Cutis

The Diagnosis: Proximal-Type Epithelioid Sarcoma

Proximal-type epithelioid sarcoma (PES) is a rare high-grade sarcoma of uncertain histogenesis that may present with a benign clinical appearance. Proximal-type epithelioid sarcoma peaks at 20 to 40 years of age and has a slight male predominance. This tumor exhibits aggressive behavior with both local recurrence and metastasis.¹ The average overall survival is poor; however, tumor size less than 5 cm and complete excision with tumor-free margin status improves the prognosis.² Proximal-type epithelioid sarcoma should not be confused with distal-type epithelioid sarcoma, which has a better prognosis and occurs in younger patients.¹ Treatment of PES is wide excision, and chemotherapy trials with tazemetostat are ongoing.³

The deceptively banal clinical appearance of PES may delay appropriate diagnosis and treatment. Proximal-type epithelioid sarcoma often grows in sheets (quiz image [top] inset) and loose nests1 but also may take on a more corded appearance mimicking myoepithelial carcinoma. The cells themselves are plump dyscohesive epithelioid cells (quiz image [top]) with large nucleoli and eosinophilic cytoplasm or hyaline globules1 (quiz image [bottom]), but cells also may be focally spindled. Myxoid stroma, hemorrhage, and necrosis often are prominent features. Epithelioid sarcomas characteristically demonstrate positive immunostaining for both epithelial and mesenchymal markers (pan-cytokeratin and vimentin),¹ with the majority having loss of expression of integrase interactor 1 (INI-1).² Histology in this case was positive for cytokeratin monoclonal antibodies CAM5.2 and OSCAR, epithelial membrane antigen, and vimentin; it showed loss of INI-1 staining (quiz image [bottom]). Negative stains included S-100, p63, cytokeratins 7 and 20, CD34, CD31, ERG, glial fibrillary acidic protein, transducin-like enhancer of split 1, CD117, myogenin, synaptophysin, chromogranin, CD10, inhibin, CD99, and estrogen receptor.

The differential diagnosis of PES includes poorly differentiated squamous cell carcinoma (Figure 1 [inset]), melanoma, myoepithelial carcinoma, and epithelioid angiosarcoma. Primary squamous cell carcinoma of the vulva presents as an endophytic or exophytic mass with raised borders. Vulvar cancer is uncommon among gynecologic malignancies, with squamous cell carcinoma being the most commonly encountered.⁴ Vulvar intraepithelial neoplasia (VIN) is increasing in incidence, while the occurrence of invasive squamous cell carcinoma remains stable.⁵ Human papillomavirus–related VIN (usual-type VIN) is less likely to progress to squamous cell carcinoma than differentiated VIN (d-VIN), a dysplasia that is unrelated to human papillomavirus that frequently harbors p53 mutations.⁴ The presence of histologic epidermal involvement can help distinguish squamous cell carcinoma from PES (Figure 1). As opposed to PES, metastatic squamous cell carcinoma is characterized by intercellular bridges and often at least focal keratinization (Figure 1). Squamous cell carcinoma demonstrates positivity with p63 and p40 immunohistochemical stains, while PES rarely stains for either.⁶

Melanoma is the second most common vulvar malignancy. Vulvar melanoma tends to occur in women of advanced age but has been reported in girls as young as 10 years old.⁷ There is some evidence that patients with lichen sclerosus may be at an increased risk for the development of vulvar melanoma.⁸ Compared to PES, primary vulvar melanoma usually demonstrates epidermal involvement as well as clinical findings of a pigmented lesion (Figure 2). A notable minority of vulvar melanomas are amelanotic.⁹ Melanoma may be distinguished from PES with a panel of melanocytic markers—human melanoma black 45, Melan-A, SRY-box transcription factor 10, S-100, and microphthalmia transcription factor—that rarely are expressed in the latter. Both PES and rhabdoid melanoma have eosinophilic and tinctorial cytoplasmic inclusions.¹⁰ Melanin pigment and more cohesive nests are helpful clues that may point to melanoma when present.

Myoepithelial carcinoma of the vulva is rare.¹¹ Myoepithelial carcinoma of soft tissue is more aggressive than its benign counterpart, with up to a 50% metastasis rate.¹² The presence of prominent corded or trabecular growth in a myxoid or hyaline background may point to the diagnosis (Figure 3). Similar to PES, myoepithelial carcinoma may lose expression of nuclear INI-1, while myoepithelial carcinoma is more likely to express S-100 and glial fibrillary acidic protein.¹³ Rearrangements of EWS RNA binding protein 1, EWSR1, have been found in half of myoepithelial neoplasms.¹²

Angiosarcomas represent 5% of cutaneous sarcomas and rarely have been reported in the vulva, primarily occurring in the setting of long-standing lymphedema and radiation.¹⁴ Angiosarcoma more often occurs on the head and neck, breasts, or extremities. Additional risk factors for the development of angiosarcoma include toxin exposure (eg, polyvinyl chloride, thorium dioxide, arsenic), anabolic steroids, and filariasis, as well as genetic disorders (eg, neurofibromatosis type 1, BRCA gene mutations, Maffucci syndrome).¹⁵ Epithelioid angiosarcoma is an infiltrative tumor composed of irregular anastomosing vascular channels with extravasated erythrocytes (Figure 4). Solid growth and necrosis may be present in more aggressive tumors. The cells themselves are pleomorphic endothelial cells with vesicular chromatin and prominent nucleoli. Epithelioid angiosarcoma may resemble carcinoma and have focal keratin expression. However, the characteristic eosinophilic cytoplasm seen in PES should not be identified in epithelioid angiosarcoma. Unlike PES, epithelioid angiosarcoma is positive for CD31 and has retained expression for INI-1. Both angiosarcoma and proximal-type epithelioid sarcoma may express vascular markers CD34 and FLI-1¹⁶; thus an expanded panel of immunohistochemical studies may be of utility.

The Diagnosis: Proximal-Type Epithelioid Sarcoma

Proximal-type epithelioid sarcoma (PES) is a rare high-grade sarcoma of uncertain histogenesis that may present with a benign clinical appearance. Proximal-type epithelioid sarcoma peaks at 20 to 40 years of age and has a slight male predominance. This tumor exhibits aggressive behavior with both local recurrence and metastasis.¹ The average overall survival is poor; however, tumor size less than 5 cm and complete excision with tumor-free margin status improves the prognosis.² Proximal-type epithelioid sarcoma should not be confused with distal-type epithelioid sarcoma, which has a better prognosis and occurs in younger patients.¹ Treatment of PES is wide excision, and chemotherapy trials with tazemetostat are ongoing.³

The deceptively banal clinical appearance of PES may delay appropriate diagnosis and treatment. Proximal-type epithelioid sarcoma often grows in sheets (quiz image [top] inset) and loose nests1 but also may take on a more corded appearance mimicking myoepithelial carcinoma. The cells themselves are plump dyscohesive epithelioid cells (quiz image [top]) with large nucleoli and eosinophilic cytoplasm or hyaline globules1 (quiz image [bottom]), but cells also may be focally spindled. Myxoid stroma, hemorrhage, and necrosis often are prominent features. Epithelioid sarcomas characteristically demonstrate positive immunostaining for both epithelial and mesenchymal markers (pan-cytokeratin and vimentin),¹ with the majority having loss of expression of integrase interactor 1 (INI-1).² Histology in this case was positive for cytokeratin monoclonal antibodies CAM5.2 and OSCAR, epithelial membrane antigen, and vimentin; it showed loss of INI-1 staining (quiz image [bottom]). Negative stains included S-100, p63, cytokeratins 7 and 20, CD34, CD31, ERG, glial fibrillary acidic protein, transducin-like enhancer of split 1, CD117, myogenin, synaptophysin, chromogranin, CD10, inhibin, CD99, and estrogen receptor.

The differential diagnosis of PES includes poorly differentiated squamous cell carcinoma (Figure 1 [inset]), melanoma, myoepithelial carcinoma, and epithelioid angiosarcoma. Primary squamous cell carcinoma of the vulva presents as an endophytic or exophytic mass with raised borders. Vulvar cancer is uncommon among gynecologic malignancies, with squamous cell carcinoma being the most commonly encountered.⁴ Vulvar intraepithelial neoplasia (VIN) is increasing in incidence, while the occurrence of invasive squamous cell carcinoma remains stable.⁵ Human papillomavirus–related VIN (usual-type VIN) is less likely to progress to squamous cell carcinoma than differentiated VIN (d-VIN), a dysplasia that is unrelated to human papillomavirus that frequently harbors p53 mutations.⁴ The presence of histologic epidermal involvement can help distinguish squamous cell carcinoma from PES (Figure 1). As opposed to PES, metastatic squamous cell carcinoma is characterized by intercellular bridges and often at least focal keratinization (Figure 1). Squamous cell carcinoma demonstrates positivity with p63 and p40 immunohistochemical stains, while PES rarely stains for either.⁶

Melanoma is the second most common vulvar malignancy. Vulvar melanoma tends to occur in women of advanced age but has been reported in girls as young as 10 years old.⁷ There is some evidence that patients with lichen sclerosus may be at an increased risk for the development of vulvar melanoma.⁸ Compared to PES, primary vulvar melanoma usually demonstrates epidermal involvement as well as clinical findings of a pigmented lesion (Figure 2). A notable minority of vulvar melanomas are amelanotic.⁹ Melanoma may be distinguished from PES with a panel of melanocytic markers—human melanoma black 45, Melan-A, SRY-box transcription factor 10, S-100, and microphthalmia transcription factor—that rarely are expressed in the latter. Both PES and rhabdoid melanoma have eosinophilic and tinctorial cytoplasmic inclusions.¹⁰ Melanin pigment and more cohesive nests are helpful clues that may point to melanoma when present.

Myoepithelial carcinoma of the vulva is rare.¹¹ Myoepithelial carcinoma of soft tissue is more aggressive than its benign counterpart, with up to a 50% metastasis rate.¹² The presence of prominent corded or trabecular growth in a myxoid or hyaline background may point to the diagnosis (Figure 3). Similar to PES, myoepithelial carcinoma may lose expression of nuclear INI-1, while myoepithelial carcinoma is more likely to express S-100 and glial fibrillary acidic protein.¹³ Rearrangements of EWS RNA binding protein 1, EWSR1, have been found in half of myoepithelial neoplasms.¹²

Angiosarcomas represent 5% of cutaneous sarcomas and rarely have been reported in the vulva, primarily occurring in the setting of long-standing lymphedema and radiation.¹⁴ Angiosarcoma more often occurs on the head and neck, breasts, or extremities. Additional risk factors for the development of angiosarcoma include toxin exposure (eg, polyvinyl chloride, thorium dioxide, arsenic), anabolic steroids, and filariasis, as well as genetic disorders (eg, neurofibromatosis type 1, BRCA gene mutations, Maffucci syndrome).¹⁵ Epithelioid angiosarcoma is an infiltrative tumor composed of irregular anastomosing vascular channels with extravasated erythrocytes (Figure 4). Solid growth and necrosis may be present in more aggressive tumors. The cells themselves are pleomorphic endothelial cells with vesicular chromatin and prominent nucleoli. Epithelioid angiosarcoma may resemble carcinoma and have focal keratin expression. However, the characteristic eosinophilic cytoplasm seen in PES should not be identified in epithelioid angiosarcoma. Unlike PES, epithelioid angiosarcoma is positive for CD31 and has retained expression for INI-1. Both angiosarcoma and proximal-type epithelioid sarcoma may express vascular markers CD34 and FLI-1¹⁶; thus an expanded panel of immunohistochemical studies may be of utility.

The Diagnosis: Proximal-Type Epithelioid Sarcoma

Proximal-type epithelioid sarcoma (PES) is a rare high-grade sarcoma of uncertain histogenesis that may present with a benign clinical appearance. Proximal-type epithelioid sarcoma peaks at 20 to 40 years of age and has a slight male predominance. This tumor exhibits aggressive behavior with both local recurrence and metastasis.¹ The average overall survival is poor; however, tumor size less than 5 cm and complete excision with tumor-free margin status improves the prognosis.² Proximal-type epithelioid sarcoma should not be confused with distal-type epithelioid sarcoma, which has a better prognosis and occurs in younger patients.¹ Treatment of PES is wide excision, and chemotherapy trials with tazemetostat are ongoing.³

The deceptively banal clinical appearance of PES may delay appropriate diagnosis and treatment. Proximal-type epithelioid sarcoma often grows in sheets (quiz image [top] inset) and loose nests1 but also may take on a more corded appearance mimicking myoepithelial carcinoma. The cells themselves are plump dyscohesive epithelioid cells (quiz image [top]) with large nucleoli and eosinophilic cytoplasm or hyaline globules1 (quiz image [bottom]), but cells also may be focally spindled. Myxoid stroma, hemorrhage, and necrosis often are prominent features. Epithelioid sarcomas characteristically demonstrate positive immunostaining for both epithelial and mesenchymal markers (pan-cytokeratin and vimentin),¹ with the majority having loss of expression of integrase interactor 1 (INI-1).² Histology in this case was positive for cytokeratin monoclonal antibodies CAM5.2 and OSCAR, epithelial membrane antigen, and vimentin; it showed loss of INI-1 staining (quiz image [bottom]). Negative stains included S-100, p63, cytokeratins 7 and 20, CD34, CD31, ERG, glial fibrillary acidic protein, transducin-like enhancer of split 1, CD117, myogenin, synaptophysin, chromogranin, CD10, inhibin, CD99, and estrogen receptor.

The differential diagnosis of PES includes poorly differentiated squamous cell carcinoma (Figure 1 [inset]), melanoma, myoepithelial carcinoma, and epithelioid angiosarcoma. Primary squamous cell carcinoma of the vulva presents as an endophytic or exophytic mass with raised borders. Vulvar cancer is uncommon among gynecologic malignancies, with squamous cell carcinoma being the most commonly encountered.⁴ Vulvar intraepithelial neoplasia (VIN) is increasing in incidence, while the occurrence of invasive squamous cell carcinoma remains stable.⁵ Human papillomavirus–related VIN (usual-type VIN) is less likely to progress to squamous cell carcinoma than differentiated VIN (d-VIN), a dysplasia that is unrelated to human papillomavirus that frequently harbors p53 mutations.⁴ The presence of histologic epidermal involvement can help distinguish squamous cell carcinoma from PES (Figure 1). As opposed to PES, metastatic squamous cell carcinoma is characterized by intercellular bridges and often at least focal keratinization (Figure 1). Squamous cell carcinoma demonstrates positivity with p63 and p40 immunohistochemical stains, while PES rarely stains for either.⁶

Melanoma is the second most common vulvar malignancy. Vulvar melanoma tends to occur in women of advanced age but has been reported in girls as young as 10 years old.⁷ There is some evidence that patients with lichen sclerosus may be at an increased risk for the development of vulvar melanoma.⁸ Compared to PES, primary vulvar melanoma usually demonstrates epidermal involvement as well as clinical findings of a pigmented lesion (Figure 2). A notable minority of vulvar melanomas are amelanotic.⁹ Melanoma may be distinguished from PES with a panel of melanocytic markers—human melanoma black 45, Melan-A, SRY-box transcription factor 10, S-100, and microphthalmia transcription factor—that rarely are expressed in the latter. Both PES and rhabdoid melanoma have eosinophilic and tinctorial cytoplasmic inclusions.¹⁰ Melanin pigment and more cohesive nests are helpful clues that may point to melanoma when present.

Myoepithelial carcinoma of the vulva is rare.¹¹ Myoepithelial carcinoma of soft tissue is more aggressive than its benign counterpart, with up to a 50% metastasis rate.¹² The presence of prominent corded or trabecular growth in a myxoid or hyaline background may point to the diagnosis (Figure 3). Similar to PES, myoepithelial carcinoma may lose expression of nuclear INI-1, while myoepithelial carcinoma is more likely to express S-100 and glial fibrillary acidic protein.¹³ Rearrangements of EWS RNA binding protein 1, EWSR1, have been found in half of myoepithelial neoplasms.¹²

Angiosarcomas represent 5% of cutaneous sarcomas and rarely have been reported in the vulva, primarily occurring in the setting of long-standing lymphedema and radiation.¹⁴ Angiosarcoma more often occurs on the head and neck, breasts, or extremities. Additional risk factors for the development of angiosarcoma include toxin exposure (eg, polyvinyl chloride, thorium dioxide, arsenic), anabolic steroids, and filariasis, as well as genetic disorders (eg, neurofibromatosis type 1, BRCA gene mutations, Maffucci syndrome).¹⁵ Epithelioid angiosarcoma is an infiltrative tumor composed of irregular anastomosing vascular channels with extravasated erythrocytes (Figure 4). Solid growth and necrosis may be present in more aggressive tumors. The cells themselves are pleomorphic endothelial cells with vesicular chromatin and prominent nucleoli. Epithelioid angiosarcoma may resemble carcinoma and have focal keratin expression. However, the characteristic eosinophilic cytoplasm seen in PES should not be identified in epithelioid angiosarcoma. Unlike PES, epithelioid angiosarcoma is positive for CD31 and has retained expression for INI-1. Both angiosarcoma and proximal-type epithelioid sarcoma may express vascular markers CD34 and FLI-1¹⁶; thus an expanded panel of immunohistochemical studies may be of utility.

To the Editor:

The internet is a popular resource for patients seeking information about dermatologic treatments. Hydroquinone (HQ) cream 4% is approved by the US Food and Drug Administration for skin hyperpigmentation.¹ The agency enforced the CARES (Coronavirus Aid, Relief, and Economic Security) Act and OTC (over-the-counter) Monograph Reform on September 25, 2020, to restrict distribution of OTC HQ.² Exogenous ochronosis is listed as a potential adverse effect in the prescribing information for HQ.¹

We sought to assess online resources on HQ for accuracy of information, including the recent OTC ban, as well as readability. The word hydroquinone was searched on 3 internet search engines—Google, Yahoo, and Bing—on December 12, 2020, each for the first 20 URLs (ie, websites)(total of 60 URLs). Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA)(Figure) reporting guidelines were used to assess a list of relevant websites to include in the final analysis. Website data were reviewed by both authors. Eighteen duplicates and 27 irrelevant and non–English-language URLs were excluded. The remaining 15 websites were analyzed. Based on a previously published and validated tool, a pro forma was designed to evaluate information on HQ for each website based on accountability, quality, readability, display, support, and transparency (Table).^1,3

Scores for all 15 websites are listed in eTable 1. The mean overall (total) score was 25.3 points (of a maximum possible score of 44 points; range, 18–34). The average accountability score was 6.3 (of a possible 10; range, 3–10); average quality score, 10.9 (of a possible 17; range, 5–16); and average readability score, 2.1 (of a possible 5; range, 0–5).

The mean display score was 0.3 (of a possible 4; range, 0–2); 66.7% of websites (10/15) had advertisements or irrelevant material. Only 6.7% and 13.3% of websites included relevant videos or images, respectively, on applying HQ (eTable 2). We identified only 3 photographs—across all 15 websites—that depicted skin, all of which were Fitzpatrick skin types II or III. Therefore, none of the websites included a diversity of images to indicate broad ethnic relatability.

The average support score was 2.5 (of a possible 4; range, 1–3); 20% (3/15) of URLs included chat sites, message boards, or forums, and approximately half (8/15 [53.3%]) included references. Only 7 URLs (46.7%) had been updated in the last 12 months. Only 4 (26.7%) were written by a board-certified dermatologist (eTable 2). Most (60%) websites contained advertising, though none were sponsored by a pharmaceutical company that manufactures HQ.

Only 46.7% (7/15) of websites recommended limiting a course of HQ treatment to 3 months; only 40% (6/15) mentioned shelf life or photochemical degradation when exposed to air. Although 93.3% (14/15) of URLs mentioned ochronosis, a clinical description of the condition was provided in only 33.3% (5/15)—none with images.

Only 2 sites (13.3%; Everyday Health and WebMD) met the accepted 7th-grade reading level for online patient education material; those sites scored lower on quality (9 of 17 and 6 of 17, respectively) than sites with higher overall scores.

None of the 15 websites studied, therefore, demonstrated optimal features on combined measures of accountability, quality, readability, display, support, and transparency regarding HQ. Notably, the American Academy of Dermatology website (www.aad.org) was not among the 15 websites studied; the AAD website mentions HQ in a section on melasma, but only minimal detail is provided.

Limitations of this study include the small number of websites analyzed and possible selection bias because only 3 internet search engines were used to identify websites for study and analysis.

Previously, we analyzed content about HQ on the video-sharing and social media platform YouTube.⁴ The most viewed YouTube videos on HQ had poor-quality information (ie, only 20% mentioned ochronosis and only 28.6% recommended sunscreen [N=70]). However, average reading level of these videos was 7th grade.^4,5 Therefore, YouTube HQ content, though comprehensible, generally is of poor quality.

By conducting a search for website content about HQ, we found that the most popular URLs had either accurate information with poor readability or lower-quality educational material that was more comprehensible. We conclude that there is a need to develop online patient education materials on HQ that are characterized by high-quality, up-to-date medical information; have been written by board-certified dermatologists; are comprehensible (ie, no more than approximately 1200 words and written at a 7th-grade reading level); and contain relevant clinical images and references. We encourage dermatologists to recognize the limitations of online patient education resources on HQ and educate patients on the proper use of the drug as well as its potential adverse effects

To the Editor:

The internet is a popular resource for patients seeking information about dermatologic treatments. Hydroquinone (HQ) cream 4% is approved by the US Food and Drug Administration for skin hyperpigmentation.¹ The agency enforced the CARES (Coronavirus Aid, Relief, and Economic Security) Act and OTC (over-the-counter) Monograph Reform on September 25, 2020, to restrict distribution of OTC HQ.² Exogenous ochronosis is listed as a potential adverse effect in the prescribing information for HQ.¹

We sought to assess online resources on HQ for accuracy of information, including the recent OTC ban, as well as readability. The word hydroquinone was searched on 3 internet search engines—Google, Yahoo, and Bing—on December 12, 2020, each for the first 20 URLs (ie, websites)(total of 60 URLs). Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA)(Figure) reporting guidelines were used to assess a list of relevant websites to include in the final analysis. Website data were reviewed by both authors. Eighteen duplicates and 27 irrelevant and non–English-language URLs were excluded. The remaining 15 websites were analyzed. Based on a previously published and validated tool, a pro forma was designed to evaluate information on HQ for each website based on accountability, quality, readability, display, support, and transparency (Table).^1,3

Scores for all 15 websites are listed in eTable 1. The mean overall (total) score was 25.3 points (of a maximum possible score of 44 points; range, 18–34). The average accountability score was 6.3 (of a possible 10; range, 3–10); average quality score, 10.9 (of a possible 17; range, 5–16); and average readability score, 2.1 (of a possible 5; range, 0–5).

The mean display score was 0.3 (of a possible 4; range, 0–2); 66.7% of websites (10/15) had advertisements or irrelevant material. Only 6.7% and 13.3% of websites included relevant videos or images, respectively, on applying HQ (eTable 2). We identified only 3 photographs—across all 15 websites—that depicted skin, all of which were Fitzpatrick skin types II or III. Therefore, none of the websites included a diversity of images to indicate broad ethnic relatability.

The average support score was 2.5 (of a possible 4; range, 1–3); 20% (3/15) of URLs included chat sites, message boards, or forums, and approximately half (8/15 [53.3%]) included references. Only 7 URLs (46.7%) had been updated in the last 12 months. Only 4 (26.7%) were written by a board-certified dermatologist (eTable 2). Most (60%) websites contained advertising, though none were sponsored by a pharmaceutical company that manufactures HQ.

Only 46.7% (7/15) of websites recommended limiting a course of HQ treatment to 3 months; only 40% (6/15) mentioned shelf life or photochemical degradation when exposed to air. Although 93.3% (14/15) of URLs mentioned ochronosis, a clinical description of the condition was provided in only 33.3% (5/15)—none with images.

Only 2 sites (13.3%; Everyday Health and WebMD) met the accepted 7th-grade reading level for online patient education material; those sites scored lower on quality (9 of 17 and 6 of 17, respectively) than sites with higher overall scores.

None of the 15 websites studied, therefore, demonstrated optimal features on combined measures of accountability, quality, readability, display, support, and transparency regarding HQ. Notably, the American Academy of Dermatology website (www.aad.org) was not among the 15 websites studied; the AAD website mentions HQ in a section on melasma, but only minimal detail is provided.

Limitations of this study include the small number of websites analyzed and possible selection bias because only 3 internet search engines were used to identify websites for study and analysis.

Previously, we analyzed content about HQ on the video-sharing and social media platform YouTube.⁴ The most viewed YouTube videos on HQ had poor-quality information (ie, only 20% mentioned ochronosis and only 28.6% recommended sunscreen [N=70]). However, average reading level of these videos was 7th grade.^4,5 Therefore, YouTube HQ content, though comprehensible, generally is of poor quality.

By conducting a search for website content about HQ, we found that the most popular URLs had either accurate information with poor readability or lower-quality educational material that was more comprehensible. We conclude that there is a need to develop online patient education materials on HQ that are characterized by high-quality, up-to-date medical information; have been written by board-certified dermatologists; are comprehensible (ie, no more than approximately 1200 words and written at a 7th-grade reading level); and contain relevant clinical images and references. We encourage dermatologists to recognize the limitations of online patient education resources on HQ and educate patients on the proper use of the drug as well as its potential adverse effects

To the Editor:

The internet is a popular resource for patients seeking information about dermatologic treatments. Hydroquinone (HQ) cream 4% is approved by the US Food and Drug Administration for skin hyperpigmentation.¹ The agency enforced the CARES (Coronavirus Aid, Relief, and Economic Security) Act and OTC (over-the-counter) Monograph Reform on September 25, 2020, to restrict distribution of OTC HQ.² Exogenous ochronosis is listed as a potential adverse effect in the prescribing information for HQ.¹

We sought to assess online resources on HQ for accuracy of information, including the recent OTC ban, as well as readability. The word hydroquinone was searched on 3 internet search engines—Google, Yahoo, and Bing—on December 12, 2020, each for the first 20 URLs (ie, websites)(total of 60 URLs). Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA)(Figure) reporting guidelines were used to assess a list of relevant websites to include in the final analysis. Website data were reviewed by both authors. Eighteen duplicates and 27 irrelevant and non–English-language URLs were excluded. The remaining 15 websites were analyzed. Based on a previously published and validated tool, a pro forma was designed to evaluate information on HQ for each website based on accountability, quality, readability, display, support, and transparency (Table).^1,3

Scores for all 15 websites are listed in eTable 1. The mean overall (total) score was 25.3 points (of a maximum possible score of 44 points; range, 18–34). The average accountability score was 6.3 (of a possible 10; range, 3–10); average quality score, 10.9 (of a possible 17; range, 5–16); and average readability score, 2.1 (of a possible 5; range, 0–5).

The mean display score was 0.3 (of a possible 4; range, 0–2); 66.7% of websites (10/15) had advertisements or irrelevant material. Only 6.7% and 13.3% of websites included relevant videos or images, respectively, on applying HQ (eTable 2). We identified only 3 photographs—across all 15 websites—that depicted skin, all of which were Fitzpatrick skin types II or III. Therefore, none of the websites included a diversity of images to indicate broad ethnic relatability.

The average support score was 2.5 (of a possible 4; range, 1–3); 20% (3/15) of URLs included chat sites, message boards, or forums, and approximately half (8/15 [53.3%]) included references. Only 7 URLs (46.7%) had been updated in the last 12 months. Only 4 (26.7%) were written by a board-certified dermatologist (eTable 2). Most (60%) websites contained advertising, though none were sponsored by a pharmaceutical company that manufactures HQ.

Only 46.7% (7/15) of websites recommended limiting a course of HQ treatment to 3 months; only 40% (6/15) mentioned shelf life or photochemical degradation when exposed to air. Although 93.3% (14/15) of URLs mentioned ochronosis, a clinical description of the condition was provided in only 33.3% (5/15)—none with images.

Only 2 sites (13.3%; Everyday Health and WebMD) met the accepted 7th-grade reading level for online patient education material; those sites scored lower on quality (9 of 17 and 6 of 17, respectively) than sites with higher overall scores.

None of the 15 websites studied, therefore, demonstrated optimal features on combined measures of accountability, quality, readability, display, support, and transparency regarding HQ. Notably, the American Academy of Dermatology website (www.aad.org) was not among the 15 websites studied; the AAD website mentions HQ in a section on melasma, but only minimal detail is provided.

Limitations of this study include the small number of websites analyzed and possible selection bias because only 3 internet search engines were used to identify websites for study and analysis.

Previously, we analyzed content about HQ on the video-sharing and social media platform YouTube.⁴ The most viewed YouTube videos on HQ had poor-quality information (ie, only 20% mentioned ochronosis and only 28.6% recommended sunscreen [N=70]). However, average reading level of these videos was 7th grade.^4,5 Therefore, YouTube HQ content, though comprehensible, generally is of poor quality.

By conducting a search for website content about HQ, we found that the most popular URLs had either accurate information with poor readability or lower-quality educational material that was more comprehensible. We conclude that there is a need to develop online patient education materials on HQ that are characterized by high-quality, up-to-date medical information; have been written by board-certified dermatologists; are comprehensible (ie, no more than approximately 1200 words and written at a 7th-grade reading level); and contain relevant clinical images and references. We encourage dermatologists to recognize the limitations of online patient education resources on HQ and educate patients on the proper use of the drug as well as its potential adverse effects

According to the US Department of Defense, the term readiness refers to the ability to recruit, train, deploy, and sustain military forces that will be ready to “fight tonight” and succeed in combat. Readiness is a top priority for military medicine, which functions to diagnose, treat, and rehabilitate service members so that they can return to the fight. This central concept drives programs across the military—from operational training events to the establishment of medical and dental standards. Readiness is tracked and scrutinized constantly, and although it is a shared responsibility, efforts to increase and sustain readiness often fall on support staff and military medical providers.

In recent years, there has been a greater awareness of the negative effects of mental illness, low morale, and suicidality on military readiness. In 2013, suicide accounted for 28.1% of all deaths that occurred in the US Armed Forces.¹ Put frankly, suicide was one of the leading causes of death among military members.

The most recent Marine Corps Order regarding the Marine Corps Suicide Prevention Program stated that “suicidal behaviors are a barrier to readiness that have lasting effects on Marines and Service Members attached to Marine Commands. . .Families, and the Marine Corps.” It goes on to say that “[e]ffective suicide prevention requires coordinated efforts within a prevention framework dedicated to promoting mental, physical, spiritual, and social fitness. . .[and] mitigating stressors that interfere with mission readiness.”² This statement supports the notion that preventing suicide is not just about treating mental illness; it also involves maximizing physical, spiritual, and social fitness. Although it is well established that various mental health disorders are associated with an increased risk for suicide, it is worth noting that, in one study, only half of individuals who died by suicide had a mental health disorder diagnosed prior to their death.³ These statistics translate to the military. The 2015 Department of Defense Suicide Event Report noted that only 28% of service members who died by suicide and 22% of members with attempted suicide had been documented as having sought mental health care and disclosed their potential for self-harm prior to the event.^1,4 In 2018, a study published by Ursano et al⁵ showed that 36.3% of US soldiers with a documented suicide attempt (N=9650) had no prior mental health diagnoses.

Expanding the scope to include mental health issues in general, only 29% of service members who reported experiencing a mental health problem actually sought mental health care in that same period. Overall, approximately 40% of service members with a reported perceived need for mental health care actually sought care over their entire course of service time,¹ which raises concern for a large population of undiagnosed and undertreated mental illnesses across the military. In response to these statistics, Reger et al³ posited that it is “essential that suicide prevention efforts move outside the silo of mental health.” The authors went on to challenge health care providers across all specialties and civilians alike to take responsibility in understanding, recognizing, and mitigating risk factors for suicide in the general population.³ Although treating a service member’s acne or offering to stand duty for a service member who has been under a great deal of stress in their personal life may appear to be indirect ways of reducing suicide in the US military, they actually may be the most critical means of prevention in a culture that emphasizes resilience and self-reliance, where seeking help for mental health struggles could be perceived as weakness.¹

In this review article, we discuss the concept of cutaneous body image (CBI) and its associated outcomes on health, satisfaction, and quality of life in military service members. We then examine the intersections between common dermatologic conditions, CBI, and mental health and explore the ability and role of the military dermatologist to serve as a positive influence on military readiness.

What is cutaneous body image?

Cutaneous body image is “the individual’s mental perception of his or her skin and its appendages (ie, hair, nails).”⁶ It is measured objectively using the Cutaneous Body Image Scale, a questionnaire that includes 7 items related to the overall satisfaction with the appearance of skin, color of skin, skin of the face, complexion of the face, hair, fingernails, and toenails. Each question is rated using a 10-point Likert scale (0=not at all; 10=very markedly).⁶

Some degree of CBI dissatisfaction is expected and has been shown in the general population at large; for example, more than 56% of women older than 30 years report some degree of dissatisfaction with their skin. Similarly, data from the American Society of Plastic Surgeons showed that while 10.9 million cosmetic procedures were performed in 2006, 9.1 million of them involved minimally invasive procedures such as botulinum toxin type A injections with the purpose of skin rejuvenation and improvement of facial appearance.⁷ However, lower than average CBI can contribute to considerable psychosocial morbidity. Dissatisfaction with CBI is associated with self-consciousness, feelings of inferiority, and social exclusion. These symptoms can be grouped into a construct called interpersonal sensitivity (IS). A 2013 study by Gupta and Gupta⁶ investigated the relationship between CBI, IS, and suicidal ideation among 312 consenting nonclinical participants in Canada. The study found that greater dissatisfaction with an individual’s CBI correlated to increased IS and increased rates of suicidal ideation and intentional self-injury.⁶

Cutaneous body image is particularly relevant to dermatologists, as many common dermatoses can cause cosmetically disfiguring skin conditions; for example, acne and rosacea have the propensity to cause notable disfigurement to the facial unit. Other common conditions such as atopic dermatitis or psoriasis can flare with stress and thereby throw patients into a vicious cycle of physical and psychosocial stress caused by social stigma, cosmetic disfigurement, and reduced CBI, in turn leading to worsening of the disease at hand. Dermatologists need to be aware that common dermatoses can impact a patient’s mental health via poor CBI.⁸ Similarly, dermatologists may be empowered by the awareness that treating common dermatoses, especially those associated with poor cosmesis, have 2-fold benefits—on the skin condition itself and on the patient’s mental health.

How are common dermatoses associated with mental health?

Acne—Acne is one of the most common skin diseases, so much so that in many cases acne has become an accepted and expected part of adolescence and young adulthood. Studies estimate that 85% of the US population aged 12 to 25 years have acne.⁹ For some adults, acne persists even longer, with 1% to 5% of adults reporting to have active lesions at 40 years of age.¹⁰ Acne is a multifactorial skin disease of the pilosebaceous unit that results in the development of inflammatory papules, pustules, and cysts. These lesions are most common on the face but can extend to other areas of the body, such as the chest and back.¹¹ Although the active lesions can be painful and disfiguring, if left untreated, acne may lead to permanent disfigurement and scarring, which can have long-lasting psychosocial impacts.

Individuals with acne have an increased likelihood of self-consciousness, social isolation, depression, and suicidal ideation. This relationship has been well established for decades. In the 1990s, a small study reported that 7 of 16 (43.8%) cases of completed suicide in dermatology patients were in patients with acne.¹² In a recent meta-analysis including 2,276,798 participants across 5 separate studies, researchers found that suicide was positively associated with acne, carrying an odds ratio of 1.50 (95% CI, 1.09-2.06).¹³

Rosacea—Rosacea is a common chronic inflammatory skin disease characterized by facial erythema, telangiectasia, phymatous changes, papules, pustules, and ocular irritation. The estimated worldwide prevalence is 5.5%.¹⁴ In addition to discomfort and irritation of the skin and eyes, rosacea often carries a higher risk of psychological and psychosocial distress due to its potentially disfiguring nature. Rosacea patients are at greater risk for having anxiety disorders and depression,¹⁵ and a 2018 study by Alinia et al¹⁶ showed that there is a direct relationship between rosacea severity and the actual level of depression.Although disease improvement certainly leads to improvements in quality of life and psychosocial status, Alinia et al¹⁶ noted that depression often is associated with poor treatment adherence due to poor motivation and hopelessness. It is critical that dermatologists are aware of these associations and maintain close follow-up with patients, even when the condition is not life-threatening, such as rosacea.

Hidradenitis Suppurativa—Hidradenitis suppurativa (HS) is a chronic inflammatory disease of the pilosebaceous unit that is characterized by the development of painful, malodorous, draining abscesses, fistulas, sinus tracts, and scars in sensitive areas such as the axillae, breasts, groin, and perineum.¹⁷ In severe cases, surgery may be required to excise affected areas. Compared to other cutaneous disease, HS is considered one of the most life-impacting disorders.¹⁸ The physical symptoms themselves often are debilitating, and patients often report considerable psychosocial and psychological impairment with decreased quality of life. Major depression frequently is noted, with 1 in 4 adults with HS also being depressed. In a large cross-sectional analysis of 38,140 adults and 1162 pediatric patients with HS, Wright et al¹⁷ reported the prevalence of depression among adults with HS as 30.0% compared to 16.9% in healthy controls. In children, the prevalence of depression was 11.7% compared to 4.1% in the general population.¹⁷ Similarly, 1 out of every 5 patients with HS experiences anxiety.¹⁸

In the military population, HS often can be duty limiting. The disease requires constant attention to wound care and frequent medical visits. For many service members operating in field training or combat environments, opportunities for and access to showers and basic hygiene is limited. Uniforms and additional necessary combat gear often are thick and occlusive. Taken as a whole, these factors may contribute to worsening of the disease and in severe cases are simply not conducive to the successful management of the condition. However, given the most commonly involved body areas and the nature of the disease, many service members with HS may feel embarrassed to disclose their condition. In uniform, the disease is not easily visible, and for unaware persons, the frequency of medical visits and limited duty status may seem unnecessary. This perception of a service member’s lack of productivity due to an unseen disease may further add to the psychosocial stress they experience.

What treatment options can be considered for military service members?

The treatments for acne, rosacea, and HS are outlined in the eTable.^11,19 Also noted are specific considerations when managing an active-duty service member due to various operational duty restrictions and constraints.

Final Thoughts

Maintaining readiness in the military is essential to the ability to not only “fight tonight” but also to win tonight in whatever operational or combat mission a service member may be. Although many factors impact readiness, the rates of suicide within the armed forces cannot be ignored. Suicide not only eliminates the readiness of the deceased service member but has lasting ripple effects on the overall readiness of their unit and command at large. Most suicides in the military occur in personnel with no prior documented mental health diagnoses or treatment. Therefore, it is the responsibility of all service members to recognize and mitigate stressors and risk factors that may lead to mental health distress and suicidality. In the medical corps, this translates to a responsibility of all medical specialists to recognize and understand unique risk factors for suicidality and to do as much as they can to reduce these risks. For military dermatologists and for civilian physicians treating military service members, it is imperative to predict and understand the relationship between common dermatoses; reduced satisfaction with CBI; and increased risk for mental health illness, self-harm, and suicide. Military dermatologists, as well as other specialists, may be limited in the care they are able to provide due to manpower, staffing, demand, and institutional guidelines; however, to better serve those who serve in a holistic manner, consideration must be given to rethink what is “medically essential” and “cosmetic” and leverage the available skills, techniques, and equipment to increase the readiness of the force.

According to the US Department of Defense, the term readiness refers to the ability to recruit, train, deploy, and sustain military forces that will be ready to “fight tonight” and succeed in combat. Readiness is a top priority for military medicine, which functions to diagnose, treat, and rehabilitate service members so that they can return to the fight. This central concept drives programs across the military—from operational training events to the establishment of medical and dental standards. Readiness is tracked and scrutinized constantly, and although it is a shared responsibility, efforts to increase and sustain readiness often fall on support staff and military medical providers.

In recent years, there has been a greater awareness of the negative effects of mental illness, low morale, and suicidality on military readiness. In 2013, suicide accounted for 28.1% of all deaths that occurred in the US Armed Forces.¹ Put frankly, suicide was one of the leading causes of death among military members.

The most recent Marine Corps Order regarding the Marine Corps Suicide Prevention Program stated that “suicidal behaviors are a barrier to readiness that have lasting effects on Marines and Service Members attached to Marine Commands. . .Families, and the Marine Corps.” It goes on to say that “[e]ffective suicide prevention requires coordinated efforts within a prevention framework dedicated to promoting mental, physical, spiritual, and social fitness. . .[and] mitigating stressors that interfere with mission readiness.”² This statement supports the notion that preventing suicide is not just about treating mental illness; it also involves maximizing physical, spiritual, and social fitness. Although it is well established that various mental health disorders are associated with an increased risk for suicide, it is worth noting that, in one study, only half of individuals who died by suicide had a mental health disorder diagnosed prior to their death.³ These statistics translate to the military. The 2015 Department of Defense Suicide Event Report noted that only 28% of service members who died by suicide and 22% of members with attempted suicide had been documented as having sought mental health care and disclosed their potential for self-harm prior to the event.^1,4 In 2018, a study published by Ursano et al⁵ showed that 36.3% of US soldiers with a documented suicide attempt (N=9650) had no prior mental health diagnoses.

Expanding the scope to include mental health issues in general, only 29% of service members who reported experiencing a mental health problem actually sought mental health care in that same period. Overall, approximately 40% of service members with a reported perceived need for mental health care actually sought care over their entire course of service time,¹ which raises concern for a large population of undiagnosed and undertreated mental illnesses across the military. In response to these statistics, Reger et al³ posited that it is “essential that suicide prevention efforts move outside the silo of mental health.” The authors went on to challenge health care providers across all specialties and civilians alike to take responsibility in understanding, recognizing, and mitigating risk factors for suicide in the general population.³ Although treating a service member’s acne or offering to stand duty for a service member who has been under a great deal of stress in their personal life may appear to be indirect ways of reducing suicide in the US military, they actually may be the most critical means of prevention in a culture that emphasizes resilience and self-reliance, where seeking help for mental health struggles could be perceived as weakness.¹

In this review article, we discuss the concept of cutaneous body image (CBI) and its associated outcomes on health, satisfaction, and quality of life in military service members. We then examine the intersections between common dermatologic conditions, CBI, and mental health and explore the ability and role of the military dermatologist to serve as a positive influence on military readiness.

What is cutaneous body image?

Cutaneous body image is “the individual’s mental perception of his or her skin and its appendages (ie, hair, nails).”⁶ It is measured objectively using the Cutaneous Body Image Scale, a questionnaire that includes 7 items related to the overall satisfaction with the appearance of skin, color of skin, skin of the face, complexion of the face, hair, fingernails, and toenails. Each question is rated using a 10-point Likert scale (0=not at all; 10=very markedly).⁶

Some degree of CBI dissatisfaction is expected and has been shown in the general population at large; for example, more than 56% of women older than 30 years report some degree of dissatisfaction with their skin. Similarly, data from the American Society of Plastic Surgeons showed that while 10.9 million cosmetic procedures were performed in 2006, 9.1 million of them involved minimally invasive procedures such as botulinum toxin type A injections with the purpose of skin rejuvenation and improvement of facial appearance.⁷ However, lower than average CBI can contribute to considerable psychosocial morbidity. Dissatisfaction with CBI is associated with self-consciousness, feelings of inferiority, and social exclusion. These symptoms can be grouped into a construct called interpersonal sensitivity (IS). A 2013 study by Gupta and Gupta⁶ investigated the relationship between CBI, IS, and suicidal ideation among 312 consenting nonclinical participants in Canada. The study found that greater dissatisfaction with an individual’s CBI correlated to increased IS and increased rates of suicidal ideation and intentional self-injury.⁶

Cutaneous body image is particularly relevant to dermatologists, as many common dermatoses can cause cosmetically disfiguring skin conditions; for example, acne and rosacea have the propensity to cause notable disfigurement to the facial unit. Other common conditions such as atopic dermatitis or psoriasis can flare with stress and thereby throw patients into a vicious cycle of physical and psychosocial stress caused by social stigma, cosmetic disfigurement, and reduced CBI, in turn leading to worsening of the disease at hand. Dermatologists need to be aware that common dermatoses can impact a patient’s mental health via poor CBI.⁸ Similarly, dermatologists may be empowered by the awareness that treating common dermatoses, especially those associated with poor cosmesis, have 2-fold benefits—on the skin condition itself and on the patient’s mental health.

How are common dermatoses associated with mental health?

Acne—Acne is one of the most common skin diseases, so much so that in many cases acne has become an accepted and expected part of adolescence and young adulthood. Studies estimate that 85% of the US population aged 12 to 25 years have acne.⁹ For some adults, acne persists even longer, with 1% to 5% of adults reporting to have active lesions at 40 years of age.¹⁰ Acne is a multifactorial skin disease of the pilosebaceous unit that results in the development of inflammatory papules, pustules, and cysts. These lesions are most common on the face but can extend to other areas of the body, such as the chest and back.¹¹ Although the active lesions can be painful and disfiguring, if left untreated, acne may lead to permanent disfigurement and scarring, which can have long-lasting psychosocial impacts.

Individuals with acne have an increased likelihood of self-consciousness, social isolation, depression, and suicidal ideation. This relationship has been well established for decades. In the 1990s, a small study reported that 7 of 16 (43.8%) cases of completed suicide in dermatology patients were in patients with acne.¹² In a recent meta-analysis including 2,276,798 participants across 5 separate studies, researchers found that suicide was positively associated with acne, carrying an odds ratio of 1.50 (95% CI, 1.09-2.06).¹³

Rosacea—Rosacea is a common chronic inflammatory skin disease characterized by facial erythema, telangiectasia, phymatous changes, papules, pustules, and ocular irritation. The estimated worldwide prevalence is 5.5%.¹⁴ In addition to discomfort and irritation of the skin and eyes, rosacea often carries a higher risk of psychological and psychosocial distress due to its potentially disfiguring nature. Rosacea patients are at greater risk for having anxiety disorders and depression,¹⁵ and a 2018 study by Alinia et al¹⁶ showed that there is a direct relationship between rosacea severity and the actual level of depression.Although disease improvement certainly leads to improvements in quality of life and psychosocial status, Alinia et al¹⁶ noted that depression often is associated with poor treatment adherence due to poor motivation and hopelessness. It is critical that dermatologists are aware of these associations and maintain close follow-up with patients, even when the condition is not life-threatening, such as rosacea.

Hidradenitis Suppurativa—Hidradenitis suppurativa (HS) is a chronic inflammatory disease of the pilosebaceous unit that is characterized by the development of painful, malodorous, draining abscesses, fistulas, sinus tracts, and scars in sensitive areas such as the axillae, breasts, groin, and perineum.¹⁷ In severe cases, surgery may be required to excise affected areas. Compared to other cutaneous disease, HS is considered one of the most life-impacting disorders.¹⁸ The physical symptoms themselves often are debilitating, and patients often report considerable psychosocial and psychological impairment with decreased quality of life. Major depression frequently is noted, with 1 in 4 adults with HS also being depressed. In a large cross-sectional analysis of 38,140 adults and 1162 pediatric patients with HS, Wright et al¹⁷ reported the prevalence of depression among adults with HS as 30.0% compared to 16.9% in healthy controls. In children, the prevalence of depression was 11.7% compared to 4.1% in the general population.¹⁷ Similarly, 1 out of every 5 patients with HS experiences anxiety.¹⁸

In the military population, HS often can be duty limiting. The disease requires constant attention to wound care and frequent medical visits. For many service members operating in field training or combat environments, opportunities for and access to showers and basic hygiene is limited. Uniforms and additional necessary combat gear often are thick and occlusive. Taken as a whole, these factors may contribute to worsening of the disease and in severe cases are simply not conducive to the successful management of the condition. However, given the most commonly involved body areas and the nature of the disease, many service members with HS may feel embarrassed to disclose their condition. In uniform, the disease is not easily visible, and for unaware persons, the frequency of medical visits and limited duty status may seem unnecessary. This perception of a service member’s lack of productivity due to an unseen disease may further add to the psychosocial stress they experience.

What treatment options can be considered for military service members?

The treatments for acne, rosacea, and HS are outlined in the eTable.^11,19 Also noted are specific considerations when managing an active-duty service member due to various operational duty restrictions and constraints.

Final Thoughts

Maintaining readiness in the military is essential to the ability to not only “fight tonight” but also to win tonight in whatever operational or combat mission a service member may be. Although many factors impact readiness, the rates of suicide within the armed forces cannot be ignored. Suicide not only eliminates the readiness of the deceased service member but has lasting ripple effects on the overall readiness of their unit and command at large. Most suicides in the military occur in personnel with no prior documented mental health diagnoses or treatment. Therefore, it is the responsibility of all service members to recognize and mitigate stressors and risk factors that may lead to mental health distress and suicidality. In the medical corps, this translates to a responsibility of all medical specialists to recognize and understand unique risk factors for suicidality and to do as much as they can to reduce these risks. For military dermatologists and for civilian physicians treating military service members, it is imperative to predict and understand the relationship between common dermatoses; reduced satisfaction with CBI; and increased risk for mental health illness, self-harm, and suicide. Military dermatologists, as well as other specialists, may be limited in the care they are able to provide due to manpower, staffing, demand, and institutional guidelines; however, to better serve those who serve in a holistic manner, consideration must be given to rethink what is “medically essential” and “cosmetic” and leverage the available skills, techniques, and equipment to increase the readiness of the force.

According to the US Department of Defense, the term readiness refers to the ability to recruit, train, deploy, and sustain military forces that will be ready to “fight tonight” and succeed in combat. Readiness is a top priority for military medicine, which functions to diagnose, treat, and rehabilitate service members so that they can return to the fight. This central concept drives programs across the military—from operational training events to the establishment of medical and dental standards. Readiness is tracked and scrutinized constantly, and although it is a shared responsibility, efforts to increase and sustain readiness often fall on support staff and military medical providers.

In recent years, there has been a greater awareness of the negative effects of mental illness, low morale, and suicidality on military readiness. In 2013, suicide accounted for 28.1% of all deaths that occurred in the US Armed Forces.¹ Put frankly, suicide was one of the leading causes of death among military members.

The most recent Marine Corps Order regarding the Marine Corps Suicide Prevention Program stated that “suicidal behaviors are a barrier to readiness that have lasting effects on Marines and Service Members attached to Marine Commands. . .Families, and the Marine Corps.” It goes on to say that “[e]ffective suicide prevention requires coordinated efforts within a prevention framework dedicated to promoting mental, physical, spiritual, and social fitness. . .[and] mitigating stressors that interfere with mission readiness.”² This statement supports the notion that preventing suicide is not just about treating mental illness; it also involves maximizing physical, spiritual, and social fitness. Although it is well established that various mental health disorders are associated with an increased risk for suicide, it is worth noting that, in one study, only half of individuals who died by suicide had a mental health disorder diagnosed prior to their death.³ These statistics translate to the military. The 2015 Department of Defense Suicide Event Report noted that only 28% of service members who died by suicide and 22% of members with attempted suicide had been documented as having sought mental health care and disclosed their potential for self-harm prior to the event.^1,4 In 2018, a study published by Ursano et al⁵ showed that 36.3% of US soldiers with a documented suicide attempt (N=9650) had no prior mental health diagnoses.

Expanding the scope to include mental health issues in general, only 29% of service members who reported experiencing a mental health problem actually sought mental health care in that same period. Overall, approximately 40% of service members with a reported perceived need for mental health care actually sought care over their entire course of service time,¹ which raises concern for a large population of undiagnosed and undertreated mental illnesses across the military. In response to these statistics, Reger et al³ posited that it is “essential that suicide prevention efforts move outside the silo of mental health.” The authors went on to challenge health care providers across all specialties and civilians alike to take responsibility in understanding, recognizing, and mitigating risk factors for suicide in the general population.³ Although treating a service member’s acne or offering to stand duty for a service member who has been under a great deal of stress in their personal life may appear to be indirect ways of reducing suicide in the US military, they actually may be the most critical means of prevention in a culture that emphasizes resilience and self-reliance, where seeking help for mental health struggles could be perceived as weakness.¹

In this review article, we discuss the concept of cutaneous body image (CBI) and its associated outcomes on health, satisfaction, and quality of life in military service members. We then examine the intersections between common dermatologic conditions, CBI, and mental health and explore the ability and role of the military dermatologist to serve as a positive influence on military readiness.

What is cutaneous body image?

Cutaneous body image is “the individual’s mental perception of his or her skin and its appendages (ie, hair, nails).”⁶ It is measured objectively using the Cutaneous Body Image Scale, a questionnaire that includes 7 items related to the overall satisfaction with the appearance of skin, color of skin, skin of the face, complexion of the face, hair, fingernails, and toenails. Each question is rated using a 10-point Likert scale (0=not at all; 10=very markedly).⁶

Some degree of CBI dissatisfaction is expected and has been shown in the general population at large; for example, more than 56% of women older than 30 years report some degree of dissatisfaction with their skin. Similarly, data from the American Society of Plastic Surgeons showed that while 10.9 million cosmetic procedures were performed in 2006, 9.1 million of them involved minimally invasive procedures such as botulinum toxin type A injections with the purpose of skin rejuvenation and improvement of facial appearance.⁷ However, lower than average CBI can contribute to considerable psychosocial morbidity. Dissatisfaction with CBI is associated with self-consciousness, feelings of inferiority, and social exclusion. These symptoms can be grouped into a construct called interpersonal sensitivity (IS). A 2013 study by Gupta and Gupta⁶ investigated the relationship between CBI, IS, and suicidal ideation among 312 consenting nonclinical participants in Canada. The study found that greater dissatisfaction with an individual’s CBI correlated to increased IS and increased rates of suicidal ideation and intentional self-injury.⁶

Cutaneous body image is particularly relevant to dermatologists, as many common dermatoses can cause cosmetically disfiguring skin conditions; for example, acne and rosacea have the propensity to cause notable disfigurement to the facial unit. Other common conditions such as atopic dermatitis or psoriasis can flare with stress and thereby throw patients into a vicious cycle of physical and psychosocial stress caused by social stigma, cosmetic disfigurement, and reduced CBI, in turn leading to worsening of the disease at hand. Dermatologists need to be aware that common dermatoses can impact a patient’s mental health via poor CBI.⁸ Similarly, dermatologists may be empowered by the awareness that treating common dermatoses, especially those associated with poor cosmesis, have 2-fold benefits—on the skin condition itself and on the patient’s mental health.

How are common dermatoses associated with mental health?

Acne—Acne is one of the most common skin diseases, so much so that in many cases acne has become an accepted and expected part of adolescence and young adulthood. Studies estimate that 85% of the US population aged 12 to 25 years have acne.⁹ For some adults, acne persists even longer, with 1% to 5% of adults reporting to have active lesions at 40 years of age.¹⁰ Acne is a multifactorial skin disease of the pilosebaceous unit that results in the development of inflammatory papules, pustules, and cysts. These lesions are most common on the face but can extend to other areas of the body, such as the chest and back.¹¹ Although the active lesions can be painful and disfiguring, if left untreated, acne may lead to permanent disfigurement and scarring, which can have long-lasting psychosocial impacts.

Individuals with acne have an increased likelihood of self-consciousness, social isolation, depression, and suicidal ideation. This relationship has been well established for decades. In the 1990s, a small study reported that 7 of 16 (43.8%) cases of completed suicide in dermatology patients were in patients with acne.¹² In a recent meta-analysis including 2,276,798 participants across 5 separate studies, researchers found that suicide was positively associated with acne, carrying an odds ratio of 1.50 (95% CI, 1.09-2.06).¹³

Rosacea—Rosacea is a common chronic inflammatory skin disease characterized by facial erythema, telangiectasia, phymatous changes, papules, pustules, and ocular irritation. The estimated worldwide prevalence is 5.5%.¹⁴ In addition to discomfort and irritation of the skin and eyes, rosacea often carries a higher risk of psychological and psychosocial distress due to its potentially disfiguring nature. Rosacea patients are at greater risk for having anxiety disorders and depression,¹⁵ and a 2018 study by Alinia et al¹⁶ showed that there is a direct relationship between rosacea severity and the actual level of depression.Although disease improvement certainly leads to improvements in quality of life and psychosocial status, Alinia et al¹⁶ noted that depression often is associated with poor treatment adherence due to poor motivation and hopelessness. It is critical that dermatologists are aware of these associations and maintain close follow-up with patients, even when the condition is not life-threatening, such as rosacea.

Hidradenitis Suppurativa—Hidradenitis suppurativa (HS) is a chronic inflammatory disease of the pilosebaceous unit that is characterized by the development of painful, malodorous, draining abscesses, fistulas, sinus tracts, and scars in sensitive areas such as the axillae, breasts, groin, and perineum.¹⁷ In severe cases, surgery may be required to excise affected areas. Compared to other cutaneous disease, HS is considered one of the most life-impacting disorders.¹⁸ The physical symptoms themselves often are debilitating, and patients often report considerable psychosocial and psychological impairment with decreased quality of life. Major depression frequently is noted, with 1 in 4 adults with HS also being depressed. In a large cross-sectional analysis of 38,140 adults and 1162 pediatric patients with HS, Wright et al¹⁷ reported the prevalence of depression among adults with HS as 30.0% compared to 16.9% in healthy controls. In children, the prevalence of depression was 11.7% compared to 4.1% in the general population.¹⁷ Similarly, 1 out of every 5 patients with HS experiences anxiety.¹⁸

In the military population, HS often can be duty limiting. The disease requires constant attention to wound care and frequent medical visits. For many service members operating in field training or combat environments, opportunities for and access to showers and basic hygiene is limited. Uniforms and additional necessary combat gear often are thick and occlusive. Taken as a whole, these factors may contribute to worsening of the disease and in severe cases are simply not conducive to the successful management of the condition. However, given the most commonly involved body areas and the nature of the disease, many service members with HS may feel embarrassed to disclose their condition. In uniform, the disease is not easily visible, and for unaware persons, the frequency of medical visits and limited duty status may seem unnecessary. This perception of a service member’s lack of productivity due to an unseen disease may further add to the psychosocial stress they experience.

What treatment options can be considered for military service members?

The treatments for acne, rosacea, and HS are outlined in the eTable.^11,19 Also noted are specific considerations when managing an active-duty service member due to various operational duty restrictions and constraints.

Final Thoughts

Maintaining readiness in the military is essential to the ability to not only “fight tonight” but also to win tonight in whatever operational or combat mission a service member may be. Although many factors impact readiness, the rates of suicide within the armed forces cannot be ignored. Suicide not only eliminates the readiness of the deceased service member but has lasting ripple effects on the overall readiness of their unit and command at large. Most suicides in the military occur in personnel with no prior documented mental health diagnoses or treatment. Therefore, it is the responsibility of all service members to recognize and mitigate stressors and risk factors that may lead to mental health distress and suicidality. In the medical corps, this translates to a responsibility of all medical specialists to recognize and understand unique risk factors for suicidality and to do as much as they can to reduce these risks. For military dermatologists and for civilian physicians treating military service members, it is imperative to predict and understand the relationship between common dermatoses; reduced satisfaction with CBI; and increased risk for mental health illness, self-harm, and suicide. Military dermatologists, as well as other specialists, may be limited in the care they are able to provide due to manpower, staffing, demand, and institutional guidelines; however, to better serve those who serve in a holistic manner, consideration must be given to rethink what is “medically essential” and “cosmetic” and leverage the available skills, techniques, and equipment to increase the readiness of the force.

Similar to other dermatologic conditions, barriers to early care in patients with vitiligo can exacerbate health disparities.¹ Delayed treatment of vitiligo is known to hamper successful disease stabilization and repigmentation, as therapies tend to work more effectively in early stages of the disease.²

To investigate the factors associated with treatment delays for patients with vitiligo, we conducted a retrospective chart review of 102 consecutive patients with vitiligo attending an academic outpatient clinic in Austin, Texas, over 36 months.

Methods

Our sample included 102 consecutive patients with vitiligo who attended an academic outpatient clinic in Austin, Texas, from January 2017 to January 2020. Demographic information, clinical characteristics of vitiligo, and treatment data were self-reported via a standardized questionnaire given to all patients with vitiligo and gathered from medical chart review. Patient characteristics are outlined in the Table. The delay to treatment was the time (in months) from the date the patient first noticed the lesion to the start date of first treatment. This retrospective chart review was reviewed by the University of Texas at Austin institutional review board and was determined to be exempt.

Statistical Analysis—The data were analyzed descriptively with a Wilcoxon rank sum test (type I error rate of .05).

Results

Of the 102 charts that were analyzed, 45 were females and 57 were males. More than half of the patients (54.9% [56/102]) were White. Sixteen were Asian, 13 were Hispanic non-White, 11 were Black/African American, and 4 were American Indian/Alaska Native. The median age of disease onset was 21 years, minimum age was 1 year, and maximum age was 83 years. The diagnosis of vitiligo was made by a dermatologist for 72 patients and by a physician of another specialty for 20 patients. Ten patients did not declare the specialty of the diagnosing physician.

Individuals older than 21 years when their disease started had a shorter delay to treatment than individuals who noticed their first lesion at an age younger than 21 years (median, 75 months vs 13 months; P<.01). Individuals diagnosed by a dermatologist had a shorter delay to treatment than individuals diagnosed by a physician of another specialty (median, 13 months vs 58 months; P<.05). White individuals had a shorter delay to treatment than individuals with skin of color (median, 13 months vs 31 months; P=.08), though this trend did not reach statistical significance. Individuals with 1% to 25% of body surface area (BSA) affected at time of presentation to clinic also had a shorter delay to treatment than those with a greater BSA affected (median, 13 months vs 74 months; P<.06), though this trend did not reach statistical significance. Type of vitiligo (P<.8), Fitzpatrick skin type (P<.6), and smoking status (P<.7) were not associated with differential delays.

Comment

Impact of Age on Vitiligo Treatment—Our data suggest that individuals who develop vitiligo at a younger age experience longer treatment delays compared to older individuals. Reasons for this are uncertain but could include access issues, medical decision-making agency, and younger patients not remembering being treated during their youth. Our data also could be influenced by some of the adult patients in our study first noticing their lesions many years ago when treatments for vitiligo were more limited. Nevertheless, detrimental effects on quality of life in children and adolescents with vitiligo suggest that motivating younger individuals with vitiligo to seek treatment or proactively making them aware of treatment opportunities may be beneficial.³

Diagnosis of Vitiligo by Nondermatologists—The increase in delay to treatment when a nondermatologist diagnoses vitiligo suggests that prompt initiation of treatment or referrals to dermatology by primary care providers may not routinely be occurring.⁴ Our data indicate the need to educate primary care providers on treatment opportunities for individuals with vitiligo and that early treatment generally is more effective.⁵

Impact of Race/Ethnicity on Vitiligo Treatment—Our data also show trends for longer treatment delays for individuals with skin of color. Although this did not reach statistical significance, we hope future studies will investigate this issue, especially because patients with skin of color experience more stigmatization and quality-of-life impacts by vitiligo than White patients.⁵

Impact of BSA on Vitiligo Treatment—Our data show that patients with a smaller BSA had a shorter delay to treatment than those with a greater BSA affected. This was a unique finding given it initially was hypothesized that patients with greater BSA would seek treatment earlier because of the associated increase in quality of life impact. This trend was not statistically significant, but further investigation would be helpful to analyze the reason behind treatment delays in patients with greater BSA affected.

Conclusion

The delay to treatment in our study population was correlated with the diagnosing physician’s specialty and patient age at disease onset, with trends also observed for race and BSA affected. These findings emphasize the need to investigate specific causes of barriers to early care to promote health equity among individuals with vitiligo.

Similar to other dermatologic conditions, barriers to early care in patients with vitiligo can exacerbate health disparities.¹ Delayed treatment of vitiligo is known to hamper successful disease stabilization and repigmentation, as therapies tend to work more effectively in early stages of the disease.²

To investigate the factors associated with treatment delays for patients with vitiligo, we conducted a retrospective chart review of 102 consecutive patients with vitiligo attending an academic outpatient clinic in Austin, Texas, over 36 months.

Methods

Our sample included 102 consecutive patients with vitiligo who attended an academic outpatient clinic in Austin, Texas, from January 2017 to January 2020. Demographic information, clinical characteristics of vitiligo, and treatment data were self-reported via a standardized questionnaire given to all patients with vitiligo and gathered from medical chart review. Patient characteristics are outlined in the Table. The delay to treatment was the time (in months) from the date the patient first noticed the lesion to the start date of first treatment. This retrospective chart review was reviewed by the University of Texas at Austin institutional review board and was determined to be exempt.

Statistical Analysis—The data were analyzed descriptively with a Wilcoxon rank sum test (type I error rate of .05).

Results

Of the 102 charts that were analyzed, 45 were females and 57 were males. More than half of the patients (54.9% [56/102]) were White. Sixteen were Asian, 13 were Hispanic non-White, 11 were Black/African American, and 4 were American Indian/Alaska Native. The median age of disease onset was 21 years, minimum age was 1 year, and maximum age was 83 years. The diagnosis of vitiligo was made by a dermatologist for 72 patients and by a physician of another specialty for 20 patients. Ten patients did not declare the specialty of the diagnosing physician.

Individuals older than 21 years when their disease started had a shorter delay to treatment than individuals who noticed their first lesion at an age younger than 21 years (median, 75 months vs 13 months; P<.01). Individuals diagnosed by a dermatologist had a shorter delay to treatment than individuals diagnosed by a physician of another specialty (median, 13 months vs 58 months; P<.05). White individuals had a shorter delay to treatment than individuals with skin of color (median, 13 months vs 31 months; P=.08), though this trend did not reach statistical significance. Individuals with 1% to 25% of body surface area (BSA) affected at time of presentation to clinic also had a shorter delay to treatment than those with a greater BSA affected (median, 13 months vs 74 months; P<.06), though this trend did not reach statistical significance. Type of vitiligo (P<.8), Fitzpatrick skin type (P<.6), and smoking status (P<.7) were not associated with differential delays.

Comment

Impact of Age on Vitiligo Treatment—Our data suggest that individuals who develop vitiligo at a younger age experience longer treatment delays compared to older individuals. Reasons for this are uncertain but could include access issues, medical decision-making agency, and younger patients not remembering being treated during their youth. Our data also could be influenced by some of the adult patients in our study first noticing their lesions many years ago when treatments for vitiligo were more limited. Nevertheless, detrimental effects on quality of life in children and adolescents with vitiligo suggest that motivating younger individuals with vitiligo to seek treatment or proactively making them aware of treatment opportunities may be beneficial.³

Diagnosis of Vitiligo by Nondermatologists—The increase in delay to treatment when a nondermatologist diagnoses vitiligo suggests that prompt initiation of treatment or referrals to dermatology by primary care providers may not routinely be occurring.⁴ Our data indicate the need to educate primary care providers on treatment opportunities for individuals with vitiligo and that early treatment generally is more effective.⁵

Impact of Race/Ethnicity on Vitiligo Treatment—Our data also show trends for longer treatment delays for individuals with skin of color. Although this did not reach statistical significance, we hope future studies will investigate this issue, especially because patients with skin of color experience more stigmatization and quality-of-life impacts by vitiligo than White patients.⁵

Impact of BSA on Vitiligo Treatment—Our data show that patients with a smaller BSA had a shorter delay to treatment than those with a greater BSA affected. This was a unique finding given it initially was hypothesized that patients with greater BSA would seek treatment earlier because of the associated increase in quality of life impact. This trend was not statistically significant, but further investigation would be helpful to analyze the reason behind treatment delays in patients with greater BSA affected.

Conclusion

The delay to treatment in our study population was correlated with the diagnosing physician’s specialty and patient age at disease onset, with trends also observed for race and BSA affected. These findings emphasize the need to investigate specific causes of barriers to early care to promote health equity among individuals with vitiligo.

Similar to other dermatologic conditions, barriers to early care in patients with vitiligo can exacerbate health disparities.¹ Delayed treatment of vitiligo is known to hamper successful disease stabilization and repigmentation, as therapies tend to work more effectively in early stages of the disease.²

To investigate the factors associated with treatment delays for patients with vitiligo, we conducted a retrospective chart review of 102 consecutive patients with vitiligo attending an academic outpatient clinic in Austin, Texas, over 36 months.

Methods

Our sample included 102 consecutive patients with vitiligo who attended an academic outpatient clinic in Austin, Texas, from January 2017 to January 2020. Demographic information, clinical characteristics of vitiligo, and treatment data were self-reported via a standardized questionnaire given to all patients with vitiligo and gathered from medical chart review. Patient characteristics are outlined in the Table. The delay to treatment was the time (in months) from the date the patient first noticed the lesion to the start date of first treatment. This retrospective chart review was reviewed by the University of Texas at Austin institutional review board and was determined to be exempt.

Statistical Analysis—The data were analyzed descriptively with a Wilcoxon rank sum test (type I error rate of .05).

Results

Of the 102 charts that were analyzed, 45 were females and 57 were males. More than half of the patients (54.9% [56/102]) were White. Sixteen were Asian, 13 were Hispanic non-White, 11 were Black/African American, and 4 were American Indian/Alaska Native. The median age of disease onset was 21 years, minimum age was 1 year, and maximum age was 83 years. The diagnosis of vitiligo was made by a dermatologist for 72 patients and by a physician of another specialty for 20 patients. Ten patients did not declare the specialty of the diagnosing physician.

Individuals older than 21 years when their disease started had a shorter delay to treatment than individuals who noticed their first lesion at an age younger than 21 years (median, 75 months vs 13 months; P<.01). Individuals diagnosed by a dermatologist had a shorter delay to treatment than individuals diagnosed by a physician of another specialty (median, 13 months vs 58 months; P<.05). White individuals had a shorter delay to treatment than individuals with skin of color (median, 13 months vs 31 months; P=.08), though this trend did not reach statistical significance. Individuals with 1% to 25% of body surface area (BSA) affected at time of presentation to clinic also had a shorter delay to treatment than those with a greater BSA affected (median, 13 months vs 74 months; P<.06), though this trend did not reach statistical significance. Type of vitiligo (P<.8), Fitzpatrick skin type (P<.6), and smoking status (P<.7) were not associated with differential delays.

Comment

Impact of Age on Vitiligo Treatment—Our data suggest that individuals who develop vitiligo at a younger age experience longer treatment delays compared to older individuals. Reasons for this are uncertain but could include access issues, medical decision-making agency, and younger patients not remembering being treated during their youth. Our data also could be influenced by some of the adult patients in our study first noticing their lesions many years ago when treatments for vitiligo were more limited. Nevertheless, detrimental effects on quality of life in children and adolescents with vitiligo suggest that motivating younger individuals with vitiligo to seek treatment or proactively making them aware of treatment opportunities may be beneficial.³

Diagnosis of Vitiligo by Nondermatologists—The increase in delay to treatment when a nondermatologist diagnoses vitiligo suggests that prompt initiation of treatment or referrals to dermatology by primary care providers may not routinely be occurring.⁴ Our data indicate the need to educate primary care providers on treatment opportunities for individuals with vitiligo and that early treatment generally is more effective.⁵

Impact of Race/Ethnicity on Vitiligo Treatment—Our data also show trends for longer treatment delays for individuals with skin of color. Although this did not reach statistical significance, we hope future studies will investigate this issue, especially because patients with skin of color experience more stigmatization and quality-of-life impacts by vitiligo than White patients.⁵

Impact of BSA on Vitiligo Treatment—Our data show that patients with a smaller BSA had a shorter delay to treatment than those with a greater BSA affected. This was a unique finding given it initially was hypothesized that patients with greater BSA would seek treatment earlier because of the associated increase in quality of life impact. This trend was not statistically significant, but further investigation would be helpful to analyze the reason behind treatment delays in patients with greater BSA affected.

Conclusion

The delay to treatment in our study population was correlated with the diagnosing physician’s specialty and patient age at disease onset, with trends also observed for race and BSA affected. These findings emphasize the need to investigate specific causes of barriers to early care to promote health equity among individuals with vitiligo.

Practice Gap

OnabotulinumtoxinA is a US Food and Drug Administration–approved second-line treatment of axillary hyperhidrosis, with a long-term success rate greater than 80% and minimal adverse effects.¹ The recommended depth and angle of injection of onabotulinumtoxinA for most cases of primary hyperhidrosis is 2 to 3 mm at a 45° angle to the skin surface.² This small depth is difficult to accurately estimate once the needle tip is in the skin.

Injection Technique

We have found that measuring 2 to 3 mm on the needle tip and then wrapping a piece of adhesive tape at that point acts as a depth guide (Figure 1). The flag shape of the tape acts as a physical barrier to prevent the needle tip from penetrating too deeply (Figure 2). This barrier also allows the injector to inject quickly to reduce the amount of pain that the patient experiences.

Practice Implications

Applying adhesive tape to a needle tip at a premeasured distance is a fast, inexpensive, and effective tool to aid accurate depth of injection for both experienced clinicians and clinicians in-training. The tape is a common office supply and the amount of tape used for a patient costs a fraction of a cent. Additionally, applying the tape takes less than 1 minute. This technique is useful for axillary hyperhidrosis injection (Figures 1 and 2) but could be used in palmar and plantar hyperhidrosis injections as well as injections other than onabotulinumtoxinA that require a specific fixed depth.

Practice Gap

OnabotulinumtoxinA is a US Food and Drug Administration–approved second-line treatment of axillary hyperhidrosis, with a long-term success rate greater than 80% and minimal adverse effects.¹ The recommended depth and angle of injection of onabotulinumtoxinA for most cases of primary hyperhidrosis is 2 to 3 mm at a 45° angle to the skin surface.² This small depth is difficult to accurately estimate once the needle tip is in the skin.

Injection Technique

We have found that measuring 2 to 3 mm on the needle tip and then wrapping a piece of adhesive tape at that point acts as a depth guide (Figure 1). The flag shape of the tape acts as a physical barrier to prevent the needle tip from penetrating too deeply (Figure 2). This barrier also allows the injector to inject quickly to reduce the amount of pain that the patient experiences.

Practice Implications

Applying adhesive tape to a needle tip at a premeasured distance is a fast, inexpensive, and effective tool to aid accurate depth of injection for both experienced clinicians and clinicians in-training. The tape is a common office supply and the amount of tape used for a patient costs a fraction of a cent. Additionally, applying the tape takes less than 1 minute. This technique is useful for axillary hyperhidrosis injection (Figures 1 and 2) but could be used in palmar and plantar hyperhidrosis injections as well as injections other than onabotulinumtoxinA that require a specific fixed depth.

Practice Gap

OnabotulinumtoxinA is a US Food and Drug Administration–approved second-line treatment of axillary hyperhidrosis, with a long-term success rate greater than 80% and minimal adverse effects.¹ The recommended depth and angle of injection of onabotulinumtoxinA for most cases of primary hyperhidrosis is 2 to 3 mm at a 45° angle to the skin surface.² This small depth is difficult to accurately estimate once the needle tip is in the skin.

Injection Technique

We have found that measuring 2 to 3 mm on the needle tip and then wrapping a piece of adhesive tape at that point acts as a depth guide (Figure 1). The flag shape of the tape acts as a physical barrier to prevent the needle tip from penetrating too deeply (Figure 2). This barrier also allows the injector to inject quickly to reduce the amount of pain that the patient experiences.

Practice Implications

Applying adhesive tape to a needle tip at a premeasured distance is a fast, inexpensive, and effective tool to aid accurate depth of injection for both experienced clinicians and clinicians in-training. The tape is a common office supply and the amount of tape used for a patient costs a fraction of a cent. Additionally, applying the tape takes less than 1 minute. This technique is useful for axillary hyperhidrosis injection (Figures 1 and 2) but could be used in palmar and plantar hyperhidrosis injections as well as injections other than onabotulinumtoxinA that require a specific fixed depth.

Lupus erythematosus tumidus (LET) is a rare photosensitive dermatosis¹ that previously was considered a subtype of chronic cutaneous lupus erythematosus; however, the clinical course and favorable prognosis of LET led to its reclassification into another category, called intermittent cutaneous lupus erythematosus.² Although known about for more than 100 years, the association of LET with systemic lupus erythematosus (SLE), its autoantibody profile, and its prognosis are not well characterized. The purpose of this study was to describe the demographics, clinical characteristics, autoantibody profile, comorbidities, and treatment of LET based on a retrospective review of patients with LET.

Methods

A retrospective review was conducted in patients with histologically diagnosed LET who presented to the Department of Dermatology at the Wake Forest School of Medicine (Winston-Salem, North Carolina) over 6 years (July 2012 to July 2018). Inclusion criteria included males or females aged 18 to 75 years with clinical and histopathology-proven LET, which was defined as a superficial and deep lymphocytic infiltrate with abundant mucin deposition in the reticular dermis and absent or focal dermoepidermal junction alterations. Exclusion criteria included males or females younger than 18 years or older than 75 years or patients without clinical and histopathologically proven LET. Medical records were evaluated for demographics, clinical characteristics, diagnoses, autoantibodies, treatment, and recurrence. Photosensitivity was confirmed by clinical history. This study was approved by the Wake Forest School of Medicine institutional review board.

Results

Twenty-five patients were included in the study (eTable). The mean age (SD) at diagnosis was 46 (10.9) years, with a male to female ratio of 1:4. Twenty-two (88%) patients were White non-Hispanic, whereas 3 (12%) were Black. Lupus erythematosus tumidus most commonly affected the trunk (18/25 [72%]) and upper extremities (18/25 [72%]), followed by the head and neck (15/25 [60%]) and lower extremities (8/25 [32%])(Figure 1). The most common morphologies were plaques (18/25 [72%]), papules (17/25 [68%]), and nodules (6/25 [24%])(Figures 2 and 3). Most patients experienced painful (14/25 [56%]) or pruritic (13/25 [52%]) lesions as well as photosensitivity (13/25 [52%]). Of all measured autoantibodies, 5 of 22 (23%) patients had positive antinuclear antibody (ANA) titers greater than 1:80, 1 of 14 (7%) patients had positive anti-Ro (anti-SSA), 1 of 14 (7%) had positive anti-La (anti-SSB), 2 of 10 (20%) had positive anti–double-stranded DNA, and 0 of 6 (0%) patients had positive anti-Smith antibodies. Four (16%) patients with SLE had skin and joint involvement, whereas 1 had lupus nephritis. One (4%) patient had discoid lupus erythematosus (DLE). Seventeen (68%) patients reported recurrences or flares. The mean duration of symptoms (SD) was 28 (44) months.

Topical corticosteroids (21/25 [84%]) and hydroxychloroquine (20/25 [80%]) were the most commonly prescribed treatments. Hydroxychloroquine monotherapy achieved clearance or almost clearance in 12 (60%) patients. Four patients were prescribed thalidomide after hydroxychloroquine monotherapy failed; 2 achieved complete clearance with thalidomide and hydroxychloroquine, 1 achieved complete clearance with thalidomide monotherapy, and 1 improved but did not clear. Four patients were concurrently started on quinacrine (mepacrine) after hydroxychloroquine monotherapy failed; 1 patient had no clearance, 1 discontinued because of allergy, 1 improved, and 1 cleared. Four patients had short courses of prednisone lasting 1 to 4 weeks. Three of 4 patients treated with methotrexate discontinued because of adverse effects, and 1 patient improved. Other prescribed treatments included topical calcineurin inhibitors (10/25 [40%]), dapsone (1/25 [4%]), and clofazimine (1/25 [4%]).

Comment

Prevalence of LET—Although other European LET case series reported a male predominance or equal male to female ratio, our case series reported female predominance (1:4).^1,3-5 Our male to female ratio resembles similar ratios in DLE and subacute lupus erythematosus, whereas relative to our study, SLE male to female ratios favored females over males.^6,7

Clinical Distribution of LET—In one study enrolling 24 patients with LET, 79% (19/24) of patients had facial involvement, 50% (12/24) had V-neck involvement, 50% (12/24) had back involvement, and 46% (11/24) had arm involvement,² whereas our study reported 72% involvement of the trunk, 72% involvement of the upper extremities, 60% involvement of the head and neck region, and 32% involvement of the lower extremities. Although our study reported more lower extremity involvement, the aforementioned study used precise topographic locations, whereas we used more generalized topographic locations. Therefore, it was difficult to compare disease distribution between both studies.²

Presence of Autoantibodies and Comorbidities—Of the 22 patients tested for ANA, 23% reported titers greater than 1:80, similar to the 20% positive ANA prevalence in an LET case series of 25 patients.⁵ Of 4 patients diagnosed with SLE, 3 had articular and skin involvement, and 1 had renal involvement. These findings resemble a similar LET case series.² Nonetheless, given the numerous skin criteria in the American College of Rheumatology SLE classification criteria, patients with predominant skin disease and positive autoantibodies are diagnosed as having SLE without notable extracutaneous involvement.² Therefore, SLE diagnosis in the setting of LET could be reassessed periodically in this population. One patient in our study was diagnosed with DLE several years later. It is uncommon for LET to be reported concomitantly with DLE.⁸

Treatment of LET—Evidence supporting efficacious treatment options for LET is limited to case series. Sun protection is recommended in all patients with LET. Earlier case series reported a high response rate with sun protection and topical corticosteroids, with 19% to 55% of patients requiring subsequent systemic antimalarials.^3,4 However, one case series presented a need for systemic antimalarials,⁵ similar to our study. Hydroxychloroquine 200 to 400 mg daily is considered the first-line systemic treatment for LET. Its response rate varies among studies and may be influenced by dosage.^1,3 Second-line treatments include methotrexate 7.5 to 25 mg once weekly, thalidomide 50 to 100 mg daily, and quinacrine. However, quinacrine is not currently commercially available. Thalidomide and quinacrine represented useful alternatives when hydroxychloroquine monotherapy failed. As with other immunomodulators, adverse effects should be monitored periodically.

Conclusion

Lupus erythematosus tumidus is characterized by erythematous papules and plaques that may be tender or pruritic. It follows an intermittent course and rarely is associated with SLE. Hydroxychloroquine is considered the first-line systemic treatment; however, recalcitrant disease could be managed with other immunomodulators, including methotrexate, thalidomide, or quinacrine.

Lupus erythematosus tumidus (LET) is a rare photosensitive dermatosis¹ that previously was considered a subtype of chronic cutaneous lupus erythematosus; however, the clinical course and favorable prognosis of LET led to its reclassification into another category, called intermittent cutaneous lupus erythematosus.² Although known about for more than 100 years, the association of LET with systemic lupus erythematosus (SLE), its autoantibody profile, and its prognosis are not well characterized. The purpose of this study was to describe the demographics, clinical characteristics, autoantibody profile, comorbidities, and treatment of LET based on a retrospective review of patients with LET.

Methods

A retrospective review was conducted in patients with histologically diagnosed LET who presented to the Department of Dermatology at the Wake Forest School of Medicine (Winston-Salem, North Carolina) over 6 years (July 2012 to July 2018). Inclusion criteria included males or females aged 18 to 75 years with clinical and histopathology-proven LET, which was defined as a superficial and deep lymphocytic infiltrate with abundant mucin deposition in the reticular dermis and absent or focal dermoepidermal junction alterations. Exclusion criteria included males or females younger than 18 years or older than 75 years or patients without clinical and histopathologically proven LET. Medical records were evaluated for demographics, clinical characteristics, diagnoses, autoantibodies, treatment, and recurrence. Photosensitivity was confirmed by clinical history. This study was approved by the Wake Forest School of Medicine institutional review board.

Results

Twenty-five patients were included in the study (eTable). The mean age (SD) at diagnosis was 46 (10.9) years, with a male to female ratio of 1:4. Twenty-two (88%) patients were White non-Hispanic, whereas 3 (12%) were Black. Lupus erythematosus tumidus most commonly affected the trunk (18/25 [72%]) and upper extremities (18/25 [72%]), followed by the head and neck (15/25 [60%]) and lower extremities (8/25 [32%])(Figure 1). The most common morphologies were plaques (18/25 [72%]), papules (17/25 [68%]), and nodules (6/25 [24%])(Figures 2 and 3). Most patients experienced painful (14/25 [56%]) or pruritic (13/25 [52%]) lesions as well as photosensitivity (13/25 [52%]). Of all measured autoantibodies, 5 of 22 (23%) patients had positive antinuclear antibody (ANA) titers greater than 1:80, 1 of 14 (7%) patients had positive anti-Ro (anti-SSA), 1 of 14 (7%) had positive anti-La (anti-SSB), 2 of 10 (20%) had positive anti–double-stranded DNA, and 0 of 6 (0%) patients had positive anti-Smith antibodies. Four (16%) patients with SLE had skin and joint involvement, whereas 1 had lupus nephritis. One (4%) patient had discoid lupus erythematosus (DLE). Seventeen (68%) patients reported recurrences or flares. The mean duration of symptoms (SD) was 28 (44) months.

Topical corticosteroids (21/25 [84%]) and hydroxychloroquine (20/25 [80%]) were the most commonly prescribed treatments. Hydroxychloroquine monotherapy achieved clearance or almost clearance in 12 (60%) patients. Four patients were prescribed thalidomide after hydroxychloroquine monotherapy failed; 2 achieved complete clearance with thalidomide and hydroxychloroquine, 1 achieved complete clearance with thalidomide monotherapy, and 1 improved but did not clear. Four patients were concurrently started on quinacrine (mepacrine) after hydroxychloroquine monotherapy failed; 1 patient had no clearance, 1 discontinued because of allergy, 1 improved, and 1 cleared. Four patients had short courses of prednisone lasting 1 to 4 weeks. Three of 4 patients treated with methotrexate discontinued because of adverse effects, and 1 patient improved. Other prescribed treatments included topical calcineurin inhibitors (10/25 [40%]), dapsone (1/25 [4%]), and clofazimine (1/25 [4%]).

Comment

Prevalence of LET—Although other European LET case series reported a male predominance or equal male to female ratio, our case series reported female predominance (1:4).^1,3-5 Our male to female ratio resembles similar ratios in DLE and subacute lupus erythematosus, whereas relative to our study, SLE male to female ratios favored females over males.^6,7

Clinical Distribution of LET—In one study enrolling 24 patients with LET, 79% (19/24) of patients had facial involvement, 50% (12/24) had V-neck involvement, 50% (12/24) had back involvement, and 46% (11/24) had arm involvement,² whereas our study reported 72% involvement of the trunk, 72% involvement of the upper extremities, 60% involvement of the head and neck region, and 32% involvement of the lower extremities. Although our study reported more lower extremity involvement, the aforementioned study used precise topographic locations, whereas we used more generalized topographic locations. Therefore, it was difficult to compare disease distribution between both studies.²

Presence of Autoantibodies and Comorbidities—Of the 22 patients tested for ANA, 23% reported titers greater than 1:80, similar to the 20% positive ANA prevalence in an LET case series of 25 patients.⁵ Of 4 patients diagnosed with SLE, 3 had articular and skin involvement, and 1 had renal involvement. These findings resemble a similar LET case series.² Nonetheless, given the numerous skin criteria in the American College of Rheumatology SLE classification criteria, patients with predominant skin disease and positive autoantibodies are diagnosed as having SLE without notable extracutaneous involvement.² Therefore, SLE diagnosis in the setting of LET could be reassessed periodically in this population. One patient in our study was diagnosed with DLE several years later. It is uncommon for LET to be reported concomitantly with DLE.⁸

Treatment of LET—Evidence supporting efficacious treatment options for LET is limited to case series. Sun protection is recommended in all patients with LET. Earlier case series reported a high response rate with sun protection and topical corticosteroids, with 19% to 55% of patients requiring subsequent systemic antimalarials.^3,4 However, one case series presented a need for systemic antimalarials,⁵ similar to our study. Hydroxychloroquine 200 to 400 mg daily is considered the first-line systemic treatment for LET. Its response rate varies among studies and may be influenced by dosage.^1,3 Second-line treatments include methotrexate 7.5 to 25 mg once weekly, thalidomide 50 to 100 mg daily, and quinacrine. However, quinacrine is not currently commercially available. Thalidomide and quinacrine represented useful alternatives when hydroxychloroquine monotherapy failed. As with other immunomodulators, adverse effects should be monitored periodically.

Conclusion

Lupus erythematosus tumidus is characterized by erythematous papules and plaques that may be tender or pruritic. It follows an intermittent course and rarely is associated with SLE. Hydroxychloroquine is considered the first-line systemic treatment; however, recalcitrant disease could be managed with other immunomodulators, including methotrexate, thalidomide, or quinacrine.

Lupus erythematosus tumidus (LET) is a rare photosensitive dermatosis¹ that previously was considered a subtype of chronic cutaneous lupus erythematosus; however, the clinical course and favorable prognosis of LET led to its reclassification into another category, called intermittent cutaneous lupus erythematosus.² Although known about for more than 100 years, the association of LET with systemic lupus erythematosus (SLE), its autoantibody profile, and its prognosis are not well characterized. The purpose of this study was to describe the demographics, clinical characteristics, autoantibody profile, comorbidities, and treatment of LET based on a retrospective review of patients with LET.

Methods

A retrospective review was conducted in patients with histologically diagnosed LET who presented to the Department of Dermatology at the Wake Forest School of Medicine (Winston-Salem, North Carolina) over 6 years (July 2012 to July 2018). Inclusion criteria included males or females aged 18 to 75 years with clinical and histopathology-proven LET, which was defined as a superficial and deep lymphocytic infiltrate with abundant mucin deposition in the reticular dermis and absent or focal dermoepidermal junction alterations. Exclusion criteria included males or females younger than 18 years or older than 75 years or patients without clinical and histopathologically proven LET. Medical records were evaluated for demographics, clinical characteristics, diagnoses, autoantibodies, treatment, and recurrence. Photosensitivity was confirmed by clinical history. This study was approved by the Wake Forest School of Medicine institutional review board.

Results

Twenty-five patients were included in the study (eTable). The mean age (SD) at diagnosis was 46 (10.9) years, with a male to female ratio of 1:4. Twenty-two (88%) patients were White non-Hispanic, whereas 3 (12%) were Black. Lupus erythematosus tumidus most commonly affected the trunk (18/25 [72%]) and upper extremities (18/25 [72%]), followed by the head and neck (15/25 [60%]) and lower extremities (8/25 [32%])(Figure 1). The most common morphologies were plaques (18/25 [72%]), papules (17/25 [68%]), and nodules (6/25 [24%])(Figures 2 and 3). Most patients experienced painful (14/25 [56%]) or pruritic (13/25 [52%]) lesions as well as photosensitivity (13/25 [52%]). Of all measured autoantibodies, 5 of 22 (23%) patients had positive antinuclear antibody (ANA) titers greater than 1:80, 1 of 14 (7%) patients had positive anti-Ro (anti-SSA), 1 of 14 (7%) had positive anti-La (anti-SSB), 2 of 10 (20%) had positive anti–double-stranded DNA, and 0 of 6 (0%) patients had positive anti-Smith antibodies. Four (16%) patients with SLE had skin and joint involvement, whereas 1 had lupus nephritis. One (4%) patient had discoid lupus erythematosus (DLE). Seventeen (68%) patients reported recurrences or flares. The mean duration of symptoms (SD) was 28 (44) months.

Topical corticosteroids (21/25 [84%]) and hydroxychloroquine (20/25 [80%]) were the most commonly prescribed treatments. Hydroxychloroquine monotherapy achieved clearance or almost clearance in 12 (60%) patients. Four patients were prescribed thalidomide after hydroxychloroquine monotherapy failed; 2 achieved complete clearance with thalidomide and hydroxychloroquine, 1 achieved complete clearance with thalidomide monotherapy, and 1 improved but did not clear. Four patients were concurrently started on quinacrine (mepacrine) after hydroxychloroquine monotherapy failed; 1 patient had no clearance, 1 discontinued because of allergy, 1 improved, and 1 cleared. Four patients had short courses of prednisone lasting 1 to 4 weeks. Three of 4 patients treated with methotrexate discontinued because of adverse effects, and 1 patient improved. Other prescribed treatments included topical calcineurin inhibitors (10/25 [40%]), dapsone (1/25 [4%]), and clofazimine (1/25 [4%]).

Comment

Prevalence of LET—Although other European LET case series reported a male predominance or equal male to female ratio, our case series reported female predominance (1:4).^1,3-5 Our male to female ratio resembles similar ratios in DLE and subacute lupus erythematosus, whereas relative to our study, SLE male to female ratios favored females over males.^6,7

Clinical Distribution of LET—In one study enrolling 24 patients with LET, 79% (19/24) of patients had facial involvement, 50% (12/24) had V-neck involvement, 50% (12/24) had back involvement, and 46% (11/24) had arm involvement,² whereas our study reported 72% involvement of the trunk, 72% involvement of the upper extremities, 60% involvement of the head and neck region, and 32% involvement of the lower extremities. Although our study reported more lower extremity involvement, the aforementioned study used precise topographic locations, whereas we used more generalized topographic locations. Therefore, it was difficult to compare disease distribution between both studies.²

Presence of Autoantibodies and Comorbidities—Of the 22 patients tested for ANA, 23% reported titers greater than 1:80, similar to the 20% positive ANA prevalence in an LET case series of 25 patients.⁵ Of 4 patients diagnosed with SLE, 3 had articular and skin involvement, and 1 had renal involvement. These findings resemble a similar LET case series.² Nonetheless, given the numerous skin criteria in the American College of Rheumatology SLE classification criteria, patients with predominant skin disease and positive autoantibodies are diagnosed as having SLE without notable extracutaneous involvement.² Therefore, SLE diagnosis in the setting of LET could be reassessed periodically in this population. One patient in our study was diagnosed with DLE several years later. It is uncommon for LET to be reported concomitantly with DLE.⁸

Treatment of LET—Evidence supporting efficacious treatment options for LET is limited to case series. Sun protection is recommended in all patients with LET. Earlier case series reported a high response rate with sun protection and topical corticosteroids, with 19% to 55% of patients requiring subsequent systemic antimalarials.^3,4 However, one case series presented a need for systemic antimalarials,⁵ similar to our study. Hydroxychloroquine 200 to 400 mg daily is considered the first-line systemic treatment for LET. Its response rate varies among studies and may be influenced by dosage.^1,3 Second-line treatments include methotrexate 7.5 to 25 mg once weekly, thalidomide 50 to 100 mg daily, and quinacrine. However, quinacrine is not currently commercially available. Thalidomide and quinacrine represented useful alternatives when hydroxychloroquine monotherapy failed. As with other immunomodulators, adverse effects should be monitored periodically.

Conclusion

Lupus erythematosus tumidus is characterized by erythematous papules and plaques that may be tender or pruritic. It follows an intermittent course and rarely is associated with SLE. Hydroxychloroquine is considered the first-line systemic treatment; however, recalcitrant disease could be managed with other immunomodulators, including methotrexate, thalidomide, or quinacrine.

Airbags are lifesaving during motor vehicle accidents (MVAs), but their deployment has been associated with skin issues such as irritant dermatitis¹; lacerations²; abrasions³; and thermal, friction, and chemical burns.^4-6 Ocular issues such as alkaline chemical keratitis⁷ and ocular alkali injuries⁸ also have been described.

Airbag deployment is triggered by rapid deceleration and impact, which ignite a sodium azide cartridge, causing the woven nylon bag to inflate with hydrocarbon gases.⁸ This leads to release of sodium hydroxide, sodium bicarbonate, and metallic oxides in an aerosolized form. If a tear in the meshwork of the airbag occurs, exposure to an even larger amount of powder containing caustic alkali chemicals can occur.⁸

We describe a patient who developed a bullous reaction to airbag contents after he was involved in an MVA in which the airbag deployed.

Case Report

A 35-year-old man with a history of type 2 diabetes mellitus and chronic hepatitis B presented to the dermatology clinic for an evaluation of new-onset blisters. The rash occurred 1 day after the patient was involved in an MVA in which he was exposed to the airbag’s contents after it burst. He had been evaluated twice in the emergency department for the skin eruption before being referred to dermatology. He noted the lesions were pruritic and painful. Prior treatments included silver sulfadiazine cream 1% and clobetasol cream 0.05%, though he discontinued using the latter because of burning with application. Physical examination revealed tense vesicles and bullae on an erythematous base on the right lower flank, forearms, and legs, with the exception of the lower right leg where a cast had been from a prior injury (Figure 1).

Two punch biopsies of the left arm were performed and sent for hematoxylin and eosin staining and direct immunofluorescence to rule out bullous diseases, such as bullous pemphigoid, linear IgA, and bullous lupus. Hematoxylin and eosin staining revealed extensive spongiosis with blister formation and a dense perivascular infiltrate in the superficial and mid dermis composed of lymphocytes with numerous scattered eosinophils (Figures 2 and 3). Direct immunofluorescence studies were negative. Treatment with oral prednisone and oral antihistamines was initiated.

At 10-day follow-up, the patient had a few residual bullae; most lesions were demonstrating various stages of healing (Figure 4). The patient’s cast had been removed, and there were no lesions in this previously covered area. At 6-week follow-up he had continued healing of the bullae and erosions as well as postinflammatory hyperpigmentation (Figure 5).

Comment

With the advent of airbags for safety purposes, these potentially lifesaving devices also have been known to cause injury.⁹ In 1998, the most commonly reported airbag injuries were ocular injuries.¹⁰ Cutaneous manifestations of airbag injury are less well known.¹¹

Two cases of airbag deployment with skin blistering have been reported in the literature based on a PubMed search of articles indexed for MEDLINE using the terms airbag blistering or airbag bullae^12,13; however, the blistering was described in the context of a burn. One case of the effects of airbag deployment residue highlights a patient arriving to the emergency department with erythema and blisters on the hands within 48 hours of airbag deployment in an MVA, and the treatment was standard burn therapy.¹² Another case report described a patient with a second-degree burn with a 12-cm blister occurring on the radial side of the hand and distal forearm following an MVA and airbag deployment, which was treated conservatively.¹³ Cases of thermal burns, chemical burns, and irritant contact dermatitis after airbag deployment have been described in the literature.^{4-6,11,12,14,15} Our patient’s distal right lower leg was covered with a cast for osteomyelitis, and no blisters had developed in this area. It is likely that the transfer of airbag contents occurred during the process of unbuckling his seatbelt, which could explain the bullae that developed on the right flank. Per the Centers for Disease Control and Prevention, individuals should quickly remove clothing and wash their body with large amounts of soap and water following exposure to sodium azide.¹⁶

In 1989, the Federal Motor Vehicle Safety Standard No. 208 (occupant crash protection) became effective, stating all cars must have vehicle crash protection.¹² Prior to 1993, it was reported that there had been no associated chemical injuries with airbag deployment. Subsequently, a 6-month retrospective study in 1993 showed that dermal injuries were found in connection with the presence of sodium hydroxide in automobile airbags.¹² By 2004, it was known that airbags could cause chemical and thermal burns in addition to traumatic injuries from deployment.¹ Since 2007, all motor vehicles have been required to have advanced airbags, which are engineered to sense the presence of passengers and determine if the airbag will deploy, and if so, how much to deploy to minimize airbag-related injury.³

The brand of car that our patient drove during the MVA is one with known airbag recalls due to safety defects; however, the year and actual model of the vehicle are not known, so specific information about the airbag in question is not available. It has been noted that some defective airbag inflators that were exposed to excess moisture during the manufacturing process could explode during deployment, causing shrapnel and airbag rupture, which has been linked to nearly 300 injuries worldwide.¹⁷

Conclusion

It is evident that the use of airbag devices reduces morbidity and mortality due to MVAs.⁹ It also had been reported that up to 96% of airbag-related injuries are relatively minor, which many would argue justifies their use.¹⁸ Furthermore, it has been reported that 99.8% of skin injuries following airbag deployment are minor.¹⁹ In the United States, it is mandated that every vehicle have functional airbags installed.⁸

This case highlights the potential for substantial airbag-induced skin reactions, specifically a bullous reaction, following airbag deployment. The persistent pruritus and lasting postinflammatory hyperpigmentation seen in this case were certainly worrisome for our patient. We also present this case to remind dermatology providers of possible treatment approaches to these skin reactions. Immediate cleansing of the affected areas of skin may help avoid such reactions.

Airbags are lifesaving during motor vehicle accidents (MVAs), but their deployment has been associated with skin issues such as irritant dermatitis¹; lacerations²; abrasions³; and thermal, friction, and chemical burns.^4-6 Ocular issues such as alkaline chemical keratitis⁷ and ocular alkali injuries⁸ also have been described.

Airbag deployment is triggered by rapid deceleration and impact, which ignite a sodium azide cartridge, causing the woven nylon bag to inflate with hydrocarbon gases.⁸ This leads to release of sodium hydroxide, sodium bicarbonate, and metallic oxides in an aerosolized form. If a tear in the meshwork of the airbag occurs, exposure to an even larger amount of powder containing caustic alkali chemicals can occur.⁸

We describe a patient who developed a bullous reaction to airbag contents after he was involved in an MVA in which the airbag deployed.

Case Report

A 35-year-old man with a history of type 2 diabetes mellitus and chronic hepatitis B presented to the dermatology clinic for an evaluation of new-onset blisters. The rash occurred 1 day after the patient was involved in an MVA in which he was exposed to the airbag’s contents after it burst. He had been evaluated twice in the emergency department for the skin eruption before being referred to dermatology. He noted the lesions were pruritic and painful. Prior treatments included silver sulfadiazine cream 1% and clobetasol cream 0.05%, though he discontinued using the latter because of burning with application. Physical examination revealed tense vesicles and bullae on an erythematous base on the right lower flank, forearms, and legs, with the exception of the lower right leg where a cast had been from a prior injury (Figure 1).

Two punch biopsies of the left arm were performed and sent for hematoxylin and eosin staining and direct immunofluorescence to rule out bullous diseases, such as bullous pemphigoid, linear IgA, and bullous lupus. Hematoxylin and eosin staining revealed extensive spongiosis with blister formation and a dense perivascular infiltrate in the superficial and mid dermis composed of lymphocytes with numerous scattered eosinophils (Figures 2 and 3). Direct immunofluorescence studies were negative. Treatment with oral prednisone and oral antihistamines was initiated.

At 10-day follow-up, the patient had a few residual bullae; most lesions were demonstrating various stages of healing (Figure 4). The patient’s cast had been removed, and there were no lesions in this previously covered area. At 6-week follow-up he had continued healing of the bullae and erosions as well as postinflammatory hyperpigmentation (Figure 5).

Comment

With the advent of airbags for safety purposes, these potentially lifesaving devices also have been known to cause injury.⁹ In 1998, the most commonly reported airbag injuries were ocular injuries.¹⁰ Cutaneous manifestations of airbag injury are less well known.¹¹

Two cases of airbag deployment with skin blistering have been reported in the literature based on a PubMed search of articles indexed for MEDLINE using the terms airbag blistering or airbag bullae^12,13; however, the blistering was described in the context of a burn. One case of the effects of airbag deployment residue highlights a patient arriving to the emergency department with erythema and blisters on the hands within 48 hours of airbag deployment in an MVA, and the treatment was standard burn therapy.¹² Another case report described a patient with a second-degree burn with a 12-cm blister occurring on the radial side of the hand and distal forearm following an MVA and airbag deployment, which was treated conservatively.¹³ Cases of thermal burns, chemical burns, and irritant contact dermatitis after airbag deployment have been described in the literature.^{4-6,11,12,14,15} Our patient’s distal right lower leg was covered with a cast for osteomyelitis, and no blisters had developed in this area. It is likely that the transfer of airbag contents occurred during the process of unbuckling his seatbelt, which could explain the bullae that developed on the right flank. Per the Centers for Disease Control and Prevention, individuals should quickly remove clothing and wash their body with large amounts of soap and water following exposure to sodium azide.¹⁶

In 1989, the Federal Motor Vehicle Safety Standard No. 208 (occupant crash protection) became effective, stating all cars must have vehicle crash protection.¹² Prior to 1993, it was reported that there had been no associated chemical injuries with airbag deployment. Subsequently, a 6-month retrospective study in 1993 showed that dermal injuries were found in connection with the presence of sodium hydroxide in automobile airbags.¹² By 2004, it was known that airbags could cause chemical and thermal burns in addition to traumatic injuries from deployment.¹ Since 2007, all motor vehicles have been required to have advanced airbags, which are engineered to sense the presence of passengers and determine if the airbag will deploy, and if so, how much to deploy to minimize airbag-related injury.³

The brand of car that our patient drove during the MVA is one with known airbag recalls due to safety defects; however, the year and actual model of the vehicle are not known, so specific information about the airbag in question is not available. It has been noted that some defective airbag inflators that were exposed to excess moisture during the manufacturing process could explode during deployment, causing shrapnel and airbag rupture, which has been linked to nearly 300 injuries worldwide.¹⁷

Conclusion

It is evident that the use of airbag devices reduces morbidity and mortality due to MVAs.⁹ It also had been reported that up to 96% of airbag-related injuries are relatively minor, which many would argue justifies their use.¹⁸ Furthermore, it has been reported that 99.8% of skin injuries following airbag deployment are minor.¹⁹ In the United States, it is mandated that every vehicle have functional airbags installed.⁸

This case highlights the potential for substantial airbag-induced skin reactions, specifically a bullous reaction, following airbag deployment. The persistent pruritus and lasting postinflammatory hyperpigmentation seen in this case were certainly worrisome for our patient. We also present this case to remind dermatology providers of possible treatment approaches to these skin reactions. Immediate cleansing of the affected areas of skin may help avoid such reactions.

Airbags are lifesaving during motor vehicle accidents (MVAs), but their deployment has been associated with skin issues such as irritant dermatitis¹; lacerations²; abrasions³; and thermal, friction, and chemical burns.^4-6 Ocular issues such as alkaline chemical keratitis⁷ and ocular alkali injuries⁸ also have been described.

Airbag deployment is triggered by rapid deceleration and impact, which ignite a sodium azide cartridge, causing the woven nylon bag to inflate with hydrocarbon gases.⁸ This leads to release of sodium hydroxide, sodium bicarbonate, and metallic oxides in an aerosolized form. If a tear in the meshwork of the airbag occurs, exposure to an even larger amount of powder containing caustic alkali chemicals can occur.⁸

We describe a patient who developed a bullous reaction to airbag contents after he was involved in an MVA in which the airbag deployed.

Case Report

A 35-year-old man with a history of type 2 diabetes mellitus and chronic hepatitis B presented to the dermatology clinic for an evaluation of new-onset blisters. The rash occurred 1 day after the patient was involved in an MVA in which he was exposed to the airbag’s contents after it burst. He had been evaluated twice in the emergency department for the skin eruption before being referred to dermatology. He noted the lesions were pruritic and painful. Prior treatments included silver sulfadiazine cream 1% and clobetasol cream 0.05%, though he discontinued using the latter because of burning with application. Physical examination revealed tense vesicles and bullae on an erythematous base on the right lower flank, forearms, and legs, with the exception of the lower right leg where a cast had been from a prior injury (Figure 1).

Two punch biopsies of the left arm were performed and sent for hematoxylin and eosin staining and direct immunofluorescence to rule out bullous diseases, such as bullous pemphigoid, linear IgA, and bullous lupus. Hematoxylin and eosin staining revealed extensive spongiosis with blister formation and a dense perivascular infiltrate in the superficial and mid dermis composed of lymphocytes with numerous scattered eosinophils (Figures 2 and 3). Direct immunofluorescence studies were negative. Treatment with oral prednisone and oral antihistamines was initiated.

At 10-day follow-up, the patient had a few residual bullae; most lesions were demonstrating various stages of healing (Figure 4). The patient’s cast had been removed, and there were no lesions in this previously covered area. At 6-week follow-up he had continued healing of the bullae and erosions as well as postinflammatory hyperpigmentation (Figure 5).

Comment

With the advent of airbags for safety purposes, these potentially lifesaving devices also have been known to cause injury.⁹ In 1998, the most commonly reported airbag injuries were ocular injuries.¹⁰ Cutaneous manifestations of airbag injury are less well known.¹¹

Two cases of airbag deployment with skin blistering have been reported in the literature based on a PubMed search of articles indexed for MEDLINE using the terms airbag blistering or airbag bullae^12,13; however, the blistering was described in the context of a burn. One case of the effects of airbag deployment residue highlights a patient arriving to the emergency department with erythema and blisters on the hands within 48 hours of airbag deployment in an MVA, and the treatment was standard burn therapy.¹² Another case report described a patient with a second-degree burn with a 12-cm blister occurring on the radial side of the hand and distal forearm following an MVA and airbag deployment, which was treated conservatively.¹³ Cases of thermal burns, chemical burns, and irritant contact dermatitis after airbag deployment have been described in the literature.^{4-6,11,12,14,15} Our patient’s distal right lower leg was covered with a cast for osteomyelitis, and no blisters had developed in this area. It is likely that the transfer of airbag contents occurred during the process of unbuckling his seatbelt, which could explain the bullae that developed on the right flank. Per the Centers for Disease Control and Prevention, individuals should quickly remove clothing and wash their body with large amounts of soap and water following exposure to sodium azide.¹⁶

In 1989, the Federal Motor Vehicle Safety Standard No. 208 (occupant crash protection) became effective, stating all cars must have vehicle crash protection.¹² Prior to 1993, it was reported that there had been no associated chemical injuries with airbag deployment. Subsequently, a 6-month retrospective study in 1993 showed that dermal injuries were found in connection with the presence of sodium hydroxide in automobile airbags.¹² By 2004, it was known that airbags could cause chemical and thermal burns in addition to traumatic injuries from deployment.¹ Since 2007, all motor vehicles have been required to have advanced airbags, which are engineered to sense the presence of passengers and determine if the airbag will deploy, and if so, how much to deploy to minimize airbag-related injury.³

The brand of car that our patient drove during the MVA is one with known airbag recalls due to safety defects; however, the year and actual model of the vehicle are not known, so specific information about the airbag in question is not available. It has been noted that some defective airbag inflators that were exposed to excess moisture during the manufacturing process could explode during deployment, causing shrapnel and airbag rupture, which has been linked to nearly 300 injuries worldwide.¹⁷

Conclusion

It is evident that the use of airbag devices reduces morbidity and mortality due to MVAs.⁹ It also had been reported that up to 96% of airbag-related injuries are relatively minor, which many would argue justifies their use.¹⁸ Furthermore, it has been reported that 99.8% of skin injuries following airbag deployment are minor.¹⁹ In the United States, it is mandated that every vehicle have functional airbags installed.⁸

This case highlights the potential for substantial airbag-induced skin reactions, specifically a bullous reaction, following airbag deployment. The persistent pruritus and lasting postinflammatory hyperpigmentation seen in this case were certainly worrisome for our patient. We also present this case to remind dermatology providers of possible treatment approaches to these skin reactions. Immediate cleansing of the affected areas of skin may help avoid such reactions.

In the 2021-2022 residency application cycle, the Association of American Medical Colleges (AAMC) piloted a supplemental application to accompany the standard residency application submitted via the AAMC’s Electronic Residency Application Service (ERAS).¹ Dermatology was 1 of 3 specialties to participate in the pilot alongside internal medicine and general surgery. The goal was to develop a tool that could align applicants with programs that best matched their career goals as well as program and geographic preferences. The Association of Professors of Dermatology Residency Program Directors Section was an early advocate for the supplemental application, and members of our leadership were involved in the design, implementation, and evaluation of the pilot supplemental application.

Participating in the supplemental application was optional for both applicants and programs. The supplemental application included a Past Experiences section, which allowed applicants to highlight their 5 most meaningful research, work, and/or volunteer experiences and to describe a challenging life event that might not otherwise be included with their application. The geographic preferences section permitted applicants to select up to 3 regions of interest as well as to indicate an urban vs rural preference. Lastly, a preference-signaling section allowed dermatology applicants to send signals to up to 3 programs of particular interest.

With the close of another application cycle, applicants and programs will begin preparing for the 2022-2023 recruitment season. In this column, we present dermatology-specific data regarding the supplemental application, highlight tentative changes for the upcoming application cycle, and offer tips for applicants and programs as we approach year 2 of the supplemental application.

Results of Supplemental Application Evaluation Surveys

During the 2021-2022 recruitment season, 93% (950/1019) of dermatology applicants submitted the supplemental application, and 87% (117/135) of dermatology residency programs participated in the pilot.² Surveys conducted by the AAMC between October 2021 and January 2022 showed that a large majority of dermatology programs used supplemental application data during initial application review when deciding who to interview. Eighty-three percent (40/48) of program directors felt that preference signals in particular helped them identify applicants they would have otherwise overlooked. Fifty-seven percent (4288/7516) of applicants across all specialties that participated in the pilot felt that preference signals would help them be noticed by their preferred programs.² Preference signals were not evenly distributed among dermatology programs. Programs received an average of 23 signals, with a range of 2 to 87 (AAMC, unpublished data, February 2022).

Additional questions remain to be answered: How does the number of signals received affect application review? How often do geographic and program signals convert to interview offers and matches? Regardless, enthusiasm among dermatology programs for the supplemental application remains. In a recent survey of Association of Professors of Dermatology program directors, all 43 respondents planned to participate in the supplemental application again in the upcoming year (Ilana Rosman, MD; unpublished data; February 2022). The pilot will be expanded to include at least 12 other specialties.¹As many who reviewed residency applications in 2021-2022 will attest, there was difficulty accessing the supplemental application data because it was not integrated into the Program Directors’ Work Station, the ERAS platform for programs to access applications, which will be remedied for the 2022-2023 iteration. Other tentative changes include modifications to the past experiences sections and timeline of the application.²

Utilizing the Supplemental Application: Recommendations to Applicants

Format of the Application—Applicants should familiarize themselves with the format of the supplemental application in advance and give themselves sufficient time to complete the application. In general, 3 to 4 hours of focused work should be enough time. Applicants should proofread for grammar and spelling before submitting.

Past Experiences—The past experiences section is intended to provide a focused snapshot of an applicant’s most meaningful activities and unique path to residency. Applicants should answer honestly based on their interests. If a student’s focus has been on volunteerism, the bulk of their 5 experiences listed may be related to service. Similarly, a student who has focused on research may preferentially highlight those experiences. In place of the long list of research, volunteer, and work experiences in the traditional ERAS application, applicants can highlight those activities in which they have been most invested. Applicants are encouraged to reflect on all genres of activities at any stage of their careers, even those not medical in nature, including work experience, military service, college athletics, or sustained musical or artistic achievement. Applicants should explain why each experience is meaningful rather than simply describing the activity.

Applicants also have the option to share a notable challenge they have overcome. It is not expected that each applicant will complete this question; in general, applicants who have not faced notable personal or professional obstacles should avoid answering. Additionally, if these challenges have been discussed in other areas of the application—for example, in the personal statement or medical student performance evaluation—it is not necessary to restate them here, though applicants can choose to do so. Examples of topics a student might discuss include being a first-generation college or medical student, growing up in poverty, facing notable personal or family health challenges, or having limited educational opportunities. It is important to share how this experience impacted an applicant’s journey to dermatology residency.

Geographic Preferences—The geographic preferences section can be difficult for applicants to navigate, as it may involve balancing a desire to attend a residency program in a particular region vs a greater desire to simply match in dermatology. In the past, programs may have made assumptions about geographic preferences based on an applicant’s birthplace, hometown, or medical school. In the supplemental application, applicants have the opportunity to directly reveal their preferences. We encourage applicants to be candid. Selecting a geographic region will not necessarily exclude applicants from consideration at other programs. For some applicants, program qualities may be more important than geography, or there may be no regional preferences. Those applicants can choose “no geographic preference.” There is considerable variability in how programs use geographic preferences. For this reason, it is in the best interest of applicants to simply respond honestly.

Preference Signaling—Preference signaling allows applicants to signal up to 3 preferred programs. Dermatology program directors agree that applicants should not signal their home program or programs at which they did in-person away rotations, as those programs would already be aware of the applicant’s interest. Although a signal increases the chances that the application will be reviewed holistically, it does not guarantee an interview offer. Programs may differentially utilize signals depending on multiple factors, including the number of signals received. We encourage applicants to discuss preference signaling strategies with advisors and focus on signaling programs in which they have genuine interest.

Recommendations to Selection Committees and Program Directors

The intent of the supplemental application is to provide a more meaningful picture of applicants and their experiences and preferences, with the goal of optimizing applicant-program fit. Programs should explicitly define for themselves the applicant characteristics and experiences they prioritize as well as their program goals. The supplemental application offers the potential to streamline holistic application review based on these elements. The short essay answers in the past experiences section permit reviewers to quickly scan for important experiences that align with the program’s recruitment goals. Importantly, reviewers should not penalize applicants who have not completed the question regarding other impactful life experiences, as not all applicants will have relevant information to share.

Some programs may find the geographic preferences section more valuable than others. Multiple factors affect how much weight will be given to geographic preferences, including program location and other characteristics that affect the desirability of the program to applicants. The competitiveness of the field, relatively low match rate, and limited number of programs may lead to less emphasis on geographic preferences in dermatology compared to other specialties. The purpose of this section is not to exclude applicants but to give programs more information that may help with alignment.

Anecdotally, many dermatology program directors were most interested in the preference signaling section of the supplemental application. Programs should consider signals to be evidence of strong preliminary interest. Programs may utilize signals differently depending on many factors such as the overall competitiveness of the program, program location, and the total number of signals the program receives. We recommend that programs holistically review all applications accompanied by a signal. Programs that utilize a points system may choose to award a certain number of points for a signal to their program. A signal might have a higher value at a program that receives only a few signals; conversely, a program that receives a large number of signals might not place tremendous value on the signal but may use it as a tiebreaker between similarly qualified applicants. Preference signaling is solely a tool for application review; because applicants’ preferences may change after the interview process, signals should not be utilized during ranking.

Next Steps

For program directors who have excitedly awaited residency application reform, the supplemental ERAS application is an important first step. Ultimately, we hope the supplemental application supplants much of the current residency application, serving as an efficient high-yield tool for holistically evaluating applicants’ academic and service records, accomplishments, and training preferences. Arriving at a new application will undoubtedly take time and discussion among the various stakeholders. Please continue to complete surveys from the AAMC, as feedback is the best method for refining the tool to serve its intended purpose.

Optimization of the application content is only one component of the reforms needed to improve the application process. Even with a revamped application tool, holistic review is challenging when programs are inundated with an ever-increasing number of applications. As such, we encourage stakeholders to simultaneously consider other potential reforms, such as caps on the number of applications, to allow programs and applicants the best opportunity for a mutually successful match.

In the 2021-2022 residency application cycle, the Association of American Medical Colleges (AAMC) piloted a supplemental application to accompany the standard residency application submitted via the AAMC’s Electronic Residency Application Service (ERAS).¹ Dermatology was 1 of 3 specialties to participate in the pilot alongside internal medicine and general surgery. The goal was to develop a tool that could align applicants with programs that best matched their career goals as well as program and geographic preferences. The Association of Professors of Dermatology Residency Program Directors Section was an early advocate for the supplemental application, and members of our leadership were involved in the design, implementation, and evaluation of the pilot supplemental application.

Participating in the supplemental application was optional for both applicants and programs. The supplemental application included a Past Experiences section, which allowed applicants to highlight their 5 most meaningful research, work, and/or volunteer experiences and to describe a challenging life event that might not otherwise be included with their application. The geographic preferences section permitted applicants to select up to 3 regions of interest as well as to indicate an urban vs rural preference. Lastly, a preference-signaling section allowed dermatology applicants to send signals to up to 3 programs of particular interest.

With the close of another application cycle, applicants and programs will begin preparing for the 2022-2023 recruitment season. In this column, we present dermatology-specific data regarding the supplemental application, highlight tentative changes for the upcoming application cycle, and offer tips for applicants and programs as we approach year 2 of the supplemental application.

Results of Supplemental Application Evaluation Surveys

During the 2021-2022 recruitment season, 93% (950/1019) of dermatology applicants submitted the supplemental application, and 87% (117/135) of dermatology residency programs participated in the pilot.² Surveys conducted by the AAMC between October 2021 and January 2022 showed that a large majority of dermatology programs used supplemental application data during initial application review when deciding who to interview. Eighty-three percent (40/48) of program directors felt that preference signals in particular helped them identify applicants they would have otherwise overlooked. Fifty-seven percent (4288/7516) of applicants across all specialties that participated in the pilot felt that preference signals would help them be noticed by their preferred programs.² Preference signals were not evenly distributed among dermatology programs. Programs received an average of 23 signals, with a range of 2 to 87 (AAMC, unpublished data, February 2022).

Additional questions remain to be answered: How does the number of signals received affect application review? How often do geographic and program signals convert to interview offers and matches? Regardless, enthusiasm among dermatology programs for the supplemental application remains. In a recent survey of Association of Professors of Dermatology program directors, all 43 respondents planned to participate in the supplemental application again in the upcoming year (Ilana Rosman, MD; unpublished data; February 2022). The pilot will be expanded to include at least 12 other specialties.¹As many who reviewed residency applications in 2021-2022 will attest, there was difficulty accessing the supplemental application data because it was not integrated into the Program Directors’ Work Station, the ERAS platform for programs to access applications, which will be remedied for the 2022-2023 iteration. Other tentative changes include modifications to the past experiences sections and timeline of the application.²

Utilizing the Supplemental Application: Recommendations to Applicants

Format of the Application—Applicants should familiarize themselves with the format of the supplemental application in advance and give themselves sufficient time to complete the application. In general, 3 to 4 hours of focused work should be enough time. Applicants should proofread for grammar and spelling before submitting.

Past Experiences—The past experiences section is intended to provide a focused snapshot of an applicant’s most meaningful activities and unique path to residency. Applicants should answer honestly based on their interests. If a student’s focus has been on volunteerism, the bulk of their 5 experiences listed may be related to service. Similarly, a student who has focused on research may preferentially highlight those experiences. In place of the long list of research, volunteer, and work experiences in the traditional ERAS application, applicants can highlight those activities in which they have been most invested. Applicants are encouraged to reflect on all genres of activities at any stage of their careers, even those not medical in nature, including work experience, military service, college athletics, or sustained musical or artistic achievement. Applicants should explain why each experience is meaningful rather than simply describing the activity.

Applicants also have the option to share a notable challenge they have overcome. It is not expected that each applicant will complete this question; in general, applicants who have not faced notable personal or professional obstacles should avoid answering. Additionally, if these challenges have been discussed in other areas of the application—for example, in the personal statement or medical student performance evaluation—it is not necessary to restate them here, though applicants can choose to do so. Examples of topics a student might discuss include being a first-generation college or medical student, growing up in poverty, facing notable personal or family health challenges, or having limited educational opportunities. It is important to share how this experience impacted an applicant’s journey to dermatology residency.

Geographic Preferences—The geographic preferences section can be difficult for applicants to navigate, as it may involve balancing a desire to attend a residency program in a particular region vs a greater desire to simply match in dermatology. In the past, programs may have made assumptions about geographic preferences based on an applicant’s birthplace, hometown, or medical school. In the supplemental application, applicants have the opportunity to directly reveal their preferences. We encourage applicants to be candid. Selecting a geographic region will not necessarily exclude applicants from consideration at other programs. For some applicants, program qualities may be more important than geography, or there may be no regional preferences. Those applicants can choose “no geographic preference.” There is considerable variability in how programs use geographic preferences. For this reason, it is in the best interest of applicants to simply respond honestly.

Preference Signaling—Preference signaling allows applicants to signal up to 3 preferred programs. Dermatology program directors agree that applicants should not signal their home program or programs at which they did in-person away rotations, as those programs would already be aware of the applicant’s interest. Although a signal increases the chances that the application will be reviewed holistically, it does not guarantee an interview offer. Programs may differentially utilize signals depending on multiple factors, including the number of signals received. We encourage applicants to discuss preference signaling strategies with advisors and focus on signaling programs in which they have genuine interest.

Recommendations to Selection Committees and Program Directors

The intent of the supplemental application is to provide a more meaningful picture of applicants and their experiences and preferences, with the goal of optimizing applicant-program fit. Programs should explicitly define for themselves the applicant characteristics and experiences they prioritize as well as their program goals. The supplemental application offers the potential to streamline holistic application review based on these elements. The short essay answers in the past experiences section permit reviewers to quickly scan for important experiences that align with the program’s recruitment goals. Importantly, reviewers should not penalize applicants who have not completed the question regarding other impactful life experiences, as not all applicants will have relevant information to share.

Some programs may find the geographic preferences section more valuable than others. Multiple factors affect how much weight will be given to geographic preferences, including program location and other characteristics that affect the desirability of the program to applicants. The competitiveness of the field, relatively low match rate, and limited number of programs may lead to less emphasis on geographic preferences in dermatology compared to other specialties. The purpose of this section is not to exclude applicants but to give programs more information that may help with alignment.

Anecdotally, many dermatology program directors were most interested in the preference signaling section of the supplemental application. Programs should consider signals to be evidence of strong preliminary interest. Programs may utilize signals differently depending on many factors such as the overall competitiveness of the program, program location, and the total number of signals the program receives. We recommend that programs holistically review all applications accompanied by a signal. Programs that utilize a points system may choose to award a certain number of points for a signal to their program. A signal might have a higher value at a program that receives only a few signals; conversely, a program that receives a large number of signals might not place tremendous value on the signal but may use it as a tiebreaker between similarly qualified applicants. Preference signaling is solely a tool for application review; because applicants’ preferences may change after the interview process, signals should not be utilized during ranking.

Next Steps

For program directors who have excitedly awaited residency application reform, the supplemental ERAS application is an important first step. Ultimately, we hope the supplemental application supplants much of the current residency application, serving as an efficient high-yield tool for holistically evaluating applicants’ academic and service records, accomplishments, and training preferences. Arriving at a new application will undoubtedly take time and discussion among the various stakeholders. Please continue to complete surveys from the AAMC, as feedback is the best method for refining the tool to serve its intended purpose.

Optimization of the application content is only one component of the reforms needed to improve the application process. Even with a revamped application tool, holistic review is challenging when programs are inundated with an ever-increasing number of applications. As such, we encourage stakeholders to simultaneously consider other potential reforms, such as caps on the number of applications, to allow programs and applicants the best opportunity for a mutually successful match.

In the 2021-2022 residency application cycle, the Association of American Medical Colleges (AAMC) piloted a supplemental application to accompany the standard residency application submitted via the AAMC’s Electronic Residency Application Service (ERAS).¹ Dermatology was 1 of 3 specialties to participate in the pilot alongside internal medicine and general surgery. The goal was to develop a tool that could align applicants with programs that best matched their career goals as well as program and geographic preferences. The Association of Professors of Dermatology Residency Program Directors Section was an early advocate for the supplemental application, and members of our leadership were involved in the design, implementation, and evaluation of the pilot supplemental application.

Participating in the supplemental application was optional for both applicants and programs. The supplemental application included a Past Experiences section, which allowed applicants to highlight their 5 most meaningful research, work, and/or volunteer experiences and to describe a challenging life event that might not otherwise be included with their application. The geographic preferences section permitted applicants to select up to 3 regions of interest as well as to indicate an urban vs rural preference. Lastly, a preference-signaling section allowed dermatology applicants to send signals to up to 3 programs of particular interest.

With the close of another application cycle, applicants and programs will begin preparing for the 2022-2023 recruitment season. In this column, we present dermatology-specific data regarding the supplemental application, highlight tentative changes for the upcoming application cycle, and offer tips for applicants and programs as we approach year 2 of the supplemental application.

Results of Supplemental Application Evaluation Surveys

During the 2021-2022 recruitment season, 93% (950/1019) of dermatology applicants submitted the supplemental application, and 87% (117/135) of dermatology residency programs participated in the pilot.² Surveys conducted by the AAMC between October 2021 and January 2022 showed that a large majority of dermatology programs used supplemental application data during initial application review when deciding who to interview. Eighty-three percent (40/48) of program directors felt that preference signals in particular helped them identify applicants they would have otherwise overlooked. Fifty-seven percent (4288/7516) of applicants across all specialties that participated in the pilot felt that preference signals would help them be noticed by their preferred programs.² Preference signals were not evenly distributed among dermatology programs. Programs received an average of 23 signals, with a range of 2 to 87 (AAMC, unpublished data, February 2022).

Additional questions remain to be answered: How does the number of signals received affect application review? How often do geographic and program signals convert to interview offers and matches? Regardless, enthusiasm among dermatology programs for the supplemental application remains. In a recent survey of Association of Professors of Dermatology program directors, all 43 respondents planned to participate in the supplemental application again in the upcoming year (Ilana Rosman, MD; unpublished data; February 2022). The pilot will be expanded to include at least 12 other specialties.¹As many who reviewed residency applications in 2021-2022 will attest, there was difficulty accessing the supplemental application data because it was not integrated into the Program Directors’ Work Station, the ERAS platform for programs to access applications, which will be remedied for the 2022-2023 iteration. Other tentative changes include modifications to the past experiences sections and timeline of the application.²

Utilizing the Supplemental Application: Recommendations to Applicants

Format of the Application—Applicants should familiarize themselves with the format of the supplemental application in advance and give themselves sufficient time to complete the application. In general, 3 to 4 hours of focused work should be enough time. Applicants should proofread for grammar and spelling before submitting.

Past Experiences—The past experiences section is intended to provide a focused snapshot of an applicant’s most meaningful activities and unique path to residency. Applicants should answer honestly based on their interests. If a student’s focus has been on volunteerism, the bulk of their 5 experiences listed may be related to service. Similarly, a student who has focused on research may preferentially highlight those experiences. In place of the long list of research, volunteer, and work experiences in the traditional ERAS application, applicants can highlight those activities in which they have been most invested. Applicants are encouraged to reflect on all genres of activities at any stage of their careers, even those not medical in nature, including work experience, military service, college athletics, or sustained musical or artistic achievement. Applicants should explain why each experience is meaningful rather than simply describing the activity.

Applicants also have the option to share a notable challenge they have overcome. It is not expected that each applicant will complete this question; in general, applicants who have not faced notable personal or professional obstacles should avoid answering. Additionally, if these challenges have been discussed in other areas of the application—for example, in the personal statement or medical student performance evaluation—it is not necessary to restate them here, though applicants can choose to do so. Examples of topics a student might discuss include being a first-generation college or medical student, growing up in poverty, facing notable personal or family health challenges, or having limited educational opportunities. It is important to share how this experience impacted an applicant’s journey to dermatology residency.

Geographic Preferences—The geographic preferences section can be difficult for applicants to navigate, as it may involve balancing a desire to attend a residency program in a particular region vs a greater desire to simply match in dermatology. In the past, programs may have made assumptions about geographic preferences based on an applicant’s birthplace, hometown, or medical school. In the supplemental application, applicants have the opportunity to directly reveal their preferences. We encourage applicants to be candid. Selecting a geographic region will not necessarily exclude applicants from consideration at other programs. For some applicants, program qualities may be more important than geography, or there may be no regional preferences. Those applicants can choose “no geographic preference.” There is considerable variability in how programs use geographic preferences. For this reason, it is in the best interest of applicants to simply respond honestly.

Preference Signaling—Preference signaling allows applicants to signal up to 3 preferred programs. Dermatology program directors agree that applicants should not signal their home program or programs at which they did in-person away rotations, as those programs would already be aware of the applicant’s interest. Although a signal increases the chances that the application will be reviewed holistically, it does not guarantee an interview offer. Programs may differentially utilize signals depending on multiple factors, including the number of signals received. We encourage applicants to discuss preference signaling strategies with advisors and focus on signaling programs in which they have genuine interest.

Recommendations to Selection Committees and Program Directors

The intent of the supplemental application is to provide a more meaningful picture of applicants and their experiences and preferences, with the goal of optimizing applicant-program fit. Programs should explicitly define for themselves the applicant characteristics and experiences they prioritize as well as their program goals. The supplemental application offers the potential to streamline holistic application review based on these elements. The short essay answers in the past experiences section permit reviewers to quickly scan for important experiences that align with the program’s recruitment goals. Importantly, reviewers should not penalize applicants who have not completed the question regarding other impactful life experiences, as not all applicants will have relevant information to share.

Some programs may find the geographic preferences section more valuable than others. Multiple factors affect how much weight will be given to geographic preferences, including program location and other characteristics that affect the desirability of the program to applicants. The competitiveness of the field, relatively low match rate, and limited number of programs may lead to less emphasis on geographic preferences in dermatology compared to other specialties. The purpose of this section is not to exclude applicants but to give programs more information that may help with alignment.

Anecdotally, many dermatology program directors were most interested in the preference signaling section of the supplemental application. Programs should consider signals to be evidence of strong preliminary interest. Programs may utilize signals differently depending on many factors such as the overall competitiveness of the program, program location, and the total number of signals the program receives. We recommend that programs holistically review all applications accompanied by a signal. Programs that utilize a points system may choose to award a certain number of points for a signal to their program. A signal might have a higher value at a program that receives only a few signals; conversely, a program that receives a large number of signals might not place tremendous value on the signal but may use it as a tiebreaker between similarly qualified applicants. Preference signaling is solely a tool for application review; because applicants’ preferences may change after the interview process, signals should not be utilized during ranking.

Next Steps

For program directors who have excitedly awaited residency application reform, the supplemental ERAS application is an important first step. Ultimately, we hope the supplemental application supplants much of the current residency application, serving as an efficient high-yield tool for holistically evaluating applicants’ academic and service records, accomplishments, and training preferences. Arriving at a new application will undoubtedly take time and discussion among the various stakeholders. Please continue to complete surveys from the AAMC, as feedback is the best method for refining the tool to serve its intended purpose.

Optimization of the application content is only one component of the reforms needed to improve the application process. Even with a revamped application tool, holistic review is challenging when programs are inundated with an ever-increasing number of applications. As such, we encourage stakeholders to simultaneously consider other potential reforms, such as caps on the number of applications, to allow programs and applicants the best opportunity for a mutually successful match.

Disorders of hyperpigmentation—melasma, postinflammatory hyperpigmentation, lichen planus pigmentosus, erythema dyschromicum perstans, and pigmented contact dermatitis, among others—are common and challenging to treat. Although they can affect individuals of all skin types, they most commonly are seen in skin of color; in fact, dyspigmentation is one of the most common chief concerns for which individuals of color see a dermatologist.^1,2

For many years, hydroquinone (HQ) was one of the main options available for use as a lightening agent. Although effective, it has the risk of causing irritant dermatitis, potentially leading to further dyspigmentation, in addition to the risk of ochronosis with long-term use. It remains an important and useful treatment for pigmentary disorders, but there are numerous other lightening agents that also can be considered in the treatment of disorders of hyperpigmentation.

Herein, we provide recommendations for traditional and newer non-HQ lightening agents that can be considered when treating disorders of hyperpigmentation.

Traditional Non-HQ Lightening Agents

Retinoids—Retinoids are topical vitamin A derivatives that have been used safely and effectively for decades in the treatment of pigmentary disorders. Retinoids have multiple mechanisms of action in improving pigmentation. In addition to impeding tyrosinase induction, they inhibit pigment transfer to keratinocytes and lead to accelerated pigment loss due to epidermal shedding.³ Over-the-counter formulations include retinol, retinaldehyde, and adapalene. Prescription formulations include tretinoin and tazarotene in different strengths and vehicle formulations.⁴

Glycolic Acid—Glycolic acid is derived from sugarcane and is considered an α-hydroxy acid that leads to rapid desquamation of pigmented keratinocytes.⁵ Glycolic acid can not only be used in chemical peels but also in topical creams. It is the most common α-hydroxy acid peel and is sometimes paired with HQ and other topical lightening agents for increased penetration. Glycolic acid peels are available in concentrations of 20% to 70% and can be used at various depths. When used incorrectly, it can cause redness, burning, and even skin discoloration; however, when used at the proper concentrations and depth according to Fitzpatrick skin type, there typically are no notable adverse effects, and clinical results are favorable.

Kojic Acid—Kojic acid is a natural metabolite derived from fungi and is widely used in Asian countries. It works by inhibiting the catecholase activity of tyrosinase⁶ and typically is available in concentrations of 1% to 4%. A study suggested that a concentration of 1% or less typically is safe to use for prolonged periods without adverse effects. Although not more effective than HQ as a monotherapy, kojic acid has been shown to haveimproved efficacy when used in combination with other lightening agents.⁷

Azelaic Acid—Azelaic acid works by inhibiting tyrosinase, mitochondrial oxidoreductase activation, and DNA synthesis. It preferentially targets heavily pigmented melanocytes and possesses anti-inflammatory and antibacterial properties.⁸ A 20% concentration of azelaic acid was compared to HQ 4% for the treatment of melasma, and results revealed that the liposomal form of azelaic acid was considerably more tolerable than HQ 4% and also more effective.⁹

Licorice Extracts—Licorice extracts have been safely used in several cosmeceutical skin lightening products.¹⁰ The main active compounds in licorice root are glabridin and liquiritin, which work to disperse melanin. These compounds often are used topically at concentrations of 10% to 40%. A study by Amer and Metwalli¹¹ found that topical liquiritin produced a reduction of pigmentary intensity, with 80% of patients showing an excellent response, which was described as no difference between the previously pigmented area and the normal skin surrounding it.

Aloesin—Aloesin is a low-molecular-weight glycoprotein found in aloe vera plants. Its mechanism of action includes competitive inhibition of the dihydroxyphenylalanine oxidation site, resulting in the inhibition of tyrosinase.¹² It often is combined with arbutin for an enhanced lightening effect.

Niacinamide—Niacinamide is a form of vitamin B₃ that works by suppressing the transfer of melanosomes to keratinocytes.¹³ In addition to its skin lightening effects, it also is photoprotective and antimicrobial, and its tolerability and safety have led to its inclusion in many cosmeceutical and prescription products.¹⁴

Ascorbic Acid—Ascorbic acid affects the monopherase activity of tyrosinase, thus reducing the synthesis of melanin. It also serves as an antioxidant in the skin by preventing the production of free radicals that can induce melanogenesis.¹⁵ Although it tends to be well tolerated with a low adverse effect profile, its relative instability and varying permeability can present a challenge. It is less effective as a monotherapy, so it often is combined with other lightening ingredients for greater efficacy.

Corticosteroids—Topical corticosteroids are anti-inflammatory and impact melanogenesis, though the mechanism of action of the latter has not been fully elucidated.^16,17 Low- to mid-potency topical steroids often are used in conjunction with skin lightening products to diminish irritation and decrease inflammation.¹⁸ However, prolonged use of corticosteroids can lead to cutaneous adverse effects such as striae, hypopigmentation, and acne, as well as systemic side effects if there is sufficient absorption over time.

Soybean Extracts—Soybean extracts contain serine protease inhibitors that reduce the transfer of melanosomes into keratinocytes by inhibiting the PAR-2 (protease-activated receptor 2) pathway.^19,20

Ellagic Acid—Ellagic acid is found in common plants such as eucalyptus and strawberry as well as green tea.²¹ It works as an antioxidant and decreases melanogenesis through inhibition of tyrosinase activity.

Paper Mulberry—Paper mulberry extract comes from the roots of the Broussonetia papyrifera tree and functions by inhibiting tyrosinase activity. It is widely used in South Africa and Europe.²²

Resveratrol—Resveratrol is an ingredient extracted from Morus alba L and functions as an antimelanogentic agent by directly inhibiting tyrosinase as well as transcriptional and posttranscriptional processing of tyrosinase.²³ It also holds antiproliferative, anti-inflammatory, and antioxidant properties and has widely been used for antiaging and skin lightening purposes.²⁴

Newer Non-HQ Lightening Agents

Silymarin—Silymarin (also known as milk thistle [Silybum marianum]), is a polyphenolic flavonoid that possesses anticarcinogenic, antioxidant, and anti-inflammatory properties. It prevents melanin production in a dose-dependent manner by inhibiting levodopa (L-dopa) oxidation activity of tyrosinase and also reduces the expression of tyrosinase protein.²⁵ In combination with vitamins C and E and hexylresorcinol, silymarin has been found to reduce the effects of photodamage, brighten skin, improve evenness and lines, as well as improve global facial appearance.²⁶

Malassezin—Malassezin is an indole produced by Malessezia furfur yeast and has recently been investigated for melanogenesis suppression. Grimes et al²⁷ assessed the efficacy of topical malassezin in 7 patients with facial hyperpigmentation applied twice daily for 14 weeks. Punch biopsies were taken at weeks 0, 8, 14, and 22. Biopsies from weeks 8 and 14 demonstrated reduced epidermal melanin compared to baseline in all participants; however, at 22 weeks, biopsies showed no difference in melanin content compared to baseline, indicating a temporary process induced by the malassezin.²⁷ More clinical studies are needed to investigate this further.

N-acetyl-glucosamine—N-acetyl-glucosamine is an aminosaccharide that inhibits the glycosylation of tyrosinase as well as its function in melanogenesis.²⁸ It is synthesized and included in topical products for wound healing, rhytides, moisturization, and pigmentation disorders.

Topical Tranexamic Acid—Tranexamic acid traditionally has been used orally for the treatment of menorrhagia but also has been found to be beneficial as a therapy for hyperpigmentation and erythema. Tranexamic acid interferes with plasmin activity, thus indirectly inhibiting melanogenesis while also inhibiting angiogenesis by targeting vascular endothelial growth factor (VEGF) receptors.²⁹ It also leads to an increase in the levels of β-endorphin and μ-opioid receptors as well as the expression of estrogen receptor β on the surface of mast cells.³⁰ Its oral benefit led to the development of topical formulations, typically in 2% to 5% concentrations. It has proven particularly beneficial in the treatment of melasma due to its effects on improving pigmentation, erythema, and skin barrier function.³¹ Topical tranexamic acid has a relatively high safety profile, with minor side effects such as transient skin irritation and erythema being reported.³²

Cysteamine—Cysteamine inhibits tyrosinase, peroxidase, and chelating copper ions necessary for melanogenesis. It has proven to be effective in treating melasma and chronic severe postinflammatory hyperpigmentation when used in a 5% cream formulation.^33,34 Lima et al³⁵ were the first to compare the effects of topical cysteamine to HQ in the treatment of facial melasma. They found that the mean reduction in modified Melasma Area and Severity Index score was 24% for cysteamine and 41% for HQ after 60 days. There were no severe adverse effects with either treatment group.³⁵

Final Thoughts

Hydroquinone remains the gold standard for treatment of hyperpigmentation; however, its side-effect profile and risk of ochronosis with long-term use has ushered in various other safe and effective skin lightening agents that can be used as monotherapies or in combination with other lightening agents. Many of these products also can be used effectively with procedural treatments such as chemical peels, lasers, and microneedling for enhanced absorption and efficacy. As newer agents are developed, additional well-designed studies will be needed to determine their safety and efficacy in different skin types as well as their role in the treatment of pigmentary disorders.

Disorders of hyperpigmentation—melasma, postinflammatory hyperpigmentation, lichen planus pigmentosus, erythema dyschromicum perstans, and pigmented contact dermatitis, among others—are common and challenging to treat. Although they can affect individuals of all skin types, they most commonly are seen in skin of color; in fact, dyspigmentation is one of the most common chief concerns for which individuals of color see a dermatologist.^1,2

For many years, hydroquinone (HQ) was one of the main options available for use as a lightening agent. Although effective, it has the risk of causing irritant dermatitis, potentially leading to further dyspigmentation, in addition to the risk of ochronosis with long-term use. It remains an important and useful treatment for pigmentary disorders, but there are numerous other lightening agents that also can be considered in the treatment of disorders of hyperpigmentation.

Herein, we provide recommendations for traditional and newer non-HQ lightening agents that can be considered when treating disorders of hyperpigmentation.

Traditional Non-HQ Lightening Agents

Retinoids—Retinoids are topical vitamin A derivatives that have been used safely and effectively for decades in the treatment of pigmentary disorders. Retinoids have multiple mechanisms of action in improving pigmentation. In addition to impeding tyrosinase induction, they inhibit pigment transfer to keratinocytes and lead to accelerated pigment loss due to epidermal shedding.³ Over-the-counter formulations include retinol, retinaldehyde, and adapalene. Prescription formulations include tretinoin and tazarotene in different strengths and vehicle formulations.⁴

Glycolic Acid—Glycolic acid is derived from sugarcane and is considered an α-hydroxy acid that leads to rapid desquamation of pigmented keratinocytes.⁵ Glycolic acid can not only be used in chemical peels but also in topical creams. It is the most common α-hydroxy acid peel and is sometimes paired with HQ and other topical lightening agents for increased penetration. Glycolic acid peels are available in concentrations of 20% to 70% and can be used at various depths. When used incorrectly, it can cause redness, burning, and even skin discoloration; however, when used at the proper concentrations and depth according to Fitzpatrick skin type, there typically are no notable adverse effects, and clinical results are favorable.

Kojic Acid—Kojic acid is a natural metabolite derived from fungi and is widely used in Asian countries. It works by inhibiting the catecholase activity of tyrosinase⁶ and typically is available in concentrations of 1% to 4%. A study suggested that a concentration of 1% or less typically is safe to use for prolonged periods without adverse effects. Although not more effective than HQ as a monotherapy, kojic acid has been shown to haveimproved efficacy when used in combination with other lightening agents.⁷

Azelaic Acid—Azelaic acid works by inhibiting tyrosinase, mitochondrial oxidoreductase activation, and DNA synthesis. It preferentially targets heavily pigmented melanocytes and possesses anti-inflammatory and antibacterial properties.⁸ A 20% concentration of azelaic acid was compared to HQ 4% for the treatment of melasma, and results revealed that the liposomal form of azelaic acid was considerably more tolerable than HQ 4% and also more effective.⁹

Licorice Extracts—Licorice extracts have been safely used in several cosmeceutical skin lightening products.¹⁰ The main active compounds in licorice root are glabridin and liquiritin, which work to disperse melanin. These compounds often are used topically at concentrations of 10% to 40%. A study by Amer and Metwalli¹¹ found that topical liquiritin produced a reduction of pigmentary intensity, with 80% of patients showing an excellent response, which was described as no difference between the previously pigmented area and the normal skin surrounding it.

Aloesin—Aloesin is a low-molecular-weight glycoprotein found in aloe vera plants. Its mechanism of action includes competitive inhibition of the dihydroxyphenylalanine oxidation site, resulting in the inhibition of tyrosinase.¹² It often is combined with arbutin for an enhanced lightening effect.

Niacinamide—Niacinamide is a form of vitamin B₃ that works by suppressing the transfer of melanosomes to keratinocytes.¹³ In addition to its skin lightening effects, it also is photoprotective and antimicrobial, and its tolerability and safety have led to its inclusion in many cosmeceutical and prescription products.¹⁴

Ascorbic Acid—Ascorbic acid affects the monopherase activity of tyrosinase, thus reducing the synthesis of melanin. It also serves as an antioxidant in the skin by preventing the production of free radicals that can induce melanogenesis.¹⁵ Although it tends to be well tolerated with a low adverse effect profile, its relative instability and varying permeability can present a challenge. It is less effective as a monotherapy, so it often is combined with other lightening ingredients for greater efficacy.

Corticosteroids—Topical corticosteroids are anti-inflammatory and impact melanogenesis, though the mechanism of action of the latter has not been fully elucidated.^16,17 Low- to mid-potency topical steroids often are used in conjunction with skin lightening products to diminish irritation and decrease inflammation.¹⁸ However, prolonged use of corticosteroids can lead to cutaneous adverse effects such as striae, hypopigmentation, and acne, as well as systemic side effects if there is sufficient absorption over time.

Soybean Extracts—Soybean extracts contain serine protease inhibitors that reduce the transfer of melanosomes into keratinocytes by inhibiting the PAR-2 (protease-activated receptor 2) pathway.^19,20

Ellagic Acid—Ellagic acid is found in common plants such as eucalyptus and strawberry as well as green tea.²¹ It works as an antioxidant and decreases melanogenesis through inhibition of tyrosinase activity.

Paper Mulberry—Paper mulberry extract comes from the roots of the Broussonetia papyrifera tree and functions by inhibiting tyrosinase activity. It is widely used in South Africa and Europe.²²

Resveratrol—Resveratrol is an ingredient extracted from Morus alba L and functions as an antimelanogentic agent by directly inhibiting tyrosinase as well as transcriptional and posttranscriptional processing of tyrosinase.²³ It also holds antiproliferative, anti-inflammatory, and antioxidant properties and has widely been used for antiaging and skin lightening purposes.²⁴

Newer Non-HQ Lightening Agents

Silymarin—Silymarin (also known as milk thistle [Silybum marianum]), is a polyphenolic flavonoid that possesses anticarcinogenic, antioxidant, and anti-inflammatory properties. It prevents melanin production in a dose-dependent manner by inhibiting levodopa (L-dopa) oxidation activity of tyrosinase and also reduces the expression of tyrosinase protein.²⁵ In combination with vitamins C and E and hexylresorcinol, silymarin has been found to reduce the effects of photodamage, brighten skin, improve evenness and lines, as well as improve global facial appearance.²⁶

Malassezin—Malassezin is an indole produced by Malessezia furfur yeast and has recently been investigated for melanogenesis suppression. Grimes et al²⁷ assessed the efficacy of topical malassezin in 7 patients with facial hyperpigmentation applied twice daily for 14 weeks. Punch biopsies were taken at weeks 0, 8, 14, and 22. Biopsies from weeks 8 and 14 demonstrated reduced epidermal melanin compared to baseline in all participants; however, at 22 weeks, biopsies showed no difference in melanin content compared to baseline, indicating a temporary process induced by the malassezin.²⁷ More clinical studies are needed to investigate this further.

N-acetyl-glucosamine—N-acetyl-glucosamine is an aminosaccharide that inhibits the glycosylation of tyrosinase as well as its function in melanogenesis.²⁸ It is synthesized and included in topical products for wound healing, rhytides, moisturization, and pigmentation disorders.

Topical Tranexamic Acid—Tranexamic acid traditionally has been used orally for the treatment of menorrhagia but also has been found to be beneficial as a therapy for hyperpigmentation and erythema. Tranexamic acid interferes with plasmin activity, thus indirectly inhibiting melanogenesis while also inhibiting angiogenesis by targeting vascular endothelial growth factor (VEGF) receptors.²⁹ It also leads to an increase in the levels of β-endorphin and μ-opioid receptors as well as the expression of estrogen receptor β on the surface of mast cells.³⁰ Its oral benefit led to the development of topical formulations, typically in 2% to 5% concentrations. It has proven particularly beneficial in the treatment of melasma due to its effects on improving pigmentation, erythema, and skin barrier function.³¹ Topical tranexamic acid has a relatively high safety profile, with minor side effects such as transient skin irritation and erythema being reported.³²

Cysteamine—Cysteamine inhibits tyrosinase, peroxidase, and chelating copper ions necessary for melanogenesis. It has proven to be effective in treating melasma and chronic severe postinflammatory hyperpigmentation when used in a 5% cream formulation.^33,34 Lima et al³⁵ were the first to compare the effects of topical cysteamine to HQ in the treatment of facial melasma. They found that the mean reduction in modified Melasma Area and Severity Index score was 24% for cysteamine and 41% for HQ after 60 days. There were no severe adverse effects with either treatment group.³⁵

Final Thoughts

Hydroquinone remains the gold standard for treatment of hyperpigmentation; however, its side-effect profile and risk of ochronosis with long-term use has ushered in various other safe and effective skin lightening agents that can be used as monotherapies or in combination with other lightening agents. Many of these products also can be used effectively with procedural treatments such as chemical peels, lasers, and microneedling for enhanced absorption and efficacy. As newer agents are developed, additional well-designed studies will be needed to determine their safety and efficacy in different skin types as well as their role in the treatment of pigmentary disorders.

Disorders of hyperpigmentation—melasma, postinflammatory hyperpigmentation, lichen planus pigmentosus, erythema dyschromicum perstans, and pigmented contact dermatitis, among others—are common and challenging to treat. Although they can affect individuals of all skin types, they most commonly are seen in skin of color; in fact, dyspigmentation is one of the most common chief concerns for which individuals of color see a dermatologist.^1,2

For many years, hydroquinone (HQ) was one of the main options available for use as a lightening agent. Although effective, it has the risk of causing irritant dermatitis, potentially leading to further dyspigmentation, in addition to the risk of ochronosis with long-term use. It remains an important and useful treatment for pigmentary disorders, but there are numerous other lightening agents that also can be considered in the treatment of disorders of hyperpigmentation.

Herein, we provide recommendations for traditional and newer non-HQ lightening agents that can be considered when treating disorders of hyperpigmentation.

Traditional Non-HQ Lightening Agents

Retinoids—Retinoids are topical vitamin A derivatives that have been used safely and effectively for decades in the treatment of pigmentary disorders. Retinoids have multiple mechanisms of action in improving pigmentation. In addition to impeding tyrosinase induction, they inhibit pigment transfer to keratinocytes and lead to accelerated pigment loss due to epidermal shedding.³ Over-the-counter formulations include retinol, retinaldehyde, and adapalene. Prescription formulations include tretinoin and tazarotene in different strengths and vehicle formulations.⁴

Glycolic Acid—Glycolic acid is derived from sugarcane and is considered an α-hydroxy acid that leads to rapid desquamation of pigmented keratinocytes.⁵ Glycolic acid can not only be used in chemical peels but also in topical creams. It is the most common α-hydroxy acid peel and is sometimes paired with HQ and other topical lightening agents for increased penetration. Glycolic acid peels are available in concentrations of 20% to 70% and can be used at various depths. When used incorrectly, it can cause redness, burning, and even skin discoloration; however, when used at the proper concentrations and depth according to Fitzpatrick skin type, there typically are no notable adverse effects, and clinical results are favorable.

Kojic Acid—Kojic acid is a natural metabolite derived from fungi and is widely used in Asian countries. It works by inhibiting the catecholase activity of tyrosinase⁶ and typically is available in concentrations of 1% to 4%. A study suggested that a concentration of 1% or less typically is safe to use for prolonged periods without adverse effects. Although not more effective than HQ as a monotherapy, kojic acid has been shown to haveimproved efficacy when used in combination with other lightening agents.⁷

Azelaic Acid—Azelaic acid works by inhibiting tyrosinase, mitochondrial oxidoreductase activation, and DNA synthesis. It preferentially targets heavily pigmented melanocytes and possesses anti-inflammatory and antibacterial properties.⁸ A 20% concentration of azelaic acid was compared to HQ 4% for the treatment of melasma, and results revealed that the liposomal form of azelaic acid was considerably more tolerable than HQ 4% and also more effective.⁹

Licorice Extracts—Licorice extracts have been safely used in several cosmeceutical skin lightening products.¹⁰ The main active compounds in licorice root are glabridin and liquiritin, which work to disperse melanin. These compounds often are used topically at concentrations of 10% to 40%. A study by Amer and Metwalli¹¹ found that topical liquiritin produced a reduction of pigmentary intensity, with 80% of patients showing an excellent response, which was described as no difference between the previously pigmented area and the normal skin surrounding it.

Aloesin—Aloesin is a low-molecular-weight glycoprotein found in aloe vera plants. Its mechanism of action includes competitive inhibition of the dihydroxyphenylalanine oxidation site, resulting in the inhibition of tyrosinase.¹² It often is combined with arbutin for an enhanced lightening effect.

Niacinamide—Niacinamide is a form of vitamin B₃ that works by suppressing the transfer of melanosomes to keratinocytes.¹³ In addition to its skin lightening effects, it also is photoprotective and antimicrobial, and its tolerability and safety have led to its inclusion in many cosmeceutical and prescription products.¹⁴

Ascorbic Acid—Ascorbic acid affects the monopherase activity of tyrosinase, thus reducing the synthesis of melanin. It also serves as an antioxidant in the skin by preventing the production of free radicals that can induce melanogenesis.¹⁵ Although it tends to be well tolerated with a low adverse effect profile, its relative instability and varying permeability can present a challenge. It is less effective as a monotherapy, so it often is combined with other lightening ingredients for greater efficacy.

Corticosteroids—Topical corticosteroids are anti-inflammatory and impact melanogenesis, though the mechanism of action of the latter has not been fully elucidated.^16,17 Low- to mid-potency topical steroids often are used in conjunction with skin lightening products to diminish irritation and decrease inflammation.¹⁸ However, prolonged use of corticosteroids can lead to cutaneous adverse effects such as striae, hypopigmentation, and acne, as well as systemic side effects if there is sufficient absorption over time.

Soybean Extracts—Soybean extracts contain serine protease inhibitors that reduce the transfer of melanosomes into keratinocytes by inhibiting the PAR-2 (protease-activated receptor 2) pathway.^19,20

Ellagic Acid—Ellagic acid is found in common plants such as eucalyptus and strawberry as well as green tea.²¹ It works as an antioxidant and decreases melanogenesis through inhibition of tyrosinase activity.

Paper Mulberry—Paper mulberry extract comes from the roots of the Broussonetia papyrifera tree and functions by inhibiting tyrosinase activity. It is widely used in South Africa and Europe.²²

Resveratrol—Resveratrol is an ingredient extracted from Morus alba L and functions as an antimelanogentic agent by directly inhibiting tyrosinase as well as transcriptional and posttranscriptional processing of tyrosinase.²³ It also holds antiproliferative, anti-inflammatory, and antioxidant properties and has widely been used for antiaging and skin lightening purposes.²⁴

Newer Non-HQ Lightening Agents

Silymarin—Silymarin (also known as milk thistle [Silybum marianum]), is a polyphenolic flavonoid that possesses anticarcinogenic, antioxidant, and anti-inflammatory properties. It prevents melanin production in a dose-dependent manner by inhibiting levodopa (L-dopa) oxidation activity of tyrosinase and also reduces the expression of tyrosinase protein.²⁵ In combination with vitamins C and E and hexylresorcinol, silymarin has been found to reduce the effects of photodamage, brighten skin, improve evenness and lines, as well as improve global facial appearance.²⁶

Malassezin—Malassezin is an indole produced by Malessezia furfur yeast and has recently been investigated for melanogenesis suppression. Grimes et al²⁷ assessed the efficacy of topical malassezin in 7 patients with facial hyperpigmentation applied twice daily for 14 weeks. Punch biopsies were taken at weeks 0, 8, 14, and 22. Biopsies from weeks 8 and 14 demonstrated reduced epidermal melanin compared to baseline in all participants; however, at 22 weeks, biopsies showed no difference in melanin content compared to baseline, indicating a temporary process induced by the malassezin.²⁷ More clinical studies are needed to investigate this further.

N-acetyl-glucosamine—N-acetyl-glucosamine is an aminosaccharide that inhibits the glycosylation of tyrosinase as well as its function in melanogenesis.²⁸ It is synthesized and included in topical products for wound healing, rhytides, moisturization, and pigmentation disorders.

Topical Tranexamic Acid—Tranexamic acid traditionally has been used orally for the treatment of menorrhagia but also has been found to be beneficial as a therapy for hyperpigmentation and erythema. Tranexamic acid interferes with plasmin activity, thus indirectly inhibiting melanogenesis while also inhibiting angiogenesis by targeting vascular endothelial growth factor (VEGF) receptors.²⁹ It also leads to an increase in the levels of β-endorphin and μ-opioid receptors as well as the expression of estrogen receptor β on the surface of mast cells.³⁰ Its oral benefit led to the development of topical formulations, typically in 2% to 5% concentrations. It has proven particularly beneficial in the treatment of melasma due to its effects on improving pigmentation, erythema, and skin barrier function.³¹ Topical tranexamic acid has a relatively high safety profile, with minor side effects such as transient skin irritation and erythema being reported.³²

Cysteamine—Cysteamine inhibits tyrosinase, peroxidase, and chelating copper ions necessary for melanogenesis. It has proven to be effective in treating melasma and chronic severe postinflammatory hyperpigmentation when used in a 5% cream formulation.^33,34 Lima et al³⁵ were the first to compare the effects of topical cysteamine to HQ in the treatment of facial melasma. They found that the mean reduction in modified Melasma Area and Severity Index score was 24% for cysteamine and 41% for HQ after 60 days. There were no severe adverse effects with either treatment group.³⁵

Final Thoughts

Hydroquinone remains the gold standard for treatment of hyperpigmentation; however, its side-effect profile and risk of ochronosis with long-term use has ushered in various other safe and effective skin lightening agents that can be used as monotherapies or in combination with other lightening agents. Many of these products also can be used effectively with procedural treatments such as chemical peels, lasers, and microneedling for enhanced absorption and efficacy. As newer agents are developed, additional well-designed studies will be needed to determine their safety and efficacy in different skin types as well as their role in the treatment of pigmentary disorders.

The Diagnosis: Cutaneous Amyloidosis

A punch biopsy confirmed the diagnosis of cutaneous amyloidosis, which is characterized by the deposition of amyloid proteins in the skin without systemic involvement. Subtypes of cutaneous amyloidosis include lichenoid, macular, and nodular amyloidosis. A mixed or biphasic amyloidosis can occur when both lichenoid and macular lesions are present.¹ Lichenoid and macular amyloidosis generally are characterized by moderate to severe pruritus. Lichenoid amyloidosis favors the shins, calves, ankles, and extensor extremities; macular amyloidosis has a predilection for the interscapular area and less frequently the upper arms, chest, and thighs.² Atypical variants also have been reported, including amyloidosis cutis dyschromica, poikilodermalike amyloidosis, and bullous amyloidosis, as well as incontinentia pigmenti–like, linear, and nevoid types.³ Macular amyloidosis has been reported to occur in association with progressive systemic sclerosis, primary biliary cirrhosis, systemic lupus erythematosus, paronychia, and multiple endocrine neoplasia type 2.²

Acanthosis nigricans typically presents on the neck and intertriginous areas as velvety hyperpigmented plaques. Confluent and reticulated papillomatosis also appears as slightly elevated papules; however, it occurs in the intermammary region in a reticulated pattern. Ichthyosis vulgaris also may occur on the lower extremities but presents with adherent large scales rather than papules. Keratosis pilaris may present on the proximal lower extremities with smaller, folliculocentric, fleshcolored to pink papules.

Treatment of cutaneous amyloidosis has long been challenging for dermatologists. The primary focus should be treatment of any underlying disease that is causing the pruritus and subsequent manipulation of skin lesions. Topical calcipotriol, phototherapy, oral cyclophosphamide, and Nd:YAG laser have demonstrated beneficial outcomes. IL-31 antibodies may be a potential future treatment.¹

The Diagnosis: Cutaneous Amyloidosis

A punch biopsy confirmed the diagnosis of cutaneous amyloidosis, which is characterized by the deposition of amyloid proteins in the skin without systemic involvement. Subtypes of cutaneous amyloidosis include lichenoid, macular, and nodular amyloidosis. A mixed or biphasic amyloidosis can occur when both lichenoid and macular lesions are present.¹ Lichenoid and macular amyloidosis generally are characterized by moderate to severe pruritus. Lichenoid amyloidosis favors the shins, calves, ankles, and extensor extremities; macular amyloidosis has a predilection for the interscapular area and less frequently the upper arms, chest, and thighs.² Atypical variants also have been reported, including amyloidosis cutis dyschromica, poikilodermalike amyloidosis, and bullous amyloidosis, as well as incontinentia pigmenti–like, linear, and nevoid types.³ Macular amyloidosis has been reported to occur in association with progressive systemic sclerosis, primary biliary cirrhosis, systemic lupus erythematosus, paronychia, and multiple endocrine neoplasia type 2.²

Acanthosis nigricans typically presents on the neck and intertriginous areas as velvety hyperpigmented plaques. Confluent and reticulated papillomatosis also appears as slightly elevated papules; however, it occurs in the intermammary region in a reticulated pattern. Ichthyosis vulgaris also may occur on the lower extremities but presents with adherent large scales rather than papules. Keratosis pilaris may present on the proximal lower extremities with smaller, folliculocentric, fleshcolored to pink papules.

Treatment of cutaneous amyloidosis has long been challenging for dermatologists. The primary focus should be treatment of any underlying disease that is causing the pruritus and subsequent manipulation of skin lesions. Topical calcipotriol, phototherapy, oral cyclophosphamide, and Nd:YAG laser have demonstrated beneficial outcomes. IL-31 antibodies may be a potential future treatment.¹

The Diagnosis: Cutaneous Amyloidosis

A punch biopsy confirmed the diagnosis of cutaneous amyloidosis, which is characterized by the deposition of amyloid proteins in the skin without systemic involvement. Subtypes of cutaneous amyloidosis include lichenoid, macular, and nodular amyloidosis. A mixed or biphasic amyloidosis can occur when both lichenoid and macular lesions are present.¹ Lichenoid and macular amyloidosis generally are characterized by moderate to severe pruritus. Lichenoid amyloidosis favors the shins, calves, ankles, and extensor extremities; macular amyloidosis has a predilection for the interscapular area and less frequently the upper arms, chest, and thighs.² Atypical variants also have been reported, including amyloidosis cutis dyschromica, poikilodermalike amyloidosis, and bullous amyloidosis, as well as incontinentia pigmenti–like, linear, and nevoid types.³ Macular amyloidosis has been reported to occur in association with progressive systemic sclerosis, primary biliary cirrhosis, systemic lupus erythematosus, paronychia, and multiple endocrine neoplasia type 2.²

Acanthosis nigricans typically presents on the neck and intertriginous areas as velvety hyperpigmented plaques. Confluent and reticulated papillomatosis also appears as slightly elevated papules; however, it occurs in the intermammary region in a reticulated pattern. Ichthyosis vulgaris also may occur on the lower extremities but presents with adherent large scales rather than papules. Keratosis pilaris may present on the proximal lower extremities with smaller, folliculocentric, fleshcolored to pink papules.

Treatment of cutaneous amyloidosis has long been challenging for dermatologists. The primary focus should be treatment of any underlying disease that is causing the pruritus and subsequent manipulation of skin lesions. Topical calcipotriol, phototherapy, oral cyclophosphamide, and Nd:YAG laser have demonstrated beneficial outcomes. IL-31 antibodies may be a potential future treatment.¹