Cutis

Autoimmune bullous dermatoses (ABDs) develop due to antibodies directed against antigens within the epidermis or at the dermoepidermal junction. They are categorized histologically by the location of acantholysis (separation of keratinocytes), clinical presentation, and presence of autoantibodies. The most common ABDs include pemphigus vulgaris, pemphigus foliaceus, and bullous pemphigoid (BP). These conditions present on a spectrum of symptoms and severity.¹

Although multiple studies have evaluated the impact of bullous dermatoses on mental health, most were designed with a small sample size, thus limiting the generalizability of each study. Sebaratnam et al² summarized several studies in 2012. In this review, we will analyze additional relevant literature and systematically combine the data to determine the psychological burden of disease of ABDs. We also will discuss the existing questionnaires frequently used in the dermatology setting to assess adverse psychosocial symptoms.

Methods

We searched PubMed, MEDLINE, and Google Scholar for articles published within the last 15 years using the terms bullous pemphigoid, pemphigus, quality of life, anxiety, and depression. We reviewed the citations in each article to further our search.

Criteria for Inclusion and Exclusion—Studies that utilized validated questionnaires to evaluate the effects of pemphigus vulgaris, pemphigus foliaceus, and/or BP on mental health were included. All research participants were 18 years and older. For the questionnaires administered, each study must have included numerical scores in the results. The studies all reported statistically significant results (P<.05), but no studies were excluded on the basis of statistical significance.

Studies were excluded if they did not use a validated questionnaire to examine quality of life (QOL) or psychological status. We also excluded database, retrospective, qualitative, and observational studies. We did not include studies with a sample size less than 20. Studies that administered questionnaires that were uncommon in this realm of research such as the Attitude to Appearance Scale or The Anxiety Questionnaire also were excluded. We did not exclude articles based on their primary language.

Results

A total of 13 studies met the inclusion criteria with a total of 1716 participants enrolled in the trials. The questionnaires most commonly used are summarized in Table 1. Tables 2 and 3 demonstrate the studies that evaluate QOL and psychological state in patients with bullous dermatoses, respectively.

The Dermatology Life Quality Index (DLQI) was the most utilized method for analyzing QOL followed by the Skindex-17, Skindex-29, and 36-Item Short Form Health Survey. The DLQI is a skin-specific measurement tool with higher scores translating to greater impairment in QOL. Healthy patients have an average score of 0.5.³ The mean DLQI scores for ABD patients as seen in Table 2 were 9.45, 10.18, 16, 10.9, and 10.1.^13-15,18,22 The most commonly reported concerns among patients included feelings about appearance and disturbances in daily activities.¹⁸ Symptoms of mucosal involvement, itching, and burning also were indicators of lower QOL.^15,18,20,22 Furthermore, women consistently had lower scores than men.^15,17,19,25 Multiple studies concluded that severity of the disease correlated with a lower QOL, though the subtype of pemphigus did not have an effect on QOL scores.^15,19,20,21 Lastly, recent onset of symptoms was associated with a worse QOL score.^15,18-20 Age, education level, and marital status did not have an effect on QOL.

To evaluate psychological state, the General Health Questionnaire (GHQ)-28 and -12 primarily were used, in addition to the Hospital Anxiety and Depression Scale; the International Classification of Diseases, Tenth Revision; the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; and the Beck Depression Inventory-II. As seen in Table 3, GHQ-12 positivity, reflecting probable minor nonpsychotic psychiatric disorders such as depression and anxiety, was identified in 47%, 39.7%, and 40% of patients with pemphigus^15,19,24; GHQ-28 positivity was seen in 77.5% of pemphigus patients.¹⁸ In the average population, GHQ positivity was found in up to 12% of patients.^26,27 Similar to the QOL scores, no significant differences were seen based on subtype of pemphigus for symptoms of depression or anxiety.^20,23

Comment

Mental Health of Patients With ABDs—Immunobullous diseases are painful, potentially lifelong conditions that have no definitive cure. These conditions are characterized by bullae and erosions of the skin and mucosae that physically are disabling and often create a stigma for patients. Across multiple different validated psychosocial assessments, the 13 studies included in this review consistently reported that ABDs have a negative effect on mental well-being of patients that is more pronounced in women and worse at the onset of symptoms.^13-25

QOL Scores in Patients With ABDs—Quality of life is a broad term that encompasses a general sense of psychological and overall well-being. A score of approximately 10 on the DLQI most often was reported in patients with ABDs, which translates to a moderate impact on QOL. Incomparison, a large cohort study reported the mean (SD) DLQI scores for patients with atopic dermatitis and psoriasis as 7.31 (5.98) and 5.93 (5.66), respectively.²⁸ In another study, Penha et al¹⁴ found that patients with psoriasis have a mean DLQI score of 10. Reasons for the similarly low QOL scores in patients with ABDs include long hospitalization periods, disease chronicity, social anxiety, inability to control symptoms, difficulty with activities of daily living, and the belief that the disease is incurable.^17,19,23 Although there is a need for increased family and social support with performing necessary daily tasks, personal relationships often are negatively affected, resulting in social isolation, loneliness, and worsening of cutaneous symptoms.

Severity of cutaneous disease and recent onset of symptoms correlated with worse QOL scores. Tabolli et al²⁰ proposed the reason for this relates to not having had enough time to find the best treatment regimen. We believe there also may be an element of habituation involved, whereby patients become accustomed to the appearance of the lesions over time and therefore they become less distressing. Interestingly, Tabolli et al¹⁷ determined that patients in the quiescent phase of the disease—without any mucosal or cutaneous lesions—still maintained lower QOL scores than the average population, particularly on the psychosocial section of the 36-Item Short Form Health Survey, which may be due to a concern of disease relapse or from adverse effects of treatment. Providers should monitor patients for mental health complications not only in the disease infancy but throughout the disease course.

Future Directions—Cause and effect of the relationship between the psychosocial variables and ABD disease state has yet to be determined. Most studies included in this review were cross-sectional in design. Although many studies concluded that bullous dermatoses were the cause of impaired QOL, Ren and colleagues²⁹ proposed that medications used to treat neuropsychiatric disorders may trigger the autoimmune antigens of BP. Possible triggers for BP have been reported including hydrochlorothiazide, ciprofloxacin, and dipeptidyl peptidase-4 inhibitors.^27,30-32 A longitudinal study design would better evaluate the causal relationship.

The effects of the medications were included in 2 cases, one in which the steroid dose was not found to have a significant impact on rates of depression²³ and another in which patients treated with a higher dose of corticosteroids (>10 mg) had worse QOL scores.¹⁷ Sung et al¹⁵ suggested this may be because patients who took higher doses of steroids had worse symptoms and therefore also had a worse QOL. It also is possible that those patients taking higher doses had increased side effects.¹⁷ Further studies that evaluate treatment modalities and timing in relation to the disease onset would be helpful.

Study Limitations—There are potential barriers to combining these data. Multiple different questionnaires were used, and it was difficult to ascertain if all the participants were experiencing active disease. Additionally, questionnaires are not always the best proxy for what is happening in everyday life. Lastly, the sample size of each individual study was small, and the studies only included adults.

Conclusion

As demonstrated by the 13 studies in this review, patients with ABDs have lower QOL scores and higher numbers of psychological symptoms. Clinicians should be mindful of this at-risk population and create opportunities in clinic to discuss personal hardship associated with the disease process and recommend psychiatric intervention if indicated. Additionally, family members often are overburdened with the chronicity of ABDs, and they should not be forgotten. Using one of the aforementioned questionnaires is a practical way to screen patients for lower QOL scores. We agree with Paradisi and colleagues¹⁹ that although these questionnaires may be helpful, clinicians still need to determine if the use of a dermatologic QOL evaluation tool in clinical practice improves patient satisfaction.

Autoimmune bullous dermatoses (ABDs) develop due to antibodies directed against antigens within the epidermis or at the dermoepidermal junction. They are categorized histologically by the location of acantholysis (separation of keratinocytes), clinical presentation, and presence of autoantibodies. The most common ABDs include pemphigus vulgaris, pemphigus foliaceus, and bullous pemphigoid (BP). These conditions present on a spectrum of symptoms and severity.¹

Although multiple studies have evaluated the impact of bullous dermatoses on mental health, most were designed with a small sample size, thus limiting the generalizability of each study. Sebaratnam et al² summarized several studies in 2012. In this review, we will analyze additional relevant literature and systematically combine the data to determine the psychological burden of disease of ABDs. We also will discuss the existing questionnaires frequently used in the dermatology setting to assess adverse psychosocial symptoms.

Methods

We searched PubMed, MEDLINE, and Google Scholar for articles published within the last 15 years using the terms bullous pemphigoid, pemphigus, quality of life, anxiety, and depression. We reviewed the citations in each article to further our search.

Criteria for Inclusion and Exclusion—Studies that utilized validated questionnaires to evaluate the effects of pemphigus vulgaris, pemphigus foliaceus, and/or BP on mental health were included. All research participants were 18 years and older. For the questionnaires administered, each study must have included numerical scores in the results. The studies all reported statistically significant results (P<.05), but no studies were excluded on the basis of statistical significance.

Studies were excluded if they did not use a validated questionnaire to examine quality of life (QOL) or psychological status. We also excluded database, retrospective, qualitative, and observational studies. We did not include studies with a sample size less than 20. Studies that administered questionnaires that were uncommon in this realm of research such as the Attitude to Appearance Scale or The Anxiety Questionnaire also were excluded. We did not exclude articles based on their primary language.

Results

A total of 13 studies met the inclusion criteria with a total of 1716 participants enrolled in the trials. The questionnaires most commonly used are summarized in Table 1. Tables 2 and 3 demonstrate the studies that evaluate QOL and psychological state in patients with bullous dermatoses, respectively.

The Dermatology Life Quality Index (DLQI) was the most utilized method for analyzing QOL followed by the Skindex-17, Skindex-29, and 36-Item Short Form Health Survey. The DLQI is a skin-specific measurement tool with higher scores translating to greater impairment in QOL. Healthy patients have an average score of 0.5.³ The mean DLQI scores for ABD patients as seen in Table 2 were 9.45, 10.18, 16, 10.9, and 10.1.^13-15,18,22 The most commonly reported concerns among patients included feelings about appearance and disturbances in daily activities.¹⁸ Symptoms of mucosal involvement, itching, and burning also were indicators of lower QOL.^15,18,20,22 Furthermore, women consistently had lower scores than men.^15,17,19,25 Multiple studies concluded that severity of the disease correlated with a lower QOL, though the subtype of pemphigus did not have an effect on QOL scores.^15,19,20,21 Lastly, recent onset of symptoms was associated with a worse QOL score.^15,18-20 Age, education level, and marital status did not have an effect on QOL.

To evaluate psychological state, the General Health Questionnaire (GHQ)-28 and -12 primarily were used, in addition to the Hospital Anxiety and Depression Scale; the International Classification of Diseases, Tenth Revision; the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; and the Beck Depression Inventory-II. As seen in Table 3, GHQ-12 positivity, reflecting probable minor nonpsychotic psychiatric disorders such as depression and anxiety, was identified in 47%, 39.7%, and 40% of patients with pemphigus^15,19,24; GHQ-28 positivity was seen in 77.5% of pemphigus patients.¹⁸ In the average population, GHQ positivity was found in up to 12% of patients.^26,27 Similar to the QOL scores, no significant differences were seen based on subtype of pemphigus for symptoms of depression or anxiety.^20,23

Comment

Mental Health of Patients With ABDs—Immunobullous diseases are painful, potentially lifelong conditions that have no definitive cure. These conditions are characterized by bullae and erosions of the skin and mucosae that physically are disabling and often create a stigma for patients. Across multiple different validated psychosocial assessments, the 13 studies included in this review consistently reported that ABDs have a negative effect on mental well-being of patients that is more pronounced in women and worse at the onset of symptoms.^13-25

QOL Scores in Patients With ABDs—Quality of life is a broad term that encompasses a general sense of psychological and overall well-being. A score of approximately 10 on the DLQI most often was reported in patients with ABDs, which translates to a moderate impact on QOL. Incomparison, a large cohort study reported the mean (SD) DLQI scores for patients with atopic dermatitis and psoriasis as 7.31 (5.98) and 5.93 (5.66), respectively.²⁸ In another study, Penha et al¹⁴ found that patients with psoriasis have a mean DLQI score of 10. Reasons for the similarly low QOL scores in patients with ABDs include long hospitalization periods, disease chronicity, social anxiety, inability to control symptoms, difficulty with activities of daily living, and the belief that the disease is incurable.^17,19,23 Although there is a need for increased family and social support with performing necessary daily tasks, personal relationships often are negatively affected, resulting in social isolation, loneliness, and worsening of cutaneous symptoms.

Severity of cutaneous disease and recent onset of symptoms correlated with worse QOL scores. Tabolli et al²⁰ proposed the reason for this relates to not having had enough time to find the best treatment regimen. We believe there also may be an element of habituation involved, whereby patients become accustomed to the appearance of the lesions over time and therefore they become less distressing. Interestingly, Tabolli et al¹⁷ determined that patients in the quiescent phase of the disease—without any mucosal or cutaneous lesions—still maintained lower QOL scores than the average population, particularly on the psychosocial section of the 36-Item Short Form Health Survey, which may be due to a concern of disease relapse or from adverse effects of treatment. Providers should monitor patients for mental health complications not only in the disease infancy but throughout the disease course.

Future Directions—Cause and effect of the relationship between the psychosocial variables and ABD disease state has yet to be determined. Most studies included in this review were cross-sectional in design. Although many studies concluded that bullous dermatoses were the cause of impaired QOL, Ren and colleagues²⁹ proposed that medications used to treat neuropsychiatric disorders may trigger the autoimmune antigens of BP. Possible triggers for BP have been reported including hydrochlorothiazide, ciprofloxacin, and dipeptidyl peptidase-4 inhibitors.^27,30-32 A longitudinal study design would better evaluate the causal relationship.

The effects of the medications were included in 2 cases, one in which the steroid dose was not found to have a significant impact on rates of depression²³ and another in which patients treated with a higher dose of corticosteroids (>10 mg) had worse QOL scores.¹⁷ Sung et al¹⁵ suggested this may be because patients who took higher doses of steroids had worse symptoms and therefore also had a worse QOL. It also is possible that those patients taking higher doses had increased side effects.¹⁷ Further studies that evaluate treatment modalities and timing in relation to the disease onset would be helpful.

Study Limitations—There are potential barriers to combining these data. Multiple different questionnaires were used, and it was difficult to ascertain if all the participants were experiencing active disease. Additionally, questionnaires are not always the best proxy for what is happening in everyday life. Lastly, the sample size of each individual study was small, and the studies only included adults.

Conclusion

As demonstrated by the 13 studies in this review, patients with ABDs have lower QOL scores and higher numbers of psychological symptoms. Clinicians should be mindful of this at-risk population and create opportunities in clinic to discuss personal hardship associated with the disease process and recommend psychiatric intervention if indicated. Additionally, family members often are overburdened with the chronicity of ABDs, and they should not be forgotten. Using one of the aforementioned questionnaires is a practical way to screen patients for lower QOL scores. We agree with Paradisi and colleagues¹⁹ that although these questionnaires may be helpful, clinicians still need to determine if the use of a dermatologic QOL evaluation tool in clinical practice improves patient satisfaction.

Autoimmune bullous dermatoses (ABDs) develop due to antibodies directed against antigens within the epidermis or at the dermoepidermal junction. They are categorized histologically by the location of acantholysis (separation of keratinocytes), clinical presentation, and presence of autoantibodies. The most common ABDs include pemphigus vulgaris, pemphigus foliaceus, and bullous pemphigoid (BP). These conditions present on a spectrum of symptoms and severity.¹

Although multiple studies have evaluated the impact of bullous dermatoses on mental health, most were designed with a small sample size, thus limiting the generalizability of each study. Sebaratnam et al² summarized several studies in 2012. In this review, we will analyze additional relevant literature and systematically combine the data to determine the psychological burden of disease of ABDs. We also will discuss the existing questionnaires frequently used in the dermatology setting to assess adverse psychosocial symptoms.

Methods

We searched PubMed, MEDLINE, and Google Scholar for articles published within the last 15 years using the terms bullous pemphigoid, pemphigus, quality of life, anxiety, and depression. We reviewed the citations in each article to further our search.

Criteria for Inclusion and Exclusion—Studies that utilized validated questionnaires to evaluate the effects of pemphigus vulgaris, pemphigus foliaceus, and/or BP on mental health were included. All research participants were 18 years and older. For the questionnaires administered, each study must have included numerical scores in the results. The studies all reported statistically significant results (P<.05), but no studies were excluded on the basis of statistical significance.

Studies were excluded if they did not use a validated questionnaire to examine quality of life (QOL) or psychological status. We also excluded database, retrospective, qualitative, and observational studies. We did not include studies with a sample size less than 20. Studies that administered questionnaires that were uncommon in this realm of research such as the Attitude to Appearance Scale or The Anxiety Questionnaire also were excluded. We did not exclude articles based on their primary language.

Results

A total of 13 studies met the inclusion criteria with a total of 1716 participants enrolled in the trials. The questionnaires most commonly used are summarized in Table 1. Tables 2 and 3 demonstrate the studies that evaluate QOL and psychological state in patients with bullous dermatoses, respectively.

The Dermatology Life Quality Index (DLQI) was the most utilized method for analyzing QOL followed by the Skindex-17, Skindex-29, and 36-Item Short Form Health Survey. The DLQI is a skin-specific measurement tool with higher scores translating to greater impairment in QOL. Healthy patients have an average score of 0.5.³ The mean DLQI scores for ABD patients as seen in Table 2 were 9.45, 10.18, 16, 10.9, and 10.1.^13-15,18,22 The most commonly reported concerns among patients included feelings about appearance and disturbances in daily activities.¹⁸ Symptoms of mucosal involvement, itching, and burning also were indicators of lower QOL.^15,18,20,22 Furthermore, women consistently had lower scores than men.^15,17,19,25 Multiple studies concluded that severity of the disease correlated with a lower QOL, though the subtype of pemphigus did not have an effect on QOL scores.^15,19,20,21 Lastly, recent onset of symptoms was associated with a worse QOL score.^15,18-20 Age, education level, and marital status did not have an effect on QOL.

To evaluate psychological state, the General Health Questionnaire (GHQ)-28 and -12 primarily were used, in addition to the Hospital Anxiety and Depression Scale; the International Classification of Diseases, Tenth Revision; the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; and the Beck Depression Inventory-II. As seen in Table 3, GHQ-12 positivity, reflecting probable minor nonpsychotic psychiatric disorders such as depression and anxiety, was identified in 47%, 39.7%, and 40% of patients with pemphigus^15,19,24; GHQ-28 positivity was seen in 77.5% of pemphigus patients.¹⁸ In the average population, GHQ positivity was found in up to 12% of patients.^26,27 Similar to the QOL scores, no significant differences were seen based on subtype of pemphigus for symptoms of depression or anxiety.^20,23

Comment

Mental Health of Patients With ABDs—Immunobullous diseases are painful, potentially lifelong conditions that have no definitive cure. These conditions are characterized by bullae and erosions of the skin and mucosae that physically are disabling and often create a stigma for patients. Across multiple different validated psychosocial assessments, the 13 studies included in this review consistently reported that ABDs have a negative effect on mental well-being of patients that is more pronounced in women and worse at the onset of symptoms.^13-25

QOL Scores in Patients With ABDs—Quality of life is a broad term that encompasses a general sense of psychological and overall well-being. A score of approximately 10 on the DLQI most often was reported in patients with ABDs, which translates to a moderate impact on QOL. Incomparison, a large cohort study reported the mean (SD) DLQI scores for patients with atopic dermatitis and psoriasis as 7.31 (5.98) and 5.93 (5.66), respectively.²⁸ In another study, Penha et al¹⁴ found that patients with psoriasis have a mean DLQI score of 10. Reasons for the similarly low QOL scores in patients with ABDs include long hospitalization periods, disease chronicity, social anxiety, inability to control symptoms, difficulty with activities of daily living, and the belief that the disease is incurable.^17,19,23 Although there is a need for increased family and social support with performing necessary daily tasks, personal relationships often are negatively affected, resulting in social isolation, loneliness, and worsening of cutaneous symptoms.

Severity of cutaneous disease and recent onset of symptoms correlated with worse QOL scores. Tabolli et al²⁰ proposed the reason for this relates to not having had enough time to find the best treatment regimen. We believe there also may be an element of habituation involved, whereby patients become accustomed to the appearance of the lesions over time and therefore they become less distressing. Interestingly, Tabolli et al¹⁷ determined that patients in the quiescent phase of the disease—without any mucosal or cutaneous lesions—still maintained lower QOL scores than the average population, particularly on the psychosocial section of the 36-Item Short Form Health Survey, which may be due to a concern of disease relapse or from adverse effects of treatment. Providers should monitor patients for mental health complications not only in the disease infancy but throughout the disease course.

Future Directions—Cause and effect of the relationship between the psychosocial variables and ABD disease state has yet to be determined. Most studies included in this review were cross-sectional in design. Although many studies concluded that bullous dermatoses were the cause of impaired QOL, Ren and colleagues²⁹ proposed that medications used to treat neuropsychiatric disorders may trigger the autoimmune antigens of BP. Possible triggers for BP have been reported including hydrochlorothiazide, ciprofloxacin, and dipeptidyl peptidase-4 inhibitors.^27,30-32 A longitudinal study design would better evaluate the causal relationship.

The effects of the medications were included in 2 cases, one in which the steroid dose was not found to have a significant impact on rates of depression²³ and another in which patients treated with a higher dose of corticosteroids (>10 mg) had worse QOL scores.¹⁷ Sung et al¹⁵ suggested this may be because patients who took higher doses of steroids had worse symptoms and therefore also had a worse QOL. It also is possible that those patients taking higher doses had increased side effects.¹⁷ Further studies that evaluate treatment modalities and timing in relation to the disease onset would be helpful.

Study Limitations—There are potential barriers to combining these data. Multiple different questionnaires were used, and it was difficult to ascertain if all the participants were experiencing active disease. Additionally, questionnaires are not always the best proxy for what is happening in everyday life. Lastly, the sample size of each individual study was small, and the studies only included adults.

Conclusion

As demonstrated by the 13 studies in this review, patients with ABDs have lower QOL scores and higher numbers of psychological symptoms. Clinicians should be mindful of this at-risk population and create opportunities in clinic to discuss personal hardship associated with the disease process and recommend psychiatric intervention if indicated. Additionally, family members often are overburdened with the chronicity of ABDs, and they should not be forgotten. Using one of the aforementioned questionnaires is a practical way to screen patients for lower QOL scores. We agree with Paradisi and colleagues¹⁹ that although these questionnaires may be helpful, clinicians still need to determine if the use of a dermatologic QOL evaluation tool in clinical practice improves patient satisfaction.

The COVID-19 pandemic largely altered the practice of medicine, including a rapid expansion of telemedicine following the March 2020 World Health Organization guidelines for social distancing, which recommended suspension of all nonurgent in-person visits.¹ Expectedly, COVID-related urgent care visits initially comprised the bulk of the new telemedicine wave: NYU Langone Health (New York, New York), for example, saw a 683% increase in virtual visits between March and April 2020, most (55.3%) of which were for respiratory concerns. In-person visits, on the other hand, concurrently fell by more than 80%. Interestingly, nonurgent ambulatory care specialties also saw a considerable uptick in virtual encounters, from less than 50 visits in a typical day to an average of 7000 in a 10-day stretch.²

As a largely ambulatory specialty that relies on visual examination, dermatology was no exception to the swing toward telemedicine, or teledermatology (TD). Before the COVID-19 pandemic, 14.1% (82 of 582 respondents) of practicing US dermatologists reported having used teledermatology, compared to 96.9% (572/591) during the pandemic.³ Even at my home institution (Massachusetts General Hospital [Boston, Massachusetts] and its 12 affiliated dermatology clinics), the number of in-person visits in April 2020 (n=67) was less than 1% of that in April 2019 (n=7919), whereas there was a total of 1564 virtual visits in April 2020 compared to zero the year prior. Virtual provider-to-provider consults (e-consultations) also saw an increase of more than 20%, suggesting that dermatology’s avid adoption of TD also had improved the perceived accessibility of our specialty.⁴

The adoption and adaptation of TD are projected to continue to grow rapidly across the globe, as digitalization has enhanced access without increasing costs, shortened wait times, and even created opportunities for primary care providers based in rural or overseas locations to learn the diagnosis and treatment of skin disease.⁵ Residents and fellows should be privy to the nuances of training and practicing in this digital era, as our careers inevitably will involve some facet of TD.

The Art of Medicine

Touch, a sense that perhaps ranks second to sight in dermatology, is absent in TD. In either synchronous (live-interactive, face video visits) or asynchronous (store-and-forward, where digital photographs and clinical information sent by patients or referring physicians are assessed at a later time) TD, the skin cannot be rubbed for texture, pinched for thickness, or pushed for blanching. Instead, all we have is vision. Irwin Braverman, MD, Professor Emeritus of Dermatology at Yale University (New Haven, Connecticut), alongside Jacqueline Dolev, MD, dermatologist and Yale graduate, and Linda Friedlaender, curator at the Yale Center for British Art, founded an observational skills workshop in which trainees learn to observe and describe the paintings housed in the museum, noting all memorable details: the color of the sky, the actions of the animals, and the facial expressions of the people. A study of 90 participants over a 2-year period found that following the workshop, the ability to identify key diagnostic details from clinical photography improved by more than 10%.⁶ Other studies also utilizing fine art as a medical training tool to improve “visual literacy” saw similarly increased sophistication in the description of clinical imagery, which translated to better diagnostic acumen.⁷ Confined to video and photographs, TD necessitates trainees and practicing dermatologists to be excellent visual diagnosticians. Although surveyed dermatologists believe TD is presently appropriate for acne, benign lesions, or follow-up appointments,³ conditions for which patients have been examined via TD have included drug eruptions, premalignant or malignant neoplasms, infections, and papulosquamous or inflammatory dermatoses.⁸ At the very least, clinicians should be versed in identifying those conditions that require in-person evaluation, as patients cannot be held responsible to distinguish which situations can and cannot be addressed virtually.

Issues of Patient-Physician Confidentiality

Teledermatology is not without its shortcomings; critics have noted diagnostic challenges with poor quality photographs or videos, inability to perform total-body skin examinations, and socioeconomic limitations due to broadband availability and speed.^5,9 Although most of these shortcomings are outside of our control, a key challenge within the purview of the provider is the protection of patient privacy.

Much of the salient concerns regarding patient-physician confidentiality involve asynchronous TD, where store-and-forward data sharing allows physicians to download patient photographs or information onto their personal email or smartphones.¹⁰ Although some hospital systems provide encryption software or hospital-sponsored devices to ensure security, physicians may opt to use their personal phones or laptops out of convenience or to save time.^10,11 One study found that less than 30% of smartphone users choose to activate user authentication on their devices, even ones as simple as a passphrase.¹¹ The digital exchange of information thus poses an immense risk for compromising protected health information (PHI), as personal devices can be easily lost, stolen, or hacked. Indeed, in 2015, more than 113 million individuals were affected by a breach of PHI, the majority over hacked network servers.¹² With the growing diversity of mediums through which PHI is exchanged, such as videoconferencing and instant messaging, the potential medicolegal risks of information breach continue to climb. The US Department of Health & Human Services urges health care providers to uphold best practices for security, including encrypting data, updating all software including antivirus software, using multifactor authentication, and following local cybersecurity regulations or recommendations.¹³ For synchronous TD, suggested best practices include utilizing headphones during live appointments, avoiding public wireless networks, and ensuring the provider and patient both scan the room with their device’s camera before the start of the visit.¹⁴

On the Horizon of Teledermatology

What can we expect in the coming years? Increased utilization of telemedicine will translate into data that will help address questions surrounding safety, diagnostic accuracy, privacy, and accessibility. One aspect of TD in need of clarity is a guideline on payment and reimbursement, and whether TD can continue to be financially attractive to providers. Starting in 2020, the Centers for Medicare & Medicaid Services removed geographic restrictions for reimbursement of telemedicine visits, enabling even urban-residing patients to enjoy the convenience of TD. This followed a prior relaxation of restrictions, where even prerecorded patient information became eligible for Medicare reimbursement.⁹ However, as virtual visits tend to be shorter with fewer diagnostic services compared to in-person visits, the reimbursement structure of TD must be nuanced, which is the subject of ongoing study and modification in the wake of the COVID-19 pandemic.¹⁵

Another point to consider is the explosion of direct-to-consumer TD, which allows patients to receive virtual dermatologic care or prescription medication without a pre-established relationship with any physician. In 2017, there were 22 direct-to-consumer TD services available to US patients in 45 states, 16 (73%) of which provided dermatologic care for any concern while 6 (27%) were limited to acne or antiaging and were largely prescription oriented. Orchestrated mostly by the for-profit private sector, direct-to-consumer companies are poorly regulated and have raised concerns over questionable practices, such as the use of non–US board-certified physicians, exorbitant fees, and failure to disclose medication side effects.¹⁶ A study of 16 direct-to-consumer telemedicine sites found substantial discordance in the suggested management of the same patient, and many of the services relied heavily on patient-provided self-diagnoses, such as a case where psoriasis medication was dispensed for a psoriasis patient who submitted a photograph of his syphilitic rash.¹⁷ Despite these problems, consumers show a willingness to pay out of pocket to access these services for their shorter waiting times and convenience.¹⁸ Hence, we must learn to ask about direct-to-consumer service use when obtaining a thorough history and be open to counseling our patients on the proper use and potential risks of direct-to-consumer TD.

Final Thoughts

The telemedicine industry is expected to reach more than $130 billion by 2025, with more than 90% of surveyed health care executives planning for the adoption and incorporation of telemedicine into their business models.¹⁹ The COVID-19 pandemic was an impetus for an exponential adoption of TD, and it would behoove current residents to realize that the practice of dermatology will continue to be increasingly digitalized within the coming years. Whether through formal training or self-assessment, we must strive to grow as proficient virtual dermatologists while upholding professionalism, patient safety, and health information privacy.

The COVID-19 pandemic largely altered the practice of medicine, including a rapid expansion of telemedicine following the March 2020 World Health Organization guidelines for social distancing, which recommended suspension of all nonurgent in-person visits.¹ Expectedly, COVID-related urgent care visits initially comprised the bulk of the new telemedicine wave: NYU Langone Health (New York, New York), for example, saw a 683% increase in virtual visits between March and April 2020, most (55.3%) of which were for respiratory concerns. In-person visits, on the other hand, concurrently fell by more than 80%. Interestingly, nonurgent ambulatory care specialties also saw a considerable uptick in virtual encounters, from less than 50 visits in a typical day to an average of 7000 in a 10-day stretch.²

As a largely ambulatory specialty that relies on visual examination, dermatology was no exception to the swing toward telemedicine, or teledermatology (TD). Before the COVID-19 pandemic, 14.1% (82 of 582 respondents) of practicing US dermatologists reported having used teledermatology, compared to 96.9% (572/591) during the pandemic.³ Even at my home institution (Massachusetts General Hospital [Boston, Massachusetts] and its 12 affiliated dermatology clinics), the number of in-person visits in April 2020 (n=67) was less than 1% of that in April 2019 (n=7919), whereas there was a total of 1564 virtual visits in April 2020 compared to zero the year prior. Virtual provider-to-provider consults (e-consultations) also saw an increase of more than 20%, suggesting that dermatology’s avid adoption of TD also had improved the perceived accessibility of our specialty.⁴

The adoption and adaptation of TD are projected to continue to grow rapidly across the globe, as digitalization has enhanced access without increasing costs, shortened wait times, and even created opportunities for primary care providers based in rural or overseas locations to learn the diagnosis and treatment of skin disease.⁵ Residents and fellows should be privy to the nuances of training and practicing in this digital era, as our careers inevitably will involve some facet of TD.

The Art of Medicine

Touch, a sense that perhaps ranks second to sight in dermatology, is absent in TD. In either synchronous (live-interactive, face video visits) or asynchronous (store-and-forward, where digital photographs and clinical information sent by patients or referring physicians are assessed at a later time) TD, the skin cannot be rubbed for texture, pinched for thickness, or pushed for blanching. Instead, all we have is vision. Irwin Braverman, MD, Professor Emeritus of Dermatology at Yale University (New Haven, Connecticut), alongside Jacqueline Dolev, MD, dermatologist and Yale graduate, and Linda Friedlaender, curator at the Yale Center for British Art, founded an observational skills workshop in which trainees learn to observe and describe the paintings housed in the museum, noting all memorable details: the color of the sky, the actions of the animals, and the facial expressions of the people. A study of 90 participants over a 2-year period found that following the workshop, the ability to identify key diagnostic details from clinical photography improved by more than 10%.⁶ Other studies also utilizing fine art as a medical training tool to improve “visual literacy” saw similarly increased sophistication in the description of clinical imagery, which translated to better diagnostic acumen.⁷ Confined to video and photographs, TD necessitates trainees and practicing dermatologists to be excellent visual diagnosticians. Although surveyed dermatologists believe TD is presently appropriate for acne, benign lesions, or follow-up appointments,³ conditions for which patients have been examined via TD have included drug eruptions, premalignant or malignant neoplasms, infections, and papulosquamous or inflammatory dermatoses.⁸ At the very least, clinicians should be versed in identifying those conditions that require in-person evaluation, as patients cannot be held responsible to distinguish which situations can and cannot be addressed virtually.

Issues of Patient-Physician Confidentiality

Teledermatology is not without its shortcomings; critics have noted diagnostic challenges with poor quality photographs or videos, inability to perform total-body skin examinations, and socioeconomic limitations due to broadband availability and speed.^5,9 Although most of these shortcomings are outside of our control, a key challenge within the purview of the provider is the protection of patient privacy.

Much of the salient concerns regarding patient-physician confidentiality involve asynchronous TD, where store-and-forward data sharing allows physicians to download patient photographs or information onto their personal email or smartphones.¹⁰ Although some hospital systems provide encryption software or hospital-sponsored devices to ensure security, physicians may opt to use their personal phones or laptops out of convenience or to save time.^10,11 One study found that less than 30% of smartphone users choose to activate user authentication on their devices, even ones as simple as a passphrase.¹¹ The digital exchange of information thus poses an immense risk for compromising protected health information (PHI), as personal devices can be easily lost, stolen, or hacked. Indeed, in 2015, more than 113 million individuals were affected by a breach of PHI, the majority over hacked network servers.¹² With the growing diversity of mediums through which PHI is exchanged, such as videoconferencing and instant messaging, the potential medicolegal risks of information breach continue to climb. The US Department of Health & Human Services urges health care providers to uphold best practices for security, including encrypting data, updating all software including antivirus software, using multifactor authentication, and following local cybersecurity regulations or recommendations.¹³ For synchronous TD, suggested best practices include utilizing headphones during live appointments, avoiding public wireless networks, and ensuring the provider and patient both scan the room with their device’s camera before the start of the visit.¹⁴

On the Horizon of Teledermatology

What can we expect in the coming years? Increased utilization of telemedicine will translate into data that will help address questions surrounding safety, diagnostic accuracy, privacy, and accessibility. One aspect of TD in need of clarity is a guideline on payment and reimbursement, and whether TD can continue to be financially attractive to providers. Starting in 2020, the Centers for Medicare & Medicaid Services removed geographic restrictions for reimbursement of telemedicine visits, enabling even urban-residing patients to enjoy the convenience of TD. This followed a prior relaxation of restrictions, where even prerecorded patient information became eligible for Medicare reimbursement.⁹ However, as virtual visits tend to be shorter with fewer diagnostic services compared to in-person visits, the reimbursement structure of TD must be nuanced, which is the subject of ongoing study and modification in the wake of the COVID-19 pandemic.¹⁵

Another point to consider is the explosion of direct-to-consumer TD, which allows patients to receive virtual dermatologic care or prescription medication without a pre-established relationship with any physician. In 2017, there were 22 direct-to-consumer TD services available to US patients in 45 states, 16 (73%) of which provided dermatologic care for any concern while 6 (27%) were limited to acne or antiaging and were largely prescription oriented. Orchestrated mostly by the for-profit private sector, direct-to-consumer companies are poorly regulated and have raised concerns over questionable practices, such as the use of non–US board-certified physicians, exorbitant fees, and failure to disclose medication side effects.¹⁶ A study of 16 direct-to-consumer telemedicine sites found substantial discordance in the suggested management of the same patient, and many of the services relied heavily on patient-provided self-diagnoses, such as a case where psoriasis medication was dispensed for a psoriasis patient who submitted a photograph of his syphilitic rash.¹⁷ Despite these problems, consumers show a willingness to pay out of pocket to access these services for their shorter waiting times and convenience.¹⁸ Hence, we must learn to ask about direct-to-consumer service use when obtaining a thorough history and be open to counseling our patients on the proper use and potential risks of direct-to-consumer TD.

Final Thoughts

The telemedicine industry is expected to reach more than $130 billion by 2025, with more than 90% of surveyed health care executives planning for the adoption and incorporation of telemedicine into their business models.¹⁹ The COVID-19 pandemic was an impetus for an exponential adoption of TD, and it would behoove current residents to realize that the practice of dermatology will continue to be increasingly digitalized within the coming years. Whether through formal training or self-assessment, we must strive to grow as proficient virtual dermatologists while upholding professionalism, patient safety, and health information privacy.

The COVID-19 pandemic largely altered the practice of medicine, including a rapid expansion of telemedicine following the March 2020 World Health Organization guidelines for social distancing, which recommended suspension of all nonurgent in-person visits.¹ Expectedly, COVID-related urgent care visits initially comprised the bulk of the new telemedicine wave: NYU Langone Health (New York, New York), for example, saw a 683% increase in virtual visits between March and April 2020, most (55.3%) of which were for respiratory concerns. In-person visits, on the other hand, concurrently fell by more than 80%. Interestingly, nonurgent ambulatory care specialties also saw a considerable uptick in virtual encounters, from less than 50 visits in a typical day to an average of 7000 in a 10-day stretch.²

As a largely ambulatory specialty that relies on visual examination, dermatology was no exception to the swing toward telemedicine, or teledermatology (TD). Before the COVID-19 pandemic, 14.1% (82 of 582 respondents) of practicing US dermatologists reported having used teledermatology, compared to 96.9% (572/591) during the pandemic.³ Even at my home institution (Massachusetts General Hospital [Boston, Massachusetts] and its 12 affiliated dermatology clinics), the number of in-person visits in April 2020 (n=67) was less than 1% of that in April 2019 (n=7919), whereas there was a total of 1564 virtual visits in April 2020 compared to zero the year prior. Virtual provider-to-provider consults (e-consultations) also saw an increase of more than 20%, suggesting that dermatology’s avid adoption of TD also had improved the perceived accessibility of our specialty.⁴

The adoption and adaptation of TD are projected to continue to grow rapidly across the globe, as digitalization has enhanced access without increasing costs, shortened wait times, and even created opportunities for primary care providers based in rural or overseas locations to learn the diagnosis and treatment of skin disease.⁵ Residents and fellows should be privy to the nuances of training and practicing in this digital era, as our careers inevitably will involve some facet of TD.

The Art of Medicine

Touch, a sense that perhaps ranks second to sight in dermatology, is absent in TD. In either synchronous (live-interactive, face video visits) or asynchronous (store-and-forward, where digital photographs and clinical information sent by patients or referring physicians are assessed at a later time) TD, the skin cannot be rubbed for texture, pinched for thickness, or pushed for blanching. Instead, all we have is vision. Irwin Braverman, MD, Professor Emeritus of Dermatology at Yale University (New Haven, Connecticut), alongside Jacqueline Dolev, MD, dermatologist and Yale graduate, and Linda Friedlaender, curator at the Yale Center for British Art, founded an observational skills workshop in which trainees learn to observe and describe the paintings housed in the museum, noting all memorable details: the color of the sky, the actions of the animals, and the facial expressions of the people. A study of 90 participants over a 2-year period found that following the workshop, the ability to identify key diagnostic details from clinical photography improved by more than 10%.⁶ Other studies also utilizing fine art as a medical training tool to improve “visual literacy” saw similarly increased sophistication in the description of clinical imagery, which translated to better diagnostic acumen.⁷ Confined to video and photographs, TD necessitates trainees and practicing dermatologists to be excellent visual diagnosticians. Although surveyed dermatologists believe TD is presently appropriate for acne, benign lesions, or follow-up appointments,³ conditions for which patients have been examined via TD have included drug eruptions, premalignant or malignant neoplasms, infections, and papulosquamous or inflammatory dermatoses.⁸ At the very least, clinicians should be versed in identifying those conditions that require in-person evaluation, as patients cannot be held responsible to distinguish which situations can and cannot be addressed virtually.

Issues of Patient-Physician Confidentiality

Teledermatology is not without its shortcomings; critics have noted diagnostic challenges with poor quality photographs or videos, inability to perform total-body skin examinations, and socioeconomic limitations due to broadband availability and speed.^5,9 Although most of these shortcomings are outside of our control, a key challenge within the purview of the provider is the protection of patient privacy.

Much of the salient concerns regarding patient-physician confidentiality involve asynchronous TD, where store-and-forward data sharing allows physicians to download patient photographs or information onto their personal email or smartphones.¹⁰ Although some hospital systems provide encryption software or hospital-sponsored devices to ensure security, physicians may opt to use their personal phones or laptops out of convenience or to save time.^10,11 One study found that less than 30% of smartphone users choose to activate user authentication on their devices, even ones as simple as a passphrase.¹¹ The digital exchange of information thus poses an immense risk for compromising protected health information (PHI), as personal devices can be easily lost, stolen, or hacked. Indeed, in 2015, more than 113 million individuals were affected by a breach of PHI, the majority over hacked network servers.¹² With the growing diversity of mediums through which PHI is exchanged, such as videoconferencing and instant messaging, the potential medicolegal risks of information breach continue to climb. The US Department of Health & Human Services urges health care providers to uphold best practices for security, including encrypting data, updating all software including antivirus software, using multifactor authentication, and following local cybersecurity regulations or recommendations.¹³ For synchronous TD, suggested best practices include utilizing headphones during live appointments, avoiding public wireless networks, and ensuring the provider and patient both scan the room with their device’s camera before the start of the visit.¹⁴

On the Horizon of Teledermatology

What can we expect in the coming years? Increased utilization of telemedicine will translate into data that will help address questions surrounding safety, diagnostic accuracy, privacy, and accessibility. One aspect of TD in need of clarity is a guideline on payment and reimbursement, and whether TD can continue to be financially attractive to providers. Starting in 2020, the Centers for Medicare & Medicaid Services removed geographic restrictions for reimbursement of telemedicine visits, enabling even urban-residing patients to enjoy the convenience of TD. This followed a prior relaxation of restrictions, where even prerecorded patient information became eligible for Medicare reimbursement.⁹ However, as virtual visits tend to be shorter with fewer diagnostic services compared to in-person visits, the reimbursement structure of TD must be nuanced, which is the subject of ongoing study and modification in the wake of the COVID-19 pandemic.¹⁵

Another point to consider is the explosion of direct-to-consumer TD, which allows patients to receive virtual dermatologic care or prescription medication without a pre-established relationship with any physician. In 2017, there were 22 direct-to-consumer TD services available to US patients in 45 states, 16 (73%) of which provided dermatologic care for any concern while 6 (27%) were limited to acne or antiaging and were largely prescription oriented. Orchestrated mostly by the for-profit private sector, direct-to-consumer companies are poorly regulated and have raised concerns over questionable practices, such as the use of non–US board-certified physicians, exorbitant fees, and failure to disclose medication side effects.¹⁶ A study of 16 direct-to-consumer telemedicine sites found substantial discordance in the suggested management of the same patient, and many of the services relied heavily on patient-provided self-diagnoses, such as a case where psoriasis medication was dispensed for a psoriasis patient who submitted a photograph of his syphilitic rash.¹⁷ Despite these problems, consumers show a willingness to pay out of pocket to access these services for their shorter waiting times and convenience.¹⁸ Hence, we must learn to ask about direct-to-consumer service use when obtaining a thorough history and be open to counseling our patients on the proper use and potential risks of direct-to-consumer TD.

Final Thoughts

The telemedicine industry is expected to reach more than $130 billion by 2025, with more than 90% of surveyed health care executives planning for the adoption and incorporation of telemedicine into their business models.¹⁹ The COVID-19 pandemic was an impetus for an exponential adoption of TD, and it would behoove current residents to realize that the practice of dermatology will continue to be increasingly digitalized within the coming years. Whether through formal training or self-assessment, we must strive to grow as proficient virtual dermatologists while upholding professionalism, patient safety, and health information privacy.

To the Editor:

With a steady increase in dermatology publications over recent decades, there is an expanding pool of evidence to address clinical questions.¹ Residency training is the time when appraising the medical literature and practicing evidence-based medicine is most honed. Evidence-based medicine is an essential component of Practice-based Learning and Improvement, a required core competency of the Accreditation Council for Graduate Medical Education.² Assimilation of new research evidence is traditionally taught through didactics and journal club discussions in residency.

However, at a time when the demand for information overwhelms safeguards that exist to evaluate its quality, it is more important than ever to be equipped with the proper tools to critically appraise novel literature. Beyond accepting a scientific article at face value, physicians must learn to ask targeted questions of the study design, results, and clinical relevance. These questions change based on the type of study, and organizations such as the Oxford Centre for Evidence-Based Medicine provide guidance through critical appraisal worksheets.³

To investigate the utility of using guided questions to evaluate the reliability, significance, and applicability of clinical evidence, we beta tested a novel web-based application in an academic dermatology setting to design and run a journal club for residents. Six dermatology residents participated in this institutional review board–approved study comprised of 3 phases: (1) independent article appraisal through the web-based application, (2) group discussion, and (3) anonymous postsurvey.

Using this platform, we uploaded a recent article into the interactive reader, which contained an integrated tool for appraisal based on specific questions. Because the article described the results of a randomized clinical trial, we used questions from the Centre for Evidence-Based Medicine’s Randomised Controlled Trials Critical Appraisal Worksheet, which has a series of questions to evaluate internal validity, results, and external validity and applicability.³

Residents used the platform to independently read the article, highlight areas of the text that corresponded to 8 critical appraisal questions, and answer yes or no to these questions. Based on residents’ answers, a final appraisal score (on a scale of 1% to 100%) was generated. Simultaneously, the attending dermatologist leading the journal club (C.W.) also completed the assignment to establish an expert score.

Scores from the residents’ independent appraisal ranged from 75% to 100% (mean, 85.4%). Upon discussing the article in a group setting, the residents established a consensus score of 75%. This consensus score matched the expert score, which suggested to us that both independently reviewing the article using guided questions and conducting a group debriefing were necessary to match the expert level of critical appraisal.

Of note, the residents’ average independent appraisal score was higher than both the consensus and expert scores, indicating that the residents evaluated the article less critically on their own. With more practice using this method, it is possible that the precision and accuracy of the residents’ critical appraisal of scientific articles will improve.

In the postsurvey, we asked residents about the critical appraisal of the medical literature. All residents agreed that evaluating the quality of evidence when reading a scientific article was somewhat important or very important to them; however, only 2 of 6 evaluated the quality of evidence all the time, and the other 4 did so half of the time or less than half of the time.

When critically appraising articles, 2 of 6 residents used specific rubrics half of the time; 4 of 6 less than half of the time. Most important, 5 of 6 residents agreed that the quality of evidence affected their management decisions more than half of the time or all of the time. Although it is clear that residents value evidence-based medicine and understand the importance of evaluating the quality of evidence, doing so currently might not be simple or practical.

An organized framework for appraising articles would streamline the process. Five of 6 residents agreed that the use of specific questions as a guide made it easier to appraise an article for the quality of its evidence. Four of 6 residents found that juxtaposing specific questions with the interactive reader was helpful; 5 of 6 agreed that they would use a web-based journal club platform if given the option.

Lastly, 5 of 6 residents agreed that if such a tool were available, a platform containing all major dermatology publications in an interactive reader format, along with relevant appraisal questions on the side, would be useful.

This pilot study augmented the typical journal club experience by emphasizing goal-directed reading and the importance of analyzing the quality of evidence. The combination of independent appraisal of an article using targeted questions and a group debrief led to better understanding of the evidence and its clinical applicability. The COVID-19 pandemic may be a better time than ever to explore innovative ways to teach evidence-based medicine in residency training.

To the Editor:

With a steady increase in dermatology publications over recent decades, there is an expanding pool of evidence to address clinical questions.¹ Residency training is the time when appraising the medical literature and practicing evidence-based medicine is most honed. Evidence-based medicine is an essential component of Practice-based Learning and Improvement, a required core competency of the Accreditation Council for Graduate Medical Education.² Assimilation of new research evidence is traditionally taught through didactics and journal club discussions in residency.

However, at a time when the demand for information overwhelms safeguards that exist to evaluate its quality, it is more important than ever to be equipped with the proper tools to critically appraise novel literature. Beyond accepting a scientific article at face value, physicians must learn to ask targeted questions of the study design, results, and clinical relevance. These questions change based on the type of study, and organizations such as the Oxford Centre for Evidence-Based Medicine provide guidance through critical appraisal worksheets.³

To investigate the utility of using guided questions to evaluate the reliability, significance, and applicability of clinical evidence, we beta tested a novel web-based application in an academic dermatology setting to design and run a journal club for residents. Six dermatology residents participated in this institutional review board–approved study comprised of 3 phases: (1) independent article appraisal through the web-based application, (2) group discussion, and (3) anonymous postsurvey.

Using this platform, we uploaded a recent article into the interactive reader, which contained an integrated tool for appraisal based on specific questions. Because the article described the results of a randomized clinical trial, we used questions from the Centre for Evidence-Based Medicine’s Randomised Controlled Trials Critical Appraisal Worksheet, which has a series of questions to evaluate internal validity, results, and external validity and applicability.³

Residents used the platform to independently read the article, highlight areas of the text that corresponded to 8 critical appraisal questions, and answer yes or no to these questions. Based on residents’ answers, a final appraisal score (on a scale of 1% to 100%) was generated. Simultaneously, the attending dermatologist leading the journal club (C.W.) also completed the assignment to establish an expert score.

Scores from the residents’ independent appraisal ranged from 75% to 100% (mean, 85.4%). Upon discussing the article in a group setting, the residents established a consensus score of 75%. This consensus score matched the expert score, which suggested to us that both independently reviewing the article using guided questions and conducting a group debriefing were necessary to match the expert level of critical appraisal.

Of note, the residents’ average independent appraisal score was higher than both the consensus and expert scores, indicating that the residents evaluated the article less critically on their own. With more practice using this method, it is possible that the precision and accuracy of the residents’ critical appraisal of scientific articles will improve.

In the postsurvey, we asked residents about the critical appraisal of the medical literature. All residents agreed that evaluating the quality of evidence when reading a scientific article was somewhat important or very important to them; however, only 2 of 6 evaluated the quality of evidence all the time, and the other 4 did so half of the time or less than half of the time.

When critically appraising articles, 2 of 6 residents used specific rubrics half of the time; 4 of 6 less than half of the time. Most important, 5 of 6 residents agreed that the quality of evidence affected their management decisions more than half of the time or all of the time. Although it is clear that residents value evidence-based medicine and understand the importance of evaluating the quality of evidence, doing so currently might not be simple or practical.

An organized framework for appraising articles would streamline the process. Five of 6 residents agreed that the use of specific questions as a guide made it easier to appraise an article for the quality of its evidence. Four of 6 residents found that juxtaposing specific questions with the interactive reader was helpful; 5 of 6 agreed that they would use a web-based journal club platform if given the option.

Lastly, 5 of 6 residents agreed that if such a tool were available, a platform containing all major dermatology publications in an interactive reader format, along with relevant appraisal questions on the side, would be useful.

This pilot study augmented the typical journal club experience by emphasizing goal-directed reading and the importance of analyzing the quality of evidence. The combination of independent appraisal of an article using targeted questions and a group debrief led to better understanding of the evidence and its clinical applicability. The COVID-19 pandemic may be a better time than ever to explore innovative ways to teach evidence-based medicine in residency training.

To the Editor:

With a steady increase in dermatology publications over recent decades, there is an expanding pool of evidence to address clinical questions.¹ Residency training is the time when appraising the medical literature and practicing evidence-based medicine is most honed. Evidence-based medicine is an essential component of Practice-based Learning and Improvement, a required core competency of the Accreditation Council for Graduate Medical Education.² Assimilation of new research evidence is traditionally taught through didactics and journal club discussions in residency.

However, at a time when the demand for information overwhelms safeguards that exist to evaluate its quality, it is more important than ever to be equipped with the proper tools to critically appraise novel literature. Beyond accepting a scientific article at face value, physicians must learn to ask targeted questions of the study design, results, and clinical relevance. These questions change based on the type of study, and organizations such as the Oxford Centre for Evidence-Based Medicine provide guidance through critical appraisal worksheets.³

To investigate the utility of using guided questions to evaluate the reliability, significance, and applicability of clinical evidence, we beta tested a novel web-based application in an academic dermatology setting to design and run a journal club for residents. Six dermatology residents participated in this institutional review board–approved study comprised of 3 phases: (1) independent article appraisal through the web-based application, (2) group discussion, and (3) anonymous postsurvey.

Using this platform, we uploaded a recent article into the interactive reader, which contained an integrated tool for appraisal based on specific questions. Because the article described the results of a randomized clinical trial, we used questions from the Centre for Evidence-Based Medicine’s Randomised Controlled Trials Critical Appraisal Worksheet, which has a series of questions to evaluate internal validity, results, and external validity and applicability.³

Residents used the platform to independently read the article, highlight areas of the text that corresponded to 8 critical appraisal questions, and answer yes or no to these questions. Based on residents’ answers, a final appraisal score (on a scale of 1% to 100%) was generated. Simultaneously, the attending dermatologist leading the journal club (C.W.) also completed the assignment to establish an expert score.

Scores from the residents’ independent appraisal ranged from 75% to 100% (mean, 85.4%). Upon discussing the article in a group setting, the residents established a consensus score of 75%. This consensus score matched the expert score, which suggested to us that both independently reviewing the article using guided questions and conducting a group debriefing were necessary to match the expert level of critical appraisal.

Of note, the residents’ average independent appraisal score was higher than both the consensus and expert scores, indicating that the residents evaluated the article less critically on their own. With more practice using this method, it is possible that the precision and accuracy of the residents’ critical appraisal of scientific articles will improve.

In the postsurvey, we asked residents about the critical appraisal of the medical literature. All residents agreed that evaluating the quality of evidence when reading a scientific article was somewhat important or very important to them; however, only 2 of 6 evaluated the quality of evidence all the time, and the other 4 did so half of the time or less than half of the time.

When critically appraising articles, 2 of 6 residents used specific rubrics half of the time; 4 of 6 less than half of the time. Most important, 5 of 6 residents agreed that the quality of evidence affected their management decisions more than half of the time or all of the time. Although it is clear that residents value evidence-based medicine and understand the importance of evaluating the quality of evidence, doing so currently might not be simple or practical.

An organized framework for appraising articles would streamline the process. Five of 6 residents agreed that the use of specific questions as a guide made it easier to appraise an article for the quality of its evidence. Four of 6 residents found that juxtaposing specific questions with the interactive reader was helpful; 5 of 6 agreed that they would use a web-based journal club platform if given the option.

Lastly, 5 of 6 residents agreed that if such a tool were available, a platform containing all major dermatology publications in an interactive reader format, along with relevant appraisal questions on the side, would be useful.

This pilot study augmented the typical journal club experience by emphasizing goal-directed reading and the importance of analyzing the quality of evidence. The combination of independent appraisal of an article using targeted questions and a group debrief led to better understanding of the evidence and its clinical applicability. The COVID-19 pandemic may be a better time than ever to explore innovative ways to teach evidence-based medicine in residency training.

The Diagnosis: Desmoplastic Spitz Nevus

Desmoplastic Spitz nevus is a rare variant of Spitz nevus that commonly presents as a red to brown papule on the head, neck, or extremities. It is pertinent to review the histologic features of this neoplasm, as it can be confused with other more sinister entities such as spitzoid melanoma. Histologically, there is a dermal infiltrate of melanocytes containing eosinophilic cytoplasm and vesicular nuclei. Junctional involvement is rare, and there should be no pagetoid spread.¹ This entity features abundant stromal fibrosis formed by dense collagen bundles, low cellular density, and polygonal-shaped melanocytes, which helps to differentiate it from melanoma.^2,3 In a retrospective study comparing the characteristics of desmoplastic Spitz nevi with desmoplastic melanoma, desmoplastic Spitz nevi histologically were more symmetric and circumscribed with greater melanocytic maturation and adnexal structure involvement.³ Although this entity demonstrates maturation from the superficial to the deep dermis, it also may feature deep dermal vascular proliferation.⁴ S-100 and SRY-related HMG box 10, SOX-10, are noted to be positive in desmoplastic Spitz nevi, which can help to differentiate it from nonmelanocytic entities (Figure 1).

Although spitzoid lesions can be ambiguous and difficult even for experts to classify, spitzoid melanoma tends to have a high Breslow thickness, high cell density, marked atypia, and an increased nucleus to cytoplasm ratio.⁵ Additionally, desmoplastic melanoma was found to more often display “melanocytic junctional nests associated with discohesive cells, variations in size and shape of the nests, lentiginous melanocytic proliferation, actinic elastosis, pagetoid spread, dermal mitosis, perineural involvement and brisk inflammatory infiltrate.”³ Given the challenge of histologically separating desmoplastic Spitz nevi from melanoma, immunostaining can be useful. For example, Hilliard et al⁶ used a p16 antibody to differentiate desmoplastic Spitz nevi from desmoplastic melanoma, finding that most desmoplastic melanomas (81.8%; n=11) were negative for p16, whereas all desmoplastic Spitz nevi were at least moderately positive. However, another study re-evaluated the utility of p16 in desmoplastic melanoma and found that 72.7% (16/22) were at least focally reactive for the immunostain.⁷ Thus, caution must be exercised when using p16.

PReferentially expressed Antigen in MElanoma (PRAME) is a newer nuclear immunohistochemical marker that tends to be positive in melanomas and negative in nevi. Desmoplastic Spitz nevi would be expected to be negative for PRAME, while desmoplastic melanoma may be positive; however, this marker seems to be less effective in desmoplastic melanoma than in most other subtypes of the malignancy. In one study, only 35% (n=20) of desmoplastic melanomas were positive for PRAME.⁸ Likewise, another study showed that some benign Spitz nevi may diffusely express PRAME.⁹ As such, PRAME should be used prudently.

For cases in which immunohistochemistry is equivocal, molecular testing may aid in differentiating Spitz nevi from melanoma. For example, comparative genomic hybridization has revealed an increased copy number of chromosome 11p in approximately 20% of Spitz nevi cases¹⁰; this finding is not seen in melanoma. Mutation analyses of HRas proto-oncogene, GTPase, HRAS; B-Raf proto-oncogene, serine/threonine kinase, BRAF; and NRAS proto-oncogene, GTPase, NRAS, also have shown some promise in distinguishing spitzoid lesions from melanoma, but these analyses may be oversimplified.¹¹ Fluorescence in situ hybridization (FISH) is another diagnostic modality that has been studied to differentiate benign nevi from melanoma. One study challenged the utility of FISH, reporting 7 of 15 desmoplastic melanomas tested positive compared to 0 of 15 sclerotic melanocytic nevi.¹² Thus, negative FISH cannot reliably rule out melanoma. Ultimately, a combination of immunostains along with FISH or another genetic study would prove to be most effective in ruling out melanoma in difficult cases. Even then, a dermatopathologist may be faced with a degree of uncertainty.

Cellular blue nevi predominantly affect adults younger than 40 years and commonly are seen on the buttocks.¹³ This benign neoplasm demonstrates areas that are distinctly sclerotic as well as those that are cellular in nature.¹⁴ This entity demonstrates a well-circumscribed dermal growth pattern with 2 main populations of cells. The sclerotic portion of the cellular blue nevus mimics that of the blue nevus in that it is noted superficially with irregular margins. The cellular aspect of the nevus features spindle cells contained within well-circumscribed nodules (Figure 2). Stromal melanophages are not uncommon, and some can be observed adjacent to nerve fibers. Although this blue nevus variant displays features of the common blue nevus, its melanocytes track along adnexal and neurovascular structures similar to the deep penetrating nevus and the desmoplastic Spitz nevus. However, these melanocytes are variable in morphology and can appear on a spectrum spanning from pale and lightly pigmented to clear.¹⁵

The breast is the most common site of origin of tumor metastasis to the skin. These cutaneous metastases can vary in both their clinical and histological presentations. For example, cutaneous metastatic breast adenocarcinoma often can present clinically as pink-violaceous papules and plaques on the breast or on other parts of the body. Histologically, it can demonstrate a varying degree of patterns such as collagen infiltration by single cells, cords, tubules, and sheets of atypical cells (Figure 3) that can be observed together in areas of mucin or can form glandular structures.16 Metastatic breast carcinoma is noted to be positive for gross cystic disease fluid protein-15, estrogen receptor, and cytokeratin 7, which can help differentiate this entity from other tumors of glandular origin.¹⁶ Although rare, primary melanoma of the breast has been reported in the literature.^17,18 These malignant melanocytic lesions easily could be differentiated from other breast tumors such as adenocarcinoma using immunohistochemical staining patterns.

Deep penetrating nevi most often are observed clinically as blue, brown, or black papules or nodules on the head or neck.¹⁹ Histologically, this lesion features a wedge-shaped infiltrate of deep dermal melanocytes with oval nuclei. It commonly extends to the reticular dermis or further into the subcutis (Figure 4).^20,21 This neoplasm frequently tracks along adnexal and neurovascular structures, resulting in a plexiform appearance.²² The adnexal involvement of deep penetrating nevi is a shared feature with desmoplastic Spitz nevi. The presence of any number of melanophages is characteristic of this lesion.²³ Lastly, there is a well-documented association between β-catenin mutations and deep penetrating nevi.²⁴ Multicentric reticulohistiocytosis (MRH) is a rare form of non-Langerhans cell histiocytosis that has the pathognomonic clinical finding of pink-red papules (coral beading) with a predilection for acral surfaces. Histology of affected skin reveals a dermal infiltrate of ground glass as well as eosinophilic histiocytes that most often stain positive for CD68 and human alveolar macrophage 56 but negative for S-100 and CD1a (Figure 5).²⁵ Although MRH is rare, negative staining for S-100 could serve as a useful diagnostic clue to differentiate it from other entities that are positive for S-100, such as the desmoplastic Spitz nevus. Arthritis mutilans is a potential complication of MRH, but a reported association with an underlying malignancy is seen in approximately 25% of cases.²⁶ Thus, the cutaneous, rheumatologic, and oncologic implications of this disease help to distinguish it from other differential diagnoses that may be considered.

The Diagnosis: Desmoplastic Spitz Nevus

Desmoplastic Spitz nevus is a rare variant of Spitz nevus that commonly presents as a red to brown papule on the head, neck, or extremities. It is pertinent to review the histologic features of this neoplasm, as it can be confused with other more sinister entities such as spitzoid melanoma. Histologically, there is a dermal infiltrate of melanocytes containing eosinophilic cytoplasm and vesicular nuclei. Junctional involvement is rare, and there should be no pagetoid spread.¹ This entity features abundant stromal fibrosis formed by dense collagen bundles, low cellular density, and polygonal-shaped melanocytes, which helps to differentiate it from melanoma.^2,3 In a retrospective study comparing the characteristics of desmoplastic Spitz nevi with desmoplastic melanoma, desmoplastic Spitz nevi histologically were more symmetric and circumscribed with greater melanocytic maturation and adnexal structure involvement.³ Although this entity demonstrates maturation from the superficial to the deep dermis, it also may feature deep dermal vascular proliferation.⁴ S-100 and SRY-related HMG box 10, SOX-10, are noted to be positive in desmoplastic Spitz nevi, which can help to differentiate it from nonmelanocytic entities (Figure 1).

Although spitzoid lesions can be ambiguous and difficult even for experts to classify, spitzoid melanoma tends to have a high Breslow thickness, high cell density, marked atypia, and an increased nucleus to cytoplasm ratio.⁵ Additionally, desmoplastic melanoma was found to more often display “melanocytic junctional nests associated with discohesive cells, variations in size and shape of the nests, lentiginous melanocytic proliferation, actinic elastosis, pagetoid spread, dermal mitosis, perineural involvement and brisk inflammatory infiltrate.”³ Given the challenge of histologically separating desmoplastic Spitz nevi from melanoma, immunostaining can be useful. For example, Hilliard et al⁶ used a p16 antibody to differentiate desmoplastic Spitz nevi from desmoplastic melanoma, finding that most desmoplastic melanomas (81.8%; n=11) were negative for p16, whereas all desmoplastic Spitz nevi were at least moderately positive. However, another study re-evaluated the utility of p16 in desmoplastic melanoma and found that 72.7% (16/22) were at least focally reactive for the immunostain.⁷ Thus, caution must be exercised when using p16.

PReferentially expressed Antigen in MElanoma (PRAME) is a newer nuclear immunohistochemical marker that tends to be positive in melanomas and negative in nevi. Desmoplastic Spitz nevi would be expected to be negative for PRAME, while desmoplastic melanoma may be positive; however, this marker seems to be less effective in desmoplastic melanoma than in most other subtypes of the malignancy. In one study, only 35% (n=20) of desmoplastic melanomas were positive for PRAME.⁸ Likewise, another study showed that some benign Spitz nevi may diffusely express PRAME.⁹ As such, PRAME should be used prudently.

For cases in which immunohistochemistry is equivocal, molecular testing may aid in differentiating Spitz nevi from melanoma. For example, comparative genomic hybridization has revealed an increased copy number of chromosome 11p in approximately 20% of Spitz nevi cases¹⁰; this finding is not seen in melanoma. Mutation analyses of HRas proto-oncogene, GTPase, HRAS; B-Raf proto-oncogene, serine/threonine kinase, BRAF; and NRAS proto-oncogene, GTPase, NRAS, also have shown some promise in distinguishing spitzoid lesions from melanoma, but these analyses may be oversimplified.¹¹ Fluorescence in situ hybridization (FISH) is another diagnostic modality that has been studied to differentiate benign nevi from melanoma. One study challenged the utility of FISH, reporting 7 of 15 desmoplastic melanomas tested positive compared to 0 of 15 sclerotic melanocytic nevi.¹² Thus, negative FISH cannot reliably rule out melanoma. Ultimately, a combination of immunostains along with FISH or another genetic study would prove to be most effective in ruling out melanoma in difficult cases. Even then, a dermatopathologist may be faced with a degree of uncertainty.

Cellular blue nevi predominantly affect adults younger than 40 years and commonly are seen on the buttocks.¹³ This benign neoplasm demonstrates areas that are distinctly sclerotic as well as those that are cellular in nature.¹⁴ This entity demonstrates a well-circumscribed dermal growth pattern with 2 main populations of cells. The sclerotic portion of the cellular blue nevus mimics that of the blue nevus in that it is noted superficially with irregular margins. The cellular aspect of the nevus features spindle cells contained within well-circumscribed nodules (Figure 2). Stromal melanophages are not uncommon, and some can be observed adjacent to nerve fibers. Although this blue nevus variant displays features of the common blue nevus, its melanocytes track along adnexal and neurovascular structures similar to the deep penetrating nevus and the desmoplastic Spitz nevus. However, these melanocytes are variable in morphology and can appear on a spectrum spanning from pale and lightly pigmented to clear.¹⁵

The breast is the most common site of origin of tumor metastasis to the skin. These cutaneous metastases can vary in both their clinical and histological presentations. For example, cutaneous metastatic breast adenocarcinoma often can present clinically as pink-violaceous papules and plaques on the breast or on other parts of the body. Histologically, it can demonstrate a varying degree of patterns such as collagen infiltration by single cells, cords, tubules, and sheets of atypical cells (Figure 3) that can be observed together in areas of mucin or can form glandular structures.16 Metastatic breast carcinoma is noted to be positive for gross cystic disease fluid protein-15, estrogen receptor, and cytokeratin 7, which can help differentiate this entity from other tumors of glandular origin.¹⁶ Although rare, primary melanoma of the breast has been reported in the literature.^17,18 These malignant melanocytic lesions easily could be differentiated from other breast tumors such as adenocarcinoma using immunohistochemical staining patterns.

Deep penetrating nevi most often are observed clinically as blue, brown, or black papules or nodules on the head or neck.¹⁹ Histologically, this lesion features a wedge-shaped infiltrate of deep dermal melanocytes with oval nuclei. It commonly extends to the reticular dermis or further into the subcutis (Figure 4).^20,21 This neoplasm frequently tracks along adnexal and neurovascular structures, resulting in a plexiform appearance.²² The adnexal involvement of deep penetrating nevi is a shared feature with desmoplastic Spitz nevi. The presence of any number of melanophages is characteristic of this lesion.²³ Lastly, there is a well-documented association between β-catenin mutations and deep penetrating nevi.²⁴ Multicentric reticulohistiocytosis (MRH) is a rare form of non-Langerhans cell histiocytosis that has the pathognomonic clinical finding of pink-red papules (coral beading) with a predilection for acral surfaces. Histology of affected skin reveals a dermal infiltrate of ground glass as well as eosinophilic histiocytes that most often stain positive for CD68 and human alveolar macrophage 56 but negative for S-100 and CD1a (Figure 5).²⁵ Although MRH is rare, negative staining for S-100 could serve as a useful diagnostic clue to differentiate it from other entities that are positive for S-100, such as the desmoplastic Spitz nevus. Arthritis mutilans is a potential complication of MRH, but a reported association with an underlying malignancy is seen in approximately 25% of cases.²⁶ Thus, the cutaneous, rheumatologic, and oncologic implications of this disease help to distinguish it from other differential diagnoses that may be considered.

The Diagnosis: Desmoplastic Spitz Nevus

Desmoplastic Spitz nevus is a rare variant of Spitz nevus that commonly presents as a red to brown papule on the head, neck, or extremities. It is pertinent to review the histologic features of this neoplasm, as it can be confused with other more sinister entities such as spitzoid melanoma. Histologically, there is a dermal infiltrate of melanocytes containing eosinophilic cytoplasm and vesicular nuclei. Junctional involvement is rare, and there should be no pagetoid spread.¹ This entity features abundant stromal fibrosis formed by dense collagen bundles, low cellular density, and polygonal-shaped melanocytes, which helps to differentiate it from melanoma.^2,3 In a retrospective study comparing the characteristics of desmoplastic Spitz nevi with desmoplastic melanoma, desmoplastic Spitz nevi histologically were more symmetric and circumscribed with greater melanocytic maturation and adnexal structure involvement.³ Although this entity demonstrates maturation from the superficial to the deep dermis, it also may feature deep dermal vascular proliferation.⁴ S-100 and SRY-related HMG box 10, SOX-10, are noted to be positive in desmoplastic Spitz nevi, which can help to differentiate it from nonmelanocytic entities (Figure 1).

Although spitzoid lesions can be ambiguous and difficult even for experts to classify, spitzoid melanoma tends to have a high Breslow thickness, high cell density, marked atypia, and an increased nucleus to cytoplasm ratio.⁵ Additionally, desmoplastic melanoma was found to more often display “melanocytic junctional nests associated with discohesive cells, variations in size and shape of the nests, lentiginous melanocytic proliferation, actinic elastosis, pagetoid spread, dermal mitosis, perineural involvement and brisk inflammatory infiltrate.”³ Given the challenge of histologically separating desmoplastic Spitz nevi from melanoma, immunostaining can be useful. For example, Hilliard et al⁶ used a p16 antibody to differentiate desmoplastic Spitz nevi from desmoplastic melanoma, finding that most desmoplastic melanomas (81.8%; n=11) were negative for p16, whereas all desmoplastic Spitz nevi were at least moderately positive. However, another study re-evaluated the utility of p16 in desmoplastic melanoma and found that 72.7% (16/22) were at least focally reactive for the immunostain.⁷ Thus, caution must be exercised when using p16.

PReferentially expressed Antigen in MElanoma (PRAME) is a newer nuclear immunohistochemical marker that tends to be positive in melanomas and negative in nevi. Desmoplastic Spitz nevi would be expected to be negative for PRAME, while desmoplastic melanoma may be positive; however, this marker seems to be less effective in desmoplastic melanoma than in most other subtypes of the malignancy. In one study, only 35% (n=20) of desmoplastic melanomas were positive for PRAME.⁸ Likewise, another study showed that some benign Spitz nevi may diffusely express PRAME.⁹ As such, PRAME should be used prudently.

For cases in which immunohistochemistry is equivocal, molecular testing may aid in differentiating Spitz nevi from melanoma. For example, comparative genomic hybridization has revealed an increased copy number of chromosome 11p in approximately 20% of Spitz nevi cases¹⁰; this finding is not seen in melanoma. Mutation analyses of HRas proto-oncogene, GTPase, HRAS; B-Raf proto-oncogene, serine/threonine kinase, BRAF; and NRAS proto-oncogene, GTPase, NRAS, also have shown some promise in distinguishing spitzoid lesions from melanoma, but these analyses may be oversimplified.¹¹ Fluorescence in situ hybridization (FISH) is another diagnostic modality that has been studied to differentiate benign nevi from melanoma. One study challenged the utility of FISH, reporting 7 of 15 desmoplastic melanomas tested positive compared to 0 of 15 sclerotic melanocytic nevi.¹² Thus, negative FISH cannot reliably rule out melanoma. Ultimately, a combination of immunostains along with FISH or another genetic study would prove to be most effective in ruling out melanoma in difficult cases. Even then, a dermatopathologist may be faced with a degree of uncertainty.

Cellular blue nevi predominantly affect adults younger than 40 years and commonly are seen on the buttocks.¹³ This benign neoplasm demonstrates areas that are distinctly sclerotic as well as those that are cellular in nature.¹⁴ This entity demonstrates a well-circumscribed dermal growth pattern with 2 main populations of cells. The sclerotic portion of the cellular blue nevus mimics that of the blue nevus in that it is noted superficially with irregular margins. The cellular aspect of the nevus features spindle cells contained within well-circumscribed nodules (Figure 2). Stromal melanophages are not uncommon, and some can be observed adjacent to nerve fibers. Although this blue nevus variant displays features of the common blue nevus, its melanocytes track along adnexal and neurovascular structures similar to the deep penetrating nevus and the desmoplastic Spitz nevus. However, these melanocytes are variable in morphology and can appear on a spectrum spanning from pale and lightly pigmented to clear.¹⁵

The breast is the most common site of origin of tumor metastasis to the skin. These cutaneous metastases can vary in both their clinical and histological presentations. For example, cutaneous metastatic breast adenocarcinoma often can present clinically as pink-violaceous papules and plaques on the breast or on other parts of the body. Histologically, it can demonstrate a varying degree of patterns such as collagen infiltration by single cells, cords, tubules, and sheets of atypical cells (Figure 3) that can be observed together in areas of mucin or can form glandular structures.16 Metastatic breast carcinoma is noted to be positive for gross cystic disease fluid protein-15, estrogen receptor, and cytokeratin 7, which can help differentiate this entity from other tumors of glandular origin.¹⁶ Although rare, primary melanoma of the breast has been reported in the literature.^17,18 These malignant melanocytic lesions easily could be differentiated from other breast tumors such as adenocarcinoma using immunohistochemical staining patterns.

Deep penetrating nevi most often are observed clinically as blue, brown, or black papules or nodules on the head or neck.¹⁹ Histologically, this lesion features a wedge-shaped infiltrate of deep dermal melanocytes with oval nuclei. It commonly extends to the reticular dermis or further into the subcutis (Figure 4).^20,21 This neoplasm frequently tracks along adnexal and neurovascular structures, resulting in a plexiform appearance.²² The adnexal involvement of deep penetrating nevi is a shared feature with desmoplastic Spitz nevi. The presence of any number of melanophages is characteristic of this lesion.²³ Lastly, there is a well-documented association between β-catenin mutations and deep penetrating nevi.²⁴ Multicentric reticulohistiocytosis (MRH) is a rare form of non-Langerhans cell histiocytosis that has the pathognomonic clinical finding of pink-red papules (coral beading) with a predilection for acral surfaces. Histology of affected skin reveals a dermal infiltrate of ground glass as well as eosinophilic histiocytes that most often stain positive for CD68 and human alveolar macrophage 56 but negative for S-100 and CD1a (Figure 5).²⁵ Although MRH is rare, negative staining for S-100 could serve as a useful diagnostic clue to differentiate it from other entities that are positive for S-100, such as the desmoplastic Spitz nevus. Arthritis mutilans is a potential complication of MRH, but a reported association with an underlying malignancy is seen in approximately 25% of cases.²⁶ Thus, the cutaneous, rheumatologic, and oncologic implications of this disease help to distinguish it from other differential diagnoses that may be considered.

On November 2, 2021, the Centers for Medicare & Medicaid Services (CMS) released its final rule for the 2022 Medicare Physician Fee Schedule (PFS) and the Quality Payment Program (QPP).^1,2 These guidelines contain updates that will remarkably impact the field of medicine—and dermatology in particular—in 2022. This article will walk you through some of the updates most relevant to dermatology and how they may affect your practice.

Process for the Final Rule

The CMS releases an annual rule for the PFS and QPP. The interim rule generally is released over the summer with preliminary guidelines for the upcoming payment year. There is then a period of open comment where those affected by these changes, including physicians and medical associations, can submit comments to support what has been proposed or advocate for any changes. This input is then reviewed, and a final rule generally is published in the fall.

For this calendar year, the interim 2022 rule was released on July 13, 2021,³ and included many of guidelines that will be discussed in more detail in this article. Many associations that represent medicine overall and specifically dermatology, including the American Medical Association and the American Academy of Dermatology, submitted comments in response to these proposals.^4,5

PFS Conversion Factor

The PFS conversion factor is updated annually to ensure budget neutrality in the setting of changes in relative value units. For 2022, the PFS conversion factor is $34.6062, representing a reduction of approximately $0.29 from the 2021 PFS conversion factor of $34.8931.⁶ This reduction does not take into account other payment adjustments due to legislative changes.

In combination, these changes previously were estimated to represent an overall payment cut of 10% or higher for dermatology, with those practitioners doing more procedural work or dermatopathology likely being impacted more heavily. However, with the passing of the Protecting Medicare and American Farmers from Sequester Cuts Act, it is estimated that the reductions in payment to dermatology will begin at 0.75% and reach 2.75% in the second half of the year with the phased-in reinstatement of the Medicare sequester.^4,5,7

Clinical Labor Pricing Updates

Starting in 2022, the CMS will utilize updated wage rates from the US Bureau of Labor Statistics to revise clinical labor costs over a 4-year period. Clinical labor rates are important, as they are used to calculate practice expense within the PFS. These clinical labor rates were last updated in 2002.⁸ Median wage data, as opposed to mean data, from the US Bureau of Labor Statistics will be utilized to calculate the updated clinical labor rates.

A multiyear implementation plan was put into place by CMS due to multiple concerns, including that current wage rates are inadequate and may not reflect current labor rate information. Additionally, comments on this proposal voiced concern that updating the supply and equipment pricing without updating the clinical labor pricing could create distortions in the allocation of direct practice expense, which also factored into the implementation of a multiyear plan.⁸

Evaluation and Management Visits

The biggest update in this area primarily is related to refining policies for split (shared) evaluation and management (E/M) visits and teaching physician activities. Split E/M visits are defined by the CMS as visits provided in the facility setting by a physician and nonphysician practitioner in the same group, with the visit billed by whomever provides the substantive portion of the visit. For 2022, the term substantive portion will be defined by the CMS as history, physical examination, medical decision-making, or more than half of the total time; for 2023, it will be defined as more than half of the total time spent.³ A split visit also can apply to an E/M visit provided in part by both a teaching physician and resident. Split visits can be reported for new or established patients. For proper reimbursement, the 2 practitioners who performed the services must be documented in the medical record, and the practitioner who provided the substantive portion must sign and date the encounter in the medical record. Additionally, the CMS has indicated the modifier FS must be included on the claim to indicate the split visit.⁹

For dermatologists who act as teaching physicians, it is important to note that many of the existing CMS policies for billing E/M services are still in place, specifically that if a resident participates in a service in a teaching setting, the teaching physician can bill for the service only if they are present for the key or critical portion of the service. A primary care exception does exist, in which teaching physicians at certain teaching hospital primary care centers can bill for some services performed independently by a resident without the physical presence of the teaching physician; however, this often is not applicable within dermatology.

With updated outpatient E/M guidelines, if time is being selected to bill, only the time that the teaching physician was present can be included to determine the overall E/M level.

Billing for Physician Assistant Services

Currently Medicare can only make payments to the employer or independent contractor of a physician assistant (PA); however, starting January 1, 2022, the CMS has authorized Medicare to make direct payments to PAs for qualifying professional services, in the same manner that nurse practitioners can currently bill. This also will allow PAs to incorporate as a group and bill Medicare for PA services. This stems from a congressional mandate within the Consolidated Appropriations Act of 2021.⁸ As a result, in states where PAs can practice independently, they can opt out of physician-led care teams and furnish services independently, including dermatologic services.

 

 

QPP Updates

Several changes were made to the Merit-Based Incentive Payment System (MIPS). Some of these changes include:

• Increase the MIPS performance threshold to 75 points from 60 points.
• Set the performance threshold at 89 points.
• Reduce the quality performance category weight from 40% to 30% of the final MIPS score.
• Increase the cost performance category weight from 20% to 30% of the final MIPS score.
• The extreme and uncontrollable circumstances application also has been extended to the end of 2022, allowing those remarkably impacted by the COVID-19 public health emergency to request for reweighting on any or all MIPS performance categories.

Cost Measures and MIPS Value Pathways

The melanoma resection cost measure will be implemented in 2022, representing the first dermatology cost measure, which will include the cost to Medicare over a 1-year period for all patient care for the excision of a melanoma. Although cost measures will be part of the MIPS value pathways (MVPs) reporting, dermatology currently is not part of the MVP; however, with the CMS moving forward with an initial set of MVPs that physicians can voluntarily report on in 2023, there is a possibility that dermatology will be asked to be part of the program in the future.¹⁰

Final Thoughts

There are many upcoming changes as part of the 2022 final rule, including to the conversion factor, E/M split visits, PA billing, and the QPP. Advocacy in these areas to the CMS and lawmakers, either directly or through dermatologic and other medical societies, is critical to help influence eventual recommendations.

On November 2, 2021, the Centers for Medicare & Medicaid Services (CMS) released its final rule for the 2022 Medicare Physician Fee Schedule (PFS) and the Quality Payment Program (QPP).^1,2 These guidelines contain updates that will remarkably impact the field of medicine—and dermatology in particular—in 2022. This article will walk you through some of the updates most relevant to dermatology and how they may affect your practice.

Process for the Final Rule

The CMS releases an annual rule for the PFS and QPP. The interim rule generally is released over the summer with preliminary guidelines for the upcoming payment year. There is then a period of open comment where those affected by these changes, including physicians and medical associations, can submit comments to support what has been proposed or advocate for any changes. This input is then reviewed, and a final rule generally is published in the fall.

For this calendar year, the interim 2022 rule was released on July 13, 2021,³ and included many of guidelines that will be discussed in more detail in this article. Many associations that represent medicine overall and specifically dermatology, including the American Medical Association and the American Academy of Dermatology, submitted comments in response to these proposals.^4,5

PFS Conversion Factor

The PFS conversion factor is updated annually to ensure budget neutrality in the setting of changes in relative value units. For 2022, the PFS conversion factor is $34.6062, representing a reduction of approximately $0.29 from the 2021 PFS conversion factor of $34.8931.⁶ This reduction does not take into account other payment adjustments due to legislative changes.

In combination, these changes previously were estimated to represent an overall payment cut of 10% or higher for dermatology, with those practitioners doing more procedural work or dermatopathology likely being impacted more heavily. However, with the passing of the Protecting Medicare and American Farmers from Sequester Cuts Act, it is estimated that the reductions in payment to dermatology will begin at 0.75% and reach 2.75% in the second half of the year with the phased-in reinstatement of the Medicare sequester.^4,5,7

Clinical Labor Pricing Updates

Starting in 2022, the CMS will utilize updated wage rates from the US Bureau of Labor Statistics to revise clinical labor costs over a 4-year period. Clinical labor rates are important, as they are used to calculate practice expense within the PFS. These clinical labor rates were last updated in 2002.⁸ Median wage data, as opposed to mean data, from the US Bureau of Labor Statistics will be utilized to calculate the updated clinical labor rates.

A multiyear implementation plan was put into place by CMS due to multiple concerns, including that current wage rates are inadequate and may not reflect current labor rate information. Additionally, comments on this proposal voiced concern that updating the supply and equipment pricing without updating the clinical labor pricing could create distortions in the allocation of direct practice expense, which also factored into the implementation of a multiyear plan.⁸

Evaluation and Management Visits

The biggest update in this area primarily is related to refining policies for split (shared) evaluation and management (E/M) visits and teaching physician activities. Split E/M visits are defined by the CMS as visits provided in the facility setting by a physician and nonphysician practitioner in the same group, with the visit billed by whomever provides the substantive portion of the visit. For 2022, the term substantive portion will be defined by the CMS as history, physical examination, medical decision-making, or more than half of the total time; for 2023, it will be defined as more than half of the total time spent.³ A split visit also can apply to an E/M visit provided in part by both a teaching physician and resident. Split visits can be reported for new or established patients. For proper reimbursement, the 2 practitioners who performed the services must be documented in the medical record, and the practitioner who provided the substantive portion must sign and date the encounter in the medical record. Additionally, the CMS has indicated the modifier FS must be included on the claim to indicate the split visit.⁹

For dermatologists who act as teaching physicians, it is important to note that many of the existing CMS policies for billing E/M services are still in place, specifically that if a resident participates in a service in a teaching setting, the teaching physician can bill for the service only if they are present for the key or critical portion of the service. A primary care exception does exist, in which teaching physicians at certain teaching hospital primary care centers can bill for some services performed independently by a resident without the physical presence of the teaching physician; however, this often is not applicable within dermatology.

With updated outpatient E/M guidelines, if time is being selected to bill, only the time that the teaching physician was present can be included to determine the overall E/M level.

Billing for Physician Assistant Services

Currently Medicare can only make payments to the employer or independent contractor of a physician assistant (PA); however, starting January 1, 2022, the CMS has authorized Medicare to make direct payments to PAs for qualifying professional services, in the same manner that nurse practitioners can currently bill. This also will allow PAs to incorporate as a group and bill Medicare for PA services. This stems from a congressional mandate within the Consolidated Appropriations Act of 2021.⁸ As a result, in states where PAs can practice independently, they can opt out of physician-led care teams and furnish services independently, including dermatologic services.

 

 

QPP Updates

Several changes were made to the Merit-Based Incentive Payment System (MIPS). Some of these changes include:

• Increase the MIPS performance threshold to 75 points from 60 points.
• Set the performance threshold at 89 points.
• Reduce the quality performance category weight from 40% to 30% of the final MIPS score.
• Increase the cost performance category weight from 20% to 30% of the final MIPS score.
• The extreme and uncontrollable circumstances application also has been extended to the end of 2022, allowing those remarkably impacted by the COVID-19 public health emergency to request for reweighting on any or all MIPS performance categories.

Cost Measures and MIPS Value Pathways

The melanoma resection cost measure will be implemented in 2022, representing the first dermatology cost measure, which will include the cost to Medicare over a 1-year period for all patient care for the excision of a melanoma. Although cost measures will be part of the MIPS value pathways (MVPs) reporting, dermatology currently is not part of the MVP; however, with the CMS moving forward with an initial set of MVPs that physicians can voluntarily report on in 2023, there is a possibility that dermatology will be asked to be part of the program in the future.¹⁰

Final Thoughts

There are many upcoming changes as part of the 2022 final rule, including to the conversion factor, E/M split visits, PA billing, and the QPP. Advocacy in these areas to the CMS and lawmakers, either directly or through dermatologic and other medical societies, is critical to help influence eventual recommendations.

On November 2, 2021, the Centers for Medicare & Medicaid Services (CMS) released its final rule for the 2022 Medicare Physician Fee Schedule (PFS) and the Quality Payment Program (QPP).^1,2 These guidelines contain updates that will remarkably impact the field of medicine—and dermatology in particular—in 2022. This article will walk you through some of the updates most relevant to dermatology and how they may affect your practice.

Process for the Final Rule

The CMS releases an annual rule for the PFS and QPP. The interim rule generally is released over the summer with preliminary guidelines for the upcoming payment year. There is then a period of open comment where those affected by these changes, including physicians and medical associations, can submit comments to support what has been proposed or advocate for any changes. This input is then reviewed, and a final rule generally is published in the fall.

For this calendar year, the interim 2022 rule was released on July 13, 2021,³ and included many of guidelines that will be discussed in more detail in this article. Many associations that represent medicine overall and specifically dermatology, including the American Medical Association and the American Academy of Dermatology, submitted comments in response to these proposals.^4,5

PFS Conversion Factor

The PFS conversion factor is updated annually to ensure budget neutrality in the setting of changes in relative value units. For 2022, the PFS conversion factor is $34.6062, representing a reduction of approximately $0.29 from the 2021 PFS conversion factor of $34.8931.⁶ This reduction does not take into account other payment adjustments due to legislative changes.

In combination, these changes previously were estimated to represent an overall payment cut of 10% or higher for dermatology, with those practitioners doing more procedural work or dermatopathology likely being impacted more heavily. However, with the passing of the Protecting Medicare and American Farmers from Sequester Cuts Act, it is estimated that the reductions in payment to dermatology will begin at 0.75% and reach 2.75% in the second half of the year with the phased-in reinstatement of the Medicare sequester.^4,5,7

Clinical Labor Pricing Updates

Starting in 2022, the CMS will utilize updated wage rates from the US Bureau of Labor Statistics to revise clinical labor costs over a 4-year period. Clinical labor rates are important, as they are used to calculate practice expense within the PFS. These clinical labor rates were last updated in 2002.⁸ Median wage data, as opposed to mean data, from the US Bureau of Labor Statistics will be utilized to calculate the updated clinical labor rates.

A multiyear implementation plan was put into place by CMS due to multiple concerns, including that current wage rates are inadequate and may not reflect current labor rate information. Additionally, comments on this proposal voiced concern that updating the supply and equipment pricing without updating the clinical labor pricing could create distortions in the allocation of direct practice expense, which also factored into the implementation of a multiyear plan.⁸

Evaluation and Management Visits

The biggest update in this area primarily is related to refining policies for split (shared) evaluation and management (E/M) visits and teaching physician activities. Split E/M visits are defined by the CMS as visits provided in the facility setting by a physician and nonphysician practitioner in the same group, with the visit billed by whomever provides the substantive portion of the visit. For 2022, the term substantive portion will be defined by the CMS as history, physical examination, medical decision-making, or more than half of the total time; for 2023, it will be defined as more than half of the total time spent.³ A split visit also can apply to an E/M visit provided in part by both a teaching physician and resident. Split visits can be reported for new or established patients. For proper reimbursement, the 2 practitioners who performed the services must be documented in the medical record, and the practitioner who provided the substantive portion must sign and date the encounter in the medical record. Additionally, the CMS has indicated the modifier FS must be included on the claim to indicate the split visit.⁹

For dermatologists who act as teaching physicians, it is important to note that many of the existing CMS policies for billing E/M services are still in place, specifically that if a resident participates in a service in a teaching setting, the teaching physician can bill for the service only if they are present for the key or critical portion of the service. A primary care exception does exist, in which teaching physicians at certain teaching hospital primary care centers can bill for some services performed independently by a resident without the physical presence of the teaching physician; however, this often is not applicable within dermatology.

With updated outpatient E/M guidelines, if time is being selected to bill, only the time that the teaching physician was present can be included to determine the overall E/M level.

Billing for Physician Assistant Services

Currently Medicare can only make payments to the employer or independent contractor of a physician assistant (PA); however, starting January 1, 2022, the CMS has authorized Medicare to make direct payments to PAs for qualifying professional services, in the same manner that nurse practitioners can currently bill. This also will allow PAs to incorporate as a group and bill Medicare for PA services. This stems from a congressional mandate within the Consolidated Appropriations Act of 2021.⁸ As a result, in states where PAs can practice independently, they can opt out of physician-led care teams and furnish services independently, including dermatologic services.

 

 

QPP Updates

Several changes were made to the Merit-Based Incentive Payment System (MIPS). Some of these changes include:

• Increase the MIPS performance threshold to 75 points from 60 points.
• Set the performance threshold at 89 points.
• Reduce the quality performance category weight from 40% to 30% of the final MIPS score.
• Increase the cost performance category weight from 20% to 30% of the final MIPS score.
• The extreme and uncontrollable circumstances application also has been extended to the end of 2022, allowing those remarkably impacted by the COVID-19 public health emergency to request for reweighting on any or all MIPS performance categories.

Cost Measures and MIPS Value Pathways

The melanoma resection cost measure will be implemented in 2022, representing the first dermatology cost measure, which will include the cost to Medicare over a 1-year period for all patient care for the excision of a melanoma. Although cost measures will be part of the MIPS value pathways (MVPs) reporting, dermatology currently is not part of the MVP; however, with the CMS moving forward with an initial set of MVPs that physicians can voluntarily report on in 2023, there is a possibility that dermatology will be asked to be part of the program in the future.¹⁰

Final Thoughts

There are many upcoming changes as part of the 2022 final rule, including to the conversion factor, E/M split visits, PA billing, and the QPP. Advocacy in these areas to the CMS and lawmakers, either directly or through dermatologic and other medical societies, is critical to help influence eventual recommendations.

Acne vulgaris is an extremely common dermatologic disease affecting 40 to 50 million individuals in the United States each year, with a prevalence of 85% in adolescents and young adults aged 12 to 24 years. For some patients, the disease may persist well into adulthood, affecting 8% of adults aged 25 and 34 years.¹ Acne negatively impacts patients’ quality of life and productivity, with an estimated direct and indirect cost of over $3 billion per year.²

Oral isotretinoin, a vitamin A derivative, is approved by the US Food and Drug Administration for the treatment of severe nodulocystic acne. Isotretinoin reduces the size and secretions of sebaceous glands, inhibits growth and resulting inflammation of Cutibacterium acnes, and normalizes the differentiation of follicular keratinocytes, resulting in permanent changes in the pathogenesis of acne that may lead to remission.³ The use of oral isotretinoin in the active-duty US Military population may cause service members to be nondeployable or limit their ability to function in special roles (eg, pilot, submariner).⁴ Treatment regimens that minimize the course duration of isotretinoin and reduce the risk for relapse that requires a retrial of isotretinoin may, in turn, increase a service member’s readiness, deployment availability, and ability to perform unique occupational roles.

Additionally, teledermatology has been increasingly utilized to maintain treatment continuity for patients on isotretinoin during the COVID-19 pandemic.⁵ Application of this technology in the military also may be used to facilitate timely isotretinoin treatment regimens in active-duty service members to minimize course duration and increase readiness.

In this article, we discuss an accelerated course of oral isotretinoin as a safe and effective option for military service members bound by duty restrictions and operational timelines and explore the role of teledermatology for the treatment of acne in military service members.

Isotretinoin for Acne

Isotretinoin typically is initiated at a dosage of 0.5 mg/kg daily, increasing to 1 mg/kg daily with a goal cumulative dose between 120 and 150 mg/kg. Relapse may occur after completing a treatment course and is associated with cumulative dosing less than 120 mg/kg.⁶ The average duration of acne treatment with oral isotretinoin is approximately 6 months.⁷ At therapeutic doses, nearly all patients experience side effects, most commonly dryness and desquamation of the skin and mucous membranes, as well as possible involvement of the lips, eyes, and nose. Notable extracutaneous side effects include headache, visual disturbances at night, idiopathic intracranial hypertension, and myalgia. Serum cholesterol, triglycerides, and transaminases may be increased in patients taking isotretinoin, which requires routine monitoring using serum lipid profiles and liver function studies. A potential association between isotretinoin and inflammatory bowel disease and changes in mood have been reported, but current data do not suggest an evidence-based link.^6,8 Isotretinoin is a potent teratogen, and in the United States, all patients are required to enroll in iPLEDGE, a US Food and Drug Administration–approved pregnancy prevention program that monitors prescribing and dispensing of the medication. For patients who can become pregnant, iPLEDGE requires use of 2 forms of contraception as well as monthly pregnancy tests prior to dispensing the medication.

Acne in Military Service Members

Acne is exceedingly common in the active-duty military population. In 2018, more than 40% of soldiers, sailors, airmen, and marines were 25 years or younger, and 75% of all US service members were 35 years or younger, corresponding to acne peak incidences.^1,9 Management of acne in this population requires unique treatment considerations due to distinctive occupational requirements of and hazards faced by military personnel. Use of personal protective equipment, including gas masks, safety restraints, parachute rigging, and flak jackets, may be limiting in individuals with moderate to severe acne.¹⁰ For example, severe nodulocystic acne on the chin and jawline can interfere with proper wear of the chin strap on a Kevlar helmet. The severity of acne often necessitates the use of oral isotretinoin therapy, which is considered disqualifying for many special military assignments, including submarine duty, nuclear field duty, and diving duty.¹¹ In military aviation communities, oral isotretinoin requires grounding for the duration of therapy plus 3 months after cessation. Slit-lamp examination, triglycerides, and transaminase levels must be normal prior to returning to unrestricted duty.¹² Furthermore, use of oral isotretinoin may limit overseas assignments or deployment eligibility.⁴

The high prevalence of acne and the operationally limiting consequences of isotretinoin therapy present a unique challenge for dermatologists treating military personnel. The average duration of isotretinoin treatment is approximately 6 months,⁷ which represents a considerable amount of time during an average 4-year enlistment contract. Therapeutic treatment strategies that (1) reduce the duration of oral isotretinoin therapy, (2) reduce the risk for relapse, and (3) increase medication compliance can reduce the operational impact of this acne treatment. Such treatment strategies are discussed below.

 

 

High-Dose Isotretinoin

An optimal isotretinoin dosing regimen would achieve swift resolution of acne lesions and reduce the overall relapse rate requiring retrial of isotretinoin, thereby minimizing the operational- and duty-limiting impacts of the medication. Cyrulnik et al¹³ studied treatment outcomes of high-dose isotretinoin for acne vulgaris using a mean dosage of 1.6 mg/kg daily with an average cumulative dosage of 290 mg/kg. They demonstrated 100% clearance of lesions over 6 months, with a 12.5% relapse rate at 3 years. Aside from an increased rate of elevated transaminases, incidence of adverse effects and laboratory abnormalities were not significantly increased compared to conventional dosing regimens.¹³ The goal cumulative dosing of 120 to 150 mg/kg can be achieved 1 to 2 months earlier using a dosage of 1.6 mg/kg daily vs a conventional dosage of 1 mg/kg daily.

It has been hypothesized that higher cumulative doses of oral isotretinoin reduce the risk for relapse of acne and retrial of oral isotretinoin.¹⁴ Blasiak et al¹⁵ studied relapse and retrial of oral isotretinoin in acne patients who received cumulative dosing higher or lower than 220 mg/kg. A clinically but not statistically significant reduced relapse rate was observed in the cohort that received cumulative dosing higher than 220 mg/kg. No statistically significant difference in rates of adverse advents was observed aside from an increase in retinoid dermatitis in the cohort that received cumulative dosing higher than 220 mg/kg. Higher but not statistically significant rates of adverse events were seen in the group that received dosing higher than 220 mg/kg.¹⁵ Cumulative doses of oral isotretinoin higher than the 120 to 150 mg/kg range may decrease the risk for acne relapse and the need for an additional course of oral isotretinoin, which would reduce a service member’s total time away from deployment and full duty.

Relapse requiring a retrial of oral isotretinoin not only increases the operational cost of acne treatment but also considerably increases the monetary cost to the health care system. In a cost-analysis model, cumulative doses of oral isotretinoin higher than 230 mg/kg have a decreased overall cost compared to traditional cumulative dosing of less than 150 mg/kg due to the cost of relapse.¹⁶

Limitations of high daily and cumulative dosing regimens of oral isotretinoin are chiefly the dose-dependent rate of adverse effects. Low-dose regimens are associated with a reduced risk of isotretinoin-related side effects.^6,17 Acute acne flares may be seen following initial administration of oral isotretinoin and are aggravated by increases in dosage.¹⁸ Isotretinoin-induced acne fulminans is a rare but devastating complication observed with high initial doses of oral isotretinoin in patients with severe acne.¹⁹ The risks and benefits of high daily and cumulatively dosed isotretinoin must be carefully considered in patients with severe acne.

Teledermatology: A Force for Readiness

The COVID-19 pandemic drastically changed the dermatology practice landscape with recommendations to cancel all elective outpatient visits in favor of teledermatology encounters.²⁰ This decreased access to care, which resulted in an increase in drug interruption for dermatology patients, including patients on oral isotretinoin.²¹ Teledermatology has been increasingly utilized to maintain continuity of care for the management of patients taking isotretinoin.⁵ Routine utilization of teledermatology evaluation in military practices could expedite care, decrease patient travel time, and allow for in-clinic visits to be utilized for higher-acuity concerns.²²

The use of teledermatology for uncomplicated oral isotretinoin management has the potential to increase medication compliance and decrease the amount of travel time for active-duty service members; for example, consider a military dermatology practice based in San Diego, California, that accepts referrals from military bases 3 hours away by car. After an initial consultation for consideration and initiation of oral isotretinoin, teledermatology appointments can save the active-duty service member 3 hours of travel time for each follow-up visit per month. This ultimately increases operational productivity, reduces barriers to accessing care, and improves patient satisfaction.²³

Although military personnel usually are located at duty stations for 2 to 4 years, training exercises and military vocational schools often temporarily take personnel away from their home station. These temporary-duty assignments have the potential to interrupt medical follow-up appointments and may cause delays in treatment for individuals who miss monthly isotretinoin visits. When deemed appropriate by the prescribing dermatologist, teledermatology allows for increased continuity of care for active-duty service members and maintenance of a therapeutic isotretinoin course despite temporary geographic displacement.

By facilitating regular follow-up appointments, teledermatology can minimize the amount of time an active-duty service member is on a course of oral isotretinoin, thereby reducing the operational and duty-limiting implications of the medication.

Final Thoughts

Acne is a common dermatologic concern within the active-duty military population. Oral isotretinoin is indicated for treatment-resistant moderate or severe acne; however, it limits the ability of service members to deploy and is disqualifying for special military assignments. High daily- and cumulative-dose isotretinoin treatment strategies can reduce the duration of therapy and may be associated with a decrease in acne relapse and the need for retrial. Teledermatology can increase access to care and facilitate the completion of oral isotretinoin courses in a timely manner. These treatment strategies may help mitigate the duty-limiting impact of oral isotretinoin therapy in military service members.

Acne vulgaris is an extremely common dermatologic disease affecting 40 to 50 million individuals in the United States each year, with a prevalence of 85% in adolescents and young adults aged 12 to 24 years. For some patients, the disease may persist well into adulthood, affecting 8% of adults aged 25 and 34 years.¹ Acne negatively impacts patients’ quality of life and productivity, with an estimated direct and indirect cost of over $3 billion per year.²

Oral isotretinoin, a vitamin A derivative, is approved by the US Food and Drug Administration for the treatment of severe nodulocystic acne. Isotretinoin reduces the size and secretions of sebaceous glands, inhibits growth and resulting inflammation of Cutibacterium acnes, and normalizes the differentiation of follicular keratinocytes, resulting in permanent changes in the pathogenesis of acne that may lead to remission.³ The use of oral isotretinoin in the active-duty US Military population may cause service members to be nondeployable or limit their ability to function in special roles (eg, pilot, submariner).⁴ Treatment regimens that minimize the course duration of isotretinoin and reduce the risk for relapse that requires a retrial of isotretinoin may, in turn, increase a service member’s readiness, deployment availability, and ability to perform unique occupational roles.

Additionally, teledermatology has been increasingly utilized to maintain treatment continuity for patients on isotretinoin during the COVID-19 pandemic.⁵ Application of this technology in the military also may be used to facilitate timely isotretinoin treatment regimens in active-duty service members to minimize course duration and increase readiness.

In this article, we discuss an accelerated course of oral isotretinoin as a safe and effective option for military service members bound by duty restrictions and operational timelines and explore the role of teledermatology for the treatment of acne in military service members.

Isotretinoin for Acne

Isotretinoin typically is initiated at a dosage of 0.5 mg/kg daily, increasing to 1 mg/kg daily with a goal cumulative dose between 120 and 150 mg/kg. Relapse may occur after completing a treatment course and is associated with cumulative dosing less than 120 mg/kg.⁶ The average duration of acne treatment with oral isotretinoin is approximately 6 months.⁷ At therapeutic doses, nearly all patients experience side effects, most commonly dryness and desquamation of the skin and mucous membranes, as well as possible involvement of the lips, eyes, and nose. Notable extracutaneous side effects include headache, visual disturbances at night, idiopathic intracranial hypertension, and myalgia. Serum cholesterol, triglycerides, and transaminases may be increased in patients taking isotretinoin, which requires routine monitoring using serum lipid profiles and liver function studies. A potential association between isotretinoin and inflammatory bowel disease and changes in mood have been reported, but current data do not suggest an evidence-based link.^6,8 Isotretinoin is a potent teratogen, and in the United States, all patients are required to enroll in iPLEDGE, a US Food and Drug Administration–approved pregnancy prevention program that monitors prescribing and dispensing of the medication. For patients who can become pregnant, iPLEDGE requires use of 2 forms of contraception as well as monthly pregnancy tests prior to dispensing the medication.

Acne in Military Service Members

Acne is exceedingly common in the active-duty military population. In 2018, more than 40% of soldiers, sailors, airmen, and marines were 25 years or younger, and 75% of all US service members were 35 years or younger, corresponding to acne peak incidences.^1,9 Management of acne in this population requires unique treatment considerations due to distinctive occupational requirements of and hazards faced by military personnel. Use of personal protective equipment, including gas masks, safety restraints, parachute rigging, and flak jackets, may be limiting in individuals with moderate to severe acne.¹⁰ For example, severe nodulocystic acne on the chin and jawline can interfere with proper wear of the chin strap on a Kevlar helmet. The severity of acne often necessitates the use of oral isotretinoin therapy, which is considered disqualifying for many special military assignments, including submarine duty, nuclear field duty, and diving duty.¹¹ In military aviation communities, oral isotretinoin requires grounding for the duration of therapy plus 3 months after cessation. Slit-lamp examination, triglycerides, and transaminase levels must be normal prior to returning to unrestricted duty.¹² Furthermore, use of oral isotretinoin may limit overseas assignments or deployment eligibility.⁴

The high prevalence of acne and the operationally limiting consequences of isotretinoin therapy present a unique challenge for dermatologists treating military personnel. The average duration of isotretinoin treatment is approximately 6 months,⁷ which represents a considerable amount of time during an average 4-year enlistment contract. Therapeutic treatment strategies that (1) reduce the duration of oral isotretinoin therapy, (2) reduce the risk for relapse, and (3) increase medication compliance can reduce the operational impact of this acne treatment. Such treatment strategies are discussed below.

 

 

High-Dose Isotretinoin

An optimal isotretinoin dosing regimen would achieve swift resolution of acne lesions and reduce the overall relapse rate requiring retrial of isotretinoin, thereby minimizing the operational- and duty-limiting impacts of the medication. Cyrulnik et al¹³ studied treatment outcomes of high-dose isotretinoin for acne vulgaris using a mean dosage of 1.6 mg/kg daily with an average cumulative dosage of 290 mg/kg. They demonstrated 100% clearance of lesions over 6 months, with a 12.5% relapse rate at 3 years. Aside from an increased rate of elevated transaminases, incidence of adverse effects and laboratory abnormalities were not significantly increased compared to conventional dosing regimens.¹³ The goal cumulative dosing of 120 to 150 mg/kg can be achieved 1 to 2 months earlier using a dosage of 1.6 mg/kg daily vs a conventional dosage of 1 mg/kg daily.

It has been hypothesized that higher cumulative doses of oral isotretinoin reduce the risk for relapse of acne and retrial of oral isotretinoin.¹⁴ Blasiak et al¹⁵ studied relapse and retrial of oral isotretinoin in acne patients who received cumulative dosing higher or lower than 220 mg/kg. A clinically but not statistically significant reduced relapse rate was observed in the cohort that received cumulative dosing higher than 220 mg/kg. No statistically significant difference in rates of adverse advents was observed aside from an increase in retinoid dermatitis in the cohort that received cumulative dosing higher than 220 mg/kg. Higher but not statistically significant rates of adverse events were seen in the group that received dosing higher than 220 mg/kg.¹⁵ Cumulative doses of oral isotretinoin higher than the 120 to 150 mg/kg range may decrease the risk for acne relapse and the need for an additional course of oral isotretinoin, which would reduce a service member’s total time away from deployment and full duty.

Relapse requiring a retrial of oral isotretinoin not only increases the operational cost of acne treatment but also considerably increases the monetary cost to the health care system. In a cost-analysis model, cumulative doses of oral isotretinoin higher than 230 mg/kg have a decreased overall cost compared to traditional cumulative dosing of less than 150 mg/kg due to the cost of relapse.¹⁶

Limitations of high daily and cumulative dosing regimens of oral isotretinoin are chiefly the dose-dependent rate of adverse effects. Low-dose regimens are associated with a reduced risk of isotretinoin-related side effects.^6,17 Acute acne flares may be seen following initial administration of oral isotretinoin and are aggravated by increases in dosage.¹⁸ Isotretinoin-induced acne fulminans is a rare but devastating complication observed with high initial doses of oral isotretinoin in patients with severe acne.¹⁹ The risks and benefits of high daily and cumulatively dosed isotretinoin must be carefully considered in patients with severe acne.

Teledermatology: A Force for Readiness

The COVID-19 pandemic drastically changed the dermatology practice landscape with recommendations to cancel all elective outpatient visits in favor of teledermatology encounters.²⁰ This decreased access to care, which resulted in an increase in drug interruption for dermatology patients, including patients on oral isotretinoin.²¹ Teledermatology has been increasingly utilized to maintain continuity of care for the management of patients taking isotretinoin.⁵ Routine utilization of teledermatology evaluation in military practices could expedite care, decrease patient travel time, and allow for in-clinic visits to be utilized for higher-acuity concerns.²²

The use of teledermatology for uncomplicated oral isotretinoin management has the potential to increase medication compliance and decrease the amount of travel time for active-duty service members; for example, consider a military dermatology practice based in San Diego, California, that accepts referrals from military bases 3 hours away by car. After an initial consultation for consideration and initiation of oral isotretinoin, teledermatology appointments can save the active-duty service member 3 hours of travel time for each follow-up visit per month. This ultimately increases operational productivity, reduces barriers to accessing care, and improves patient satisfaction.²³

Although military personnel usually are located at duty stations for 2 to 4 years, training exercises and military vocational schools often temporarily take personnel away from their home station. These temporary-duty assignments have the potential to interrupt medical follow-up appointments and may cause delays in treatment for individuals who miss monthly isotretinoin visits. When deemed appropriate by the prescribing dermatologist, teledermatology allows for increased continuity of care for active-duty service members and maintenance of a therapeutic isotretinoin course despite temporary geographic displacement.

By facilitating regular follow-up appointments, teledermatology can minimize the amount of time an active-duty service member is on a course of oral isotretinoin, thereby reducing the operational and duty-limiting implications of the medication.

Final Thoughts

Acne is a common dermatologic concern within the active-duty military population. Oral isotretinoin is indicated for treatment-resistant moderate or severe acne; however, it limits the ability of service members to deploy and is disqualifying for special military assignments. High daily- and cumulative-dose isotretinoin treatment strategies can reduce the duration of therapy and may be associated with a decrease in acne relapse and the need for retrial. Teledermatology can increase access to care and facilitate the completion of oral isotretinoin courses in a timely manner. These treatment strategies may help mitigate the duty-limiting impact of oral isotretinoin therapy in military service members.

Acne vulgaris is an extremely common dermatologic disease affecting 40 to 50 million individuals in the United States each year, with a prevalence of 85% in adolescents and young adults aged 12 to 24 years. For some patients, the disease may persist well into adulthood, affecting 8% of adults aged 25 and 34 years.¹ Acne negatively impacts patients’ quality of life and productivity, with an estimated direct and indirect cost of over $3 billion per year.²

Oral isotretinoin, a vitamin A derivative, is approved by the US Food and Drug Administration for the treatment of severe nodulocystic acne. Isotretinoin reduces the size and secretions of sebaceous glands, inhibits growth and resulting inflammation of Cutibacterium acnes, and normalizes the differentiation of follicular keratinocytes, resulting in permanent changes in the pathogenesis of acne that may lead to remission.³ The use of oral isotretinoin in the active-duty US Military population may cause service members to be nondeployable or limit their ability to function in special roles (eg, pilot, submariner).⁴ Treatment regimens that minimize the course duration of isotretinoin and reduce the risk for relapse that requires a retrial of isotretinoin may, in turn, increase a service member’s readiness, deployment availability, and ability to perform unique occupational roles.

Additionally, teledermatology has been increasingly utilized to maintain treatment continuity for patients on isotretinoin during the COVID-19 pandemic.⁵ Application of this technology in the military also may be used to facilitate timely isotretinoin treatment regimens in active-duty service members to minimize course duration and increase readiness.

In this article, we discuss an accelerated course of oral isotretinoin as a safe and effective option for military service members bound by duty restrictions and operational timelines and explore the role of teledermatology for the treatment of acne in military service members.

Isotretinoin for Acne

Isotretinoin typically is initiated at a dosage of 0.5 mg/kg daily, increasing to 1 mg/kg daily with a goal cumulative dose between 120 and 150 mg/kg. Relapse may occur after completing a treatment course and is associated with cumulative dosing less than 120 mg/kg.⁶ The average duration of acne treatment with oral isotretinoin is approximately 6 months.⁷ At therapeutic doses, nearly all patients experience side effects, most commonly dryness and desquamation of the skin and mucous membranes, as well as possible involvement of the lips, eyes, and nose. Notable extracutaneous side effects include headache, visual disturbances at night, idiopathic intracranial hypertension, and myalgia. Serum cholesterol, triglycerides, and transaminases may be increased in patients taking isotretinoin, which requires routine monitoring using serum lipid profiles and liver function studies. A potential association between isotretinoin and inflammatory bowel disease and changes in mood have been reported, but current data do not suggest an evidence-based link.^6,8 Isotretinoin is a potent teratogen, and in the United States, all patients are required to enroll in iPLEDGE, a US Food and Drug Administration–approved pregnancy prevention program that monitors prescribing and dispensing of the medication. For patients who can become pregnant, iPLEDGE requires use of 2 forms of contraception as well as monthly pregnancy tests prior to dispensing the medication.

Acne in Military Service Members

Acne is exceedingly common in the active-duty military population. In 2018, more than 40% of soldiers, sailors, airmen, and marines were 25 years or younger, and 75% of all US service members were 35 years or younger, corresponding to acne peak incidences.^1,9 Management of acne in this population requires unique treatment considerations due to distinctive occupational requirements of and hazards faced by military personnel. Use of personal protective equipment, including gas masks, safety restraints, parachute rigging, and flak jackets, may be limiting in individuals with moderate to severe acne.¹⁰ For example, severe nodulocystic acne on the chin and jawline can interfere with proper wear of the chin strap on a Kevlar helmet. The severity of acne often necessitates the use of oral isotretinoin therapy, which is considered disqualifying for many special military assignments, including submarine duty, nuclear field duty, and diving duty.¹¹ In military aviation communities, oral isotretinoin requires grounding for the duration of therapy plus 3 months after cessation. Slit-lamp examination, triglycerides, and transaminase levels must be normal prior to returning to unrestricted duty.¹² Furthermore, use of oral isotretinoin may limit overseas assignments or deployment eligibility.⁴

The high prevalence of acne and the operationally limiting consequences of isotretinoin therapy present a unique challenge for dermatologists treating military personnel. The average duration of isotretinoin treatment is approximately 6 months,⁷ which represents a considerable amount of time during an average 4-year enlistment contract. Therapeutic treatment strategies that (1) reduce the duration of oral isotretinoin therapy, (2) reduce the risk for relapse, and (3) increase medication compliance can reduce the operational impact of this acne treatment. Such treatment strategies are discussed below.

 

 

High-Dose Isotretinoin

An optimal isotretinoin dosing regimen would achieve swift resolution of acne lesions and reduce the overall relapse rate requiring retrial of isotretinoin, thereby minimizing the operational- and duty-limiting impacts of the medication. Cyrulnik et al¹³ studied treatment outcomes of high-dose isotretinoin for acne vulgaris using a mean dosage of 1.6 mg/kg daily with an average cumulative dosage of 290 mg/kg. They demonstrated 100% clearance of lesions over 6 months, with a 12.5% relapse rate at 3 years. Aside from an increased rate of elevated transaminases, incidence of adverse effects and laboratory abnormalities were not significantly increased compared to conventional dosing regimens.¹³ The goal cumulative dosing of 120 to 150 mg/kg can be achieved 1 to 2 months earlier using a dosage of 1.6 mg/kg daily vs a conventional dosage of 1 mg/kg daily.

It has been hypothesized that higher cumulative doses of oral isotretinoin reduce the risk for relapse of acne and retrial of oral isotretinoin.¹⁴ Blasiak et al¹⁵ studied relapse and retrial of oral isotretinoin in acne patients who received cumulative dosing higher or lower than 220 mg/kg. A clinically but not statistically significant reduced relapse rate was observed in the cohort that received cumulative dosing higher than 220 mg/kg. No statistically significant difference in rates of adverse advents was observed aside from an increase in retinoid dermatitis in the cohort that received cumulative dosing higher than 220 mg/kg. Higher but not statistically significant rates of adverse events were seen in the group that received dosing higher than 220 mg/kg.¹⁵ Cumulative doses of oral isotretinoin higher than the 120 to 150 mg/kg range may decrease the risk for acne relapse and the need for an additional course of oral isotretinoin, which would reduce a service member’s total time away from deployment and full duty.

Relapse requiring a retrial of oral isotretinoin not only increases the operational cost of acne treatment but also considerably increases the monetary cost to the health care system. In a cost-analysis model, cumulative doses of oral isotretinoin higher than 230 mg/kg have a decreased overall cost compared to traditional cumulative dosing of less than 150 mg/kg due to the cost of relapse.¹⁶

Limitations of high daily and cumulative dosing regimens of oral isotretinoin are chiefly the dose-dependent rate of adverse effects. Low-dose regimens are associated with a reduced risk of isotretinoin-related side effects.^6,17 Acute acne flares may be seen following initial administration of oral isotretinoin and are aggravated by increases in dosage.¹⁸ Isotretinoin-induced acne fulminans is a rare but devastating complication observed with high initial doses of oral isotretinoin in patients with severe acne.¹⁹ The risks and benefits of high daily and cumulatively dosed isotretinoin must be carefully considered in patients with severe acne.

Teledermatology: A Force for Readiness

The COVID-19 pandemic drastically changed the dermatology practice landscape with recommendations to cancel all elective outpatient visits in favor of teledermatology encounters.²⁰ This decreased access to care, which resulted in an increase in drug interruption for dermatology patients, including patients on oral isotretinoin.²¹ Teledermatology has been increasingly utilized to maintain continuity of care for the management of patients taking isotretinoin.⁵ Routine utilization of teledermatology evaluation in military practices could expedite care, decrease patient travel time, and allow for in-clinic visits to be utilized for higher-acuity concerns.²²

The use of teledermatology for uncomplicated oral isotretinoin management has the potential to increase medication compliance and decrease the amount of travel time for active-duty service members; for example, consider a military dermatology practice based in San Diego, California, that accepts referrals from military bases 3 hours away by car. After an initial consultation for consideration and initiation of oral isotretinoin, teledermatology appointments can save the active-duty service member 3 hours of travel time for each follow-up visit per month. This ultimately increases operational productivity, reduces barriers to accessing care, and improves patient satisfaction.²³

Although military personnel usually are located at duty stations for 2 to 4 years, training exercises and military vocational schools often temporarily take personnel away from their home station. These temporary-duty assignments have the potential to interrupt medical follow-up appointments and may cause delays in treatment for individuals who miss monthly isotretinoin visits. When deemed appropriate by the prescribing dermatologist, teledermatology allows for increased continuity of care for active-duty service members and maintenance of a therapeutic isotretinoin course despite temporary geographic displacement.

By facilitating regular follow-up appointments, teledermatology can minimize the amount of time an active-duty service member is on a course of oral isotretinoin, thereby reducing the operational and duty-limiting implications of the medication.

Final Thoughts

Acne is a common dermatologic concern within the active-duty military population. Oral isotretinoin is indicated for treatment-resistant moderate or severe acne; however, it limits the ability of service members to deploy and is disqualifying for special military assignments. High daily- and cumulative-dose isotretinoin treatment strategies can reduce the duration of therapy and may be associated with a decrease in acne relapse and the need for retrial. Teledermatology can increase access to care and facilitate the completion of oral isotretinoin courses in a timely manner. These treatment strategies may help mitigate the duty-limiting impact of oral isotretinoin therapy in military service members.

The Diagnosis: Histiocytoid Sweet Syndrome

The patient was admitted for clinical study and treatment monitoring. During the first 72 hours of admittance, the lesions and general malaise further developed along with C-reactive protein elevation (126 mg/L). Administration of intravenous prednisone at a dosage of 1 mg/kg daily was accompanied by substantial improvement after 1 week of treatment, with subsequent follow-up and outpatient monitoring. An underlying neoplasia was ruled out after review of medical history, physical examination, complete blood cell count, chest radiography, abdominal ultrasonography, colonoscopy, and bone marrow aspiration.

A 4-mm skin biopsy was performed from a lesion on the neck (Figure 1). Histology revealed a dermis with prominent edema alongside superficial, deep, and periadnexal perivascular inflammatory infiltrates, as well as predominant lymphocytes and cells with a histiocytoid profile (Figure 2). These findings were accompanied by isolated neutrophil foci. The absence of leukocytoclastic vasculitis was noted. Immunohistochemistry demonstrated that the histiocyte population was positive for myeloperoxidase and CD68, which categorized them as immature cells of myeloid origin (Figure 3). Clinical and histopathologic findings led to a definitive diagnosis of histiocytoid Sweet syndrome (SS). Sweet syndrome consists of a neutrophilic dermatosis profile. Clinically, it manifests as a sudden onset of painful nodules and plaques accompanied by fever, malaise, and leukocytosis.

Histiocytoid SS is a rare histologic variant of SS initially described by Requena et al1 in 2005. In histiocytoid SS, the main inflammatory infiltrates are promyelocytes and myelocytes.² Immunohistochemistry shows positivity for myeloperoxidase, CD15, CD43, CD45, CD68, MAC-386, and HAM56.¹ The diagnosis is determined by exclusion after adequate clinical and histopathologic correlation, which also should exclude other diagnoses such as leukemia cutis and interstitial granulomatous dermatitis.³ Histiocytoid SS may be related to an increased risk for underlying malignancy. Haber et al⁴ performed a systematic review in which they concluded that approximately 40% of patients newly diagnosed with histiocytoid SS subsequently were diagnosed or already were diagnosed with a hematologic or solid cancer vs 21% in the classical neutrophilic infiltrate of SS (NSS). Histiocytoid SS more commonly was associated with myelodysplastic syndrome (46% vs 2.5% in NSS) and hematologic malignancies (42.5% vs 25% in SS).

The initial differential diagnoses include inflammatory dermatoses, infections, neoplasms, and systemic diseases. In exudative erythema multiforme, early lesions are composed of typical target lesions with mucosal involvement in 25% to 60% of patients.⁵ Erythema elevatum diutinum is a chronic dermatosis characterized by asymptomatic papules and red-violet nodules. The most characteristic histologic finding is leukocytoclastic vasculitis.⁶ The absence of vasculitis is part of the major diagnostic criteria for SS.⁷ Wells syndrome is associated with general malaise, and edematous and erythematous-violet plaques or nodules appear on the limbs; however, it frequently is associated with eosinophilia in peripheral blood, and histology shows that the main cell population of the inflammatory infiltrate also is eosinophilic.⁸ Painful, superficial, and erosive blisters appear preferentially on the face and backs of the arms in bullous pyoderma gangrenosum. It usually is not associated with the typical systemic manifestations of SS (ie, fever, arthralgia, damage to target organs). On histopathology, the neutrophilic infiltrate is accompanied by subepidermal vesicles.⁹

Histiocytoid SS responds dramatically to corticosteroids. Other first-line treatments that avoid use of corticosteroids are colchicine, dapsone, and potassium iodide. Multiple treatments were attempted in our patient, including corticosteroids, methotrexate, dapsone, colchicine, and anakinra. Despite patients responding well to treatment, a possible underlying neoplasm, most frequently of hematologic origin, must be excluded.¹⁰

The Diagnosis: Histiocytoid Sweet Syndrome

The patient was admitted for clinical study and treatment monitoring. During the first 72 hours of admittance, the lesions and general malaise further developed along with C-reactive protein elevation (126 mg/L). Administration of intravenous prednisone at a dosage of 1 mg/kg daily was accompanied by substantial improvement after 1 week of treatment, with subsequent follow-up and outpatient monitoring. An underlying neoplasia was ruled out after review of medical history, physical examination, complete blood cell count, chest radiography, abdominal ultrasonography, colonoscopy, and bone marrow aspiration.

A 4-mm skin biopsy was performed from a lesion on the neck (Figure 1). Histology revealed a dermis with prominent edema alongside superficial, deep, and periadnexal perivascular inflammatory infiltrates, as well as predominant lymphocytes and cells with a histiocytoid profile (Figure 2). These findings were accompanied by isolated neutrophil foci. The absence of leukocytoclastic vasculitis was noted. Immunohistochemistry demonstrated that the histiocyte population was positive for myeloperoxidase and CD68, which categorized them as immature cells of myeloid origin (Figure 3). Clinical and histopathologic findings led to a definitive diagnosis of histiocytoid Sweet syndrome (SS). Sweet syndrome consists of a neutrophilic dermatosis profile. Clinically, it manifests as a sudden onset of painful nodules and plaques accompanied by fever, malaise, and leukocytosis.

Histiocytoid SS is a rare histologic variant of SS initially described by Requena et al1 in 2005. In histiocytoid SS, the main inflammatory infiltrates are promyelocytes and myelocytes.² Immunohistochemistry shows positivity for myeloperoxidase, CD15, CD43, CD45, CD68, MAC-386, and HAM56.¹ The diagnosis is determined by exclusion after adequate clinical and histopathologic correlation, which also should exclude other diagnoses such as leukemia cutis and interstitial granulomatous dermatitis.³ Histiocytoid SS may be related to an increased risk for underlying malignancy. Haber et al⁴ performed a systematic review in which they concluded that approximately 40% of patients newly diagnosed with histiocytoid SS subsequently were diagnosed or already were diagnosed with a hematologic or solid cancer vs 21% in the classical neutrophilic infiltrate of SS (NSS). Histiocytoid SS more commonly was associated with myelodysplastic syndrome (46% vs 2.5% in NSS) and hematologic malignancies (42.5% vs 25% in SS).

The initial differential diagnoses include inflammatory dermatoses, infections, neoplasms, and systemic diseases. In exudative erythema multiforme, early lesions are composed of typical target lesions with mucosal involvement in 25% to 60% of patients.⁵ Erythema elevatum diutinum is a chronic dermatosis characterized by asymptomatic papules and red-violet nodules. The most characteristic histologic finding is leukocytoclastic vasculitis.⁶ The absence of vasculitis is part of the major diagnostic criteria for SS.⁷ Wells syndrome is associated with general malaise, and edematous and erythematous-violet plaques or nodules appear on the limbs; however, it frequently is associated with eosinophilia in peripheral blood, and histology shows that the main cell population of the inflammatory infiltrate also is eosinophilic.⁸ Painful, superficial, and erosive blisters appear preferentially on the face and backs of the arms in bullous pyoderma gangrenosum. It usually is not associated with the typical systemic manifestations of SS (ie, fever, arthralgia, damage to target organs). On histopathology, the neutrophilic infiltrate is accompanied by subepidermal vesicles.⁹

Histiocytoid SS responds dramatically to corticosteroids. Other first-line treatments that avoid use of corticosteroids are colchicine, dapsone, and potassium iodide. Multiple treatments were attempted in our patient, including corticosteroids, methotrexate, dapsone, colchicine, and anakinra. Despite patients responding well to treatment, a possible underlying neoplasm, most frequently of hematologic origin, must be excluded.¹⁰

The Diagnosis: Histiocytoid Sweet Syndrome

The patient was admitted for clinical study and treatment monitoring. During the first 72 hours of admittance, the lesions and general malaise further developed along with C-reactive protein elevation (126 mg/L). Administration of intravenous prednisone at a dosage of 1 mg/kg daily was accompanied by substantial improvement after 1 week of treatment, with subsequent follow-up and outpatient monitoring. An underlying neoplasia was ruled out after review of medical history, physical examination, complete blood cell count, chest radiography, abdominal ultrasonography, colonoscopy, and bone marrow aspiration.

A 4-mm skin biopsy was performed from a lesion on the neck (Figure 1). Histology revealed a dermis with prominent edema alongside superficial, deep, and periadnexal perivascular inflammatory infiltrates, as well as predominant lymphocytes and cells with a histiocytoid profile (Figure 2). These findings were accompanied by isolated neutrophil foci. The absence of leukocytoclastic vasculitis was noted. Immunohistochemistry demonstrated that the histiocyte population was positive for myeloperoxidase and CD68, which categorized them as immature cells of myeloid origin (Figure 3). Clinical and histopathologic findings led to a definitive diagnosis of histiocytoid Sweet syndrome (SS). Sweet syndrome consists of a neutrophilic dermatosis profile. Clinically, it manifests as a sudden onset of painful nodules and plaques accompanied by fever, malaise, and leukocytosis.

Histiocytoid SS is a rare histologic variant of SS initially described by Requena et al1 in 2005. In histiocytoid SS, the main inflammatory infiltrates are promyelocytes and myelocytes.² Immunohistochemistry shows positivity for myeloperoxidase, CD15, CD43, CD45, CD68, MAC-386, and HAM56.¹ The diagnosis is determined by exclusion after adequate clinical and histopathologic correlation, which also should exclude other diagnoses such as leukemia cutis and interstitial granulomatous dermatitis.³ Histiocytoid SS may be related to an increased risk for underlying malignancy. Haber et al⁴ performed a systematic review in which they concluded that approximately 40% of patients newly diagnosed with histiocytoid SS subsequently were diagnosed or already were diagnosed with a hematologic or solid cancer vs 21% in the classical neutrophilic infiltrate of SS (NSS). Histiocytoid SS more commonly was associated with myelodysplastic syndrome (46% vs 2.5% in NSS) and hematologic malignancies (42.5% vs 25% in SS).

The initial differential diagnoses include inflammatory dermatoses, infections, neoplasms, and systemic diseases. In exudative erythema multiforme, early lesions are composed of typical target lesions with mucosal involvement in 25% to 60% of patients.⁵ Erythema elevatum diutinum is a chronic dermatosis characterized by asymptomatic papules and red-violet nodules. The most characteristic histologic finding is leukocytoclastic vasculitis.⁶ The absence of vasculitis is part of the major diagnostic criteria for SS.⁷ Wells syndrome is associated with general malaise, and edematous and erythematous-violet plaques or nodules appear on the limbs; however, it frequently is associated with eosinophilia in peripheral blood, and histology shows that the main cell population of the inflammatory infiltrate also is eosinophilic.⁸ Painful, superficial, and erosive blisters appear preferentially on the face and backs of the arms in bullous pyoderma gangrenosum. It usually is not associated with the typical systemic manifestations of SS (ie, fever, arthralgia, damage to target organs). On histopathology, the neutrophilic infiltrate is accompanied by subepidermal vesicles.⁹

Histiocytoid SS responds dramatically to corticosteroids. Other first-line treatments that avoid use of corticosteroids are colchicine, dapsone, and potassium iodide. Multiple treatments were attempted in our patient, including corticosteroids, methotrexate, dapsone, colchicine, and anakinra. Despite patients responding well to treatment, a possible underlying neoplasm, most frequently of hematologic origin, must be excluded.¹⁰

The Diagnosis: Kaposi Sarcoma

A punch biopsy of a lesion on the right side of the back revealed a diffuse, poorly circumscribed, spindle cell neoplasm of the papillary and reticular dermis with associated vascular and pseudovascular spaces distended by erythrocytes (Figure 1). Immunostaining was positive for human herpesvirus 8 (HHV-8)(Figure 2), ETS-related gene, CD31, and CD34 and negative for pan cytokeratin, confirming the diagnosis of Kaposi sarcoma (KS). Bacterial, fungal, and mycobacterial tissue cultures were negative. The patient was tested for HIV and referred to infectious disease and oncology. He subsequently was found to have HIV with a viral load greater than 1 million copies. He was started on antiretroviral therapy and Pneumocystis jirovecii pneumonia prophylaxis. Computed tomography of the chest, abdomen, and pelvis showed bilateral, multifocal, perihilar, flame-shaped consolidations suggestive of KS. The patient later disclosed having an intermittent dry cough of more than a year’s duration with occasional bright red blood per rectum after bowel movements. After workup, the patient was found to have cytomegalovirus esophagitis/gastritis and candidal esophagitis that were treated with valganciclovir and fluconazole, respectively.

Kaposi sarcoma is an angioproliferative, AIDSdefining disease associated with HHV-8. There are 4 types of KS as defined by the populations they affect. AIDS-associated KS occurs in individuals with HIV, as seen in our patient. It often is accompanied by extensive mucocutaneous and visceral lesions, as well as systemic symptoms such as fever, weight loss, and diarrhea.¹ Classic KS is a variant that presents in older men of Mediterranean, Eastern European, and South American descent. Cutaneous lesions typically are distributed on the lower extremities.^2,3 Endemic (African) KS is seen in HIV-negative children and young adults in equatorial Africa. It most commonly affects the lower extremities or lymph nodes and usually follows a more aggressive course.² Lastly, iatrogenic KS is associated with immunosuppressive medications or conditions, such as organ transplantation, chemotherapy, and rheumatologic disorders.^3,4

Kaposi sarcoma commonly presents as violaceous or dark red macules, patches, papules, plaques, and nodules on various parts of the body (Figure 3). Lesions typically begin as macules and progress into plaques or nodules. Our patient presented as a deceptively healthy young man with lesions at various stages of development. In addition to the skin and oral mucosa, the lungs, lymph nodes, and gastrointestinal tract commonly are involved in AIDS-associated KS.⁵ Patients may experience symptoms of internal involvement, including bleeding, hematochezia, odynophagia, or dyspnea.

The differential diagnosis includes conditions that can mimic KS, including bacillary angiomatosis, angioinvasive fungal disease, sarcoid, and other malignancies. A skin biopsy is the gold standard for definitive diagnosis of KS. Histopathology shows a vascular proliferation in the dermis and spindle cell proliferation.⁶ Kaposi sarcoma stains positively for factor VIII–related antigen, CD31, and CD34.² Additionally, staining for HHV-8 gene products, such as latency-associated nuclear antigen 1, is helpful in differentiating KS from other conditions.⁷

In HIV-associated KS, the mainstay of treatment is initiation of highly active antiretroviral therapy. Typically, as the CD4 count rises with treatment, the tumor burden classic KS, effective treatment options include recurrent cryotherapy or intralesional chemotherapeutics, such as vincristine, for localized lesions; for widespread disease, pegylated liposomal doxorubicin or radiation have been found to be effective options. Lastly, for patients with iatrogenic KS, reducing immunosuppressive medications is a reasonable first step in management. If this does not yield adequate improvement, transitioning from calcineurin inhibitors (eg, cyclosporine) to proliferation signal inhibitors (eg, sirolimus) may lead to resolution.⁷

The Diagnosis: Kaposi Sarcoma

A punch biopsy of a lesion on the right side of the back revealed a diffuse, poorly circumscribed, spindle cell neoplasm of the papillary and reticular dermis with associated vascular and pseudovascular spaces distended by erythrocytes (Figure 1). Immunostaining was positive for human herpesvirus 8 (HHV-8)(Figure 2), ETS-related gene, CD31, and CD34 and negative for pan cytokeratin, confirming the diagnosis of Kaposi sarcoma (KS). Bacterial, fungal, and mycobacterial tissue cultures were negative. The patient was tested for HIV and referred to infectious disease and oncology. He subsequently was found to have HIV with a viral load greater than 1 million copies. He was started on antiretroviral therapy and Pneumocystis jirovecii pneumonia prophylaxis. Computed tomography of the chest, abdomen, and pelvis showed bilateral, multifocal, perihilar, flame-shaped consolidations suggestive of KS. The patient later disclosed having an intermittent dry cough of more than a year’s duration with occasional bright red blood per rectum after bowel movements. After workup, the patient was found to have cytomegalovirus esophagitis/gastritis and candidal esophagitis that were treated with valganciclovir and fluconazole, respectively.

Kaposi sarcoma is an angioproliferative, AIDSdefining disease associated with HHV-8. There are 4 types of KS as defined by the populations they affect. AIDS-associated KS occurs in individuals with HIV, as seen in our patient. It often is accompanied by extensive mucocutaneous and visceral lesions, as well as systemic symptoms such as fever, weight loss, and diarrhea.¹ Classic KS is a variant that presents in older men of Mediterranean, Eastern European, and South American descent. Cutaneous lesions typically are distributed on the lower extremities.^2,3 Endemic (African) KS is seen in HIV-negative children and young adults in equatorial Africa. It most commonly affects the lower extremities or lymph nodes and usually follows a more aggressive course.² Lastly, iatrogenic KS is associated with immunosuppressive medications or conditions, such as organ transplantation, chemotherapy, and rheumatologic disorders.^3,4

Kaposi sarcoma commonly presents as violaceous or dark red macules, patches, papules, plaques, and nodules on various parts of the body (Figure 3). Lesions typically begin as macules and progress into plaques or nodules. Our patient presented as a deceptively healthy young man with lesions at various stages of development. In addition to the skin and oral mucosa, the lungs, lymph nodes, and gastrointestinal tract commonly are involved in AIDS-associated KS.⁵ Patients may experience symptoms of internal involvement, including bleeding, hematochezia, odynophagia, or dyspnea.

The differential diagnosis includes conditions that can mimic KS, including bacillary angiomatosis, angioinvasive fungal disease, sarcoid, and other malignancies. A skin biopsy is the gold standard for definitive diagnosis of KS. Histopathology shows a vascular proliferation in the dermis and spindle cell proliferation.⁶ Kaposi sarcoma stains positively for factor VIII–related antigen, CD31, and CD34.² Additionally, staining for HHV-8 gene products, such as latency-associated nuclear antigen 1, is helpful in differentiating KS from other conditions.⁷

In HIV-associated KS, the mainstay of treatment is initiation of highly active antiretroviral therapy. Typically, as the CD4 count rises with treatment, the tumor burden classic KS, effective treatment options include recurrent cryotherapy or intralesional chemotherapeutics, such as vincristine, for localized lesions; for widespread disease, pegylated liposomal doxorubicin or radiation have been found to be effective options. Lastly, for patients with iatrogenic KS, reducing immunosuppressive medications is a reasonable first step in management. If this does not yield adequate improvement, transitioning from calcineurin inhibitors (eg, cyclosporine) to proliferation signal inhibitors (eg, sirolimus) may lead to resolution.⁷

The Diagnosis: Kaposi Sarcoma

A punch biopsy of a lesion on the right side of the back revealed a diffuse, poorly circumscribed, spindle cell neoplasm of the papillary and reticular dermis with associated vascular and pseudovascular spaces distended by erythrocytes (Figure 1). Immunostaining was positive for human herpesvirus 8 (HHV-8)(Figure 2), ETS-related gene, CD31, and CD34 and negative for pan cytokeratin, confirming the diagnosis of Kaposi sarcoma (KS). Bacterial, fungal, and mycobacterial tissue cultures were negative. The patient was tested for HIV and referred to infectious disease and oncology. He subsequently was found to have HIV with a viral load greater than 1 million copies. He was started on antiretroviral therapy and Pneumocystis jirovecii pneumonia prophylaxis. Computed tomography of the chest, abdomen, and pelvis showed bilateral, multifocal, perihilar, flame-shaped consolidations suggestive of KS. The patient later disclosed having an intermittent dry cough of more than a year’s duration with occasional bright red blood per rectum after bowel movements. After workup, the patient was found to have cytomegalovirus esophagitis/gastritis and candidal esophagitis that were treated with valganciclovir and fluconazole, respectively.

Kaposi sarcoma is an angioproliferative, AIDSdefining disease associated with HHV-8. There are 4 types of KS as defined by the populations they affect. AIDS-associated KS occurs in individuals with HIV, as seen in our patient. It often is accompanied by extensive mucocutaneous and visceral lesions, as well as systemic symptoms such as fever, weight loss, and diarrhea.¹ Classic KS is a variant that presents in older men of Mediterranean, Eastern European, and South American descent. Cutaneous lesions typically are distributed on the lower extremities.^2,3 Endemic (African) KS is seen in HIV-negative children and young adults in equatorial Africa. It most commonly affects the lower extremities or lymph nodes and usually follows a more aggressive course.² Lastly, iatrogenic KS is associated with immunosuppressive medications or conditions, such as organ transplantation, chemotherapy, and rheumatologic disorders.^3,4

Kaposi sarcoma commonly presents as violaceous or dark red macules, patches, papules, plaques, and nodules on various parts of the body (Figure 3). Lesions typically begin as macules and progress into plaques or nodules. Our patient presented as a deceptively healthy young man with lesions at various stages of development. In addition to the skin and oral mucosa, the lungs, lymph nodes, and gastrointestinal tract commonly are involved in AIDS-associated KS.⁵ Patients may experience symptoms of internal involvement, including bleeding, hematochezia, odynophagia, or dyspnea.

The differential diagnosis includes conditions that can mimic KS, including bacillary angiomatosis, angioinvasive fungal disease, sarcoid, and other malignancies. A skin biopsy is the gold standard for definitive diagnosis of KS. Histopathology shows a vascular proliferation in the dermis and spindle cell proliferation.⁶ Kaposi sarcoma stains positively for factor VIII–related antigen, CD31, and CD34.² Additionally, staining for HHV-8 gene products, such as latency-associated nuclear antigen 1, is helpful in differentiating KS from other conditions.⁷

In HIV-associated KS, the mainstay of treatment is initiation of highly active antiretroviral therapy. Typically, as the CD4 count rises with treatment, the tumor burden classic KS, effective treatment options include recurrent cryotherapy or intralesional chemotherapeutics, such as vincristine, for localized lesions; for widespread disease, pegylated liposomal doxorubicin or radiation have been found to be effective options. Lastly, for patients with iatrogenic KS, reducing immunosuppressive medications is a reasonable first step in management. If this does not yield adequate improvement, transitioning from calcineurin inhibitors (eg, cyclosporine) to proliferation signal inhibitors (eg, sirolimus) may lead to resolution.⁷

Psoriasis vulgaris is a chronic inflammatory skin condition associated with notable elevation in helper T cell (T_H) production of T_H1/T_H17-mediated inflammatory cytokines, including IL-17A.¹ Upon binding of IL-17A to IL-17 receptors in the skin, an inflammatory cascade is triggered, resulting in the classic clinical appearance of psoriasis. Moderate to severe psoriasis often is managed by suppressing T_H1/T_H17-mediated inflammation using targeted immune therapy such as secukinumab, an IL-17A inhibitor.² Atopic dermatitis (AD), another chronic inflammatory dermatosis, is associated with substantial elevation in T_H2-mediated inflammatory cytokines, such as IL-4.³ Dupilumab, which interacts with IL-4R, disrupts the IL-4 and IL-13 signaling pathways and demonstrates considerable efficacy in the treatment of moderate to severe AD.⁴

A case series has shown that suppression of the T_H1/T_H17-mediated inflammation of psoriasis may paradoxically result in the development of T_H2-mediated AD.⁵ Similarly, a recent case report described a patient who developed psoriasis following treatment of AD with dupilumab.⁶ Herein, we describe a patient with a history of psoriasis that was well controlled with secukinumab who developed severe refractory erythrodermic AD that resolved with dupilumab treatment. Following clearance of AD with dupilumab, he exhibited psoriasis recurrence.

Case Report

A 39-year-old man with a lifelong history of psoriasis was admitted to the hospital for management of severe erythroderma. Four years prior, secukinumab was initiated for treatment of psoriasis, resulting in excellent clinical response. He discontinued secukinumab after 2 years of treatment because of insurance coverage issues and managed his condition with only topical corticosteroids. He restarted secukinumab 10 months before admission because of a psoriasis flare. Shortly after resuming secukinumab, he developed a severe exfoliative erythroderma that was not responsive to corticosteroids, etanercept, methotrexate, or ustekinumab.

On initial presentation, physical examination revealed diffuse erythema and scaling with associated edema of the face, trunk, and extremities (Figure 1). A biopsy from the patient’s right arm demonstrated a superficial perivascular inflammatory infiltrate composed of lymphocytes, histiocytes, and scattered eosinophils consistent with spongiotic dermatitis (Figure 2). Cyclosporine 225 mg twice daily and topical corticosteroids were started.

Over the next several months, the patient had several admissions secondary to recurrent skin abscesses in the setting of refractory erythroderma. He underwent trials of infliximab, corticosteroids, intravenous immunoglobulin, guselkumab, and acitretin with minimal improvement. He underwent an extensive laboratory and radiologic workup, which was notable for cyclical peripheral eosinophilia and elevated IgE levels correlating with the erythroderma flares. A second biopsy was obtained and continued to demonstrate changes consistent with AD.

Four months after the initial hospitalization, all psoriasis medications were stopped, and the patient was started on dupilumab 300 mg/2 mL every 2 weeks and an 8-week oral prednisone taper. This combination led to notable clinical improvement and resolution of peripheral eosinophilia. Several months after disease remission, he began to develop worsening erythema and pruritus on the trunk and extremities, followed by the development of new psoriatic lesions (Figure 3) with a biopsy consistent with psoriasis (Figure 4). The patient was continued on dupilumab, but cyclosporine was added. The patient self-discontinued dupilumab owing to injection-site discomfort and has been slowly weaning off oral cyclosporine with 1 to 2 remaining eczematous plaques and 1 to 2 psoriatic plaques managed by topical corticosteroids.

Comment

We present a patient with psoriasis that was well controlled on secukinumab who developed severe AD following treatment with secukinumab. The AD resolved following treatment with dupilumab and a tapering dose of prednisone. However, after several months of treatment with dupilumab alone, he began to develop psoriatic lesions again. This case supports findings in a case series describing the development of AD in patients with psoriasis treated with IL-17 inhibitors⁵ and a recent case report describing a patient with AD who developed psoriasis following treatment with an IL-4/IL-13 inhibitor.⁶

Recognized adverse effects demonstrate biologic medications’ contributions to both normal as well as aberrant immunologic responses. For example, IL-17 plays an essential role in innate and adaptive immune responses against infections at mucosal and cutaneous interfaces, as demonstrated by chronic mucocutaneous candidiasis in patients with genetic defects in IL-17–related pathways.⁷ Similarly, in patients taking IL-17 antagonists, an increase in the incidence of Candida infections has been observed.⁸ In patients with concurrent psoriasis and inflammatory bowel disease (IBD), treatment with IL-17 inhibitors is contraindicated due to the risk of exacerbating the IBD. This observation is somewhat paradoxical, as increased IL-17 release by T_H17 cells is implicated in the pathogenesis of IBD.⁹ Interestingly, it is now thought that IL-17 may play a protective role in T-cell–driven intestinal inflammation through induction of protective intestinal epithelial gene expression and increased mucosal defense against gut microbes, explaining the worsening of IBD in patients on IL-17 inhibitors.¹⁰ These adverse effects illustrate the complicated and varied roles biologic medications play in immunologic response.

Given that T_H1 and T_H2 exert opposing immune mechanisms, it is uncommon for psoriasis and AD to coexist in a single patient. However, patients who exhibit concurrent findings may represent a unique population in which psoriasis and AD coexist, perhaps because of an underlying genetic predisposition. Moreover, targeted treatment of pathways unique to these disease processes may result in paradoxical flaring of the nontargeted pathway. It also is possible that inhibition of a specific T-cell pathway in a subset of patients will result in an immunologic imbalance, favoring increased activity of the opposing pathway in the absence of coexisting disease. In the case presented here, the findings may be explained by secukinumab’s inhibition of T_H1/T_H17-mediated inflammation, which resulted in a shift to a T_H2-mediated inflammatory response manifesting as AD, as well as dupilumab’s inhibition of T_H2-mediated inflammation, which caused a shift back to T_H1-mediated inflammatory pathways. Additionally, for patients with changing morphologies exacerbated by biologic medications, alternative diagnoses, such as cutaneous T-cell lymphoma, may be considered.

Conclusion

We report an unusual case of secukinumab-induced AD in a patient with psoriasis that resolved following several months of treatment with dupilumab and a tapering dose of prednisone. Subsequently, this same patient developed re-emergence of psoriatic lesions with continued use of dupilumab, which was eventually discontinued by the patient despite appropriate disease control. In addition to illustrating the underlying pathophysiologic mechanisms of 2 common inflammatory dermatologic conditions, this case highlights how pharmacologic interventions targeted at specific immunologic pathways may have unintended consequences. Further investigation into the effects of targeted biologics on the T_H1/T_H2 immune axis is warranted to better understand the mechanism and possible implications of the phenotypic switching presented in this case.

Psoriasis vulgaris is a chronic inflammatory skin condition associated with notable elevation in helper T cell (T_H) production of T_H1/T_H17-mediated inflammatory cytokines, including IL-17A.¹ Upon binding of IL-17A to IL-17 receptors in the skin, an inflammatory cascade is triggered, resulting in the classic clinical appearance of psoriasis. Moderate to severe psoriasis often is managed by suppressing T_H1/T_H17-mediated inflammation using targeted immune therapy such as secukinumab, an IL-17A inhibitor.² Atopic dermatitis (AD), another chronic inflammatory dermatosis, is associated with substantial elevation in T_H2-mediated inflammatory cytokines, such as IL-4.³ Dupilumab, which interacts with IL-4R, disrupts the IL-4 and IL-13 signaling pathways and demonstrates considerable efficacy in the treatment of moderate to severe AD.⁴

A case series has shown that suppression of the T_H1/T_H17-mediated inflammation of psoriasis may paradoxically result in the development of T_H2-mediated AD.⁵ Similarly, a recent case report described a patient who developed psoriasis following treatment of AD with dupilumab.⁶ Herein, we describe a patient with a history of psoriasis that was well controlled with secukinumab who developed severe refractory erythrodermic AD that resolved with dupilumab treatment. Following clearance of AD with dupilumab, he exhibited psoriasis recurrence.

Case Report

A 39-year-old man with a lifelong history of psoriasis was admitted to the hospital for management of severe erythroderma. Four years prior, secukinumab was initiated for treatment of psoriasis, resulting in excellent clinical response. He discontinued secukinumab after 2 years of treatment because of insurance coverage issues and managed his condition with only topical corticosteroids. He restarted secukinumab 10 months before admission because of a psoriasis flare. Shortly after resuming secukinumab, he developed a severe exfoliative erythroderma that was not responsive to corticosteroids, etanercept, methotrexate, or ustekinumab.

On initial presentation, physical examination revealed diffuse erythema and scaling with associated edema of the face, trunk, and extremities (Figure 1). A biopsy from the patient’s right arm demonstrated a superficial perivascular inflammatory infiltrate composed of lymphocytes, histiocytes, and scattered eosinophils consistent with spongiotic dermatitis (Figure 2). Cyclosporine 225 mg twice daily and topical corticosteroids were started.

Over the next several months, the patient had several admissions secondary to recurrent skin abscesses in the setting of refractory erythroderma. He underwent trials of infliximab, corticosteroids, intravenous immunoglobulin, guselkumab, and acitretin with minimal improvement. He underwent an extensive laboratory and radiologic workup, which was notable for cyclical peripheral eosinophilia and elevated IgE levels correlating with the erythroderma flares. A second biopsy was obtained and continued to demonstrate changes consistent with AD.

Four months after the initial hospitalization, all psoriasis medications were stopped, and the patient was started on dupilumab 300 mg/2 mL every 2 weeks and an 8-week oral prednisone taper. This combination led to notable clinical improvement and resolution of peripheral eosinophilia. Several months after disease remission, he began to develop worsening erythema and pruritus on the trunk and extremities, followed by the development of new psoriatic lesions (Figure 3) with a biopsy consistent with psoriasis (Figure 4). The patient was continued on dupilumab, but cyclosporine was added. The patient self-discontinued dupilumab owing to injection-site discomfort and has been slowly weaning off oral cyclosporine with 1 to 2 remaining eczematous plaques and 1 to 2 psoriatic plaques managed by topical corticosteroids.

Comment

We present a patient with psoriasis that was well controlled on secukinumab who developed severe AD following treatment with secukinumab. The AD resolved following treatment with dupilumab and a tapering dose of prednisone. However, after several months of treatment with dupilumab alone, he began to develop psoriatic lesions again. This case supports findings in a case series describing the development of AD in patients with psoriasis treated with IL-17 inhibitors⁵ and a recent case report describing a patient with AD who developed psoriasis following treatment with an IL-4/IL-13 inhibitor.⁶

Recognized adverse effects demonstrate biologic medications’ contributions to both normal as well as aberrant immunologic responses. For example, IL-17 plays an essential role in innate and adaptive immune responses against infections at mucosal and cutaneous interfaces, as demonstrated by chronic mucocutaneous candidiasis in patients with genetic defects in IL-17–related pathways.⁷ Similarly, in patients taking IL-17 antagonists, an increase in the incidence of Candida infections has been observed.⁸ In patients with concurrent psoriasis and inflammatory bowel disease (IBD), treatment with IL-17 inhibitors is contraindicated due to the risk of exacerbating the IBD. This observation is somewhat paradoxical, as increased IL-17 release by T_H17 cells is implicated in the pathogenesis of IBD.⁹ Interestingly, it is now thought that IL-17 may play a protective role in T-cell–driven intestinal inflammation through induction of protective intestinal epithelial gene expression and increased mucosal defense against gut microbes, explaining the worsening of IBD in patients on IL-17 inhibitors.¹⁰ These adverse effects illustrate the complicated and varied roles biologic medications play in immunologic response.

Given that T_H1 and T_H2 exert opposing immune mechanisms, it is uncommon for psoriasis and AD to coexist in a single patient. However, patients who exhibit concurrent findings may represent a unique population in which psoriasis and AD coexist, perhaps because of an underlying genetic predisposition. Moreover, targeted treatment of pathways unique to these disease processes may result in paradoxical flaring of the nontargeted pathway. It also is possible that inhibition of a specific T-cell pathway in a subset of patients will result in an immunologic imbalance, favoring increased activity of the opposing pathway in the absence of coexisting disease. In the case presented here, the findings may be explained by secukinumab’s inhibition of T_H1/T_H17-mediated inflammation, which resulted in a shift to a T_H2-mediated inflammatory response manifesting as AD, as well as dupilumab’s inhibition of T_H2-mediated inflammation, which caused a shift back to T_H1-mediated inflammatory pathways. Additionally, for patients with changing morphologies exacerbated by biologic medications, alternative diagnoses, such as cutaneous T-cell lymphoma, may be considered.

Conclusion

We report an unusual case of secukinumab-induced AD in a patient with psoriasis that resolved following several months of treatment with dupilumab and a tapering dose of prednisone. Subsequently, this same patient developed re-emergence of psoriatic lesions with continued use of dupilumab, which was eventually discontinued by the patient despite appropriate disease control. In addition to illustrating the underlying pathophysiologic mechanisms of 2 common inflammatory dermatologic conditions, this case highlights how pharmacologic interventions targeted at specific immunologic pathways may have unintended consequences. Further investigation into the effects of targeted biologics on the T_H1/T_H2 immune axis is warranted to better understand the mechanism and possible implications of the phenotypic switching presented in this case.

Psoriasis vulgaris is a chronic inflammatory skin condition associated with notable elevation in helper T cell (T_H) production of T_H1/T_H17-mediated inflammatory cytokines, including IL-17A.¹ Upon binding of IL-17A to IL-17 receptors in the skin, an inflammatory cascade is triggered, resulting in the classic clinical appearance of psoriasis. Moderate to severe psoriasis often is managed by suppressing T_H1/T_H17-mediated inflammation using targeted immune therapy such as secukinumab, an IL-17A inhibitor.² Atopic dermatitis (AD), another chronic inflammatory dermatosis, is associated with substantial elevation in T_H2-mediated inflammatory cytokines, such as IL-4.³ Dupilumab, which interacts with IL-4R, disrupts the IL-4 and IL-13 signaling pathways and demonstrates considerable efficacy in the treatment of moderate to severe AD.⁴

A case series has shown that suppression of the T_H1/T_H17-mediated inflammation of psoriasis may paradoxically result in the development of T_H2-mediated AD.⁵ Similarly, a recent case report described a patient who developed psoriasis following treatment of AD with dupilumab.⁶ Herein, we describe a patient with a history of psoriasis that was well controlled with secukinumab who developed severe refractory erythrodermic AD that resolved with dupilumab treatment. Following clearance of AD with dupilumab, he exhibited psoriasis recurrence.

Case Report

A 39-year-old man with a lifelong history of psoriasis was admitted to the hospital for management of severe erythroderma. Four years prior, secukinumab was initiated for treatment of psoriasis, resulting in excellent clinical response. He discontinued secukinumab after 2 years of treatment because of insurance coverage issues and managed his condition with only topical corticosteroids. He restarted secukinumab 10 months before admission because of a psoriasis flare. Shortly after resuming secukinumab, he developed a severe exfoliative erythroderma that was not responsive to corticosteroids, etanercept, methotrexate, or ustekinumab.

On initial presentation, physical examination revealed diffuse erythema and scaling with associated edema of the face, trunk, and extremities (Figure 1). A biopsy from the patient’s right arm demonstrated a superficial perivascular inflammatory infiltrate composed of lymphocytes, histiocytes, and scattered eosinophils consistent with spongiotic dermatitis (Figure 2). Cyclosporine 225 mg twice daily and topical corticosteroids were started.

Over the next several months, the patient had several admissions secondary to recurrent skin abscesses in the setting of refractory erythroderma. He underwent trials of infliximab, corticosteroids, intravenous immunoglobulin, guselkumab, and acitretin with minimal improvement. He underwent an extensive laboratory and radiologic workup, which was notable for cyclical peripheral eosinophilia and elevated IgE levels correlating with the erythroderma flares. A second biopsy was obtained and continued to demonstrate changes consistent with AD.

Four months after the initial hospitalization, all psoriasis medications were stopped, and the patient was started on dupilumab 300 mg/2 mL every 2 weeks and an 8-week oral prednisone taper. This combination led to notable clinical improvement and resolution of peripheral eosinophilia. Several months after disease remission, he began to develop worsening erythema and pruritus on the trunk and extremities, followed by the development of new psoriatic lesions (Figure 3) with a biopsy consistent with psoriasis (Figure 4). The patient was continued on dupilumab, but cyclosporine was added. The patient self-discontinued dupilumab owing to injection-site discomfort and has been slowly weaning off oral cyclosporine with 1 to 2 remaining eczematous plaques and 1 to 2 psoriatic plaques managed by topical corticosteroids.

Comment

We present a patient with psoriasis that was well controlled on secukinumab who developed severe AD following treatment with secukinumab. The AD resolved following treatment with dupilumab and a tapering dose of prednisone. However, after several months of treatment with dupilumab alone, he began to develop psoriatic lesions again. This case supports findings in a case series describing the development of AD in patients with psoriasis treated with IL-17 inhibitors⁵ and a recent case report describing a patient with AD who developed psoriasis following treatment with an IL-4/IL-13 inhibitor.⁶

Recognized adverse effects demonstrate biologic medications’ contributions to both normal as well as aberrant immunologic responses. For example, IL-17 plays an essential role in innate and adaptive immune responses against infections at mucosal and cutaneous interfaces, as demonstrated by chronic mucocutaneous candidiasis in patients with genetic defects in IL-17–related pathways.⁷ Similarly, in patients taking IL-17 antagonists, an increase in the incidence of Candida infections has been observed.⁸ In patients with concurrent psoriasis and inflammatory bowel disease (IBD), treatment with IL-17 inhibitors is contraindicated due to the risk of exacerbating the IBD. This observation is somewhat paradoxical, as increased IL-17 release by T_H17 cells is implicated in the pathogenesis of IBD.⁹ Interestingly, it is now thought that IL-17 may play a protective role in T-cell–driven intestinal inflammation through induction of protective intestinal epithelial gene expression and increased mucosal defense against gut microbes, explaining the worsening of IBD in patients on IL-17 inhibitors.¹⁰ These adverse effects illustrate the complicated and varied roles biologic medications play in immunologic response.

Given that T_H1 and T_H2 exert opposing immune mechanisms, it is uncommon for psoriasis and AD to coexist in a single patient. However, patients who exhibit concurrent findings may represent a unique population in which psoriasis and AD coexist, perhaps because of an underlying genetic predisposition. Moreover, targeted treatment of pathways unique to these disease processes may result in paradoxical flaring of the nontargeted pathway. It also is possible that inhibition of a specific T-cell pathway in a subset of patients will result in an immunologic imbalance, favoring increased activity of the opposing pathway in the absence of coexisting disease. In the case presented here, the findings may be explained by secukinumab’s inhibition of T_H1/T_H17-mediated inflammation, which resulted in a shift to a T_H2-mediated inflammatory response manifesting as AD, as well as dupilumab’s inhibition of T_H2-mediated inflammation, which caused a shift back to T_H1-mediated inflammatory pathways. Additionally, for patients with changing morphologies exacerbated by biologic medications, alternative diagnoses, such as cutaneous T-cell lymphoma, may be considered.

Conclusion

We report an unusual case of secukinumab-induced AD in a patient with psoriasis that resolved following several months of treatment with dupilumab and a tapering dose of prednisone. Subsequently, this same patient developed re-emergence of psoriatic lesions with continued use of dupilumab, which was eventually discontinued by the patient despite appropriate disease control. In addition to illustrating the underlying pathophysiologic mechanisms of 2 common inflammatory dermatologic conditions, this case highlights how pharmacologic interventions targeted at specific immunologic pathways may have unintended consequences. Further investigation into the effects of targeted biologics on the T_H1/T_H2 immune axis is warranted to better understand the mechanism and possible implications of the phenotypic switching presented in this case.

Cutis Reviewers, JANUARY TO DECEMBER 2021

Jennifer L. Adams, MD

Brandon Adler, MD

Iris Ahronowitz, MD

Abdullah Aleisa, MD

Justin Bandino, MD

Robert Baran, MD

Naiara S. Barbosa, MD

Kristina R. Burke, MD

Craig Burkhart, MD

Jeffrey P. Callen, MD

Charles Camisa, MD

Ashley B. Crew, MD

Zoe Diana Draelos, MD

Joseph S. Eastern, MD

Nada Elbuluk, MD, MSc

Joseph C. English III, MD

Tammie C. Ferringer, MD

Bahar F. Firoz, MD, MPH

John R. Griffin, MD

Kristi Hawley, DO

Thomas N. Helm, MD

Stephen Ellsworth Helms, MD

Brian P. Hibler, MD

Ranella J. Hirsch, MD

Jenny Hu, MD, MPH

Erick Jacobson-Dunlop, MD

William D. James, MD

Camilla K. Janniger, MD

Ronald Belle Johnston Jr, MD

Theodora Karagounis, MD

Michael Kasperkiewicz, MD

Brett H. Keeling, MD

Chesahna Kindred, MD, MBA

Christina Nicole Kraus, MD

Eun Ji Kwon, MD

Eden Lake, MD

Nicholas Logemann, DO

Michele S. Maroon, MD

Cathy Massoud, MD

Elizabeth I. McBurney, MD

Lynn J. McKinley-Grant, MD

Amy J. McMichael, MD

Darius R. Mehregan, MD

Jon Hamilton Meyerle, MD

Robert Micheletti, MD

Binh Ngo, MD

Anh Nguyen, MD

Josephine Nguyen, MD, MHCDS

Joe Niamtu III, DMD

Rajiv I. Nijhawan, MD

Michael A. Nowak, MD

Maria T. Ochoa, MD

Chika Ohata, MD

Lawrence C. Parish, MD

Marion Apter Quinn, MD

Phoebe Rich, MD

Maureen Riegert, MD

Bethany Rohr, MD

Lorraine L. Rosamilia, MD

Ted Rosen, MD

Robert I. Rudolph, MD

Elizabeth K. Satter, MD, MPH

Robert A. Schwartz, MD, MPH

Michael J. Scott III, DO, MD, MPH

Jane Scribner, MD

Bridget E. Shields, MD

Daniel Mark Siegel, MD, MS

Nanette B. Silverberg, MD

Steven Brett Sloan, MD

Leonard Sperling, MD

Stephen P. Stone, MD

Brian L. Swick, MD

Susan C. Taylor, MD

Manuel Valdebran, MD

Richard F. Wagner Jr, MD

Emily Wong, MD

Julie Woodward, MD

Scott Worswick, MD

Julia Wu, MD

If you are interested in serving as a reviewer, please email the Editorial Office at [email protected].

Cutis Reviewers, JANUARY TO DECEMBER 2021

Jennifer L. Adams, MD

Brandon Adler, MD

Iris Ahronowitz, MD

Abdullah Aleisa, MD

Justin Bandino, MD

Robert Baran, MD

Naiara S. Barbosa, MD

Kristina R. Burke, MD

Craig Burkhart, MD

Jeffrey P. Callen, MD

Charles Camisa, MD

Ashley B. Crew, MD

Zoe Diana Draelos, MD

Joseph S. Eastern, MD

Nada Elbuluk, MD, MSc

Joseph C. English III, MD

Tammie C. Ferringer, MD

Bahar F. Firoz, MD, MPH

John R. Griffin, MD

Kristi Hawley, DO

Thomas N. Helm, MD

Stephen Ellsworth Helms, MD

Brian P. Hibler, MD

Ranella J. Hirsch, MD

Jenny Hu, MD, MPH

Erick Jacobson-Dunlop, MD

William D. James, MD

Camilla K. Janniger, MD

Ronald Belle Johnston Jr, MD

Theodora Karagounis, MD

Michael Kasperkiewicz, MD

Brett H. Keeling, MD

Chesahna Kindred, MD, MBA

Christina Nicole Kraus, MD

Eun Ji Kwon, MD

Eden Lake, MD

Nicholas Logemann, DO

Michele S. Maroon, MD

Cathy Massoud, MD

Elizabeth I. McBurney, MD

Lynn J. McKinley-Grant, MD

Amy J. McMichael, MD

Darius R. Mehregan, MD

Jon Hamilton Meyerle, MD

Robert Micheletti, MD

Binh Ngo, MD

Anh Nguyen, MD

Josephine Nguyen, MD, MHCDS

Joe Niamtu III, DMD

Rajiv I. Nijhawan, MD

Michael A. Nowak, MD

Maria T. Ochoa, MD

Chika Ohata, MD

Lawrence C. Parish, MD

Marion Apter Quinn, MD

Phoebe Rich, MD

Maureen Riegert, MD

Bethany Rohr, MD

Lorraine L. Rosamilia, MD

Ted Rosen, MD

Robert I. Rudolph, MD

Elizabeth K. Satter, MD, MPH

Robert A. Schwartz, MD, MPH

Michael J. Scott III, DO, MD, MPH

Jane Scribner, MD

Bridget E. Shields, MD

Daniel Mark Siegel, MD, MS

Nanette B. Silverberg, MD

Steven Brett Sloan, MD

Leonard Sperling, MD

Stephen P. Stone, MD

Brian L. Swick, MD

Susan C. Taylor, MD

Manuel Valdebran, MD

Richard F. Wagner Jr, MD

Emily Wong, MD

Julie Woodward, MD

Scott Worswick, MD

Julia Wu, MD

If you are interested in serving as a reviewer, please email the Editorial Office at [email protected].

Cutis Reviewers, JANUARY TO DECEMBER 2021

Jennifer L. Adams, MD

Brandon Adler, MD

Iris Ahronowitz, MD

Abdullah Aleisa, MD

Justin Bandino, MD

Robert Baran, MD

Naiara S. Barbosa, MD

Kristina R. Burke, MD

Craig Burkhart, MD

Jeffrey P. Callen, MD

Charles Camisa, MD

Ashley B. Crew, MD

Zoe Diana Draelos, MD

Joseph S. Eastern, MD

Nada Elbuluk, MD, MSc

Joseph C. English III, MD

Tammie C. Ferringer, MD

Bahar F. Firoz, MD, MPH

John R. Griffin, MD

Kristi Hawley, DO

Thomas N. Helm, MD

Stephen Ellsworth Helms, MD

Brian P. Hibler, MD

Ranella J. Hirsch, MD

Jenny Hu, MD, MPH

Erick Jacobson-Dunlop, MD

William D. James, MD

Camilla K. Janniger, MD

Ronald Belle Johnston Jr, MD

Theodora Karagounis, MD

Michael Kasperkiewicz, MD

Brett H. Keeling, MD

Chesahna Kindred, MD, MBA

Christina Nicole Kraus, MD

Eun Ji Kwon, MD

Eden Lake, MD

Nicholas Logemann, DO

Michele S. Maroon, MD

Cathy Massoud, MD

Elizabeth I. McBurney, MD

Lynn J. McKinley-Grant, MD

Amy J. McMichael, MD

Darius R. Mehregan, MD

Jon Hamilton Meyerle, MD

Robert Micheletti, MD

Binh Ngo, MD

Anh Nguyen, MD

Josephine Nguyen, MD, MHCDS

Joe Niamtu III, DMD

Rajiv I. Nijhawan, MD

Michael A. Nowak, MD

Maria T. Ochoa, MD

Chika Ohata, MD

Lawrence C. Parish, MD

Marion Apter Quinn, MD

Phoebe Rich, MD

Maureen Riegert, MD

Bethany Rohr, MD

Lorraine L. Rosamilia, MD

Ted Rosen, MD

Robert I. Rudolph, MD

Elizabeth K. Satter, MD, MPH

Robert A. Schwartz, MD, MPH

Michael J. Scott III, DO, MD, MPH

Jane Scribner, MD

Bridget E. Shields, MD

Daniel Mark Siegel, MD, MS

Nanette B. Silverberg, MD

Steven Brett Sloan, MD

Leonard Sperling, MD

Stephen P. Stone, MD

Brian L. Swick, MD

Susan C. Taylor, MD

Manuel Valdebran, MD

Richard F. Wagner Jr, MD

Emily Wong, MD

Julie Woodward, MD

Scott Worswick, MD

Julia Wu, MD

If you are interested in serving as a reviewer, please email the Editorial Office at [email protected].