012, adherence to an oral formulation remains a significant issue. One study of > 13,000 people found that daily oral PrEP was discontinued by 52% of participants, only 60% of whom reinitiated the therapy after discontinuation.² Although the federal government has required Medicaid and other insurance providers to cover PrEP in an effort to increase access to the medication, this does not necessarily increase adherence to a daily medication in an often otherwise healthy population.

Long-acting injectable forms of PrEP, which have a reduced dosing frequency that may support adherence, have been studied to potentially replace daily oral pills. This latest study compared cabotegravir (CAB-LA), a long-acting IM injection given every 8 weeks, to daily oral PrEP with tenofovir disoproxil fumarate–emtricitabine (TDF-FTC).¹

STUDY SUMMARY

Decreased seroconversion without daily pills

This randomized, double-blind, double-dummy, noninferiority trial compared long-acting injectable vs daily oral PrEP formulations for the prevention of HIV across an international population. Patients were randomized to receive either CAB-LA 600 mg IM every 8 weeks or TDF-FTC 300/200 mg orally daily. The double-dummy methodology meant that those patients receiving active CAB-LA also received a daily oral placebo, while those patients receiving active TDF-FTC also received a placebo injection every 8 weeks.

Study participants were cisgender MSM or transgender women who have sex with men; ages 18 years and older; and in good health but considered to be at high risk for HIV infection. To be included, participants had to have a negative HIV serologic test at enrollment, undetectable blood HIV RNA viral load within 14 days of enrollment, and creatinine clearance ≥ 60 mL/min. Exclusion criteria included intravenous (IV) drug use within 90 days of enrollment, coagulopathy, buttock implants or fillers, a seizure disorder, or a QTc interval > 500 ms.¹

HIV seroconversion occurred in 0.57% of patients receiving long-acting injectable PrEP vs 1.7% of patients receiving daily oral PrEP.

The intention-to-treat population included 4566 patients: 2282 in the CAB-LA group and 2284 in the TDF-FTC group. Demographic characteristics—including age, race, geographic region, and cohort (MSM vs transgender women)—were not significantly different between groups at baseline. The study lasted 153 weeks, and > 86% of patients were retained at 1 year (median follow-up, 1.4 years; interquartile range, 0.8-1.9).

Continue to: The primary efficacy and safety...

The primary efficacy and safety outcomes of interest were HIV infection and occurrence of a grade ≥ 2 adverse drug reaction, respectively. HIV seroconversion occurred in 13 of 2282 (0.57%) patients in the CAB-LA group and 39 of 2284 (1.7%) patients in the TDF-FTC group (hazard ratio = 0.34; 95% CI, 0.18-0.62). The rate of severe adverse drug reactions was similar between groups. The study was stopped early due to the superiority of CAB-LA.

WHAT’S NEW

Demonstrated superiority of injectable vs oral PrEP

The results of this study could have a monumental impact on the spread of HIV. Since adherence is a known limitation of daily oral PrEP, a long-acting injectable is an intriguing option. The 8-week period between injections offers convenience, allowing primary care physicians (PCPs) to schedule their patients in advance. And because every injection is administered in the office, this option would help PCPs track adherence. Witnessed adherence to the medication, and its demonstrated superiority, could have a significant effect on HIV prevention.

The limited serious adverse effects reported by both groups may ease some PCPs’ hesitation to prescribe CAB-LA.

CAVEATS

More injection-site reactions (but little impact on adherence)

Notably, 81.4% of patients in the CAB-LA group had injection-site reactions vs 31.3% in the TDF-FTC group. However, only 2.4% of patients in the CAB-LA group opted to stop receiving the injections because of these reactions.

Standard PrEP reduces the risk for HIV acquisition from IV drug use by 74%.² However, because IV drug use was an exclusion criterion in this study, future research will need to assess CAB-LA’s effectiveness in that population.

CHALLENGES TO IMPLEMENTATION

Price and storage requirementsof CAB-LA may create issues

CAB-LA is expensive, costing more than $25,000 per year—significantly outpricing TDF-FTC, which costs approximately $8300 per year.³ Insurance coverage for PrEP, including CAB-LA, varies widely. Given the superiority reflected in this study, more efforts should be made to lower the cost of the medication.

Another hurdle for CAB-LA is that it requires refrigeration for storage. Although likely not an issue in most of the United States, it will make adoption of this method difficult in other parts of the world.

ILLUSTRATIVE CASE

A 24-year-old cisgender man with no significant past medical history comes to your office requesting PrEP after starting a new sexual relationship. His partner is a 26-year-old cisgender man with known HIV. The patient reports that balancing graduate school and work has made him very forgetful, and he worries that he won’t remember to take a daily pill. Are there any other PrEP methods you can offer?

The efficacy of PrEP to reduce HIV acquisition has been established across varying populations at high risk for transmission.¹ PrEP has been found to reduce the risk for sexual acquisition of HIV by nearly 99%.²

Although the use of PrEP in the United States has increased steadily since 2012, adherence to an oral formulation remains a significant issue. One study of > 13,000 people found that daily oral PrEP was discontinued by 52% of participants, only 60% of whom reinitiated the therapy after discontinuation.² Although the federal government has required Medicaid and other insurance providers to cover PrEP in an effort to increase access to the medication, this does not necessarily increase adherence to a daily medication in an often otherwise healthy population.

Long-acting injectable forms of PrEP, which have a reduced dosing frequency that may support adherence, have been studied to potentially replace daily oral pills. This latest study compared cabotegravir (CAB-LA), a long-acting IM injection given every 8 weeks, to daily oral PrEP with tenofovir disoproxil fumarate–emtricitabine (TDF-FTC).¹

STUDY SUMMARY

Decreased seroconversion without daily pills

This randomized, double-blind, double-dummy, noninferiority trial compared long-acting injectable vs daily oral PrEP formulations for the prevention of HIV across an international population. Patients were randomized to receive either CAB-LA 600 mg IM every 8 weeks or TDF-FTC 300/200 mg orally daily. The double-dummy methodology meant that those patients receiving active CAB-LA also received a daily oral placebo, while those patients receiving active TDF-FTC also received a placebo injection every 8 weeks.

Study participants were cisgender MSM or transgender women who have sex with men; ages 18 years and older; and in good health but considered to be at high risk for HIV infection. To be included, participants had to have a negative HIV serologic test at enrollment, undetectable blood HIV RNA viral load within 14 days of enrollment, and creatinine clearance ≥ 60 mL/min. Exclusion criteria included intravenous (IV) drug use within 90 days of enrollment, coagulopathy, buttock implants or fillers, a seizure disorder, or a QTc interval > 500 ms.¹

HIV seroconversion occurred in 0.57% of patients receiving long-acting injectable PrEP vs 1.7% of patients receiving daily oral PrEP.

The intention-to-treat population included 4566 patients: 2282 in the CAB-LA group and 2284 in the TDF-FTC group. Demographic characteristics—including age, race, geographic region, and cohort (MSM vs transgender women)—were not significantly different between groups at baseline. The study lasted 153 weeks, and > 86% of patients were retained at 1 year (median follow-up, 1.4 years; interquartile range, 0.8-1.9).

Continue to: The primary efficacy and safety...

The primary efficacy and safety outcomes of interest were HIV infection and occurrence of a grade ≥ 2 adverse drug reaction, respectively. HIV seroconversion occurred in 13 of 2282 (0.57%) patients in the CAB-LA group and 39 of 2284 (1.7%) patients in the TDF-FTC group (hazard ratio = 0.34; 95% CI, 0.18-0.62). The rate of severe adverse drug reactions was similar between groups. The study was stopped early due to the superiority of CAB-LA.

WHAT’S NEW

Demonstrated superiority of injectable vs oral PrEP

The results of this study could have a monumental impact on the spread of HIV. Since adherence is a known limitation of daily oral PrEP, a long-acting injectable is an intriguing option. The 8-week period between injections offers convenience, allowing primary care physicians (PCPs) to schedule their patients in advance. And because every injection is administered in the office, this option would help PCPs track adherence. Witnessed adherence to the medication, and its demonstrated superiority, could have a significant effect on HIV prevention.

The limited serious adverse effects reported by both groups may ease some PCPs’ hesitation to prescribe CAB-LA.

CAVEATS

More injection-site reactions (but little impact on adherence)

Notably, 81.4% of patients in the CAB-LA group had injection-site reactions vs 31.3% in the TDF-FTC group. However, only 2.4% of patients in the CAB-LA group opted to stop receiving the injections because of these reactions.

Standard PrEP reduces the risk for HIV acquisition from IV drug use by 74%.² However, because IV drug use was an exclusion criterion in this study, future research will need to assess CAB-LA’s effectiveness in that population.

CHALLENGES TO IMPLEMENTATION

Price and storage requirementsof CAB-LA may create issues

CAB-LA is expensive, costing more than $25,000 per year—significantly outpricing TDF-FTC, which costs approximately $8300 per year.³ Insurance coverage for PrEP, including CAB-LA, varies widely. Given the superiority reflected in this study, more efforts should be made to lower the cost of the medication.

Another hurdle for CAB-LA is that it requires refrigeration for storage. Although likely not an issue in most of the United States, it will make adoption of this method difficult in other parts of the world.

The Centers for Disease Control and Prevention (CDC) recently published new recommendations on screening for hepatitis B infection.¹ They recommend screening all adults (ages 18 years and older) at least once.

These recommendations differ in a few ways from those of the US Preventive Services­ Task Force (USPSTF).² This Practice Alert will highlight these differences but also point out areas of agreement between the 2 sets of ­recommendations—and discuss why 2 separate agencies in the US Department of Health and Human Services reached different conclusions on some issues.

First, some background on hepatitis B

An estimated 580,000 to 2.4 million people in the United States have chronic hepatitis B (CHB) infection—and as many as two-thirds are unaware of it.³ In 2020, the Department of Health and Human Services published the Viral Hepatitis National Strategic Plan for the United States with a stated goal of increasing awareness of infection status among those with hepatitis B virus (HBV) from 32% to 90% by 2030.⁴ People living in the United States but born outside the country are at highest risk for CHB; they account for 69% of those with the infection.⁵

The incidence of acute HBV infection has declined markedly since the HBV vaccine was recommended for high-risk adults in 1982 and universally for infants in 1991.^6,7 Overall rates of HBV infection declined fairly steadily starting around 1987—but in 2014, rates began to increase, especially in those ages 40 to 59 years.^8,9 In 2019, 3192 cases were reported; but when one factors in underreporting, the CDC estimates that the number is likely closer to 20,700.¹⁰ This uptick is one reason the Advisory Committee on Immunization Practices changed its HBV vaccination recommendation for adults from a risk-based to a universal recommendation for all unvaccinated adults through age 60 years.¹⁰

Chronic hepatitis B infection has serious consequences

The proportion of those infected with HBV who develop CHB differs by age at infection: 80% to 90% if infected during infancy, 30% if infected before age 6 years, and 1% to 12% if infected as an older child or adult.⁸

CHB infection can lead to chronic liver disease, including cirrhosis of the liver, liver cancer, and liver failure. About 25% of those who develop CHB infection during childhood and 15% of those who develop chronic infection after childhood will die prematurely from cirrhosis or liver cancer.⁸

The American Association for the Study of Liver Diseases (AASLD) classifies CHB into 4 phases that reflect the rate of viral replication and the patient’s immune response.¹¹ These phases are:

• immune-tolerant (minimal inflammation and fibrosis)
• hepatitis B e-antigen (HBeAg)-positive immune-active (moderate-to-severe inflammation or fibrosis)
• inactive CHB (minimal necroinflammation but variable fibrosis), and
• HBeAg-negative immune reactivation (moderate-to-severe inflammation or fibrosis).¹¹

Continue to: The progression from one phase...

The progression from one phase to the next varies by patient, and not all patients will progress through each phase. The AASLD recommends periodically monitoring the HBV DNA and alanine aminotransferase (ALT) levels in those with CHB to track the progression from one phase to the next and to guide treatment decisions.

Treatment can be beneficial for those who meet criteria

The evidence report prepared for USPSTF found that antiviral treatment of those with CHB infection resulted in improved intermediate outcomes (histologic improvement, loss of hepatitis B surface antigen [HBsAg], loss of HBeAg, HBeAg seroconversion, virologic suppression, and normalization of ALT levels). The magnitude of benefit varied by location and study design.¹²

In addition, the evidence review found that antiviral therapy was associated with a decreased risk for overall mortality (relative risk [RR] = 0.15; 95% CI, 0.03-0.69), cirrhosis (RR = 0.72; 95% CI, 0.29-1.77), and hepatocellular carcinoma (RR = 0.60; 95% CI, 0.16-2.33). However, these results came from studies that were “limited due to small numbers of trials, few events, and insufficient duration of follow-up.”¹²

The USPSTF and the CDC both judged that the intermediate outcome results, as well as findings that improved intermediate outcomes lead to decreases in chronic liver disease, are strong enough evidence for their recommendations.

However, not all patients with CHB infection require treatment; estimates of patients with HBV infection meeting AASLD criteria for treatment range from 24% to 48%.¹ The AASLD guideline on the treatment of CHB infection is an excellent resource that makes recommendations on the initial evaluation, ongoing monitoring, and treatment decisions for those with CHB.¹¹

Continue to: How CDC and USPSTF guidance on HBV screeinng differs

The CDC and USPSTF recommendations for HBV screening differ in 3 aspects: whom to screen, whom to classify as at high risk for HBV infection, and what tests to use for screening.

Who should be screened?

The USPSTF recommends screening adults and adolescents who are at high risk for HBV. The CDC recommends screening all adults at least once. Both entities agree that those who are at increased risk should be screened periodically, although the optimal frequency has not been established. The USPSTF does not recommend against screening for the general population, so universal screening (as advocated by the CDC) is not in direct conflict with the USPSTF’s recommendations.

Who is at increased risk for HBV infection?

The CDC and the USPSTF differ slightly on the factors they consider to constitute increased risk for HBV infection. These are listed in ­TABLE 1.^1,2

The CDC lists 6 categories that the ­USPSTF does not mention. However, 4 of these categories are mentioned indirectly in the USPSTF evidence report that accompanies the recommendations, via statements that certain settings have high proportions of people at risk for HBV infection: sexually transmitted infection clinics; HIV testing and treatment centers; health care settings that target services toward people who inject drugs and men who have sex with men; correctional facilities; hemodialysis facilities; and institutions and nonresidential daycare centers for developmentally disabled persons. People who are served at most of these facilities are also at risk for hepatitis C virus infection.

Three categories are listed by the CDC and not by the USPSTF, in either the recommendation or evidence report. These include a history of multiple sex partners; elevated ALT or aspartate aminotransferase levels of unknown origin; and patient request for testing (because they may not want to reveal risk factors).

Continue to: What test(s) should be ordered?

What test(s) should be ordered? 

The USPSTF recommends screening using HBsAg. The CDC recommends using triple-panel screening: HBsAg, anti-hepatitis B surface antigen (anti-HBs), and total antibody to hepatitis B core antigen (anti-HBc).

HBsAg indicates HBV infection, either acute or chronic, or a recent dose of HBV vaccine. Anti-HBs indicate recovery from HBV infection, response to HBV vaccine, or recent receipt of hepatitis B immune globulin. Total anti-HBc develops in all HBV infections, resolved or current, and usually persists for life. Vaccine-induced immunity does not cause anti-HBc to develop.

The USPSTF’s rationale is that testing for HBsAg is more than 98% sensitive and specific for detecting HBV infections.² The CDC recommends triple testing because it can detect those with asymptomatic active HBV infections (this would be a rare occurrence); those who have resolved infection and might be susceptible to reactivation (eg, those who are immunosuppressed); and those who are susceptible and need vaccination.

Interpretation of HBV test results and suggested actions are described in TABLE 2.^1,8,13

Why do the CDC and USPSTF differ?

While it would be optimal if the CDC and the USPSTF coordinated and harmonized recommendations, this is difficult to achieve given their different missions. The USPSTF is charged to make evidence-based recommendations about preventive services such as screenings, behavioral counseling, and preventive medications, which are provided by clinicians to individual patients. The Task Force uses a very strict evidence-based process and will not make recommendations unless there is adequate evidence of efficacy and safety. Members of the Task Force are primary care professionals, and their collaborating professional organizations are primary care focused.

Based on practice-specific characteristics, family physicians should decide if they want to screen all adults or only those at increased risk, and whether to use singleor triple-test screening.

The CDC takes a community-wide, public health perspective. The professionals that work there are not always clinicians. They strive to prevent as much illness as possible, using public health measures and making recommendations to clinicians. They collaborate with professional organizations; on topics such as hepatitis and other infectious diseases, they collaborate with specialty-oriented societies. Given the imperative to act with the best evidence available, their evidence assessment process is not as strict.

The result, at times, is slight differences in recommendations. However, the HBV screening recommendations from the CDC and the USPSTF agree more than they do not. Based on practice-specific characteristics, family physicians should decide if they want to screen all adults or only those at increased risk, and whether to use single- or triple-test screening.

The Centers for Disease Control and Prevention (CDC) recently published new recommendations on screening for hepatitis B infection.¹ They recommend screening all adults (ages 18 years and older) at least once.

These recommendations differ in a few ways from those of the US Preventive Services­ Task Force (USPSTF).² This Practice Alert will highlight these differences but also point out areas of agreement between the 2 sets of ­recommendations—and discuss why 2 separate agencies in the US Department of Health and Human Services reached different conclusions on some issues.

First, some background on hepatitis B

An estimated 580,000 to 2.4 million people in the United States have chronic hepatitis B (CHB) infection—and as many as two-thirds are unaware of it.³ In 2020, the Department of Health and Human Services published the Viral Hepatitis National Strategic Plan for the United States with a stated goal of increasing awareness of infection status among those with hepatitis B virus (HBV) from 32% to 90% by 2030.⁴ People living in the United States but born outside the country are at highest risk for CHB; they account for 69% of those with the infection.⁵

The incidence of acute HBV infection has declined markedly since the HBV vaccine was recommended for high-risk adults in 1982 and universally for infants in 1991.^6,7 Overall rates of HBV infection declined fairly steadily starting around 1987—but in 2014, rates began to increase, especially in those ages 40 to 59 years.^8,9 In 2019, 3192 cases were reported; but when one factors in underreporting, the CDC estimates that the number is likely closer to 20,700.¹⁰ This uptick is one reason the Advisory Committee on Immunization Practices changed its HBV vaccination recommendation for adults from a risk-based to a universal recommendation for all unvaccinated adults through age 60 years.¹⁰

Chronic hepatitis B infection has serious consequences

The proportion of those infected with HBV who develop CHB differs by age at infection: 80% to 90% if infected during infancy, 30% if infected before age 6 years, and 1% to 12% if infected as an older child or adult.⁸

CHB infection can lead to chronic liver disease, including cirrhosis of the liver, liver cancer, and liver failure. About 25% of those who develop CHB infection during childhood and 15% of those who develop chronic infection after childhood will die prematurely from cirrhosis or liver cancer.⁸

The American Association for the Study of Liver Diseases (AASLD) classifies CHB into 4 phases that reflect the rate of viral replication and the patient’s immune response.¹¹ These phases are:

• immune-tolerant (minimal inflammation and fibrosis)
• hepatitis B e-antigen (HBeAg)-positive immune-active (moderate-to-severe inflammation or fibrosis)
• inactive CHB (minimal necroinflammation but variable fibrosis), and
• HBeAg-negative immune reactivation (moderate-to-severe inflammation or fibrosis).¹¹

Continue to: The progression from one phase...

The progression from one phase to the next varies by patient, and not all patients will progress through each phase. The AASLD recommends periodically monitoring the HBV DNA and alanine aminotransferase (ALT) levels in those with CHB to track the progression from one phase to the next and to guide treatment decisions.

Treatment can be beneficial for those who meet criteria

The evidence report prepared for USPSTF found that antiviral treatment of those with CHB infection resulted in improved intermediate outcomes (histologic improvement, loss of hepatitis B surface antigen [HBsAg], loss of HBeAg, HBeAg seroconversion, virologic suppression, and normalization of ALT levels). The magnitude of benefit varied by location and study design.¹²

In addition, the evidence review found that antiviral therapy was associated with a decreased risk for overall mortality (relative risk [RR] = 0.15; 95% CI, 0.03-0.69), cirrhosis (RR = 0.72; 95% CI, 0.29-1.77), and hepatocellular carcinoma (RR = 0.60; 95% CI, 0.16-2.33). However, these results came from studies that were “limited due to small numbers of trials, few events, and insufficient duration of follow-up.”¹²

The USPSTF and the CDC both judged that the intermediate outcome results, as well as findings that improved intermediate outcomes lead to decreases in chronic liver disease, are strong enough evidence for their recommendations.

However, not all patients with CHB infection require treatment; estimates of patients with HBV infection meeting AASLD criteria for treatment range from 24% to 48%.¹ The AASLD guideline on the treatment of CHB infection is an excellent resource that makes recommendations on the initial evaluation, ongoing monitoring, and treatment decisions for those with CHB.¹¹

Continue to: How CDC and USPSTF guidance on HBV screeinng differs

The CDC and USPSTF recommendations for HBV screening differ in 3 aspects: whom to screen, whom to classify as at high risk for HBV infection, and what tests to use for screening.

Who should be screened?

The USPSTF recommends screening adults and adolescents who are at high risk for HBV. The CDC recommends screening all adults at least once. Both entities agree that those who are at increased risk should be screened periodically, although the optimal frequency has not been established. The USPSTF does not recommend against screening for the general population, so universal screening (as advocated by the CDC) is not in direct conflict with the USPSTF’s recommendations.

Who is at increased risk for HBV infection?

The CDC and the USPSTF differ slightly on the factors they consider to constitute increased risk for HBV infection. These are listed in ­TABLE 1.^1,2

The CDC lists 6 categories that the ­USPSTF does not mention. However, 4 of these categories are mentioned indirectly in the USPSTF evidence report that accompanies the recommendations, via statements that certain settings have high proportions of people at risk for HBV infection: sexually transmitted infection clinics; HIV testing and treatment centers; health care settings that target services toward people who inject drugs and men who have sex with men; correctional facilities; hemodialysis facilities; and institutions and nonresidential daycare centers for developmentally disabled persons. People who are served at most of these facilities are also at risk for hepatitis C virus infection.

Three categories are listed by the CDC and not by the USPSTF, in either the recommendation or evidence report. These include a history of multiple sex partners; elevated ALT or aspartate aminotransferase levels of unknown origin; and patient request for testing (because they may not want to reveal risk factors).

Continue to: What test(s) should be ordered?

What test(s) should be ordered? 

The USPSTF recommends screening using HBsAg. The CDC recommends using triple-panel screening: HBsAg, anti-hepatitis B surface antigen (anti-HBs), and total antibody to hepatitis B core antigen (anti-HBc).

HBsAg indicates HBV infection, either acute or chronic, or a recent dose of HBV vaccine. Anti-HBs indicate recovery from HBV infection, response to HBV vaccine, or recent receipt of hepatitis B immune globulin. Total anti-HBc develops in all HBV infections, resolved or current, and usually persists for life. Vaccine-induced immunity does not cause anti-HBc to develop.

The USPSTF’s rationale is that testing for HBsAg is more than 98% sensitive and specific for detecting HBV infections.² The CDC recommends triple testing because it can detect those with asymptomatic active HBV infections (this would be a rare occurrence); those who have resolved infection and might be susceptible to reactivation (eg, those who are immunosuppressed); and those who are susceptible and need vaccination.

Interpretation of HBV test results and suggested actions are described in TABLE 2.^1,8,13

Why do the CDC and USPSTF differ?

While it would be optimal if the CDC and the USPSTF coordinated and harmonized recommendations, this is difficult to achieve given their different missions. The USPSTF is charged to make evidence-based recommendations about preventive services such as screenings, behavioral counseling, and preventive medications, which are provided by clinicians to individual patients. The Task Force uses a very strict evidence-based process and will not make recommendations unless there is adequate evidence of efficacy and safety. Members of the Task Force are primary care professionals, and their collaborating professional organizations are primary care focused.

Based on practice-specific characteristics, family physicians should decide if they want to screen all adults or only those at increased risk, and whether to use singleor triple-test screening.

The CDC takes a community-wide, public health perspective. The professionals that work there are not always clinicians. They strive to prevent as much illness as possible, using public health measures and making recommendations to clinicians. They collaborate with professional organizations; on topics such as hepatitis and other infectious diseases, they collaborate with specialty-oriented societies. Given the imperative to act with the best evidence available, their evidence assessment process is not as strict.

The result, at times, is slight differences in recommendations. However, the HBV screening recommendations from the CDC and the USPSTF agree more than they do not. Based on practice-specific characteristics, family physicians should decide if they want to screen all adults or only those at increased risk, and whether to use single- or triple-test screening.

The Centers for Disease Control and Prevention (CDC) recently published new recommendations on screening for hepatitis B infection.¹ They recommend screening all adults (ages 18 years and older) at least once.

These recommendations differ in a few ways from those of the US Preventive Services­ Task Force (USPSTF).² This Practice Alert will highlight these differences but also point out areas of agreement between the 2 sets of ­recommendations—and discuss why 2 separate agencies in the US Department of Health and Human Services reached different conclusions on some issues.

First, some background on hepatitis B

An estimated 580,000 to 2.4 million people in the United States have chronic hepatitis B (CHB) infection—and as many as two-thirds are unaware of it.³ In 2020, the Department of Health and Human Services published the Viral Hepatitis National Strategic Plan for the United States with a stated goal of increasing awareness of infection status among those with hepatitis B virus (HBV) from 32% to 90% by 2030.⁴ People living in the United States but born outside the country are at highest risk for CHB; they account for 69% of those with the infection.⁵

The incidence of acute HBV infection has declined markedly since the HBV vaccine was recommended for high-risk adults in 1982 and universally for infants in 1991.^6,7 Overall rates of HBV infection declined fairly steadily starting around 1987—but in 2014, rates began to increase, especially in those ages 40 to 59 years.^8,9 In 2019, 3192 cases were reported; but when one factors in underreporting, the CDC estimates that the number is likely closer to 20,700.¹⁰ This uptick is one reason the Advisory Committee on Immunization Practices changed its HBV vaccination recommendation for adults from a risk-based to a universal recommendation for all unvaccinated adults through age 60 years.¹⁰

Chronic hepatitis B infection has serious consequences

The proportion of those infected with HBV who develop CHB differs by age at infection: 80% to 90% if infected during infancy, 30% if infected before age 6 years, and 1% to 12% if infected as an older child or adult.⁸

CHB infection can lead to chronic liver disease, including cirrhosis of the liver, liver cancer, and liver failure. About 25% of those who develop CHB infection during childhood and 15% of those who develop chronic infection after childhood will die prematurely from cirrhosis or liver cancer.⁸

The American Association for the Study of Liver Diseases (AASLD) classifies CHB into 4 phases that reflect the rate of viral replication and the patient’s immune response.¹¹ These phases are:

• immune-tolerant (minimal inflammation and fibrosis)
• hepatitis B e-antigen (HBeAg)-positive immune-active (moderate-to-severe inflammation or fibrosis)
• inactive CHB (minimal necroinflammation but variable fibrosis), and
• HBeAg-negative immune reactivation (moderate-to-severe inflammation or fibrosis).¹¹

Continue to: The progression from one phase...

The progression from one phase to the next varies by patient, and not all patients will progress through each phase. The AASLD recommends periodically monitoring the HBV DNA and alanine aminotransferase (ALT) levels in those with CHB to track the progression from one phase to the next and to guide treatment decisions.

Treatment can be beneficial for those who meet criteria

The evidence report prepared for USPSTF found that antiviral treatment of those with CHB infection resulted in improved intermediate outcomes (histologic improvement, loss of hepatitis B surface antigen [HBsAg], loss of HBeAg, HBeAg seroconversion, virologic suppression, and normalization of ALT levels). The magnitude of benefit varied by location and study design.¹²

In addition, the evidence review found that antiviral therapy was associated with a decreased risk for overall mortality (relative risk [RR] = 0.15; 95% CI, 0.03-0.69), cirrhosis (RR = 0.72; 95% CI, 0.29-1.77), and hepatocellular carcinoma (RR = 0.60; 95% CI, 0.16-2.33). However, these results came from studies that were “limited due to small numbers of trials, few events, and insufficient duration of follow-up.”¹²

The USPSTF and the CDC both judged that the intermediate outcome results, as well as findings that improved intermediate outcomes lead to decreases in chronic liver disease, are strong enough evidence for their recommendations.

However, not all patients with CHB infection require treatment; estimates of patients with HBV infection meeting AASLD criteria for treatment range from 24% to 48%.¹ The AASLD guideline on the treatment of CHB infection is an excellent resource that makes recommendations on the initial evaluation, ongoing monitoring, and treatment decisions for those with CHB.¹¹

Continue to: How CDC and USPSTF guidance on HBV screeinng differs

The CDC and USPSTF recommendations for HBV screening differ in 3 aspects: whom to screen, whom to classify as at high risk for HBV infection, and what tests to use for screening.

Who should be screened?

The USPSTF recommends screening adults and adolescents who are at high risk for HBV. The CDC recommends screening all adults at least once. Both entities agree that those who are at increased risk should be screened periodically, although the optimal frequency has not been established. The USPSTF does not recommend against screening for the general population, so universal screening (as advocated by the CDC) is not in direct conflict with the USPSTF’s recommendations.

Who is at increased risk for HBV infection?

The CDC and the USPSTF differ slightly on the factors they consider to constitute increased risk for HBV infection. These are listed in ­TABLE 1.^1,2

The CDC lists 6 categories that the ­USPSTF does not mention. However, 4 of these categories are mentioned indirectly in the USPSTF evidence report that accompanies the recommendations, via statements that certain settings have high proportions of people at risk for HBV infection: sexually transmitted infection clinics; HIV testing and treatment centers; health care settings that target services toward people who inject drugs and men who have sex with men; correctional facilities; hemodialysis facilities; and institutions and nonresidential daycare centers for developmentally disabled persons. People who are served at most of these facilities are also at risk for hepatitis C virus infection.

Three categories are listed by the CDC and not by the USPSTF, in either the recommendation or evidence report. These include a history of multiple sex partners; elevated ALT or aspartate aminotransferase levels of unknown origin; and patient request for testing (because they may not want to reveal risk factors).

Continue to: What test(s) should be ordered?

What test(s) should be ordered? 

The USPSTF recommends screening using HBsAg. The CDC recommends using triple-panel screening: HBsAg, anti-hepatitis B surface antigen (anti-HBs), and total antibody to hepatitis B core antigen (anti-HBc).

HBsAg indicates HBV infection, either acute or chronic, or a recent dose of HBV vaccine. Anti-HBs indicate recovery from HBV infection, response to HBV vaccine, or recent receipt of hepatitis B immune globulin. Total anti-HBc develops in all HBV infections, resolved or current, and usually persists for life. Vaccine-induced immunity does not cause anti-HBc to develop.

The USPSTF’s rationale is that testing for HBsAg is more than 98% sensitive and specific for detecting HBV infections.² The CDC recommends triple testing because it can detect those with asymptomatic active HBV infections (this would be a rare occurrence); those who have resolved infection and might be susceptible to reactivation (eg, those who are immunosuppressed); and those who are susceptible and need vaccination.

Interpretation of HBV test results and suggested actions are described in TABLE 2.^1,8,13

Why do the CDC and USPSTF differ?

While it would be optimal if the CDC and the USPSTF coordinated and harmonized recommendations, this is difficult to achieve given their different missions. The USPSTF is charged to make evidence-based recommendations about preventive services such as screenings, behavioral counseling, and preventive medications, which are provided by clinicians to individual patients. The Task Force uses a very strict evidence-based process and will not make recommendations unless there is adequate evidence of efficacy and safety. Members of the Task Force are primary care professionals, and their collaborating professional organizations are primary care focused.

Based on practice-specific characteristics, family physicians should decide if they want to screen all adults or only those at increased risk, and whether to use singleor triple-test screening.

The CDC takes a community-wide, public health perspective. The professionals that work there are not always clinicians. They strive to prevent as much illness as possible, using public health measures and making recommendations to clinicians. They collaborate with professional organizations; on topics such as hepatitis and other infectious diseases, they collaborate with specialty-oriented societies. Given the imperative to act with the best evidence available, their evidence assessment process is not as strict.

The result, at times, is slight differences in recommendations. However, the HBV screening recommendations from the CDC and the USPSTF agree more than they do not. Based on practice-specific characteristics, family physicians should decide if they want to screen all adults or only those at increased risk, and whether to use single- or triple-test screening.

Evidence supports what family physicians know to be true: Knee pain is an exceedingly common presenting problem in the primary care office. Estimates of lifetime incidence reach as high as 54%,¹ and the prevalence of knee pain in the general population is increasing.² Knee disability can result from acute or traumatic injuries as well as chronic, degenerative conditions such as osteoarthritis (OA). The decision to pursue orthopedic consultation for a particular injury or painful knee condition can be challenging. To address this, we highlight specific knee diagnoses known to cause pain, with the aim of describing which conditions likely will necessitate surgical consultation—and which won’t.

Acute or nondegenerative knee injuries and pain

Acute knee injuries range in severity from simple contusions and sprains to high-energy, traumatic injuries with resulting joint instability and potential neurovascular compromise. While conservative treatment often is successful for many simple injuries, surgical management—sometimes urgently or emergently—is needed in other cases, as will be detailed shortly.

Neurovascular injury associated with knee dislocations

Acute neurovascular injuries often require emergent surgical intervention. Although rare, tibiofemoral (knee) dislocations pose a significant challenge to the clinician in both diagnosis and management. The reported frequency of popliteal artery injury or rupture following a dislocation varies widely, with rates ranging from 5% to 64%, according to older studies; more recent data, however, suggest the rate is actually as low as 3.3%.³ Vascular injury can lead to irreversible tissue damage and even limb loss if not promptly identified. Identifying a knee dislocation can prove challenging, as spontaneous joint reduction occurs in as many as 50% of cases, potentially shrouding the severity of the injury on initial evaluation.⁴

Immediate immobilization and emergency department transport for monitoring, orthopedics consultation, and vascular ­studies or vascular surgery consultation is recommended in the case of a suspected knee dislocation. In one cross-sectional cohort study, the surgical management of knee ­dislocations yielded favorable outcomes in > 75% of cases.⁵

Tibial plateau fracture

This fracture often occurs as a result of high-energy trauma, such as contact sports or motor vehicle accidents, and is characterized by a proximal tibial fracture line with extension to the articular surface. X-rays often are sufficient for initial diagnosis. Computed tomo­graphy can help rule out a fracture line when clinical suspicion is high and x-rays are nondiagnostic. As noted earlier, any suggestion of neurovascular compromise on physical exam requires an emergent orthopedic surgeon consultation for a possible displaced and unstable (or more complex) injury (FIGURE 1).^6-8

Nondisplaced tibial plateau fractures without supraphysiologic ligamentous laxity on valgus or varus stress testing can be managed safely with protection and early mobilization, gradual progression of weight-bearing, and serial x-rays to ensure fracture healing and stability. Surgical management and fixation are required emergently for open fractures or gross joint instability with vascular or neurologic compromise. Suspicion of these complications is raised by distal neuropathic symptoms of paresthesia or skin anesthesia, progressively worsening pain distal to the knee, or vascular signs of pallor, delayed or lost capillary refill, or decreased or absent distal pulses.

Gross joint instability identified by positive valgus or varus stress testing, positive anterior or posterior drawer testing, or patient inability to tolerate these maneuvers due to pain similarly should raise suspicion for a more significant fracture at risk for concurrent neurovascular injury. Acute compartment syndrome also is a known complication of tibial plateau fractures and similarly requires emergent operative management. Urgent surgical consultation is recommended for fractures with displaced fracture fragments, tibial articular surface step-off or depression, fractures with concurrent joint laxity, or medial plateau fractures.^6-8

Continue to: Patella fractures

Patella fractures

These fractures occur as a direct blow to the front of the knee, such as falling forward onto a hard surface, or indirectly due to a sudden extreme eccentric contraction of the quadriceps muscle. Nondisplaced fractures with an intact knee extension mechanism, which is examined via a supine straight-leg raise or seated knee extension, are managed with weight-bearing as tolerated in strict immobilization in full extension for 4 to 6 weeks, with active range-of-motion and isometric quadriceps exercises beginning in 1 to 2 weeks. Serial x-rays also are obtained to ensure fracture displacement does not occur during the rehabilitation process.⁹

High-quality evidence guiding follow-up care and comparing outcomes of surgical and nonsurgical management of patella fractures is lacking, and studies comparing different surgical techniques are of lower methodological quality.¹⁰ Nevertheless, displaced or comminuted patellar fractures are referred urgently to orthopedic surgical care for fixation, as are those with concurrent loose bodies, chondral surface injuries or articular step-off, or osteochondral fractures.⁹ Inability to perform a straight-leg raise (ie, clinical loss of the knee extension mechanism) suggests a fracture under tension that likely also requires surgical fixation for successful recovery. Neurovascular injuries are unlikely in most patellar fractures but would require emergent surgical consultation.⁹

Ligamentous injury

Tibiofemoral joint laxity occurs as a result of ligamentous injury, with or without tibial plateau fracture. The anterior cruciate ligament (ACL), posterior cruciate ligament (PCL), medial collateral ligament (MCL), and lateral collateral ligament (LCL) comprise the 4 main ligaments of the knee. The ACL resists anterior tibial translation and rotational forces, while the PCL resists posterior tibial translation. The MCL and LCL resist valgus and varus stress, respectively.

Ligament injuries are classified as Grades 1 to 3¹¹:

• Grade 1 sprains. The ligament is stretched, but there is no macroscopic tearing; joint stability is maintained.
• Grade 2 sprains. There are partial macroscopic ligament tears. There is joint laxity due to the partial loss of the ligament’s structural integrity.
• Grade 3 sprains. The ligament is fully avulsed or ruptured with resultant gross joint instability.

Vascular injury can lead to irreversible tissue damage and even limb loss if not promptly identified.

The decision to pursue surgical repair of a knee sprain depends heavily on the likelihood of keeping or regaining and maintaining functional joint stability during the injury recovery and postinjury time periods. Injuries that do not result in joint instability or injuries with a high likelihood of returning to a stable state with conservative measures often do not require surgical intervention.

Continue to: ACL tears

ACL tears occur most commonly via a noncontact event, as when an individual plants their foot and suddenly changes direction during sport or other physical activity. Treatment hinges on patient activity levels and participation in sports. Patients who do not plan to engage in athletic movements (that require changes in direction or planting and twisting) and who otherwise maintain satisfactory joint stability during activities of daily living may elect to defer or even altogether avoid surgical reconstruction of isolated ACL tears. One pair of studies demonstrated equivalent outcomes in surgical and nonsurgical management in 121 young, nonelite athletes at 2- and 5-year follow-up, although the crossover from the nonsurgical to surgical groups was high.^12,13 Athletes who regain satisfactory function and stability nonoperatively can defer surgical intervention. However, the majority of active patients and athletes will require surgical ACL reconstruction to return to pre-injury functional levels.¹⁴

PCL sprains occur as a result of sudden posteriorly directed force on the tibia, such as when the knee is hyperextended or a patient falls directly onto a flexed knee. Patients with Grade 1 and 2 isolated sprains generally will recover with conservative care, as will patients with some Grade 3 complete tears that do not fully compromise joint stability. However, high-grade PCL injuries often are comorbid with posterolateral corner or other injuries, leading to a higher likelihood of joint instability and thus the need for surgical intervention for the best chance at an optimal outcome.¹⁵

MCL sprain. Surgical management is not required in an isolated Grade 1 or 2 MCL sprain, as the hallmarks of recovery—return of joint stability, knee strength and range of motion, and pain ­reduction—can be achieved successfully with conservative management. Isolated Grade 3 MCL sprains are also successfully managed nonoperatively¹⁶ except in specific cases, such as a concurrent large avulsion fracture.¹⁷

LCL sprain. Similarly, isolated Grade 1 and 2 LCL sprains generally do not require surgical intervention. However, Grade 3 LCL injuries usually do, as persistent joint instability and poor functional outcomes are more common with nonsurgical management.^18-20 Additionally, high-grade LCL injuries frequently manifest with comorbid meniscus injuries or sprains of the posterolateral corner of the knee, a complex anatomic structure that provides both static and dynamic tibiofemoral joint stability. Surgical repair or reconstruction of the posterolateral corner frequently is necessary for optimal functional outcomes.²¹

Multiligamentous sprains frequently lead to gross joint instability and necessitate orthopedic surgeon consultation to determine the best treatment plan; this should be done emergently if neurovascular compromise is suspected. A common injury combination is simultaneous ACL and MCL sprains with or without meniscus injury. In these cases, some surgeons will choose to defer ACL reconstruction until after MCL healing is achieved. This allows the patient to regain valgus stability of the joint prior to performing ACL reconstruction to regain rotational and anterior stability.²⁰

Continue to: Patellar dislocations

Patellar dislocations represent a relatively common knee injury in young active patients, often occurring in a noncontact fashion when a valgus force is applied to an externally rotated and planted lower leg. A chief risk factor for a patellar dislocation is a history of prior dislocation. If rehabilitation following a dislocation is insufficient to regain patellofemoral joint stability, or if certain risk factors for recurrent dislocation are present, surgical intervention, such as medial patellofemoral ligament (MPFL) reconstruction or tibial tubercle transfer, is considered.²² A systematic review concluded that MPFL reconstruction following a first-time dislocation yielded lower redislocation rates of 7% compared to 30% with nonoperative treatment.²³

Major tendon rupture

Patellar tendon ruptures occur when a sudden eccentric force is applied to the knee, such as when landing from a jump with the knee flexed. Patellar tendon ruptures frequently are clinically apparent, with patients demonstrating a high-riding patella and loss of active knee extension. Quadriceps tendon ruptures often result from a similar injury mechanism in older patients, with a similar loss of active knee extension and a palpable gap superior to the patella.²⁴

Partial tears in patients who can maintain full extension of the knee against gravity are treated nonoperatively, but early surgical repair is indicated for complete quadriceps or patellar tendon ruptures to achieve optimal outcomes. Prompt diagnosis and treatment are critical, as repair delayed beyond 1 to 2 weeks postinjury is associated with worse outcomes.^25-28

Surgical management and fixation are required emergently for open fractures or gross joint instability with vascular or neurologic compromise.

Even with prompt treatment, return to sport is not guaranteed. According to a recent systematic review, athletes returned to play 88.9% and 89.8% of the time following patellar and quadriceps tendon repairs, respectively. However, returning to the same level of play was less common and achieved 80.8% (patellar tendon repair) and 70% (quadriceps tendon repair) of the time. Return-to-work rates were higher, at 96% for both surgical treatments.²⁹

Locked knee and acute meniscus tears in younger patients

In some acute knee injuries, meniscus tears, loose cartilage bodies or osteochondral defects, or other internal structures can become interposed between the femoral and tibial surfaces, preventing both active and passive knee extension. Such injuries are often severely painful and functionally debilitating. While manipulation under anesthesia can acutely restore joint function,³⁰ diagnostic and therapeutic arthroscopy often is pursued for definitive treatment.³¹ Compared to the gold standard of diagnostic arthroscopy, preoperative magnetic resonance imaging (MRI) carries positive and negative predictive values of 85% and 77%, respectively, in identifying or ruling out the anatomic structure responsible for a locked knee. ³² As such, MRI has been proposed as a method to avoid performing arthroscopy on a patient with a “pseudo-locked” knee, or loss of range of motion due to pain but without a true mechanical block.³²

Continue to: Depending on the location...

Depending on the location, size, and shape of an acute meniscus tear in younger patients, surgical repair may be an option to preserve long-term joint function. In one case series of patients younger than 20 years, 62% of meniscus repairs yielded good outcomes after a mean follow-up period of 16.8 years.³³

Osteochondritis dissecans

Osteochondritis dissecans is characterized by subchondral bone osteonecrosis that most often occurs in pediatric patients, potentially causing the separation of a fragment of articular cartilage and subchondral bone into the joint space (FIGURE 2). In early stages, nonoperative treatment consisting of prolonged rest followed by physical therapy to gradually return to activity is recommended to prevent small, low-grade lesions from progressing to unstable or separated fragments. Arthroscopy, which consists of microfracture or other surgical resurfacing techniques to restore joint integrity, is pursued in more advanced cases of unstable or separated fragments.

High-quality data guiding the management of osteochondritis dissecans are lacking, and these recommendations are based on consensus guidelines.³⁴

Septic arthritis

Septic arthritis is a medical emergency caused by the hematogenous spread of microorganisms, most often staphylococci and streptococci species. Less commonly, it arises from direct inoculation through an open wound or, rarely, iatrogenically following a joint injection procedure. Clinical signs of septic arthritis include joint pain, joint swelling, and fever. Passive range of motion of the joint is often severely painful. Synovial fluid studies consistent with septic arthritis include an elevated white blood cell count greater than 25,000/mcL with polymorphonuclear cell predominance.³⁵ The knee accounts for more than 50% of septic arthritis cases, and surgical drainage usually is required to achieve infection source control and decrease morbidity and mortality due to destruction of articular cartilage when treatment is delayed.³⁶

Chronic knee injuries and pain

Surgical intervention for chronic knee injuries and pain generally is considered when patients demonstrate significant functional impairment and persistent symptoms despite pursuing numerous nonsurgical treatment options. A significant portion of chronic knee pain is due to degenerative processes such as OA or meniscus injuries, or tears without a history of trauma that do not cause locking of the knee. Treatments for degenerative knee pain include supervised exercise, physical therapy, bracing, offloading with a cane or other equipment, topical or oral ­anti-inflammatories or analgesics, and injectable therapies such as intra-articular ­corticosteroids.³⁷

Continue to: Other common causes...

Other common causes of chronic knee pain include chronic tendinopathy or biomechanical syndromes such as patellofemoral pain syndrome or iliotibial band syndrome. Surgical treatment of these conditions is pursued in select cases and only after exhausting nonoperative treatment programs, as recommended by international consensus statements,³⁸ societal guidelines,³⁹ and expert opinion.⁴⁰ High-quality data on the effectiveness, or ineffectiveness, of surgical intervention for these conditions are lacking.

A chief risk factor for a patellar dislocation is a history of prior dislocation.

Despite being one of the most commonly performed surgical procedures in the United States,⁴¹ arthroscopic partial meniscectomy treatment of degenerative meniscus tears does not lead to improved outcomes compared to nonsurgical management, according to multiple recent studies.^42-45 Evidence does not support routine arthroscopic intervention for degenerative meniscus tears or OA,⁴² and recent guidelines recommend against it⁴⁶ or to pursue it only after nonsurgical treatments have failed.³⁷

Surgical management of degenerative knee conditions generally consists of partial or total arthroplasty and is similarly considered after failure of conservative measures. Appropriate use criteria that account for multiple clinical and patient factors are used to enhance patient selection for the procedure.⁴⁷

Takeaways

Primary care clinicians will treat patients sustaining knee injuries and see many patients with knee pain in the outpatient setting. Treatment options vary considerably depending on the underlying diagnosis and resulting functional losses. Several categories of clinical presentation, including neurovascular injury, unstable or displaced fractures, joint instability, major tendon rupture, significant mechanical symptoms such as a locked knee, certain osteochondral injuries, and septic arthritis, likely or almost always warrant surgical consultation ­(TABLE^3-10,12-36). Occasionally, as in the case of neurovascular injury or septic arthritis, such consultation should be emergent.

CORRESPONDENCE
David M. Siebert, MD, Sports Medicine Center at Husky Stadium, 3800 Montlake Boulevard NE, Seattle, WA 98195; [email protected]

Evidence supports what family physicians know to be true: Knee pain is an exceedingly common presenting problem in the primary care office. Estimates of lifetime incidence reach as high as 54%,¹ and the prevalence of knee pain in the general population is increasing.² Knee disability can result from acute or traumatic injuries as well as chronic, degenerative conditions such as osteoarthritis (OA). The decision to pursue orthopedic consultation for a particular injury or painful knee condition can be challenging. To address this, we highlight specific knee diagnoses known to cause pain, with the aim of describing which conditions likely will necessitate surgical consultation—and which won’t.

Acute or nondegenerative knee injuries and pain

Acute knee injuries range in severity from simple contusions and sprains to high-energy, traumatic injuries with resulting joint instability and potential neurovascular compromise. While conservative treatment often is successful for many simple injuries, surgical management—sometimes urgently or emergently—is needed in other cases, as will be detailed shortly.

Neurovascular injury associated with knee dislocations

Acute neurovascular injuries often require emergent surgical intervention. Although rare, tibiofemoral (knee) dislocations pose a significant challenge to the clinician in both diagnosis and management. The reported frequency of popliteal artery injury or rupture following a dislocation varies widely, with rates ranging from 5% to 64%, according to older studies; more recent data, however, suggest the rate is actually as low as 3.3%.³ Vascular injury can lead to irreversible tissue damage and even limb loss if not promptly identified. Identifying a knee dislocation can prove challenging, as spontaneous joint reduction occurs in as many as 50% of cases, potentially shrouding the severity of the injury on initial evaluation.⁴

Immediate immobilization and emergency department transport for monitoring, orthopedics consultation, and vascular ­studies or vascular surgery consultation is recommended in the case of a suspected knee dislocation. In one cross-sectional cohort study, the surgical management of knee ­dislocations yielded favorable outcomes in > 75% of cases.⁵

Tibial plateau fracture

This fracture often occurs as a result of high-energy trauma, such as contact sports or motor vehicle accidents, and is characterized by a proximal tibial fracture line with extension to the articular surface. X-rays often are sufficient for initial diagnosis. Computed tomo­graphy can help rule out a fracture line when clinical suspicion is high and x-rays are nondiagnostic. As noted earlier, any suggestion of neurovascular compromise on physical exam requires an emergent orthopedic surgeon consultation for a possible displaced and unstable (or more complex) injury (FIGURE 1).^6-8

Nondisplaced tibial plateau fractures without supraphysiologic ligamentous laxity on valgus or varus stress testing can be managed safely with protection and early mobilization, gradual progression of weight-bearing, and serial x-rays to ensure fracture healing and stability. Surgical management and fixation are required emergently for open fractures or gross joint instability with vascular or neurologic compromise. Suspicion of these complications is raised by distal neuropathic symptoms of paresthesia or skin anesthesia, progressively worsening pain distal to the knee, or vascular signs of pallor, delayed or lost capillary refill, or decreased or absent distal pulses.

Gross joint instability identified by positive valgus or varus stress testing, positive anterior or posterior drawer testing, or patient inability to tolerate these maneuvers due to pain similarly should raise suspicion for a more significant fracture at risk for concurrent neurovascular injury. Acute compartment syndrome also is a known complication of tibial plateau fractures and similarly requires emergent operative management. Urgent surgical consultation is recommended for fractures with displaced fracture fragments, tibial articular surface step-off or depression, fractures with concurrent joint laxity, or medial plateau fractures.^6-8

Continue to: Patella fractures

Patella fractures

These fractures occur as a direct blow to the front of the knee, such as falling forward onto a hard surface, or indirectly due to a sudden extreme eccentric contraction of the quadriceps muscle. Nondisplaced fractures with an intact knee extension mechanism, which is examined via a supine straight-leg raise or seated knee extension, are managed with weight-bearing as tolerated in strict immobilization in full extension for 4 to 6 weeks, with active range-of-motion and isometric quadriceps exercises beginning in 1 to 2 weeks. Serial x-rays also are obtained to ensure fracture displacement does not occur during the rehabilitation process.⁹

High-quality evidence guiding follow-up care and comparing outcomes of surgical and nonsurgical management of patella fractures is lacking, and studies comparing different surgical techniques are of lower methodological quality.¹⁰ Nevertheless, displaced or comminuted patellar fractures are referred urgently to orthopedic surgical care for fixation, as are those with concurrent loose bodies, chondral surface injuries or articular step-off, or osteochondral fractures.⁹ Inability to perform a straight-leg raise (ie, clinical loss of the knee extension mechanism) suggests a fracture under tension that likely also requires surgical fixation for successful recovery. Neurovascular injuries are unlikely in most patellar fractures but would require emergent surgical consultation.⁹

Ligamentous injury

Tibiofemoral joint laxity occurs as a result of ligamentous injury, with or without tibial plateau fracture. The anterior cruciate ligament (ACL), posterior cruciate ligament (PCL), medial collateral ligament (MCL), and lateral collateral ligament (LCL) comprise the 4 main ligaments of the knee. The ACL resists anterior tibial translation and rotational forces, while the PCL resists posterior tibial translation. The MCL and LCL resist valgus and varus stress, respectively.

Ligament injuries are classified as Grades 1 to 3¹¹:

• Grade 1 sprains. The ligament is stretched, but there is no macroscopic tearing; joint stability is maintained.
• Grade 2 sprains. There are partial macroscopic ligament tears. There is joint laxity due to the partial loss of the ligament’s structural integrity.
• Grade 3 sprains. The ligament is fully avulsed or ruptured with resultant gross joint instability.

Vascular injury can lead to irreversible tissue damage and even limb loss if not promptly identified.

The decision to pursue surgical repair of a knee sprain depends heavily on the likelihood of keeping or regaining and maintaining functional joint stability during the injury recovery and postinjury time periods. Injuries that do not result in joint instability or injuries with a high likelihood of returning to a stable state with conservative measures often do not require surgical intervention.

Continue to: ACL tears

ACL tears occur most commonly via a noncontact event, as when an individual plants their foot and suddenly changes direction during sport or other physical activity. Treatment hinges on patient activity levels and participation in sports. Patients who do not plan to engage in athletic movements (that require changes in direction or planting and twisting) and who otherwise maintain satisfactory joint stability during activities of daily living may elect to defer or even altogether avoid surgical reconstruction of isolated ACL tears. One pair of studies demonstrated equivalent outcomes in surgical and nonsurgical management in 121 young, nonelite athletes at 2- and 5-year follow-up, although the crossover from the nonsurgical to surgical groups was high.^12,13 Athletes who regain satisfactory function and stability nonoperatively can defer surgical intervention. However, the majority of active patients and athletes will require surgical ACL reconstruction to return to pre-injury functional levels.¹⁴

PCL sprains occur as a result of sudden posteriorly directed force on the tibia, such as when the knee is hyperextended or a patient falls directly onto a flexed knee. Patients with Grade 1 and 2 isolated sprains generally will recover with conservative care, as will patients with some Grade 3 complete tears that do not fully compromise joint stability. However, high-grade PCL injuries often are comorbid with posterolateral corner or other injuries, leading to a higher likelihood of joint instability and thus the need for surgical intervention for the best chance at an optimal outcome.¹⁵

MCL sprain. Surgical management is not required in an isolated Grade 1 or 2 MCL sprain, as the hallmarks of recovery—return of joint stability, knee strength and range of motion, and pain ­reduction—can be achieved successfully with conservative management. Isolated Grade 3 MCL sprains are also successfully managed nonoperatively¹⁶ except in specific cases, such as a concurrent large avulsion fracture.¹⁷

LCL sprain. Similarly, isolated Grade 1 and 2 LCL sprains generally do not require surgical intervention. However, Grade 3 LCL injuries usually do, as persistent joint instability and poor functional outcomes are more common with nonsurgical management.^18-20 Additionally, high-grade LCL injuries frequently manifest with comorbid meniscus injuries or sprains of the posterolateral corner of the knee, a complex anatomic structure that provides both static and dynamic tibiofemoral joint stability. Surgical repair or reconstruction of the posterolateral corner frequently is necessary for optimal functional outcomes.²¹

Multiligamentous sprains frequently lead to gross joint instability and necessitate orthopedic surgeon consultation to determine the best treatment plan; this should be done emergently if neurovascular compromise is suspected. A common injury combination is simultaneous ACL and MCL sprains with or without meniscus injury. In these cases, some surgeons will choose to defer ACL reconstruction until after MCL healing is achieved. This allows the patient to regain valgus stability of the joint prior to performing ACL reconstruction to regain rotational and anterior stability.²⁰

Continue to: Patellar dislocations

Patellar dislocations represent a relatively common knee injury in young active patients, often occurring in a noncontact fashion when a valgus force is applied to an externally rotated and planted lower leg. A chief risk factor for a patellar dislocation is a history of prior dislocation. If rehabilitation following a dislocation is insufficient to regain patellofemoral joint stability, or if certain risk factors for recurrent dislocation are present, surgical intervention, such as medial patellofemoral ligament (MPFL) reconstruction or tibial tubercle transfer, is considered.²² A systematic review concluded that MPFL reconstruction following a first-time dislocation yielded lower redislocation rates of 7% compared to 30% with nonoperative treatment.²³

Major tendon rupture

Patellar tendon ruptures occur when a sudden eccentric force is applied to the knee, such as when landing from a jump with the knee flexed. Patellar tendon ruptures frequently are clinically apparent, with patients demonstrating a high-riding patella and loss of active knee extension. Quadriceps tendon ruptures often result from a similar injury mechanism in older patients, with a similar loss of active knee extension and a palpable gap superior to the patella.²⁴

Partial tears in patients who can maintain full extension of the knee against gravity are treated nonoperatively, but early surgical repair is indicated for complete quadriceps or patellar tendon ruptures to achieve optimal outcomes. Prompt diagnosis and treatment are critical, as repair delayed beyond 1 to 2 weeks postinjury is associated with worse outcomes.^25-28

Surgical management and fixation are required emergently for open fractures or gross joint instability with vascular or neurologic compromise.

Even with prompt treatment, return to sport is not guaranteed. According to a recent systematic review, athletes returned to play 88.9% and 89.8% of the time following patellar and quadriceps tendon repairs, respectively. However, returning to the same level of play was less common and achieved 80.8% (patellar tendon repair) and 70% (quadriceps tendon repair) of the time. Return-to-work rates were higher, at 96% for both surgical treatments.²⁹

Locked knee and acute meniscus tears in younger patients

In some acute knee injuries, meniscus tears, loose cartilage bodies or osteochondral defects, or other internal structures can become interposed between the femoral and tibial surfaces, preventing both active and passive knee extension. Such injuries are often severely painful and functionally debilitating. While manipulation under anesthesia can acutely restore joint function,³⁰ diagnostic and therapeutic arthroscopy often is pursued for definitive treatment.³¹ Compared to the gold standard of diagnostic arthroscopy, preoperative magnetic resonance imaging (MRI) carries positive and negative predictive values of 85% and 77%, respectively, in identifying or ruling out the anatomic structure responsible for a locked knee. ³² As such, MRI has been proposed as a method to avoid performing arthroscopy on a patient with a “pseudo-locked” knee, or loss of range of motion due to pain but without a true mechanical block.³²

Continue to: Depending on the location...

Depending on the location, size, and shape of an acute meniscus tear in younger patients, surgical repair may be an option to preserve long-term joint function. In one case series of patients younger than 20 years, 62% of meniscus repairs yielded good outcomes after a mean follow-up period of 16.8 years.³³

Osteochondritis dissecans

Osteochondritis dissecans is characterized by subchondral bone osteonecrosis that most often occurs in pediatric patients, potentially causing the separation of a fragment of articular cartilage and subchondral bone into the joint space (FIGURE 2). In early stages, nonoperative treatment consisting of prolonged rest followed by physical therapy to gradually return to activity is recommended to prevent small, low-grade lesions from progressing to unstable or separated fragments. Arthroscopy, which consists of microfracture or other surgical resurfacing techniques to restore joint integrity, is pursued in more advanced cases of unstable or separated fragments.

High-quality data guiding the management of osteochondritis dissecans are lacking, and these recommendations are based on consensus guidelines.³⁴

Septic arthritis

Septic arthritis is a medical emergency caused by the hematogenous spread of microorganisms, most often staphylococci and streptococci species. Less commonly, it arises from direct inoculation through an open wound or, rarely, iatrogenically following a joint injection procedure. Clinical signs of septic arthritis include joint pain, joint swelling, and fever. Passive range of motion of the joint is often severely painful. Synovial fluid studies consistent with septic arthritis include an elevated white blood cell count greater than 25,000/mcL with polymorphonuclear cell predominance.³⁵ The knee accounts for more than 50% of septic arthritis cases, and surgical drainage usually is required to achieve infection source control and decrease morbidity and mortality due to destruction of articular cartilage when treatment is delayed.³⁶

Chronic knee injuries and pain

Surgical intervention for chronic knee injuries and pain generally is considered when patients demonstrate significant functional impairment and persistent symptoms despite pursuing numerous nonsurgical treatment options. A significant portion of chronic knee pain is due to degenerative processes such as OA or meniscus injuries, or tears without a history of trauma that do not cause locking of the knee. Treatments for degenerative knee pain include supervised exercise, physical therapy, bracing, offloading with a cane or other equipment, topical or oral ­anti-inflammatories or analgesics, and injectable therapies such as intra-articular ­corticosteroids.³⁷

Continue to: Other common causes...

Other common causes of chronic knee pain include chronic tendinopathy or biomechanical syndromes such as patellofemoral pain syndrome or iliotibial band syndrome. Surgical treatment of these conditions is pursued in select cases and only after exhausting nonoperative treatment programs, as recommended by international consensus statements,³⁸ societal guidelines,³⁹ and expert opinion.⁴⁰ High-quality data on the effectiveness, or ineffectiveness, of surgical intervention for these conditions are lacking.

A chief risk factor for a patellar dislocation is a history of prior dislocation.

Despite being one of the most commonly performed surgical procedures in the United States,⁴¹ arthroscopic partial meniscectomy treatment of degenerative meniscus tears does not lead to improved outcomes compared to nonsurgical management, according to multiple recent studies.^42-45 Evidence does not support routine arthroscopic intervention for degenerative meniscus tears or OA,⁴² and recent guidelines recommend against it⁴⁶ or to pursue it only after nonsurgical treatments have failed.³⁷

Surgical management of degenerative knee conditions generally consists of partial or total arthroplasty and is similarly considered after failure of conservative measures. Appropriate use criteria that account for multiple clinical and patient factors are used to enhance patient selection for the procedure.⁴⁷

Takeaways

Primary care clinicians will treat patients sustaining knee injuries and see many patients with knee pain in the outpatient setting. Treatment options vary considerably depending on the underlying diagnosis and resulting functional losses. Several categories of clinical presentation, including neurovascular injury, unstable or displaced fractures, joint instability, major tendon rupture, significant mechanical symptoms such as a locked knee, certain osteochondral injuries, and septic arthritis, likely or almost always warrant surgical consultation ­(TABLE^3-10,12-36). Occasionally, as in the case of neurovascular injury or septic arthritis, such consultation should be emergent.

CORRESPONDENCE
David M. Siebert, MD, Sports Medicine Center at Husky Stadium, 3800 Montlake Boulevard NE, Seattle, WA 98195; [email protected]

Evidence supports what family physicians know to be true: Knee pain is an exceedingly common presenting problem in the primary care office. Estimates of lifetime incidence reach as high as 54%,¹ and the prevalence of knee pain in the general population is increasing.² Knee disability can result from acute or traumatic injuries as well as chronic, degenerative conditions such as osteoarthritis (OA). The decision to pursue orthopedic consultation for a particular injury or painful knee condition can be challenging. To address this, we highlight specific knee diagnoses known to cause pain, with the aim of describing which conditions likely will necessitate surgical consultation—and which won’t.

Acute or nondegenerative knee injuries and pain

Acute knee injuries range in severity from simple contusions and sprains to high-energy, traumatic injuries with resulting joint instability and potential neurovascular compromise. While conservative treatment often is successful for many simple injuries, surgical management—sometimes urgently or emergently—is needed in other cases, as will be detailed shortly.

Neurovascular injury associated with knee dislocations

Acute neurovascular injuries often require emergent surgical intervention. Although rare, tibiofemoral (knee) dislocations pose a significant challenge to the clinician in both diagnosis and management. The reported frequency of popliteal artery injury or rupture following a dislocation varies widely, with rates ranging from 5% to 64%, according to older studies; more recent data, however, suggest the rate is actually as low as 3.3%.³ Vascular injury can lead to irreversible tissue damage and even limb loss if not promptly identified. Identifying a knee dislocation can prove challenging, as spontaneous joint reduction occurs in as many as 50% of cases, potentially shrouding the severity of the injury on initial evaluation.⁴

Immediate immobilization and emergency department transport for monitoring, orthopedics consultation, and vascular ­studies or vascular surgery consultation is recommended in the case of a suspected knee dislocation. In one cross-sectional cohort study, the surgical management of knee ­dislocations yielded favorable outcomes in > 75% of cases.⁵

Tibial plateau fracture

This fracture often occurs as a result of high-energy trauma, such as contact sports or motor vehicle accidents, and is characterized by a proximal tibial fracture line with extension to the articular surface. X-rays often are sufficient for initial diagnosis. Computed tomo­graphy can help rule out a fracture line when clinical suspicion is high and x-rays are nondiagnostic. As noted earlier, any suggestion of neurovascular compromise on physical exam requires an emergent orthopedic surgeon consultation for a possible displaced and unstable (or more complex) injury (FIGURE 1).^6-8

Nondisplaced tibial plateau fractures without supraphysiologic ligamentous laxity on valgus or varus stress testing can be managed safely with protection and early mobilization, gradual progression of weight-bearing, and serial x-rays to ensure fracture healing and stability. Surgical management and fixation are required emergently for open fractures or gross joint instability with vascular or neurologic compromise. Suspicion of these complications is raised by distal neuropathic symptoms of paresthesia or skin anesthesia, progressively worsening pain distal to the knee, or vascular signs of pallor, delayed or lost capillary refill, or decreased or absent distal pulses.

Gross joint instability identified by positive valgus or varus stress testing, positive anterior or posterior drawer testing, or patient inability to tolerate these maneuvers due to pain similarly should raise suspicion for a more significant fracture at risk for concurrent neurovascular injury. Acute compartment syndrome also is a known complication of tibial plateau fractures and similarly requires emergent operative management. Urgent surgical consultation is recommended for fractures with displaced fracture fragments, tibial articular surface step-off or depression, fractures with concurrent joint laxity, or medial plateau fractures.^6-8

Continue to: Patella fractures

Patella fractures

These fractures occur as a direct blow to the front of the knee, such as falling forward onto a hard surface, or indirectly due to a sudden extreme eccentric contraction of the quadriceps muscle. Nondisplaced fractures with an intact knee extension mechanism, which is examined via a supine straight-leg raise or seated knee extension, are managed with weight-bearing as tolerated in strict immobilization in full extension for 4 to 6 weeks, with active range-of-motion and isometric quadriceps exercises beginning in 1 to 2 weeks. Serial x-rays also are obtained to ensure fracture displacement does not occur during the rehabilitation process.⁹

High-quality evidence guiding follow-up care and comparing outcomes of surgical and nonsurgical management of patella fractures is lacking, and studies comparing different surgical techniques are of lower methodological quality.¹⁰ Nevertheless, displaced or comminuted patellar fractures are referred urgently to orthopedic surgical care for fixation, as are those with concurrent loose bodies, chondral surface injuries or articular step-off, or osteochondral fractures.⁹ Inability to perform a straight-leg raise (ie, clinical loss of the knee extension mechanism) suggests a fracture under tension that likely also requires surgical fixation for successful recovery. Neurovascular injuries are unlikely in most patellar fractures but would require emergent surgical consultation.⁹

Ligamentous injury

Tibiofemoral joint laxity occurs as a result of ligamentous injury, with or without tibial plateau fracture. The anterior cruciate ligament (ACL), posterior cruciate ligament (PCL), medial collateral ligament (MCL), and lateral collateral ligament (LCL) comprise the 4 main ligaments of the knee. The ACL resists anterior tibial translation and rotational forces, while the PCL resists posterior tibial translation. The MCL and LCL resist valgus and varus stress, respectively.

Ligament injuries are classified as Grades 1 to 3¹¹:

• Grade 1 sprains. The ligament is stretched, but there is no macroscopic tearing; joint stability is maintained.
• Grade 2 sprains. There are partial macroscopic ligament tears. There is joint laxity due to the partial loss of the ligament’s structural integrity.
• Grade 3 sprains. The ligament is fully avulsed or ruptured with resultant gross joint instability.

Vascular injury can lead to irreversible tissue damage and even limb loss if not promptly identified.

The decision to pursue surgical repair of a knee sprain depends heavily on the likelihood of keeping or regaining and maintaining functional joint stability during the injury recovery and postinjury time periods. Injuries that do not result in joint instability or injuries with a high likelihood of returning to a stable state with conservative measures often do not require surgical intervention.

Continue to: ACL tears

ACL tears occur most commonly via a noncontact event, as when an individual plants their foot and suddenly changes direction during sport or other physical activity. Treatment hinges on patient activity levels and participation in sports. Patients who do not plan to engage in athletic movements (that require changes in direction or planting and twisting) and who otherwise maintain satisfactory joint stability during activities of daily living may elect to defer or even altogether avoid surgical reconstruction of isolated ACL tears. One pair of studies demonstrated equivalent outcomes in surgical and nonsurgical management in 121 young, nonelite athletes at 2- and 5-year follow-up, although the crossover from the nonsurgical to surgical groups was high.^12,13 Athletes who regain satisfactory function and stability nonoperatively can defer surgical intervention. However, the majority of active patients and athletes will require surgical ACL reconstruction to return to pre-injury functional levels.¹⁴

PCL sprains occur as a result of sudden posteriorly directed force on the tibia, such as when the knee is hyperextended or a patient falls directly onto a flexed knee. Patients with Grade 1 and 2 isolated sprains generally will recover with conservative care, as will patients with some Grade 3 complete tears that do not fully compromise joint stability. However, high-grade PCL injuries often are comorbid with posterolateral corner or other injuries, leading to a higher likelihood of joint instability and thus the need for surgical intervention for the best chance at an optimal outcome.¹⁵

MCL sprain. Surgical management is not required in an isolated Grade 1 or 2 MCL sprain, as the hallmarks of recovery—return of joint stability, knee strength and range of motion, and pain ­reduction—can be achieved successfully with conservative management. Isolated Grade 3 MCL sprains are also successfully managed nonoperatively¹⁶ except in specific cases, such as a concurrent large avulsion fracture.¹⁷

LCL sprain. Similarly, isolated Grade 1 and 2 LCL sprains generally do not require surgical intervention. However, Grade 3 LCL injuries usually do, as persistent joint instability and poor functional outcomes are more common with nonsurgical management.^18-20 Additionally, high-grade LCL injuries frequently manifest with comorbid meniscus injuries or sprains of the posterolateral corner of the knee, a complex anatomic structure that provides both static and dynamic tibiofemoral joint stability. Surgical repair or reconstruction of the posterolateral corner frequently is necessary for optimal functional outcomes.²¹

Multiligamentous sprains frequently lead to gross joint instability and necessitate orthopedic surgeon consultation to determine the best treatment plan; this should be done emergently if neurovascular compromise is suspected. A common injury combination is simultaneous ACL and MCL sprains with or without meniscus injury. In these cases, some surgeons will choose to defer ACL reconstruction until after MCL healing is achieved. This allows the patient to regain valgus stability of the joint prior to performing ACL reconstruction to regain rotational and anterior stability.²⁰

Continue to: Patellar dislocations

Patellar dislocations represent a relatively common knee injury in young active patients, often occurring in a noncontact fashion when a valgus force is applied to an externally rotated and planted lower leg. A chief risk factor for a patellar dislocation is a history of prior dislocation. If rehabilitation following a dislocation is insufficient to regain patellofemoral joint stability, or if certain risk factors for recurrent dislocation are present, surgical intervention, such as medial patellofemoral ligament (MPFL) reconstruction or tibial tubercle transfer, is considered.²² A systematic review concluded that MPFL reconstruction following a first-time dislocation yielded lower redislocation rates of 7% compared to 30% with nonoperative treatment.²³

Major tendon rupture

Patellar tendon ruptures occur when a sudden eccentric force is applied to the knee, such as when landing from a jump with the knee flexed. Patellar tendon ruptures frequently are clinically apparent, with patients demonstrating a high-riding patella and loss of active knee extension. Quadriceps tendon ruptures often result from a similar injury mechanism in older patients, with a similar loss of active knee extension and a palpable gap superior to the patella.²⁴

Partial tears in patients who can maintain full extension of the knee against gravity are treated nonoperatively, but early surgical repair is indicated for complete quadriceps or patellar tendon ruptures to achieve optimal outcomes. Prompt diagnosis and treatment are critical, as repair delayed beyond 1 to 2 weeks postinjury is associated with worse outcomes.^25-28

Surgical management and fixation are required emergently for open fractures or gross joint instability with vascular or neurologic compromise.

Even with prompt treatment, return to sport is not guaranteed. According to a recent systematic review, athletes returned to play 88.9% and 89.8% of the time following patellar and quadriceps tendon repairs, respectively. However, returning to the same level of play was less common and achieved 80.8% (patellar tendon repair) and 70% (quadriceps tendon repair) of the time. Return-to-work rates were higher, at 96% for both surgical treatments.²⁹

Locked knee and acute meniscus tears in younger patients

In some acute knee injuries, meniscus tears, loose cartilage bodies or osteochondral defects, or other internal structures can become interposed between the femoral and tibial surfaces, preventing both active and passive knee extension. Such injuries are often severely painful and functionally debilitating. While manipulation under anesthesia can acutely restore joint function,³⁰ diagnostic and therapeutic arthroscopy often is pursued for definitive treatment.³¹ Compared to the gold standard of diagnostic arthroscopy, preoperative magnetic resonance imaging (MRI) carries positive and negative predictive values of 85% and 77%, respectively, in identifying or ruling out the anatomic structure responsible for a locked knee. ³² As such, MRI has been proposed as a method to avoid performing arthroscopy on a patient with a “pseudo-locked” knee, or loss of range of motion due to pain but without a true mechanical block.³²

Continue to: Depending on the location...

Depending on the location, size, and shape of an acute meniscus tear in younger patients, surgical repair may be an option to preserve long-term joint function. In one case series of patients younger than 20 years, 62% of meniscus repairs yielded good outcomes after a mean follow-up period of 16.8 years.³³

Osteochondritis dissecans

Osteochondritis dissecans is characterized by subchondral bone osteonecrosis that most often occurs in pediatric patients, potentially causing the separation of a fragment of articular cartilage and subchondral bone into the joint space (FIGURE 2). In early stages, nonoperative treatment consisting of prolonged rest followed by physical therapy to gradually return to activity is recommended to prevent small, low-grade lesions from progressing to unstable or separated fragments. Arthroscopy, which consists of microfracture or other surgical resurfacing techniques to restore joint integrity, is pursued in more advanced cases of unstable or separated fragments.

High-quality data guiding the management of osteochondritis dissecans are lacking, and these recommendations are based on consensus guidelines.³⁴

Septic arthritis

Septic arthritis is a medical emergency caused by the hematogenous spread of microorganisms, most often staphylococci and streptococci species. Less commonly, it arises from direct inoculation through an open wound or, rarely, iatrogenically following a joint injection procedure. Clinical signs of septic arthritis include joint pain, joint swelling, and fever. Passive range of motion of the joint is often severely painful. Synovial fluid studies consistent with septic arthritis include an elevated white blood cell count greater than 25,000/mcL with polymorphonuclear cell predominance.³⁵ The knee accounts for more than 50% of septic arthritis cases, and surgical drainage usually is required to achieve infection source control and decrease morbidity and mortality due to destruction of articular cartilage when treatment is delayed.³⁶

Chronic knee injuries and pain

Surgical intervention for chronic knee injuries and pain generally is considered when patients demonstrate significant functional impairment and persistent symptoms despite pursuing numerous nonsurgical treatment options. A significant portion of chronic knee pain is due to degenerative processes such as OA or meniscus injuries, or tears without a history of trauma that do not cause locking of the knee. Treatments for degenerative knee pain include supervised exercise, physical therapy, bracing, offloading with a cane or other equipment, topical or oral ­anti-inflammatories or analgesics, and injectable therapies such as intra-articular ­corticosteroids.³⁷

Continue to: Other common causes...

Other common causes of chronic knee pain include chronic tendinopathy or biomechanical syndromes such as patellofemoral pain syndrome or iliotibial band syndrome. Surgical treatment of these conditions is pursued in select cases and only after exhausting nonoperative treatment programs, as recommended by international consensus statements,³⁸ societal guidelines,³⁹ and expert opinion.⁴⁰ High-quality data on the effectiveness, or ineffectiveness, of surgical intervention for these conditions are lacking.

A chief risk factor for a patellar dislocation is a history of prior dislocation.

Despite being one of the most commonly performed surgical procedures in the United States,⁴¹ arthroscopic partial meniscectomy treatment of degenerative meniscus tears does not lead to improved outcomes compared to nonsurgical management, according to multiple recent studies.^42-45 Evidence does not support routine arthroscopic intervention for degenerative meniscus tears or OA,⁴² and recent guidelines recommend against it⁴⁶ or to pursue it only after nonsurgical treatments have failed.³⁷

Surgical management of degenerative knee conditions generally consists of partial or total arthroplasty and is similarly considered after failure of conservative measures. Appropriate use criteria that account for multiple clinical and patient factors are used to enhance patient selection for the procedure.⁴⁷

Takeaways

Primary care clinicians will treat patients sustaining knee injuries and see many patients with knee pain in the outpatient setting. Treatment options vary considerably depending on the underlying diagnosis and resulting functional losses. Several categories of clinical presentation, including neurovascular injury, unstable or displaced fractures, joint instability, major tendon rupture, significant mechanical symptoms such as a locked knee, certain osteochondral injuries, and septic arthritis, likely or almost always warrant surgical consultation ­(TABLE^3-10,12-36). Occasionally, as in the case of neurovascular injury or septic arthritis, such consultation should be emergent.

CORRESPONDENCE
David M. Siebert, MD, Sports Medicine Center at Husky Stadium, 3800 Montlake Boulevard NE, Seattle, WA 98195; [email protected]

Four medications comprise the drug category known as direct oral anticoagulants (DOACs). Dabigatran (Pradaxa)¹ was the first to gain approval. It was approved by the US Food and Drug Administration (FDA) in 2010 for the reduction of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (AF). This was followed by approvals for rivaroxaban (Xarelto)² in 2011, apixaban (Eliquis)³ in 2012, and edoxaban (Savaysa)⁴ in 2015. Betrixaban (Bevyxxa)⁵ was approved in 2017 for venous thromboembolism (VTE) prophylaxis in acutely ill hospitalized patients with restricted mobility, but it was removed from the market in 2020.

IMAGE: © KO STUDIOS

In addition to stroke prevention in nonvalvular AF, each DOAC has been approved for other indications and has been addressed further in guideline-based recommendations outside FDA-approved indications. This review highlights the evolving use of DOACs and the expansion of applications for multiple adult patient populations.

Overview of DOACs

Dabigatran is the only direct thrombin inhibitor; the other agents inhibit factor Xa. TABLE 1^1-4 summarizes FDA-­approved indications and dosing and guideline-based dosing. Dabigatran and edoxaban require parenteral anticoagulation for 5 to 10 days prior to initiation for acute VTE, limiting their use.^1,4TABLE 2^1-4 highlights pharmacokinetic differences among the agents. For example, dabigatran is 80% renally cleared, is somewhat dialyzable, and can accumulate in patients with renal dysfunction.¹ Edoxaban is contraindicated for nonvalvular AF in patients with a creatinine clearance (CrCl) > 95 mL/min because an increased stroke risk was demonstrated.⁴ Therefore, rivaroxaban and apixaban are prescribed most often in the United States.^6,7

Applications in special patient populations

Obesity

As of 2020, more than 40% of adults in the United States were obese (body mass index [BMI] ≥ 30), with 9% classified as class 3 or severely obese (BMI ≥ 40).⁸ Altered drug pharmacokinetics in patients with severe obesity raises concern for undertreatment with fixed-dose DOACs. Phase III DOAC approval trials included patients with obesity, but weight cutoffs differed, making extrapolating efficacy and safety data difficult across different obesity stages.⁹ Although no FDA-labeled dosing adjustments exist for patients with obesity, the International Society on Thrombosis and Haemostasis (ISTH) does provide such recommendations.

ISTH changes position on measuring drug levels. ISTH previously recommended avoiding DOACs in those with a BMI > 40 or body weight > 120 kg. If a DOAC was used, ISTH advised obtaining peak and trough drug levels.¹⁰ However, DOAC drug levels have not been associated with clinical outcomes or sufficient degrees of anticoagulation.¹¹

Men and women are affected equally by fibrolipomas. Prevalence does not differ by race or ethnicity.

In April 2021, ISTH updated guidance on DOACs in obesity, indicating standard doses of rivaroxaban or apixaban can be used for the treatment and prevention of VTE in all patients regardless of weight or BMI. Because data in obesity are lacking for dabigatran and edoxaban, avoid using these agents in patients with a BMI > 40 or weight > 120 kg. Additionally, assessing drug levels is no longer recommended, as there is insufficient evidence that these impact clinical outcomes.¹²

The 2021 American College of Chest Physicians (CHEST) guideline update does not recommend adjustments based on weight,¹³ and the 2019 European Society of Cardiology (ESC) guidelines make no mention of weight when treating acute pulmonary embolism.¹⁴

Continue to: Effectiveness of DOACs for AF in patients with obesity isn't clear

Effectiveness of DOACs for AF in patients with obesity isn’t clear, as most data are from retrospective cohort analyses. In patients weighing > 120 kg, dabigatran has shown efficacy in thrombosis prevention similar to that achieved in those weighing ≤ 120 kg, but it has increased the risk for gastrointestinal (GI) bleeding.¹⁵ Another study indicated a 15-mg dose of rivaroxaban may be associated with increased thromboembolic complications in patients with a BMI ≥ 35.¹⁶ Alternatively, another retrospective study of rivaroxaban demonstrated a small absolute risk reduction in ischemic stroke among patients in all stages of obesity and no difference in significant bleeding events.¹⁷ One further retrospective cohort showed that, in patients with a BMI ≥ 50 kg, the effectiveness of rivaroxaban and apixaban in thrombosis prevention and bleeding safety outcomes was comparable to that seen in those with a BMI < 30.¹⁸

As a result of conflicting data, and a lack of prospective randomized controlled trials (RCTs), ISTH continued recommending international normalized ratio (INR)–based dosing of warfarin for class 3 or severely obese patients with AF. The 2018 CHEST guidelines¹⁹ and the 2020 ESC guidelines²⁰ make no mention of DOAC avoidance in patients with obesity and AF.

Advanced and end-stage renal disease

DOACs are renally dosed based on indication, drug-drug interactions, and degree of renal function (TABLE 3^1-4). For example, patients with AF who are anticoagulated with apixaban are prescribed 2.5 mg twice daily when 2 of the 3 following criteria are met: age ≥ 80 years, body weight ≤ 60 kg, serum creatinine ≥ 1.5 mg/dL. However, no dosage adjustment is necessary for VTE treatment or prophylaxis with apixaban regardless of renal function.³

Data supporting the safety and efficacy of DOACs in end-stage renal disease (ESRD) are sparse. All DOACs are renally cleared to varying degrees (TABLE 2^1-4), theoretically increasing bleeding risk as kidney disease progresses. Apixaban is the least renally cleared of the DOACs and has been evaluated in the greatest number of trials for patients with ESRD for both VTE treatment and prevention and nonvalvular AF.²¹ As a result, the FDA approved standard-dose apixaban (5 mg twice daily) for VTE treatment and prevention and nonvalvular AF in patients with ESRD, even those requiring dialysis. Use the reduced apixaban dose (2.5 mg twice daily) in patients with ESRD and AF only if they are ≥ 80 years of age or their body weight is ≤ 60 kg.³

Patients with cancer

Cancer-associated acute VTE treatment. Cancer is an established risk factor for acute VTE but it also increases the risk for treatment-­associated bleeding compared with patients without cancer.²² Historically, low-molecular-weight heparin (LMWH) was recommended over warfarin and DOACs for cancer-associated thromboses (CAT).²³ Compared with warfarin, LMWH reduced the rate of recurrent VTE and had similar or reduced bleeding rates at 6 to 12 months.^24-26 However, clinicians and patients often chose warfarin to avoid subcutaneous injections.²⁷

CHEST guidelines recommend oral Xa inhibitors over LMWH for the treatment of CAT.¹³ The 2020 guidelines of the National Institute for Health and Care Excellence (NICE) recommend DOACs as an option for CAT along with LMWH or LMWH transitioned to warfarin.²⁸ The American Society of Clinical Oncology (ASCO) recommends rivaroxaban for acute VTE treatment in CAT. No head-to-head trials have evaluated comparative efficacy of DOACs for CAT. However, edoxaban and rivaroxaban are associated with a greater risk for GI bleeding; therefore, apixaban is preferred in patients with GI malignancies.²⁹ Standard DOAC VTE treatment dosing is recommended for all 3 agents.^2-4

When using DOACs for patients with CAT, consider potential drug-drug interactions with chemotherapy regimens. All DOACs­ are transported by p-glycoprotein, while rivaroxaban and apixaban are substrates of cytochrome P450, leading to potentially significant drug-drug interactions.³⁰ These interactions could affect the patient’s chemotherapeutic regimen, decrease the efficacy of the DOAC, or increase the risk for bleeding. Therefore, anticoagulation choice should be made in collaboration with the ­hematology/oncology team.

Continue to: Cancer-associated VTE prophylaxis...

Cancer-associated VTE prophylaxis. VTE prophylaxis for patients with cancer is complex and necessitates a global assessment of cancer location and treatment regimen and setting. Hospitalized patients receiving chemotherapy are at high risk for VTE if mobility is reduced or if other VTE risk factors are present. The International Initiative on Thrombosis and Cancer (ITAC)³¹ and ISTH³² recommend VTE prophylaxis with unfractionated heparin or LMWH (ISTH recommends LMWH more strongly). The 2020 ASCO Guidelines recommend pharmacologic anticoagulation but make no drug-specific recommendation.²⁹ Parenteral treatment in hospitalized patients is not as burdensome as it is in ambulatory patients; therefore, these recommendations are less likely to elicit inpatient opposition.

In the ambulatory setting, patient avoidance of subcutaneous injections necessitates consideration of DOACs for CAT prophylaxis. The Khorana Risk Score (KRS) is a validated tool (scale, 0-7) to predict VTE risk in ambulatory patients receiving chemotherapy.³³ KRS scores ≥ 2 indicate high thrombotic risk and the need for prophylactic anticoagulation. ASCO recommends apixaban, rivaroxaban, or LMWH.²⁹ ISTH and ITAC both recommend apixaban or rivaroxaban over LMWH.^31,34 An RCT published in June 2023 confirmed that, for adults with cancer and VTE, DOACs were noninferior to LMWH for preventing recurrent VTE for 6 months.³⁵ The recommended doses for apixaban (2.5 mg twice daily) and rivaroxaban (10 mg daily) for CAT VTE prophylaxis are lower than FDA-approved treatment doses.³¹

Patients with thrombophilia: VTE prevention

Thrombophilias are broadly categorized as inherited or acquired, with inherited thrombophilia being more prevalent. The Factor V Leiden (FVL) variant affects 2% to 7% of the population, and prothrombin gene mutation (PGM) affects 1% to 2% of the population.³⁶ Other forms of inherited thrombophilia, such as protein C deficiency, protein S deficiency, and antithrombin deficiency, occur less commonly (< 0.7% of the population).³⁶ Antiphospholipid syndrome (APS), the most common acquired thrombophilia, affects approximately 2% of the population.³⁶ APS involves multiple antibodies: anticardiolipin antibodies, lupus anticoagulant, and anti-beta-2 glycoprotein 1 antibodies. Establishing risk for thrombosis across the varying types of thrombophilia has proven difficult, but APS is considered the most thrombogenic thrombophilia apart from extremely rare homozygous inherited thrombophilias.³⁶ Therefore, DOAC recommendations are thrombophilia specific.

Assessing DOAC blood levels is no longer recommended for patients with obesity, as there is insufficient evidence that these measures affect clinical outcomes.

A prospective cohort study evaluated DOACs compared with heparin/warfarin for VTE treatment in patients with inherited thrombophilias.³⁷ Although all 4 available DOACs were included, most patients (61.1%) received rivaroxaban. Patients with an array of inherited thrombophilias, including rare homozygous mutations, were enrolled in this trial. While most patients (66.9%) had a “mild thrombophilia” defined as either FVL or PGM, the remainder had more severe thrombophilias.³⁷ VTE recurrence was similar and uncommon in the DOAC and heparin/warfarin groups, consistent with a previous meta-analysis.³⁸ Surprisingly, an increase in the cumulative risk for bleeding was seen in the DOAC group compared with the warfarin group, a finding inconsistent with prior trials.³⁸ There were no major bleeding events in the DOAC group, but 3 such events occurred in the heparin/warfarin group, including 2 intracranial hemorrhages.

Currently NICE, CHEST, and ISTH do not make a recommendation for a preferred agent in patients with an acute VTE and inherited thrombophilia; however, DOACs would not be inappropriate.^23,28,32 The American Society of Hematology (ASH) had planned to release recommendations related to the treatment of thrombophilia in 2020, but they were delayed by the COVID-19 pandemic.³⁹

APS presents challenges for acute VTE anticoagulation. First, it causes a strongly thrombogenic state necessitating therapeutic anticoagulation. Second, for patients with positive lupus anticoagulant, INR monitoring and standardized INR goals may be inadequate.⁴⁰ Therefore, using fixed-dose DOACs without the need for therapeutic monitoring is appealing, but significant concerns exist for using DOACs in patients with APS.^41-45 ISTH and CHEST recommend warfarin for the treatment and prevention of acute VTE in patients with APS, especially those with triple-­positive (anticardiolipin, lupus anticoagulant, and anti-beta-2 glycoprotein 1) APS.^13,46 Package labeling for all DOACs recommends avoidance in triple-positive APS.^1-4

ASTRO-APS is the most recent RCT to compare apixaban and warfarin for patients with APS,⁴⁷ and it was terminated early after 6 of 23 patients in the apixaban group had thrombotic events, while no one in the warfarin group had such an event.⁴⁸ Subsequently, a meta-analysis⁴⁹ demonstrated that patients with thrombotic APS appear to have a greater risk for arterial thrombosis when treated with DOACs compared with warfarin. These 2 studies may lead to changes in recommendations to avoid DOACs in all patients with APS or may prompt more focused trials for DOAC use in patients with APS plus an antiplatelet to mitigate arterial thrombotic risk.

Continue to: Expanded clinical indications

Expanded clinical indications

Superficial vein thrombosis

Superficial thrombophlebitis or superficial vein thrombosis (SVT) is estimated to occur 6 times more frequently than VTE.⁵⁰ Management of patients with isolated, uncomplicated thrombophlebitis who are at low risk for extension of the SVT involves symptomatic treatment with nonsteroidal anti-inflammatory drugs, topical agents, or compression therapy. However, depending on risk for progression, anticoagulation may be recommended.⁵¹

Patients at intermediate risk for extension or propagation of SVT are candidates for anticoagulation. The CHEST guidelines recommend fondaparinux 2.5 mg subcutaneous injections daily for 45 days instead of LMWH or warfarin.¹³ However, if patients decline 6 weeks of daily injections, the guidelines acknowledge that rivaroxaban 10 mg daily may be an alternative.¹³

Certain situations should prompt one to consider using a treatment dose of a DOAC for 3 months. These include cases in which the SVT is located within 3 cm of the deep venous system, expands despite an appropriate prophylactic regimen, or recurs after discontinuation of prophylactic anticoagulation.^13,50

Acute coronary syndrome

The American College of Cardiology/­American Heart Association (ACC/AHA) recommend combination antiplatelet therapy and anticoagulation for management of acute coronary syndrome in hospitalized patients.⁵² Data are mixed regarding longer-term anticoagulation in addition to dual antiplatelet therapy in outpatient settings to prevent thrombosis recurrence in the absence of AF.

For patients at intermediate risk for extension of superficial vein thrombosis who decline daily subcutaneous injections of fondaparinux, rivaroxaban 10 mg/d may be an alternative.

The APPRAISE-2 trial enrolled high-risk patients with ACS within 7 days of the event.⁵³ Apixaban 5 mg twice daily was compared with placebo in patients taking aspirin or aspirin plus clopidogrel. The trial was terminated early because major bleeding events increased with apixaban without reduction in recurrent ischemic events. The ATLAS ACS-TIMI 46 trial evaluated different rivaroxaban doses (5-20 mg daily) in ACS patients.⁵⁴ The study revealed possible thrombosis benefit but also increased risk for bleeding, particularly at higher doses. As a result, another study—ATLAS ACS 2-TIMI 51—was conducted and compared the use of low-dose rivaroxaban (2.5 mg twice daily or 5 mg twice daily) vs placebo for patients with recent ACS.⁵⁵ All patients were receiving low-dose aspirin, and approximately 93% of patients in each group also were receiving clopidogrel or ticlopidine. As in the APPRAISE-2 trial, rivaroxaban increased the rate of major bleeding and intracranial hemorrhage; however, it did not increase the incidence of fatal bleeding. Unlike APPRAISE-2, rivaroxaban significantly reduced the primary efficacy end point, a composite of death from cardiovascular causes, myocardial infarction, or stroke (absolute risk reduction = 1.8%; number needed to treat = 56 for combined rivaroxaban doses).⁵⁵

A secondary subgroup analysis combined data from the ATLAS ACMS-TIMI 46 and ATLAS ACS 2-TIMI 51 trials to evaluate outcomes in patients receiving aspirin monotherapy when combined with rivaroxaban 2.5 mg twice daily or 5 mg twice daily or with placebo.⁵⁶ The primary efficacy end point was a composite of cardiovascular death, myocardial infarction, or stroke. When the 2 trials were evaluated separately, neither rivaroxaban dose was associated with reduction of the primary efficacy outcomes compared with aspirin alone. However, when the data were pooled, both the combined rivaroxaban doses (particularly the 5-mg dose) were associated with reduced cardiovascular outcomes. From a safety perspective, the 2.5-mg twice-daily dose of rivaroxaban was the only dose not associated with increased major bleeding risk. Thus, the 2.5-mg twice-daily dose of rivaroxaban may not provide sufficient cardiovascular benefit in patients with ACS, while the larger dose may increase the risk for nonfatal major bleeding events.⁵⁶

The European Medicines Agency⁵⁷ approved rivaroxaban 2.5 mg twice daily for ACS, and the 2020 ESC guidelines⁵⁸ consider it an appropriate therapeutic option in addition to aspirin for patients at high ischemic risk and low bleeding risk. ACS is not an FDA-approved indication for DOACs, and the ACC/AHA Guideline for the Management of ACS, last updated in 2014, does not include DOACs for ACS unless patients have AF.⁵² Ongoing trials are further investigating rivaroxaban for ACS, so the use of DOACs in the post-acute phase of ACS may become clearer in the future.⁵⁹

Continue to: Heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia

Historically, nonheparin parenteral anticoagulants argatroban, bivalirudin, and fondaparinux were recommended for patients at risk for or who had heparin-induced thrombocytopenia (HIT). Argatroban is the only drug FDA approved for the treatment and prophylaxis of HIT; recommendations for the others are based on guideline recommendations.^23,60,61 The nonheparin parenteral anticoagulants cost between $700 and $1500 per day; therefore most patients with HIT are transitioned to warfarin.⁶² However, protein C and S inhibition and a subsequent prothrombotic state conveyed by warfarin initiation necessitates a minimum 5-day bridge to therapeutic warfarin with a nonheparin parenteral anticoagulant.

In vitro tests show that DOACs do not promote development of HIT antibodies⁶³ or affect platelet activation or aggregation.⁶⁴ A literature summary of DOACs for HIT determined that in 104 patients, all but 1 achieved platelet recovery (defined as > 150,000/mcL) within a median time of 7 days. Therapeutically, DOACs prevented new or recurrent VTE in 102/104 cases (98%), and only 3% of patients experienced significant bleeding events.⁶²

The ACC/AHA recommend combination antiplatelet therapy and anticoagulation for management of acute coronary syndrome in hospitalized patients.

The 2018 ASH guidelines for VTE management in HIT include (with very low certainty of evidence) dabigatran, rivaroxaban, or apixaban for consideration in addition to previously recommended nonheparin parenteral anticoagulants.⁶¹ The dosing of each agent is contingent upon treatment of patients with HIT and an acute thrombosis (HITT) or HIT in the absence of VTE. For patients with HITT, treatment doses for acute VTE should be used for the appropriate duration of therapy (ie, 3 months). Importantly, dabigatran requires a 5-day pretreatment period with a parenteral anticoagulant, so it is not an ideal option. When treating isolated HIT (in the absence of VTE), ASH recommends all agents be dosed twice daily—dabigatran 150 mg twice daily (no 5-day parenteral pretreatment necessary), rivaroxaban 15 mg twice daily, or apixaban 5 mg twice daily—until platelet recovery (≥ 150,000/mcL) is achieved.⁶¹

CORRESPONDENCE
Kevin Schleich, PharmD, BCACP, Departments of Pharmaceutical Care and Family Medicine, University of Iowa, 200 Hawkins Drive, 01102-D PFP, Iowa City, IA, 52242; [email protected]

Four medications comprise the drug category known as direct oral anticoagulants (DOACs). Dabigatran (Pradaxa)¹ was the first to gain approval. It was approved by the US Food and Drug Administration (FDA) in 2010 for the reduction of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (AF). This was followed by approvals for rivaroxaban (Xarelto)² in 2011, apixaban (Eliquis)³ in 2012, and edoxaban (Savaysa)⁴ in 2015. Betrixaban (Bevyxxa)⁵ was approved in 2017 for venous thromboembolism (VTE) prophylaxis in acutely ill hospitalized patients with restricted mobility, but it was removed from the market in 2020.

IMAGE: © KO STUDIOS

In addition to stroke prevention in nonvalvular AF, each DOAC has been approved for other indications and has been addressed further in guideline-based recommendations outside FDA-approved indications. This review highlights the evolving use of DOACs and the expansion of applications for multiple adult patient populations.

Overview of DOACs

Dabigatran is the only direct thrombin inhibitor; the other agents inhibit factor Xa. TABLE 1^1-4 summarizes FDA-­approved indications and dosing and guideline-based dosing. Dabigatran and edoxaban require parenteral anticoagulation for 5 to 10 days prior to initiation for acute VTE, limiting their use.^1,4TABLE 2^1-4 highlights pharmacokinetic differences among the agents. For example, dabigatran is 80% renally cleared, is somewhat dialyzable, and can accumulate in patients with renal dysfunction.¹ Edoxaban is contraindicated for nonvalvular AF in patients with a creatinine clearance (CrCl) > 95 mL/min because an increased stroke risk was demonstrated.⁴ Therefore, rivaroxaban and apixaban are prescribed most often in the United States.^6,7

Applications in special patient populations

Obesity

As of 2020, more than 40% of adults in the United States were obese (body mass index [BMI] ≥ 30), with 9% classified as class 3 or severely obese (BMI ≥ 40).⁸ Altered drug pharmacokinetics in patients with severe obesity raises concern for undertreatment with fixed-dose DOACs. Phase III DOAC approval trials included patients with obesity, but weight cutoffs differed, making extrapolating efficacy and safety data difficult across different obesity stages.⁹ Although no FDA-labeled dosing adjustments exist for patients with obesity, the International Society on Thrombosis and Haemostasis (ISTH) does provide such recommendations.

ISTH changes position on measuring drug levels. ISTH previously recommended avoiding DOACs in those with a BMI > 40 or body weight > 120 kg. If a DOAC was used, ISTH advised obtaining peak and trough drug levels.¹⁰ However, DOAC drug levels have not been associated with clinical outcomes or sufficient degrees of anticoagulation.¹¹

Men and women are affected equally by fibrolipomas. Prevalence does not differ by race or ethnicity.

In April 2021, ISTH updated guidance on DOACs in obesity, indicating standard doses of rivaroxaban or apixaban can be used for the treatment and prevention of VTE in all patients regardless of weight or BMI. Because data in obesity are lacking for dabigatran and edoxaban, avoid using these agents in patients with a BMI > 40 or weight > 120 kg. Additionally, assessing drug levels is no longer recommended, as there is insufficient evidence that these impact clinical outcomes.¹²

The 2021 American College of Chest Physicians (CHEST) guideline update does not recommend adjustments based on weight,¹³ and the 2019 European Society of Cardiology (ESC) guidelines make no mention of weight when treating acute pulmonary embolism.¹⁴

Continue to: Effectiveness of DOACs for AF in patients with obesity isn't clear

Effectiveness of DOACs for AF in patients with obesity isn’t clear, as most data are from retrospective cohort analyses. In patients weighing > 120 kg, dabigatran has shown efficacy in thrombosis prevention similar to that achieved in those weighing ≤ 120 kg, but it has increased the risk for gastrointestinal (GI) bleeding.¹⁵ Another study indicated a 15-mg dose of rivaroxaban may be associated with increased thromboembolic complications in patients with a BMI ≥ 35.¹⁶ Alternatively, another retrospective study of rivaroxaban demonstrated a small absolute risk reduction in ischemic stroke among patients in all stages of obesity and no difference in significant bleeding events.¹⁷ One further retrospective cohort showed that, in patients with a BMI ≥ 50 kg, the effectiveness of rivaroxaban and apixaban in thrombosis prevention and bleeding safety outcomes was comparable to that seen in those with a BMI < 30.¹⁸

As a result of conflicting data, and a lack of prospective randomized controlled trials (RCTs), ISTH continued recommending international normalized ratio (INR)–based dosing of warfarin for class 3 or severely obese patients with AF. The 2018 CHEST guidelines¹⁹ and the 2020 ESC guidelines²⁰ make no mention of DOAC avoidance in patients with obesity and AF.

Advanced and end-stage renal disease

DOACs are renally dosed based on indication, drug-drug interactions, and degree of renal function (TABLE 3^1-4). For example, patients with AF who are anticoagulated with apixaban are prescribed 2.5 mg twice daily when 2 of the 3 following criteria are met: age ≥ 80 years, body weight ≤ 60 kg, serum creatinine ≥ 1.5 mg/dL. However, no dosage adjustment is necessary for VTE treatment or prophylaxis with apixaban regardless of renal function.³

Data supporting the safety and efficacy of DOACs in end-stage renal disease (ESRD) are sparse. All DOACs are renally cleared to varying degrees (TABLE 2^1-4), theoretically increasing bleeding risk as kidney disease progresses. Apixaban is the least renally cleared of the DOACs and has been evaluated in the greatest number of trials for patients with ESRD for both VTE treatment and prevention and nonvalvular AF.²¹ As a result, the FDA approved standard-dose apixaban (5 mg twice daily) for VTE treatment and prevention and nonvalvular AF in patients with ESRD, even those requiring dialysis. Use the reduced apixaban dose (2.5 mg twice daily) in patients with ESRD and AF only if they are ≥ 80 years of age or their body weight is ≤ 60 kg.³

Patients with cancer

Cancer-associated acute VTE treatment. Cancer is an established risk factor for acute VTE but it also increases the risk for treatment-­associated bleeding compared with patients without cancer.²² Historically, low-molecular-weight heparin (LMWH) was recommended over warfarin and DOACs for cancer-associated thromboses (CAT).²³ Compared with warfarin, LMWH reduced the rate of recurrent VTE and had similar or reduced bleeding rates at 6 to 12 months.^24-26 However, clinicians and patients often chose warfarin to avoid subcutaneous injections.²⁷

CHEST guidelines recommend oral Xa inhibitors over LMWH for the treatment of CAT.¹³ The 2020 guidelines of the National Institute for Health and Care Excellence (NICE) recommend DOACs as an option for CAT along with LMWH or LMWH transitioned to warfarin.²⁸ The American Society of Clinical Oncology (ASCO) recommends rivaroxaban for acute VTE treatment in CAT. No head-to-head trials have evaluated comparative efficacy of DOACs for CAT. However, edoxaban and rivaroxaban are associated with a greater risk for GI bleeding; therefore, apixaban is preferred in patients with GI malignancies.²⁹ Standard DOAC VTE treatment dosing is recommended for all 3 agents.^2-4

When using DOACs for patients with CAT, consider potential drug-drug interactions with chemotherapy regimens. All DOACs­ are transported by p-glycoprotein, while rivaroxaban and apixaban are substrates of cytochrome P450, leading to potentially significant drug-drug interactions.³⁰ These interactions could affect the patient’s chemotherapeutic regimen, decrease the efficacy of the DOAC, or increase the risk for bleeding. Therefore, anticoagulation choice should be made in collaboration with the ­hematology/oncology team.

Continue to: Cancer-associated VTE prophylaxis...

Cancer-associated VTE prophylaxis. VTE prophylaxis for patients with cancer is complex and necessitates a global assessment of cancer location and treatment regimen and setting. Hospitalized patients receiving chemotherapy are at high risk for VTE if mobility is reduced or if other VTE risk factors are present. The International Initiative on Thrombosis and Cancer (ITAC)³¹ and ISTH³² recommend VTE prophylaxis with unfractionated heparin or LMWH (ISTH recommends LMWH more strongly). The 2020 ASCO Guidelines recommend pharmacologic anticoagulation but make no drug-specific recommendation.²⁹ Parenteral treatment in hospitalized patients is not as burdensome as it is in ambulatory patients; therefore, these recommendations are less likely to elicit inpatient opposition.

In the ambulatory setting, patient avoidance of subcutaneous injections necessitates consideration of DOACs for CAT prophylaxis. The Khorana Risk Score (KRS) is a validated tool (scale, 0-7) to predict VTE risk in ambulatory patients receiving chemotherapy.³³ KRS scores ≥ 2 indicate high thrombotic risk and the need for prophylactic anticoagulation. ASCO recommends apixaban, rivaroxaban, or LMWH.²⁹ ISTH and ITAC both recommend apixaban or rivaroxaban over LMWH.^31,34 An RCT published in June 2023 confirmed that, for adults with cancer and VTE, DOACs were noninferior to LMWH for preventing recurrent VTE for 6 months.³⁵ The recommended doses for apixaban (2.5 mg twice daily) and rivaroxaban (10 mg daily) for CAT VTE prophylaxis are lower than FDA-approved treatment doses.³¹

Patients with thrombophilia: VTE prevention

Thrombophilias are broadly categorized as inherited or acquired, with inherited thrombophilia being more prevalent. The Factor V Leiden (FVL) variant affects 2% to 7% of the population, and prothrombin gene mutation (PGM) affects 1% to 2% of the population.³⁶ Other forms of inherited thrombophilia, such as protein C deficiency, protein S deficiency, and antithrombin deficiency, occur less commonly (< 0.7% of the population).³⁶ Antiphospholipid syndrome (APS), the most common acquired thrombophilia, affects approximately 2% of the population.³⁶ APS involves multiple antibodies: anticardiolipin antibodies, lupus anticoagulant, and anti-beta-2 glycoprotein 1 antibodies. Establishing risk for thrombosis across the varying types of thrombophilia has proven difficult, but APS is considered the most thrombogenic thrombophilia apart from extremely rare homozygous inherited thrombophilias.³⁶ Therefore, DOAC recommendations are thrombophilia specific.

Assessing DOAC blood levels is no longer recommended for patients with obesity, as there is insufficient evidence that these measures affect clinical outcomes.

A prospective cohort study evaluated DOACs compared with heparin/warfarin for VTE treatment in patients with inherited thrombophilias.³⁷ Although all 4 available DOACs were included, most patients (61.1%) received rivaroxaban. Patients with an array of inherited thrombophilias, including rare homozygous mutations, were enrolled in this trial. While most patients (66.9%) had a “mild thrombophilia” defined as either FVL or PGM, the remainder had more severe thrombophilias.³⁷ VTE recurrence was similar and uncommon in the DOAC and heparin/warfarin groups, consistent with a previous meta-analysis.³⁸ Surprisingly, an increase in the cumulative risk for bleeding was seen in the DOAC group compared with the warfarin group, a finding inconsistent with prior trials.³⁸ There were no major bleeding events in the DOAC group, but 3 such events occurred in the heparin/warfarin group, including 2 intracranial hemorrhages.

Currently NICE, CHEST, and ISTH do not make a recommendation for a preferred agent in patients with an acute VTE and inherited thrombophilia; however, DOACs would not be inappropriate.^23,28,32 The American Society of Hematology (ASH) had planned to release recommendations related to the treatment of thrombophilia in 2020, but they were delayed by the COVID-19 pandemic.³⁹

APS presents challenges for acute VTE anticoagulation. First, it causes a strongly thrombogenic state necessitating therapeutic anticoagulation. Second, for patients with positive lupus anticoagulant, INR monitoring and standardized INR goals may be inadequate.⁴⁰ Therefore, using fixed-dose DOACs without the need for therapeutic monitoring is appealing, but significant concerns exist for using DOACs in patients with APS.^41-45 ISTH and CHEST recommend warfarin for the treatment and prevention of acute VTE in patients with APS, especially those with triple-­positive (anticardiolipin, lupus anticoagulant, and anti-beta-2 glycoprotein 1) APS.^13,46 Package labeling for all DOACs recommends avoidance in triple-positive APS.^1-4

ASTRO-APS is the most recent RCT to compare apixaban and warfarin for patients with APS,⁴⁷ and it was terminated early after 6 of 23 patients in the apixaban group had thrombotic events, while no one in the warfarin group had such an event.⁴⁸ Subsequently, a meta-analysis⁴⁹ demonstrated that patients with thrombotic APS appear to have a greater risk for arterial thrombosis when treated with DOACs compared with warfarin. These 2 studies may lead to changes in recommendations to avoid DOACs in all patients with APS or may prompt more focused trials for DOAC use in patients with APS plus an antiplatelet to mitigate arterial thrombotic risk.

Continue to: Expanded clinical indications

Expanded clinical indications

Superficial vein thrombosis

Superficial thrombophlebitis or superficial vein thrombosis (SVT) is estimated to occur 6 times more frequently than VTE.⁵⁰ Management of patients with isolated, uncomplicated thrombophlebitis who are at low risk for extension of the SVT involves symptomatic treatment with nonsteroidal anti-inflammatory drugs, topical agents, or compression therapy. However, depending on risk for progression, anticoagulation may be recommended.⁵¹

Patients at intermediate risk for extension or propagation of SVT are candidates for anticoagulation. The CHEST guidelines recommend fondaparinux 2.5 mg subcutaneous injections daily for 45 days instead of LMWH or warfarin.¹³ However, if patients decline 6 weeks of daily injections, the guidelines acknowledge that rivaroxaban 10 mg daily may be an alternative.¹³

Certain situations should prompt one to consider using a treatment dose of a DOAC for 3 months. These include cases in which the SVT is located within 3 cm of the deep venous system, expands despite an appropriate prophylactic regimen, or recurs after discontinuation of prophylactic anticoagulation.^13,50

Acute coronary syndrome

The American College of Cardiology/­American Heart Association (ACC/AHA) recommend combination antiplatelet therapy and anticoagulation for management of acute coronary syndrome in hospitalized patients.⁵² Data are mixed regarding longer-term anticoagulation in addition to dual antiplatelet therapy in outpatient settings to prevent thrombosis recurrence in the absence of AF.

For patients at intermediate risk for extension of superficial vein thrombosis who decline daily subcutaneous injections of fondaparinux, rivaroxaban 10 mg/d may be an alternative.

The APPRAISE-2 trial enrolled high-risk patients with ACS within 7 days of the event.⁵³ Apixaban 5 mg twice daily was compared with placebo in patients taking aspirin or aspirin plus clopidogrel. The trial was terminated early because major bleeding events increased with apixaban without reduction in recurrent ischemic events. The ATLAS ACS-TIMI 46 trial evaluated different rivaroxaban doses (5-20 mg daily) in ACS patients.⁵⁴ The study revealed possible thrombosis benefit but also increased risk for bleeding, particularly at higher doses. As a result, another study—ATLAS ACS 2-TIMI 51—was conducted and compared the use of low-dose rivaroxaban (2.5 mg twice daily or 5 mg twice daily) vs placebo for patients with recent ACS.⁵⁵ All patients were receiving low-dose aspirin, and approximately 93% of patients in each group also were receiving clopidogrel or ticlopidine. As in the APPRAISE-2 trial, rivaroxaban increased the rate of major bleeding and intracranial hemorrhage; however, it did not increase the incidence of fatal bleeding. Unlike APPRAISE-2, rivaroxaban significantly reduced the primary efficacy end point, a composite of death from cardiovascular causes, myocardial infarction, or stroke (absolute risk reduction = 1.8%; number needed to treat = 56 for combined rivaroxaban doses).⁵⁵

A secondary subgroup analysis combined data from the ATLAS ACMS-TIMI 46 and ATLAS ACS 2-TIMI 51 trials to evaluate outcomes in patients receiving aspirin monotherapy when combined with rivaroxaban 2.5 mg twice daily or 5 mg twice daily or with placebo.⁵⁶ The primary efficacy end point was a composite of cardiovascular death, myocardial infarction, or stroke. When the 2 trials were evaluated separately, neither rivaroxaban dose was associated with reduction of the primary efficacy outcomes compared with aspirin alone. However, when the data were pooled, both the combined rivaroxaban doses (particularly the 5-mg dose) were associated with reduced cardiovascular outcomes. From a safety perspective, the 2.5-mg twice-daily dose of rivaroxaban was the only dose not associated with increased major bleeding risk. Thus, the 2.5-mg twice-daily dose of rivaroxaban may not provide sufficient cardiovascular benefit in patients with ACS, while the larger dose may increase the risk for nonfatal major bleeding events.⁵⁶

The European Medicines Agency⁵⁷ approved rivaroxaban 2.5 mg twice daily for ACS, and the 2020 ESC guidelines⁵⁸ consider it an appropriate therapeutic option in addition to aspirin for patients at high ischemic risk and low bleeding risk. ACS is not an FDA-approved indication for DOACs, and the ACC/AHA Guideline for the Management of ACS, last updated in 2014, does not include DOACs for ACS unless patients have AF.⁵² Ongoing trials are further investigating rivaroxaban for ACS, so the use of DOACs in the post-acute phase of ACS may become clearer in the future.⁵⁹

Continue to: Heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia

Historically, nonheparin parenteral anticoagulants argatroban, bivalirudin, and fondaparinux were recommended for patients at risk for or who had heparin-induced thrombocytopenia (HIT). Argatroban is the only drug FDA approved for the treatment and prophylaxis of HIT; recommendations for the others are based on guideline recommendations.^23,60,61 The nonheparin parenteral anticoagulants cost between $700 and $1500 per day; therefore most patients with HIT are transitioned to warfarin.⁶² However, protein C and S inhibition and a subsequent prothrombotic state conveyed by warfarin initiation necessitates a minimum 5-day bridge to therapeutic warfarin with a nonheparin parenteral anticoagulant.

In vitro tests show that DOACs do not promote development of HIT antibodies⁶³ or affect platelet activation or aggregation.⁶⁴ A literature summary of DOACs for HIT determined that in 104 patients, all but 1 achieved platelet recovery (defined as > 150,000/mcL) within a median time of 7 days. Therapeutically, DOACs prevented new or recurrent VTE in 102/104 cases (98%), and only 3% of patients experienced significant bleeding events.⁶²

The ACC/AHA recommend combination antiplatelet therapy and anticoagulation for management of acute coronary syndrome in hospitalized patients.

The 2018 ASH guidelines for VTE management in HIT include (with very low certainty of evidence) dabigatran, rivaroxaban, or apixaban for consideration in addition to previously recommended nonheparin parenteral anticoagulants.⁶¹ The dosing of each agent is contingent upon treatment of patients with HIT and an acute thrombosis (HITT) or HIT in the absence of VTE. For patients with HITT, treatment doses for acute VTE should be used for the appropriate duration of therapy (ie, 3 months). Importantly, dabigatran requires a 5-day pretreatment period with a parenteral anticoagulant, so it is not an ideal option. When treating isolated HIT (in the absence of VTE), ASH recommends all agents be dosed twice daily—dabigatran 150 mg twice daily (no 5-day parenteral pretreatment necessary), rivaroxaban 15 mg twice daily, or apixaban 5 mg twice daily—until platelet recovery (≥ 150,000/mcL) is achieved.⁶¹

CORRESPONDENCE
Kevin Schleich, PharmD, BCACP, Departments of Pharmaceutical Care and Family Medicine, University of Iowa, 200 Hawkins Drive, 01102-D PFP, Iowa City, IA, 52242; [email protected]

Four medications comprise the drug category known as direct oral anticoagulants (DOACs). Dabigatran (Pradaxa)¹ was the first to gain approval. It was approved by the US Food and Drug Administration (FDA) in 2010 for the reduction of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (AF). This was followed by approvals for rivaroxaban (Xarelto)² in 2011, apixaban (Eliquis)³ in 2012, and edoxaban (Savaysa)⁴ in 2015. Betrixaban (Bevyxxa)⁵ was approved in 2017 for venous thromboembolism (VTE) prophylaxis in acutely ill hospitalized patients with restricted mobility, but it was removed from the market in 2020.

IMAGE: © KO STUDIOS

In addition to stroke prevention in nonvalvular AF, each DOAC has been approved for other indications and has been addressed further in guideline-based recommendations outside FDA-approved indications. This review highlights the evolving use of DOACs and the expansion of applications for multiple adult patient populations.

Overview of DOACs

Dabigatran is the only direct thrombin inhibitor; the other agents inhibit factor Xa. TABLE 1^1-4 summarizes FDA-­approved indications and dosing and guideline-based dosing. Dabigatran and edoxaban require parenteral anticoagulation for 5 to 10 days prior to initiation for acute VTE, limiting their use.^1,4TABLE 2^1-4 highlights pharmacokinetic differences among the agents. For example, dabigatran is 80% renally cleared, is somewhat dialyzable, and can accumulate in patients with renal dysfunction.¹ Edoxaban is contraindicated for nonvalvular AF in patients with a creatinine clearance (CrCl) > 95 mL/min because an increased stroke risk was demonstrated.⁴ Therefore, rivaroxaban and apixaban are prescribed most often in the United States.^6,7

Applications in special patient populations

Obesity

As of 2020, more than 40% of adults in the United States were obese (body mass index [BMI] ≥ 30), with 9% classified as class 3 or severely obese (BMI ≥ 40).⁸ Altered drug pharmacokinetics in patients with severe obesity raises concern for undertreatment with fixed-dose DOACs. Phase III DOAC approval trials included patients with obesity, but weight cutoffs differed, making extrapolating efficacy and safety data difficult across different obesity stages.⁹ Although no FDA-labeled dosing adjustments exist for patients with obesity, the International Society on Thrombosis and Haemostasis (ISTH) does provide such recommendations.

ISTH changes position on measuring drug levels. ISTH previously recommended avoiding DOACs in those with a BMI > 40 or body weight > 120 kg. If a DOAC was used, ISTH advised obtaining peak and trough drug levels.¹⁰ However, DOAC drug levels have not been associated with clinical outcomes or sufficient degrees of anticoagulation.¹¹

Men and women are affected equally by fibrolipomas. Prevalence does not differ by race or ethnicity.

In April 2021, ISTH updated guidance on DOACs in obesity, indicating standard doses of rivaroxaban or apixaban can be used for the treatment and prevention of VTE in all patients regardless of weight or BMI. Because data in obesity are lacking for dabigatran and edoxaban, avoid using these agents in patients with a BMI > 40 or weight > 120 kg. Additionally, assessing drug levels is no longer recommended, as there is insufficient evidence that these impact clinical outcomes.¹²

The 2021 American College of Chest Physicians (CHEST) guideline update does not recommend adjustments based on weight,¹³ and the 2019 European Society of Cardiology (ESC) guidelines make no mention of weight when treating acute pulmonary embolism.¹⁴

Continue to: Effectiveness of DOACs for AF in patients with obesity isn't clear

Effectiveness of DOACs for AF in patients with obesity isn’t clear, as most data are from retrospective cohort analyses. In patients weighing > 120 kg, dabigatran has shown efficacy in thrombosis prevention similar to that achieved in those weighing ≤ 120 kg, but it has increased the risk for gastrointestinal (GI) bleeding.¹⁵ Another study indicated a 15-mg dose of rivaroxaban may be associated with increased thromboembolic complications in patients with a BMI ≥ 35.¹⁶ Alternatively, another retrospective study of rivaroxaban demonstrated a small absolute risk reduction in ischemic stroke among patients in all stages of obesity and no difference in significant bleeding events.¹⁷ One further retrospective cohort showed that, in patients with a BMI ≥ 50 kg, the effectiveness of rivaroxaban and apixaban in thrombosis prevention and bleeding safety outcomes was comparable to that seen in those with a BMI < 30.¹⁸

As a result of conflicting data, and a lack of prospective randomized controlled trials (RCTs), ISTH continued recommending international normalized ratio (INR)–based dosing of warfarin for class 3 or severely obese patients with AF. The 2018 CHEST guidelines¹⁹ and the 2020 ESC guidelines²⁰ make no mention of DOAC avoidance in patients with obesity and AF.

Advanced and end-stage renal disease

DOACs are renally dosed based on indication, drug-drug interactions, and degree of renal function (TABLE 3^1-4). For example, patients with AF who are anticoagulated with apixaban are prescribed 2.5 mg twice daily when 2 of the 3 following criteria are met: age ≥ 80 years, body weight ≤ 60 kg, serum creatinine ≥ 1.5 mg/dL. However, no dosage adjustment is necessary for VTE treatment or prophylaxis with apixaban regardless of renal function.³

Data supporting the safety and efficacy of DOACs in end-stage renal disease (ESRD) are sparse. All DOACs are renally cleared to varying degrees (TABLE 2^1-4), theoretically increasing bleeding risk as kidney disease progresses. Apixaban is the least renally cleared of the DOACs and has been evaluated in the greatest number of trials for patients with ESRD for both VTE treatment and prevention and nonvalvular AF.²¹ As a result, the FDA approved standard-dose apixaban (5 mg twice daily) for VTE treatment and prevention and nonvalvular AF in patients with ESRD, even those requiring dialysis. Use the reduced apixaban dose (2.5 mg twice daily) in patients with ESRD and AF only if they are ≥ 80 years of age or their body weight is ≤ 60 kg.³

Patients with cancer

Cancer-associated acute VTE treatment. Cancer is an established risk factor for acute VTE but it also increases the risk for treatment-­associated bleeding compared with patients without cancer.²² Historically, low-molecular-weight heparin (LMWH) was recommended over warfarin and DOACs for cancer-associated thromboses (CAT).²³ Compared with warfarin, LMWH reduced the rate of recurrent VTE and had similar or reduced bleeding rates at 6 to 12 months.^24-26 However, clinicians and patients often chose warfarin to avoid subcutaneous injections.²⁷

CHEST guidelines recommend oral Xa inhibitors over LMWH for the treatment of CAT.¹³ The 2020 guidelines of the National Institute for Health and Care Excellence (NICE) recommend DOACs as an option for CAT along with LMWH or LMWH transitioned to warfarin.²⁸ The American Society of Clinical Oncology (ASCO) recommends rivaroxaban for acute VTE treatment in CAT. No head-to-head trials have evaluated comparative efficacy of DOACs for CAT. However, edoxaban and rivaroxaban are associated with a greater risk for GI bleeding; therefore, apixaban is preferred in patients with GI malignancies.²⁹ Standard DOAC VTE treatment dosing is recommended for all 3 agents.^2-4

When using DOACs for patients with CAT, consider potential drug-drug interactions with chemotherapy regimens. All DOACs­ are transported by p-glycoprotein, while rivaroxaban and apixaban are substrates of cytochrome P450, leading to potentially significant drug-drug interactions.³⁰ These interactions could affect the patient’s chemotherapeutic regimen, decrease the efficacy of the DOAC, or increase the risk for bleeding. Therefore, anticoagulation choice should be made in collaboration with the ­hematology/oncology team.

Continue to: Cancer-associated VTE prophylaxis...

Cancer-associated VTE prophylaxis. VTE prophylaxis for patients with cancer is complex and necessitates a global assessment of cancer location and treatment regimen and setting. Hospitalized patients receiving chemotherapy are at high risk for VTE if mobility is reduced or if other VTE risk factors are present. The International Initiative on Thrombosis and Cancer (ITAC)³¹ and ISTH³² recommend VTE prophylaxis with unfractionated heparin or LMWH (ISTH recommends LMWH more strongly). The 2020 ASCO Guidelines recommend pharmacologic anticoagulation but make no drug-specific recommendation.²⁹ Parenteral treatment in hospitalized patients is not as burdensome as it is in ambulatory patients; therefore, these recommendations are less likely to elicit inpatient opposition.

In the ambulatory setting, patient avoidance of subcutaneous injections necessitates consideration of DOACs for CAT prophylaxis. The Khorana Risk Score (KRS) is a validated tool (scale, 0-7) to predict VTE risk in ambulatory patients receiving chemotherapy.³³ KRS scores ≥ 2 indicate high thrombotic risk and the need for prophylactic anticoagulation. ASCO recommends apixaban, rivaroxaban, or LMWH.²⁹ ISTH and ITAC both recommend apixaban or rivaroxaban over LMWH.^31,34 An RCT published in June 2023 confirmed that, for adults with cancer and VTE, DOACs were noninferior to LMWH for preventing recurrent VTE for 6 months.³⁵ The recommended doses for apixaban (2.5 mg twice daily) and rivaroxaban (10 mg daily) for CAT VTE prophylaxis are lower than FDA-approved treatment doses.³¹

Patients with thrombophilia: VTE prevention

Thrombophilias are broadly categorized as inherited or acquired, with inherited thrombophilia being more prevalent. The Factor V Leiden (FVL) variant affects 2% to 7% of the population, and prothrombin gene mutation (PGM) affects 1% to 2% of the population.³⁶ Other forms of inherited thrombophilia, such as protein C deficiency, protein S deficiency, and antithrombin deficiency, occur less commonly (< 0.7% of the population).³⁶ Antiphospholipid syndrome (APS), the most common acquired thrombophilia, affects approximately 2% of the population.³⁶ APS involves multiple antibodies: anticardiolipin antibodies, lupus anticoagulant, and anti-beta-2 glycoprotein 1 antibodies. Establishing risk for thrombosis across the varying types of thrombophilia has proven difficult, but APS is considered the most thrombogenic thrombophilia apart from extremely rare homozygous inherited thrombophilias.³⁶ Therefore, DOAC recommendations are thrombophilia specific.

Assessing DOAC blood levels is no longer recommended for patients with obesity, as there is insufficient evidence that these measures affect clinical outcomes.

A prospective cohort study evaluated DOACs compared with heparin/warfarin for VTE treatment in patients with inherited thrombophilias.³⁷ Although all 4 available DOACs were included, most patients (61.1%) received rivaroxaban. Patients with an array of inherited thrombophilias, including rare homozygous mutations, were enrolled in this trial. While most patients (66.9%) had a “mild thrombophilia” defined as either FVL or PGM, the remainder had more severe thrombophilias.³⁷ VTE recurrence was similar and uncommon in the DOAC and heparin/warfarin groups, consistent with a previous meta-analysis.³⁸ Surprisingly, an increase in the cumulative risk for bleeding was seen in the DOAC group compared with the warfarin group, a finding inconsistent with prior trials.³⁸ There were no major bleeding events in the DOAC group, but 3 such events occurred in the heparin/warfarin group, including 2 intracranial hemorrhages.

Currently NICE, CHEST, and ISTH do not make a recommendation for a preferred agent in patients with an acute VTE and inherited thrombophilia; however, DOACs would not be inappropriate.^23,28,32 The American Society of Hematology (ASH) had planned to release recommendations related to the treatment of thrombophilia in 2020, but they were delayed by the COVID-19 pandemic.³⁹

APS presents challenges for acute VTE anticoagulation. First, it causes a strongly thrombogenic state necessitating therapeutic anticoagulation. Second, for patients with positive lupus anticoagulant, INR monitoring and standardized INR goals may be inadequate.⁴⁰ Therefore, using fixed-dose DOACs without the need for therapeutic monitoring is appealing, but significant concerns exist for using DOACs in patients with APS.^41-45 ISTH and CHEST recommend warfarin for the treatment and prevention of acute VTE in patients with APS, especially those with triple-­positive (anticardiolipin, lupus anticoagulant, and anti-beta-2 glycoprotein 1) APS.^13,46 Package labeling for all DOACs recommends avoidance in triple-positive APS.^1-4

ASTRO-APS is the most recent RCT to compare apixaban and warfarin for patients with APS,⁴⁷ and it was terminated early after 6 of 23 patients in the apixaban group had thrombotic events, while no one in the warfarin group had such an event.⁴⁸ Subsequently, a meta-analysis⁴⁹ demonstrated that patients with thrombotic APS appear to have a greater risk for arterial thrombosis when treated with DOACs compared with warfarin. These 2 studies may lead to changes in recommendations to avoid DOACs in all patients with APS or may prompt more focused trials for DOAC use in patients with APS plus an antiplatelet to mitigate arterial thrombotic risk.

Continue to: Expanded clinical indications

Expanded clinical indications

Superficial vein thrombosis

Superficial thrombophlebitis or superficial vein thrombosis (SVT) is estimated to occur 6 times more frequently than VTE.⁵⁰ Management of patients with isolated, uncomplicated thrombophlebitis who are at low risk for extension of the SVT involves symptomatic treatment with nonsteroidal anti-inflammatory drugs, topical agents, or compression therapy. However, depending on risk for progression, anticoagulation may be recommended.⁵¹

Patients at intermediate risk for extension or propagation of SVT are candidates for anticoagulation. The CHEST guidelines recommend fondaparinux 2.5 mg subcutaneous injections daily for 45 days instead of LMWH or warfarin.¹³ However, if patients decline 6 weeks of daily injections, the guidelines acknowledge that rivaroxaban 10 mg daily may be an alternative.¹³

Certain situations should prompt one to consider using a treatment dose of a DOAC for 3 months. These include cases in which the SVT is located within 3 cm of the deep venous system, expands despite an appropriate prophylactic regimen, or recurs after discontinuation of prophylactic anticoagulation.^13,50

Acute coronary syndrome

The American College of Cardiology/­American Heart Association (ACC/AHA) recommend combination antiplatelet therapy and anticoagulation for management of acute coronary syndrome in hospitalized patients.⁵² Data are mixed regarding longer-term anticoagulation in addition to dual antiplatelet therapy in outpatient settings to prevent thrombosis recurrence in the absence of AF.

For patients at intermediate risk for extension of superficial vein thrombosis who decline daily subcutaneous injections of fondaparinux, rivaroxaban 10 mg/d may be an alternative.

The APPRAISE-2 trial enrolled high-risk patients with ACS within 7 days of the event.⁵³ Apixaban 5 mg twice daily was compared with placebo in patients taking aspirin or aspirin plus clopidogrel. The trial was terminated early because major bleeding events increased with apixaban without reduction in recurrent ischemic events. The ATLAS ACS-TIMI 46 trial evaluated different rivaroxaban doses (5-20 mg daily) in ACS patients.⁵⁴ The study revealed possible thrombosis benefit but also increased risk for bleeding, particularly at higher doses. As a result, another study—ATLAS ACS 2-TIMI 51—was conducted and compared the use of low-dose rivaroxaban (2.5 mg twice daily or 5 mg twice daily) vs placebo for patients with recent ACS.⁵⁵ All patients were receiving low-dose aspirin, and approximately 93% of patients in each group also were receiving clopidogrel or ticlopidine. As in the APPRAISE-2 trial, rivaroxaban increased the rate of major bleeding and intracranial hemorrhage; however, it did not increase the incidence of fatal bleeding. Unlike APPRAISE-2, rivaroxaban significantly reduced the primary efficacy end point, a composite of death from cardiovascular causes, myocardial infarction, or stroke (absolute risk reduction = 1.8%; number needed to treat = 56 for combined rivaroxaban doses).⁵⁵

A secondary subgroup analysis combined data from the ATLAS ACMS-TIMI 46 and ATLAS ACS 2-TIMI 51 trials to evaluate outcomes in patients receiving aspirin monotherapy when combined with rivaroxaban 2.5 mg twice daily or 5 mg twice daily or with placebo.⁵⁶ The primary efficacy end point was a composite of cardiovascular death, myocardial infarction, or stroke. When the 2 trials were evaluated separately, neither rivaroxaban dose was associated with reduction of the primary efficacy outcomes compared with aspirin alone. However, when the data were pooled, both the combined rivaroxaban doses (particularly the 5-mg dose) were associated with reduced cardiovascular outcomes. From a safety perspective, the 2.5-mg twice-daily dose of rivaroxaban was the only dose not associated with increased major bleeding risk. Thus, the 2.5-mg twice-daily dose of rivaroxaban may not provide sufficient cardiovascular benefit in patients with ACS, while the larger dose may increase the risk for nonfatal major bleeding events.⁵⁶

The European Medicines Agency⁵⁷ approved rivaroxaban 2.5 mg twice daily for ACS, and the 2020 ESC guidelines⁵⁸ consider it an appropriate therapeutic option in addition to aspirin for patients at high ischemic risk and low bleeding risk. ACS is not an FDA-approved indication for DOACs, and the ACC/AHA Guideline for the Management of ACS, last updated in 2014, does not include DOACs for ACS unless patients have AF.⁵² Ongoing trials are further investigating rivaroxaban for ACS, so the use of DOACs in the post-acute phase of ACS may become clearer in the future.⁵⁹

Continue to: Heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia

Historically, nonheparin parenteral anticoagulants argatroban, bivalirudin, and fondaparinux were recommended for patients at risk for or who had heparin-induced thrombocytopenia (HIT). Argatroban is the only drug FDA approved for the treatment and prophylaxis of HIT; recommendations for the others are based on guideline recommendations.^23,60,61 The nonheparin parenteral anticoagulants cost between $700 and $1500 per day; therefore most patients with HIT are transitioned to warfarin.⁶² However, protein C and S inhibition and a subsequent prothrombotic state conveyed by warfarin initiation necessitates a minimum 5-day bridge to therapeutic warfarin with a nonheparin parenteral anticoagulant.

In vitro tests show that DOACs do not promote development of HIT antibodies⁶³ or affect platelet activation or aggregation.⁶⁴ A literature summary of DOACs for HIT determined that in 104 patients, all but 1 achieved platelet recovery (defined as > 150,000/mcL) within a median time of 7 days. Therapeutically, DOACs prevented new or recurrent VTE in 102/104 cases (98%), and only 3% of patients experienced significant bleeding events.⁶²

The ACC/AHA recommend combination antiplatelet therapy and anticoagulation for management of acute coronary syndrome in hospitalized patients.

The 2018 ASH guidelines for VTE management in HIT include (with very low certainty of evidence) dabigatran, rivaroxaban, or apixaban for consideration in addition to previously recommended nonheparin parenteral anticoagulants.⁶¹ The dosing of each agent is contingent upon treatment of patients with HIT and an acute thrombosis (HITT) or HIT in the absence of VTE. For patients with HITT, treatment doses for acute VTE should be used for the appropriate duration of therapy (ie, 3 months). Importantly, dabigatran requires a 5-day pretreatment period with a parenteral anticoagulant, so it is not an ideal option. When treating isolated HIT (in the absence of VTE), ASH recommends all agents be dosed twice daily—dabigatran 150 mg twice daily (no 5-day parenteral pretreatment necessary), rivaroxaban 15 mg twice daily, or apixaban 5 mg twice daily—until platelet recovery (≥ 150,000/mcL) is achieved.⁶¹

CORRESPONDENCE
Kevin Schleich, PharmD, BCACP, Departments of Pharmaceutical Care and Family Medicine, University of Iowa, 200 Hawkins Drive, 01102-D PFP, Iowa City, IA, 52242; [email protected]

Metabolic syndrome, type 2 diabetes mellitus (T2DM), and the “diabetes syndrome,” are interrelated, serious health conditions that share common risk factors and mechanisms. While they are each distinct conditions, a significant association exists between them, with metabolic syndrome often being considered a precursor to the development of typical T2DM.

Metabolic syndrome is a cluster of individual metabolic abnormalities that includes a combination of risk factors such as abdominal obesity, high blood pressure, elevated insulin levels, high triglyceride levels, and low levels of high-density lipoprotein (HDL) cholesterol related to genes and epigenetic changes associated with insulin resistance. These risk factors increase the likelihood of developing cardiovascular diseases, such as heart disease and stroke, and, when combined with significant damage to β -cell function and the influence of concordant environmental precipitants, result in hyperglycemia/overt diabetes—classically defined as T2DM.

It is estimated that there will be a staggering 3.1 billion people living with T2DM by 2050, according to a recent article in The Lancet. This devastating number will place a heavy burden on the health care system. 

However, this typical pathophysiologic definition of T2DM is imprecise. Twenty percent of patients with T2DM have islet-cell antibodies that are typical of the immune destruction of β-cells in patients with type 1 diabetes mellitus (T1DM). Furthermore, approximately 40% of patients with T1DM have insulin resistance.

Thus, to better understand and distinguish the disease processes unique to each individual, we have defined a new beta cell classification for all forms of diabetes mellitus (DM). In this classification, there are 4 common pathophysiologic causes of all DM (including classic T2DM), with resultant damage to the β-cells (ie, genetic and epigenetic changes, inflammation, an abnormal environment, and insulin resistance), which results in 11 mechanisms of hyperglycemia, represented as “the egregious eleven” in Figure 1. 

Additionally, Figure 2 illustrates the association between overlapping genes/epigenetic changes responsible for DM and the increased susceptibility to developing various microvascular complications commonly observed in all forms of DM, including classic T2DM. These complications, now recognized as components of the diabetes syndrome, encompass a range of conditions with shared interrelated pathophysiologic mechanisms, such as arteriosclerotic vascular disease (ASVD), dementia, some cancers, nonalcoholic fatty liver disease or nonalcoholic steatohepatitis (NAFLD/NASH), or psoriasis. 

The likelihood of developing a specific type of DM, with classic complications or associated conditions, is contingent on an individual’s genes, epigenetic factors, inflammation, insulin resistance, and environmental exposures over time. It has now been postulated that these factors can be identified in a particular individual by a set of genomics, metabolomics, proteomics, and markers of these processes. 

This more precise approach has the added benefit of giving rise to a more accurate individualization of therapy—precision medicine.

Precision medicine is an approach to healthcare that considers an individual's specific characteristics, such as genetic makeup, lifestyle, and environmental factors, to tailor medical treatments and interventions. In the context of this discussion on T2DM, precision medicine’s goal is to provide targeted therapies and interventions based on an individual's unique -omic profile to improve treatment outcomes and minimize side effects. An additional benefit of precision medicine use in diabetes syndrome is giving the diabetes specialist the opportunity to treat the whole patient, looking for complications and associated conditions earlier via defining the presence or absence of various markers of their individual pathophysiology. Additionally, we have come to recognize that many of the medications for treating T2DM (eg, glucagon-like peptide 1 receptor agonists [GLP-1 RA], dipeptidyl peptidase 4 inhibitors [DPP-4 inhibitors], sodium-glucose cotransporter-2 inhibitors [SGLT-2 inhibitors], metformin, Cycloset [bromocriptine mesylate]) can offer other benefits for the patient—treating not only multiple mechanisms of hyperglycemia (the egregious eleven: use the fewest number of agents in combination to treat the most number of mechanisms of hyperglycemia) but also recognize that they can prevent and treat the complications and associated conditions of the diabetes syndrome: cardiovascular, renal, liver, some cancers, psoriasis, and dementia. 

The classic link between metabolic syndrome and T2DM is important to consider when applying precision medicine approaches to the management of T2DM. Here are some examples of how precision medicine is being applied in the management of T2DM:

• Genetic testing: Genetic testing can help identify specific genetic variants or mutations that may influence an individual's risk of developing T2DM or their response to certain medications. By understanding a person's genetic predisposition, clinicians can make more informed decisions about treatment options and develop personalized strategies for their patients.

• Pharmacogenomics: Certain genetic variations can impact how a person metabolizes and responds to specific diabetes medications. By analyzing an individual's genetic profile, medications that are more likely to be effective and have fewer adverse effects for that patient may be selected.

• Continuous glucose monitoring (CGM): CGM devices provide real-time information about an individual’s blood glucose levels, allowing for more precise management of diabetes. By continuously monitoring glucose levels, patterns can be identified, allowing for adjustments to medication dosages, dietary recommendations, and lifestyle modifications on an individualized basis.

• Lifestyle interventions: Precision medicine also recognizes that lifestyle factors play a crucial role in the development and management of T2DM. Lifestyle interventions, such as diet and exercise plans, based on an individual's preferences, metabolic profile, and response to different interventions can be personalized (ie, some individuals may benefit more from a low-carbohydrate diet, while others may respond better to a Mediterranean-style diet).

• Predictive modeling and risk stratification: Precision medicine leverages data analytics and predictive modeling to assess an individual's risk of developing complications associated with T2DM. By analyzing various factors such as medical history, genetics, lifestyle, and biomarkers, individuals who are at a higher risk of developing complications can be identified, and their treatment plans can be tailored accordingly. Precision medicine enables early identification of individuals who are at a higher risk of developing T2DM based on their metabolic syndrome status.

In summary, precision medicine for T2DM considers the link between metabolic syndrome and diabetes syndrome to develop personalized approaches for prevention, early intervention, and treatment. By understanding an individual's metabolic and genetic profile, targeted strategies to optimize management and improve outcomes for patients with metabolic syndrome and those at risk of developing diabetes can be implemented. 

It is important to note that while precision medicine holds promise in improving diabetes management, it is still an evolving field, and its widespread implementation is not yet fully realized. Collaboration between clinicians, researchers, and technological advancements will continue to drive the progress of precision medicine in T2DM management.

Metabolic syndrome, type 2 diabetes mellitus (T2DM), and the “diabetes syndrome,” are interrelated, serious health conditions that share common risk factors and mechanisms. While they are each distinct conditions, a significant association exists between them, with metabolic syndrome often being considered a precursor to the development of typical T2DM.

Metabolic syndrome is a cluster of individual metabolic abnormalities that includes a combination of risk factors such as abdominal obesity, high blood pressure, elevated insulin levels, high triglyceride levels, and low levels of high-density lipoprotein (HDL) cholesterol related to genes and epigenetic changes associated with insulin resistance. These risk factors increase the likelihood of developing cardiovascular diseases, such as heart disease and stroke, and, when combined with significant damage to β -cell function and the influence of concordant environmental precipitants, result in hyperglycemia/overt diabetes—classically defined as T2DM.

It is estimated that there will be a staggering 3.1 billion people living with T2DM by 2050, according to a recent article in The Lancet. This devastating number will place a heavy burden on the health care system. 

However, this typical pathophysiologic definition of T2DM is imprecise. Twenty percent of patients with T2DM have islet-cell antibodies that are typical of the immune destruction of β-cells in patients with type 1 diabetes mellitus (T1DM). Furthermore, approximately 40% of patients with T1DM have insulin resistance.

Thus, to better understand and distinguish the disease processes unique to each individual, we have defined a new beta cell classification for all forms of diabetes mellitus (DM). In this classification, there are 4 common pathophysiologic causes of all DM (including classic T2DM), with resultant damage to the β-cells (ie, genetic and epigenetic changes, inflammation, an abnormal environment, and insulin resistance), which results in 11 mechanisms of hyperglycemia, represented as “the egregious eleven” in Figure 1. 

Additionally, Figure 2 illustrates the association between overlapping genes/epigenetic changes responsible for DM and the increased susceptibility to developing various microvascular complications commonly observed in all forms of DM, including classic T2DM. These complications, now recognized as components of the diabetes syndrome, encompass a range of conditions with shared interrelated pathophysiologic mechanisms, such as arteriosclerotic vascular disease (ASVD), dementia, some cancers, nonalcoholic fatty liver disease or nonalcoholic steatohepatitis (NAFLD/NASH), or psoriasis. 

The likelihood of developing a specific type of DM, with classic complications or associated conditions, is contingent on an individual’s genes, epigenetic factors, inflammation, insulin resistance, and environmental exposures over time. It has now been postulated that these factors can be identified in a particular individual by a set of genomics, metabolomics, proteomics, and markers of these processes. 

This more precise approach has the added benefit of giving rise to a more accurate individualization of therapy—precision medicine.

Precision medicine is an approach to healthcare that considers an individual's specific characteristics, such as genetic makeup, lifestyle, and environmental factors, to tailor medical treatments and interventions. In the context of this discussion on T2DM, precision medicine’s goal is to provide targeted therapies and interventions based on an individual's unique -omic profile to improve treatment outcomes and minimize side effects. An additional benefit of precision medicine use in diabetes syndrome is giving the diabetes specialist the opportunity to treat the whole patient, looking for complications and associated conditions earlier via defining the presence or absence of various markers of their individual pathophysiology. Additionally, we have come to recognize that many of the medications for treating T2DM (eg, glucagon-like peptide 1 receptor agonists [GLP-1 RA], dipeptidyl peptidase 4 inhibitors [DPP-4 inhibitors], sodium-glucose cotransporter-2 inhibitors [SGLT-2 inhibitors], metformin, Cycloset [bromocriptine mesylate]) can offer other benefits for the patient—treating not only multiple mechanisms of hyperglycemia (the egregious eleven: use the fewest number of agents in combination to treat the most number of mechanisms of hyperglycemia) but also recognize that they can prevent and treat the complications and associated conditions of the diabetes syndrome: cardiovascular, renal, liver, some cancers, psoriasis, and dementia. 

The classic link between metabolic syndrome and T2DM is important to consider when applying precision medicine approaches to the management of T2DM. Here are some examples of how precision medicine is being applied in the management of T2DM:

• Genetic testing: Genetic testing can help identify specific genetic variants or mutations that may influence an individual's risk of developing T2DM or their response to certain medications. By understanding a person's genetic predisposition, clinicians can make more informed decisions about treatment options and develop personalized strategies for their patients.

• Pharmacogenomics: Certain genetic variations can impact how a person metabolizes and responds to specific diabetes medications. By analyzing an individual's genetic profile, medications that are more likely to be effective and have fewer adverse effects for that patient may be selected.

• Continuous glucose monitoring (CGM): CGM devices provide real-time information about an individual’s blood glucose levels, allowing for more precise management of diabetes. By continuously monitoring glucose levels, patterns can be identified, allowing for adjustments to medication dosages, dietary recommendations, and lifestyle modifications on an individualized basis.

• Lifestyle interventions: Precision medicine also recognizes that lifestyle factors play a crucial role in the development and management of T2DM. Lifestyle interventions, such as diet and exercise plans, based on an individual's preferences, metabolic profile, and response to different interventions can be personalized (ie, some individuals may benefit more from a low-carbohydrate diet, while others may respond better to a Mediterranean-style diet).

• Predictive modeling and risk stratification: Precision medicine leverages data analytics and predictive modeling to assess an individual's risk of developing complications associated with T2DM. By analyzing various factors such as medical history, genetics, lifestyle, and biomarkers, individuals who are at a higher risk of developing complications can be identified, and their treatment plans can be tailored accordingly. Precision medicine enables early identification of individuals who are at a higher risk of developing T2DM based on their metabolic syndrome status.

In summary, precision medicine for T2DM considers the link between metabolic syndrome and diabetes syndrome to develop personalized approaches for prevention, early intervention, and treatment. By understanding an individual's metabolic and genetic profile, targeted strategies to optimize management and improve outcomes for patients with metabolic syndrome and those at risk of developing diabetes can be implemented. 

It is important to note that while precision medicine holds promise in improving diabetes management, it is still an evolving field, and its widespread implementation is not yet fully realized. Collaboration between clinicians, researchers, and technological advancements will continue to drive the progress of precision medicine in T2DM management.

Metabolic syndrome, type 2 diabetes mellitus (T2DM), and the “diabetes syndrome,” are interrelated, serious health conditions that share common risk factors and mechanisms. While they are each distinct conditions, a significant association exists between them, with metabolic syndrome often being considered a precursor to the development of typical T2DM.

Metabolic syndrome is a cluster of individual metabolic abnormalities that includes a combination of risk factors such as abdominal obesity, high blood pressure, elevated insulin levels, high triglyceride levels, and low levels of high-density lipoprotein (HDL) cholesterol related to genes and epigenetic changes associated with insulin resistance. These risk factors increase the likelihood of developing cardiovascular diseases, such as heart disease and stroke, and, when combined with significant damage to β -cell function and the influence of concordant environmental precipitants, result in hyperglycemia/overt diabetes—classically defined as T2DM.

It is estimated that there will be a staggering 3.1 billion people living with T2DM by 2050, according to a recent article in The Lancet. This devastating number will place a heavy burden on the health care system. 

However, this typical pathophysiologic definition of T2DM is imprecise. Twenty percent of patients with T2DM have islet-cell antibodies that are typical of the immune destruction of β-cells in patients with type 1 diabetes mellitus (T1DM). Furthermore, approximately 40% of patients with T1DM have insulin resistance.

Thus, to better understand and distinguish the disease processes unique to each individual, we have defined a new beta cell classification for all forms of diabetes mellitus (DM). In this classification, there are 4 common pathophysiologic causes of all DM (including classic T2DM), with resultant damage to the β-cells (ie, genetic and epigenetic changes, inflammation, an abnormal environment, and insulin resistance), which results in 11 mechanisms of hyperglycemia, represented as “the egregious eleven” in Figure 1. 

Additionally, Figure 2 illustrates the association between overlapping genes/epigenetic changes responsible for DM and the increased susceptibility to developing various microvascular complications commonly observed in all forms of DM, including classic T2DM. These complications, now recognized as components of the diabetes syndrome, encompass a range of conditions with shared interrelated pathophysiologic mechanisms, such as arteriosclerotic vascular disease (ASVD), dementia, some cancers, nonalcoholic fatty liver disease or nonalcoholic steatohepatitis (NAFLD/NASH), or psoriasis. 

The likelihood of developing a specific type of DM, with classic complications or associated conditions, is contingent on an individual’s genes, epigenetic factors, inflammation, insulin resistance, and environmental exposures over time. It has now been postulated that these factors can be identified in a particular individual by a set of genomics, metabolomics, proteomics, and markers of these processes. 

This more precise approach has the added benefit of giving rise to a more accurate individualization of therapy—precision medicine.

Precision medicine is an approach to healthcare that considers an individual's specific characteristics, such as genetic makeup, lifestyle, and environmental factors, to tailor medical treatments and interventions. In the context of this discussion on T2DM, precision medicine’s goal is to provide targeted therapies and interventions based on an individual's unique -omic profile to improve treatment outcomes and minimize side effects. An additional benefit of precision medicine use in diabetes syndrome is giving the diabetes specialist the opportunity to treat the whole patient, looking for complications and associated conditions earlier via defining the presence or absence of various markers of their individual pathophysiology. Additionally, we have come to recognize that many of the medications for treating T2DM (eg, glucagon-like peptide 1 receptor agonists [GLP-1 RA], dipeptidyl peptidase 4 inhibitors [DPP-4 inhibitors], sodium-glucose cotransporter-2 inhibitors [SGLT-2 inhibitors], metformin, Cycloset [bromocriptine mesylate]) can offer other benefits for the patient—treating not only multiple mechanisms of hyperglycemia (the egregious eleven: use the fewest number of agents in combination to treat the most number of mechanisms of hyperglycemia) but also recognize that they can prevent and treat the complications and associated conditions of the diabetes syndrome: cardiovascular, renal, liver, some cancers, psoriasis, and dementia. 

The classic link between metabolic syndrome and T2DM is important to consider when applying precision medicine approaches to the management of T2DM. Here are some examples of how precision medicine is being applied in the management of T2DM:

• Genetic testing: Genetic testing can help identify specific genetic variants or mutations that may influence an individual's risk of developing T2DM or their response to certain medications. By understanding a person's genetic predisposition, clinicians can make more informed decisions about treatment options and develop personalized strategies for their patients.

• Pharmacogenomics: Certain genetic variations can impact how a person metabolizes and responds to specific diabetes medications. By analyzing an individual's genetic profile, medications that are more likely to be effective and have fewer adverse effects for that patient may be selected.

• Continuous glucose monitoring (CGM): CGM devices provide real-time information about an individual’s blood glucose levels, allowing for more precise management of diabetes. By continuously monitoring glucose levels, patterns can be identified, allowing for adjustments to medication dosages, dietary recommendations, and lifestyle modifications on an individualized basis.

• Lifestyle interventions: Precision medicine also recognizes that lifestyle factors play a crucial role in the development and management of T2DM. Lifestyle interventions, such as diet and exercise plans, based on an individual's preferences, metabolic profile, and response to different interventions can be personalized (ie, some individuals may benefit more from a low-carbohydrate diet, while others may respond better to a Mediterranean-style diet).

• Predictive modeling and risk stratification: Precision medicine leverages data analytics and predictive modeling to assess an individual's risk of developing complications associated with T2DM. By analyzing various factors such as medical history, genetics, lifestyle, and biomarkers, individuals who are at a higher risk of developing complications can be identified, and their treatment plans can be tailored accordingly. Precision medicine enables early identification of individuals who are at a higher risk of developing T2DM based on their metabolic syndrome status.

In summary, precision medicine for T2DM considers the link between metabolic syndrome and diabetes syndrome to develop personalized approaches for prevention, early intervention, and treatment. By understanding an individual's metabolic and genetic profile, targeted strategies to optimize management and improve outcomes for patients with metabolic syndrome and those at risk of developing diabetes can be implemented. 

It is important to note that while precision medicine holds promise in improving diabetes management, it is still an evolving field, and its widespread implementation is not yet fully realized. Collaboration between clinicians, researchers, and technological advancements will continue to drive the progress of precision medicine in T2DM management.

To the Editor:

Citation number and Hirsch index (h-index) have long been employed as metrics of productivity for academic scholarship. The h-index is defined as the highest number of publications (the maximum h value) of an author who has published at least h papers, each cited by other authors at least h times.¹ In a bibliometric analysis of the most frequently cited authors in dermatology from 1974 to 2019 (N=378,276), females comprised 12% of first and 11% of senior authors of the most cited publications, and 6 of the most cited authors in dermatology were women.² In another study analyzing the most prolific dermatologic authors based on h-index, 0% from 1980 to 1989 and 19% from 2010 to 2019 were female (N=393,488).³ Because citation number and h-index favor longer-practicing dermatologists, we examined dermatology author productivity and gender trends by recent publication rates.

The Scopus database was searched for dermatology publications by using the field category “dermatology”from January 1, 2017, to October 7, 2022. Nondermatologists and authors with the same initials were excluded. Authors were ranked by number of publications, including original articles, case reports, letters, and reviews. Sex, degree, and years of experience were determined via a Google search of the author’s name. The h-index; number of citations; and percentages of first, middle, and last authorship were recorded.

Of the top 50 published dermatologists, 30% were female (n=15) and 56% (n=28) held both MD and PhD degrees (Table). The mean years of experience was 26.27 years (range, 6–44 years), with a mean of 29.23 years in females and 25.87 years in males. The mean h-index was 27.96 (range, 8–88), with 24.87 for females and 29.29 for males. The mean number of citations was 4032.64 (range, 235–36,908), with 2891.13 for females and 4521.86 for males. Thirty-one authors were most frequently middle authors, 18 were senior authors, and 1 was a first author. On average (SD), authors were senior or first author in 47.97% (20.08%) of their publications (range, 6.32%–94.93%).

Our study shows that females were more highly represented as top dermatology authors (30%) as measured by publication numbers from 2017 to 2022 than in studies measuring citation rate from 1974 to 2019 (12%)² or h-index from 2010 to 2019 (19%).³ Similarly, in a study of dermatology authorship from 2009 to 2019, on average, females represented 51.06% first and 38.18% last authors.⁴

The proportion of females in the dermatology workforce has increased, with 3964 of 10,385 (38.2%) active dermatologists in 2007⁵ being female vs 6372 of 12,505 (51.0%) in 2019.⁶ The lower proportion of practicing female dermatologists in earlier years likely accounts for the lower percentage of females in dermatology citations and h-index top lists during that time, given that citation and h-index metrics are biased to dermatologists with longer careers.

Although our data are encouraging, females still accounted for less than one-third of the top 50 authors by publication numbers. Gender inequalities persist, with only one-third of a total of 1292 National Institutes of Health dermatology grants and one-fourth of Research Project Grant Program (R01) grants being awarded to females in the years 2009 to 2014.⁷ Therefore, formal and informal mentorship, protected time for research, resources for childcare, and opportunities for funding will be critical in supporting female dermatologists to both publish highly impactful research and obtain research grants.

Limitations of our study include the omission of authors with identical initials and the inability to account for name changes. Furthermore, Scopus does not include all articles published by each author. Finally, publication number reflects quantity but may not reflect quality.

By quantitating dermatology author publication numbers, we found better representation of female authors compared with studies measuring citation number and h-index. With higher proportions of female dermatology trainees and efforts to increase mentorship and research support for female dermatologists, we expect improved equality in top lists of dermatology citations and h-index values.

To the Editor:

Citation number and Hirsch index (h-index) have long been employed as metrics of productivity for academic scholarship. The h-index is defined as the highest number of publications (the maximum h value) of an author who has published at least h papers, each cited by other authors at least h times.¹ In a bibliometric analysis of the most frequently cited authors in dermatology from 1974 to 2019 (N=378,276), females comprised 12% of first and 11% of senior authors of the most cited publications, and 6 of the most cited authors in dermatology were women.² In another study analyzing the most prolific dermatologic authors based on h-index, 0% from 1980 to 1989 and 19% from 2010 to 2019 were female (N=393,488).³ Because citation number and h-index favor longer-practicing dermatologists, we examined dermatology author productivity and gender trends by recent publication rates.

The Scopus database was searched for dermatology publications by using the field category “dermatology”from January 1, 2017, to October 7, 2022. Nondermatologists and authors with the same initials were excluded. Authors were ranked by number of publications, including original articles, case reports, letters, and reviews. Sex, degree, and years of experience were determined via a Google search of the author’s name. The h-index; number of citations; and percentages of first, middle, and last authorship were recorded.

Of the top 50 published dermatologists, 30% were female (n=15) and 56% (n=28) held both MD and PhD degrees (Table). The mean years of experience was 26.27 years (range, 6–44 years), with a mean of 29.23 years in females and 25.87 years in males. The mean h-index was 27.96 (range, 8–88), with 24.87 for females and 29.29 for males. The mean number of citations was 4032.64 (range, 235–36,908), with 2891.13 for females and 4521.86 for males. Thirty-one authors were most frequently middle authors, 18 were senior authors, and 1 was a first author. On average (SD), authors were senior or first author in 47.97% (20.08%) of their publications (range, 6.32%–94.93%).

Our study shows that females were more highly represented as top dermatology authors (30%) as measured by publication numbers from 2017 to 2022 than in studies measuring citation rate from 1974 to 2019 (12%)² or h-index from 2010 to 2019 (19%).³ Similarly, in a study of dermatology authorship from 2009 to 2019, on average, females represented 51.06% first and 38.18% last authors.⁴

The proportion of females in the dermatology workforce has increased, with 3964 of 10,385 (38.2%) active dermatologists in 2007⁵ being female vs 6372 of 12,505 (51.0%) in 2019.⁶ The lower proportion of practicing female dermatologists in earlier years likely accounts for the lower percentage of females in dermatology citations and h-index top lists during that time, given that citation and h-index metrics are biased to dermatologists with longer careers.

Although our data are encouraging, females still accounted for less than one-third of the top 50 authors by publication numbers. Gender inequalities persist, with only one-third of a total of 1292 National Institutes of Health dermatology grants and one-fourth of Research Project Grant Program (R01) grants being awarded to females in the years 2009 to 2014.⁷ Therefore, formal and informal mentorship, protected time for research, resources for childcare, and opportunities for funding will be critical in supporting female dermatologists to both publish highly impactful research and obtain research grants.

Limitations of our study include the omission of authors with identical initials and the inability to account for name changes. Furthermore, Scopus does not include all articles published by each author. Finally, publication number reflects quantity but may not reflect quality.

By quantitating dermatology author publication numbers, we found better representation of female authors compared with studies measuring citation number and h-index. With higher proportions of female dermatology trainees and efforts to increase mentorship and research support for female dermatologists, we expect improved equality in top lists of dermatology citations and h-index values.

To the Editor:

Citation number and Hirsch index (h-index) have long been employed as metrics of productivity for academic scholarship. The h-index is defined as the highest number of publications (the maximum h value) of an author who has published at least h papers, each cited by other authors at least h times.¹ In a bibliometric analysis of the most frequently cited authors in dermatology from 1974 to 2019 (N=378,276), females comprised 12% of first and 11% of senior authors of the most cited publications, and 6 of the most cited authors in dermatology were women.² In another study analyzing the most prolific dermatologic authors based on h-index, 0% from 1980 to 1989 and 19% from 2010 to 2019 were female (N=393,488).³ Because citation number and h-index favor longer-practicing dermatologists, we examined dermatology author productivity and gender trends by recent publication rates.

The Scopus database was searched for dermatology publications by using the field category “dermatology”from January 1, 2017, to October 7, 2022. Nondermatologists and authors with the same initials were excluded. Authors were ranked by number of publications, including original articles, case reports, letters, and reviews. Sex, degree, and years of experience were determined via a Google search of the author’s name. The h-index; number of citations; and percentages of first, middle, and last authorship were recorded.

Of the top 50 published dermatologists, 30% were female (n=15) and 56% (n=28) held both MD and PhD degrees (Table). The mean years of experience was 26.27 years (range, 6–44 years), with a mean of 29.23 years in females and 25.87 years in males. The mean h-index was 27.96 (range, 8–88), with 24.87 for females and 29.29 for males. The mean number of citations was 4032.64 (range, 235–36,908), with 2891.13 for females and 4521.86 for males. Thirty-one authors were most frequently middle authors, 18 were senior authors, and 1 was a first author. On average (SD), authors were senior or first author in 47.97% (20.08%) of their publications (range, 6.32%–94.93%).

Our study shows that females were more highly represented as top dermatology authors (30%) as measured by publication numbers from 2017 to 2022 than in studies measuring citation rate from 1974 to 2019 (12%)² or h-index from 2010 to 2019 (19%).³ Similarly, in a study of dermatology authorship from 2009 to 2019, on average, females represented 51.06% first and 38.18% last authors.⁴

The proportion of females in the dermatology workforce has increased, with 3964 of 10,385 (38.2%) active dermatologists in 2007⁵ being female vs 6372 of 12,505 (51.0%) in 2019.⁶ The lower proportion of practicing female dermatologists in earlier years likely accounts for the lower percentage of females in dermatology citations and h-index top lists during that time, given that citation and h-index metrics are biased to dermatologists with longer careers.

Although our data are encouraging, females still accounted for less than one-third of the top 50 authors by publication numbers. Gender inequalities persist, with only one-third of a total of 1292 National Institutes of Health dermatology grants and one-fourth of Research Project Grant Program (R01) grants being awarded to females in the years 2009 to 2014.⁷ Therefore, formal and informal mentorship, protected time for research, resources for childcare, and opportunities for funding will be critical in supporting female dermatologists to both publish highly impactful research and obtain research grants.

Limitations of our study include the omission of authors with identical initials and the inability to account for name changes. Furthermore, Scopus does not include all articles published by each author. Finally, publication number reflects quantity but may not reflect quality.

By quantitating dermatology author publication numbers, we found better representation of female authors compared with studies measuring citation number and h-index. With higher proportions of female dermatology trainees and efforts to increase mentorship and research support for female dermatologists, we expect improved equality in top lists of dermatology citations and h-index values.

Similar to medical school, residency is a time to drink out of the proverbial firehose of knowledge. Along with clinical duties, there is a plethora of information ranging from clinical management decisions to boards fodder that dermatology residents are expected to know, leaving residents to adopt study habits from medical school. Flash cards remain a popular study tool in the medical education community. The use of Anki, a web-based and mobile flash card application (app) that features custom and premade flash card decks made and shared by users, has become increasingly popular. In a 2021 study, Lu et al¹ found that Anki flash card usage was associated with higher US Medical Licensing Examination scores. Herein, I provide an updated review of the top 3 most comprehensive premade Anki decks for dermatology residents, per my assessment.

COMPREHENSIVE DERMATOLOGY DECKS

Dolphin Dermatology

• Creator: Reddit user, Unknown²
• Date created: December 2020
• Last updated: April 2022
• Number of cards: 13,833
• Resources covered: Photographs of common dermatologic diagnoses from online sources such as VisualDx (https://www.visualdx.com/) and DermNet (https://dermnetnz.org/).
• Format of cards: One image or factoid per card.
• Card tags (allow separation of Anki decks into subcategories): Each general dermatology card is tagged by the diagnosis name. Pediatric dermatology cards are tagged by affected body location.
• Advantages: As you may glean by the sheer number of flash cards, this deck is a comprehensive review of clinical dermatology. Most cards feature clinical vignettes with clinical photographs of a dermatologic condition or histologic slide and ask what the diagnosis may be. It features photographs of pathology on a range of skin tones and many different images of each diagnosis. This is a great deck for residents who need to study clinical photographs of dermatologic diagnoses.
• Disadvantages: This deck does not cover dermatopathology, basic science, treatment options, or pharmacology in depth. Additionally, is difficult to find a link to download this resource.
• At the time of publication of this article, users are unable to download this deck.

vismo_djib’s Review of Dermatology Anki

• Creator: Reddit user vismo_djib³
• Date created: June 2020
• Last updated: February 2022
• Number of cards: 8454
• Resources covered: Alikhan and Hocker’s Review of Dermatology⁴ is the main resource with supplemental images from VisualDx, Bolognia et al’s Dermatology,⁵ Patterson’s Weedon’s Skin Pathology Essentials,⁶ Elston et al’s Dermatopathology,⁷ Soyer et al’s Dermoscopy: The Essentials,⁸ and Robinson et al’s Surgery of the Skin: Procedural Dermatology.⁹
• Format of cards: Cards mostly feature a diagnosis with color-coded categories including epidemiology, pathogenesis, clinical features, histopathology, and treatment.
• Card tags (allow separation of Anki decks into subcategories): Cards are tagged with chapter numbers from Alikhan and Hocker’s Review of Dermatology.⁴
• Advantages: This impressive comprehensive review of dermatology is a great option for residents studying for the American Board of Dermatology CORE examinations and users looking to solidify the information in Alikhan and Hocker’s Review of Dermatology,⁴ a frequently used resource among dermatology residents. It currently is my favorite deck because it features holistic information on diagnosis, epidemiology, pathogenesis, histopathology, and treatment with excellent clinical photographs.
• Disadvantages: For some purposes, this deck may be too lofty. For maximum benefit, it may require user customization including separating cards by tag and other add-ons that allow only 1 card per note, which will separate the information on each card into smaller increments. The mostly free-response format and lengthy slides may make it difficult to practice recall.

AnKingMed Dermki

• Creator: Reddit user AnKingMed^10,11
• Date created: April 2023
• Last updated: This deck features a dynamic add-on and collaboration application called AnkiHub, which allows for real-time updates. At the time this article was written, the deck was last updated on June 19, 2023.
• Number of cards: 7889
• Resources covered: Currently 75% of Alikhan and Hocker’s Review of Dermatology⁴ with supplemental images from DermNet and Eleryan and Friedman’s The Full Spectrum of Dermatology: A Diverse and Inclusive Atlas.¹²
• Format of cards: Cards are in a fill-in-the-blank format.
• Card tags (allow separation of Anki decks into subcategories): Cards are tagged by chapter number and subsection of Alikhan and Hocker’s Review of Dermatology.⁴
• Advantages: As the newest contribution to the dermatology Anki card compendium, this deck is up to date, innovative, and dynamic. It features an optional add-on application—AnkiHub—which allows users to keep up with live updates and collaborations. The deck features a fill-in-the-blank format that may be preferred to a free-response format for information recall. It features Alikhan and Hocker’s Review of Dermatology,⁴ which is a high-yield review of clinical dermatology, dermatopathology, surgical dermatology, pharmacology, and histopathology for dermatology residents.
• Disadvantages: The deck is still currently in a development phase, covering 75% of Alikhan and Hocker’s Review of Dermatology⁴ with plans to add the remaining 25%. The add-on to access the most up-to-date version of the flashcards requires a paid monthly or annual subscription; however, the creator announced they will release periodic free updates of the deck.

Final Thoughts

As a collaborative platform, new flash card decks are always being added to Anki. This article is not comprehensive of all dermatologic flash card decks available. There are decks better suited for medical students covering topics such as the American Academy of Dermatology Basic Dermatology Curriculum, UWorld United States Medical Licensing Examination dermatology, and dermatology in internal medicine. Furthermore, specific study tools in dermatology may have their own accompanying Anki decks (ie, The Grenz Zone podcast, Dermnemonics). Flash cards can be a valuable study tool to trainees in medicine, and residents are immensely grateful to our peers who make them for our use.

Similar to medical school, residency is a time to drink out of the proverbial firehose of knowledge. Along with clinical duties, there is a plethora of information ranging from clinical management decisions to boards fodder that dermatology residents are expected to know, leaving residents to adopt study habits from medical school. Flash cards remain a popular study tool in the medical education community. The use of Anki, a web-based and mobile flash card application (app) that features custom and premade flash card decks made and shared by users, has become increasingly popular. In a 2021 study, Lu et al¹ found that Anki flash card usage was associated with higher US Medical Licensing Examination scores. Herein, I provide an updated review of the top 3 most comprehensive premade Anki decks for dermatology residents, per my assessment.

COMPREHENSIVE DERMATOLOGY DECKS

Dolphin Dermatology

• Creator: Reddit user, Unknown²
• Date created: December 2020
• Last updated: April 2022
• Number of cards: 13,833
• Resources covered: Photographs of common dermatologic diagnoses from online sources such as VisualDx (https://www.visualdx.com/) and DermNet (https://dermnetnz.org/).
• Format of cards: One image or factoid per card.
• Card tags (allow separation of Anki decks into subcategories): Each general dermatology card is tagged by the diagnosis name. Pediatric dermatology cards are tagged by affected body location.
• Advantages: As you may glean by the sheer number of flash cards, this deck is a comprehensive review of clinical dermatology. Most cards feature clinical vignettes with clinical photographs of a dermatologic condition or histologic slide and ask what the diagnosis may be. It features photographs of pathology on a range of skin tones and many different images of each diagnosis. This is a great deck for residents who need to study clinical photographs of dermatologic diagnoses.
• Disadvantages: This deck does not cover dermatopathology, basic science, treatment options, or pharmacology in depth. Additionally, is difficult to find a link to download this resource.
• At the time of publication of this article, users are unable to download this deck.

vismo_djib’s Review of Dermatology Anki

• Creator: Reddit user vismo_djib³
• Date created: June 2020
• Last updated: February 2022
• Number of cards: 8454
• Resources covered: Alikhan and Hocker’s Review of Dermatology⁴ is the main resource with supplemental images from VisualDx, Bolognia et al’s Dermatology,⁵ Patterson’s Weedon’s Skin Pathology Essentials,⁶ Elston et al’s Dermatopathology,⁷ Soyer et al’s Dermoscopy: The Essentials,⁸ and Robinson et al’s Surgery of the Skin: Procedural Dermatology.⁹
• Format of cards: Cards mostly feature a diagnosis with color-coded categories including epidemiology, pathogenesis, clinical features, histopathology, and treatment.
• Card tags (allow separation of Anki decks into subcategories): Cards are tagged with chapter numbers from Alikhan and Hocker’s Review of Dermatology.⁴
• Advantages: This impressive comprehensive review of dermatology is a great option for residents studying for the American Board of Dermatology CORE examinations and users looking to solidify the information in Alikhan and Hocker’s Review of Dermatology,⁴ a frequently used resource among dermatology residents. It currently is my favorite deck because it features holistic information on diagnosis, epidemiology, pathogenesis, histopathology, and treatment with excellent clinical photographs.
• Disadvantages: For some purposes, this deck may be too lofty. For maximum benefit, it may require user customization including separating cards by tag and other add-ons that allow only 1 card per note, which will separate the information on each card into smaller increments. The mostly free-response format and lengthy slides may make it difficult to practice recall.

AnKingMed Dermki

• Creator: Reddit user AnKingMed^10,11
• Date created: April 2023
• Last updated: This deck features a dynamic add-on and collaboration application called AnkiHub, which allows for real-time updates. At the time this article was written, the deck was last updated on June 19, 2023.
• Number of cards: 7889
• Resources covered: Currently 75% of Alikhan and Hocker’s Review of Dermatology⁴ with supplemental images from DermNet and Eleryan and Friedman’s The Full Spectrum of Dermatology: A Diverse and Inclusive Atlas.¹²
• Format of cards: Cards are in a fill-in-the-blank format.
• Card tags (allow separation of Anki decks into subcategories): Cards are tagged by chapter number and subsection of Alikhan and Hocker’s Review of Dermatology.⁴
• Advantages: As the newest contribution to the dermatology Anki card compendium, this deck is up to date, innovative, and dynamic. It features an optional add-on application—AnkiHub—which allows users to keep up with live updates and collaborations. The deck features a fill-in-the-blank format that may be preferred to a free-response format for information recall. It features Alikhan and Hocker’s Review of Dermatology,⁴ which is a high-yield review of clinical dermatology, dermatopathology, surgical dermatology, pharmacology, and histopathology for dermatology residents.
• Disadvantages: The deck is still currently in a development phase, covering 75% of Alikhan and Hocker’s Review of Dermatology⁴ with plans to add the remaining 25%. The add-on to access the most up-to-date version of the flashcards requires a paid monthly or annual subscription; however, the creator announced they will release periodic free updates of the deck.

Final Thoughts

As a collaborative platform, new flash card decks are always being added to Anki. This article is not comprehensive of all dermatologic flash card decks available. There are decks better suited for medical students covering topics such as the American Academy of Dermatology Basic Dermatology Curriculum, UWorld United States Medical Licensing Examination dermatology, and dermatology in internal medicine. Furthermore, specific study tools in dermatology may have their own accompanying Anki decks (ie, The Grenz Zone podcast, Dermnemonics). Flash cards can be a valuable study tool to trainees in medicine, and residents are immensely grateful to our peers who make them for our use.

Similar to medical school, residency is a time to drink out of the proverbial firehose of knowledge. Along with clinical duties, there is a plethora of information ranging from clinical management decisions to boards fodder that dermatology residents are expected to know, leaving residents to adopt study habits from medical school. Flash cards remain a popular study tool in the medical education community. The use of Anki, a web-based and mobile flash card application (app) that features custom and premade flash card decks made and shared by users, has become increasingly popular. In a 2021 study, Lu et al¹ found that Anki flash card usage was associated with higher US Medical Licensing Examination scores. Herein, I provide an updated review of the top 3 most comprehensive premade Anki decks for dermatology residents, per my assessment.

COMPREHENSIVE DERMATOLOGY DECKS

Dolphin Dermatology

• Creator: Reddit user, Unknown²
• Date created: December 2020
• Last updated: April 2022
• Number of cards: 13,833
• Resources covered: Photographs of common dermatologic diagnoses from online sources such as VisualDx (https://www.visualdx.com/) and DermNet (https://dermnetnz.org/).
• Format of cards: One image or factoid per card.
• Card tags (allow separation of Anki decks into subcategories): Each general dermatology card is tagged by the diagnosis name. Pediatric dermatology cards are tagged by affected body location.
• Advantages: As you may glean by the sheer number of flash cards, this deck is a comprehensive review of clinical dermatology. Most cards feature clinical vignettes with clinical photographs of a dermatologic condition or histologic slide and ask what the diagnosis may be. It features photographs of pathology on a range of skin tones and many different images of each diagnosis. This is a great deck for residents who need to study clinical photographs of dermatologic diagnoses.
• Disadvantages: This deck does not cover dermatopathology, basic science, treatment options, or pharmacology in depth. Additionally, is difficult to find a link to download this resource.
• At the time of publication of this article, users are unable to download this deck.

vismo_djib’s Review of Dermatology Anki

• Creator: Reddit user vismo_djib³
• Date created: June 2020
• Last updated: February 2022
• Number of cards: 8454
• Resources covered: Alikhan and Hocker’s Review of Dermatology⁴ is the main resource with supplemental images from VisualDx, Bolognia et al’s Dermatology,⁵ Patterson’s Weedon’s Skin Pathology Essentials,⁶ Elston et al’s Dermatopathology,⁷ Soyer et al’s Dermoscopy: The Essentials,⁸ and Robinson et al’s Surgery of the Skin: Procedural Dermatology.⁹
• Format of cards: Cards mostly feature a diagnosis with color-coded categories including epidemiology, pathogenesis, clinical features, histopathology, and treatment.
• Card tags (allow separation of Anki decks into subcategories): Cards are tagged with chapter numbers from Alikhan and Hocker’s Review of Dermatology.⁴
• Advantages: This impressive comprehensive review of dermatology is a great option for residents studying for the American Board of Dermatology CORE examinations and users looking to solidify the information in Alikhan and Hocker’s Review of Dermatology,⁴ a frequently used resource among dermatology residents. It currently is my favorite deck because it features holistic information on diagnosis, epidemiology, pathogenesis, histopathology, and treatment with excellent clinical photographs.
• Disadvantages: For some purposes, this deck may be too lofty. For maximum benefit, it may require user customization including separating cards by tag and other add-ons that allow only 1 card per note, which will separate the information on each card into smaller increments. The mostly free-response format and lengthy slides may make it difficult to practice recall.

AnKingMed Dermki

• Creator: Reddit user AnKingMed^10,11
• Date created: April 2023
• Last updated: This deck features a dynamic add-on and collaboration application called AnkiHub, which allows for real-time updates. At the time this article was written, the deck was last updated on June 19, 2023.
• Number of cards: 7889
• Resources covered: Currently 75% of Alikhan and Hocker’s Review of Dermatology⁴ with supplemental images from DermNet and Eleryan and Friedman’s The Full Spectrum of Dermatology: A Diverse and Inclusive Atlas.¹²
• Format of cards: Cards are in a fill-in-the-blank format.
• Card tags (allow separation of Anki decks into subcategories): Cards are tagged by chapter number and subsection of Alikhan and Hocker’s Review of Dermatology.⁴
• Advantages: As the newest contribution to the dermatology Anki card compendium, this deck is up to date, innovative, and dynamic. It features an optional add-on application—AnkiHub—which allows users to keep up with live updates and collaborations. The deck features a fill-in-the-blank format that may be preferred to a free-response format for information recall. It features Alikhan and Hocker’s Review of Dermatology,⁴ which is a high-yield review of clinical dermatology, dermatopathology, surgical dermatology, pharmacology, and histopathology for dermatology residents.
• Disadvantages: The deck is still currently in a development phase, covering 75% of Alikhan and Hocker’s Review of Dermatology⁴ with plans to add the remaining 25%. The add-on to access the most up-to-date version of the flashcards requires a paid monthly or annual subscription; however, the creator announced they will release periodic free updates of the deck.

Final Thoughts

As a collaborative platform, new flash card decks are always being added to Anki. This article is not comprehensive of all dermatologic flash card decks available. There are decks better suited for medical students covering topics such as the American Academy of Dermatology Basic Dermatology Curriculum, UWorld United States Medical Licensing Examination dermatology, and dermatology in internal medicine. Furthermore, specific study tools in dermatology may have their own accompanying Anki decks (ie, The Grenz Zone podcast, Dermnemonics). Flash cards can be a valuable study tool to trainees in medicine, and residents are immensely grateful to our peers who make them for our use.

Pigmented purpuric dermatoses (PPDs) are characterized by petechiae, dusky macules representative of postinflammatory hyperpigmentation and dermal hemosiderin, and purpura generally localized to the lower extremities. They typically represent a spectrum of lymphocytic capillaritis, variable erythrocyte extravasation from papillary dermal blood vessels, and deposition of hemosiderin, yielding the classic red to orange to golden-brown findings on gross examination. Clinical overlap exists, but variants include Schamberg disease (SD), Majocchi purpura, Gougerot-Blum purpura, eczematoid purpura of Doucas and Kapetanakis (DK), and lichen aureus.¹ Other forms are rarer, including linear, granulomatous, quadrantic, transitory, and familial variants. It remains controversial whether PPD may precede or have an association with cutaneous T-cell lymphoma.² Dermoscopy usually shows copper-red pigmentation in the background, oval red dots, linear vessels, brown globules, and follicular openings. Although these findings may be useful in PPD diagnosis, they are not applicable in differentiating among the variants.

Pigmented purpuric dermatoses can easily be mistaken for stasis dermatitis or cellulitis, as these may occur concomitantly or in populations at risk for all 3 conditions, such as women older than 50 years with recent trauma or infection in the affected area. Tissue biopsy and clinical laboratory evaluation may be required to differentiate between PPD from leukocytoclastic vasculitis or the myriad causes of retiform purpura. Importantly, clinicians also should differentiate PPD from the purpuric eruptions of the lower extremities associated with COVID-19 infection.

Pigmented Purpuric Dermatoses

Schamberg Disease—In 1901, Jay Frank Schamberg, a distinguished professor of dermatology in Philadelphia, Pennsylvania, described “a peculiar progressive pigmentary disease of the skin” in a 15-year-old adolescent boy.³ Schamberg disease is the most common PPD, characterized by pruritic spots resembling cayenne pepper (Figure 1) with orange-brown pigmented macules on the legs and feet.⁴ Although platelet dysfunction, coagulation deficiencies, or dermal atrophy may contribute to hemorrhaging that manifests as petechiae or ecchymoses, SD typically is not associated with any laboratory abnormalities, and petechial eruption is not widespread.⁵ Capillary fragility can be assessed by the tourniquet test, in which pressure is applied to the forearm with a blood pressure cuff inflated between systolic and diastolic blood pressure for 5 to 10 minutes. Upon removing the cuff, a positive test is indicated by 15 or more petechiae in an area 5 cm in diameter due to poor platelet function. A positive result may be seen in SD.⁶

Histologically, SD is characterized by patchy parakeratosis, mild spongiosis of the stratum Malpighi, and lymphoid capillaritis (Figure 2).⁷ In addition to CD3⁺, CD4⁺, CD8⁺, CD1a⁺, and CD36⁺ lymphocytes, histology also may contain dendritic cells and cellular adhesion molecules (intercellular adhesion molecule 1, epithelial cell adhesion molecule 1) within the superficial perivascular infiltrate.⁸ There is no definitive therapy, but first-line interventions include emollients, topical steroids, and oral antihistamines. Nonpharmacologic management includes compression or support stockings, elevation of the lower extremities, and avoidance of offending medications (if identifiable).¹

Majocchi Purpura—Domenico Majocchi was a renowned Italian dermatologist who described an entity in 1898 that he called purpura annularis telangiectodes, now also known as Majocchi purpura.⁹ It is more common in females, young adults, and children. Majocchi purpura has rarely been reported in families with a possible autosomal-dominant inheritance.¹⁰ Typically, bluish-red annular macules with central atrophy surrounded by hyperpigmentation may be seen on the lower extremities, potentially extending to the upper extremities.¹ Treatment of Majocchi purpura remains a challenge but may respond to narrowband UVB phototherapy. Emollients and topical steroids also are used as first-line treatments. Biopsy demonstrates telangiectasia, pericapillary infiltration of mononuclear lymphocytes, and papillary dermal hemosiderin.¹¹

Gougerot-Blum Purpura—In 1925, French dermatologists Henri Gougerot and Paul Blum described a pigmented purpuric lichenoid dermatitis known as Gougerot-Blum purpura,¹² a rare PPD characterized by lichenoid papules that eventually coalesce into plaques of various colors, along with red-brown hyperpigmentation.⁴ As with other PPD variants, the legs are most involved, with rare extension to the trunk or thighs. The plaques may resemble and be mistaken for Kaposi sarcoma, cutaneous vasculitis, traumatic purpura, or mycosis fungoides. Dermoscopic examination reveals small, polygonal or round, red dots underlying brown scaly patches.¹³ Gougerot-Blum purpura is found more commonly in adult men and rarely affects children.⁴ Histologically, a lichenoid and superficial perivascular infiltrate composed of lymphocytes and macrophages is seen. Various therapies have been described, including topical steroids, antihistamines, psoralen plus UVA phototherapy, and cyclosporin A.¹⁴

Eczematoid Purpura of Doucas and Kapetanakis—In 1949, Greek dermatologists Christopher Doucas and John Kapetanakis observed several cases of purpuric dermatosis similar in form to the “pigmented purpuric lichenoid dermatitis” of Gougerot-Blum purpura¹² and to the “progressive pigmentary dermatitis” of Schamberg disease.³ After observing a gradual disappearance of the classic yellow color from hemosiderin deposition, Doucas and Kapetanakis described a new bright red eruption with lichenification.¹⁵ Eczematoid purpura of Doucas and Kapetanakis is rare and predominantly seen in middle-aged males. Hyperpigmented or dark brown macules may develop bilaterally on the legs, progressing to the thighs and upper extremities. Unlike the other types of PPD, DK is extensive and severely pruritic.⁴

Although most PPD can be drug induced, DK has shown the greatest tendency for pruritic erythematous plaques following drug usage including but not limited to amlodipine, aspirin, acetaminophen, thiamine, interferon alfa, chlordiazepoxide, and isotretinoin. Additionally, DK has been associated with a contact allergy to clothing dyes and rubber.⁴ On histology, epidermal spongiosis may be seen, correlating with the eczematoid clinical findings. Spontaneous remission also is more common compared to the other PPDs. Treatment consists of topical corticosteroids and antihistamines.¹⁶

Lichen Aureus—Lichen aureus was first observed by the dermatologist R.H. Martin in 1958.¹⁷ It is clinically characterized by closely aggregated purpuric papules with a distinctive golden-brown color more often localized to the lower extremities and sometimes in a dermatomal distribution. Lichen aureus affects males and females equally, and similar to Majocchi purpura can be seen in children.⁴ Histopathologic examination reveals a prominent lichenoid plus superficial and deep perivascular lymphocytic infiltrate, extravasated erythrocytes, papillary dermal edema, hemosiderophages, and an unaffected epidermis. In rare cases, perineural infiltrates may be seen. Topical steroids usually are ineffective in lichen aureus treatment, but responses to psoralen plus UVA therapy also have been noted.¹⁷

Differential Diagnosis

COVID-19–Related Cutaneous Changes—Because COVID-19–related pathology is now a common differential diagnosis for many cutaneous eruptions,one must be mindful of the possibility for patients to have PPD, cutaneous changes from underlying COVID-19, or both.¹⁸ The microvascular changes from COVID-19 infection can be variable.¹⁹ Besides the presence of erythema along a distal digit, manifestations can include reticulated dusky erythema mimicking livedoid vasculopathy or inflammatory purpura.¹⁹

Retiform Purpura—Retiform purpura may occur in the setting of microvascular occlusion and can represent the pattern of underlying dermal vasculature. It is nonblanching and typically stellate or branching.²⁰ The microvascular occlusion may be a result of hypercoagulability or may be secondary to cutaneous vasculitis, resulting in thrombosis and subsequent vascular occlusion.²¹ There are many reasons for hypercoagulability in retiform purpura, including disseminated intravascular coagulation in the setting of COVID-19 infection.²² The treatment of retiform purpura is aimed at alleviating the underlying cause and providing symptomatic relief. Conversely, the PPDs generally are benign and require minimal workup.

Leukocytoclastic Vasculitis—The hallmark of leukocytoclastic vasculitis is palpable purpura, often appearing as nonblanchable papules, typically in a dependent distribution such as the lower extremities (Figure 3). Although it primarily affects children, Henoch-Schönlein purpura is a type of leukocytoclastic vasculitis with lesions potentially similar in appearance to those of PPD.²³ Palpable purpura may be painful and may ulcerate but rarely is pruritic. Leukocytoclastic vasculitis represents perivascular infiltrates composed of neutrophils, lymphocytes, and occasionally eosinophils, along with karyorrhexis, luminal fibrin, and fibrinoid degeneration of blood vessel walls, often resulting from immune complex deposition. Leukocytoclastic vasculitis may affect blood vessels of any size and requires further clinical and laboratory evaluation for infection (including COVID-19), hypercoagulability, autoimmune disease, or medication-related reactions.²⁴

Stasis Dermatitis—Stasis dermatitis, a chronic inflammatory condition stemming from retrograde venous flow due to incompetent venous valves, mimics PPD. Stasis dermatitis initially appears as demarcated erythematous plaques, fissures, and scaling of the lower legs bilaterally, usually involving the medial malleolus.²⁵ With time, the affected region develops overlying brawny hyperpigmentation and fibrosis (Figure 4). Pruritus or pain are common features, while fissures and superficial erosions may heal and recur, leading to lichenification.

Although both commonly appear on the lower extremities, duplex ultrasonography may be helpful to distinguish PPDs from stasis dermatitis since the latter occurs in the context of chronic venous insufficiency, varicose veins, soft tissue edema, and lymphedema.²⁵ Additionally, pruritus, lichenification, and edema often are not seen in most PPD variants, although stasis dermatitis and PPD may occur in tandem. Conservative treatment involves elevation of the extremities, compression, and topical steroids for symptomatic relief.

Cellulitis—The key characteristics of cellulitis are redness, swelling, warmth, tenderness, fever, and leukocytosis. A history of trauma, such as a prior break in the skin, and pain in the affected area suggest cellulitis. Several skin conditions present similarly to cellulitis, including PPD, and thus approximately 30% of cases are misdiagnosed.²⁶ Cellulitis rarely presents in a bilateral or diffusely scattered pattern as seen in PPDs. Rather, it is unilateral with smooth indistinct borders. Variables suggestive of cellulitis include immunosuppression, rapid progression, and previous occurrences. Hyperpigmented plaques or thickening of the skin are more indicative of a chronic process such as stasis dermatitis or lipodermatosclerosis rather than acute cellulitis. Purpura is not a typical finding in most cases of soft tissue cellulitis. Treatment may be case specific depending on severity, presence or absence of sepsis, findings on blood cultures, or other pathologic evaluation. Antibiotics are directed to the causative organism, typically Streptococcus and Staphylococcus species, although coverage against various gram-negative organisms may be indicated.²⁷

Caution With Teledermatology

COVID-19 has established the value of telemedicine in providing access to health care services for at-risk or underserved individuals. The PPDs are benign, often asymptomatic, and potentially identifiable with teledermatology alone; however, they also can easily be mistaken for COVID-19–related eruptions, vasculitis, other types of purpura, stasis dermatitis, or other complications of lower extremity stasis and lymphedema, especially in an aging population. If tissue biopsy is required, as in the workup of vasculitis, the efficacy of telemedicine becomes more questionable. It is important to delineate the potentially confusing PPDs from other potentially dangerous or life-threatening inflammatory dermatoses.²⁸

Pigmented purpuric dermatoses (PPDs) are characterized by petechiae, dusky macules representative of postinflammatory hyperpigmentation and dermal hemosiderin, and purpura generally localized to the lower extremities. They typically represent a spectrum of lymphocytic capillaritis, variable erythrocyte extravasation from papillary dermal blood vessels, and deposition of hemosiderin, yielding the classic red to orange to golden-brown findings on gross examination. Clinical overlap exists, but variants include Schamberg disease (SD), Majocchi purpura, Gougerot-Blum purpura, eczematoid purpura of Doucas and Kapetanakis (DK), and lichen aureus.¹ Other forms are rarer, including linear, granulomatous, quadrantic, transitory, and familial variants. It remains controversial whether PPD may precede or have an association with cutaneous T-cell lymphoma.² Dermoscopy usually shows copper-red pigmentation in the background, oval red dots, linear vessels, brown globules, and follicular openings. Although these findings may be useful in PPD diagnosis, they are not applicable in differentiating among the variants.

Pigmented purpuric dermatoses can easily be mistaken for stasis dermatitis or cellulitis, as these may occur concomitantly or in populations at risk for all 3 conditions, such as women older than 50 years with recent trauma or infection in the affected area. Tissue biopsy and clinical laboratory evaluation may be required to differentiate between PPD from leukocytoclastic vasculitis or the myriad causes of retiform purpura. Importantly, clinicians also should differentiate PPD from the purpuric eruptions of the lower extremities associated with COVID-19 infection.

Pigmented Purpuric Dermatoses

Schamberg Disease—In 1901, Jay Frank Schamberg, a distinguished professor of dermatology in Philadelphia, Pennsylvania, described “a peculiar progressive pigmentary disease of the skin” in a 15-year-old adolescent boy.³ Schamberg disease is the most common PPD, characterized by pruritic spots resembling cayenne pepper (Figure 1) with orange-brown pigmented macules on the legs and feet.⁴ Although platelet dysfunction, coagulation deficiencies, or dermal atrophy may contribute to hemorrhaging that manifests as petechiae or ecchymoses, SD typically is not associated with any laboratory abnormalities, and petechial eruption is not widespread.⁵ Capillary fragility can be assessed by the tourniquet test, in which pressure is applied to the forearm with a blood pressure cuff inflated between systolic and diastolic blood pressure for 5 to 10 minutes. Upon removing the cuff, a positive test is indicated by 15 or more petechiae in an area 5 cm in diameter due to poor platelet function. A positive result may be seen in SD.⁶

Histologically, SD is characterized by patchy parakeratosis, mild spongiosis of the stratum Malpighi, and lymphoid capillaritis (Figure 2).⁷ In addition to CD3⁺, CD4⁺, CD8⁺, CD1a⁺, and CD36⁺ lymphocytes, histology also may contain dendritic cells and cellular adhesion molecules (intercellular adhesion molecule 1, epithelial cell adhesion molecule 1) within the superficial perivascular infiltrate.⁸ There is no definitive therapy, but first-line interventions include emollients, topical steroids, and oral antihistamines. Nonpharmacologic management includes compression or support stockings, elevation of the lower extremities, and avoidance of offending medications (if identifiable).¹

Majocchi Purpura—Domenico Majocchi was a renowned Italian dermatologist who described an entity in 1898 that he called purpura annularis telangiectodes, now also known as Majocchi purpura.⁹ It is more common in females, young adults, and children. Majocchi purpura has rarely been reported in families with a possible autosomal-dominant inheritance.¹⁰ Typically, bluish-red annular macules with central atrophy surrounded by hyperpigmentation may be seen on the lower extremities, potentially extending to the upper extremities.¹ Treatment of Majocchi purpura remains a challenge but may respond to narrowband UVB phototherapy. Emollients and topical steroids also are used as first-line treatments. Biopsy demonstrates telangiectasia, pericapillary infiltration of mononuclear lymphocytes, and papillary dermal hemosiderin.¹¹

Gougerot-Blum Purpura—In 1925, French dermatologists Henri Gougerot and Paul Blum described a pigmented purpuric lichenoid dermatitis known as Gougerot-Blum purpura,¹² a rare PPD characterized by lichenoid papules that eventually coalesce into plaques of various colors, along with red-brown hyperpigmentation.⁴ As with other PPD variants, the legs are most involved, with rare extension to the trunk or thighs. The plaques may resemble and be mistaken for Kaposi sarcoma, cutaneous vasculitis, traumatic purpura, or mycosis fungoides. Dermoscopic examination reveals small, polygonal or round, red dots underlying brown scaly patches.¹³ Gougerot-Blum purpura is found more commonly in adult men and rarely affects children.⁴ Histologically, a lichenoid and superficial perivascular infiltrate composed of lymphocytes and macrophages is seen. Various therapies have been described, including topical steroids, antihistamines, psoralen plus UVA phototherapy, and cyclosporin A.¹⁴

Eczematoid Purpura of Doucas and Kapetanakis—In 1949, Greek dermatologists Christopher Doucas and John Kapetanakis observed several cases of purpuric dermatosis similar in form to the “pigmented purpuric lichenoid dermatitis” of Gougerot-Blum purpura¹² and to the “progressive pigmentary dermatitis” of Schamberg disease.³ After observing a gradual disappearance of the classic yellow color from hemosiderin deposition, Doucas and Kapetanakis described a new bright red eruption with lichenification.¹⁵ Eczematoid purpura of Doucas and Kapetanakis is rare and predominantly seen in middle-aged males. Hyperpigmented or dark brown macules may develop bilaterally on the legs, progressing to the thighs and upper extremities. Unlike the other types of PPD, DK is extensive and severely pruritic.⁴

Although most PPD can be drug induced, DK has shown the greatest tendency for pruritic erythematous plaques following drug usage including but not limited to amlodipine, aspirin, acetaminophen, thiamine, interferon alfa, chlordiazepoxide, and isotretinoin. Additionally, DK has been associated with a contact allergy to clothing dyes and rubber.⁴ On histology, epidermal spongiosis may be seen, correlating with the eczematoid clinical findings. Spontaneous remission also is more common compared to the other PPDs. Treatment consists of topical corticosteroids and antihistamines.¹⁶

Lichen Aureus—Lichen aureus was first observed by the dermatologist R.H. Martin in 1958.¹⁷ It is clinically characterized by closely aggregated purpuric papules with a distinctive golden-brown color more often localized to the lower extremities and sometimes in a dermatomal distribution. Lichen aureus affects males and females equally, and similar to Majocchi purpura can be seen in children.⁴ Histopathologic examination reveals a prominent lichenoid plus superficial and deep perivascular lymphocytic infiltrate, extravasated erythrocytes, papillary dermal edema, hemosiderophages, and an unaffected epidermis. In rare cases, perineural infiltrates may be seen. Topical steroids usually are ineffective in lichen aureus treatment, but responses to psoralen plus UVA therapy also have been noted.¹⁷

Differential Diagnosis

COVID-19–Related Cutaneous Changes—Because COVID-19–related pathology is now a common differential diagnosis for many cutaneous eruptions,one must be mindful of the possibility for patients to have PPD, cutaneous changes from underlying COVID-19, or both.¹⁸ The microvascular changes from COVID-19 infection can be variable.¹⁹ Besides the presence of erythema along a distal digit, manifestations can include reticulated dusky erythema mimicking livedoid vasculopathy or inflammatory purpura.¹⁹

Retiform Purpura—Retiform purpura may occur in the setting of microvascular occlusion and can represent the pattern of underlying dermal vasculature. It is nonblanching and typically stellate or branching.²⁰ The microvascular occlusion may be a result of hypercoagulability or may be secondary to cutaneous vasculitis, resulting in thrombosis and subsequent vascular occlusion.²¹ There are many reasons for hypercoagulability in retiform purpura, including disseminated intravascular coagulation in the setting of COVID-19 infection.²² The treatment of retiform purpura is aimed at alleviating the underlying cause and providing symptomatic relief. Conversely, the PPDs generally are benign and require minimal workup.

Leukocytoclastic Vasculitis—The hallmark of leukocytoclastic vasculitis is palpable purpura, often appearing as nonblanchable papules, typically in a dependent distribution such as the lower extremities (Figure 3). Although it primarily affects children, Henoch-Schönlein purpura is a type of leukocytoclastic vasculitis with lesions potentially similar in appearance to those of PPD.²³ Palpable purpura may be painful and may ulcerate but rarely is pruritic. Leukocytoclastic vasculitis represents perivascular infiltrates composed of neutrophils, lymphocytes, and occasionally eosinophils, along with karyorrhexis, luminal fibrin, and fibrinoid degeneration of blood vessel walls, often resulting from immune complex deposition. Leukocytoclastic vasculitis may affect blood vessels of any size and requires further clinical and laboratory evaluation for infection (including COVID-19), hypercoagulability, autoimmune disease, or medication-related reactions.²⁴

Stasis Dermatitis—Stasis dermatitis, a chronic inflammatory condition stemming from retrograde venous flow due to incompetent venous valves, mimics PPD. Stasis dermatitis initially appears as demarcated erythematous plaques, fissures, and scaling of the lower legs bilaterally, usually involving the medial malleolus.²⁵ With time, the affected region develops overlying brawny hyperpigmentation and fibrosis (Figure 4). Pruritus or pain are common features, while fissures and superficial erosions may heal and recur, leading to lichenification.

Although both commonly appear on the lower extremities, duplex ultrasonography may be helpful to distinguish PPDs from stasis dermatitis since the latter occurs in the context of chronic venous insufficiency, varicose veins, soft tissue edema, and lymphedema.²⁵ Additionally, pruritus, lichenification, and edema often are not seen in most PPD variants, although stasis dermatitis and PPD may occur in tandem. Conservative treatment involves elevation of the extremities, compression, and topical steroids for symptomatic relief.

Cellulitis—The key characteristics of cellulitis are redness, swelling, warmth, tenderness, fever, and leukocytosis. A history of trauma, such as a prior break in the skin, and pain in the affected area suggest cellulitis. Several skin conditions present similarly to cellulitis, including PPD, and thus approximately 30% of cases are misdiagnosed.²⁶ Cellulitis rarely presents in a bilateral or diffusely scattered pattern as seen in PPDs. Rather, it is unilateral with smooth indistinct borders. Variables suggestive of cellulitis include immunosuppression, rapid progression, and previous occurrences. Hyperpigmented plaques or thickening of the skin are more indicative of a chronic process such as stasis dermatitis or lipodermatosclerosis rather than acute cellulitis. Purpura is not a typical finding in most cases of soft tissue cellulitis. Treatment may be case specific depending on severity, presence or absence of sepsis, findings on blood cultures, or other pathologic evaluation. Antibiotics are directed to the causative organism, typically Streptococcus and Staphylococcus species, although coverage against various gram-negative organisms may be indicated.²⁷

Caution With Teledermatology

COVID-19 has established the value of telemedicine in providing access to health care services for at-risk or underserved individuals. The PPDs are benign, often asymptomatic, and potentially identifiable with teledermatology alone; however, they also can easily be mistaken for COVID-19–related eruptions, vasculitis, other types of purpura, stasis dermatitis, or other complications of lower extremity stasis and lymphedema, especially in an aging population. If tissue biopsy is required, as in the workup of vasculitis, the efficacy of telemedicine becomes more questionable. It is important to delineate the potentially confusing PPDs from other potentially dangerous or life-threatening inflammatory dermatoses.²⁸

Pigmented purpuric dermatoses (PPDs) are characterized by petechiae, dusky macules representative of postinflammatory hyperpigmentation and dermal hemosiderin, and purpura generally localized to the lower extremities. They typically represent a spectrum of lymphocytic capillaritis, variable erythrocyte extravasation from papillary dermal blood vessels, and deposition of hemosiderin, yielding the classic red to orange to golden-brown findings on gross examination. Clinical overlap exists, but variants include Schamberg disease (SD), Majocchi purpura, Gougerot-Blum purpura, eczematoid purpura of Doucas and Kapetanakis (DK), and lichen aureus.¹ Other forms are rarer, including linear, granulomatous, quadrantic, transitory, and familial variants. It remains controversial whether PPD may precede or have an association with cutaneous T-cell lymphoma.² Dermoscopy usually shows copper-red pigmentation in the background, oval red dots, linear vessels, brown globules, and follicular openings. Although these findings may be useful in PPD diagnosis, they are not applicable in differentiating among the variants.

Pigmented purpuric dermatoses can easily be mistaken for stasis dermatitis or cellulitis, as these may occur concomitantly or in populations at risk for all 3 conditions, such as women older than 50 years with recent trauma or infection in the affected area. Tissue biopsy and clinical laboratory evaluation may be required to differentiate between PPD from leukocytoclastic vasculitis or the myriad causes of retiform purpura. Importantly, clinicians also should differentiate PPD from the purpuric eruptions of the lower extremities associated with COVID-19 infection.

Pigmented Purpuric Dermatoses

Schamberg Disease—In 1901, Jay Frank Schamberg, a distinguished professor of dermatology in Philadelphia, Pennsylvania, described “a peculiar progressive pigmentary disease of the skin” in a 15-year-old adolescent boy.³ Schamberg disease is the most common PPD, characterized by pruritic spots resembling cayenne pepper (Figure 1) with orange-brown pigmented macules on the legs and feet.⁴ Although platelet dysfunction, coagulation deficiencies, or dermal atrophy may contribute to hemorrhaging that manifests as petechiae or ecchymoses, SD typically is not associated with any laboratory abnormalities, and petechial eruption is not widespread.⁵ Capillary fragility can be assessed by the tourniquet test, in which pressure is applied to the forearm with a blood pressure cuff inflated between systolic and diastolic blood pressure for 5 to 10 minutes. Upon removing the cuff, a positive test is indicated by 15 or more petechiae in an area 5 cm in diameter due to poor platelet function. A positive result may be seen in SD.⁶

Histologically, SD is characterized by patchy parakeratosis, mild spongiosis of the stratum Malpighi, and lymphoid capillaritis (Figure 2).⁷ In addition to CD3⁺, CD4⁺, CD8⁺, CD1a⁺, and CD36⁺ lymphocytes, histology also may contain dendritic cells and cellular adhesion molecules (intercellular adhesion molecule 1, epithelial cell adhesion molecule 1) within the superficial perivascular infiltrate.⁸ There is no definitive therapy, but first-line interventions include emollients, topical steroids, and oral antihistamines. Nonpharmacologic management includes compression or support stockings, elevation of the lower extremities, and avoidance of offending medications (if identifiable).¹

Majocchi Purpura—Domenico Majocchi was a renowned Italian dermatologist who described an entity in 1898 that he called purpura annularis telangiectodes, now also known as Majocchi purpura.⁹ It is more common in females, young adults, and children. Majocchi purpura has rarely been reported in families with a possible autosomal-dominant inheritance.¹⁰ Typically, bluish-red annular macules with central atrophy surrounded by hyperpigmentation may be seen on the lower extremities, potentially extending to the upper extremities.¹ Treatment of Majocchi purpura remains a challenge but may respond to narrowband UVB phototherapy. Emollients and topical steroids also are used as first-line treatments. Biopsy demonstrates telangiectasia, pericapillary infiltration of mononuclear lymphocytes, and papillary dermal hemosiderin.¹¹

Gougerot-Blum Purpura—In 1925, French dermatologists Henri Gougerot and Paul Blum described a pigmented purpuric lichenoid dermatitis known as Gougerot-Blum purpura,¹² a rare PPD characterized by lichenoid papules that eventually coalesce into plaques of various colors, along with red-brown hyperpigmentation.⁴ As with other PPD variants, the legs are most involved, with rare extension to the trunk or thighs. The plaques may resemble and be mistaken for Kaposi sarcoma, cutaneous vasculitis, traumatic purpura, or mycosis fungoides. Dermoscopic examination reveals small, polygonal or round, red dots underlying brown scaly patches.¹³ Gougerot-Blum purpura is found more commonly in adult men and rarely affects children.⁴ Histologically, a lichenoid and superficial perivascular infiltrate composed of lymphocytes and macrophages is seen. Various therapies have been described, including topical steroids, antihistamines, psoralen plus UVA phototherapy, and cyclosporin A.¹⁴

Eczematoid Purpura of Doucas and Kapetanakis—In 1949, Greek dermatologists Christopher Doucas and John Kapetanakis observed several cases of purpuric dermatosis similar in form to the “pigmented purpuric lichenoid dermatitis” of Gougerot-Blum purpura¹² and to the “progressive pigmentary dermatitis” of Schamberg disease.³ After observing a gradual disappearance of the classic yellow color from hemosiderin deposition, Doucas and Kapetanakis described a new bright red eruption with lichenification.¹⁵ Eczematoid purpura of Doucas and Kapetanakis is rare and predominantly seen in middle-aged males. Hyperpigmented or dark brown macules may develop bilaterally on the legs, progressing to the thighs and upper extremities. Unlike the other types of PPD, DK is extensive and severely pruritic.⁴

Although most PPD can be drug induced, DK has shown the greatest tendency for pruritic erythematous plaques following drug usage including but not limited to amlodipine, aspirin, acetaminophen, thiamine, interferon alfa, chlordiazepoxide, and isotretinoin. Additionally, DK has been associated with a contact allergy to clothing dyes and rubber.⁴ On histology, epidermal spongiosis may be seen, correlating with the eczematoid clinical findings. Spontaneous remission also is more common compared to the other PPDs. Treatment consists of topical corticosteroids and antihistamines.¹⁶

Lichen Aureus—Lichen aureus was first observed by the dermatologist R.H. Martin in 1958.¹⁷ It is clinically characterized by closely aggregated purpuric papules with a distinctive golden-brown color more often localized to the lower extremities and sometimes in a dermatomal distribution. Lichen aureus affects males and females equally, and similar to Majocchi purpura can be seen in children.⁴ Histopathologic examination reveals a prominent lichenoid plus superficial and deep perivascular lymphocytic infiltrate, extravasated erythrocytes, papillary dermal edema, hemosiderophages, and an unaffected epidermis. In rare cases, perineural infiltrates may be seen. Topical steroids usually are ineffective in lichen aureus treatment, but responses to psoralen plus UVA therapy also have been noted.¹⁷

Differential Diagnosis

COVID-19–Related Cutaneous Changes—Because COVID-19–related pathology is now a common differential diagnosis for many cutaneous eruptions,one must be mindful of the possibility for patients to have PPD, cutaneous changes from underlying COVID-19, or both.¹⁸ The microvascular changes from COVID-19 infection can be variable.¹⁹ Besides the presence of erythema along a distal digit, manifestations can include reticulated dusky erythema mimicking livedoid vasculopathy or inflammatory purpura.¹⁹

Retiform Purpura—Retiform purpura may occur in the setting of microvascular occlusion and can represent the pattern of underlying dermal vasculature. It is nonblanching and typically stellate or branching.²⁰ The microvascular occlusion may be a result of hypercoagulability or may be secondary to cutaneous vasculitis, resulting in thrombosis and subsequent vascular occlusion.²¹ There are many reasons for hypercoagulability in retiform purpura, including disseminated intravascular coagulation in the setting of COVID-19 infection.²² The treatment of retiform purpura is aimed at alleviating the underlying cause and providing symptomatic relief. Conversely, the PPDs generally are benign and require minimal workup.

Leukocytoclastic Vasculitis—The hallmark of leukocytoclastic vasculitis is palpable purpura, often appearing as nonblanchable papules, typically in a dependent distribution such as the lower extremities (Figure 3). Although it primarily affects children, Henoch-Schönlein purpura is a type of leukocytoclastic vasculitis with lesions potentially similar in appearance to those of PPD.²³ Palpable purpura may be painful and may ulcerate but rarely is pruritic. Leukocytoclastic vasculitis represents perivascular infiltrates composed of neutrophils, lymphocytes, and occasionally eosinophils, along with karyorrhexis, luminal fibrin, and fibrinoid degeneration of blood vessel walls, often resulting from immune complex deposition. Leukocytoclastic vasculitis may affect blood vessels of any size and requires further clinical and laboratory evaluation for infection (including COVID-19), hypercoagulability, autoimmune disease, or medication-related reactions.²⁴

Stasis Dermatitis—Stasis dermatitis, a chronic inflammatory condition stemming from retrograde venous flow due to incompetent venous valves, mimics PPD. Stasis dermatitis initially appears as demarcated erythematous plaques, fissures, and scaling of the lower legs bilaterally, usually involving the medial malleolus.²⁵ With time, the affected region develops overlying brawny hyperpigmentation and fibrosis (Figure 4). Pruritus or pain are common features, while fissures and superficial erosions may heal and recur, leading to lichenification.

Although both commonly appear on the lower extremities, duplex ultrasonography may be helpful to distinguish PPDs from stasis dermatitis since the latter occurs in the context of chronic venous insufficiency, varicose veins, soft tissue edema, and lymphedema.²⁵ Additionally, pruritus, lichenification, and edema often are not seen in most PPD variants, although stasis dermatitis and PPD may occur in tandem. Conservative treatment involves elevation of the extremities, compression, and topical steroids for symptomatic relief.

Cellulitis—The key characteristics of cellulitis are redness, swelling, warmth, tenderness, fever, and leukocytosis. A history of trauma, such as a prior break in the skin, and pain in the affected area suggest cellulitis. Several skin conditions present similarly to cellulitis, including PPD, and thus approximately 30% of cases are misdiagnosed.²⁶ Cellulitis rarely presents in a bilateral or diffusely scattered pattern as seen in PPDs. Rather, it is unilateral with smooth indistinct borders. Variables suggestive of cellulitis include immunosuppression, rapid progression, and previous occurrences. Hyperpigmented plaques or thickening of the skin are more indicative of a chronic process such as stasis dermatitis or lipodermatosclerosis rather than acute cellulitis. Purpura is not a typical finding in most cases of soft tissue cellulitis. Treatment may be case specific depending on severity, presence or absence of sepsis, findings on blood cultures, or other pathologic evaluation. Antibiotics are directed to the causative organism, typically Streptococcus and Staphylococcus species, although coverage against various gram-negative organisms may be indicated.²⁷

Caution With Teledermatology

COVID-19 has established the value of telemedicine in providing access to health care services for at-risk or underserved individuals. The PPDs are benign, often asymptomatic, and potentially identifiable with teledermatology alone; however, they also can easily be mistaken for COVID-19–related eruptions, vasculitis, other types of purpura, stasis dermatitis, or other complications of lower extremity stasis and lymphedema, especially in an aging population. If tissue biopsy is required, as in the workup of vasculitis, the efficacy of telemedicine becomes more questionable. It is important to delineate the potentially confusing PPDs from other potentially dangerous or life-threatening inflammatory dermatoses.²⁸

To the Editor:

Herpes vegetans (HV) is an uncommon infection caused by human herpesvirus (HHV) in patients who are immunocompromised, such as those who are HIV positive.¹ Unlike typical HHV infection, HV can present with exophytic exudative ulcers and papillomatous vegetations. The presentation of ulcerated genital nodules, especially in an immunocompromised patient, yields an array of disorders in the differential diagnosis, including condyloma latum, condyloma acuminatum, pyogenic granuloma (PG), and verrucous carcinoma.^2,3 Histopathology of HV reveals pseudoepitheliomatous hyperplasia, plasma cell infiltration, and positivity for HHV type 1 (HHV-1) and/or HHV type 2 (HHV-2). Herpes vegetans lesions typically require a multimodal treatment approach because many cases are resistant to acyclovir. Treatment options include the nucleoside analogues foscarnet and cidofovir; immunomodulators such as topical imiquimod; and the topical antiviral trifluridine.^1,4-6 We describe a case of HV in a patient with a history of well-controlled HIV infection who presented with a painful fungating penile lesion.

A 55-year-old man presented to the hospital with a painful expanding mass on the distal aspect of the penis of 3 months’ duration. He had a history of HIV infection that was well-controlled by antiretroviral therapy, prior hepatitis B virus infection and acyclovir-resistant genital HHV-2 infection. Physical examination revealed a large, firm, circumferential, exophytic, verrucous plaque with various areas of ulceration and purulent drainage on the distal shaft and glans of the penis (Figure 1). The patient’s most recent absolute CD4 count was 425 cells/mm³ (reference range, 500–1500 cells/mm³). His HIV viral load was undetectable at less than 30 copies/mL. Histopathology with hematoxylin and eosin staining of biopsy material from the penile lesion demonstrated pseudoepitheliomatous epidermal hyperplasia with focal ulceration and a mixed inflammatory infiltrate (Figure 2A). At higher magnification, clear viral cytopathic changes of HHV were noted, including multinucleation, nuclear molding, and homogenous gray nuclei (Figure 2B). Additional staining for fungi, mycobacteria, and spirochetes was negative. In-situ hybridization was negative for human papillomavirus subtypes. A bacterial culture of swabs of the purulent drainage was positive for Staphylococcus aureus and Proteus mirabilis.

Given the patient’s known history of acyclovir-resistant HHV-2 infection, he received a 28-day course of intravenous foscarnet 40 mg/kg every 12 hours. He also was given a 14-day course of intravenous ampicillin-sulbactam 3 g every 6 hours. The patient gradually improved during a 35-day hospital stay. He was discharged with cidofovir cream 1% and oral valacyclovir; the latter was subsequently discontinued by dermatology because of his known history of acyclovir resistance. Four months after discharge, the patient underwent a circumcision performed by urology to decrease the risk for recurrence and achieve the best cosmetic outcome. At the 6-month follow-up visit, dramatic clinical improvement was evident, with complete resolution of the plaque and only isolated areas of scarring (Figure 3). The patient reported that penile function was preserved.

Herpes vegetans represents a rare infection with HHV-1 or HHV-2, typically in patients who are considerably immunosuppressed, such as those with cancer, those undergoing transplantation, and those with uncontrolled HIV infection.¹ Few cases of HV have been described in an immunocompetent patient.² Our case is unique because the patient’s HIV infection was well controlled at the time HV was diagnosed, demonstrated by his modestly low CD4 count and undetectable HIV viral load.

Patients with HV can present diagnostic and therapeutic challenges. Typically, a diagnosis of cutaneous HHV infection does not require a biopsy; most cases appear as clustered vesicular lesions, making the disease easy to diagnose clinically. However, biopsies and cultures are necessary to identify the underlying cause of atypical verrucous exophytic lesions. Other conditions with clinical features similar to HV include squamous cell carcinoma, condyloma acuminatum, and deep fungal and mycobacterial infections.^2,3 A tissue biopsy, histologic staining, and tissue culture should be performed to identify the causative pathogen and potential targets for treatment. Definitive diagnosis is vital to deliver proper treatment modalities, which often involve a multimodal multidisciplinary approach. 

Several pathogenic mechanisms of HV have been proposed. One theory suggests that in an immunocompetent patient, HHV typically triggers a lymphocytic response, which leads to activation of interferon alpha. However, in an immunocompromised patient, such as an individual with AIDS, this interferon response is diminished, which explains why these patients typically have a chronic and resistant HHV infection. HIV has an affinity for infecting dermal dendritic cells, which signals activation of tumor necrosis factor and interleukin.⁶ Both cytokines contribute to an antiapoptotic environment that promotes continued proliferation of these viral cells in the epidermis. Over time, propagation of disinhibited cells can lead to the verrucous and hyperkeratotic-appearing skin that is common in patients with HV.⁷

Another theorized mechanism underlying hypertrophic herpetic lesions was described in the context of HHV-1 infection and subsequent PG. El Hayderi et al⁸ reported that histologic and immunohistochemical examination of a patient’s lesion revealed sparse epithelial cell aggregates within PG as well as HHV-1 antigens in the nuclei and cytoplasm of normal-appearing and cytopathic epithelial cells. Immunohistochemical examination also revealed vascular endothelial growth factor within HHV-1–infected epithelial cells and PG endothelial cells, suggesting that PG formation may be indirectly driven by vascular endothelial growth factor and its proangiogenic properties. The pathogenesis of PG in the setting of HHV-1 infection displays many similarities to hyperkeratotic lesions observed in atypical cutaneous manifestations of HHV-2.⁸

The management of patients with HV continues to be complex, often requiring a multimodal regimen. Although acyclovir has been shown to be highly effective for treating and preventing most HHV infections, acyclovir resistance frequently has been reported in immunocompromised populations.⁵ Acyclovir resistance can be correlated with the severity of immunodeficiency as well as the duration of acyclovir exposure. Resistance to acyclovir often results from deficient intracellular phosphorylation, which is required for activation of the drug. If patients show resistance to acyclovir and its derivatives, alternate drug classes that do not depend on thymidine kinase phosphorylation should be considered.

Our patient received a combination of intravenous foscarnet and a course of ampicillin-sulbactam while an inpatient due to his documented history of acyclovir-resistant HHV-2 infection, and he was discharged on cidofovir cream 1%. Cidofovir is US Food and Drug Administration approved for treating cytomegalovirus retinitis in patients with AIDS. Although data are limited, topical and intralesional cidofovir have been used to treat acyclovir-resistant cases of HV with documented success.^1,9 In refractory HV or when the disease is slow to resolve, intralesional cidofovir has been documented to be an additional treatment option. Intralesional and topical cidofovir carry a much lower risk for adverse effects such as kidney dysfunction compared to intravenous cidofovir¹ and can be considered in patients with minimal clinical improvement and those at increased risk for side effects.

Our case demonstrated how a patient with HV may require a complex and prolonged hospital course for appropriate treatment. Our patient required an array of both medical and surgical modalities to reach the desired outcome. Here, a multitude of specialties including infectious disease, dermatology, and urology worked together to reach a positive clinical and cosmetic outcome for this patient. 

To the Editor:

Herpes vegetans (HV) is an uncommon infection caused by human herpesvirus (HHV) in patients who are immunocompromised, such as those who are HIV positive.¹ Unlike typical HHV infection, HV can present with exophytic exudative ulcers and papillomatous vegetations. The presentation of ulcerated genital nodules, especially in an immunocompromised patient, yields an array of disorders in the differential diagnosis, including condyloma latum, condyloma acuminatum, pyogenic granuloma (PG), and verrucous carcinoma.^2,3 Histopathology of HV reveals pseudoepitheliomatous hyperplasia, plasma cell infiltration, and positivity for HHV type 1 (HHV-1) and/or HHV type 2 (HHV-2). Herpes vegetans lesions typically require a multimodal treatment approach because many cases are resistant to acyclovir. Treatment options include the nucleoside analogues foscarnet and cidofovir; immunomodulators such as topical imiquimod; and the topical antiviral trifluridine.^1,4-6 We describe a case of HV in a patient with a history of well-controlled HIV infection who presented with a painful fungating penile lesion.

A 55-year-old man presented to the hospital with a painful expanding mass on the distal aspect of the penis of 3 months’ duration. He had a history of HIV infection that was well-controlled by antiretroviral therapy, prior hepatitis B virus infection and acyclovir-resistant genital HHV-2 infection. Physical examination revealed a large, firm, circumferential, exophytic, verrucous plaque with various areas of ulceration and purulent drainage on the distal shaft and glans of the penis (Figure 1). The patient’s most recent absolute CD4 count was 425 cells/mm³ (reference range, 500–1500 cells/mm³). His HIV viral load was undetectable at less than 30 copies/mL. Histopathology with hematoxylin and eosin staining of biopsy material from the penile lesion demonstrated pseudoepitheliomatous epidermal hyperplasia with focal ulceration and a mixed inflammatory infiltrate (Figure 2A). At higher magnification, clear viral cytopathic changes of HHV were noted, including multinucleation, nuclear molding, and homogenous gray nuclei (Figure 2B). Additional staining for fungi, mycobacteria, and spirochetes was negative. In-situ hybridization was negative for human papillomavirus subtypes. A bacterial culture of swabs of the purulent drainage was positive for Staphylococcus aureus and Proteus mirabilis.

Given the patient’s known history of acyclovir-resistant HHV-2 infection, he received a 28-day course of intravenous foscarnet 40 mg/kg every 12 hours. He also was given a 14-day course of intravenous ampicillin-sulbactam 3 g every 6 hours. The patient gradually improved during a 35-day hospital stay. He was discharged with cidofovir cream 1% and oral valacyclovir; the latter was subsequently discontinued by dermatology because of his known history of acyclovir resistance. Four months after discharge, the patient underwent a circumcision performed by urology to decrease the risk for recurrence and achieve the best cosmetic outcome. At the 6-month follow-up visit, dramatic clinical improvement was evident, with complete resolution of the plaque and only isolated areas of scarring (Figure 3). The patient reported that penile function was preserved.

Herpes vegetans represents a rare infection with HHV-1 or HHV-2, typically in patients who are considerably immunosuppressed, such as those with cancer, those undergoing transplantation, and those with uncontrolled HIV infection.¹ Few cases of HV have been described in an immunocompetent patient.² Our case is unique because the patient’s HIV infection was well controlled at the time HV was diagnosed, demonstrated by his modestly low CD4 count and undetectable HIV viral load.

Patients with HV can present diagnostic and therapeutic challenges. Typically, a diagnosis of cutaneous HHV infection does not require a biopsy; most cases appear as clustered vesicular lesions, making the disease easy to diagnose clinically. However, biopsies and cultures are necessary to identify the underlying cause of atypical verrucous exophytic lesions. Other conditions with clinical features similar to HV include squamous cell carcinoma, condyloma acuminatum, and deep fungal and mycobacterial infections.^2,3 A tissue biopsy, histologic staining, and tissue culture should be performed to identify the causative pathogen and potential targets for treatment. Definitive diagnosis is vital to deliver proper treatment modalities, which often involve a multimodal multidisciplinary approach. 

Several pathogenic mechanisms of HV have been proposed. One theory suggests that in an immunocompetent patient, HHV typically triggers a lymphocytic response, which leads to activation of interferon alpha. However, in an immunocompromised patient, such as an individual with AIDS, this interferon response is diminished, which explains why these patients typically have a chronic and resistant HHV infection. HIV has an affinity for infecting dermal dendritic cells, which signals activation of tumor necrosis factor and interleukin.⁶ Both cytokines contribute to an antiapoptotic environment that promotes continued proliferation of these viral cells in the epidermis. Over time, propagation of disinhibited cells can lead to the verrucous and hyperkeratotic-appearing skin that is common in patients with HV.⁷

Another theorized mechanism underlying hypertrophic herpetic lesions was described in the context of HHV-1 infection and subsequent PG. El Hayderi et al⁸ reported that histologic and immunohistochemical examination of a patient’s lesion revealed sparse epithelial cell aggregates within PG as well as HHV-1 antigens in the nuclei and cytoplasm of normal-appearing and cytopathic epithelial cells. Immunohistochemical examination also revealed vascular endothelial growth factor within HHV-1–infected epithelial cells and PG endothelial cells, suggesting that PG formation may be indirectly driven by vascular endothelial growth factor and its proangiogenic properties. The pathogenesis of PG in the setting of HHV-1 infection displays many similarities to hyperkeratotic lesions observed in atypical cutaneous manifestations of HHV-2.⁸

The management of patients with HV continues to be complex, often requiring a multimodal regimen. Although acyclovir has been shown to be highly effective for treating and preventing most HHV infections, acyclovir resistance frequently has been reported in immunocompromised populations.⁵ Acyclovir resistance can be correlated with the severity of immunodeficiency as well as the duration of acyclovir exposure. Resistance to acyclovir often results from deficient intracellular phosphorylation, which is required for activation of the drug. If patients show resistance to acyclovir and its derivatives, alternate drug classes that do not depend on thymidine kinase phosphorylation should be considered.

Our patient received a combination of intravenous foscarnet and a course of ampicillin-sulbactam while an inpatient due to his documented history of acyclovir-resistant HHV-2 infection, and he was discharged on cidofovir cream 1%. Cidofovir is US Food and Drug Administration approved for treating cytomegalovirus retinitis in patients with AIDS. Although data are limited, topical and intralesional cidofovir have been used to treat acyclovir-resistant cases of HV with documented success.^1,9 In refractory HV or when the disease is slow to resolve, intralesional cidofovir has been documented to be an additional treatment option. Intralesional and topical cidofovir carry a much lower risk for adverse effects such as kidney dysfunction compared to intravenous cidofovir¹ and can be considered in patients with minimal clinical improvement and those at increased risk for side effects.

Our case demonstrated how a patient with HV may require a complex and prolonged hospital course for appropriate treatment. Our patient required an array of both medical and surgical modalities to reach the desired outcome. Here, a multitude of specialties including infectious disease, dermatology, and urology worked together to reach a positive clinical and cosmetic outcome for this patient. 

To the Editor:

Herpes vegetans (HV) is an uncommon infection caused by human herpesvirus (HHV) in patients who are immunocompromised, such as those who are HIV positive.¹ Unlike typical HHV infection, HV can present with exophytic exudative ulcers and papillomatous vegetations. The presentation of ulcerated genital nodules, especially in an immunocompromised patient, yields an array of disorders in the differential diagnosis, including condyloma latum, condyloma acuminatum, pyogenic granuloma (PG), and verrucous carcinoma.^2,3 Histopathology of HV reveals pseudoepitheliomatous hyperplasia, plasma cell infiltration, and positivity for HHV type 1 (HHV-1) and/or HHV type 2 (HHV-2). Herpes vegetans lesions typically require a multimodal treatment approach because many cases are resistant to acyclovir. Treatment options include the nucleoside analogues foscarnet and cidofovir; immunomodulators such as topical imiquimod; and the topical antiviral trifluridine.^1,4-6 We describe a case of HV in a patient with a history of well-controlled HIV infection who presented with a painful fungating penile lesion.

A 55-year-old man presented to the hospital with a painful expanding mass on the distal aspect of the penis of 3 months’ duration. He had a history of HIV infection that was well-controlled by antiretroviral therapy, prior hepatitis B virus infection and acyclovir-resistant genital HHV-2 infection. Physical examination revealed a large, firm, circumferential, exophytic, verrucous plaque with various areas of ulceration and purulent drainage on the distal shaft and glans of the penis (Figure 1). The patient’s most recent absolute CD4 count was 425 cells/mm³ (reference range, 500–1500 cells/mm³). His HIV viral load was undetectable at less than 30 copies/mL. Histopathology with hematoxylin and eosin staining of biopsy material from the penile lesion demonstrated pseudoepitheliomatous epidermal hyperplasia with focal ulceration and a mixed inflammatory infiltrate (Figure 2A). At higher magnification, clear viral cytopathic changes of HHV were noted, including multinucleation, nuclear molding, and homogenous gray nuclei (Figure 2B). Additional staining for fungi, mycobacteria, and spirochetes was negative. In-situ hybridization was negative for human papillomavirus subtypes. A bacterial culture of swabs of the purulent drainage was positive for Staphylococcus aureus and Proteus mirabilis.

Given the patient’s known history of acyclovir-resistant HHV-2 infection, he received a 28-day course of intravenous foscarnet 40 mg/kg every 12 hours. He also was given a 14-day course of intravenous ampicillin-sulbactam 3 g every 6 hours. The patient gradually improved during a 35-day hospital stay. He was discharged with cidofovir cream 1% and oral valacyclovir; the latter was subsequently discontinued by dermatology because of his known history of acyclovir resistance. Four months after discharge, the patient underwent a circumcision performed by urology to decrease the risk for recurrence and achieve the best cosmetic outcome. At the 6-month follow-up visit, dramatic clinical improvement was evident, with complete resolution of the plaque and only isolated areas of scarring (Figure 3). The patient reported that penile function was preserved.

Herpes vegetans represents a rare infection with HHV-1 or HHV-2, typically in patients who are considerably immunosuppressed, such as those with cancer, those undergoing transplantation, and those with uncontrolled HIV infection.¹ Few cases of HV have been described in an immunocompetent patient.² Our case is unique because the patient’s HIV infection was well controlled at the time HV was diagnosed, demonstrated by his modestly low CD4 count and undetectable HIV viral load.

Patients with HV can present diagnostic and therapeutic challenges. Typically, a diagnosis of cutaneous HHV infection does not require a biopsy; most cases appear as clustered vesicular lesions, making the disease easy to diagnose clinically. However, biopsies and cultures are necessary to identify the underlying cause of atypical verrucous exophytic lesions. Other conditions with clinical features similar to HV include squamous cell carcinoma, condyloma acuminatum, and deep fungal and mycobacterial infections.^2,3 A tissue biopsy, histologic staining, and tissue culture should be performed to identify the causative pathogen and potential targets for treatment. Definitive diagnosis is vital to deliver proper treatment modalities, which often involve a multimodal multidisciplinary approach. 

Several pathogenic mechanisms of HV have been proposed. One theory suggests that in an immunocompetent patient, HHV typically triggers a lymphocytic response, which leads to activation of interferon alpha. However, in an immunocompromised patient, such as an individual with AIDS, this interferon response is diminished, which explains why these patients typically have a chronic and resistant HHV infection. HIV has an affinity for infecting dermal dendritic cells, which signals activation of tumor necrosis factor and interleukin.⁶ Both cytokines contribute to an antiapoptotic environment that promotes continued proliferation of these viral cells in the epidermis. Over time, propagation of disinhibited cells can lead to the verrucous and hyperkeratotic-appearing skin that is common in patients with HV.⁷

Another theorized mechanism underlying hypertrophic herpetic lesions was described in the context of HHV-1 infection and subsequent PG. El Hayderi et al⁸ reported that histologic and immunohistochemical examination of a patient’s lesion revealed sparse epithelial cell aggregates within PG as well as HHV-1 antigens in the nuclei and cytoplasm of normal-appearing and cytopathic epithelial cells. Immunohistochemical examination also revealed vascular endothelial growth factor within HHV-1–infected epithelial cells and PG endothelial cells, suggesting that PG formation may be indirectly driven by vascular endothelial growth factor and its proangiogenic properties. The pathogenesis of PG in the setting of HHV-1 infection displays many similarities to hyperkeratotic lesions observed in atypical cutaneous manifestations of HHV-2.⁸

The management of patients with HV continues to be complex, often requiring a multimodal regimen. Although acyclovir has been shown to be highly effective for treating and preventing most HHV infections, acyclovir resistance frequently has been reported in immunocompromised populations.⁵ Acyclovir resistance can be correlated with the severity of immunodeficiency as well as the duration of acyclovir exposure. Resistance to acyclovir often results from deficient intracellular phosphorylation, which is required for activation of the drug. If patients show resistance to acyclovir and its derivatives, alternate drug classes that do not depend on thymidine kinase phosphorylation should be considered.

Our patient received a combination of intravenous foscarnet and a course of ampicillin-sulbactam while an inpatient due to his documented history of acyclovir-resistant HHV-2 infection, and he was discharged on cidofovir cream 1%. Cidofovir is US Food and Drug Administration approved for treating cytomegalovirus retinitis in patients with AIDS. Although data are limited, topical and intralesional cidofovir have been used to treat acyclovir-resistant cases of HV with documented success.^1,9 In refractory HV or when the disease is slow to resolve, intralesional cidofovir has been documented to be an additional treatment option. Intralesional and topical cidofovir carry a much lower risk for adverse effects such as kidney dysfunction compared to intravenous cidofovir¹ and can be considered in patients with minimal clinical improvement and those at increased risk for side effects.

Our case demonstrated how a patient with HV may require a complex and prolonged hospital course for appropriate treatment. Our patient required an array of both medical and surgical modalities to reach the desired outcome. Here, a multitude of specialties including infectious disease, dermatology, and urology worked together to reach a positive clinical and cosmetic outcome for this patient. 

To the Editor:

Most cutaneous squamous cell carcinomas (cSCCs) are successfully treated with standard modalities such as surgical excision; however, a subset of tumors is not amenable to surgical resection.^1,2 Patients who are not able to undergo surgical treatment may instead receive radiation therapy, topical 5-fluorouracil (5-FU), imiquimod, cryosurgery, photodynamic therapy, or systemic treatment (eg, immunotherapy) in addition to intralesional approaches for localized disease.^1-4 However, the adverse effects associated with these treatments and their modest effect in preventing the recurrence of cutaneous lesions limit their efficacy against unresectable cSCC.^4-6 We present a case that demonstrates the efficacy of electrodesiccation and curettage (ED&C) followed by topical 5-FU for an invasive cSCC not amenable to surgical therapy.

A 58-year-old woman presented for evaluation of a 3.5×3.4-cm, incisional biopsy–proven, invasive stage T2a cSCC (Brigham and Women’s Hospital tumor staging system [Boston, Massachusetts]) on the dorsal aspect of the left foot, which had developed over several months (Figure 1A). She had a history of treatment with psoralen plus UV light therapy for erythroderma of unknown cause and peripheral neuropathy. She was not a surgical candidate because of suspected underlying cutaneous sclerosis and a history of poor wound healing on the lower legs.

Prior to presentation to dermatology, the patient had been treated with intralesional methotrexate, intralesional 5-FU, and the antiangiogenic and antiproliferative combination agent OLCAT-005³—consisting of equal parts [by volume] of diclofenac gel 3%, imiquimod cream 5%, hydrocortisone valerate cream 0.2%, calcipotriene cream 0.005%, and tretinoin cream 0.05—which failed, and the patient reported that OLCAT-005 made the pain from the cSCC worse.

Upon growth of the lesion over several months, the patient was referred to the High-Risk Skin Cancer Clinic at Massachusetts General Hospital (Boston, Massachusetts). A repeat biopsy demonstrated an invasive well-differentiated cSCC (Figure 2). The size and invasive features of the lesion on clinical examination prompted a referral to surgical oncology for a wide local excision. However, surgical oncology concluded she was not a surgical candidate.

Magnetic resonance imaging showed no deep invasion of the cSCC to the tendons or bones. Electrodesiccation and curettage was performed to debulk the tumor, followed by twice-daily application of topical 5-FU for 4 weeks to improve the odds of tumor clearance (Figure 1B). Fourteen weeks after completion of 5-FU treatment, the cSCC showed complete clinical regression (Figure 1C). No recurrence has been detected clinically more than 3 years following treatment.

Prior to the advent of Mohs micrographic surgery, ED&C commonly was used to treat skin cancer, with a lower cost and a cure rate close to 95%.^7,8 We postulate that the mechanism of tumor regression in our patient was ED&C-mediated removal and necrosis of neoplastic tissue combined with 5-FU–induced cancer-cell DNA damage and apoptosis. An antitumor immune response also may have contributed to the complete regression of the cSCC.

Although antiangiogenic and antiproliferative agents are suitable for primary cSCC treatment, it is possible that this patient’s prior therapies alone—in the absence of debulking by ED&C to sufficiently reduce disease burden—did not allow for tumor clearance and were ineffective. Many clinicians are reluctant to apply 5-FU to a wound bed because it can impede wound healing.⁹ In this case, re-epithelialization likely occurred primarily after completion of 5-FU treatment.

We recommend consideration of ED&C with 5-FU for similar malignant lesions that are not amenable to surgical excision. Nevertheless, Mohs micrographic surgery and wide local excision remain the gold standards for definitive treatment of invasive skin cancer in a patient who is a candidate for surgical treatment.

To the Editor:

Most cutaneous squamous cell carcinomas (cSCCs) are successfully treated with standard modalities such as surgical excision; however, a subset of tumors is not amenable to surgical resection.^1,2 Patients who are not able to undergo surgical treatment may instead receive radiation therapy, topical 5-fluorouracil (5-FU), imiquimod, cryosurgery, photodynamic therapy, or systemic treatment (eg, immunotherapy) in addition to intralesional approaches for localized disease.^1-4 However, the adverse effects associated with these treatments and their modest effect in preventing the recurrence of cutaneous lesions limit their efficacy against unresectable cSCC.^4-6 We present a case that demonstrates the efficacy of electrodesiccation and curettage (ED&C) followed by topical 5-FU for an invasive cSCC not amenable to surgical therapy.

A 58-year-old woman presented for evaluation of a 3.5×3.4-cm, incisional biopsy–proven, invasive stage T2a cSCC (Brigham and Women’s Hospital tumor staging system [Boston, Massachusetts]) on the dorsal aspect of the left foot, which had developed over several months (Figure 1A). She had a history of treatment with psoralen plus UV light therapy for erythroderma of unknown cause and peripheral neuropathy. She was not a surgical candidate because of suspected underlying cutaneous sclerosis and a history of poor wound healing on the lower legs.

Prior to presentation to dermatology, the patient had been treated with intralesional methotrexate, intralesional 5-FU, and the antiangiogenic and antiproliferative combination agent OLCAT-005³—consisting of equal parts [by volume] of diclofenac gel 3%, imiquimod cream 5%, hydrocortisone valerate cream 0.2%, calcipotriene cream 0.005%, and tretinoin cream 0.05—which failed, and the patient reported that OLCAT-005 made the pain from the cSCC worse.

Upon growth of the lesion over several months, the patient was referred to the High-Risk Skin Cancer Clinic at Massachusetts General Hospital (Boston, Massachusetts). A repeat biopsy demonstrated an invasive well-differentiated cSCC (Figure 2). The size and invasive features of the lesion on clinical examination prompted a referral to surgical oncology for a wide local excision. However, surgical oncology concluded she was not a surgical candidate.

Magnetic resonance imaging showed no deep invasion of the cSCC to the tendons or bones. Electrodesiccation and curettage was performed to debulk the tumor, followed by twice-daily application of topical 5-FU for 4 weeks to improve the odds of tumor clearance (Figure 1B). Fourteen weeks after completion of 5-FU treatment, the cSCC showed complete clinical regression (Figure 1C). No recurrence has been detected clinically more than 3 years following treatment.

Prior to the advent of Mohs micrographic surgery, ED&C commonly was used to treat skin cancer, with a lower cost and a cure rate close to 95%.^7,8 We postulate that the mechanism of tumor regression in our patient was ED&C-mediated removal and necrosis of neoplastic tissue combined with 5-FU–induced cancer-cell DNA damage and apoptosis. An antitumor immune response also may have contributed to the complete regression of the cSCC.

Although antiangiogenic and antiproliferative agents are suitable for primary cSCC treatment, it is possible that this patient’s prior therapies alone—in the absence of debulking by ED&C to sufficiently reduce disease burden—did not allow for tumor clearance and were ineffective. Many clinicians are reluctant to apply 5-FU to a wound bed because it can impede wound healing.⁹ In this case, re-epithelialization likely occurred primarily after completion of 5-FU treatment.

We recommend consideration of ED&C with 5-FU for similar malignant lesions that are not amenable to surgical excision. Nevertheless, Mohs micrographic surgery and wide local excision remain the gold standards for definitive treatment of invasive skin cancer in a patient who is a candidate for surgical treatment.

To the Editor:

Most cutaneous squamous cell carcinomas (cSCCs) are successfully treated with standard modalities such as surgical excision; however, a subset of tumors is not amenable to surgical resection.^1,2 Patients who are not able to undergo surgical treatment may instead receive radiation therapy, topical 5-fluorouracil (5-FU), imiquimod, cryosurgery, photodynamic therapy, or systemic treatment (eg, immunotherapy) in addition to intralesional approaches for localized disease.^1-4 However, the adverse effects associated with these treatments and their modest effect in preventing the recurrence of cutaneous lesions limit their efficacy against unresectable cSCC.^4-6 We present a case that demonstrates the efficacy of electrodesiccation and curettage (ED&C) followed by topical 5-FU for an invasive cSCC not amenable to surgical therapy.

A 58-year-old woman presented for evaluation of a 3.5×3.4-cm, incisional biopsy–proven, invasive stage T2a cSCC (Brigham and Women’s Hospital tumor staging system [Boston, Massachusetts]) on the dorsal aspect of the left foot, which had developed over several months (Figure 1A). She had a history of treatment with psoralen plus UV light therapy for erythroderma of unknown cause and peripheral neuropathy. She was not a surgical candidate because of suspected underlying cutaneous sclerosis and a history of poor wound healing on the lower legs.

Prior to presentation to dermatology, the patient had been treated with intralesional methotrexate, intralesional 5-FU, and the antiangiogenic and antiproliferative combination agent OLCAT-005³—consisting of equal parts [by volume] of diclofenac gel 3%, imiquimod cream 5%, hydrocortisone valerate cream 0.2%, calcipotriene cream 0.005%, and tretinoin cream 0.05—which failed, and the patient reported that OLCAT-005 made the pain from the cSCC worse.

Upon growth of the lesion over several months, the patient was referred to the High-Risk Skin Cancer Clinic at Massachusetts General Hospital (Boston, Massachusetts). A repeat biopsy demonstrated an invasive well-differentiated cSCC (Figure 2). The size and invasive features of the lesion on clinical examination prompted a referral to surgical oncology for a wide local excision. However, surgical oncology concluded she was not a surgical candidate.

Magnetic resonance imaging showed no deep invasion of the cSCC to the tendons or bones. Electrodesiccation and curettage was performed to debulk the tumor, followed by twice-daily application of topical 5-FU for 4 weeks to improve the odds of tumor clearance (Figure 1B). Fourteen weeks after completion of 5-FU treatment, the cSCC showed complete clinical regression (Figure 1C). No recurrence has been detected clinically more than 3 years following treatment.

Prior to the advent of Mohs micrographic surgery, ED&C commonly was used to treat skin cancer, with a lower cost and a cure rate close to 95%.^7,8 We postulate that the mechanism of tumor regression in our patient was ED&C-mediated removal and necrosis of neoplastic tissue combined with 5-FU–induced cancer-cell DNA damage and apoptosis. An antitumor immune response also may have contributed to the complete regression of the cSCC.

Although antiangiogenic and antiproliferative agents are suitable for primary cSCC treatment, it is possible that this patient’s prior therapies alone—in the absence of debulking by ED&C to sufficiently reduce disease burden—did not allow for tumor clearance and were ineffective. Many clinicians are reluctant to apply 5-FU to a wound bed because it can impede wound healing.⁹ In this case, re-epithelialization likely occurred primarily after completion of 5-FU treatment.

We recommend consideration of ED&C with 5-FU for similar malignant lesions that are not amenable to surgical excision. Nevertheless, Mohs micrographic surgery and wide local excision remain the gold standards for definitive treatment of invasive skin cancer in a patient who is a candidate for surgical treatment.