Article

Medical students often perform away rotations (also called visiting electives) to gain exposure to educational experiences in a particular specialty, learn about a program, and show interest in a certain program. Away rotations also allow applicants to meet and form relationships with mentors and faculty outside of their home institution. For residency programs, away rotations provide an opportunity for a holistic review of applicants by allowing program directors to get to know potential residency applicants and assess their performance in the clinical environment and among the program’s team. In a National Resident Matching Program survey, program directors (n=17) reported that prior knowledge of an applicant is an important factor in selecting applicants to interview (82.4%) and rank (58.8%).¹

In this article, we discuss the importance of away rotations in dermatology and provide an overview of the Organization of Program Director Associations (OPDA) and Association of Professors of Dermatology (APD) guidelines for away rotations.

Importance of the Away Rotation in the Match

According to the Association of American Medical Colleges, 86.7% of dermatology applicants (N=345) completed one or more away rotations (mean, 2.7) in 2020.² Winterton et al³ reported that 47% of dermatology applicants (N=45) matched at a program where they completed an away rotation. Prior to the COVID-19 pandemic, the number of applicants matching to their home program was reported as 26.7% (N=641), which jumped to 40.3% (N=231) in the 2020-2021 cycle.⁴ Given that the majority of dermatology applicants reportedly match either at their home program or at programs where they completed an away rotation, the benefits of away rotations are high, particularly in a competitive specialty such as dermatology and particularly for applicants without a dermatology program at their home institution. However, it must be acknowledged that correlation does not necessarily mean causation, as away rotations have not necessarily been shown to increase applicants’ chances of matching for the most competitive specialties.⁵

OPDA Guidelines for Away Rotations

In 2021, the Coalition of Physician Accountability’s Undergraduate Medical Education-Graduate Medical Education Review Committee recommended creating a workgroup to explore the function and value of away rotations for medical students, programs, and institutions, with a particular focus on issues of equity (eg, accessibility, assessment, opportunity) for underrepresented in medicine students and those with financial disadvantages.⁶ The OPDA workgroup evaluated the advantages and disadvantages of away rotations across specialties. The disadvantages included that away rotations may decrease resources to students at their own institution, particularly if faculty time and energy are funneled/dedicated to away rotators instead of internal rotators, and may impart bias into the recruitment process. Additionally, there is a consideration of equity given the considerable cost and time commitment of travel and housing for students at another institution. In 2022, the estimated cost of an away rotation in dermatology ranged from $1390 to $5500 per rotation.⁷ Visiting scholarships may be available at some institutions but typically are reserved for underrepresented in medicine students.⁸ Virtual rotations offered at some programs offset the cost-prohibitiveness of an in-person away rotation; however, they are not universally offered and may be limited in allowing for meaningful interactions between students and program faculty and residents.

The OPDA away rotation workgroup recommended that (1) each specialty publish guidelines regarding the necessity and number of recommended away rotations; (2) specialties publish explicit language regarding the use of program preference signals to programs where students rotated; (3) programs be transparent about the purpose and value of an away rotation, including explicitly stating whether a formal interview is guaranteed; and (4) the Association of American Medical Colleges create a repository of these specialty-specific recommendations.⁹

APD Guidelines for Away Rotations

In response to the OPDA recommendations, the APD Residency Program Directors Section developed dermatology-specific guidelines for away rotations and established guidelines in other specialties.¹⁰ The APD recommends completing up to 2 away rotations, or 3 for those without a home program, if desired. This number was chosen in acknowledgment of the importance of external program experiences, along with the recognition of the financial and time restrictions associated with away rotations as well as the limited number of spots for rotating students. Away rotations are not mandatory. The APD guidelines explain the purpose and value of an away rotation while also noting that these rotations do not necessarily guarantee a formal interview and recommending that programs be transparent about their policies on interview invitations, which may vary.¹⁰

Final Thoughts

Publishing specialty-specific guidelines on away rotations is one step toward streamlining the process as well as increasing transparency on the importance of these external program experiences in the application process and residency match. Ideally, away rotations provide a valuable educational experience in which students and program directors get to know each other in a mutually beneficial manner; however, away rotations are not required for securing an interview or matching at a program, and there also are recognized disadvantages to away rotations, particularly with regard to equity, that we must continue to weigh as a specialty. The APD will continue its collaborative work to evaluate our application processes to support a sustainable and equitable system.

Medical students often perform away rotations (also called visiting electives) to gain exposure to educational experiences in a particular specialty, learn about a program, and show interest in a certain program. Away rotations also allow applicants to meet and form relationships with mentors and faculty outside of their home institution. For residency programs, away rotations provide an opportunity for a holistic review of applicants by allowing program directors to get to know potential residency applicants and assess their performance in the clinical environment and among the program’s team. In a National Resident Matching Program survey, program directors (n=17) reported that prior knowledge of an applicant is an important factor in selecting applicants to interview (82.4%) and rank (58.8%).¹

In this article, we discuss the importance of away rotations in dermatology and provide an overview of the Organization of Program Director Associations (OPDA) and Association of Professors of Dermatology (APD) guidelines for away rotations.

Importance of the Away Rotation in the Match

According to the Association of American Medical Colleges, 86.7% of dermatology applicants (N=345) completed one or more away rotations (mean, 2.7) in 2020.² Winterton et al³ reported that 47% of dermatology applicants (N=45) matched at a program where they completed an away rotation. Prior to the COVID-19 pandemic, the number of applicants matching to their home program was reported as 26.7% (N=641), which jumped to 40.3% (N=231) in the 2020-2021 cycle.⁴ Given that the majority of dermatology applicants reportedly match either at their home program or at programs where they completed an away rotation, the benefits of away rotations are high, particularly in a competitive specialty such as dermatology and particularly for applicants without a dermatology program at their home institution. However, it must be acknowledged that correlation does not necessarily mean causation, as away rotations have not necessarily been shown to increase applicants’ chances of matching for the most competitive specialties.⁵

OPDA Guidelines for Away Rotations

In 2021, the Coalition of Physician Accountability’s Undergraduate Medical Education-Graduate Medical Education Review Committee recommended creating a workgroup to explore the function and value of away rotations for medical students, programs, and institutions, with a particular focus on issues of equity (eg, accessibility, assessment, opportunity) for underrepresented in medicine students and those with financial disadvantages.⁶ The OPDA workgroup evaluated the advantages and disadvantages of away rotations across specialties. The disadvantages included that away rotations may decrease resources to students at their own institution, particularly if faculty time and energy are funneled/dedicated to away rotators instead of internal rotators, and may impart bias into the recruitment process. Additionally, there is a consideration of equity given the considerable cost and time commitment of travel and housing for students at another institution. In 2022, the estimated cost of an away rotation in dermatology ranged from $1390 to $5500 per rotation.⁷ Visiting scholarships may be available at some institutions but typically are reserved for underrepresented in medicine students.⁸ Virtual rotations offered at some programs offset the cost-prohibitiveness of an in-person away rotation; however, they are not universally offered and may be limited in allowing for meaningful interactions between students and program faculty and residents.

The OPDA away rotation workgroup recommended that (1) each specialty publish guidelines regarding the necessity and number of recommended away rotations; (2) specialties publish explicit language regarding the use of program preference signals to programs where students rotated; (3) programs be transparent about the purpose and value of an away rotation, including explicitly stating whether a formal interview is guaranteed; and (4) the Association of American Medical Colleges create a repository of these specialty-specific recommendations.⁹

APD Guidelines for Away Rotations

In response to the OPDA recommendations, the APD Residency Program Directors Section developed dermatology-specific guidelines for away rotations and established guidelines in other specialties.¹⁰ The APD recommends completing up to 2 away rotations, or 3 for those without a home program, if desired. This number was chosen in acknowledgment of the importance of external program experiences, along with the recognition of the financial and time restrictions associated with away rotations as well as the limited number of spots for rotating students. Away rotations are not mandatory. The APD guidelines explain the purpose and value of an away rotation while also noting that these rotations do not necessarily guarantee a formal interview and recommending that programs be transparent about their policies on interview invitations, which may vary.¹⁰

Final Thoughts

Publishing specialty-specific guidelines on away rotations is one step toward streamlining the process as well as increasing transparency on the importance of these external program experiences in the application process and residency match. Ideally, away rotations provide a valuable educational experience in which students and program directors get to know each other in a mutually beneficial manner; however, away rotations are not required for securing an interview or matching at a program, and there also are recognized disadvantages to away rotations, particularly with regard to equity, that we must continue to weigh as a specialty. The APD will continue its collaborative work to evaluate our application processes to support a sustainable and equitable system.

Medical students often perform away rotations (also called visiting electives) to gain exposure to educational experiences in a particular specialty, learn about a program, and show interest in a certain program. Away rotations also allow applicants to meet and form relationships with mentors and faculty outside of their home institution. For residency programs, away rotations provide an opportunity for a holistic review of applicants by allowing program directors to get to know potential residency applicants and assess their performance in the clinical environment and among the program’s team. In a National Resident Matching Program survey, program directors (n=17) reported that prior knowledge of an applicant is an important factor in selecting applicants to interview (82.4%) and rank (58.8%).¹

In this article, we discuss the importance of away rotations in dermatology and provide an overview of the Organization of Program Director Associations (OPDA) and Association of Professors of Dermatology (APD) guidelines for away rotations.

Importance of the Away Rotation in the Match

According to the Association of American Medical Colleges, 86.7% of dermatology applicants (N=345) completed one or more away rotations (mean, 2.7) in 2020.² Winterton et al³ reported that 47% of dermatology applicants (N=45) matched at a program where they completed an away rotation. Prior to the COVID-19 pandemic, the number of applicants matching to their home program was reported as 26.7% (N=641), which jumped to 40.3% (N=231) in the 2020-2021 cycle.⁴ Given that the majority of dermatology applicants reportedly match either at their home program or at programs where they completed an away rotation, the benefits of away rotations are high, particularly in a competitive specialty such as dermatology and particularly for applicants without a dermatology program at their home institution. However, it must be acknowledged that correlation does not necessarily mean causation, as away rotations have not necessarily been shown to increase applicants’ chances of matching for the most competitive specialties.⁵

OPDA Guidelines for Away Rotations

In 2021, the Coalition of Physician Accountability’s Undergraduate Medical Education-Graduate Medical Education Review Committee recommended creating a workgroup to explore the function and value of away rotations for medical students, programs, and institutions, with a particular focus on issues of equity (eg, accessibility, assessment, opportunity) for underrepresented in medicine students and those with financial disadvantages.⁶ The OPDA workgroup evaluated the advantages and disadvantages of away rotations across specialties. The disadvantages included that away rotations may decrease resources to students at their own institution, particularly if faculty time and energy are funneled/dedicated to away rotators instead of internal rotators, and may impart bias into the recruitment process. Additionally, there is a consideration of equity given the considerable cost and time commitment of travel and housing for students at another institution. In 2022, the estimated cost of an away rotation in dermatology ranged from $1390 to $5500 per rotation.⁷ Visiting scholarships may be available at some institutions but typically are reserved for underrepresented in medicine students.⁸ Virtual rotations offered at some programs offset the cost-prohibitiveness of an in-person away rotation; however, they are not universally offered and may be limited in allowing for meaningful interactions between students and program faculty and residents.

The OPDA away rotation workgroup recommended that (1) each specialty publish guidelines regarding the necessity and number of recommended away rotations; (2) specialties publish explicit language regarding the use of program preference signals to programs where students rotated; (3) programs be transparent about the purpose and value of an away rotation, including explicitly stating whether a formal interview is guaranteed; and (4) the Association of American Medical Colleges create a repository of these specialty-specific recommendations.⁹

APD Guidelines for Away Rotations

In response to the OPDA recommendations, the APD Residency Program Directors Section developed dermatology-specific guidelines for away rotations and established guidelines in other specialties.¹⁰ The APD recommends completing up to 2 away rotations, or 3 for those without a home program, if desired. This number was chosen in acknowledgment of the importance of external program experiences, along with the recognition of the financial and time restrictions associated with away rotations as well as the limited number of spots for rotating students. Away rotations are not mandatory. The APD guidelines explain the purpose and value of an away rotation while also noting that these rotations do not necessarily guarantee a formal interview and recommending that programs be transparent about their policies on interview invitations, which may vary.¹⁰

Final Thoughts

Publishing specialty-specific guidelines on away rotations is one step toward streamlining the process as well as increasing transparency on the importance of these external program experiences in the application process and residency match. Ideally, away rotations provide a valuable educational experience in which students and program directors get to know each other in a mutually beneficial manner; however, away rotations are not required for securing an interview or matching at a program, and there also are recognized disadvantages to away rotations, particularly with regard to equity, that we must continue to weigh as a specialty. The APD will continue its collaborative work to evaluate our application processes to support a sustainable and equitable system.

Nearly all dermatologists are aware that psoriatic arthritis (PsA) is one of the most prevalent comorbidities associated with psoriasis, yet we may lack the insight regarding how to utilize this information. After all, we specialize in the skin, not the joints, right?

When I graduated from residency in 2014, I began staffing our psoriasis clinic, where we care for the toughest, most complicated psoriasis patients, many of them struggling with both severe recalcitrant psoriasis as well as debilitating PsA. In 2016, we partnered with rheumatology to open a multidisciplinary psoriasis and PsA clinic, and I quickly began to appreciate how much PsA was being overlooked simply because patients with psoriasis were not being asked about their joints.

To start, let’s look at several facts:

1. One quarter of patients with psoriasis also have PsA.¹
2. Skin disease most commonly develops before PsA.¹
3. Fifteen percent of PsA cases go undiagnosed, which dramatically increases the risk for deformed joints, erosions, osteolysis, sacroiliitis, and arthritis mutilans² and also increases the cost of health care.³
4. Everyone is crazy busy—rheumatology wait lists often are months long.

Given that dermatologists are the ones who already are seeing the majority of patients who develop PsA, we play a key role in screening for this debilitating comorbidity and starting therapy for patients with both psoriasis and PsA. We, too, are crazy busy; therefore, we need to make this process quick and efficient but also reliable. Fortunately, the Psoriasis Epidemiology Screening Tool (PEST) is effective, fast, and very easy. With only 5 questions and a sensitivity and specificity of around 70%,⁴ this short and simple questionnaire can be incorporated into an intake form or rooming note or can just be asked during the visit. The questions include whether the patient currently has or has had a swollen joint, nail pits, heel pain, and/or dactylitis, as well as if they have been told by a physician that they have arthritis. A score of 3 or higher is considered positive and a referral to rheumatology should be considered. At the bare minimum, I highly encourage all dermatologists to incorporate the PEST screening tool into their practice.

During the physical examination itself, be sure to look at the patient’s nails and also look for joint swelling and redness, especially in the hands. When palpating a swollen joint, the presence of inflammatory arthritis will feel spongy or boggy, while the osteophytes associated with osteoarthritis will feel hard. Radiography of the affected joint may be helpful, but keep in mind that bone changes are latter sequelae of PsA, and negative radiographs do not rule out PsA.

If you highly suspect PsA after using the PEST screening tool and palpating any swollen joints, then a rheumatology referral certainly is warranted. Medication that covers both psoriasis and PsA also can be initiated. Although methotrexate often is used for joints, higher doses (ie, >15 mg/wk) usually are needed. A 2019 Cochrane review found that low-dose methotrexate (ie, ≤15 mg/wk) may be only slightly more effective then placebo⁵—certainly not a ringing endorsement for its use in PsA. Additionally, quality data demonstrating methotrexate’s efficacy for enthesitis or axial spondyloarthritis is lacking, and methotrexate has not demonstrated an ability to slow the radiographic progression of joints. In contrast, the anti–tumor necrosis factor agents, including adalimumab, infliximab, etanercept, and certolizumab, as well as ustekinumab and the anti–IL-17 biologics secukinumab and ixekizumab have demonstrated efficacy in American College of Rheumatology (ACR) scores, enthesitis, dactylitis, and prevention of radiographic progression of joints.^6,7 Although brodalumab, an anti–IL-17 receptor inhibitor, demonstrated improvement in ACR scores, enthesitis, and dactylitis, data on its effects on radiographic progression of joints were inconclusive given the phase III trial’s premature ending due to suicidal ideation and behavior in participants.⁸ Several of the anti–IL-23 agents also may help PsA, with trials demonstrating improvements in ACR scores, enthesitis, and dactylitis; however, only guselkumab 100 mg every 4 weeks decreased radiographic progression of joints.⁹ Additionally, with the age of the Janus kinase (JAK) inhibitor upon us, there are several JAK/TYK2 inhibitors that are approved by the US Food and Drug Administration for psoriasis (deucravacitinib) as well as for PsA (tofacitinib, upadacitinib), and there are more JAK inhibitors in the pipeline. These medications are effective; however, I do encourage caution and careful consideration in selecting the appropriate patient, as data demonstrated an increased risk for major adverse cardiovascular events and cancer in older (>50 years) rheumatoid arthritis patients who had at least 1 cardiovascular risk factor and were treated with tofacitinib.¹⁰ Although several other trials have not demonstrated this increased risk, further data are needed to determine risk for both pan-JAK inhibitors as well as selective JAK inhibitors and TYK2 inhibitors. Additionally, given psoriasis already is closely linked with many cardiovascular risk factors including heart disease, obesity, hypertension, hyperlipidemia, and diabetes mellitus,¹¹ it will be important to have long-term safety information for JAK inhibitors in the psoriasis and PsA population.

Dermatologists are in a pivotal position to identify patients affected by PsA and start an appropriate systemic medication. We can help make an enormous impact on our patients’ lives as well as help decrease the economic impact of untreated disease. Let’s join the effort to save the joints!

Nearly all dermatologists are aware that psoriatic arthritis (PsA) is one of the most prevalent comorbidities associated with psoriasis, yet we may lack the insight regarding how to utilize this information. After all, we specialize in the skin, not the joints, right?

When I graduated from residency in 2014, I began staffing our psoriasis clinic, where we care for the toughest, most complicated psoriasis patients, many of them struggling with both severe recalcitrant psoriasis as well as debilitating PsA. In 2016, we partnered with rheumatology to open a multidisciplinary psoriasis and PsA clinic, and I quickly began to appreciate how much PsA was being overlooked simply because patients with psoriasis were not being asked about their joints.

To start, let’s look at several facts:

1. One quarter of patients with psoriasis also have PsA.¹
2. Skin disease most commonly develops before PsA.¹
3. Fifteen percent of PsA cases go undiagnosed, which dramatically increases the risk for deformed joints, erosions, osteolysis, sacroiliitis, and arthritis mutilans² and also increases the cost of health care.³
4. Everyone is crazy busy—rheumatology wait lists often are months long.

Given that dermatologists are the ones who already are seeing the majority of patients who develop PsA, we play a key role in screening for this debilitating comorbidity and starting therapy for patients with both psoriasis and PsA. We, too, are crazy busy; therefore, we need to make this process quick and efficient but also reliable. Fortunately, the Psoriasis Epidemiology Screening Tool (PEST) is effective, fast, and very easy. With only 5 questions and a sensitivity and specificity of around 70%,⁴ this short and simple questionnaire can be incorporated into an intake form or rooming note or can just be asked during the visit. The questions include whether the patient currently has or has had a swollen joint, nail pits, heel pain, and/or dactylitis, as well as if they have been told by a physician that they have arthritis. A score of 3 or higher is considered positive and a referral to rheumatology should be considered. At the bare minimum, I highly encourage all dermatologists to incorporate the PEST screening tool into their practice.

During the physical examination itself, be sure to look at the patient’s nails and also look for joint swelling and redness, especially in the hands. When palpating a swollen joint, the presence of inflammatory arthritis will feel spongy or boggy, while the osteophytes associated with osteoarthritis will feel hard. Radiography of the affected joint may be helpful, but keep in mind that bone changes are latter sequelae of PsA, and negative radiographs do not rule out PsA.

If you highly suspect PsA after using the PEST screening tool and palpating any swollen joints, then a rheumatology referral certainly is warranted. Medication that covers both psoriasis and PsA also can be initiated. Although methotrexate often is used for joints, higher doses (ie, >15 mg/wk) usually are needed. A 2019 Cochrane review found that low-dose methotrexate (ie, ≤15 mg/wk) may be only slightly more effective then placebo⁵—certainly not a ringing endorsement for its use in PsA. Additionally, quality data demonstrating methotrexate’s efficacy for enthesitis or axial spondyloarthritis is lacking, and methotrexate has not demonstrated an ability to slow the radiographic progression of joints. In contrast, the anti–tumor necrosis factor agents, including adalimumab, infliximab, etanercept, and certolizumab, as well as ustekinumab and the anti–IL-17 biologics secukinumab and ixekizumab have demonstrated efficacy in American College of Rheumatology (ACR) scores, enthesitis, dactylitis, and prevention of radiographic progression of joints.^6,7 Although brodalumab, an anti–IL-17 receptor inhibitor, demonstrated improvement in ACR scores, enthesitis, and dactylitis, data on its effects on radiographic progression of joints were inconclusive given the phase III trial’s premature ending due to suicidal ideation and behavior in participants.⁸ Several of the anti–IL-23 agents also may help PsA, with trials demonstrating improvements in ACR scores, enthesitis, and dactylitis; however, only guselkumab 100 mg every 4 weeks decreased radiographic progression of joints.⁹ Additionally, with the age of the Janus kinase (JAK) inhibitor upon us, there are several JAK/TYK2 inhibitors that are approved by the US Food and Drug Administration for psoriasis (deucravacitinib) as well as for PsA (tofacitinib, upadacitinib), and there are more JAK inhibitors in the pipeline. These medications are effective; however, I do encourage caution and careful consideration in selecting the appropriate patient, as data demonstrated an increased risk for major adverse cardiovascular events and cancer in older (>50 years) rheumatoid arthritis patients who had at least 1 cardiovascular risk factor and were treated with tofacitinib.¹⁰ Although several other trials have not demonstrated this increased risk, further data are needed to determine risk for both pan-JAK inhibitors as well as selective JAK inhibitors and TYK2 inhibitors. Additionally, given psoriasis already is closely linked with many cardiovascular risk factors including heart disease, obesity, hypertension, hyperlipidemia, and diabetes mellitus,¹¹ it will be important to have long-term safety information for JAK inhibitors in the psoriasis and PsA population.

Dermatologists are in a pivotal position to identify patients affected by PsA and start an appropriate systemic medication. We can help make an enormous impact on our patients’ lives as well as help decrease the economic impact of untreated disease. Let’s join the effort to save the joints!

Nearly all dermatologists are aware that psoriatic arthritis (PsA) is one of the most prevalent comorbidities associated with psoriasis, yet we may lack the insight regarding how to utilize this information. After all, we specialize in the skin, not the joints, right?

When I graduated from residency in 2014, I began staffing our psoriasis clinic, where we care for the toughest, most complicated psoriasis patients, many of them struggling with both severe recalcitrant psoriasis as well as debilitating PsA. In 2016, we partnered with rheumatology to open a multidisciplinary psoriasis and PsA clinic, and I quickly began to appreciate how much PsA was being overlooked simply because patients with psoriasis were not being asked about their joints.

To start, let’s look at several facts:

1. One quarter of patients with psoriasis also have PsA.¹
2. Skin disease most commonly develops before PsA.¹
3. Fifteen percent of PsA cases go undiagnosed, which dramatically increases the risk for deformed joints, erosions, osteolysis, sacroiliitis, and arthritis mutilans² and also increases the cost of health care.³
4. Everyone is crazy busy—rheumatology wait lists often are months long.

Given that dermatologists are the ones who already are seeing the majority of patients who develop PsA, we play a key role in screening for this debilitating comorbidity and starting therapy for patients with both psoriasis and PsA. We, too, are crazy busy; therefore, we need to make this process quick and efficient but also reliable. Fortunately, the Psoriasis Epidemiology Screening Tool (PEST) is effective, fast, and very easy. With only 5 questions and a sensitivity and specificity of around 70%,⁴ this short and simple questionnaire can be incorporated into an intake form or rooming note or can just be asked during the visit. The questions include whether the patient currently has or has had a swollen joint, nail pits, heel pain, and/or dactylitis, as well as if they have been told by a physician that they have arthritis. A score of 3 or higher is considered positive and a referral to rheumatology should be considered. At the bare minimum, I highly encourage all dermatologists to incorporate the PEST screening tool into their practice.

During the physical examination itself, be sure to look at the patient’s nails and also look for joint swelling and redness, especially in the hands. When palpating a swollen joint, the presence of inflammatory arthritis will feel spongy or boggy, while the osteophytes associated with osteoarthritis will feel hard. Radiography of the affected joint may be helpful, but keep in mind that bone changes are latter sequelae of PsA, and negative radiographs do not rule out PsA.

If you highly suspect PsA after using the PEST screening tool and palpating any swollen joints, then a rheumatology referral certainly is warranted. Medication that covers both psoriasis and PsA also can be initiated. Although methotrexate often is used for joints, higher doses (ie, >15 mg/wk) usually are needed. A 2019 Cochrane review found that low-dose methotrexate (ie, ≤15 mg/wk) may be only slightly more effective then placebo⁵—certainly not a ringing endorsement for its use in PsA. Additionally, quality data demonstrating methotrexate’s efficacy for enthesitis or axial spondyloarthritis is lacking, and methotrexate has not demonstrated an ability to slow the radiographic progression of joints. In contrast, the anti–tumor necrosis factor agents, including adalimumab, infliximab, etanercept, and certolizumab, as well as ustekinumab and the anti–IL-17 biologics secukinumab and ixekizumab have demonstrated efficacy in American College of Rheumatology (ACR) scores, enthesitis, dactylitis, and prevention of radiographic progression of joints.^6,7 Although brodalumab, an anti–IL-17 receptor inhibitor, demonstrated improvement in ACR scores, enthesitis, and dactylitis, data on its effects on radiographic progression of joints were inconclusive given the phase III trial’s premature ending due to suicidal ideation and behavior in participants.⁸ Several of the anti–IL-23 agents also may help PsA, with trials demonstrating improvements in ACR scores, enthesitis, and dactylitis; however, only guselkumab 100 mg every 4 weeks decreased radiographic progression of joints.⁹ Additionally, with the age of the Janus kinase (JAK) inhibitor upon us, there are several JAK/TYK2 inhibitors that are approved by the US Food and Drug Administration for psoriasis (deucravacitinib) as well as for PsA (tofacitinib, upadacitinib), and there are more JAK inhibitors in the pipeline. These medications are effective; however, I do encourage caution and careful consideration in selecting the appropriate patient, as data demonstrated an increased risk for major adverse cardiovascular events and cancer in older (>50 years) rheumatoid arthritis patients who had at least 1 cardiovascular risk factor and were treated with tofacitinib.¹⁰ Although several other trials have not demonstrated this increased risk, further data are needed to determine risk for both pan-JAK inhibitors as well as selective JAK inhibitors and TYK2 inhibitors. Additionally, given psoriasis already is closely linked with many cardiovascular risk factors including heart disease, obesity, hypertension, hyperlipidemia, and diabetes mellitus,¹¹ it will be important to have long-term safety information for JAK inhibitors in the psoriasis and PsA population.

Dermatologists are in a pivotal position to identify patients affected by PsA and start an appropriate systemic medication. We can help make an enormous impact on our patients’ lives as well as help decrease the economic impact of untreated disease. Let’s join the effort to save the joints!

Patients are finding it easier to use online resources to discover health care providers who fit their personalized needs. In the United States, approximately 70% of individuals use the internet to find health care information, and 80% are influenced by the information presented to them on health care websites.¹ Patients utilize the internet to better understand treatments offered by providers and their prices as well as how other patients have rated their experience. Providers in private practice also have noticed that many patients are referring themselves vs obtaining a referral from another provider.² As a result, it is critical for practice websites to have information that is of value to their patients, including the unique qualities and treatments offered. The purpose of this study was to analyze the differences between the content presented on dermatology private practice websites and academic institutional websites.

Methods

Websites Searched —All 140 academic dermatology programs, including both allopathic and osteopathic programs, were queried from the Association of American Medical Colleges (AAMC) database in March 2022. ³ First, the dermatology departmental websites for each program were analyzed to see if they contained information pertinent to patients. Any website that lacked this information or only had information relevant to the dermatology residency program was excluded from the study. After exclusion, a total of 113 websites were used in the academic website cohort. The private practices were found through an incognito Google search with the search term dermatologist and matched to be within 5 miles of each academic institution. The private practices that included at least one board-certified dermatologist and received the highest number of reviews on Google compared to other practices in the same region—a measure of online reputation—were selected to be in the private practice cohort (N = 113). Any duplicate practices, practices belonging to the same conglomerate company, or multispecialty clinics were excluded from the study. Board-certified dermatologists were confirmed using the Find a Dermatologist tool on the American Academy of Dermatology (AAD) website. ⁴

Website Assessments —Each website was assessed using 23 criteria divided into 4 categories: practice, physician(s), patient, and treatment/procedure (Table). Criteria for social media and publicity were further assessed. Criteria for social media included links on the website to a Facebook page, an Instagram account, a Twitter account, a Pinterest account, a LinkedIn account, a blog, a Yelp page, a YouTube channel, and/or any other social media. Criteria for publicity included links on the website to local television news, national news, newspapers, and/or magazines. ^5-8 Ease of site access was determined if the website was the first search result found on Google when searching for each website. Nondermatology professionals included listing of mid-level providers or researchers.

Four individuals (V.S.J., A.C.B., M.E.O., and M.B.B.) independently assessed each of the websites using the established criteria. Each criterion was defined and discussed prior to data collection to maintain consistency. The criteria were determined as being present if the website clearly displayed, stated, explained, or linked to the relevant content. If the website did not directly contain the content, it was determined that the criteria were absent. One other individual (J.P.) independently cross-examined the data for consistency and evaluated for any discrepancies. ⁸

A raw analysis was done between each cohort. Another analysis was done that controlled for population density and the proportionate population age in each city ⁹ in which an academic institution/private practice was located. We proposed that more densely populated cities naturally may have more competition between practices, which may result in more optimized websites. ¹⁰ We also anticipated similar findings in cities with younger populations, as the younger demographic may be more likely to utilize and value online information when compared to older populations. ¹¹ The websites for each cohort were equally divided into 3 tiers of population density (not shown) and population age (not shown).

Statistical Analysis —Statistical analysis was completed using descriptive statistics, χ ² testing, and Fisher exact tests where appropriate with a predetermined level of significance of P < .05 in Microsoft Excel.

Results

Demographics —A total of 226 websites from both private practices and academic institutions were evaluated. Of them, only 108 private practices and 108 academic institutions listed practicing dermatologists on their site. Of 108 private practices, 76 (70.4%) had more than one practicing board-certified dermatologist. Of 108 academic institutions, all 108 (100%) institutions had more than one practicing board-certified dermatologist.

Of the dermatologists who practiced at academic institutions (n=2014) and private practices (n=817), 1157 (57.4%) and 419 (51.2%) were females, respectively. The population density of the cities with each of these practices/institutions ranged from 137 individuals per square kilometer to 11,232 individuals per square kilometer (mean [SD] population density, 2579 [2485] individuals per square kilometer). Densely populated, moderately populated, and sparsely populated cities had a median population density of 4618, 1708, and 760 individuals per square kilometer, respectively. The data also were divided into 3 age groups. In the older population tier, the median percentage of individuals older than 64 years was 14.2%, the median percentage of individuals aged 18 to 64 years was 63.8%, and the median percentage of individuals aged 5 to 17 years was 14.9%. In the moderately aged population tier, the median percentage of individuals older than 64 years was 10.2%, the median percentage of individuals aged 18 to 64 years was 70.3%, and the median percentage of individuals aged 5 to 17 years was 13.6%. In the younger population tier, the median percentage of individuals older than 64 years was 12%, the median percentage of individuals aged 18 to 64 years was 66.8%, and the median percentage of individuals aged 5 to 17 years was 15%.

Practice and Physician Content—In the raw analysis (Figure), the most commonly listed types of content (>90% of websites) in both private practice and academic sites was address (range, 95% to 100%), telephone number (range, 97% to 100%), and dermatologist profiles (both 92%). The least commonly listed types of content in both cohorts was publicity (range, 20% to 23%). Private practices were more likely to list profiles of nondermatology professionals (73% vs 56%; P<.02), email (47% vs 17%; P<.0001), and social media (29% vs 8%; P<.0001) compared with academic institution websites. Although Facebook was the most-linked social media account for both groups, 75% of private practice sites included the link compared with 16% of academic institutions. Academic institutions were more likely to list fellowship availability (66% vs 1%; P<.0001). Accessing each website was significantly easier in the private practice cohort (99% vs 61%; P<.0001).

When controlling for population density, private practices were only more likely to list nondermatology professionals’ profiles in densely populated cities when compared with academic institutions (73% vs 41%; P<.01). Academic institutions continued to list fellowship availability more often than private practices regardless of population density. The same trend was observed for private practices with ease of site access and listing of social media.

When controlling for population age, similar trends were seen as when controlling for population density. However, private practices listing nondermatology professionals’ profiles was only more likely in the cities with a proportionately younger population when compared with academic institutions (74% vs 47%; P<.04). 

Patient and Treatment/Procedure—The most commonly listed content types on both private practice websites and academic institution websites were available treatments/procedures (range, 89% to 98%). The least commonly listed content included financing for elective procedures (range, 4% to 16%), consultation fees (range, 1% to 2%), FAQs (frequently asked questions)(range, 4% to 20%), and HIPAA (Health Insurance Portability and Accountability Act) policy (range, 12% to 22%). Private practices were more likely to list patient testimonials (52% vs 35%; P<.005), financing (16% vs 4%; P<.005), FAQs (20% vs 4%; P<.001), online appointments (77% vs 56%; P<.001), available treatments/procedures (98% vs 86%; P<.004), product advertisements (66% vs 16%; P<.0001), pictures of dermatology conditions (33% vs 13%; P<.001), and HIPAA policy (22% vs 12%; P<.04). Academic institutions were more likely to list research trials (65% vs 13%; P<.0001).

When controlling for population density, private practices were only more likely to list patient testimonials in densely populated (P=.035) and moderately populated cities (P=.019). The same trend was observed for online appointments in densely populated (P=.0023) and moderately populated cities (P=.037). Private practices continued to list product availability more often than academic institutions regardless of population density or population age. Academic institutions also continued to list research trials more often than private practices regardless of population density or population age. 

Comment

Our study uniquely analyzed the differences in website content between private practices and academic institutions in dermatology. Of the 140 academic institutions accredited by the Accreditation Council for Graduate Medical Education (ACGME), only 113 had patient-pertinent websites.

Access to Websites —There was a significant difference in many website content criteria between the 2 groups. Private practice sites were easier to access via a Google search when compared with academic sites, which likely is influenced by the Google search algorithm that ranks websites higher based on several criteria including but not limited to keyword use in the title tag, link popularity of the site, and historic ranking. ^12,13 Academic sites often were only accessible through portals found on their main institutional site or institution’s residency site.

Role of Social Media —Social media has been found to assist in educating patients on medical practices as well as selecting a physician. ^14,15 Our study found that private practice websites listed links to social media more often than their academic counterparts. Social media consumption is increasing, in part due to the COVID-19 pandemic, and it may be optimal for patients and practices alike to include links on their websites. ¹⁶ Facebook and Instagram were listed more often on private practice sites when compared with academic institution sites, which was similar to a recent study analyzing the websites of plastic surgery private practices (N = 310) in which 90% of private practices included some type of social media, with Instagram and Facebook being the most used. ⁸ Social networking accounts can act as convenient platforms for marketing, providing patient education, and generating referrals, which suggests that the prominence of their usage in private practice poses benefits in patient decision-making when seeking care. ^17-19 A study analyzing the impact of Facebook in medicine concluded that a Facebook page can serve as an effective vehicle for medical education, particularly in younger generations that favor technology-oriented teaching methods. ²⁰ A survey on trends in cosmetic facial procedures in plastic surgery found that the most influential online methods patients used for choosing their providers were social media platforms and practice websites. Front-page placement on Google also was commonly associated with the number of social media followers. ^21,22 A lack of social media prominence could hinder a website’s potential to reach patients.

Communication With Practices —Our study also found significant differences in other metrics related to a patient’s ability to directly communicate with a practice, such as physical addresses, telephone numbers, products available for direct purchase, and online appointment booking, all of which were listed more often on private practice websites compared with academic institution websites. Online appointment booking also was found more frequently on private practice websites. Although physical addresses and telephone numbers were listed significantly more often on private practice sites, this information was ubiquitous and easily accessible elsewhere. Academic institution websites listed research trials and fellowship training significantly more often than private practices. These differences imply a divergence in focus between private practices and academic institutions, likely because academic institutions are funded in large part from research grants, begetting a cycle of academic contribution. ²³ In contrast, private practices may not rely as heavily on academic revenue and may be more likely to prioritize other revenue streams such as product sales. ²⁴  

HIPAA Policy —Surprisingly, HIPAA policy rarely was listed on any private (22%) or academic site (12%). Conversely, in the plastic surgery study, HIPAA policy was listed much more often, with more than half of private practices with board-certified plastic surgeons accredited in the year 2015 including it on their website, ⁸ which may suggest that surgically oriented specialties, particularly cosmetic subspecialties, aim to more noticeably display their privacy policies for patient reassurance.

Study Limitations —There are several limitations of our study. First, it is common for a conglomerate company to own multiple private practices in different specialties. As with academic sites, private practice sites may be limited by the hosting platforms, which often are tedious to navigate. Also noteworthy is the emergence of designated social media management positions—both by practice employees and by third-party firms ²⁵ —but the impact of these positions in private practices and academic institutions has not been fully explored. Finally, inclusion criteria and standardized criteria definitions were chosen based on the precedent established by the authors of similar analyses in plastic surgery and radiology. ^5-8 Further investigation into the most valued aspects of care by patients within the context of the type of practice chosen would be valuable in refining inclusion criteria. Additionally, this study did not stratify the data collected based on factors such as gender, race, and geographical location; studies conducted on website traffic analysis patterns that focus on these aspects likely would further explain the significance of these findings. Differences in the length of time to the next available appointment between private practices and academic institutions also may help support our findings. Finally, there is a need for further investigation into the preferences of patients themselves garnered from website traffic alone.

Conclusion

Our study examined a diverse compilation of private practice and academic institution websites and uncovered numerous differences in content. As technology and health care continuously evolve, it is imperative that both private practices and academic institutions are actively adapting to optimize their online presence. In doing so, patients will be better equipped at accessing provider information, gaining familiarity with the practice, and understanding treatment options.  

Patients are finding it easier to use online resources to discover health care providers who fit their personalized needs. In the United States, approximately 70% of individuals use the internet to find health care information, and 80% are influenced by the information presented to them on health care websites.¹ Patients utilize the internet to better understand treatments offered by providers and their prices as well as how other patients have rated their experience. Providers in private practice also have noticed that many patients are referring themselves vs obtaining a referral from another provider.² As a result, it is critical for practice websites to have information that is of value to their patients, including the unique qualities and treatments offered. The purpose of this study was to analyze the differences between the content presented on dermatology private practice websites and academic institutional websites.

Methods

Websites Searched —All 140 academic dermatology programs, including both allopathic and osteopathic programs, were queried from the Association of American Medical Colleges (AAMC) database in March 2022. ³ First, the dermatology departmental websites for each program were analyzed to see if they contained information pertinent to patients. Any website that lacked this information or only had information relevant to the dermatology residency program was excluded from the study. After exclusion, a total of 113 websites were used in the academic website cohort. The private practices were found through an incognito Google search with the search term dermatologist and matched to be within 5 miles of each academic institution. The private practices that included at least one board-certified dermatologist and received the highest number of reviews on Google compared to other practices in the same region—a measure of online reputation—were selected to be in the private practice cohort (N = 113). Any duplicate practices, practices belonging to the same conglomerate company, or multispecialty clinics were excluded from the study. Board-certified dermatologists were confirmed using the Find a Dermatologist tool on the American Academy of Dermatology (AAD) website. ⁴

Website Assessments —Each website was assessed using 23 criteria divided into 4 categories: practice, physician(s), patient, and treatment/procedure (Table). Criteria for social media and publicity were further assessed. Criteria for social media included links on the website to a Facebook page, an Instagram account, a Twitter account, a Pinterest account, a LinkedIn account, a blog, a Yelp page, a YouTube channel, and/or any other social media. Criteria for publicity included links on the website to local television news, national news, newspapers, and/or magazines. ^5-8 Ease of site access was determined if the website was the first search result found on Google when searching for each website. Nondermatology professionals included listing of mid-level providers or researchers.

Four individuals (V.S.J., A.C.B., M.E.O., and M.B.B.) independently assessed each of the websites using the established criteria. Each criterion was defined and discussed prior to data collection to maintain consistency. The criteria were determined as being present if the website clearly displayed, stated, explained, or linked to the relevant content. If the website did not directly contain the content, it was determined that the criteria were absent. One other individual (J.P.) independently cross-examined the data for consistency and evaluated for any discrepancies. ⁸

A raw analysis was done between each cohort. Another analysis was done that controlled for population density and the proportionate population age in each city ⁹ in which an academic institution/private practice was located. We proposed that more densely populated cities naturally may have more competition between practices, which may result in more optimized websites. ¹⁰ We also anticipated similar findings in cities with younger populations, as the younger demographic may be more likely to utilize and value online information when compared to older populations. ¹¹ The websites for each cohort were equally divided into 3 tiers of population density (not shown) and population age (not shown).

Statistical Analysis —Statistical analysis was completed using descriptive statistics, χ ² testing, and Fisher exact tests where appropriate with a predetermined level of significance of P < .05 in Microsoft Excel.

Results

Demographics —A total of 226 websites from both private practices and academic institutions were evaluated. Of them, only 108 private practices and 108 academic institutions listed practicing dermatologists on their site. Of 108 private practices, 76 (70.4%) had more than one practicing board-certified dermatologist. Of 108 academic institutions, all 108 (100%) institutions had more than one practicing board-certified dermatologist.

Of the dermatologists who practiced at academic institutions (n=2014) and private practices (n=817), 1157 (57.4%) and 419 (51.2%) were females, respectively. The population density of the cities with each of these practices/institutions ranged from 137 individuals per square kilometer to 11,232 individuals per square kilometer (mean [SD] population density, 2579 [2485] individuals per square kilometer). Densely populated, moderately populated, and sparsely populated cities had a median population density of 4618, 1708, and 760 individuals per square kilometer, respectively. The data also were divided into 3 age groups. In the older population tier, the median percentage of individuals older than 64 years was 14.2%, the median percentage of individuals aged 18 to 64 years was 63.8%, and the median percentage of individuals aged 5 to 17 years was 14.9%. In the moderately aged population tier, the median percentage of individuals older than 64 years was 10.2%, the median percentage of individuals aged 18 to 64 years was 70.3%, and the median percentage of individuals aged 5 to 17 years was 13.6%. In the younger population tier, the median percentage of individuals older than 64 years was 12%, the median percentage of individuals aged 18 to 64 years was 66.8%, and the median percentage of individuals aged 5 to 17 years was 15%.

Practice and Physician Content—In the raw analysis (Figure), the most commonly listed types of content (>90% of websites) in both private practice and academic sites was address (range, 95% to 100%), telephone number (range, 97% to 100%), and dermatologist profiles (both 92%). The least commonly listed types of content in both cohorts was publicity (range, 20% to 23%). Private practices were more likely to list profiles of nondermatology professionals (73% vs 56%; P<.02), email (47% vs 17%; P<.0001), and social media (29% vs 8%; P<.0001) compared with academic institution websites. Although Facebook was the most-linked social media account for both groups, 75% of private practice sites included the link compared with 16% of academic institutions. Academic institutions were more likely to list fellowship availability (66% vs 1%; P<.0001). Accessing each website was significantly easier in the private practice cohort (99% vs 61%; P<.0001).

When controlling for population density, private practices were only more likely to list nondermatology professionals’ profiles in densely populated cities when compared with academic institutions (73% vs 41%; P<.01). Academic institutions continued to list fellowship availability more often than private practices regardless of population density. The same trend was observed for private practices with ease of site access and listing of social media.

When controlling for population age, similar trends were seen as when controlling for population density. However, private practices listing nondermatology professionals’ profiles was only more likely in the cities with a proportionately younger population when compared with academic institutions (74% vs 47%; P<.04). 

Patient and Treatment/Procedure—The most commonly listed content types on both private practice websites and academic institution websites were available treatments/procedures (range, 89% to 98%). The least commonly listed content included financing for elective procedures (range, 4% to 16%), consultation fees (range, 1% to 2%), FAQs (frequently asked questions)(range, 4% to 20%), and HIPAA (Health Insurance Portability and Accountability Act) policy (range, 12% to 22%). Private practices were more likely to list patient testimonials (52% vs 35%; P<.005), financing (16% vs 4%; P<.005), FAQs (20% vs 4%; P<.001), online appointments (77% vs 56%; P<.001), available treatments/procedures (98% vs 86%; P<.004), product advertisements (66% vs 16%; P<.0001), pictures of dermatology conditions (33% vs 13%; P<.001), and HIPAA policy (22% vs 12%; P<.04). Academic institutions were more likely to list research trials (65% vs 13%; P<.0001).

When controlling for population density, private practices were only more likely to list patient testimonials in densely populated (P=.035) and moderately populated cities (P=.019). The same trend was observed for online appointments in densely populated (P=.0023) and moderately populated cities (P=.037). Private practices continued to list product availability more often than academic institutions regardless of population density or population age. Academic institutions also continued to list research trials more often than private practices regardless of population density or population age. 

Comment

Our study uniquely analyzed the differences in website content between private practices and academic institutions in dermatology. Of the 140 academic institutions accredited by the Accreditation Council for Graduate Medical Education (ACGME), only 113 had patient-pertinent websites.

Access to Websites —There was a significant difference in many website content criteria between the 2 groups. Private practice sites were easier to access via a Google search when compared with academic sites, which likely is influenced by the Google search algorithm that ranks websites higher based on several criteria including but not limited to keyword use in the title tag, link popularity of the site, and historic ranking. ^12,13 Academic sites often were only accessible through portals found on their main institutional site or institution’s residency site.

Role of Social Media —Social media has been found to assist in educating patients on medical practices as well as selecting a physician. ^14,15 Our study found that private practice websites listed links to social media more often than their academic counterparts. Social media consumption is increasing, in part due to the COVID-19 pandemic, and it may be optimal for patients and practices alike to include links on their websites. ¹⁶ Facebook and Instagram were listed more often on private practice sites when compared with academic institution sites, which was similar to a recent study analyzing the websites of plastic surgery private practices (N = 310) in which 90% of private practices included some type of social media, with Instagram and Facebook being the most used. ⁸ Social networking accounts can act as convenient platforms for marketing, providing patient education, and generating referrals, which suggests that the prominence of their usage in private practice poses benefits in patient decision-making when seeking care. ^17-19 A study analyzing the impact of Facebook in medicine concluded that a Facebook page can serve as an effective vehicle for medical education, particularly in younger generations that favor technology-oriented teaching methods. ²⁰ A survey on trends in cosmetic facial procedures in plastic surgery found that the most influential online methods patients used for choosing their providers were social media platforms and practice websites. Front-page placement on Google also was commonly associated with the number of social media followers. ^21,22 A lack of social media prominence could hinder a website’s potential to reach patients.

Communication With Practices —Our study also found significant differences in other metrics related to a patient’s ability to directly communicate with a practice, such as physical addresses, telephone numbers, products available for direct purchase, and online appointment booking, all of which were listed more often on private practice websites compared with academic institution websites. Online appointment booking also was found more frequently on private practice websites. Although physical addresses and telephone numbers were listed significantly more often on private practice sites, this information was ubiquitous and easily accessible elsewhere. Academic institution websites listed research trials and fellowship training significantly more often than private practices. These differences imply a divergence in focus between private practices and academic institutions, likely because academic institutions are funded in large part from research grants, begetting a cycle of academic contribution. ²³ In contrast, private practices may not rely as heavily on academic revenue and may be more likely to prioritize other revenue streams such as product sales. ²⁴  

HIPAA Policy —Surprisingly, HIPAA policy rarely was listed on any private (22%) or academic site (12%). Conversely, in the plastic surgery study, HIPAA policy was listed much more often, with more than half of private practices with board-certified plastic surgeons accredited in the year 2015 including it on their website, ⁸ which may suggest that surgically oriented specialties, particularly cosmetic subspecialties, aim to more noticeably display their privacy policies for patient reassurance.

Study Limitations —There are several limitations of our study. First, it is common for a conglomerate company to own multiple private practices in different specialties. As with academic sites, private practice sites may be limited by the hosting platforms, which often are tedious to navigate. Also noteworthy is the emergence of designated social media management positions—both by practice employees and by third-party firms ²⁵ —but the impact of these positions in private practices and academic institutions has not been fully explored. Finally, inclusion criteria and standardized criteria definitions were chosen based on the precedent established by the authors of similar analyses in plastic surgery and radiology. ^5-8 Further investigation into the most valued aspects of care by patients within the context of the type of practice chosen would be valuable in refining inclusion criteria. Additionally, this study did not stratify the data collected based on factors such as gender, race, and geographical location; studies conducted on website traffic analysis patterns that focus on these aspects likely would further explain the significance of these findings. Differences in the length of time to the next available appointment between private practices and academic institutions also may help support our findings. Finally, there is a need for further investigation into the preferences of patients themselves garnered from website traffic alone.

Conclusion

Our study examined a diverse compilation of private practice and academic institution websites and uncovered numerous differences in content. As technology and health care continuously evolve, it is imperative that both private practices and academic institutions are actively adapting to optimize their online presence. In doing so, patients will be better equipped at accessing provider information, gaining familiarity with the practice, and understanding treatment options.  

Patients are finding it easier to use online resources to discover health care providers who fit their personalized needs. In the United States, approximately 70% of individuals use the internet to find health care information, and 80% are influenced by the information presented to them on health care websites.¹ Patients utilize the internet to better understand treatments offered by providers and their prices as well as how other patients have rated their experience. Providers in private practice also have noticed that many patients are referring themselves vs obtaining a referral from another provider.² As a result, it is critical for practice websites to have information that is of value to their patients, including the unique qualities and treatments offered. The purpose of this study was to analyze the differences between the content presented on dermatology private practice websites and academic institutional websites.

Methods

Websites Searched —All 140 academic dermatology programs, including both allopathic and osteopathic programs, were queried from the Association of American Medical Colleges (AAMC) database in March 2022. ³ First, the dermatology departmental websites for each program were analyzed to see if they contained information pertinent to patients. Any website that lacked this information or only had information relevant to the dermatology residency program was excluded from the study. After exclusion, a total of 113 websites were used in the academic website cohort. The private practices were found through an incognito Google search with the search term dermatologist and matched to be within 5 miles of each academic institution. The private practices that included at least one board-certified dermatologist and received the highest number of reviews on Google compared to other practices in the same region—a measure of online reputation—were selected to be in the private practice cohort (N = 113). Any duplicate practices, practices belonging to the same conglomerate company, or multispecialty clinics were excluded from the study. Board-certified dermatologists were confirmed using the Find a Dermatologist tool on the American Academy of Dermatology (AAD) website. ⁴

Website Assessments —Each website was assessed using 23 criteria divided into 4 categories: practice, physician(s), patient, and treatment/procedure (Table). Criteria for social media and publicity were further assessed. Criteria for social media included links on the website to a Facebook page, an Instagram account, a Twitter account, a Pinterest account, a LinkedIn account, a blog, a Yelp page, a YouTube channel, and/or any other social media. Criteria for publicity included links on the website to local television news, national news, newspapers, and/or magazines. ^5-8 Ease of site access was determined if the website was the first search result found on Google when searching for each website. Nondermatology professionals included listing of mid-level providers or researchers.

Four individuals (V.S.J., A.C.B., M.E.O., and M.B.B.) independently assessed each of the websites using the established criteria. Each criterion was defined and discussed prior to data collection to maintain consistency. The criteria were determined as being present if the website clearly displayed, stated, explained, or linked to the relevant content. If the website did not directly contain the content, it was determined that the criteria were absent. One other individual (J.P.) independently cross-examined the data for consistency and evaluated for any discrepancies. ⁸

A raw analysis was done between each cohort. Another analysis was done that controlled for population density and the proportionate population age in each city ⁹ in which an academic institution/private practice was located. We proposed that more densely populated cities naturally may have more competition between practices, which may result in more optimized websites. ¹⁰ We also anticipated similar findings in cities with younger populations, as the younger demographic may be more likely to utilize and value online information when compared to older populations. ¹¹ The websites for each cohort were equally divided into 3 tiers of population density (not shown) and population age (not shown).

Statistical Analysis —Statistical analysis was completed using descriptive statistics, χ ² testing, and Fisher exact tests where appropriate with a predetermined level of significance of P < .05 in Microsoft Excel.

Results

Demographics —A total of 226 websites from both private practices and academic institutions were evaluated. Of them, only 108 private practices and 108 academic institutions listed practicing dermatologists on their site. Of 108 private practices, 76 (70.4%) had more than one practicing board-certified dermatologist. Of 108 academic institutions, all 108 (100%) institutions had more than one practicing board-certified dermatologist.

Of the dermatologists who practiced at academic institutions (n=2014) and private practices (n=817), 1157 (57.4%) and 419 (51.2%) were females, respectively. The population density of the cities with each of these practices/institutions ranged from 137 individuals per square kilometer to 11,232 individuals per square kilometer (mean [SD] population density, 2579 [2485] individuals per square kilometer). Densely populated, moderately populated, and sparsely populated cities had a median population density of 4618, 1708, and 760 individuals per square kilometer, respectively. The data also were divided into 3 age groups. In the older population tier, the median percentage of individuals older than 64 years was 14.2%, the median percentage of individuals aged 18 to 64 years was 63.8%, and the median percentage of individuals aged 5 to 17 years was 14.9%. In the moderately aged population tier, the median percentage of individuals older than 64 years was 10.2%, the median percentage of individuals aged 18 to 64 years was 70.3%, and the median percentage of individuals aged 5 to 17 years was 13.6%. In the younger population tier, the median percentage of individuals older than 64 years was 12%, the median percentage of individuals aged 18 to 64 years was 66.8%, and the median percentage of individuals aged 5 to 17 years was 15%.

Practice and Physician Content—In the raw analysis (Figure), the most commonly listed types of content (>90% of websites) in both private practice and academic sites was address (range, 95% to 100%), telephone number (range, 97% to 100%), and dermatologist profiles (both 92%). The least commonly listed types of content in both cohorts was publicity (range, 20% to 23%). Private practices were more likely to list profiles of nondermatology professionals (73% vs 56%; P<.02), email (47% vs 17%; P<.0001), and social media (29% vs 8%; P<.0001) compared with academic institution websites. Although Facebook was the most-linked social media account for both groups, 75% of private practice sites included the link compared with 16% of academic institutions. Academic institutions were more likely to list fellowship availability (66% vs 1%; P<.0001). Accessing each website was significantly easier in the private practice cohort (99% vs 61%; P<.0001).

When controlling for population density, private practices were only more likely to list nondermatology professionals’ profiles in densely populated cities when compared with academic institutions (73% vs 41%; P<.01). Academic institutions continued to list fellowship availability more often than private practices regardless of population density. The same trend was observed for private practices with ease of site access and listing of social media.

When controlling for population age, similar trends were seen as when controlling for population density. However, private practices listing nondermatology professionals’ profiles was only more likely in the cities with a proportionately younger population when compared with academic institutions (74% vs 47%; P<.04). 

Patient and Treatment/Procedure—The most commonly listed content types on both private practice websites and academic institution websites were available treatments/procedures (range, 89% to 98%). The least commonly listed content included financing for elective procedures (range, 4% to 16%), consultation fees (range, 1% to 2%), FAQs (frequently asked questions)(range, 4% to 20%), and HIPAA (Health Insurance Portability and Accountability Act) policy (range, 12% to 22%). Private practices were more likely to list patient testimonials (52% vs 35%; P<.005), financing (16% vs 4%; P<.005), FAQs (20% vs 4%; P<.001), online appointments (77% vs 56%; P<.001), available treatments/procedures (98% vs 86%; P<.004), product advertisements (66% vs 16%; P<.0001), pictures of dermatology conditions (33% vs 13%; P<.001), and HIPAA policy (22% vs 12%; P<.04). Academic institutions were more likely to list research trials (65% vs 13%; P<.0001).

When controlling for population density, private practices were only more likely to list patient testimonials in densely populated (P=.035) and moderately populated cities (P=.019). The same trend was observed for online appointments in densely populated (P=.0023) and moderately populated cities (P=.037). Private practices continued to list product availability more often than academic institutions regardless of population density or population age. Academic institutions also continued to list research trials more often than private practices regardless of population density or population age. 

Comment

Our study uniquely analyzed the differences in website content between private practices and academic institutions in dermatology. Of the 140 academic institutions accredited by the Accreditation Council for Graduate Medical Education (ACGME), only 113 had patient-pertinent websites.

Access to Websites —There was a significant difference in many website content criteria between the 2 groups. Private practice sites were easier to access via a Google search when compared with academic sites, which likely is influenced by the Google search algorithm that ranks websites higher based on several criteria including but not limited to keyword use in the title tag, link popularity of the site, and historic ranking. ^12,13 Academic sites often were only accessible through portals found on their main institutional site or institution’s residency site.

Role of Social Media —Social media has been found to assist in educating patients on medical practices as well as selecting a physician. ^14,15 Our study found that private practice websites listed links to social media more often than their academic counterparts. Social media consumption is increasing, in part due to the COVID-19 pandemic, and it may be optimal for patients and practices alike to include links on their websites. ¹⁶ Facebook and Instagram were listed more often on private practice sites when compared with academic institution sites, which was similar to a recent study analyzing the websites of plastic surgery private practices (N = 310) in which 90% of private practices included some type of social media, with Instagram and Facebook being the most used. ⁸ Social networking accounts can act as convenient platforms for marketing, providing patient education, and generating referrals, which suggests that the prominence of their usage in private practice poses benefits in patient decision-making when seeking care. ^17-19 A study analyzing the impact of Facebook in medicine concluded that a Facebook page can serve as an effective vehicle for medical education, particularly in younger generations that favor technology-oriented teaching methods. ²⁰ A survey on trends in cosmetic facial procedures in plastic surgery found that the most influential online methods patients used for choosing their providers were social media platforms and practice websites. Front-page placement on Google also was commonly associated with the number of social media followers. ^21,22 A lack of social media prominence could hinder a website’s potential to reach patients.

Communication With Practices —Our study also found significant differences in other metrics related to a patient’s ability to directly communicate with a practice, such as physical addresses, telephone numbers, products available for direct purchase, and online appointment booking, all of which were listed more often on private practice websites compared with academic institution websites. Online appointment booking also was found more frequently on private practice websites. Although physical addresses and telephone numbers were listed significantly more often on private practice sites, this information was ubiquitous and easily accessible elsewhere. Academic institution websites listed research trials and fellowship training significantly more often than private practices. These differences imply a divergence in focus between private practices and academic institutions, likely because academic institutions are funded in large part from research grants, begetting a cycle of academic contribution. ²³ In contrast, private practices may not rely as heavily on academic revenue and may be more likely to prioritize other revenue streams such as product sales. ²⁴  

HIPAA Policy —Surprisingly, HIPAA policy rarely was listed on any private (22%) or academic site (12%). Conversely, in the plastic surgery study, HIPAA policy was listed much more often, with more than half of private practices with board-certified plastic surgeons accredited in the year 2015 including it on their website, ⁸ which may suggest that surgically oriented specialties, particularly cosmetic subspecialties, aim to more noticeably display their privacy policies for patient reassurance.

Study Limitations —There are several limitations of our study. First, it is common for a conglomerate company to own multiple private practices in different specialties. As with academic sites, private practice sites may be limited by the hosting platforms, which often are tedious to navigate. Also noteworthy is the emergence of designated social media management positions—both by practice employees and by third-party firms ²⁵ —but the impact of these positions in private practices and academic institutions has not been fully explored. Finally, inclusion criteria and standardized criteria definitions were chosen based on the precedent established by the authors of similar analyses in plastic surgery and radiology. ^5-8 Further investigation into the most valued aspects of care by patients within the context of the type of practice chosen would be valuable in refining inclusion criteria. Additionally, this study did not stratify the data collected based on factors such as gender, race, and geographical location; studies conducted on website traffic analysis patterns that focus on these aspects likely would further explain the significance of these findings. Differences in the length of time to the next available appointment between private practices and academic institutions also may help support our findings. Finally, there is a need for further investigation into the preferences of patients themselves garnered from website traffic alone.

Conclusion

Our study examined a diverse compilation of private practice and academic institution websites and uncovered numerous differences in content. As technology and health care continuously evolve, it is imperative that both private practices and academic institutions are actively adapting to optimize their online presence. In doing so, patients will be better equipped at accessing provider information, gaining familiarity with the practice, and understanding treatment options.  

Practice Gap

Nail art can skew the results of optical coherence tomography (OCT), a noninvasive imaging technology that is used to visualize nail morphology in diseases such as psoriatic arthritis and onychomycosis, with a penetration depth of 2 mm and high-resolution images.¹ Few studies have evaluated the effects of nail art on OCT. Saleah and colleagues¹ found that clear, semitransparent, and red nail polishes do not interfere with visualization of the nail plate, whereas nontransparent gel polish and art stones obscure the image. They did not comment on the effect of glitter nail art in their study, though they did test 1 nail that contained glitter.¹ Monpeurt et al² compared matte and glossy nail polishes. They found that matte polish was readily identifiable from the nail plate, whereas glossy polish presented a greater number of artifacts.²

The Solution

We looked at 3 glitter nail polishes—gold, pink, and silver—that were scanned by OCT to assess the effect of the polish on the resulting image. We determined that glitter particles completely obscured the nail bed and nail plate, regardless of color (Figure 1). Glossy clear polish imparted a distinct film on the top of the nail plate that did not obscure the nail plate or the nail bed (Figure 2).

We conclude that glitter nail polish contains numerous reflective solid particles that interfere with OCT imaging of the nail plate and nail bed. As a result, we recommend removal of nail art to properly assess nail pathology. Because removal may need to be conducted by a nail technician, the treating clinician should inform the patient ahead of time to come to the appointment with bare (ie, unpolished) nails.

Practice Implications

Bringing awareness to the necessity of removing nail art prior to OCT imaging is crucial because many patients partake in its application, and removal may require the involvement of a professional nail technician. If a patient can be made aware that they should remove all nail art in advance, they will be better prepared for an OCT imaging session. Such a protocol increases efficiency, decreases diagnostic delay, and reduces cost associated with multiple office visits.

Practice Gap

Nail art can skew the results of optical coherence tomography (OCT), a noninvasive imaging technology that is used to visualize nail morphology in diseases such as psoriatic arthritis and onychomycosis, with a penetration depth of 2 mm and high-resolution images.¹ Few studies have evaluated the effects of nail art on OCT. Saleah and colleagues¹ found that clear, semitransparent, and red nail polishes do not interfere with visualization of the nail plate, whereas nontransparent gel polish and art stones obscure the image. They did not comment on the effect of glitter nail art in their study, though they did test 1 nail that contained glitter.¹ Monpeurt et al² compared matte and glossy nail polishes. They found that matte polish was readily identifiable from the nail plate, whereas glossy polish presented a greater number of artifacts.²

The Solution

We looked at 3 glitter nail polishes—gold, pink, and silver—that were scanned by OCT to assess the effect of the polish on the resulting image. We determined that glitter particles completely obscured the nail bed and nail plate, regardless of color (Figure 1). Glossy clear polish imparted a distinct film on the top of the nail plate that did not obscure the nail plate or the nail bed (Figure 2).

We conclude that glitter nail polish contains numerous reflective solid particles that interfere with OCT imaging of the nail plate and nail bed. As a result, we recommend removal of nail art to properly assess nail pathology. Because removal may need to be conducted by a nail technician, the treating clinician should inform the patient ahead of time to come to the appointment with bare (ie, unpolished) nails.

Practice Implications

Bringing awareness to the necessity of removing nail art prior to OCT imaging is crucial because many patients partake in its application, and removal may require the involvement of a professional nail technician. If a patient can be made aware that they should remove all nail art in advance, they will be better prepared for an OCT imaging session. Such a protocol increases efficiency, decreases diagnostic delay, and reduces cost associated with multiple office visits.

Practice Gap

Nail art can skew the results of optical coherence tomography (OCT), a noninvasive imaging technology that is used to visualize nail morphology in diseases such as psoriatic arthritis and onychomycosis, with a penetration depth of 2 mm and high-resolution images.¹ Few studies have evaluated the effects of nail art on OCT. Saleah and colleagues¹ found that clear, semitransparent, and red nail polishes do not interfere with visualization of the nail plate, whereas nontransparent gel polish and art stones obscure the image. They did not comment on the effect of glitter nail art in their study, though they did test 1 nail that contained glitter.¹ Monpeurt et al² compared matte and glossy nail polishes. They found that matte polish was readily identifiable from the nail plate, whereas glossy polish presented a greater number of artifacts.²

The Solution

We looked at 3 glitter nail polishes—gold, pink, and silver—that were scanned by OCT to assess the effect of the polish on the resulting image. We determined that glitter particles completely obscured the nail bed and nail plate, regardless of color (Figure 1). Glossy clear polish imparted a distinct film on the top of the nail plate that did not obscure the nail plate or the nail bed (Figure 2).

We conclude that glitter nail polish contains numerous reflective solid particles that interfere with OCT imaging of the nail plate and nail bed. As a result, we recommend removal of nail art to properly assess nail pathology. Because removal may need to be conducted by a nail technician, the treating clinician should inform the patient ahead of time to come to the appointment with bare (ie, unpolished) nails.

Practice Implications

Bringing awareness to the necessity of removing nail art prior to OCT imaging is crucial because many patients partake in its application, and removal may require the involvement of a professional nail technician. If a patient can be made aware that they should remove all nail art in advance, they will be better prepared for an OCT imaging session. Such a protocol increases efficiency, decreases diagnostic delay, and reduces cost associated with multiple office visits.

The Diagnosis: Poroma

Histopathology showed an endophytic expansion of the epidermis by bland, uniform, basaloid epithelial cells with focal ductal differentiation and an abrupt transition with surrounding epidermal keratinocytes (Figure), consistent with a diagnosis of poroma. The patient elected to monitor the lesion rather than to have it excised.

Eccrine poroma, used interchangeably with the term poroma, is a rare benign adnexal tumor of the eccrine sweat glands resulting from proliferation of the acrosyringium.^1,2 It often occurs on the palms or soles, though it also can arise anywhere sweat glands are present.¹ Eccrine poromas often appear in middle-aged individuals as singular, well-circumscribed, red-brown papules or nodules.³ A characteristic feature is a shallow, cup-shaped depression within the larger papule or nodule.¹

Because the condition is benign and often asymptomatic, it can be safely monitored for progression.¹ However, if the lesion is symptomatic or located in a sensitive area, complete excision is curative.⁴ Eccrine poromas can recur, making close monitoring following excision important.⁵ The development of bleeding, itching, or pain in a previously asymptomatic lesion may indicate possible malignant transformation, which occurs in only 18% of cases.⁶

The differential diagnosis includes basal cell carcinoma, circumscribed acral hypokeratosis, Kaposi sarcoma, and pyogenic granuloma. Basal cell carcinoma is the most common type of skin cancer.⁷ In rare cases it has been shown to present on the palms or soles as a slowgrowing, reddish-pink papule or plaque with central ulceration. It typically is asymptomatic. Histopathology shows dermal nests of basaloid cells with peripheral palisading, stromal mucin, and peritumoral clefts. Treatment is surgical excision.⁷

Circumscribed acral hypokeratosis presents on the palms or soles as a solitary, shallow, well-defined lesion with a flat base and raised border.⁸ It often is red-pink in color and most frequently occurs in middle-aged women. Although the cause of the condition is unknown, it is thought to be the result of trauma or human papillomavirus infection.8 Biopsy results characteristically show hypokeratosis demarcated by a sharp and frayed cutoff from uninvolved acral skin with discrete hypogranulosis, dilated blood vessels in the papillary dermis, and slightly thickened collagen fibers in the reticular dermis.⁹ Surgical excision is a potential treatment option, as topical corticosteroids, retinoids, and calcipotriene have not been shown to be effective; spontaneous resolution has been reported.⁸

Kaposi sarcoma is a vascular neoplasm that is associated with human herpesvirus 8 infection.¹⁰ It typically presents on mucocutaneous sites and the lower extremities. Palmar involvement has been reported in rare cases, occurring as a solitary, well-demarcated, violaceous macule or patch that may be painful.^10-12 Characteristic histopathologic features include a proliferation in the dermis of slitlike vascular spaces and spindle cell proliferation.¹³ Treatment options include cryosurgery; pulsed dye laser; and topical, intralesional, or systemic chemotherapy agents, depending on the stage of the patient’s disease. Antiretroviral therapy is indicated for patients with Kaposi sarcoma secondary to AIDS.¹⁴

Pyogenic granuloma presents as a solitary red-brown or bluish-black papule or nodule that bleeds easily when manipulated.¹⁵ It commonly occurs following trauma, typically on the fingers, feet, and lips.⁶ Although benign, potential complications include ulceration and blood loss. Pyogenic granulomas can be treated via curettage and cautery, excision, cryosurgery, or pulsed dye laser.¹⁵

The Diagnosis: Poroma

Histopathology showed an endophytic expansion of the epidermis by bland, uniform, basaloid epithelial cells with focal ductal differentiation and an abrupt transition with surrounding epidermal keratinocytes (Figure), consistent with a diagnosis of poroma. The patient elected to monitor the lesion rather than to have it excised.

Eccrine poroma, used interchangeably with the term poroma, is a rare benign adnexal tumor of the eccrine sweat glands resulting from proliferation of the acrosyringium.^1,2 It often occurs on the palms or soles, though it also can arise anywhere sweat glands are present.¹ Eccrine poromas often appear in middle-aged individuals as singular, well-circumscribed, red-brown papules or nodules.³ A characteristic feature is a shallow, cup-shaped depression within the larger papule or nodule.¹

Because the condition is benign and often asymptomatic, it can be safely monitored for progression.¹ However, if the lesion is symptomatic or located in a sensitive area, complete excision is curative.⁴ Eccrine poromas can recur, making close monitoring following excision important.⁵ The development of bleeding, itching, or pain in a previously asymptomatic lesion may indicate possible malignant transformation, which occurs in only 18% of cases.⁶

The differential diagnosis includes basal cell carcinoma, circumscribed acral hypokeratosis, Kaposi sarcoma, and pyogenic granuloma. Basal cell carcinoma is the most common type of skin cancer.⁷ In rare cases it has been shown to present on the palms or soles as a slowgrowing, reddish-pink papule or plaque with central ulceration. It typically is asymptomatic. Histopathology shows dermal nests of basaloid cells with peripheral palisading, stromal mucin, and peritumoral clefts. Treatment is surgical excision.⁷

Circumscribed acral hypokeratosis presents on the palms or soles as a solitary, shallow, well-defined lesion with a flat base and raised border.⁸ It often is red-pink in color and most frequently occurs in middle-aged women. Although the cause of the condition is unknown, it is thought to be the result of trauma or human papillomavirus infection.8 Biopsy results characteristically show hypokeratosis demarcated by a sharp and frayed cutoff from uninvolved acral skin with discrete hypogranulosis, dilated blood vessels in the papillary dermis, and slightly thickened collagen fibers in the reticular dermis.⁹ Surgical excision is a potential treatment option, as topical corticosteroids, retinoids, and calcipotriene have not been shown to be effective; spontaneous resolution has been reported.⁸

Kaposi sarcoma is a vascular neoplasm that is associated with human herpesvirus 8 infection.¹⁰ It typically presents on mucocutaneous sites and the lower extremities. Palmar involvement has been reported in rare cases, occurring as a solitary, well-demarcated, violaceous macule or patch that may be painful.^10-12 Characteristic histopathologic features include a proliferation in the dermis of slitlike vascular spaces and spindle cell proliferation.¹³ Treatment options include cryosurgery; pulsed dye laser; and topical, intralesional, or systemic chemotherapy agents, depending on the stage of the patient’s disease. Antiretroviral therapy is indicated for patients with Kaposi sarcoma secondary to AIDS.¹⁴

Pyogenic granuloma presents as a solitary red-brown or bluish-black papule or nodule that bleeds easily when manipulated.¹⁵ It commonly occurs following trauma, typically on the fingers, feet, and lips.⁶ Although benign, potential complications include ulceration and blood loss. Pyogenic granulomas can be treated via curettage and cautery, excision, cryosurgery, or pulsed dye laser.¹⁵

The Diagnosis: Poroma

Histopathology showed an endophytic expansion of the epidermis by bland, uniform, basaloid epithelial cells with focal ductal differentiation and an abrupt transition with surrounding epidermal keratinocytes (Figure), consistent with a diagnosis of poroma. The patient elected to monitor the lesion rather than to have it excised.

Eccrine poroma, used interchangeably with the term poroma, is a rare benign adnexal tumor of the eccrine sweat glands resulting from proliferation of the acrosyringium.^1,2 It often occurs on the palms or soles, though it also can arise anywhere sweat glands are present.¹ Eccrine poromas often appear in middle-aged individuals as singular, well-circumscribed, red-brown papules or nodules.³ A characteristic feature is a shallow, cup-shaped depression within the larger papule or nodule.¹

Because the condition is benign and often asymptomatic, it can be safely monitored for progression.¹ However, if the lesion is symptomatic or located in a sensitive area, complete excision is curative.⁴ Eccrine poromas can recur, making close monitoring following excision important.⁵ The development of bleeding, itching, or pain in a previously asymptomatic lesion may indicate possible malignant transformation, which occurs in only 18% of cases.⁶

The differential diagnosis includes basal cell carcinoma, circumscribed acral hypokeratosis, Kaposi sarcoma, and pyogenic granuloma. Basal cell carcinoma is the most common type of skin cancer.⁷ In rare cases it has been shown to present on the palms or soles as a slowgrowing, reddish-pink papule or plaque with central ulceration. It typically is asymptomatic. Histopathology shows dermal nests of basaloid cells with peripheral palisading, stromal mucin, and peritumoral clefts. Treatment is surgical excision.⁷

Circumscribed acral hypokeratosis presents on the palms or soles as a solitary, shallow, well-defined lesion with a flat base and raised border.⁸ It often is red-pink in color and most frequently occurs in middle-aged women. Although the cause of the condition is unknown, it is thought to be the result of trauma or human papillomavirus infection.8 Biopsy results characteristically show hypokeratosis demarcated by a sharp and frayed cutoff from uninvolved acral skin with discrete hypogranulosis, dilated blood vessels in the papillary dermis, and slightly thickened collagen fibers in the reticular dermis.⁹ Surgical excision is a potential treatment option, as topical corticosteroids, retinoids, and calcipotriene have not been shown to be effective; spontaneous resolution has been reported.⁸

Kaposi sarcoma is a vascular neoplasm that is associated with human herpesvirus 8 infection.¹⁰ It typically presents on mucocutaneous sites and the lower extremities. Palmar involvement has been reported in rare cases, occurring as a solitary, well-demarcated, violaceous macule or patch that may be painful.^10-12 Characteristic histopathologic features include a proliferation in the dermis of slitlike vascular spaces and spindle cell proliferation.¹³ Treatment options include cryosurgery; pulsed dye laser; and topical, intralesional, or systemic chemotherapy agents, depending on the stage of the patient’s disease. Antiretroviral therapy is indicated for patients with Kaposi sarcoma secondary to AIDS.¹⁴

Pyogenic granuloma presents as a solitary red-brown or bluish-black papule or nodule that bleeds easily when manipulated.¹⁵ It commonly occurs following trauma, typically on the fingers, feet, and lips.⁶ Although benign, potential complications include ulceration and blood loss. Pyogenic granulomas can be treated via curettage and cautery, excision, cryosurgery, or pulsed dye laser.¹⁵

Pain and pruritus are the most common complaints in patients who present to vulvar clinics.¹ These symptoms can be related to a variety of conditions, including vulvar lesions. There are both common and uncommon vulvar lesions. Vulvar lesions can be skin colored, yellow, and red. Certain lesions can be diagnosed with history and physical examination alone. Some more common lesions include acrochordons (skin tags), benign growths that are common in patients with diabetes, obesity, and pregnancy.^2,3 Other common vulvar lesions are papillomatosis, lichen simplex chronicus, and epidermoid cysts. Other lesions include low- and high-grade squamous intraepithelial lesions (HSIL).⁴ These lesions require biopsy for diagnosis as high-grade lesions require treatment. HSIL of the vulva is considered a premalignancy that necessitates treatment.⁵ Other lesions that can present with vulvar complaints are molluscum contagiosum, Bartholin gland duct cyst, intradermal melanocytic nevus, and squamous cell carcinoma. 

Rarely, other less common conditions can present as vulvar lesions. Syringomas are benign eccrine sweat gland neoplasms. They are more commonly found on the face, neck, or chest.⁶ On the vulva they are generally small subcutaneous skin-colored papules.⁷ They may be asymptomatic and noted only on routine examination. 

Vulvar syringomas also may present with symptoms. On the vulva, syringomas often present as pruritic papules that can be isolated or multifocal. Often on the labia majora they range in size from 2 to 20 mm.⁸

They can coalesce to form a larger lesion. They also may be described as painful. When  syringomas are pruritic, the overlying skin may appear thickened from rubbing or scratching, and excoriations may be present. 

Since vulvar syringomas are rare, there is no standard treatment. Biopsy is necessary for definitive diagnosis. For asymptomatic cases, expectant management is warranted. In symptomatic cases treatment can be considered. Treatment options include cryotherapy, laser ablation, and intralesional electrodissection.⁸ Intralesional electrodissection and curettage also has been described as treatment.⁹ Other treatment options include surgical excision of individual lesions or larger excisions if multifocal. 

The case study described in "Case letter: Vulvar syringoma" highlights the diagnostic and therapeutic challenges associated with rare lesions of the vulva. Referral to a specialty clinic may be warranted in these challenging cases. ●

Pain and pruritus are the most common complaints in patients who present to vulvar clinics.¹ These symptoms can be related to a variety of conditions, including vulvar lesions. There are both common and uncommon vulvar lesions. Vulvar lesions can be skin colored, yellow, and red. Certain lesions can be diagnosed with history and physical examination alone. Some more common lesions include acrochordons (skin tags), benign growths that are common in patients with diabetes, obesity, and pregnancy.^2,3 Other common vulvar lesions are papillomatosis, lichen simplex chronicus, and epidermoid cysts. Other lesions include low- and high-grade squamous intraepithelial lesions (HSIL).⁴ These lesions require biopsy for diagnosis as high-grade lesions require treatment. HSIL of the vulva is considered a premalignancy that necessitates treatment.⁵ Other lesions that can present with vulvar complaints are molluscum contagiosum, Bartholin gland duct cyst, intradermal melanocytic nevus, and squamous cell carcinoma. 

Rarely, other less common conditions can present as vulvar lesions. Syringomas are benign eccrine sweat gland neoplasms. They are more commonly found on the face, neck, or chest.⁶ On the vulva they are generally small subcutaneous skin-colored papules.⁷ They may be asymptomatic and noted only on routine examination. 

Vulvar syringomas also may present with symptoms. On the vulva, syringomas often present as pruritic papules that can be isolated or multifocal. Often on the labia majora they range in size from 2 to 20 mm.⁸

They can coalesce to form a larger lesion. They also may be described as painful. When  syringomas are pruritic, the overlying skin may appear thickened from rubbing or scratching, and excoriations may be present. 

Since vulvar syringomas are rare, there is no standard treatment. Biopsy is necessary for definitive diagnosis. For asymptomatic cases, expectant management is warranted. In symptomatic cases treatment can be considered. Treatment options include cryotherapy, laser ablation, and intralesional electrodissection.⁸ Intralesional electrodissection and curettage also has been described as treatment.⁹ Other treatment options include surgical excision of individual lesions or larger excisions if multifocal. 

The case study described in "Case letter: Vulvar syringoma" highlights the diagnostic and therapeutic challenges associated with rare lesions of the vulva. Referral to a specialty clinic may be warranted in these challenging cases. ●

Pain and pruritus are the most common complaints in patients who present to vulvar clinics.¹ These symptoms can be related to a variety of conditions, including vulvar lesions. There are both common and uncommon vulvar lesions. Vulvar lesions can be skin colored, yellow, and red. Certain lesions can be diagnosed with history and physical examination alone. Some more common lesions include acrochordons (skin tags), benign growths that are common in patients with diabetes, obesity, and pregnancy.^2,3 Other common vulvar lesions are papillomatosis, lichen simplex chronicus, and epidermoid cysts. Other lesions include low- and high-grade squamous intraepithelial lesions (HSIL).⁴ These lesions require biopsy for diagnosis as high-grade lesions require treatment. HSIL of the vulva is considered a premalignancy that necessitates treatment.⁵ Other lesions that can present with vulvar complaints are molluscum contagiosum, Bartholin gland duct cyst, intradermal melanocytic nevus, and squamous cell carcinoma. 

Rarely, other less common conditions can present as vulvar lesions. Syringomas are benign eccrine sweat gland neoplasms. They are more commonly found on the face, neck, or chest.⁶ On the vulva they are generally small subcutaneous skin-colored papules.⁷ They may be asymptomatic and noted only on routine examination. 

Vulvar syringomas also may present with symptoms. On the vulva, syringomas often present as pruritic papules that can be isolated or multifocal. Often on the labia majora they range in size from 2 to 20 mm.⁸

They can coalesce to form a larger lesion. They also may be described as painful. When  syringomas are pruritic, the overlying skin may appear thickened from rubbing or scratching, and excoriations may be present. 

Since vulvar syringomas are rare, there is no standard treatment. Biopsy is necessary for definitive diagnosis. For asymptomatic cases, expectant management is warranted. In symptomatic cases treatment can be considered. Treatment options include cryotherapy, laser ablation, and intralesional electrodissection.⁸ Intralesional electrodissection and curettage also has been described as treatment.⁹ Other treatment options include surgical excision of individual lesions or larger excisions if multifocal. 

The case study described in "Case letter: Vulvar syringoma" highlights the diagnostic and therapeutic challenges associated with rare lesions of the vulva. Referral to a specialty clinic may be warranted in these challenging cases. ●

Scabies is caused by cutaneous ectoparasitic infection by the mite Sarcoptes scabiei var hominis. The infection is highly contagious via direct skin-to-skin contact or indirectly through infested bedding, clothing or fomites.^1,2 Scabies occurs at all ages, in all ethnic groups, and at all socioeconomic levels.¹ Analysis by the Global Burden of Disease estimates that 200 million individuals have been infected with scabies worldwide. The World Health Organization has declared scabies a neglected tropical disease.³

Crusted scabies is a severe and rare form of scabies, with hyperinfestation of thousands to millions of mites, and more commonly is associated with immunosuppressed states, including HIV and hematologic malignancies.^1,2,4 Crusted scabies has a high mortality rate due to sepsis when left untreated.^3,5

Occasionally, iatrogenic immunosuppression contributes to the development of crusted scabies.^1,2 Iatrogenic immunosuppression leading to crusted scabies most commonly occurs secondary to immunosuppression after bone marrow or solid organ transplantation.⁶ Less often, crusted scabies is caused by iatrogenic immunosuppression from other clinical scenarios.^1,2

We describe a patient with iatrogenic immunosuppression due to azathioprine-induced myelosuppression for the treatment of granulomatosis with polyangiitis (GPA) who developed crusted scabies that clinically presented as erythroderma. Crusted scabies should be included in the differential diagnosis of erythroderma, especially in the setting of iatrogenic immunosuppression, for timely and appropriate management.

Case Report

An 84-year-old man presented with worsening pruritus, erythema, and thick yellow scale that progressed to erythroderma over the last 2 weeks. He was diagnosed with GPA 6 months prior to presentation and was treated with azathioprine 150 mg/d, prednisone 10 mg/d, and sulfamethoxazole 800 mg plus trimethoprim 160 mg twice weekly for prophylaxis against Pneumocystis jirovecii pneumonia.

Three weeks prior to presentation, the patient was hospitalized for pancytopenia attributed to azathioprine-induced myelosuppression (hemoglobin, 6.1 g/dL [reference range, 13.5–18.0 g/dL]; hematocrit, 17.5% [reference range, 42%–52%]; white blood cell count, 1.66×10³/μL [reference range, 4.0–10.5×10³/μL]; platelet count, 146×10³/μL [reference range, 150–450×10³/μL]; absolute neutrophil count, 1.29×10³/μL [reference range, 1.4–6.5×10³/μL]). He was transferred to a skilled nursing facility after discharge and referred to dermatology for evaluation of the worsening pruritic rash.

At the current presentation, the patient denied close contact with anyone who had a similar rash at home or at the skilled nursing facility. Physical examination revealed diffuse erythroderma with yellow scale on the scalp, trunk, arms, and legs (Figure 1). The palms showed scattered 2- to 3-mm pustules. The mucosal surfaces did not have lesions. A punch biopsy of a pustule from the right arm revealed focal spongiosis, parakeratosis, and acanthosis, as well as a perivascular and interstitial mixed inflammatory infiltrate with lymphocytes and eosinophils. Organisms morphologically compatible with scabies were found in the stratum corneum (Figure 2). Another punch biopsy of a pustule from the right arm was performed for direct immunofluorescence (DIF) and was negative for immunoglobulin deposition. Mineral oil preparation from pustules on the palm was positive for mites.

The patient was treated with permethrin cream 5% and oral ivermectin 200 μg/kg on day 1 and day 10. The prednisone dosage was increased from 10 mg/d to 50 mg/d and tapered over 2 weeks to treat the symptomatic rash and GPA. He remains on maintenance rituximab for GPA, without recurrence of scabies.

Comment

Pathogenesis—As an obligate parasite, S scabiei spends its entire life cycle within the host. Impregnated female mites burrow into the epidermis after mating and lay eggs daily for 1 to 2 months. Eggs hatch 2 or 3 days later. Larvae then migrate to the skin surface; burrow into the stratum corneum, where they mature into adults; and then mate on the skin surface.^1,4

Clinical Presentation and Sequelae—Typically, scabies presents 2 to 6 weeks after initial exposure with generalized and intense itching and inflammatory pruritic papules on the finger webs, wrists, elbows, axillae, buttocks, umbilicus, genitalia, and areolae.¹ Burrows are specific for scabies but may not always be present. Often, there are nonspecific secondary lesions, including excoriations, dermatitis, and impetiginization.

Complications of scabies can be severe, with initial colonization and infection of the skin resulting in impetigo and cellulitis. Systematic sequelae from local skin infection include post-streptococcal glomerulonephritis, rheumatic fever, and sepsis. Mortality from sepsis in scabies can be high.^3,5

Classic Crusted Scabies and Other Variants—Crusted scabies presents with psoriasiform hyperkeratotic plaques involving the hands and feet with potential nail involvement that can become more generalized.¹ Alterations in CD4⁺ T-cell function have been implicated in the development of crusted scabies, in which an excessive helper T cell (T_H2) response is elicited against the ectoparasite, which may help explain the intense pruritus of scabies.⁶ Occasionally, iatrogenic immunosuppression contributes to development of crusted scabies,¹ as was the case with our patient. However, it is rare for crusted scabies to present with erythroderma.⁷

Other atypical presentations of scabies include a seborrheic dermatitis–like presentation in infants, nodular lesions in the groin and axillae in more chronic scabies, and vesicles or bullous lesions.¹

Diagnosis—Identification of mites, eggs, or feces is necessary for definitive diagnosis of scabies.⁸ These materials can be obtained through skin scrapings with mineral oil and observed under light microscopy or direct dermoscopy. Multiple scrapings on many lesions should be performed because failure to identify mites can be common and does not rule out scabies. Dermoscopic examination of active lesions under low power also can be helpful, given that identification of dark brown triangular structures can correspond to visualization of the pigmented anterior section of the mite.^9-11 A skin biopsy can help identify mites, but histopathology often shows a nonspecific hypersensitivity reaction.¹² Therefore, empiric treatment often is necessary.

Differential Diagnosis—The differential diagnosis of erythroderma is broad and includes a drug eruption; Sézary syndrome; and pre-existing skin diseases, including psoriasis, atopic dermatitis, pityriasis rubra pilaris, pemphigus foliaceus, and bullous pemphigoid. Histopathology is critical to differentiate these diagnoses. Bullous pemphigoid and pemphigus foliaceus are immunobullous diseases that typically are positive for immunoglobulin deposition on DIF. In rare cases, scabies also can present with bullae and positive DIF test results.¹³

Treatment—First-line treatment of crusted scabies in the United States is permethrin cream 5%, followed by oral ivermectin 200 μg/kg.^4,5,14,15 Other scabicides include topicals such as benzyl benzoate 10% to 25%; precipitated sulfur 2% to 10%; crotamiton 10%; malathion 0.5%; and lindane 1%.⁵ The association of neurotoxicity with lindane has considerably reduced the drug’s use.¹

During treatment of scabies, it is important to isolate patients to mitigate the possibility of spread.⁴ Pruritus can persist for a few weeks after completion of therapy.⁵ Patients should be closely monitored to ensure that this symptom is secondary to skin inflammation and not incomplete treatment.

Treatment of crusted scabies may require repeated treatments to decrease the notable mite burden as well as the associated crusting and scale. Adding a keratolytic such as 5% to 10% salicylic acid in petrolatum to the treatment regimen may be useful for breaking up thick scale.⁵

Immunosuppression—With numerous immunomodulatory drugs for treating autoimmunity comes an increased risk for iatrogenic immunosuppression that may contribute to the development of crusted scabies.¹⁶ In a number of autoimmune diseases such as rheumatoid arthritis,^17-19 psoriasis,^20,21 pemphigus vulgaris,²² systemic lupus erythematosus,²³ systemic sclerosis,^22,24 bullous pemphigoid,^25,26 and dermatomyositis,²⁷ patients have developed crusted scabies secondary to treatment-related immunosuppression. These immunosuppressive therapies include systemic steroids,^22-24,26-31 methotrexate,²³ infliximab,¹⁸ adalimumab,²¹ toclizumab,¹⁹ and etanercept.²⁰ In a case of drug-induced Stevens-Johnson syndrome, the patient developed crusted scabies during long-term use of oral steroids.²²

Patients with a malignancy who are being treated with chemotherapy also can develop crusted scabies.²⁸ Crusted scabies has even been associated with long-term topical steroid^32-34 and topical calcineurin inhibitor use.¹⁶

Iatrogenic immunosuppression in our patient resulted from treatment of GPA with azathioprine, an immunosuppressive drug that acts as an antagonist of the breakdown of purines, leading to inhibition of DNA, RNA, and protein synthesis.³⁵ On occasion, azathioprine can induce immunosuppression in the form of myelosuppression and resulting pancytopenia, as was the case with our patient.

Conclusion

Although scabies is designated as a neglected tropical disease by the World Health Organization, it still causes a notable burden worldwide, regardless of the economics. Our case highlights an unusual presentation of scabies as erythroderma in the setting of iatrogenic immunosuppression from azathioprine use. Dermatologists should consider crusted scabies in the differential diagnosis of erythroderma, especially in immunocompromised patients, to avoid delays in diagnosis and treatment. Immunosuppressive therapy is an important mainstay in the treatment of many conditions, but it is important to consider that these medications can place patients at an increased risk for rare opportunistic infections. Therefore, patients receiving such treatment should be closely monitored.

Scabies is caused by cutaneous ectoparasitic infection by the mite Sarcoptes scabiei var hominis. The infection is highly contagious via direct skin-to-skin contact or indirectly through infested bedding, clothing or fomites.^1,2 Scabies occurs at all ages, in all ethnic groups, and at all socioeconomic levels.¹ Analysis by the Global Burden of Disease estimates that 200 million individuals have been infected with scabies worldwide. The World Health Organization has declared scabies a neglected tropical disease.³

Crusted scabies is a severe and rare form of scabies, with hyperinfestation of thousands to millions of mites, and more commonly is associated with immunosuppressed states, including HIV and hematologic malignancies.^1,2,4 Crusted scabies has a high mortality rate due to sepsis when left untreated.^3,5

Occasionally, iatrogenic immunosuppression contributes to the development of crusted scabies.^1,2 Iatrogenic immunosuppression leading to crusted scabies most commonly occurs secondary to immunosuppression after bone marrow or solid organ transplantation.⁶ Less often, crusted scabies is caused by iatrogenic immunosuppression from other clinical scenarios.^1,2

We describe a patient with iatrogenic immunosuppression due to azathioprine-induced myelosuppression for the treatment of granulomatosis with polyangiitis (GPA) who developed crusted scabies that clinically presented as erythroderma. Crusted scabies should be included in the differential diagnosis of erythroderma, especially in the setting of iatrogenic immunosuppression, for timely and appropriate management.

Case Report

An 84-year-old man presented with worsening pruritus, erythema, and thick yellow scale that progressed to erythroderma over the last 2 weeks. He was diagnosed with GPA 6 months prior to presentation and was treated with azathioprine 150 mg/d, prednisone 10 mg/d, and sulfamethoxazole 800 mg plus trimethoprim 160 mg twice weekly for prophylaxis against Pneumocystis jirovecii pneumonia.

Three weeks prior to presentation, the patient was hospitalized for pancytopenia attributed to azathioprine-induced myelosuppression (hemoglobin, 6.1 g/dL [reference range, 13.5–18.0 g/dL]; hematocrit, 17.5% [reference range, 42%–52%]; white blood cell count, 1.66×10³/μL [reference range, 4.0–10.5×10³/μL]; platelet count, 146×10³/μL [reference range, 150–450×10³/μL]; absolute neutrophil count, 1.29×10³/μL [reference range, 1.4–6.5×10³/μL]). He was transferred to a skilled nursing facility after discharge and referred to dermatology for evaluation of the worsening pruritic rash.

At the current presentation, the patient denied close contact with anyone who had a similar rash at home or at the skilled nursing facility. Physical examination revealed diffuse erythroderma with yellow scale on the scalp, trunk, arms, and legs (Figure 1). The palms showed scattered 2- to 3-mm pustules. The mucosal surfaces did not have lesions. A punch biopsy of a pustule from the right arm revealed focal spongiosis, parakeratosis, and acanthosis, as well as a perivascular and interstitial mixed inflammatory infiltrate with lymphocytes and eosinophils. Organisms morphologically compatible with scabies were found in the stratum corneum (Figure 2). Another punch biopsy of a pustule from the right arm was performed for direct immunofluorescence (DIF) and was negative for immunoglobulin deposition. Mineral oil preparation from pustules on the palm was positive for mites.

The patient was treated with permethrin cream 5% and oral ivermectin 200 μg/kg on day 1 and day 10. The prednisone dosage was increased from 10 mg/d to 50 mg/d and tapered over 2 weeks to treat the symptomatic rash and GPA. He remains on maintenance rituximab for GPA, without recurrence of scabies.

Comment

Pathogenesis—As an obligate parasite, S scabiei spends its entire life cycle within the host. Impregnated female mites burrow into the epidermis after mating and lay eggs daily for 1 to 2 months. Eggs hatch 2 or 3 days later. Larvae then migrate to the skin surface; burrow into the stratum corneum, where they mature into adults; and then mate on the skin surface.^1,4

Clinical Presentation and Sequelae—Typically, scabies presents 2 to 6 weeks after initial exposure with generalized and intense itching and inflammatory pruritic papules on the finger webs, wrists, elbows, axillae, buttocks, umbilicus, genitalia, and areolae.¹ Burrows are specific for scabies but may not always be present. Often, there are nonspecific secondary lesions, including excoriations, dermatitis, and impetiginization.

Complications of scabies can be severe, with initial colonization and infection of the skin resulting in impetigo and cellulitis. Systematic sequelae from local skin infection include post-streptococcal glomerulonephritis, rheumatic fever, and sepsis. Mortality from sepsis in scabies can be high.^3,5

Classic Crusted Scabies and Other Variants—Crusted scabies presents with psoriasiform hyperkeratotic plaques involving the hands and feet with potential nail involvement that can become more generalized.¹ Alterations in CD4⁺ T-cell function have been implicated in the development of crusted scabies, in which an excessive helper T cell (T_H2) response is elicited against the ectoparasite, which may help explain the intense pruritus of scabies.⁶ Occasionally, iatrogenic immunosuppression contributes to development of crusted scabies,¹ as was the case with our patient. However, it is rare for crusted scabies to present with erythroderma.⁷

Other atypical presentations of scabies include a seborrheic dermatitis–like presentation in infants, nodular lesions in the groin and axillae in more chronic scabies, and vesicles or bullous lesions.¹

Diagnosis—Identification of mites, eggs, or feces is necessary for definitive diagnosis of scabies.⁸ These materials can be obtained through skin scrapings with mineral oil and observed under light microscopy or direct dermoscopy. Multiple scrapings on many lesions should be performed because failure to identify mites can be common and does not rule out scabies. Dermoscopic examination of active lesions under low power also can be helpful, given that identification of dark brown triangular structures can correspond to visualization of the pigmented anterior section of the mite.^9-11 A skin biopsy can help identify mites, but histopathology often shows a nonspecific hypersensitivity reaction.¹² Therefore, empiric treatment often is necessary.

Differential Diagnosis—The differential diagnosis of erythroderma is broad and includes a drug eruption; Sézary syndrome; and pre-existing skin diseases, including psoriasis, atopic dermatitis, pityriasis rubra pilaris, pemphigus foliaceus, and bullous pemphigoid. Histopathology is critical to differentiate these diagnoses. Bullous pemphigoid and pemphigus foliaceus are immunobullous diseases that typically are positive for immunoglobulin deposition on DIF. In rare cases, scabies also can present with bullae and positive DIF test results.¹³

Treatment—First-line treatment of crusted scabies in the United States is permethrin cream 5%, followed by oral ivermectin 200 μg/kg.^4,5,14,15 Other scabicides include topicals such as benzyl benzoate 10% to 25%; precipitated sulfur 2% to 10%; crotamiton 10%; malathion 0.5%; and lindane 1%.⁵ The association of neurotoxicity with lindane has considerably reduced the drug’s use.¹

During treatment of scabies, it is important to isolate patients to mitigate the possibility of spread.⁴ Pruritus can persist for a few weeks after completion of therapy.⁵ Patients should be closely monitored to ensure that this symptom is secondary to skin inflammation and not incomplete treatment.

Treatment of crusted scabies may require repeated treatments to decrease the notable mite burden as well as the associated crusting and scale. Adding a keratolytic such as 5% to 10% salicylic acid in petrolatum to the treatment regimen may be useful for breaking up thick scale.⁵

Immunosuppression—With numerous immunomodulatory drugs for treating autoimmunity comes an increased risk for iatrogenic immunosuppression that may contribute to the development of crusted scabies.¹⁶ In a number of autoimmune diseases such as rheumatoid arthritis,^17-19 psoriasis,^20,21 pemphigus vulgaris,²² systemic lupus erythematosus,²³ systemic sclerosis,^22,24 bullous pemphigoid,^25,26 and dermatomyositis,²⁷ patients have developed crusted scabies secondary to treatment-related immunosuppression. These immunosuppressive therapies include systemic steroids,^22-24,26-31 methotrexate,²³ infliximab,¹⁸ adalimumab,²¹ toclizumab,¹⁹ and etanercept.²⁰ In a case of drug-induced Stevens-Johnson syndrome, the patient developed crusted scabies during long-term use of oral steroids.²²

Patients with a malignancy who are being treated with chemotherapy also can develop crusted scabies.²⁸ Crusted scabies has even been associated with long-term topical steroid^32-34 and topical calcineurin inhibitor use.¹⁶

Iatrogenic immunosuppression in our patient resulted from treatment of GPA with azathioprine, an immunosuppressive drug that acts as an antagonist of the breakdown of purines, leading to inhibition of DNA, RNA, and protein synthesis.³⁵ On occasion, azathioprine can induce immunosuppression in the form of myelosuppression and resulting pancytopenia, as was the case with our patient.

Conclusion

Although scabies is designated as a neglected tropical disease by the World Health Organization, it still causes a notable burden worldwide, regardless of the economics. Our case highlights an unusual presentation of scabies as erythroderma in the setting of iatrogenic immunosuppression from azathioprine use. Dermatologists should consider crusted scabies in the differential diagnosis of erythroderma, especially in immunocompromised patients, to avoid delays in diagnosis and treatment. Immunosuppressive therapy is an important mainstay in the treatment of many conditions, but it is important to consider that these medications can place patients at an increased risk for rare opportunistic infections. Therefore, patients receiving such treatment should be closely monitored.

Scabies is caused by cutaneous ectoparasitic infection by the mite Sarcoptes scabiei var hominis. The infection is highly contagious via direct skin-to-skin contact or indirectly through infested bedding, clothing or fomites.^1,2 Scabies occurs at all ages, in all ethnic groups, and at all socioeconomic levels.¹ Analysis by the Global Burden of Disease estimates that 200 million individuals have been infected with scabies worldwide. The World Health Organization has declared scabies a neglected tropical disease.³

Crusted scabies is a severe and rare form of scabies, with hyperinfestation of thousands to millions of mites, and more commonly is associated with immunosuppressed states, including HIV and hematologic malignancies.^1,2,4 Crusted scabies has a high mortality rate due to sepsis when left untreated.^3,5

Occasionally, iatrogenic immunosuppression contributes to the development of crusted scabies.^1,2 Iatrogenic immunosuppression leading to crusted scabies most commonly occurs secondary to immunosuppression after bone marrow or solid organ transplantation.⁶ Less often, crusted scabies is caused by iatrogenic immunosuppression from other clinical scenarios.^1,2

We describe a patient with iatrogenic immunosuppression due to azathioprine-induced myelosuppression for the treatment of granulomatosis with polyangiitis (GPA) who developed crusted scabies that clinically presented as erythroderma. Crusted scabies should be included in the differential diagnosis of erythroderma, especially in the setting of iatrogenic immunosuppression, for timely and appropriate management.

Case Report

An 84-year-old man presented with worsening pruritus, erythema, and thick yellow scale that progressed to erythroderma over the last 2 weeks. He was diagnosed with GPA 6 months prior to presentation and was treated with azathioprine 150 mg/d, prednisone 10 mg/d, and sulfamethoxazole 800 mg plus trimethoprim 160 mg twice weekly for prophylaxis against Pneumocystis jirovecii pneumonia.

Three weeks prior to presentation, the patient was hospitalized for pancytopenia attributed to azathioprine-induced myelosuppression (hemoglobin, 6.1 g/dL [reference range, 13.5–18.0 g/dL]; hematocrit, 17.5% [reference range, 42%–52%]; white blood cell count, 1.66×10³/μL [reference range, 4.0–10.5×10³/μL]; platelet count, 146×10³/μL [reference range, 150–450×10³/μL]; absolute neutrophil count, 1.29×10³/μL [reference range, 1.4–6.5×10³/μL]). He was transferred to a skilled nursing facility after discharge and referred to dermatology for evaluation of the worsening pruritic rash.

At the current presentation, the patient denied close contact with anyone who had a similar rash at home or at the skilled nursing facility. Physical examination revealed diffuse erythroderma with yellow scale on the scalp, trunk, arms, and legs (Figure 1). The palms showed scattered 2- to 3-mm pustules. The mucosal surfaces did not have lesions. A punch biopsy of a pustule from the right arm revealed focal spongiosis, parakeratosis, and acanthosis, as well as a perivascular and interstitial mixed inflammatory infiltrate with lymphocytes and eosinophils. Organisms morphologically compatible with scabies were found in the stratum corneum (Figure 2). Another punch biopsy of a pustule from the right arm was performed for direct immunofluorescence (DIF) and was negative for immunoglobulin deposition. Mineral oil preparation from pustules on the palm was positive for mites.

The patient was treated with permethrin cream 5% and oral ivermectin 200 μg/kg on day 1 and day 10. The prednisone dosage was increased from 10 mg/d to 50 mg/d and tapered over 2 weeks to treat the symptomatic rash and GPA. He remains on maintenance rituximab for GPA, without recurrence of scabies.

Comment

Pathogenesis—As an obligate parasite, S scabiei spends its entire life cycle within the host. Impregnated female mites burrow into the epidermis after mating and lay eggs daily for 1 to 2 months. Eggs hatch 2 or 3 days later. Larvae then migrate to the skin surface; burrow into the stratum corneum, where they mature into adults; and then mate on the skin surface.^1,4

Clinical Presentation and Sequelae—Typically, scabies presents 2 to 6 weeks after initial exposure with generalized and intense itching and inflammatory pruritic papules on the finger webs, wrists, elbows, axillae, buttocks, umbilicus, genitalia, and areolae.¹ Burrows are specific for scabies but may not always be present. Often, there are nonspecific secondary lesions, including excoriations, dermatitis, and impetiginization.

Complications of scabies can be severe, with initial colonization and infection of the skin resulting in impetigo and cellulitis. Systematic sequelae from local skin infection include post-streptococcal glomerulonephritis, rheumatic fever, and sepsis. Mortality from sepsis in scabies can be high.^3,5

Classic Crusted Scabies and Other Variants—Crusted scabies presents with psoriasiform hyperkeratotic plaques involving the hands and feet with potential nail involvement that can become more generalized.¹ Alterations in CD4⁺ T-cell function have been implicated in the development of crusted scabies, in which an excessive helper T cell (T_H2) response is elicited against the ectoparasite, which may help explain the intense pruritus of scabies.⁶ Occasionally, iatrogenic immunosuppression contributes to development of crusted scabies,¹ as was the case with our patient. However, it is rare for crusted scabies to present with erythroderma.⁷

Other atypical presentations of scabies include a seborrheic dermatitis–like presentation in infants, nodular lesions in the groin and axillae in more chronic scabies, and vesicles or bullous lesions.¹

Diagnosis—Identification of mites, eggs, or feces is necessary for definitive diagnosis of scabies.⁸ These materials can be obtained through skin scrapings with mineral oil and observed under light microscopy or direct dermoscopy. Multiple scrapings on many lesions should be performed because failure to identify mites can be common and does not rule out scabies. Dermoscopic examination of active lesions under low power also can be helpful, given that identification of dark brown triangular structures can correspond to visualization of the pigmented anterior section of the mite.^9-11 A skin biopsy can help identify mites, but histopathology often shows a nonspecific hypersensitivity reaction.¹² Therefore, empiric treatment often is necessary.

Differential Diagnosis—The differential diagnosis of erythroderma is broad and includes a drug eruption; Sézary syndrome; and pre-existing skin diseases, including psoriasis, atopic dermatitis, pityriasis rubra pilaris, pemphigus foliaceus, and bullous pemphigoid. Histopathology is critical to differentiate these diagnoses. Bullous pemphigoid and pemphigus foliaceus are immunobullous diseases that typically are positive for immunoglobulin deposition on DIF. In rare cases, scabies also can present with bullae and positive DIF test results.¹³

Treatment—First-line treatment of crusted scabies in the United States is permethrin cream 5%, followed by oral ivermectin 200 μg/kg.^4,5,14,15 Other scabicides include topicals such as benzyl benzoate 10% to 25%; precipitated sulfur 2% to 10%; crotamiton 10%; malathion 0.5%; and lindane 1%.⁵ The association of neurotoxicity with lindane has considerably reduced the drug’s use.¹

During treatment of scabies, it is important to isolate patients to mitigate the possibility of spread.⁴ Pruritus can persist for a few weeks after completion of therapy.⁵ Patients should be closely monitored to ensure that this symptom is secondary to skin inflammation and not incomplete treatment.

Treatment of crusted scabies may require repeated treatments to decrease the notable mite burden as well as the associated crusting and scale. Adding a keratolytic such as 5% to 10% salicylic acid in petrolatum to the treatment regimen may be useful for breaking up thick scale.⁵

Immunosuppression—With numerous immunomodulatory drugs for treating autoimmunity comes an increased risk for iatrogenic immunosuppression that may contribute to the development of crusted scabies.¹⁶ In a number of autoimmune diseases such as rheumatoid arthritis,^17-19 psoriasis,^20,21 pemphigus vulgaris,²² systemic lupus erythematosus,²³ systemic sclerosis,^22,24 bullous pemphigoid,^25,26 and dermatomyositis,²⁷ patients have developed crusted scabies secondary to treatment-related immunosuppression. These immunosuppressive therapies include systemic steroids,^22-24,26-31 methotrexate,²³ infliximab,¹⁸ adalimumab,²¹ toclizumab,¹⁹ and etanercept.²⁰ In a case of drug-induced Stevens-Johnson syndrome, the patient developed crusted scabies during long-term use of oral steroids.²²

Patients with a malignancy who are being treated with chemotherapy also can develop crusted scabies.²⁸ Crusted scabies has even been associated with long-term topical steroid^32-34 and topical calcineurin inhibitor use.¹⁶

Iatrogenic immunosuppression in our patient resulted from treatment of GPA with azathioprine, an immunosuppressive drug that acts as an antagonist of the breakdown of purines, leading to inhibition of DNA, RNA, and protein synthesis.³⁵ On occasion, azathioprine can induce immunosuppression in the form of myelosuppression and resulting pancytopenia, as was the case with our patient.

Conclusion

Although scabies is designated as a neglected tropical disease by the World Health Organization, it still causes a notable burden worldwide, regardless of the economics. Our case highlights an unusual presentation of scabies as erythroderma in the setting of iatrogenic immunosuppression from azathioprine use. Dermatologists should consider crusted scabies in the differential diagnosis of erythroderma, especially in immunocompromised patients, to avoid delays in diagnosis and treatment. Immunosuppressive therapy is an important mainstay in the treatment of many conditions, but it is important to consider that these medications can place patients at an increased risk for rare opportunistic infections. Therefore, patients receiving such treatment should be closely monitored.

To the Editor:

A 47-year-old man presented to the dermatology service with an asymptomatic plaque on the right thigh of 2 months’ duration. He had a medical history of HIV and Kaposi sarcoma as well as a recently relapsed primary effusion lymphoma (PEL) subsequent to an allogeneic bone marrow transplant. He initially was diagnosed with PEL 3 years prior to the current presentation during a workup for fever and weight loss. Imaging at the time demonstrated a bladder mass, which was biopsied and demonstrated PEL. Further imaging demonstrated both sinus and bone marrow involvement. Prior to dermatologic consultation, he had been treated with 6 cycles of etoposide, prednisolone, vincristine, cyclophosphamide, and doxorubicin (EPOCH); 6 cycles of brentuximab; 4 cycles of rituximab with gemcitabine and oxaliplatin; and 2 cycles of ifosfamide, carboplatin, and etoposide. Despite these therapies, he had 3 relapses, and oncology determined the need for a matched unrelated donor allogeneic stem cell transplant for his PEL.

At the time of dermatology consultation, the patient was being managed on daratumumab and bortezomib. Physical examination revealed an infiltrative plaque on the right inferomedial thigh measuring approximately 6.0 cm (largest dimension) with a small amount of peripheral scale (Figure 1). An ultrasound revealed notable subcutaneous tissue edema and increased vascularity without a discrete mass or fluid collection. A 4-mm punch biopsy demonstrated a dense infiltrate comprised of collections of histiocytes admixed with scattered plasma cells and mature lymphoid aggregates. Additionally, rare enlarged plasmablastic cells with scant basophilic cytoplasm and slightly irregular nuclear contours were visualized (Figure 2A). Immunohistochemistry was positive for CD3 with a normal CD4:CD8 ratio, CD68-highlighted histiocytes within the lymphoid aggregates, and human herpesvirus 8 (HHV-8)(or Kaposi sarcoma–associated herpesvirus) demonstrated stippled nuclear staining within the scattered large cells (Figure 2B). Epstein-Barr virus–encoded RNA staining was negative, though the area of interest was lost on deeper sectioning of the tissue block. The histopathologic findings were consistent with cutaneous extracavitary PEL. Shortly after this diagnosis, he died from disease complications.

Primary effusion lymphoma is an aggressive non-Hodgkin B-cell lymphoma that was first described by Knowles et al¹ in 1989. Primary effusion lymphoma occurs exclusively in the setting of HHV-8 infection and typically is associated with chronic immunosuppression related to HIV/AIDS. Cases that are negative for HIV-1 are rare but have been reported in organ transplant recipients and elderly men from areas with a high prevalence of HHV-8 infections. Most HIV-associated cases show concurrent Epstein-Barr virus infection, though the pathogenic meaning of this co-infection remains unclear.^2,3

Primary effusion lymphoma classically presents as an isolated effusion of malignant lymphoid cells within body cavities in the absence of solid tumor masses. The pleural, peritoneal, and pericardial spaces most commonly are involved. Extracavitary PEL, a rare variant, may present as a solid mass without effusion. In general, extracavitary tumors may occur in the setting of de novo malignancy or recurrent PEL.⁴ Cutaneous manifestations associated with extracavitary PEL are rare; 4 cases have been described in which skin lesions were the heralding sign of the disease.³ Interestingly, despite obligatory underlying HHV-8 infection, a review by Pielasinski et al³ noted only 2 patients with cutaneous PEL who had prior or concurrent Kaposi sarcoma. This heterogeneity in HHV-8–related phenotypes may be related to differences in microRNA expression, but further study is needed.⁵

The diagnosis of PEL relies on histologic, immunophenotypic, and molecular analysis of the affected tissue. The malignant cells typically are large with round to irregular nuclei. These cells may demonstrate a variety of appearances, including anaplastic, plasmablastic, and immunoblastic morphologies.^6,7 The immunophenotype displays CD45 positivity and markers of lymphocyte activation (CD30, CD38, CD71), while typical B-cell (CD19, CD20, CD79a) and T-cell (CD3, CD4, CD8) markers often are absent.^6-8 Human herpesvirus 8 detection by polymerase chain reaction testing of the peripheral blood or by immunohistochemistry staining of the affected tissue is required for diagnosis.^6,7 Epstein-Barr virus infection may be detected via in situ hybridization, though it is not required for diagnosis.

The overall prognosis for PEL is poor; Brimo et al⁶ reported a median survival of less than 6 months, and Guillet et al⁹ reported 5-year overall survival (OS) for PEL vs extracavitary PEL to be 43% vs 39%. Another review noted variation in survival contingent on the number of body cavities involved; patients with a single body cavity involved experienced a median OS of 18 months, whereas patients with multiple involved cavities experienced a median OS of 4 months,⁷ possibly due to the limited study of treatment regimens or disease aggressiveness. Even in cases of successful initial treatment, relapse within 6 to 8 months is common. Extracavitary PEL may have improved disease-free survival relative to classic PEL, though the data were less clear for OS.⁹ Limitations of the Guillet et al⁹ study included a small sample size, the impossibility to randomize to disease type, and loss of power on the log-rank test for OS in the setting of possible nonproportional hazards (crossing survival curves). Overall, prognostic differences between the groups may be challenging to ascertain until further data are obtained.

As with many HIV-associated neoplasms, antiretroviral treatment (ART) for HIV-positive patients affords a better prognosis when used in addition to therapy directed at malignancy.⁷ The general approach is for concurrent ART with systemic therapies such as rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone for the rare CD20⁺ cases, and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or dose-adjusted EPOCH therapy in the more common CD20⁻ PEL cases. Narkhede et al⁷ suggested avoidance of methotrexate in patients with effusions because of increased toxicity, but it is unclear if this recommendation is applicable in extracavitary PEL patients without an effusion. Additionally, second-line treatment modalities include radiation for solid PEL masses, HHV-8–targeted antivirals, and stem cell transplantation, though evidence is limited. Of note, there is a phase I-II trial (ClinicalTrials.gov identifier NCT02911142) ongoing for treatment-naïve PEL patients involving the experimental treatment DA-EPOCH-R plus lenalidomide, but the trial is ongoing.¹⁰

We report a case of cutaneous PEL in a patient with a history of Kaposi sarcoma. The patient’s deterioration and ultimate death despite initial treatment with EPOCH and bone marrow transplantation followed by final management with daratumumab and bortezomib confirm other reports that PEL has a poor prognosis and that optimal treatments are not well delineated for these patients. In general, the current approach is to utilize ART for HIV-positive patients and to then implement chemotherapy such as CHOP. Without continued research and careful planning of treatments, data will remain limited on how best to serve patients with PEL.

To the Editor:

A 47-year-old man presented to the dermatology service with an asymptomatic plaque on the right thigh of 2 months’ duration. He had a medical history of HIV and Kaposi sarcoma as well as a recently relapsed primary effusion lymphoma (PEL) subsequent to an allogeneic bone marrow transplant. He initially was diagnosed with PEL 3 years prior to the current presentation during a workup for fever and weight loss. Imaging at the time demonstrated a bladder mass, which was biopsied and demonstrated PEL. Further imaging demonstrated both sinus and bone marrow involvement. Prior to dermatologic consultation, he had been treated with 6 cycles of etoposide, prednisolone, vincristine, cyclophosphamide, and doxorubicin (EPOCH); 6 cycles of brentuximab; 4 cycles of rituximab with gemcitabine and oxaliplatin; and 2 cycles of ifosfamide, carboplatin, and etoposide. Despite these therapies, he had 3 relapses, and oncology determined the need for a matched unrelated donor allogeneic stem cell transplant for his PEL.

At the time of dermatology consultation, the patient was being managed on daratumumab and bortezomib. Physical examination revealed an infiltrative plaque on the right inferomedial thigh measuring approximately 6.0 cm (largest dimension) with a small amount of peripheral scale (Figure 1). An ultrasound revealed notable subcutaneous tissue edema and increased vascularity without a discrete mass or fluid collection. A 4-mm punch biopsy demonstrated a dense infiltrate comprised of collections of histiocytes admixed with scattered plasma cells and mature lymphoid aggregates. Additionally, rare enlarged plasmablastic cells with scant basophilic cytoplasm and slightly irregular nuclear contours were visualized (Figure 2A). Immunohistochemistry was positive for CD3 with a normal CD4:CD8 ratio, CD68-highlighted histiocytes within the lymphoid aggregates, and human herpesvirus 8 (HHV-8)(or Kaposi sarcoma–associated herpesvirus) demonstrated stippled nuclear staining within the scattered large cells (Figure 2B). Epstein-Barr virus–encoded RNA staining was negative, though the area of interest was lost on deeper sectioning of the tissue block. The histopathologic findings were consistent with cutaneous extracavitary PEL. Shortly after this diagnosis, he died from disease complications.

Primary effusion lymphoma is an aggressive non-Hodgkin B-cell lymphoma that was first described by Knowles et al¹ in 1989. Primary effusion lymphoma occurs exclusively in the setting of HHV-8 infection and typically is associated with chronic immunosuppression related to HIV/AIDS. Cases that are negative for HIV-1 are rare but have been reported in organ transplant recipients and elderly men from areas with a high prevalence of HHV-8 infections. Most HIV-associated cases show concurrent Epstein-Barr virus infection, though the pathogenic meaning of this co-infection remains unclear.^2,3

Primary effusion lymphoma classically presents as an isolated effusion of malignant lymphoid cells within body cavities in the absence of solid tumor masses. The pleural, peritoneal, and pericardial spaces most commonly are involved. Extracavitary PEL, a rare variant, may present as a solid mass without effusion. In general, extracavitary tumors may occur in the setting of de novo malignancy or recurrent PEL.⁴ Cutaneous manifestations associated with extracavitary PEL are rare; 4 cases have been described in which skin lesions were the heralding sign of the disease.³ Interestingly, despite obligatory underlying HHV-8 infection, a review by Pielasinski et al³ noted only 2 patients with cutaneous PEL who had prior or concurrent Kaposi sarcoma. This heterogeneity in HHV-8–related phenotypes may be related to differences in microRNA expression, but further study is needed.⁵

The diagnosis of PEL relies on histologic, immunophenotypic, and molecular analysis of the affected tissue. The malignant cells typically are large with round to irregular nuclei. These cells may demonstrate a variety of appearances, including anaplastic, plasmablastic, and immunoblastic morphologies.^6,7 The immunophenotype displays CD45 positivity and markers of lymphocyte activation (CD30, CD38, CD71), while typical B-cell (CD19, CD20, CD79a) and T-cell (CD3, CD4, CD8) markers often are absent.^6-8 Human herpesvirus 8 detection by polymerase chain reaction testing of the peripheral blood or by immunohistochemistry staining of the affected tissue is required for diagnosis.^6,7 Epstein-Barr virus infection may be detected via in situ hybridization, though it is not required for diagnosis.

The overall prognosis for PEL is poor; Brimo et al⁶ reported a median survival of less than 6 months, and Guillet et al⁹ reported 5-year overall survival (OS) for PEL vs extracavitary PEL to be 43% vs 39%. Another review noted variation in survival contingent on the number of body cavities involved; patients with a single body cavity involved experienced a median OS of 18 months, whereas patients with multiple involved cavities experienced a median OS of 4 months,⁷ possibly due to the limited study of treatment regimens or disease aggressiveness. Even in cases of successful initial treatment, relapse within 6 to 8 months is common. Extracavitary PEL may have improved disease-free survival relative to classic PEL, though the data were less clear for OS.⁹ Limitations of the Guillet et al⁹ study included a small sample size, the impossibility to randomize to disease type, and loss of power on the log-rank test for OS in the setting of possible nonproportional hazards (crossing survival curves). Overall, prognostic differences between the groups may be challenging to ascertain until further data are obtained.

As with many HIV-associated neoplasms, antiretroviral treatment (ART) for HIV-positive patients affords a better prognosis when used in addition to therapy directed at malignancy.⁷ The general approach is for concurrent ART with systemic therapies such as rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone for the rare CD20⁺ cases, and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or dose-adjusted EPOCH therapy in the more common CD20⁻ PEL cases. Narkhede et al⁷ suggested avoidance of methotrexate in patients with effusions because of increased toxicity, but it is unclear if this recommendation is applicable in extracavitary PEL patients without an effusion. Additionally, second-line treatment modalities include radiation for solid PEL masses, HHV-8–targeted antivirals, and stem cell transplantation, though evidence is limited. Of note, there is a phase I-II trial (ClinicalTrials.gov identifier NCT02911142) ongoing for treatment-naïve PEL patients involving the experimental treatment DA-EPOCH-R plus lenalidomide, but the trial is ongoing.¹⁰

We report a case of cutaneous PEL in a patient with a history of Kaposi sarcoma. The patient’s deterioration and ultimate death despite initial treatment with EPOCH and bone marrow transplantation followed by final management with daratumumab and bortezomib confirm other reports that PEL has a poor prognosis and that optimal treatments are not well delineated for these patients. In general, the current approach is to utilize ART for HIV-positive patients and to then implement chemotherapy such as CHOP. Without continued research and careful planning of treatments, data will remain limited on how best to serve patients with PEL.

To the Editor:

A 47-year-old man presented to the dermatology service with an asymptomatic plaque on the right thigh of 2 months’ duration. He had a medical history of HIV and Kaposi sarcoma as well as a recently relapsed primary effusion lymphoma (PEL) subsequent to an allogeneic bone marrow transplant. He initially was diagnosed with PEL 3 years prior to the current presentation during a workup for fever and weight loss. Imaging at the time demonstrated a bladder mass, which was biopsied and demonstrated PEL. Further imaging demonstrated both sinus and bone marrow involvement. Prior to dermatologic consultation, he had been treated with 6 cycles of etoposide, prednisolone, vincristine, cyclophosphamide, and doxorubicin (EPOCH); 6 cycles of brentuximab; 4 cycles of rituximab with gemcitabine and oxaliplatin; and 2 cycles of ifosfamide, carboplatin, and etoposide. Despite these therapies, he had 3 relapses, and oncology determined the need for a matched unrelated donor allogeneic stem cell transplant for his PEL.

At the time of dermatology consultation, the patient was being managed on daratumumab and bortezomib. Physical examination revealed an infiltrative plaque on the right inferomedial thigh measuring approximately 6.0 cm (largest dimension) with a small amount of peripheral scale (Figure 1). An ultrasound revealed notable subcutaneous tissue edema and increased vascularity without a discrete mass or fluid collection. A 4-mm punch biopsy demonstrated a dense infiltrate comprised of collections of histiocytes admixed with scattered plasma cells and mature lymphoid aggregates. Additionally, rare enlarged plasmablastic cells with scant basophilic cytoplasm and slightly irregular nuclear contours were visualized (Figure 2A). Immunohistochemistry was positive for CD3 with a normal CD4:CD8 ratio, CD68-highlighted histiocytes within the lymphoid aggregates, and human herpesvirus 8 (HHV-8)(or Kaposi sarcoma–associated herpesvirus) demonstrated stippled nuclear staining within the scattered large cells (Figure 2B). Epstein-Barr virus–encoded RNA staining was negative, though the area of interest was lost on deeper sectioning of the tissue block. The histopathologic findings were consistent with cutaneous extracavitary PEL. Shortly after this diagnosis, he died from disease complications.

Primary effusion lymphoma is an aggressive non-Hodgkin B-cell lymphoma that was first described by Knowles et al¹ in 1989. Primary effusion lymphoma occurs exclusively in the setting of HHV-8 infection and typically is associated with chronic immunosuppression related to HIV/AIDS. Cases that are negative for HIV-1 are rare but have been reported in organ transplant recipients and elderly men from areas with a high prevalence of HHV-8 infections. Most HIV-associated cases show concurrent Epstein-Barr virus infection, though the pathogenic meaning of this co-infection remains unclear.^2,3

Primary effusion lymphoma classically presents as an isolated effusion of malignant lymphoid cells within body cavities in the absence of solid tumor masses. The pleural, peritoneal, and pericardial spaces most commonly are involved. Extracavitary PEL, a rare variant, may present as a solid mass without effusion. In general, extracavitary tumors may occur in the setting of de novo malignancy or recurrent PEL.⁴ Cutaneous manifestations associated with extracavitary PEL are rare; 4 cases have been described in which skin lesions were the heralding sign of the disease.³ Interestingly, despite obligatory underlying HHV-8 infection, a review by Pielasinski et al³ noted only 2 patients with cutaneous PEL who had prior or concurrent Kaposi sarcoma. This heterogeneity in HHV-8–related phenotypes may be related to differences in microRNA expression, but further study is needed.⁵

The diagnosis of PEL relies on histologic, immunophenotypic, and molecular analysis of the affected tissue. The malignant cells typically are large with round to irregular nuclei. These cells may demonstrate a variety of appearances, including anaplastic, plasmablastic, and immunoblastic morphologies.^6,7 The immunophenotype displays CD45 positivity and markers of lymphocyte activation (CD30, CD38, CD71), while typical B-cell (CD19, CD20, CD79a) and T-cell (CD3, CD4, CD8) markers often are absent.^6-8 Human herpesvirus 8 detection by polymerase chain reaction testing of the peripheral blood or by immunohistochemistry staining of the affected tissue is required for diagnosis.^6,7 Epstein-Barr virus infection may be detected via in situ hybridization, though it is not required for diagnosis.

The overall prognosis for PEL is poor; Brimo et al⁶ reported a median survival of less than 6 months, and Guillet et al⁹ reported 5-year overall survival (OS) for PEL vs extracavitary PEL to be 43% vs 39%. Another review noted variation in survival contingent on the number of body cavities involved; patients with a single body cavity involved experienced a median OS of 18 months, whereas patients with multiple involved cavities experienced a median OS of 4 months,⁷ possibly due to the limited study of treatment regimens or disease aggressiveness. Even in cases of successful initial treatment, relapse within 6 to 8 months is common. Extracavitary PEL may have improved disease-free survival relative to classic PEL, though the data were less clear for OS.⁹ Limitations of the Guillet et al⁹ study included a small sample size, the impossibility to randomize to disease type, and loss of power on the log-rank test for OS in the setting of possible nonproportional hazards (crossing survival curves). Overall, prognostic differences between the groups may be challenging to ascertain until further data are obtained.

As with many HIV-associated neoplasms, antiretroviral treatment (ART) for HIV-positive patients affords a better prognosis when used in addition to therapy directed at malignancy.⁷ The general approach is for concurrent ART with systemic therapies such as rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone for the rare CD20⁺ cases, and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or dose-adjusted EPOCH therapy in the more common CD20⁻ PEL cases. Narkhede et al⁷ suggested avoidance of methotrexate in patients with effusions because of increased toxicity, but it is unclear if this recommendation is applicable in extracavitary PEL patients without an effusion. Additionally, second-line treatment modalities include radiation for solid PEL masses, HHV-8–targeted antivirals, and stem cell transplantation, though evidence is limited. Of note, there is a phase I-II trial (ClinicalTrials.gov identifier NCT02911142) ongoing for treatment-naïve PEL patients involving the experimental treatment DA-EPOCH-R plus lenalidomide, but the trial is ongoing.¹⁰

We report a case of cutaneous PEL in a patient with a history of Kaposi sarcoma. The patient’s deterioration and ultimate death despite initial treatment with EPOCH and bone marrow transplantation followed by final management with daratumumab and bortezomib confirm other reports that PEL has a poor prognosis and that optimal treatments are not well delineated for these patients. In general, the current approach is to utilize ART for HIV-positive patients and to then implement chemotherapy such as CHOP. Without continued research and careful planning of treatments, data will remain limited on how best to serve patients with PEL.

In this piece, Dr. Mickey Karram & Dr. Roger R. Dmochowski discuss how although UTIs have demonstrated widespread occurrence and significant healthcare costs, there is not yet a “gold standard” definition for complicated UTI. To avoid the overuse of antimicrobial agents and their associated issues, it is vital that clinicians evaluate test results in the context of a patient’s overall risk and history of UTIs and current clinical presentation and utilize testing that enables more informed decisions.

Click here to read more

In this piece, Dr. Mickey Karram & Dr. Roger R. Dmochowski discuss how although UTIs have demonstrated widespread occurrence and significant healthcare costs, there is not yet a “gold standard” definition for complicated UTI. To avoid the overuse of antimicrobial agents and their associated issues, it is vital that clinicians evaluate test results in the context of a patient’s overall risk and history of UTIs and current clinical presentation and utilize testing that enables more informed decisions.

Click here to read more

In this piece, Dr. Mickey Karram & Dr. Roger R. Dmochowski discuss how although UTIs have demonstrated widespread occurrence and significant healthcare costs, there is not yet a “gold standard” definition for complicated UTI. To avoid the overuse of antimicrobial agents and their associated issues, it is vital that clinicians evaluate test results in the context of a patient’s overall risk and history of UTIs and current clinical presentation and utilize testing that enables more informed decisions.

Click here to read more

Though once the main treatment for anxiety disorders—often as monotherapy¹—benzodiazepines are now primarily used as adjunctive agents.^2-4 Their ability to produce rapid anxiolysis represents a significant therapeutic advantage, but in recent decades their tolerability, class-specific risks, and lack of antidepressant properties contributed to benzodiazepines being largely replaced by selective serotonin reuptake inhibitors (SSRIs) for the pharmacologic treatment of anxiety. This shift within the pharmacologic armamentarium has decreased many clinicians’ familiarity with benzodiazepines.

While benzodiazepines continue to have an important role in managing anxiety disorders, particularly treatment-resistant anxiety,⁴ clinicians must consider the limitations of these agents. Benzodiazepines can be associated with abuse and dependence, and overdose risk when combined with opiates.^5,6 They may cause memory impairment^7,8 and conflicting data suggest they may contribute to the risk of developing cognitive disorders.^9-11 Benzodiazepines also have been associated with falls and fractures,¹² and worse outcomes in patients with posttraumatic stress disorder.¹³ Some studies of patients with chronic obstructive pulmonary disease (COPD) found benzodiazepines may increase the risk of COPD exacerbations and accidental overdose,¹⁴ though others found that was not always the case.¹⁵ Benzodiazepines may be associated with an increased risk of spontaneous abortion when used early in pregnancy.¹⁶ Prospective research in women who were breastfeeding found benzodiazepines may cause sedation in up to 2% of infants.¹⁷

Despite the potential for adverse effects, benzodiazepine use remains common.¹⁸ These medications have a rapid onset of action, are useful for breakthrough symptoms, may enhance treatment adherence, and alleviate activating symptoms of SSRIs. Like other commonly used medications, benzodiazepines have the potential for both harm and benefit.¹⁹ Similar to other medications with tolerability concerns but established efficacy, particularly in treatment-resistant anxiety disorders, it is important to balance “overprescribing … to patients at risk and underusing these effective medications when indicated.”¹⁹ Though the use of benzodiazepines has been discouraged and perceptions have shifted, knowledge of benzodiazepines and benzodiazepine pharmacology also has been degraded contemporaneously.

This article provides a synthesis of the clinically relevant pharmacology of benzodiazepines, with a focus on orally administered benzodiazepines, which are more common in outpatient clinical practice. Specifically, this review describes the pharmacology of benzodiazepines, benzo­diazepine medication interactions, the relationship between pharmacologic characteristics and treatment response/tolerability, and selection and dosing of oral benzodiazepines (Table²⁰).

Benzodiazepine pharmacodynamics

Benzodiazepines act at the gamma-aminobutyric acid (GABA)-A receptor complex and bind allosterically.^21-23 Comprised of 5 glycoprotein subunits (2 alpha subunits, 2 beta subunits, and 1 gamma subunit), the receptor has 2 distinct sites at which the endogenous inhibitory transmitter GABA binds and 1 benzodiazepine binding site. Benzodiazepines bind within a socket created by the alpha and gamma subunits²² and after binding induce a conformational change in the receptor, which enhances GABA binding. There are 2 types of benzodiazepine receptors: BZ1 and BZ2. The subunits play a critical role in driving the pharmacologic characteristics of the receptor.²⁴ BZ1 and BZ2 receptors bind benzodiazepines, although they are differentially distributed within the brain. Binding at BZ1 receptors—which are distributed in cortical, thalamic, and cerebellar regions—contributes to sedation and deleterious effects of benzodiazepines on memory (eg, anterograde amnesia). BZ2 receptors (which contain gamma-2 subunits) are responsible for anxiolytic and muscle-relaxing effects. They are distributed throughout limbic regions and motor tracts, including motor neurons and neurons in the dorsal horn of the spinal cord.²⁴

Benzodiazepines—positive GABA-A receptor allosteric modulators—produce phasic inhibition, largely through the alpha and gamma subunits discussed above. In contrast, newer positive allosteric modulators (eg, zuranolone) bind at the alpha/beta subunits.²⁵ Mechanistically, endogenous neuroactive steroids and nonbenzodiazepine GABA-A–positive allosteric modulators such as zuranolone and ganaxolone also differ in their regulation of GABA-A (downregulated with benzodiazepines and hypothetically upregulated with zuranolone)²⁶ and their synaptic effects (benzodiazepines synaptically vs endogenous neurosteroids and nonbenzodiazpine positive allosteric modulators extrasynaptically).²⁷

From a developmental perspective, benzodiazepines may have less efficacy for anxiolysis and worse tolerability in some pediatric patients,²⁸ although they generally appear effective for immediate use to treat anxiety in acute settings.²⁹ The differences in efficacy and tolerability may be related to pharmacodynamic differences between pediatric populations and adults. GABA receptor expression and function do not reach adult levels until age 14 to 17½ for subcortical regions and age 18 to 22 for cortical regions, although girls reach adult expression of GABA receptors slightly earlier than boys.³⁰ Data from multiple randomized controlled trials of pediatric patients with anxiety disorders do not suggest efficacy as benzodiazepines are poorly tolerated, especially compared to other psychopharmacologic interventions for pediatric anxiety disorders.³⁰

Continue to: Pharmacology and clinical effects

 

 

Pharmacology and clinical effects

Benzodiazepine pharmacokinetics are intimately linked with the onset of action and duration of clinical effect and vary based on the route of administration, absorption, and distribution/redistribution.³¹ In this review, we focus on oral administration as opposed to IV, IM, sublingual, or intranasal administration.

Absorption

Benzodiazepines are rapidly absorbed after oral administration and quickly enter the systemic circulation. However, absorption rates vary depending on specific aspects of the gastrointestinal milieu and intrinsic properties of the benzodiazepine. For example, alprazolam is more rapidly absorbed than most other benzodiazepines, with a Tmax of 1.8 hours compared to lorazepam, which has a Tmax of approximately 2 hours. These pharmacokinetic effects instantiate differences in tolerability and efficacy. Thus, following single doses of alprazolam and diazepam, self-rated sedating effects and impairment on a task of working memory suggest that effects have a more rapid onset for alprazolam relative to lorazepam.³² Food and concomitant medications can significantly affect benzodiazepine absorption. A single-dose, 3-way crossover study demonstrated that taking diazepam concomitantly with an antacid (eg, aluminum hydroxide) decreased peak concentrations and prolonged absorption by approximately 30 minutes. However, total absorption of the medication was unaffected.³³ Additionally, administration of diazepam with food significantly slows absorption from 1 hour 15 minutes to approximately 2 hours 30 minutes and increases benzodiazepine absorption by 25% (Figure 1³⁴); the fat content of the meal appears important in moderating this effect.³⁵ The impact of food on alprazolam varies by formulation. For example, when administered in an extended-release (XR) formulation with a high-fat meal, alprazolam absorption increases by one-third, while absorption for administration of the orally disintegrating tablet with a high-fat meal increases from 1 hour 30 minutes to 2 hours. Similarly, for lorazepam, administration with a meal delays absorption by approximately 2 hours; however, this effect does not appear present with the XR formulation. Administering benzodiazepines with food can be clinically leveraged to either accelerate the onset of action or decrease peak-associated adverse effects. Thus, when a highly lipophilic benzodiazepine is needed to treat acute anxiety or prior to an expected anxiogenic stimuli, administering the medication without food may produce a faster onset of action.

CNS penetration

Benzodiazepines enter the CNS by passive diffusion. Because of this, lipophilicity at physiologic pH influences the rate at which a benzodiazepine crosses the blood-brain barrier. The rate at which benzodiazepines enter the CNS influences their clinical effects and the speed at which both efficacy (ie, anxiolysis) and adverse effects (ie, sedation, slowed cognition) are observed. In general, more lipophilic medications initiate their anxiolytic effect more quickly. However, by quickly leaving the CNS (through the same mechanism that allowed them to enter the CNS at such speed), their effects rapidly cease as they redistribute into fat. Thus, highly lipophilic benzodiazepines produce more intense effects compared to less lipophilic benzodiazepines. For these reasons, lipophilicity is more important than half-life for determining the duration of effect in most patients.

Lipophilicity and duration of effect

Benzodiazepines and their metabolites tend to be highly protein-bound and distributed in fat- and lipid-enriched areas such as the CNS. As a result, the more lipophilic agents generally have the highest rates of absorption and the fastest onset of clinical effects. The duration of action for many benzodiazepines is determined by the rate and extent of distribution (a function of lipophilicity) rather than by the rate of elimination. For example, diazepam has a longer half-life than lorazepam, but its duration of action following a single dose is shorter. This is because diazepam is more lipophilic and therefore more extensively distributed (particularly to adipose tissue). This results in it leaving the brain and blood and distributing to other tissues. In turn, its CNS effect (ie, anxiolytic effects) are more quickly terminated.

By contrast, less lipophilic benzodiazepines maintain their CNS concentrations longer; they have a longer duration of action because of their slower redistribution, which culminates in a shorter half-life, and are less extensively distributed to peripheral tissues. In essence, this means that (other things being equal) a less lipophilic benzodiazepine produces a more sustained anxiolytic effect compared to a highly lipophilic benzodiazepine.³⁶ Lipophilicity is also important in predicting some cognitive adverse effects, including amnesia. Benzodiazepines with high lipophilicity have greater absorption and faster onset of action as well as more rapid amnestic effects.^37,38 These effects may relate to overall efficacy differences for oral benzodiazepines. A recent meta-analysis by Stimpfl et al³⁶ found that less lipophilic benzodiazepines produced a greater response compared to more lipophilic benzodiazepines.

Continue to: Metabolism

 

 

Metabolism

Regarding cytochrome P450 (CYP) metabolism, polymorphic CYP2C19 and CYP3A4/5 are involved in the metabolism of several benzodiazepines³⁹ and CYP2B6 has been recognized as a contributor to diazepam metabolism. CYP3A5 gene polymorphisms may produce variation in alprazolam metabolism; however, the predominant cytochrome involved in the metabolism of oxidatively metabolized benzodiazepines (ie, benzodiazepines other than lorazepam, oxazepam, and temazepam) is primarily CYP3A4, and most effects on CYP3A4 activity are related to concomitant medications and other non­genetic factors.

Drug-drug interactions

Apart from lorazepam,^40,41 oxazepam,^42,43 and temazepam, most benzodiazepines are metabolized through oxidative mechanisms that involve CYP3A4 (Figure 2²⁰).³⁹ As such, their metabolism is influenced by medications that impact CYP3A4, including antifungals (eg, ketoconazole), calcium channel blockers (eg, verapamil, diltiazem), nefazodone, some protease inhibitors, and macrolide antibiotics. Research has examined the impact of low-dose estrogen oral contraceptives (OCPs) on exposure (eg, plasma concentrations) of several benzodiazepines. The mechanism for this interaction is likely complex and putatively involves multiple pathways, including inhibition of CYP3A4 by OCPs. The effects of OCPs on benzodiazepine pharmacokinetics vary based on the metabolism of the benzodiazepine. In general, medications oxidized and nitroreduced (eg, chlordiazepoxide, alprazolam, diazepam, and nitrazepam) have decreased clearance in patients treated with OCPs. Regarding nonoxidatively metabolized benzodiazepines, data are mixed. Research found no OCP-related effects on the pharmacokinetics of nonoxidatively metabolized benzodiazepines⁴⁴; another study suggested that clearance of these medications—through increased glucuronidation—may be increased.³¹ The effect of smoking on benzodiazepine concentration has been well documented. Smoking increases the clearance of orally administered diazepam,⁴⁵ but not IV diazepam, midazolam, or lorazepam, suggesting that this represents a first-pass effect.⁴⁶ For alprazolam, plasma concentrations are reduced by 15% to 30% in smokers and total body clearance is 24% greater compared to nonsmokers, which results in an approximately 50% increase in half-life in nonsmokers compared to smokers.⁴⁷ The most notable interaction between benzodiazepines and SSRIs is seen with fluvoxamine. Because fluvoxamine moderately inhibits CYP2C19 and CYP3A4 and potently inhibits CYP1A2,⁴⁸ the clearance of oxidatively metabolized benzodiazepines is reduced.⁴⁹ Additionally, the effects of grapefruit juice—a potent inhibitor of CYP3A4—has been evaluated for several benzodiazepines. Yasui et al⁵⁰ found grapefruit juice did not alter alprazolam plasma concentrations. However, in separate research, grapefruit juice tripled diazepam exposure, increased peak concentrations 1.5-fold, and prolonged absorption.⁵¹

Hepatic disease

Exposure to benzodiazepines—other than lorazepam, oxazepam, and temazepam—is influenced by intrinsic hepatic disease and requires dose adjustment in individuals with significant hepatic impairment. The impact of hepatic disease on the clinical pharmacology of benzodiazepines may relate to 2 factors: protein binding and metabolism. In a study of individuals with cirrhosis, lorazepam binding was decreased, although its metabolism and clearance were largely unaffected.⁴⁰

Aging and benzodiazepine metabolism/clearance

Aging is associated with myriad physiologic changes (eg, decrease in renal clearance after age 40, changes in body fat distribution, changes in activity of cytochromes) that are relevant to benzodiazepine pharmacology. They may underlie differences in the tolerability of benzodiazepines and other clinically relevant characteristics (eg, duration of action, accumulation).

Several studies have evaluated the impact of aging on the clearance and disposition of selected benzodiazepines. The respective half-lives of chlordiazepoxide and diazepam increase from 4- to 6-fold from age 20 to 80. Further, with chronic dosing, highly lipophilic benzodiazepines may require additional attention in geriatric patients. In a study that included individuals up to age 78, steady-state plasma concentrations of diazepam and its metabolite, desmethyldiazepam (DMDZ), were 30% to 35% higher in older patients compared to younger individuals.⁵² In this study, the half-lives for the young and older patients were 31 hours and 86 hours, respectively, for diazepam, and 40 hours and 80 hours, respectively, for the active metabolite. The half-life of diazepam is increased by “1 hour for each year of age beginning with a half-life of 20 hours at 20 years of age, as the volume of distribution is increased, and clearance is decreased.”⁵² Clinically, this implies that in older adults, clinicians should expect lower peak concentrations (Cmax), higher trough concentrations (Cmin), and that diazepam will take longer to reach steady-state concentrations. Taken together, these findings raised concern that “slow accumulation and delayed washout of diazepam and DMDZ is probable.”⁵² These findings—which may have more clinical relevance than those of single-dose studies—suggest that the effects related to diazepam would also take longer to resolve in older patients. Finally, lorazepam clearance or distribution does not appear to be affected by aging, at least in patients age 15 to 73.⁴⁰ Alprazolam is more slowly cleared in geriatric patients and its effects may be potentiated by reduced protein binding.

Continue to: Obesity

 

 

Obesity

The distribution of medications, including benzodiazepines, is altered in patients who are obese because of increased adipose tissue.^53,54 This increase in the volume of distribution can attenuate the onset of action, increase medication accumulation in fat, and potentiate the duration of action.^55,56

Obesity may also affect hepatic metabolism by induction of CYP1A2, CYP2C9, and CYP2C19, and inhibition of CYP3A4.⁵⁷ Triazolam, which is metabolized by CYP3A4, is associated with a greater exposure (ie, plasma concentrations) in individuals who are obese.⁵⁸ However, when considering differences in benzodiazepine pharmacokinetics in patients who are obese, clinicians must remember that elimination half-life depends on both volume of distribution and clearance. In patients who are obese (compared to patients who are not obese), the half-lives are increased for alprazolam (22 hours vs 11 hours, P < .001)⁵⁹ and diazepam (82 hours vs 32 hours, P < .005).⁶⁰ In a pharmacokinetic study of diazepam in individuals who were obese and individuals who were not obese, total metabolic clearance did not differ. Rather, the increased half-life was related to a tripling of the volume of distribution in obese patients (228 liters vs 70 liters, P < .01). This indicates that patients who are obese may experience a much slower onset of maximal effect compared to patients who are not obese because the accumulation of the medication is delayed. Additionally, for benzodiazepines that are conjugated (lorazepam and oxazepam), clearance is significantly enhanced in patients who are obese. For example, lorazepam clearance is 102 mL/min in individuals who are obese compared to 63 mL/min in individuals who are not obese; for oxazepam, clearance is 181 mL/min in patients who are obese compared to 98 mL/min in individuals who are not obese.⁶¹ These differences are attributed to increased uridine diphosphate glucuronyl transferase in obesity and to increases in liver size in obesity.⁵³

How quickly do benzodiazepines work?

Benzodiazepines act quickly. Meta-analyses³⁶ suggest that improvement in anxiety symptoms compared to placebo is greatest initially and then the rate of improvement slows over successive weeks. Research on benzodiazepines reveals statistically significant differences between benzodiazepines and placebo within the first week of treatment, with >80% of the expected improvement by Week 8 of treatment emerging by Week 4 (Figure 3³⁶). The rapid reduction in anxiety symptoms seen with benzodiazepines has important treatment implications, given that traditional psycho­therapeutic and antidepressant treatments are slow to produce improvements. Consistent data suggesting that benzodiazepines work faster than other treatments support that they may have a role during the initiation of other treatments.

What is the ‘best’ dose?

As seen with other classes of psychotropic medications,⁴ the relationship between benzodiazepine dose and response is complex. In a recent meta-analysis of 65 placebo-controlled trials of benzodiazepines in adults with anxiety disorders, there was a superior response over time for low-dose benzodiazepines (<3 mg/d in lorazepam equivalents) compared to a medium dose (3 to 6 mg/d; P = .042); high-dose benzodiazepines (>6 mg/d) yielded less improvement compared to medium doses (P = .001).³⁶ A study of adults with panic disorder similarly found the greatest responses with alprazolam plasma concentrations of 20 to 40 ng/mL, with no additional benefit at <20 ng/mL or >40 ng/mL.⁴⁹ As plasma concentrations increase, adverse effects such as sedation also increase, which may confound the observed loss of a dose-response relationship at higher doses and plasma concentrations.⁶² This may, in part, account for the observation that higher doses of benzodiazepines are associated with greater depressive symptoms and disrupted sleep.⁶³ As such, low doses may represent a delicate equipoise between efficacy and tolerability, yielding the most optimal clinical response.

Which benzodiazepine should I prescribe?

Comparing benzodiazepines is difficult, given the differences in dosing and disorders studied and differences in how each individual clinical trial was conducted. A meta-analysis by Stimpfl et al³⁶ that used Bayesian hierarchical modeling, which allowed some of this heterogeneity to be addressed, found that relative to the reference benzodiazepine (lorazepam), clonazepam had the greatest trajectory/magnitude of response (other specific benzodiazepines did not statistically differ from lorazepam) (Figure 4³⁶).

Continue to: Another aspect of the superiority...

Another aspect of the superiority of clonazepam in some research relates to its pharma­cokinetic properties, particularly when compared with benzodiazepines that have very short half-lives. Short half-life benzodiazepines have been associated with rebound anxiety, which is defined as “the relative worsening of symptoms on discontinuation of treatment as compared to baseline symptoms” and is distinct from withdrawal.⁶⁴ While it is difficult to assess this in clinical trials, Herman et al⁶⁵ provided insight into the contribution of rebound anxiety in a study of patients with panic disorder treated with alprazolam who experienced “interdose anxiety symptoms.” Of the 48 patients in this study, 41 switched to clonazepam, and most who switched (82%) experienced improvement. The improvement was attributed to the decreased frequency of clonazepam (vs alprazolam) administration and lack of interdose anxiety. When selecting an oral benzodiazepine, consider the duration, onset of action, and differences in metabolism that produce varying levels of effectiveness for individual patients. In situations where rapid onset is desired, a short-acting benzodiazepine may be preferable, while a longer-acting benzodiazepine would be preferable in situations where the patient needs sustained effects.

Regarding lipophilicity, differences among benzodiazepines could contribute to differences in psychological dependence and differential utility in some situations. For example, alprazolam rapidly enters the CNS, producing an immediate anxiolytic effect. However, its egress from the CNS is equally rapid, and its anxiolytic effects disappear quickly. This may be desirable for addressing acute, predictable anxiety, but could have unintended consequences in treating chronic anxiety, where it could facilitate psychological dependence.

Practical considerations

When prescribing benzodiazepines, consider a myriad of patient- and medication-specific factors, as these have clinically relevant implications on treatment response. This information, taken together, supports the importance of an individualized approach to benzodiazepine use. Before selecting a benzodiazepine and during treatment, important elements of the patient’s history must be considered, including age, body weight, concomitant medication use (eg, antacids, CYP3A4 inhibitors, OCPs), smoking status, and history of hepatic or renal disease.

Patients age <18 are unlikely to have full expression of GABA receptors in the brain³⁰ and therefore benzodiazepines may not be as efficacious for anxiolysis in this population. Moreover, compared to younger patients, older patients may experience higher steady-state concentrations of benzo­diazepines, especially lipophilic agents, due to an increased volume of distribution and decreased clearance. In patients treated with OCPs, some benzodiazepines may take longer to reach steady-state, and dose adjustments may need to be considered. In patients who smoke, clearance of some oral benzo­diazepines is also accelerated, potentially decreasing half-life by up to 50%.

When dosing and titrating benzodiazepines, consider the patient’s body weight, particularly if they are obese. The effects of obesity on benzodiazepine pharmacokinetics are complex. For glucuronidated benzodiazepines, clearance is increased in patients who are obese; however, the volume of distribution is also increased in such patients, meaning it will take longer for benzodiazepines to achieve steady-state in these individuals compared to patients who are not obese. These effects suggest it may take longer to achieve a response at a given dose in patients who are obese compared to individuals who are not obese.

Continue to: The properties of individual benzodiazepines...

The properties of individual benzodiazepines should also be considered when selecting a benzodiazepine treatment. If circumstances necessitate rapid symptom relief, a lipophilic benzodiazepine, such as diazepam, may be preferred for quick onset and offset of action. Onset of action may also be hastened by taking the benzodiazepine without food; conversely, if peak adverse effects are problematic, concurrent consumption of a high-fat meal may help decrease peak concentration and prolonging absorption. In other circumstances, such as if sustained anxiolysis is desired, a clinician may opt for a less lipophilic benzodiazepine, such as clonazepam. Finally, in terms of general treatment response, benzodiazepines separate from placebo in the first week of treatment, which supports the idea they may be useful during the introduction of other medications (eg, SSRIs) that take a longer time to achieve clinical effect.

Bottom Line

The pharmacokinetics of benzodiazepines are intimately linked with the onset of action and duration of clinical effect and vary based on individual absorption and distribution/redistribution. Benzodiazepines’ clinical profile derives from their pharmacokinetic differences and is influenced by many factors, including age, body weight, concomitant medication use, smoking status, and hepatic or renal disease. Consider these factors to individualize the approach to using benzodiazepines and optimize tolerability and efficacy.

Related Resources

• Weber SR, Duchemin AM. Benzodiazepines: sensible prescribing in light of the risks. Current Psychiatry. 2018;17(2):22-27.
• Balon R. Benzodiazepines for anxious depression. Current Psychiatry. 2018;17(8):9-12.

Drug Brand Names

Alprazolam • Xanax
Chlordiazepoxide • Librium
Clobazam • Onfi
Clonazepam • Klonopin
Clorazepate • Gen-Xene
Diazepam • Valium
Diltiazem • Cardizem
Fluvoxamine • Luvox
Ganaxolone • Ztalmy
Ketoconazole • Nizoral
Lorazepam • Ativan
Midazolam • Versed
Temazepam • Restoril
Triazolam • Halcion
Verapamil • Calan

Though once the main treatment for anxiety disorders—often as monotherapy¹—benzodiazepines are now primarily used as adjunctive agents.^2-4 Their ability to produce rapid anxiolysis represents a significant therapeutic advantage, but in recent decades their tolerability, class-specific risks, and lack of antidepressant properties contributed to benzodiazepines being largely replaced by selective serotonin reuptake inhibitors (SSRIs) for the pharmacologic treatment of anxiety. This shift within the pharmacologic armamentarium has decreased many clinicians’ familiarity with benzodiazepines.

While benzodiazepines continue to have an important role in managing anxiety disorders, particularly treatment-resistant anxiety,⁴ clinicians must consider the limitations of these agents. Benzodiazepines can be associated with abuse and dependence, and overdose risk when combined with opiates.^5,6 They may cause memory impairment^7,8 and conflicting data suggest they may contribute to the risk of developing cognitive disorders.^9-11 Benzodiazepines also have been associated with falls and fractures,¹² and worse outcomes in patients with posttraumatic stress disorder.¹³ Some studies of patients with chronic obstructive pulmonary disease (COPD) found benzodiazepines may increase the risk of COPD exacerbations and accidental overdose,¹⁴ though others found that was not always the case.¹⁵ Benzodiazepines may be associated with an increased risk of spontaneous abortion when used early in pregnancy.¹⁶ Prospective research in women who were breastfeeding found benzodiazepines may cause sedation in up to 2% of infants.¹⁷

Despite the potential for adverse effects, benzodiazepine use remains common.¹⁸ These medications have a rapid onset of action, are useful for breakthrough symptoms, may enhance treatment adherence, and alleviate activating symptoms of SSRIs. Like other commonly used medications, benzodiazepines have the potential for both harm and benefit.¹⁹ Similar to other medications with tolerability concerns but established efficacy, particularly in treatment-resistant anxiety disorders, it is important to balance “overprescribing … to patients at risk and underusing these effective medications when indicated.”¹⁹ Though the use of benzodiazepines has been discouraged and perceptions have shifted, knowledge of benzodiazepines and benzodiazepine pharmacology also has been degraded contemporaneously.

This article provides a synthesis of the clinically relevant pharmacology of benzodiazepines, with a focus on orally administered benzodiazepines, which are more common in outpatient clinical practice. Specifically, this review describes the pharmacology of benzodiazepines, benzo­diazepine medication interactions, the relationship between pharmacologic characteristics and treatment response/tolerability, and selection and dosing of oral benzodiazepines (Table²⁰).

Benzodiazepine pharmacodynamics

Benzodiazepines act at the gamma-aminobutyric acid (GABA)-A receptor complex and bind allosterically.^21-23 Comprised of 5 glycoprotein subunits (2 alpha subunits, 2 beta subunits, and 1 gamma subunit), the receptor has 2 distinct sites at which the endogenous inhibitory transmitter GABA binds and 1 benzodiazepine binding site. Benzodiazepines bind within a socket created by the alpha and gamma subunits²² and after binding induce a conformational change in the receptor, which enhances GABA binding. There are 2 types of benzodiazepine receptors: BZ1 and BZ2. The subunits play a critical role in driving the pharmacologic characteristics of the receptor.²⁴ BZ1 and BZ2 receptors bind benzodiazepines, although they are differentially distributed within the brain. Binding at BZ1 receptors—which are distributed in cortical, thalamic, and cerebellar regions—contributes to sedation and deleterious effects of benzodiazepines on memory (eg, anterograde amnesia). BZ2 receptors (which contain gamma-2 subunits) are responsible for anxiolytic and muscle-relaxing effects. They are distributed throughout limbic regions and motor tracts, including motor neurons and neurons in the dorsal horn of the spinal cord.²⁴

Benzodiazepines—positive GABA-A receptor allosteric modulators—produce phasic inhibition, largely through the alpha and gamma subunits discussed above. In contrast, newer positive allosteric modulators (eg, zuranolone) bind at the alpha/beta subunits.²⁵ Mechanistically, endogenous neuroactive steroids and nonbenzodiazepine GABA-A–positive allosteric modulators such as zuranolone and ganaxolone also differ in their regulation of GABA-A (downregulated with benzodiazepines and hypothetically upregulated with zuranolone)²⁶ and their synaptic effects (benzodiazepines synaptically vs endogenous neurosteroids and nonbenzodiazpine positive allosteric modulators extrasynaptically).²⁷

From a developmental perspective, benzodiazepines may have less efficacy for anxiolysis and worse tolerability in some pediatric patients,²⁸ although they generally appear effective for immediate use to treat anxiety in acute settings.²⁹ The differences in efficacy and tolerability may be related to pharmacodynamic differences between pediatric populations and adults. GABA receptor expression and function do not reach adult levels until age 14 to 17½ for subcortical regions and age 18 to 22 for cortical regions, although girls reach adult expression of GABA receptors slightly earlier than boys.³⁰ Data from multiple randomized controlled trials of pediatric patients with anxiety disorders do not suggest efficacy as benzodiazepines are poorly tolerated, especially compared to other psychopharmacologic interventions for pediatric anxiety disorders.³⁰

Continue to: Pharmacology and clinical effects

 

 

Pharmacology and clinical effects

Benzodiazepine pharmacokinetics are intimately linked with the onset of action and duration of clinical effect and vary based on the route of administration, absorption, and distribution/redistribution.³¹ In this review, we focus on oral administration as opposed to IV, IM, sublingual, or intranasal administration.

Absorption

Benzodiazepines are rapidly absorbed after oral administration and quickly enter the systemic circulation. However, absorption rates vary depending on specific aspects of the gastrointestinal milieu and intrinsic properties of the benzodiazepine. For example, alprazolam is more rapidly absorbed than most other benzodiazepines, with a Tmax of 1.8 hours compared to lorazepam, which has a Tmax of approximately 2 hours. These pharmacokinetic effects instantiate differences in tolerability and efficacy. Thus, following single doses of alprazolam and diazepam, self-rated sedating effects and impairment on a task of working memory suggest that effects have a more rapid onset for alprazolam relative to lorazepam.³² Food and concomitant medications can significantly affect benzodiazepine absorption. A single-dose, 3-way crossover study demonstrated that taking diazepam concomitantly with an antacid (eg, aluminum hydroxide) decreased peak concentrations and prolonged absorption by approximately 30 minutes. However, total absorption of the medication was unaffected.³³ Additionally, administration of diazepam with food significantly slows absorption from 1 hour 15 minutes to approximately 2 hours 30 minutes and increases benzodiazepine absorption by 25% (Figure 1³⁴); the fat content of the meal appears important in moderating this effect.³⁵ The impact of food on alprazolam varies by formulation. For example, when administered in an extended-release (XR) formulation with a high-fat meal, alprazolam absorption increases by one-third, while absorption for administration of the orally disintegrating tablet with a high-fat meal increases from 1 hour 30 minutes to 2 hours. Similarly, for lorazepam, administration with a meal delays absorption by approximately 2 hours; however, this effect does not appear present with the XR formulation. Administering benzodiazepines with food can be clinically leveraged to either accelerate the onset of action or decrease peak-associated adverse effects. Thus, when a highly lipophilic benzodiazepine is needed to treat acute anxiety or prior to an expected anxiogenic stimuli, administering the medication without food may produce a faster onset of action.

CNS penetration

Benzodiazepines enter the CNS by passive diffusion. Because of this, lipophilicity at physiologic pH influences the rate at which a benzodiazepine crosses the blood-brain barrier. The rate at which benzodiazepines enter the CNS influences their clinical effects and the speed at which both efficacy (ie, anxiolysis) and adverse effects (ie, sedation, slowed cognition) are observed. In general, more lipophilic medications initiate their anxiolytic effect more quickly. However, by quickly leaving the CNS (through the same mechanism that allowed them to enter the CNS at such speed), their effects rapidly cease as they redistribute into fat. Thus, highly lipophilic benzodiazepines produce more intense effects compared to less lipophilic benzodiazepines. For these reasons, lipophilicity is more important than half-life for determining the duration of effect in most patients.

Lipophilicity and duration of effect

Benzodiazepines and their metabolites tend to be highly protein-bound and distributed in fat- and lipid-enriched areas such as the CNS. As a result, the more lipophilic agents generally have the highest rates of absorption and the fastest onset of clinical effects. The duration of action for many benzodiazepines is determined by the rate and extent of distribution (a function of lipophilicity) rather than by the rate of elimination. For example, diazepam has a longer half-life than lorazepam, but its duration of action following a single dose is shorter. This is because diazepam is more lipophilic and therefore more extensively distributed (particularly to adipose tissue). This results in it leaving the brain and blood and distributing to other tissues. In turn, its CNS effect (ie, anxiolytic effects) are more quickly terminated.

By contrast, less lipophilic benzodiazepines maintain their CNS concentrations longer; they have a longer duration of action because of their slower redistribution, which culminates in a shorter half-life, and are less extensively distributed to peripheral tissues. In essence, this means that (other things being equal) a less lipophilic benzodiazepine produces a more sustained anxiolytic effect compared to a highly lipophilic benzodiazepine.³⁶ Lipophilicity is also important in predicting some cognitive adverse effects, including amnesia. Benzodiazepines with high lipophilicity have greater absorption and faster onset of action as well as more rapid amnestic effects.^37,38 These effects may relate to overall efficacy differences for oral benzodiazepines. A recent meta-analysis by Stimpfl et al³⁶ found that less lipophilic benzodiazepines produced a greater response compared to more lipophilic benzodiazepines.

Continue to: Metabolism

 

 

Metabolism

Regarding cytochrome P450 (CYP) metabolism, polymorphic CYP2C19 and CYP3A4/5 are involved in the metabolism of several benzodiazepines³⁹ and CYP2B6 has been recognized as a contributor to diazepam metabolism. CYP3A5 gene polymorphisms may produce variation in alprazolam metabolism; however, the predominant cytochrome involved in the metabolism of oxidatively metabolized benzodiazepines (ie, benzodiazepines other than lorazepam, oxazepam, and temazepam) is primarily CYP3A4, and most effects on CYP3A4 activity are related to concomitant medications and other non­genetic factors.

Drug-drug interactions

Apart from lorazepam,^40,41 oxazepam,^42,43 and temazepam, most benzodiazepines are metabolized through oxidative mechanisms that involve CYP3A4 (Figure 2²⁰).³⁹ As such, their metabolism is influenced by medications that impact CYP3A4, including antifungals (eg, ketoconazole), calcium channel blockers (eg, verapamil, diltiazem), nefazodone, some protease inhibitors, and macrolide antibiotics. Research has examined the impact of low-dose estrogen oral contraceptives (OCPs) on exposure (eg, plasma concentrations) of several benzodiazepines. The mechanism for this interaction is likely complex and putatively involves multiple pathways, including inhibition of CYP3A4 by OCPs. The effects of OCPs on benzodiazepine pharmacokinetics vary based on the metabolism of the benzodiazepine. In general, medications oxidized and nitroreduced (eg, chlordiazepoxide, alprazolam, diazepam, and nitrazepam) have decreased clearance in patients treated with OCPs. Regarding nonoxidatively metabolized benzodiazepines, data are mixed. Research found no OCP-related effects on the pharmacokinetics of nonoxidatively metabolized benzodiazepines⁴⁴; another study suggested that clearance of these medications—through increased glucuronidation—may be increased.³¹ The effect of smoking on benzodiazepine concentration has been well documented. Smoking increases the clearance of orally administered diazepam,⁴⁵ but not IV diazepam, midazolam, or lorazepam, suggesting that this represents a first-pass effect.⁴⁶ For alprazolam, plasma concentrations are reduced by 15% to 30% in smokers and total body clearance is 24% greater compared to nonsmokers, which results in an approximately 50% increase in half-life in nonsmokers compared to smokers.⁴⁷ The most notable interaction between benzodiazepines and SSRIs is seen with fluvoxamine. Because fluvoxamine moderately inhibits CYP2C19 and CYP3A4 and potently inhibits CYP1A2,⁴⁸ the clearance of oxidatively metabolized benzodiazepines is reduced.⁴⁹ Additionally, the effects of grapefruit juice—a potent inhibitor of CYP3A4—has been evaluated for several benzodiazepines. Yasui et al⁵⁰ found grapefruit juice did not alter alprazolam plasma concentrations. However, in separate research, grapefruit juice tripled diazepam exposure, increased peak concentrations 1.5-fold, and prolonged absorption.⁵¹

Hepatic disease

Exposure to benzodiazepines—other than lorazepam, oxazepam, and temazepam—is influenced by intrinsic hepatic disease and requires dose adjustment in individuals with significant hepatic impairment. The impact of hepatic disease on the clinical pharmacology of benzodiazepines may relate to 2 factors: protein binding and metabolism. In a study of individuals with cirrhosis, lorazepam binding was decreased, although its metabolism and clearance were largely unaffected.⁴⁰

Aging and benzodiazepine metabolism/clearance

Aging is associated with myriad physiologic changes (eg, decrease in renal clearance after age 40, changes in body fat distribution, changes in activity of cytochromes) that are relevant to benzodiazepine pharmacology. They may underlie differences in the tolerability of benzodiazepines and other clinically relevant characteristics (eg, duration of action, accumulation).

Several studies have evaluated the impact of aging on the clearance and disposition of selected benzodiazepines. The respective half-lives of chlordiazepoxide and diazepam increase from 4- to 6-fold from age 20 to 80. Further, with chronic dosing, highly lipophilic benzodiazepines may require additional attention in geriatric patients. In a study that included individuals up to age 78, steady-state plasma concentrations of diazepam and its metabolite, desmethyldiazepam (DMDZ), were 30% to 35% higher in older patients compared to younger individuals.⁵² In this study, the half-lives for the young and older patients were 31 hours and 86 hours, respectively, for diazepam, and 40 hours and 80 hours, respectively, for the active metabolite. The half-life of diazepam is increased by “1 hour for each year of age beginning with a half-life of 20 hours at 20 years of age, as the volume of distribution is increased, and clearance is decreased.”⁵² Clinically, this implies that in older adults, clinicians should expect lower peak concentrations (Cmax), higher trough concentrations (Cmin), and that diazepam will take longer to reach steady-state concentrations. Taken together, these findings raised concern that “slow accumulation and delayed washout of diazepam and DMDZ is probable.”⁵² These findings—which may have more clinical relevance than those of single-dose studies—suggest that the effects related to diazepam would also take longer to resolve in older patients. Finally, lorazepam clearance or distribution does not appear to be affected by aging, at least in patients age 15 to 73.⁴⁰ Alprazolam is more slowly cleared in geriatric patients and its effects may be potentiated by reduced protein binding.

Continue to: Obesity

 

 

Obesity

The distribution of medications, including benzodiazepines, is altered in patients who are obese because of increased adipose tissue.^53,54 This increase in the volume of distribution can attenuate the onset of action, increase medication accumulation in fat, and potentiate the duration of action.^55,56

Obesity may also affect hepatic metabolism by induction of CYP1A2, CYP2C9, and CYP2C19, and inhibition of CYP3A4.⁵⁷ Triazolam, which is metabolized by CYP3A4, is associated with a greater exposure (ie, plasma concentrations) in individuals who are obese.⁵⁸ However, when considering differences in benzodiazepine pharmacokinetics in patients who are obese, clinicians must remember that elimination half-life depends on both volume of distribution and clearance. In patients who are obese (compared to patients who are not obese), the half-lives are increased for alprazolam (22 hours vs 11 hours, P < .001)⁵⁹ and diazepam (82 hours vs 32 hours, P < .005).⁶⁰ In a pharmacokinetic study of diazepam in individuals who were obese and individuals who were not obese, total metabolic clearance did not differ. Rather, the increased half-life was related to a tripling of the volume of distribution in obese patients (228 liters vs 70 liters, P < .01). This indicates that patients who are obese may experience a much slower onset of maximal effect compared to patients who are not obese because the accumulation of the medication is delayed. Additionally, for benzodiazepines that are conjugated (lorazepam and oxazepam), clearance is significantly enhanced in patients who are obese. For example, lorazepam clearance is 102 mL/min in individuals who are obese compared to 63 mL/min in individuals who are not obese; for oxazepam, clearance is 181 mL/min in patients who are obese compared to 98 mL/min in individuals who are not obese.⁶¹ These differences are attributed to increased uridine diphosphate glucuronyl transferase in obesity and to increases in liver size in obesity.⁵³

How quickly do benzodiazepines work?

Benzodiazepines act quickly. Meta-analyses³⁶ suggest that improvement in anxiety symptoms compared to placebo is greatest initially and then the rate of improvement slows over successive weeks. Research on benzodiazepines reveals statistically significant differences between benzodiazepines and placebo within the first week of treatment, with >80% of the expected improvement by Week 8 of treatment emerging by Week 4 (Figure 3³⁶). The rapid reduction in anxiety symptoms seen with benzodiazepines has important treatment implications, given that traditional psycho­therapeutic and antidepressant treatments are slow to produce improvements. Consistent data suggesting that benzodiazepines work faster than other treatments support that they may have a role during the initiation of other treatments.

What is the ‘best’ dose?

As seen with other classes of psychotropic medications,⁴ the relationship between benzodiazepine dose and response is complex. In a recent meta-analysis of 65 placebo-controlled trials of benzodiazepines in adults with anxiety disorders, there was a superior response over time for low-dose benzodiazepines (<3 mg/d in lorazepam equivalents) compared to a medium dose (3 to 6 mg/d; P = .042); high-dose benzodiazepines (>6 mg/d) yielded less improvement compared to medium doses (P = .001).³⁶ A study of adults with panic disorder similarly found the greatest responses with alprazolam plasma concentrations of 20 to 40 ng/mL, with no additional benefit at <20 ng/mL or >40 ng/mL.⁴⁹ As plasma concentrations increase, adverse effects such as sedation also increase, which may confound the observed loss of a dose-response relationship at higher doses and plasma concentrations.⁶² This may, in part, account for the observation that higher doses of benzodiazepines are associated with greater depressive symptoms and disrupted sleep.⁶³ As such, low doses may represent a delicate equipoise between efficacy and tolerability, yielding the most optimal clinical response.

Which benzodiazepine should I prescribe?

Comparing benzodiazepines is difficult, given the differences in dosing and disorders studied and differences in how each individual clinical trial was conducted. A meta-analysis by Stimpfl et al³⁶ that used Bayesian hierarchical modeling, which allowed some of this heterogeneity to be addressed, found that relative to the reference benzodiazepine (lorazepam), clonazepam had the greatest trajectory/magnitude of response (other specific benzodiazepines did not statistically differ from lorazepam) (Figure 4³⁶).

Continue to: Another aspect of the superiority...

Another aspect of the superiority of clonazepam in some research relates to its pharma­cokinetic properties, particularly when compared with benzodiazepines that have very short half-lives. Short half-life benzodiazepines have been associated with rebound anxiety, which is defined as “the relative worsening of symptoms on discontinuation of treatment as compared to baseline symptoms” and is distinct from withdrawal.⁶⁴ While it is difficult to assess this in clinical trials, Herman et al⁶⁵ provided insight into the contribution of rebound anxiety in a study of patients with panic disorder treated with alprazolam who experienced “interdose anxiety symptoms.” Of the 48 patients in this study, 41 switched to clonazepam, and most who switched (82%) experienced improvement. The improvement was attributed to the decreased frequency of clonazepam (vs alprazolam) administration and lack of interdose anxiety. When selecting an oral benzodiazepine, consider the duration, onset of action, and differences in metabolism that produce varying levels of effectiveness for individual patients. In situations where rapid onset is desired, a short-acting benzodiazepine may be preferable, while a longer-acting benzodiazepine would be preferable in situations where the patient needs sustained effects.

Regarding lipophilicity, differences among benzodiazepines could contribute to differences in psychological dependence and differential utility in some situations. For example, alprazolam rapidly enters the CNS, producing an immediate anxiolytic effect. However, its egress from the CNS is equally rapid, and its anxiolytic effects disappear quickly. This may be desirable for addressing acute, predictable anxiety, but could have unintended consequences in treating chronic anxiety, where it could facilitate psychological dependence.

Practical considerations

When prescribing benzodiazepines, consider a myriad of patient- and medication-specific factors, as these have clinically relevant implications on treatment response. This information, taken together, supports the importance of an individualized approach to benzodiazepine use. Before selecting a benzodiazepine and during treatment, important elements of the patient’s history must be considered, including age, body weight, concomitant medication use (eg, antacids, CYP3A4 inhibitors, OCPs), smoking status, and history of hepatic or renal disease.

Patients age <18 are unlikely to have full expression of GABA receptors in the brain³⁰ and therefore benzodiazepines may not be as efficacious for anxiolysis in this population. Moreover, compared to younger patients, older patients may experience higher steady-state concentrations of benzo­diazepines, especially lipophilic agents, due to an increased volume of distribution and decreased clearance. In patients treated with OCPs, some benzodiazepines may take longer to reach steady-state, and dose adjustments may need to be considered. In patients who smoke, clearance of some oral benzo­diazepines is also accelerated, potentially decreasing half-life by up to 50%.

When dosing and titrating benzodiazepines, consider the patient’s body weight, particularly if they are obese. The effects of obesity on benzodiazepine pharmacokinetics are complex. For glucuronidated benzodiazepines, clearance is increased in patients who are obese; however, the volume of distribution is also increased in such patients, meaning it will take longer for benzodiazepines to achieve steady-state in these individuals compared to patients who are not obese. These effects suggest it may take longer to achieve a response at a given dose in patients who are obese compared to individuals who are not obese.

Continue to: The properties of individual benzodiazepines...

The properties of individual benzodiazepines should also be considered when selecting a benzodiazepine treatment. If circumstances necessitate rapid symptom relief, a lipophilic benzodiazepine, such as diazepam, may be preferred for quick onset and offset of action. Onset of action may also be hastened by taking the benzodiazepine without food; conversely, if peak adverse effects are problematic, concurrent consumption of a high-fat meal may help decrease peak concentration and prolonging absorption. In other circumstances, such as if sustained anxiolysis is desired, a clinician may opt for a less lipophilic benzodiazepine, such as clonazepam. Finally, in terms of general treatment response, benzodiazepines separate from placebo in the first week of treatment, which supports the idea they may be useful during the introduction of other medications (eg, SSRIs) that take a longer time to achieve clinical effect.

Bottom Line

The pharmacokinetics of benzodiazepines are intimately linked with the onset of action and duration of clinical effect and vary based on individual absorption and distribution/redistribution. Benzodiazepines’ clinical profile derives from their pharmacokinetic differences and is influenced by many factors, including age, body weight, concomitant medication use, smoking status, and hepatic or renal disease. Consider these factors to individualize the approach to using benzodiazepines and optimize tolerability and efficacy.

Related Resources

• Weber SR, Duchemin AM. Benzodiazepines: sensible prescribing in light of the risks. Current Psychiatry. 2018;17(2):22-27.
• Balon R. Benzodiazepines for anxious depression. Current Psychiatry. 2018;17(8):9-12.

Drug Brand Names

Alprazolam • Xanax
Chlordiazepoxide • Librium
Clobazam • Onfi
Clonazepam • Klonopin
Clorazepate • Gen-Xene
Diazepam • Valium
Diltiazem • Cardizem
Fluvoxamine • Luvox
Ganaxolone • Ztalmy
Ketoconazole • Nizoral
Lorazepam • Ativan
Midazolam • Versed
Temazepam • Restoril
Triazolam • Halcion
Verapamil • Calan

Though once the main treatment for anxiety disorders—often as monotherapy¹—benzodiazepines are now primarily used as adjunctive agents.^2-4 Their ability to produce rapid anxiolysis represents a significant therapeutic advantage, but in recent decades their tolerability, class-specific risks, and lack of antidepressant properties contributed to benzodiazepines being largely replaced by selective serotonin reuptake inhibitors (SSRIs) for the pharmacologic treatment of anxiety. This shift within the pharmacologic armamentarium has decreased many clinicians’ familiarity with benzodiazepines.

While benzodiazepines continue to have an important role in managing anxiety disorders, particularly treatment-resistant anxiety,⁴ clinicians must consider the limitations of these agents. Benzodiazepines can be associated with abuse and dependence, and overdose risk when combined with opiates.^5,6 They may cause memory impairment^7,8 and conflicting data suggest they may contribute to the risk of developing cognitive disorders.^9-11 Benzodiazepines also have been associated with falls and fractures,¹² and worse outcomes in patients with posttraumatic stress disorder.¹³ Some studies of patients with chronic obstructive pulmonary disease (COPD) found benzodiazepines may increase the risk of COPD exacerbations and accidental overdose,¹⁴ though others found that was not always the case.¹⁵ Benzodiazepines may be associated with an increased risk of spontaneous abortion when used early in pregnancy.¹⁶ Prospective research in women who were breastfeeding found benzodiazepines may cause sedation in up to 2% of infants.¹⁷

Despite the potential for adverse effects, benzodiazepine use remains common.¹⁸ These medications have a rapid onset of action, are useful for breakthrough symptoms, may enhance treatment adherence, and alleviate activating symptoms of SSRIs. Like other commonly used medications, benzodiazepines have the potential for both harm and benefit.¹⁹ Similar to other medications with tolerability concerns but established efficacy, particularly in treatment-resistant anxiety disorders, it is important to balance “overprescribing … to patients at risk and underusing these effective medications when indicated.”¹⁹ Though the use of benzodiazepines has been discouraged and perceptions have shifted, knowledge of benzodiazepines and benzodiazepine pharmacology also has been degraded contemporaneously.

This article provides a synthesis of the clinically relevant pharmacology of benzodiazepines, with a focus on orally administered benzodiazepines, which are more common in outpatient clinical practice. Specifically, this review describes the pharmacology of benzodiazepines, benzo­diazepine medication interactions, the relationship between pharmacologic characteristics and treatment response/tolerability, and selection and dosing of oral benzodiazepines (Table²⁰).

Benzodiazepine pharmacodynamics

Benzodiazepines act at the gamma-aminobutyric acid (GABA)-A receptor complex and bind allosterically.^21-23 Comprised of 5 glycoprotein subunits (2 alpha subunits, 2 beta subunits, and 1 gamma subunit), the receptor has 2 distinct sites at which the endogenous inhibitory transmitter GABA binds and 1 benzodiazepine binding site. Benzodiazepines bind within a socket created by the alpha and gamma subunits²² and after binding induce a conformational change in the receptor, which enhances GABA binding. There are 2 types of benzodiazepine receptors: BZ1 and BZ2. The subunits play a critical role in driving the pharmacologic characteristics of the receptor.²⁴ BZ1 and BZ2 receptors bind benzodiazepines, although they are differentially distributed within the brain. Binding at BZ1 receptors—which are distributed in cortical, thalamic, and cerebellar regions—contributes to sedation and deleterious effects of benzodiazepines on memory (eg, anterograde amnesia). BZ2 receptors (which contain gamma-2 subunits) are responsible for anxiolytic and muscle-relaxing effects. They are distributed throughout limbic regions and motor tracts, including motor neurons and neurons in the dorsal horn of the spinal cord.²⁴

Benzodiazepines—positive GABA-A receptor allosteric modulators—produce phasic inhibition, largely through the alpha and gamma subunits discussed above. In contrast, newer positive allosteric modulators (eg, zuranolone) bind at the alpha/beta subunits.²⁵ Mechanistically, endogenous neuroactive steroids and nonbenzodiazepine GABA-A–positive allosteric modulators such as zuranolone and ganaxolone also differ in their regulation of GABA-A (downregulated with benzodiazepines and hypothetically upregulated with zuranolone)²⁶ and their synaptic effects (benzodiazepines synaptically vs endogenous neurosteroids and nonbenzodiazpine positive allosteric modulators extrasynaptically).²⁷

From a developmental perspective, benzodiazepines may have less efficacy for anxiolysis and worse tolerability in some pediatric patients,²⁸ although they generally appear effective for immediate use to treat anxiety in acute settings.²⁹ The differences in efficacy and tolerability may be related to pharmacodynamic differences between pediatric populations and adults. GABA receptor expression and function do not reach adult levels until age 14 to 17½ for subcortical regions and age 18 to 22 for cortical regions, although girls reach adult expression of GABA receptors slightly earlier than boys.³⁰ Data from multiple randomized controlled trials of pediatric patients with anxiety disorders do not suggest efficacy as benzodiazepines are poorly tolerated, especially compared to other psychopharmacologic interventions for pediatric anxiety disorders.³⁰

Continue to: Pharmacology and clinical effects

 

 

Pharmacology and clinical effects

Benzodiazepine pharmacokinetics are intimately linked with the onset of action and duration of clinical effect and vary based on the route of administration, absorption, and distribution/redistribution.³¹ In this review, we focus on oral administration as opposed to IV, IM, sublingual, or intranasal administration.

Absorption

Benzodiazepines are rapidly absorbed after oral administration and quickly enter the systemic circulation. However, absorption rates vary depending on specific aspects of the gastrointestinal milieu and intrinsic properties of the benzodiazepine. For example, alprazolam is more rapidly absorbed than most other benzodiazepines, with a Tmax of 1.8 hours compared to lorazepam, which has a Tmax of approximately 2 hours. These pharmacokinetic effects instantiate differences in tolerability and efficacy. Thus, following single doses of alprazolam and diazepam, self-rated sedating effects and impairment on a task of working memory suggest that effects have a more rapid onset for alprazolam relative to lorazepam.³² Food and concomitant medications can significantly affect benzodiazepine absorption. A single-dose, 3-way crossover study demonstrated that taking diazepam concomitantly with an antacid (eg, aluminum hydroxide) decreased peak concentrations and prolonged absorption by approximately 30 minutes. However, total absorption of the medication was unaffected.³³ Additionally, administration of diazepam with food significantly slows absorption from 1 hour 15 minutes to approximately 2 hours 30 minutes and increases benzodiazepine absorption by 25% (Figure 1³⁴); the fat content of the meal appears important in moderating this effect.³⁵ The impact of food on alprazolam varies by formulation. For example, when administered in an extended-release (XR) formulation with a high-fat meal, alprazolam absorption increases by one-third, while absorption for administration of the orally disintegrating tablet with a high-fat meal increases from 1 hour 30 minutes to 2 hours. Similarly, for lorazepam, administration with a meal delays absorption by approximately 2 hours; however, this effect does not appear present with the XR formulation. Administering benzodiazepines with food can be clinically leveraged to either accelerate the onset of action or decrease peak-associated adverse effects. Thus, when a highly lipophilic benzodiazepine is needed to treat acute anxiety or prior to an expected anxiogenic stimuli, administering the medication without food may produce a faster onset of action.

CNS penetration

Benzodiazepines enter the CNS by passive diffusion. Because of this, lipophilicity at physiologic pH influences the rate at which a benzodiazepine crosses the blood-brain barrier. The rate at which benzodiazepines enter the CNS influences their clinical effects and the speed at which both efficacy (ie, anxiolysis) and adverse effects (ie, sedation, slowed cognition) are observed. In general, more lipophilic medications initiate their anxiolytic effect more quickly. However, by quickly leaving the CNS (through the same mechanism that allowed them to enter the CNS at such speed), their effects rapidly cease as they redistribute into fat. Thus, highly lipophilic benzodiazepines produce more intense effects compared to less lipophilic benzodiazepines. For these reasons, lipophilicity is more important than half-life for determining the duration of effect in most patients.

Lipophilicity and duration of effect

Benzodiazepines and their metabolites tend to be highly protein-bound and distributed in fat- and lipid-enriched areas such as the CNS. As a result, the more lipophilic agents generally have the highest rates of absorption and the fastest onset of clinical effects. The duration of action for many benzodiazepines is determined by the rate and extent of distribution (a function of lipophilicity) rather than by the rate of elimination. For example, diazepam has a longer half-life than lorazepam, but its duration of action following a single dose is shorter. This is because diazepam is more lipophilic and therefore more extensively distributed (particularly to adipose tissue). This results in it leaving the brain and blood and distributing to other tissues. In turn, its CNS effect (ie, anxiolytic effects) are more quickly terminated.

By contrast, less lipophilic benzodiazepines maintain their CNS concentrations longer; they have a longer duration of action because of their slower redistribution, which culminates in a shorter half-life, and are less extensively distributed to peripheral tissues. In essence, this means that (other things being equal) a less lipophilic benzodiazepine produces a more sustained anxiolytic effect compared to a highly lipophilic benzodiazepine.³⁶ Lipophilicity is also important in predicting some cognitive adverse effects, including amnesia. Benzodiazepines with high lipophilicity have greater absorption and faster onset of action as well as more rapid amnestic effects.^37,38 These effects may relate to overall efficacy differences for oral benzodiazepines. A recent meta-analysis by Stimpfl et al³⁶ found that less lipophilic benzodiazepines produced a greater response compared to more lipophilic benzodiazepines.

Continue to: Metabolism

 

 

Metabolism

Regarding cytochrome P450 (CYP) metabolism, polymorphic CYP2C19 and CYP3A4/5 are involved in the metabolism of several benzodiazepines³⁹ and CYP2B6 has been recognized as a contributor to diazepam metabolism. CYP3A5 gene polymorphisms may produce variation in alprazolam metabolism; however, the predominant cytochrome involved in the metabolism of oxidatively metabolized benzodiazepines (ie, benzodiazepines other than lorazepam, oxazepam, and temazepam) is primarily CYP3A4, and most effects on CYP3A4 activity are related to concomitant medications and other non­genetic factors.

Drug-drug interactions

Apart from lorazepam,^40,41 oxazepam,^42,43 and temazepam, most benzodiazepines are metabolized through oxidative mechanisms that involve CYP3A4 (Figure 2²⁰).³⁹ As such, their metabolism is influenced by medications that impact CYP3A4, including antifungals (eg, ketoconazole), calcium channel blockers (eg, verapamil, diltiazem), nefazodone, some protease inhibitors, and macrolide antibiotics. Research has examined the impact of low-dose estrogen oral contraceptives (OCPs) on exposure (eg, plasma concentrations) of several benzodiazepines. The mechanism for this interaction is likely complex and putatively involves multiple pathways, including inhibition of CYP3A4 by OCPs. The effects of OCPs on benzodiazepine pharmacokinetics vary based on the metabolism of the benzodiazepine. In general, medications oxidized and nitroreduced (eg, chlordiazepoxide, alprazolam, diazepam, and nitrazepam) have decreased clearance in patients treated with OCPs. Regarding nonoxidatively metabolized benzodiazepines, data are mixed. Research found no OCP-related effects on the pharmacokinetics of nonoxidatively metabolized benzodiazepines⁴⁴; another study suggested that clearance of these medications—through increased glucuronidation—may be increased.³¹ The effect of smoking on benzodiazepine concentration has been well documented. Smoking increases the clearance of orally administered diazepam,⁴⁵ but not IV diazepam, midazolam, or lorazepam, suggesting that this represents a first-pass effect.⁴⁶ For alprazolam, plasma concentrations are reduced by 15% to 30% in smokers and total body clearance is 24% greater compared to nonsmokers, which results in an approximately 50% increase in half-life in nonsmokers compared to smokers.⁴⁷ The most notable interaction between benzodiazepines and SSRIs is seen with fluvoxamine. Because fluvoxamine moderately inhibits CYP2C19 and CYP3A4 and potently inhibits CYP1A2,⁴⁸ the clearance of oxidatively metabolized benzodiazepines is reduced.⁴⁹ Additionally, the effects of grapefruit juice—a potent inhibitor of CYP3A4—has been evaluated for several benzodiazepines. Yasui et al⁵⁰ found grapefruit juice did not alter alprazolam plasma concentrations. However, in separate research, grapefruit juice tripled diazepam exposure, increased peak concentrations 1.5-fold, and prolonged absorption.⁵¹

Hepatic disease

Exposure to benzodiazepines—other than lorazepam, oxazepam, and temazepam—is influenced by intrinsic hepatic disease and requires dose adjustment in individuals with significant hepatic impairment. The impact of hepatic disease on the clinical pharmacology of benzodiazepines may relate to 2 factors: protein binding and metabolism. In a study of individuals with cirrhosis, lorazepam binding was decreased, although its metabolism and clearance were largely unaffected.⁴⁰

Aging and benzodiazepine metabolism/clearance

Aging is associated with myriad physiologic changes (eg, decrease in renal clearance after age 40, changes in body fat distribution, changes in activity of cytochromes) that are relevant to benzodiazepine pharmacology. They may underlie differences in the tolerability of benzodiazepines and other clinically relevant characteristics (eg, duration of action, accumulation).

Several studies have evaluated the impact of aging on the clearance and disposition of selected benzodiazepines. The respective half-lives of chlordiazepoxide and diazepam increase from 4- to 6-fold from age 20 to 80. Further, with chronic dosing, highly lipophilic benzodiazepines may require additional attention in geriatric patients. In a study that included individuals up to age 78, steady-state plasma concentrations of diazepam and its metabolite, desmethyldiazepam (DMDZ), were 30% to 35% higher in older patients compared to younger individuals.⁵² In this study, the half-lives for the young and older patients were 31 hours and 86 hours, respectively, for diazepam, and 40 hours and 80 hours, respectively, for the active metabolite. The half-life of diazepam is increased by “1 hour for each year of age beginning with a half-life of 20 hours at 20 years of age, as the volume of distribution is increased, and clearance is decreased.”⁵² Clinically, this implies that in older adults, clinicians should expect lower peak concentrations (Cmax), higher trough concentrations (Cmin), and that diazepam will take longer to reach steady-state concentrations. Taken together, these findings raised concern that “slow accumulation and delayed washout of diazepam and DMDZ is probable.”⁵² These findings—which may have more clinical relevance than those of single-dose studies—suggest that the effects related to diazepam would also take longer to resolve in older patients. Finally, lorazepam clearance or distribution does not appear to be affected by aging, at least in patients age 15 to 73.⁴⁰ Alprazolam is more slowly cleared in geriatric patients and its effects may be potentiated by reduced protein binding.

Continue to: Obesity

 

 

Obesity

The distribution of medications, including benzodiazepines, is altered in patients who are obese because of increased adipose tissue.^53,54 This increase in the volume of distribution can attenuate the onset of action, increase medication accumulation in fat, and potentiate the duration of action.^55,56

Obesity may also affect hepatic metabolism by induction of CYP1A2, CYP2C9, and CYP2C19, and inhibition of CYP3A4.⁵⁷ Triazolam, which is metabolized by CYP3A4, is associated with a greater exposure (ie, plasma concentrations) in individuals who are obese.⁵⁸ However, when considering differences in benzodiazepine pharmacokinetics in patients who are obese, clinicians must remember that elimination half-life depends on both volume of distribution and clearance. In patients who are obese (compared to patients who are not obese), the half-lives are increased for alprazolam (22 hours vs 11 hours, P < .001)⁵⁹ and diazepam (82 hours vs 32 hours, P < .005).⁶⁰ In a pharmacokinetic study of diazepam in individuals who were obese and individuals who were not obese, total metabolic clearance did not differ. Rather, the increased half-life was related to a tripling of the volume of distribution in obese patients (228 liters vs 70 liters, P < .01). This indicates that patients who are obese may experience a much slower onset of maximal effect compared to patients who are not obese because the accumulation of the medication is delayed. Additionally, for benzodiazepines that are conjugated (lorazepam and oxazepam), clearance is significantly enhanced in patients who are obese. For example, lorazepam clearance is 102 mL/min in individuals who are obese compared to 63 mL/min in individuals who are not obese; for oxazepam, clearance is 181 mL/min in patients who are obese compared to 98 mL/min in individuals who are not obese.⁶¹ These differences are attributed to increased uridine diphosphate glucuronyl transferase in obesity and to increases in liver size in obesity.⁵³

How quickly do benzodiazepines work?

Benzodiazepines act quickly. Meta-analyses³⁶ suggest that improvement in anxiety symptoms compared to placebo is greatest initially and then the rate of improvement slows over successive weeks. Research on benzodiazepines reveals statistically significant differences between benzodiazepines and placebo within the first week of treatment, with >80% of the expected improvement by Week 8 of treatment emerging by Week 4 (Figure 3³⁶). The rapid reduction in anxiety symptoms seen with benzodiazepines has important treatment implications, given that traditional psycho­therapeutic and antidepressant treatments are slow to produce improvements. Consistent data suggesting that benzodiazepines work faster than other treatments support that they may have a role during the initiation of other treatments.

What is the ‘best’ dose?

As seen with other classes of psychotropic medications,⁴ the relationship between benzodiazepine dose and response is complex. In a recent meta-analysis of 65 placebo-controlled trials of benzodiazepines in adults with anxiety disorders, there was a superior response over time for low-dose benzodiazepines (<3 mg/d in lorazepam equivalents) compared to a medium dose (3 to 6 mg/d; P = .042); high-dose benzodiazepines (>6 mg/d) yielded less improvement compared to medium doses (P = .001).³⁶ A study of adults with panic disorder similarly found the greatest responses with alprazolam plasma concentrations of 20 to 40 ng/mL, with no additional benefit at <20 ng/mL or >40 ng/mL.⁴⁹ As plasma concentrations increase, adverse effects such as sedation also increase, which may confound the observed loss of a dose-response relationship at higher doses and plasma concentrations.⁶² This may, in part, account for the observation that higher doses of benzodiazepines are associated with greater depressive symptoms and disrupted sleep.⁶³ As such, low doses may represent a delicate equipoise between efficacy and tolerability, yielding the most optimal clinical response.

Which benzodiazepine should I prescribe?

Comparing benzodiazepines is difficult, given the differences in dosing and disorders studied and differences in how each individual clinical trial was conducted. A meta-analysis by Stimpfl et al³⁶ that used Bayesian hierarchical modeling, which allowed some of this heterogeneity to be addressed, found that relative to the reference benzodiazepine (lorazepam), clonazepam had the greatest trajectory/magnitude of response (other specific benzodiazepines did not statistically differ from lorazepam) (Figure 4³⁶).

Continue to: Another aspect of the superiority...

Another aspect of the superiority of clonazepam in some research relates to its pharma­cokinetic properties, particularly when compared with benzodiazepines that have very short half-lives. Short half-life benzodiazepines have been associated with rebound anxiety, which is defined as “the relative worsening of symptoms on discontinuation of treatment as compared to baseline symptoms” and is distinct from withdrawal.⁶⁴ While it is difficult to assess this in clinical trials, Herman et al⁶⁵ provided insight into the contribution of rebound anxiety in a study of patients with panic disorder treated with alprazolam who experienced “interdose anxiety symptoms.” Of the 48 patients in this study, 41 switched to clonazepam, and most who switched (82%) experienced improvement. The improvement was attributed to the decreased frequency of clonazepam (vs alprazolam) administration and lack of interdose anxiety. When selecting an oral benzodiazepine, consider the duration, onset of action, and differences in metabolism that produce varying levels of effectiveness for individual patients. In situations where rapid onset is desired, a short-acting benzodiazepine may be preferable, while a longer-acting benzodiazepine would be preferable in situations where the patient needs sustained effects.

Regarding lipophilicity, differences among benzodiazepines could contribute to differences in psychological dependence and differential utility in some situations. For example, alprazolam rapidly enters the CNS, producing an immediate anxiolytic effect. However, its egress from the CNS is equally rapid, and its anxiolytic effects disappear quickly. This may be desirable for addressing acute, predictable anxiety, but could have unintended consequences in treating chronic anxiety, where it could facilitate psychological dependence.

Practical considerations

When prescribing benzodiazepines, consider a myriad of patient- and medication-specific factors, as these have clinically relevant implications on treatment response. This information, taken together, supports the importance of an individualized approach to benzodiazepine use. Before selecting a benzodiazepine and during treatment, important elements of the patient’s history must be considered, including age, body weight, concomitant medication use (eg, antacids, CYP3A4 inhibitors, OCPs), smoking status, and history of hepatic or renal disease.

Patients age <18 are unlikely to have full expression of GABA receptors in the brain³⁰ and therefore benzodiazepines may not be as efficacious for anxiolysis in this population. Moreover, compared to younger patients, older patients may experience higher steady-state concentrations of benzo­diazepines, especially lipophilic agents, due to an increased volume of distribution and decreased clearance. In patients treated with OCPs, some benzodiazepines may take longer to reach steady-state, and dose adjustments may need to be considered. In patients who smoke, clearance of some oral benzo­diazepines is also accelerated, potentially decreasing half-life by up to 50%.

When dosing and titrating benzodiazepines, consider the patient’s body weight, particularly if they are obese. The effects of obesity on benzodiazepine pharmacokinetics are complex. For glucuronidated benzodiazepines, clearance is increased in patients who are obese; however, the volume of distribution is also increased in such patients, meaning it will take longer for benzodiazepines to achieve steady-state in these individuals compared to patients who are not obese. These effects suggest it may take longer to achieve a response at a given dose in patients who are obese compared to individuals who are not obese.

Continue to: The properties of individual benzodiazepines...

The properties of individual benzodiazepines should also be considered when selecting a benzodiazepine treatment. If circumstances necessitate rapid symptom relief, a lipophilic benzodiazepine, such as diazepam, may be preferred for quick onset and offset of action. Onset of action may also be hastened by taking the benzodiazepine without food; conversely, if peak adverse effects are problematic, concurrent consumption of a high-fat meal may help decrease peak concentration and prolonging absorption. In other circumstances, such as if sustained anxiolysis is desired, a clinician may opt for a less lipophilic benzodiazepine, such as clonazepam. Finally, in terms of general treatment response, benzodiazepines separate from placebo in the first week of treatment, which supports the idea they may be useful during the introduction of other medications (eg, SSRIs) that take a longer time to achieve clinical effect.

Bottom Line

The pharmacokinetics of benzodiazepines are intimately linked with the onset of action and duration of clinical effect and vary based on individual absorption and distribution/redistribution. Benzodiazepines’ clinical profile derives from their pharmacokinetic differences and is influenced by many factors, including age, body weight, concomitant medication use, smoking status, and hepatic or renal disease. Consider these factors to individualize the approach to using benzodiazepines and optimize tolerability and efficacy.

Related Resources

• Weber SR, Duchemin AM. Benzodiazepines: sensible prescribing in light of the risks. Current Psychiatry. 2018;17(2):22-27.
• Balon R. Benzodiazepines for anxious depression. Current Psychiatry. 2018;17(8):9-12.

Drug Brand Names

Alprazolam • Xanax
Chlordiazepoxide • Librium
Clobazam • Onfi
Clonazepam • Klonopin
Clorazepate • Gen-Xene
Diazepam • Valium
Diltiazem • Cardizem
Fluvoxamine • Luvox
Ganaxolone • Ztalmy
Ketoconazole • Nizoral
Lorazepam • Ativan
Midazolam • Versed
Temazepam • Restoril
Triazolam • Halcion
Verapamil • Calan