Internet platforms have become a common source of medical information for individuals with a broad range of skin conditions including vitiligo. The prevalence of vitiligo among US adults ranges from 0.76% to 1.11%, with approximately 40% of adult cases of vitiligo in the United States remaining undiagnosed.¹ The vitiligo community has become more inquisitive of the relationship between diet and vitiligo, turning to online sources for suggestions on diet modifications that may be beneficial for their condition. Although there is an abundance of online information, few diets or foods have been medically recognized to definitively improve or worsen vitiligo symptoms. We reviewed the top online web pages accessible to the public regarding diet suggestions that affect vitiligo symptoms. We then compared these online results to published peer-reviewed scientific literature.

Methods

Two independent online searches were performed by Researcher 1 (Y.A.) and Researcher 2 (I.M.) using Google Advanced Search. The independent searches were performed by the reviewers in neighboring areas of Chicago, Illinois, using the same Internet browser (Google Chrome). The primary search terms were diet and vitiligo along with the optional additional terms dietary supplement(s), food(s), nutrition, herb(s), or vitamin(s). Our search included any web pages published or updated from January 1, 2010, to December 31, 2021, and originally scribed in the English language. The domains “.com,” “.org,” “.edu,” and “.cc” were included.

From this initial search, Researcher 1 identified 312 web pages and Researcher 2 identified 314 web pages. Each reviewer sorted their respective search results to identify the number of eligible records to be screened. Records were defined as unique web pages that met the search criteria. After removing duplicates, Researcher 1 screened 102 web pages and Researcher 2 screened 76 web pages. Of these records, web pages were excluded if they did not include any diet recommendations for vitiligo patients. Each reviewer independently created a list of eligible records, and the independent lists were then merged for a total of 58 web pages. Among these 58 web pages, there were 24 duplicate records and 3 records that were deemed ineligible for the study due to lack of subject matter relevance. A final total of 31 web pages were included in the data analysis (Figure). Of the 31 records selected, the reviewers jointly evaluated each web page and recorded the diet components that were recommended for individuals with vitiligo to either include or avoid (eTable).

For comparison and support from published scientific literature, a search of PubMed articles indexed for MEDLINE was conducted using the terms diet and vitiligo. Relevant human clinical studies published in the English-language literature were reviewed for content regarding the relationship between diet and vitiligo.

Results

Our online search revealed an abundance of information regarding various dietary modifications suggested to aid in the management of vitiligo symptoms. Most web pages (27/31 [87%]) were not authored by medical professionals or dermatologists. There were 27 diet components mentioned 8 or more times within the 31 total web pages. These diet components were selected for further review via PubMed. Each item was searched on PubMed using the term “[respective diet component] and vitiligo” among all published literature in the English language. Our study focused on summarizing the data on dietary components for which we were able to gather scientific support. These data have been organized into the following categories: vitamins, fruits, omega-3 fatty acids, grains, minerals, vegetables, and nuts.

Vitamins—The online literature recommended inclusion of vitamin supplements, in particular vitamins D and B₁₂, which aligned with published scientific literature.^2,3 Eleven of 31 (35%) web pages recommended vitamin D in vitiligo. A 2010 study analyzing patients with vitiligo vulgaris (N=45) found that 68.9% of the cohort had insufficient (<30 ng/mL) 25-hydroxyvitamin D levels.² A prospective study of 30 individuals found that the use of tacrolimus ointment plus oral vitamin D supplementation was found to be more successful in repigmentation than topical tacrolimus alone.³ Vitamin D dosage ranged from 1500 IU/d if the patient’s serum 25-hydroxyvitamin D levels were less than 20 ng/mL to 3000 IU/d if the serum levels were less than 10 ng/mL for 6 months.

Dairy products are a source of vitamin D.^2,3 Of the web pages that mentioned dairy, a subtle majority (4/7 [57%]) recommended the inclusion of dairy products. Although many web pages did not specify whether oral vitamin D supplementation vs dietary food consumption is preferred, a 2013 controlled study of 16 vitiligo patients who received high doses of vitamin D supplementation with a low-calcium diet found that 4 patients showed 1% to 25% repigmentation, 5 patients showed 26% to 50% repigmentation, and 5 patients showed 51% to 75% repigmentation of the affected areas.⁴

Eleven of 31 (35%) web pages recommended inclusion of vitamin B₁₂ supplementation in vitiligo. A 2-year study with 100 participants showed that supplementation with folic acid and vitamin B₁₂ along with sun exposure yielded more effective repigmentation than either vitamins or sun exposure alone.⁵ An additional hypothesis suggested vitamin B₁₂ may aid in repigmentation through its role in the homocysteine pathway. Although the theory is unproven, it is proposed that inhibition of homocysteine via vitamin B₁₂ or folic acid supplementation may play a role in reducing melanocyte destruction and restoring melanin synthesis.⁶

There were mixed recommendations regarding vitamin C via supplementation and/or eating citrus fruits such as oranges. Although there are limited clinical studies on the use of vitamin C and the treatment of vitiligo, a 6-year prospective study from Madagascar consisting of approximately 300 participants with vitiligo who were treated with a combination of topical corticosteroids, oral vitamin C, and oral vitamin B₁₂ supplementation showed excellent repigmentation (defined by repigmentation of more than 76% of the originally affected area) in 50 participants.⁷

Fruits—Most web pages had mixed recommendations on whether to include or avoid certain fruits. Interestingly, inclusion of mangoes and apricots in the diet were highly recommended (9/31 [29%] and 8/31 [26%], respectively) while fruits such as oranges, lemons, papayas, and grapes were discouraged (10/31 [32%], 8/31 [26%], 6/31 [19%], and 7/31 [23%], respectively). Although some web pages suggested that vitamin C–rich produce including citrus and berries may help to increase melanin formation, others strongly suggested avoiding these fruits. There is limited information on the effects of citrus on vitiligo, but a 2022 study indicated that 5-demethylnobiletin, a flavonoid found in sweet citrus fruits, may stimulate melanin synthesis, which can possibly be beneficial for vitiligo.⁸

Omega-3 Fatty Acids—Seven of 31 (23%) web pages recommended the inclusion of omega-3 fatty acids for their role as antioxidants to improve vitiligo symptoms. Research has indicated a strong association between vitiligo and oxidative stress.⁹ A 2007 controlled clinical trial that included 28 vitiligo patients demonstrated that oral antioxidant supplementation in combination with narrowband UVB phototherapy can significantly decrease vitiligo-associated oxidative stress (P<.05); 8 of 17 (47%) patients in the treatment group saw greater than 75% repigmentation after antioxidant treatment.¹⁰

Grains—Five of 31 (16%) web pages suggested avoiding gluten—a protein naturally found in some grains including wheat, barley, and rye—to improve vitiligo symptoms. A 2021 review suggested that a gluten-free diet may be effective in managing celiac disease, and it is hypothesized that vitiligo may be managed with similar dietary adjustments.¹¹ Studies have shown that celiac disease and vitiligo—both autoimmune conditions—involve IL-2, IL-6, IL-7, and IL-21 in their disease pathways.^12,13 Their shared immunogenic mechanism may account for similar management options.

Upon review, 2 case reports were identified that discussed a relationship between a gluten-free diet and vitiligo symptom improvement. In one report, a 9-year-old child diagnosed with both celiac disease and vitiligo saw intense repigmentation of the skin after adhering to a gluten-free diet for 1 year.¹⁴ Another case study reported a 22-year-old woman with vitiligo whose symptoms improved after 1 month of a gluten-free diet following 2 years of failed treatment with a topical steroid and phototherapy.¹⁵

Seven of 31 (23%) web pages suggested that individuals with vitiligo should include wheat in their diet. There is no published literature discussing the relationship between vitiligo and wheat. Of the 31 web pages reviewed, 10 (32%) suggested including whole grain. There is no relevant scientific evidence or hypotheses describing how whole grains may be beneficial in vitiligo.

Minerals—Eight of 31 (26%) web pages suggested including zinc in the diet to improve vitiligo symptoms. A 2020 study evaluated how different serum levels of zinc in vitiligo patients might be affiliated with interleukin activity. Fifty patients diagnosed with active vitiligo were tested for serum levels of zinc, IL-4, IL-6, and IL-17.¹⁶ The results showed that mean serum levels of zinc were lower in vitiligo patients compared with patients without vitiligo. The study concluded that zinc could possibly be used as a supplement to improve vitiligo, though the dosage needs to be further studied and confirmed.¹⁶

Vegetables—Eleven of 31 (35%) web pages recommended leafy green vegetables and 13 of 31 (42%) recommended spinach for patients with vitiligo. Spinach and other leafy green vegetables are known to be rich in antioxidants, which may have protective effects against reactive oxygen species that are thought to contribute to vitiligo progression.^17,18

Nuts—Walnuts were recommended in 11 of 31 (35%) web pages. Nuts may be beneficial in reducing inflammation and providing protection against oxidative stress.⁹ However, there is no specific scientific literature that supports the inclusion of nuts in the diet to manage vitiligo symptoms.

Comment

With a growing amount of research suggesting that diet modifications may contribute to management of certain skin conditions, vitiligo patients often inquire about foods or supplements that may help improve their condition.¹⁹ Our review highlighted what information was available to the public regarding diet and vitiligo, with preliminary support of the following primary diet components: vitamin D, vitamin B₁₂, zinc, and omega-3 fatty acids. Our review showed no support in the literature for the items that were recommended to avoid. It is important to note that 27 of 31 (87%) web pages from our online search were not authored by medical professionals or dermatologists. Additionally, many web pages suggested conflicting information, making it difficult to draw concrete conclusions about what diet modifications will be beneficial to the vitiligo community. Further controlled clinical trials are warranted due to the lack of formal studies that assess the relationship between diet and vitiligo.

Internet platforms have become a common source of medical information for individuals with a broad range of skin conditions including vitiligo. The prevalence of vitiligo among US adults ranges from 0.76% to 1.11%, with approximately 40% of adult cases of vitiligo in the United States remaining undiagnosed.¹ The vitiligo community has become more inquisitive of the relationship between diet and vitiligo, turning to online sources for suggestions on diet modifications that may be beneficial for their condition. Although there is an abundance of online information, few diets or foods have been medically recognized to definitively improve or worsen vitiligo symptoms. We reviewed the top online web pages accessible to the public regarding diet suggestions that affect vitiligo symptoms. We then compared these online results to published peer-reviewed scientific literature.

Methods

Two independent online searches were performed by Researcher 1 (Y.A.) and Researcher 2 (I.M.) using Google Advanced Search. The independent searches were performed by the reviewers in neighboring areas of Chicago, Illinois, using the same Internet browser (Google Chrome). The primary search terms were diet and vitiligo along with the optional additional terms dietary supplement(s), food(s), nutrition, herb(s), or vitamin(s). Our search included any web pages published or updated from January 1, 2010, to December 31, 2021, and originally scribed in the English language. The domains “.com,” “.org,” “.edu,” and “.cc” were included.

From this initial search, Researcher 1 identified 312 web pages and Researcher 2 identified 314 web pages. Each reviewer sorted their respective search results to identify the number of eligible records to be screened. Records were defined as unique web pages that met the search criteria. After removing duplicates, Researcher 1 screened 102 web pages and Researcher 2 screened 76 web pages. Of these records, web pages were excluded if they did not include any diet recommendations for vitiligo patients. Each reviewer independently created a list of eligible records, and the independent lists were then merged for a total of 58 web pages. Among these 58 web pages, there were 24 duplicate records and 3 records that were deemed ineligible for the study due to lack of subject matter relevance. A final total of 31 web pages were included in the data analysis (Figure). Of the 31 records selected, the reviewers jointly evaluated each web page and recorded the diet components that were recommended for individuals with vitiligo to either include or avoid (eTable).

For comparison and support from published scientific literature, a search of PubMed articles indexed for MEDLINE was conducted using the terms diet and vitiligo. Relevant human clinical studies published in the English-language literature were reviewed for content regarding the relationship between diet and vitiligo.

Results

Our online search revealed an abundance of information regarding various dietary modifications suggested to aid in the management of vitiligo symptoms. Most web pages (27/31 [87%]) were not authored by medical professionals or dermatologists. There were 27 diet components mentioned 8 or more times within the 31 total web pages. These diet components were selected for further review via PubMed. Each item was searched on PubMed using the term “[respective diet component] and vitiligo” among all published literature in the English language. Our study focused on summarizing the data on dietary components for which we were able to gather scientific support. These data have been organized into the following categories: vitamins, fruits, omega-3 fatty acids, grains, minerals, vegetables, and nuts.

Vitamins—The online literature recommended inclusion of vitamin supplements, in particular vitamins D and B₁₂, which aligned with published scientific literature.^2,3 Eleven of 31 (35%) web pages recommended vitamin D in vitiligo. A 2010 study analyzing patients with vitiligo vulgaris (N=45) found that 68.9% of the cohort had insufficient (<30 ng/mL) 25-hydroxyvitamin D levels.² A prospective study of 30 individuals found that the use of tacrolimus ointment plus oral vitamin D supplementation was found to be more successful in repigmentation than topical tacrolimus alone.³ Vitamin D dosage ranged from 1500 IU/d if the patient’s serum 25-hydroxyvitamin D levels were less than 20 ng/mL to 3000 IU/d if the serum levels were less than 10 ng/mL for 6 months.

Dairy products are a source of vitamin D.^2,3 Of the web pages that mentioned dairy, a subtle majority (4/7 [57%]) recommended the inclusion of dairy products. Although many web pages did not specify whether oral vitamin D supplementation vs dietary food consumption is preferred, a 2013 controlled study of 16 vitiligo patients who received high doses of vitamin D supplementation with a low-calcium diet found that 4 patients showed 1% to 25% repigmentation, 5 patients showed 26% to 50% repigmentation, and 5 patients showed 51% to 75% repigmentation of the affected areas.⁴

Eleven of 31 (35%) web pages recommended inclusion of vitamin B₁₂ supplementation in vitiligo. A 2-year study with 100 participants showed that supplementation with folic acid and vitamin B₁₂ along with sun exposure yielded more effective repigmentation than either vitamins or sun exposure alone.⁵ An additional hypothesis suggested vitamin B₁₂ may aid in repigmentation through its role in the homocysteine pathway. Although the theory is unproven, it is proposed that inhibition of homocysteine via vitamin B₁₂ or folic acid supplementation may play a role in reducing melanocyte destruction and restoring melanin synthesis.⁶

There were mixed recommendations regarding vitamin C via supplementation and/or eating citrus fruits such as oranges. Although there are limited clinical studies on the use of vitamin C and the treatment of vitiligo, a 6-year prospective study from Madagascar consisting of approximately 300 participants with vitiligo who were treated with a combination of topical corticosteroids, oral vitamin C, and oral vitamin B₁₂ supplementation showed excellent repigmentation (defined by repigmentation of more than 76% of the originally affected area) in 50 participants.⁷

Fruits—Most web pages had mixed recommendations on whether to include or avoid certain fruits. Interestingly, inclusion of mangoes and apricots in the diet were highly recommended (9/31 [29%] and 8/31 [26%], respectively) while fruits such as oranges, lemons, papayas, and grapes were discouraged (10/31 [32%], 8/31 [26%], 6/31 [19%], and 7/31 [23%], respectively). Although some web pages suggested that vitamin C–rich produce including citrus and berries may help to increase melanin formation, others strongly suggested avoiding these fruits. There is limited information on the effects of citrus on vitiligo, but a 2022 study indicated that 5-demethylnobiletin, a flavonoid found in sweet citrus fruits, may stimulate melanin synthesis, which can possibly be beneficial for vitiligo.⁸

Omega-3 Fatty Acids—Seven of 31 (23%) web pages recommended the inclusion of omega-3 fatty acids for their role as antioxidants to improve vitiligo symptoms. Research has indicated a strong association between vitiligo and oxidative stress.⁹ A 2007 controlled clinical trial that included 28 vitiligo patients demonstrated that oral antioxidant supplementation in combination with narrowband UVB phototherapy can significantly decrease vitiligo-associated oxidative stress (P<.05); 8 of 17 (47%) patients in the treatment group saw greater than 75% repigmentation after antioxidant treatment.¹⁰

Grains—Five of 31 (16%) web pages suggested avoiding gluten—a protein naturally found in some grains including wheat, barley, and rye—to improve vitiligo symptoms. A 2021 review suggested that a gluten-free diet may be effective in managing celiac disease, and it is hypothesized that vitiligo may be managed with similar dietary adjustments.¹¹ Studies have shown that celiac disease and vitiligo—both autoimmune conditions—involve IL-2, IL-6, IL-7, and IL-21 in their disease pathways.^12,13 Their shared immunogenic mechanism may account for similar management options.

Upon review, 2 case reports were identified that discussed a relationship between a gluten-free diet and vitiligo symptom improvement. In one report, a 9-year-old child diagnosed with both celiac disease and vitiligo saw intense repigmentation of the skin after adhering to a gluten-free diet for 1 year.¹⁴ Another case study reported a 22-year-old woman with vitiligo whose symptoms improved after 1 month of a gluten-free diet following 2 years of failed treatment with a topical steroid and phototherapy.¹⁵

Seven of 31 (23%) web pages suggested that individuals with vitiligo should include wheat in their diet. There is no published literature discussing the relationship between vitiligo and wheat. Of the 31 web pages reviewed, 10 (32%) suggested including whole grain. There is no relevant scientific evidence or hypotheses describing how whole grains may be beneficial in vitiligo.

Minerals—Eight of 31 (26%) web pages suggested including zinc in the diet to improve vitiligo symptoms. A 2020 study evaluated how different serum levels of zinc in vitiligo patients might be affiliated with interleukin activity. Fifty patients diagnosed with active vitiligo were tested for serum levels of zinc, IL-4, IL-6, and IL-17.¹⁶ The results showed that mean serum levels of zinc were lower in vitiligo patients compared with patients without vitiligo. The study concluded that zinc could possibly be used as a supplement to improve vitiligo, though the dosage needs to be further studied and confirmed.¹⁶

Vegetables—Eleven of 31 (35%) web pages recommended leafy green vegetables and 13 of 31 (42%) recommended spinach for patients with vitiligo. Spinach and other leafy green vegetables are known to be rich in antioxidants, which may have protective effects against reactive oxygen species that are thought to contribute to vitiligo progression.^17,18

Nuts—Walnuts were recommended in 11 of 31 (35%) web pages. Nuts may be beneficial in reducing inflammation and providing protection against oxidative stress.⁹ However, there is no specific scientific literature that supports the inclusion of nuts in the diet to manage vitiligo symptoms.

Comment

With a growing amount of research suggesting that diet modifications may contribute to management of certain skin conditions, vitiligo patients often inquire about foods or supplements that may help improve their condition.¹⁹ Our review highlighted what information was available to the public regarding diet and vitiligo, with preliminary support of the following primary diet components: vitamin D, vitamin B₁₂, zinc, and omega-3 fatty acids. Our review showed no support in the literature for the items that were recommended to avoid. It is important to note that 27 of 31 (87%) web pages from our online search were not authored by medical professionals or dermatologists. Additionally, many web pages suggested conflicting information, making it difficult to draw concrete conclusions about what diet modifications will be beneficial to the vitiligo community. Further controlled clinical trials are warranted due to the lack of formal studies that assess the relationship between diet and vitiligo.

Internet platforms have become a common source of medical information for individuals with a broad range of skin conditions including vitiligo. The prevalence of vitiligo among US adults ranges from 0.76% to 1.11%, with approximately 40% of adult cases of vitiligo in the United States remaining undiagnosed.¹ The vitiligo community has become more inquisitive of the relationship between diet and vitiligo, turning to online sources for suggestions on diet modifications that may be beneficial for their condition. Although there is an abundance of online information, few diets or foods have been medically recognized to definitively improve or worsen vitiligo symptoms. We reviewed the top online web pages accessible to the public regarding diet suggestions that affect vitiligo symptoms. We then compared these online results to published peer-reviewed scientific literature.

Methods

Two independent online searches were performed by Researcher 1 (Y.A.) and Researcher 2 (I.M.) using Google Advanced Search. The independent searches were performed by the reviewers in neighboring areas of Chicago, Illinois, using the same Internet browser (Google Chrome). The primary search terms were diet and vitiligo along with the optional additional terms dietary supplement(s), food(s), nutrition, herb(s), or vitamin(s). Our search included any web pages published or updated from January 1, 2010, to December 31, 2021, and originally scribed in the English language. The domains “.com,” “.org,” “.edu,” and “.cc” were included.

From this initial search, Researcher 1 identified 312 web pages and Researcher 2 identified 314 web pages. Each reviewer sorted their respective search results to identify the number of eligible records to be screened. Records were defined as unique web pages that met the search criteria. After removing duplicates, Researcher 1 screened 102 web pages and Researcher 2 screened 76 web pages. Of these records, web pages were excluded if they did not include any diet recommendations for vitiligo patients. Each reviewer independently created a list of eligible records, and the independent lists were then merged for a total of 58 web pages. Among these 58 web pages, there were 24 duplicate records and 3 records that were deemed ineligible for the study due to lack of subject matter relevance. A final total of 31 web pages were included in the data analysis (Figure). Of the 31 records selected, the reviewers jointly evaluated each web page and recorded the diet components that were recommended for individuals with vitiligo to either include or avoid (eTable).

For comparison and support from published scientific literature, a search of PubMed articles indexed for MEDLINE was conducted using the terms diet and vitiligo. Relevant human clinical studies published in the English-language literature were reviewed for content regarding the relationship between diet and vitiligo.

Results

Our online search revealed an abundance of information regarding various dietary modifications suggested to aid in the management of vitiligo symptoms. Most web pages (27/31 [87%]) were not authored by medical professionals or dermatologists. There were 27 diet components mentioned 8 or more times within the 31 total web pages. These diet components were selected for further review via PubMed. Each item was searched on PubMed using the term “[respective diet component] and vitiligo” among all published literature in the English language. Our study focused on summarizing the data on dietary components for which we were able to gather scientific support. These data have been organized into the following categories: vitamins, fruits, omega-3 fatty acids, grains, minerals, vegetables, and nuts.

Vitamins—The online literature recommended inclusion of vitamin supplements, in particular vitamins D and B₁₂, which aligned with published scientific literature.^2,3 Eleven of 31 (35%) web pages recommended vitamin D in vitiligo. A 2010 study analyzing patients with vitiligo vulgaris (N=45) found that 68.9% of the cohort had insufficient (<30 ng/mL) 25-hydroxyvitamin D levels.² A prospective study of 30 individuals found that the use of tacrolimus ointment plus oral vitamin D supplementation was found to be more successful in repigmentation than topical tacrolimus alone.³ Vitamin D dosage ranged from 1500 IU/d if the patient’s serum 25-hydroxyvitamin D levels were less than 20 ng/mL to 3000 IU/d if the serum levels were less than 10 ng/mL for 6 months.

Dairy products are a source of vitamin D.^2,3 Of the web pages that mentioned dairy, a subtle majority (4/7 [57%]) recommended the inclusion of dairy products. Although many web pages did not specify whether oral vitamin D supplementation vs dietary food consumption is preferred, a 2013 controlled study of 16 vitiligo patients who received high doses of vitamin D supplementation with a low-calcium diet found that 4 patients showed 1% to 25% repigmentation, 5 patients showed 26% to 50% repigmentation, and 5 patients showed 51% to 75% repigmentation of the affected areas.⁴

Eleven of 31 (35%) web pages recommended inclusion of vitamin B₁₂ supplementation in vitiligo. A 2-year study with 100 participants showed that supplementation with folic acid and vitamin B₁₂ along with sun exposure yielded more effective repigmentation than either vitamins or sun exposure alone.⁵ An additional hypothesis suggested vitamin B₁₂ may aid in repigmentation through its role in the homocysteine pathway. Although the theory is unproven, it is proposed that inhibition of homocysteine via vitamin B₁₂ or folic acid supplementation may play a role in reducing melanocyte destruction and restoring melanin synthesis.⁶

There were mixed recommendations regarding vitamin C via supplementation and/or eating citrus fruits such as oranges. Although there are limited clinical studies on the use of vitamin C and the treatment of vitiligo, a 6-year prospective study from Madagascar consisting of approximately 300 participants with vitiligo who were treated with a combination of topical corticosteroids, oral vitamin C, and oral vitamin B₁₂ supplementation showed excellent repigmentation (defined by repigmentation of more than 76% of the originally affected area) in 50 participants.⁷

Fruits—Most web pages had mixed recommendations on whether to include or avoid certain fruits. Interestingly, inclusion of mangoes and apricots in the diet were highly recommended (9/31 [29%] and 8/31 [26%], respectively) while fruits such as oranges, lemons, papayas, and grapes were discouraged (10/31 [32%], 8/31 [26%], 6/31 [19%], and 7/31 [23%], respectively). Although some web pages suggested that vitamin C–rich produce including citrus and berries may help to increase melanin formation, others strongly suggested avoiding these fruits. There is limited information on the effects of citrus on vitiligo, but a 2022 study indicated that 5-demethylnobiletin, a flavonoid found in sweet citrus fruits, may stimulate melanin synthesis, which can possibly be beneficial for vitiligo.⁸

Omega-3 Fatty Acids—Seven of 31 (23%) web pages recommended the inclusion of omega-3 fatty acids for their role as antioxidants to improve vitiligo symptoms. Research has indicated a strong association between vitiligo and oxidative stress.⁹ A 2007 controlled clinical trial that included 28 vitiligo patients demonstrated that oral antioxidant supplementation in combination with narrowband UVB phototherapy can significantly decrease vitiligo-associated oxidative stress (P<.05); 8 of 17 (47%) patients in the treatment group saw greater than 75% repigmentation after antioxidant treatment.¹⁰

Grains—Five of 31 (16%) web pages suggested avoiding gluten—a protein naturally found in some grains including wheat, barley, and rye—to improve vitiligo symptoms. A 2021 review suggested that a gluten-free diet may be effective in managing celiac disease, and it is hypothesized that vitiligo may be managed with similar dietary adjustments.¹¹ Studies have shown that celiac disease and vitiligo—both autoimmune conditions—involve IL-2, IL-6, IL-7, and IL-21 in their disease pathways.^12,13 Their shared immunogenic mechanism may account for similar management options.

Upon review, 2 case reports were identified that discussed a relationship between a gluten-free diet and vitiligo symptom improvement. In one report, a 9-year-old child diagnosed with both celiac disease and vitiligo saw intense repigmentation of the skin after adhering to a gluten-free diet for 1 year.¹⁴ Another case study reported a 22-year-old woman with vitiligo whose symptoms improved after 1 month of a gluten-free diet following 2 years of failed treatment with a topical steroid and phototherapy.¹⁵

Seven of 31 (23%) web pages suggested that individuals with vitiligo should include wheat in their diet. There is no published literature discussing the relationship between vitiligo and wheat. Of the 31 web pages reviewed, 10 (32%) suggested including whole grain. There is no relevant scientific evidence or hypotheses describing how whole grains may be beneficial in vitiligo.

Minerals—Eight of 31 (26%) web pages suggested including zinc in the diet to improve vitiligo symptoms. A 2020 study evaluated how different serum levels of zinc in vitiligo patients might be affiliated with interleukin activity. Fifty patients diagnosed with active vitiligo were tested for serum levels of zinc, IL-4, IL-6, and IL-17.¹⁶ The results showed that mean serum levels of zinc were lower in vitiligo patients compared with patients without vitiligo. The study concluded that zinc could possibly be used as a supplement to improve vitiligo, though the dosage needs to be further studied and confirmed.¹⁶

Vegetables—Eleven of 31 (35%) web pages recommended leafy green vegetables and 13 of 31 (42%) recommended spinach for patients with vitiligo. Spinach and other leafy green vegetables are known to be rich in antioxidants, which may have protective effects against reactive oxygen species that are thought to contribute to vitiligo progression.^17,18

Nuts—Walnuts were recommended in 11 of 31 (35%) web pages. Nuts may be beneficial in reducing inflammation and providing protection against oxidative stress.⁹ However, there is no specific scientific literature that supports the inclusion of nuts in the diet to manage vitiligo symptoms.

Comment

With a growing amount of research suggesting that diet modifications may contribute to management of certain skin conditions, vitiligo patients often inquire about foods or supplements that may help improve their condition.¹⁹ Our review highlighted what information was available to the public regarding diet and vitiligo, with preliminary support of the following primary diet components: vitamin D, vitamin B₁₂, zinc, and omega-3 fatty acids. Our review showed no support in the literature for the items that were recommended to avoid. It is important to note that 27 of 31 (87%) web pages from our online search were not authored by medical professionals or dermatologists. Additionally, many web pages suggested conflicting information, making it difficult to draw concrete conclusions about what diet modifications will be beneficial to the vitiligo community. Further controlled clinical trials are warranted due to the lack of formal studies that assess the relationship between diet and vitiligo.

A new analysis supports using the smallpox antiviral tecovirimat (TPOXX/ST-246) in HIV patients showing the first symptoms of the human smallpox disease mpox (monkeypox), caused by the variola virus.

In a small prospective matched cohort analysis, people with HIV (PWH) and mpox disease who received tecovirimat within 7 days of symptom onset were 13 times less likely to experience progression, compared with PWH not prescribed tecovirimat within that window. In a matched cohort of 112 PWH, mpox disease progression occurred in 5.4% in an early tecovirimat group and in 26.8% in a late- or no-tecovirimat group, for a paired odds ratio of 13.00 (95% CI, 1.71-99.40; P = .002).

“Results of the present study suggest that tecovirimat treatment should be started early at the time of suspected mpox diagnosis in all PWH, especially in those with nonsuppressed HIV viremia or mucosal site involvement,” wrote a team led by Bruce Aldred, MD, of the Division of Infectious Diseases in the Department of Medicine at Emory University School of Medicine in Atlanta, in JAMA Internal Medicine. Early symptoms of mpox include skin rash and mucosal lesions, along with viral symptoms such as fever, headache, muscle aches, back pain, low energy, and swollen lymph nodes.

As of March 1 of last year, the United States reported more than 30,000 cases, while cases numbered more than 86,000 worldwide.

Despite a lack of effectiveness data in humans, tecovirimat was widely prescribed to PWH with mpox during the 2022 epidemic, which disproportionately affected PWH, particularly those with low CD4+ T-cell counts or severe mpox clinical manifestations who needed urgent therapy. Developed to treat smallpox, tecovirimat has antiviral activity against other orthopoxviruses, and has reduced mpox-related morbidity and mortality in animals.

Based on the animal data, approval was granted by the US Food and Drug Administration (FDA) for human mpox treatment. Dr. Aldred and colleagues undertook this cohort analysis in the absence of human data and with the postoutbreak decline in cases impeding recruitment to a full-scale clinical trial.

Study design

The preponderantly Black cohort included 112 PWH diagnosed with mpox at four Atlanta hospitals from June 1 to October 7, 2022. Patients were grouped in an early cohort receiving tecovirimat within 7 days of symptom onset or a no or late cohort (no tecovirimat or treatment more than 7 days after symptom onset. Multivariate logistic regression models identified factors associated with progression, defined as development of at least one severe CDC mpox criterion after symptom day 7.

The cohorts were then matched 1:1 using propensity scores based on the identified factors, and mpox disease progression was compared.

Of 112 PWH, 56 receive early tecovirimat and 56 received no or late treatment. In the early group, the median (interquartile range [IQR]) age was 35 (30-42) years; 54 individuals (96.4%) were cisgender men, 46 (82.1%) were Black, and 10 (17.9%) were, variously, White, American Indian, Alaska Native, Asian, Native Hawaiian or Other Pacific Islander, or of unknown race.

In the late- or no-tecovirimat group, the median (IQR) age was 36 (32-43) years; 54 (96.4%) were cisgender men, 49 (87.5%) were Black, and 7 (12.5%) were individuals of other or unknown race. Mpox disease progression occurred in 3 PWH in the early-tecovirimat group and 15 PWH (26.8%) in the late- or no-tecovirimat group.

Dr. Aldred and colleagues acknowledged that more research is needed to confirm the findings and cited several study limitations. These included the small sample size, the preponderance of Black participants, and the possibility that unmatched confounding variables could have led to the observation of fewer cases of severe disease in the early-tecovirimat cohort.

This study was supported by a grant from the Emory Center for AIDS Research. Coauthors reported grants from various institutes at the National Institutes of Health as well as from multiple pharmaceutical companies.

A new analysis supports using the smallpox antiviral tecovirimat (TPOXX/ST-246) in HIV patients showing the first symptoms of the human smallpox disease mpox (monkeypox), caused by the variola virus.

In a small prospective matched cohort analysis, people with HIV (PWH) and mpox disease who received tecovirimat within 7 days of symptom onset were 13 times less likely to experience progression, compared with PWH not prescribed tecovirimat within that window. In a matched cohort of 112 PWH, mpox disease progression occurred in 5.4% in an early tecovirimat group and in 26.8% in a late- or no-tecovirimat group, for a paired odds ratio of 13.00 (95% CI, 1.71-99.40; P = .002).

“Results of the present study suggest that tecovirimat treatment should be started early at the time of suspected mpox diagnosis in all PWH, especially in those with nonsuppressed HIV viremia or mucosal site involvement,” wrote a team led by Bruce Aldred, MD, of the Division of Infectious Diseases in the Department of Medicine at Emory University School of Medicine in Atlanta, in JAMA Internal Medicine. Early symptoms of mpox include skin rash and mucosal lesions, along with viral symptoms such as fever, headache, muscle aches, back pain, low energy, and swollen lymph nodes.

As of March 1 of last year, the United States reported more than 30,000 cases, while cases numbered more than 86,000 worldwide.

Despite a lack of effectiveness data in humans, tecovirimat was widely prescribed to PWH with mpox during the 2022 epidemic, which disproportionately affected PWH, particularly those with low CD4+ T-cell counts or severe mpox clinical manifestations who needed urgent therapy. Developed to treat smallpox, tecovirimat has antiviral activity against other orthopoxviruses, and has reduced mpox-related morbidity and mortality in animals.

Based on the animal data, approval was granted by the US Food and Drug Administration (FDA) for human mpox treatment. Dr. Aldred and colleagues undertook this cohort analysis in the absence of human data and with the postoutbreak decline in cases impeding recruitment to a full-scale clinical trial.

Study design

The preponderantly Black cohort included 112 PWH diagnosed with mpox at four Atlanta hospitals from June 1 to October 7, 2022. Patients were grouped in an early cohort receiving tecovirimat within 7 days of symptom onset or a no or late cohort (no tecovirimat or treatment more than 7 days after symptom onset. Multivariate logistic regression models identified factors associated with progression, defined as development of at least one severe CDC mpox criterion after symptom day 7.

The cohorts were then matched 1:1 using propensity scores based on the identified factors, and mpox disease progression was compared.

Of 112 PWH, 56 receive early tecovirimat and 56 received no or late treatment. In the early group, the median (interquartile range [IQR]) age was 35 (30-42) years; 54 individuals (96.4%) were cisgender men, 46 (82.1%) were Black, and 10 (17.9%) were, variously, White, American Indian, Alaska Native, Asian, Native Hawaiian or Other Pacific Islander, or of unknown race.

In the late- or no-tecovirimat group, the median (IQR) age was 36 (32-43) years; 54 (96.4%) were cisgender men, 49 (87.5%) were Black, and 7 (12.5%) were individuals of other or unknown race. Mpox disease progression occurred in 3 PWH in the early-tecovirimat group and 15 PWH (26.8%) in the late- or no-tecovirimat group.

Dr. Aldred and colleagues acknowledged that more research is needed to confirm the findings and cited several study limitations. These included the small sample size, the preponderance of Black participants, and the possibility that unmatched confounding variables could have led to the observation of fewer cases of severe disease in the early-tecovirimat cohort.

This study was supported by a grant from the Emory Center for AIDS Research. Coauthors reported grants from various institutes at the National Institutes of Health as well as from multiple pharmaceutical companies.

A new analysis supports using the smallpox antiviral tecovirimat (TPOXX/ST-246) in HIV patients showing the first symptoms of the human smallpox disease mpox (monkeypox), caused by the variola virus.

In a small prospective matched cohort analysis, people with HIV (PWH) and mpox disease who received tecovirimat within 7 days of symptom onset were 13 times less likely to experience progression, compared with PWH not prescribed tecovirimat within that window. In a matched cohort of 112 PWH, mpox disease progression occurred in 5.4% in an early tecovirimat group and in 26.8% in a late- or no-tecovirimat group, for a paired odds ratio of 13.00 (95% CI, 1.71-99.40; P = .002).

“Results of the present study suggest that tecovirimat treatment should be started early at the time of suspected mpox diagnosis in all PWH, especially in those with nonsuppressed HIV viremia or mucosal site involvement,” wrote a team led by Bruce Aldred, MD, of the Division of Infectious Diseases in the Department of Medicine at Emory University School of Medicine in Atlanta, in JAMA Internal Medicine. Early symptoms of mpox include skin rash and mucosal lesions, along with viral symptoms such as fever, headache, muscle aches, back pain, low energy, and swollen lymph nodes.

As of March 1 of last year, the United States reported more than 30,000 cases, while cases numbered more than 86,000 worldwide.

Despite a lack of effectiveness data in humans, tecovirimat was widely prescribed to PWH with mpox during the 2022 epidemic, which disproportionately affected PWH, particularly those with low CD4+ T-cell counts or severe mpox clinical manifestations who needed urgent therapy. Developed to treat smallpox, tecovirimat has antiviral activity against other orthopoxviruses, and has reduced mpox-related morbidity and mortality in animals.

Based on the animal data, approval was granted by the US Food and Drug Administration (FDA) for human mpox treatment. Dr. Aldred and colleagues undertook this cohort analysis in the absence of human data and with the postoutbreak decline in cases impeding recruitment to a full-scale clinical trial.

Study design

The preponderantly Black cohort included 112 PWH diagnosed with mpox at four Atlanta hospitals from June 1 to October 7, 2022. Patients were grouped in an early cohort receiving tecovirimat within 7 days of symptom onset or a no or late cohort (no tecovirimat or treatment more than 7 days after symptom onset. Multivariate logistic regression models identified factors associated with progression, defined as development of at least one severe CDC mpox criterion after symptom day 7.

The cohorts were then matched 1:1 using propensity scores based on the identified factors, and mpox disease progression was compared.

Of 112 PWH, 56 receive early tecovirimat and 56 received no or late treatment. In the early group, the median (interquartile range [IQR]) age was 35 (30-42) years; 54 individuals (96.4%) were cisgender men, 46 (82.1%) were Black, and 10 (17.9%) were, variously, White, American Indian, Alaska Native, Asian, Native Hawaiian or Other Pacific Islander, or of unknown race.

In the late- or no-tecovirimat group, the median (IQR) age was 36 (32-43) years; 54 (96.4%) were cisgender men, 49 (87.5%) were Black, and 7 (12.5%) were individuals of other or unknown race. Mpox disease progression occurred in 3 PWH in the early-tecovirimat group and 15 PWH (26.8%) in the late- or no-tecovirimat group.

Dr. Aldred and colleagues acknowledged that more research is needed to confirm the findings and cited several study limitations. These included the small sample size, the preponderance of Black participants, and the possibility that unmatched confounding variables could have led to the observation of fewer cases of severe disease in the early-tecovirimat cohort.

This study was supported by a grant from the Emory Center for AIDS Research. Coauthors reported grants from various institutes at the National Institutes of Health as well as from multiple pharmaceutical companies.

Medication-induced telogen effluvium (TE) is a nonscarring alopecia that typically is reversible. Appropriate management requires identification of the underlying trigger and cessation of potential culprit medications. In part 2 of this series, we review anticoagulant and antihypertensive medications as potential contributors to TE.

Anticoagulants

Anticoagulants target various parts of the coagulation cascade to prevent clot formation in patients with conditions that increase their risk for thromboembolic events. Common indications for initiating anticoagulant therapy include atrial fibrillation,¹ venous thromboembolism,² acute myocardial infarction,³ malignancy,⁴ and hypercoagulable states.⁵ Traditional anticoagulants include heparin and warfarin. Heparin is a glycosaminoglycan that exerts its anticoagulant effects through binding with antithrombin, greatly increasing its inactivation of thrombin and factor Xa of the coagulation cascade.⁶ Warfarin is a coumarin derivative that inhibits activation of vitamin K, subsequently limiting the function of vitamin K–dependent factors II, VII, IX, and X.^7,8 Watras et al⁹ noted that heparin and warfarin were implicated in alopecia as their clinical use became widespread throughout the mid-20th century. Onset of alopecia following the use of heparin or warfarin was reported at 3 weeks to 3 months following medication initiation, with most cases clinically consistent with TE.⁹ Heparin and warfarin both have alopecia reported as a potential adverse effect in their structured product labeling documents.^10,11

Heparin is further classified into unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH); the latter is a heterogeneous group of medications derived from chemical or enzymatic depolymerization of UFH.¹² In contrast to UFH, LMWH exerts its anticoagulant effects through inactivation of factor Xa without the ability to bind thrombin.¹² An animal study using anagen-induced mice demonstrated that intraperitoneal administration of heparin inhibited the development of anagen follicles, while in vitro studies showed that the addition of heparin inhibited mouse dermal papilla cell proliferation.¹³ Other animal and in vitro studies have examined the inhibitory effects of heparin on signaling pathways in tumor lymphangiogenesis, including the vascular endothelial growth factor C/vascular endothelial growth factor receptor 3 axis.^14,15 Clinically, it has been demonstrated that heparin, especially LMWHs, may be associated with a survival benefit among certain cancer patients,^16,17 with the impact of LMWHs attributed to antimitotic and antimetastatic effects of heparin on tumor growth.¹⁴ It is hypothesized that such antiangiogenic and antimitotic effects also are involved in the pathomechanisms of heparin-induced alopecia.¹⁸

More recently, the use of direct oral anticoagulants (DOACs) such as dabigatran, rivaroxaban, and apixaban has increased due to their more favorable adverse-effect profile and minimal monitoring requirements. Bonaldo et al¹⁹ conducted an analysis of reports submitted to the World Health Organization’s VigiBase database of alopecia associated with DOACs until May 2, 2018. They found 1316 nonduplicate DOAC-induced cases of alopecia, with rivaroxaban as the most reported drug associated with alopecia development (58.8% [774/1316]). Only 4 cases demonstrated alopecia with DOAC rechallenge, suggesting onset of alopecia may have been unrelated to DOAC use or caused by a different trigger. Among 243 cases with a documented time to onset of alopecia, the median was 28 days, with an interquartile range of 63 days. Because TE most commonly occurs 3 to 4 months after the inciting event or medication trigger, there is little evidence to suggest DOACs as the cause of TE, and the observed cases of alopecia may be attributable to another preceding medical event and/or medication exposure.¹⁹ More studies are needed to examine the impact of anticoagulant medications on the hair cycle.

Antihypertensives

Hypertension is a modifiable risk factor for several ­cardiovascular diseases.²⁰ According to the 2019 American College of Cardiology/American Heart Association Guideline on the Primary Prevention of Cardiovascular Disease,²¹ first-line medications include thiazide diuretics, calcium channel blockers, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor ­blockers (ARBs).

Angiotensin-converting enzyme inhibitors exert their antihypertensive effects by reducing conversion of angiotensin I to angiotensin II, thereby limiting the downstream effects of vasoconstriction as well as sodium and water retention. Given the proven mortality benefit of ACE inhibition in patients with congestive heart failure, ACE inhibitors are used as first-line therapy in these patients.^22,23 Alopecia associated with ACE inhibitors is rare and limited to case reports following their introduction and approval in 1981.^24-28 In one case, a woman in her 60s with congestive heart failure initiated captopril with development of an erythematous pruritic rash on the extremities and diffuse scalp hair loss 2 months later; spontaneous hair growth resumed 1 month following captopril discontinuation.²⁵ In this case, the hair loss may be secondary to the drug eruption rather than true medication-induced TE. Initiation of enalapril in a woman in her 30s with hypertension was associated with diffuse scalp alopecia 4 weeks later that resolved with cessation of the suspected culprit, enalapril; rechallenge with enalapril several months later reproduced the hair loss.²⁷ Given limited reports of ACE inhibitor–associated hair loss relative to their pervasive use, a direct causal role between ACE inhibition and TE is unlikely, or it has not been rigorously identified. The structured product labeling for captopril includes alopecia in its list of adverse effects reported in approximately 0.5% to 2% of patients but did not appear at increased frequency compared to placebo or other treatments used in controlled trials.²⁹ Alternative inciting causes of alopecia in patients prescribed ACE inhibitors may include use of other medications, hospitalization, or metabolic derangements related to their underlying cardiac disease.

Although not indicated as a primary treatment for hypertension, β-blockers have US Food and Drug Administration approval for the treatment of certain arrhythmias, hypertension, heart failure, myocardial infarction, hyperthyroidism, and other conditions.³⁰β-Blockers are competitive antagonists of β-adrenergic receptors that limit the production of intracellular cyclic adenosine monophosphate, but the mechanism of β-blockers as antihypertensives is unclear.³¹ Evidence supporting the role of β-adrenergic antagonists in TE is limited to case reports. Widespread alopecia across the scalp and arms was noted in a man in his 30s several months after starting propranolol.³² Biopsy of an affected area of the scalp demonstrated an increased number of telogen follicles with no other abnormalities. Near-complete resolution of alopecia was seen 4 months following cessation of propranolol, which recurred within 4 weeks of rechallenge.³² Although the histopathologic features are compatible with TE, the loss of body hair and rapid recurrence within 4 weeks of rechallenge are atypical for TE. As such, the use of propranolol and the reported alopecia may be coincidental or evidence of an atypical drug reaction distinct from medication-induced TE. Only a handful of other case reports have been published describing TE in patients treated with β-blockers, including metoprolol and propranolol.^33,34 Alopecia has been reported with the use of carvedilol in up to 0.1% of participants.³⁵ Although cases have been reported, TE appears to be an uncommon occurrence following β-blocker therapy.

Minoxidil—Oral minoxidil originally was approved for use in patients with resistant hypertension, defined as blood pressure elevated above goal despite concurrent use of the maximum dose of 3 classes of antihypertensives.³⁶ Unlike other antihypertensive medications, minoxidil appears to cause reversible hypertrichosis that affects nearly all patients using oral minoxidil for longer than 1 month.³⁷ This common adverse effect was a desired outcome in patients affected by hair loss, and a topical formulation of minoxidil was approved for androgenetic alopecia in men and women in 1988 and 1991, respectively.³⁸ Since its approval, topical minoxidil has been commonly prescribed in the treatment of several types of alopecia, though evidence of its efficacy in the treatment of TE is limited.^39,40 Low-dose oral minoxidil also has been reported to aid hair growth in androgenetic alopecia and TE.⁴¹ Taken orally, minoxidil is converted by sulfotransferases in the liver to minoxidil sulfate, which causes opening of plasma membrane adenosine ­triphosphate–sensitive potassium channels.^42-44 The subsequent membrane hyperpolarization reduces calcium ion influx, which also reduces cell excitability, and inhibits contraction in vascular smooth muscle cells, which results in the arteriolar vasodilatory and antihypertensive effects of minoxidil.^43,45 The potassium channel–opening effects of minoxidil may underly its hair growth stimulatory action. Unrelated potassium channel openers such as diazoxide and pinacidil also cause hypertrichosis.^46-48 An animal study showed that topical minoxidil, cromakalim (potassium channel opener), and P1075 (pinacidil analog) applied daily to the scalps of balding stump-tailed macaques led to significant increases in hair weight over a 20-week treatment period compared with the vehicle control group (P<.05 for minoxidil 100 mM and 250 mM, cromakalim 100 mM, and P1075 100 mM and 250 mM).⁵⁰ For minoxidil, this effect on hair growth appears to be dose dependent, as cumulative hair weights for the study period were significantly greater in the 250-mM concentration compared with 100-mM minoxidil (P<.05).⁴⁹ The potassium channel–opening activity of minoxidil may induce stimulation of microcirculation around hair follicles conducive to hair growth.⁵⁰ Other proposed mechanisms for hair growth with minoxidil include effects on keratinocyte and fibroblast cell proliferation,^51-53 collagen synthesis,^52,54 and prostaglandin activity.^44,55

Final Thoughts

Medication-induced TE is an undesired adverse effect of many commonly used medications, including retinoids, azole antifungals, mood stabilizers, anticoagulants, and antihypertensives. In part 1⁵⁶ of this 2-part series, we reviewed the existing literature on hair loss from retinoids, antifungals, and psychotropic medications. Herein, we focused on anticoagulant and antihypertensive medications as potential culprits of TE. Heparin and its derivatives have been associated with development of diffuse alopecia weeks to months after the start of treatment. Alopecia associated with ACE inhibitors and β-blockers has been described only in case reports, suggesting that they may be unlikely causes of TE. In contrast, minoxidil is an antihypertensive that can result in hypertrichosis and is used in the treatment of androgenetic alopecia. It should not be assumed that medications that share an indication or are part of the same medication class would similarly induce TE. The development of diffuse nonscarring alopecia should prompt suspicion for TE and thorough investigation of medications initiated 1 to 6 months prior to onset of clinically apparent alopecia. Suspected culprit medications should be carefully assessed for their likelihood of inducing TE.

Medication-induced telogen effluvium (TE) is a nonscarring alopecia that typically is reversible. Appropriate management requires identification of the underlying trigger and cessation of potential culprit medications. In part 2 of this series, we review anticoagulant and antihypertensive medications as potential contributors to TE.

Anticoagulants

Anticoagulants target various parts of the coagulation cascade to prevent clot formation in patients with conditions that increase their risk for thromboembolic events. Common indications for initiating anticoagulant therapy include atrial fibrillation,¹ venous thromboembolism,² acute myocardial infarction,³ malignancy,⁴ and hypercoagulable states.⁵ Traditional anticoagulants include heparin and warfarin. Heparin is a glycosaminoglycan that exerts its anticoagulant effects through binding with antithrombin, greatly increasing its inactivation of thrombin and factor Xa of the coagulation cascade.⁶ Warfarin is a coumarin derivative that inhibits activation of vitamin K, subsequently limiting the function of vitamin K–dependent factors II, VII, IX, and X.^7,8 Watras et al⁹ noted that heparin and warfarin were implicated in alopecia as their clinical use became widespread throughout the mid-20th century. Onset of alopecia following the use of heparin or warfarin was reported at 3 weeks to 3 months following medication initiation, with most cases clinically consistent with TE.⁹ Heparin and warfarin both have alopecia reported as a potential adverse effect in their structured product labeling documents.^10,11

Heparin is further classified into unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH); the latter is a heterogeneous group of medications derived from chemical or enzymatic depolymerization of UFH.¹² In contrast to UFH, LMWH exerts its anticoagulant effects through inactivation of factor Xa without the ability to bind thrombin.¹² An animal study using anagen-induced mice demonstrated that intraperitoneal administration of heparin inhibited the development of anagen follicles, while in vitro studies showed that the addition of heparin inhibited mouse dermal papilla cell proliferation.¹³ Other animal and in vitro studies have examined the inhibitory effects of heparin on signaling pathways in tumor lymphangiogenesis, including the vascular endothelial growth factor C/vascular endothelial growth factor receptor 3 axis.^14,15 Clinically, it has been demonstrated that heparin, especially LMWHs, may be associated with a survival benefit among certain cancer patients,^16,17 with the impact of LMWHs attributed to antimitotic and antimetastatic effects of heparin on tumor growth.¹⁴ It is hypothesized that such antiangiogenic and antimitotic effects also are involved in the pathomechanisms of heparin-induced alopecia.¹⁸

More recently, the use of direct oral anticoagulants (DOACs) such as dabigatran, rivaroxaban, and apixaban has increased due to their more favorable adverse-effect profile and minimal monitoring requirements. Bonaldo et al¹⁹ conducted an analysis of reports submitted to the World Health Organization’s VigiBase database of alopecia associated with DOACs until May 2, 2018. They found 1316 nonduplicate DOAC-induced cases of alopecia, with rivaroxaban as the most reported drug associated with alopecia development (58.8% [774/1316]). Only 4 cases demonstrated alopecia with DOAC rechallenge, suggesting onset of alopecia may have been unrelated to DOAC use or caused by a different trigger. Among 243 cases with a documented time to onset of alopecia, the median was 28 days, with an interquartile range of 63 days. Because TE most commonly occurs 3 to 4 months after the inciting event or medication trigger, there is little evidence to suggest DOACs as the cause of TE, and the observed cases of alopecia may be attributable to another preceding medical event and/or medication exposure.¹⁹ More studies are needed to examine the impact of anticoagulant medications on the hair cycle.

Antihypertensives

Hypertension is a modifiable risk factor for several ­cardiovascular diseases.²⁰ According to the 2019 American College of Cardiology/American Heart Association Guideline on the Primary Prevention of Cardiovascular Disease,²¹ first-line medications include thiazide diuretics, calcium channel blockers, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor ­blockers (ARBs).

Angiotensin-converting enzyme inhibitors exert their antihypertensive effects by reducing conversion of angiotensin I to angiotensin II, thereby limiting the downstream effects of vasoconstriction as well as sodium and water retention. Given the proven mortality benefit of ACE inhibition in patients with congestive heart failure, ACE inhibitors are used as first-line therapy in these patients.^22,23 Alopecia associated with ACE inhibitors is rare and limited to case reports following their introduction and approval in 1981.^24-28 In one case, a woman in her 60s with congestive heart failure initiated captopril with development of an erythematous pruritic rash on the extremities and diffuse scalp hair loss 2 months later; spontaneous hair growth resumed 1 month following captopril discontinuation.²⁵ In this case, the hair loss may be secondary to the drug eruption rather than true medication-induced TE. Initiation of enalapril in a woman in her 30s with hypertension was associated with diffuse scalp alopecia 4 weeks later that resolved with cessation of the suspected culprit, enalapril; rechallenge with enalapril several months later reproduced the hair loss.²⁷ Given limited reports of ACE inhibitor–associated hair loss relative to their pervasive use, a direct causal role between ACE inhibition and TE is unlikely, or it has not been rigorously identified. The structured product labeling for captopril includes alopecia in its list of adverse effects reported in approximately 0.5% to 2% of patients but did not appear at increased frequency compared to placebo or other treatments used in controlled trials.²⁹ Alternative inciting causes of alopecia in patients prescribed ACE inhibitors may include use of other medications, hospitalization, or metabolic derangements related to their underlying cardiac disease.

Although not indicated as a primary treatment for hypertension, β-blockers have US Food and Drug Administration approval for the treatment of certain arrhythmias, hypertension, heart failure, myocardial infarction, hyperthyroidism, and other conditions.³⁰β-Blockers are competitive antagonists of β-adrenergic receptors that limit the production of intracellular cyclic adenosine monophosphate, but the mechanism of β-blockers as antihypertensives is unclear.³¹ Evidence supporting the role of β-adrenergic antagonists in TE is limited to case reports. Widespread alopecia across the scalp and arms was noted in a man in his 30s several months after starting propranolol.³² Biopsy of an affected area of the scalp demonstrated an increased number of telogen follicles with no other abnormalities. Near-complete resolution of alopecia was seen 4 months following cessation of propranolol, which recurred within 4 weeks of rechallenge.³² Although the histopathologic features are compatible with TE, the loss of body hair and rapid recurrence within 4 weeks of rechallenge are atypical for TE. As such, the use of propranolol and the reported alopecia may be coincidental or evidence of an atypical drug reaction distinct from medication-induced TE. Only a handful of other case reports have been published describing TE in patients treated with β-blockers, including metoprolol and propranolol.^33,34 Alopecia has been reported with the use of carvedilol in up to 0.1% of participants.³⁵ Although cases have been reported, TE appears to be an uncommon occurrence following β-blocker therapy.

Minoxidil—Oral minoxidil originally was approved for use in patients with resistant hypertension, defined as blood pressure elevated above goal despite concurrent use of the maximum dose of 3 classes of antihypertensives.³⁶ Unlike other antihypertensive medications, minoxidil appears to cause reversible hypertrichosis that affects nearly all patients using oral minoxidil for longer than 1 month.³⁷ This common adverse effect was a desired outcome in patients affected by hair loss, and a topical formulation of minoxidil was approved for androgenetic alopecia in men and women in 1988 and 1991, respectively.³⁸ Since its approval, topical minoxidil has been commonly prescribed in the treatment of several types of alopecia, though evidence of its efficacy in the treatment of TE is limited.^39,40 Low-dose oral minoxidil also has been reported to aid hair growth in androgenetic alopecia and TE.⁴¹ Taken orally, minoxidil is converted by sulfotransferases in the liver to minoxidil sulfate, which causes opening of plasma membrane adenosine ­triphosphate–sensitive potassium channels.^42-44 The subsequent membrane hyperpolarization reduces calcium ion influx, which also reduces cell excitability, and inhibits contraction in vascular smooth muscle cells, which results in the arteriolar vasodilatory and antihypertensive effects of minoxidil.^43,45 The potassium channel–opening effects of minoxidil may underly its hair growth stimulatory action. Unrelated potassium channel openers such as diazoxide and pinacidil also cause hypertrichosis.^46-48 An animal study showed that topical minoxidil, cromakalim (potassium channel opener), and P1075 (pinacidil analog) applied daily to the scalps of balding stump-tailed macaques led to significant increases in hair weight over a 20-week treatment period compared with the vehicle control group (P<.05 for minoxidil 100 mM and 250 mM, cromakalim 100 mM, and P1075 100 mM and 250 mM).⁵⁰ For minoxidil, this effect on hair growth appears to be dose dependent, as cumulative hair weights for the study period were significantly greater in the 250-mM concentration compared with 100-mM minoxidil (P<.05).⁴⁹ The potassium channel–opening activity of minoxidil may induce stimulation of microcirculation around hair follicles conducive to hair growth.⁵⁰ Other proposed mechanisms for hair growth with minoxidil include effects on keratinocyte and fibroblast cell proliferation,^51-53 collagen synthesis,^52,54 and prostaglandin activity.^44,55

Final Thoughts

Medication-induced TE is an undesired adverse effect of many commonly used medications, including retinoids, azole antifungals, mood stabilizers, anticoagulants, and antihypertensives. In part 1⁵⁶ of this 2-part series, we reviewed the existing literature on hair loss from retinoids, antifungals, and psychotropic medications. Herein, we focused on anticoagulant and antihypertensive medications as potential culprits of TE. Heparin and its derivatives have been associated with development of diffuse alopecia weeks to months after the start of treatment. Alopecia associated with ACE inhibitors and β-blockers has been described only in case reports, suggesting that they may be unlikely causes of TE. In contrast, minoxidil is an antihypertensive that can result in hypertrichosis and is used in the treatment of androgenetic alopecia. It should not be assumed that medications that share an indication or are part of the same medication class would similarly induce TE. The development of diffuse nonscarring alopecia should prompt suspicion for TE and thorough investigation of medications initiated 1 to 6 months prior to onset of clinically apparent alopecia. Suspected culprit medications should be carefully assessed for their likelihood of inducing TE.

Medication-induced telogen effluvium (TE) is a nonscarring alopecia that typically is reversible. Appropriate management requires identification of the underlying trigger and cessation of potential culprit medications. In part 2 of this series, we review anticoagulant and antihypertensive medications as potential contributors to TE.

Anticoagulants

Anticoagulants target various parts of the coagulation cascade to prevent clot formation in patients with conditions that increase their risk for thromboembolic events. Common indications for initiating anticoagulant therapy include atrial fibrillation,¹ venous thromboembolism,² acute myocardial infarction,³ malignancy,⁴ and hypercoagulable states.⁵ Traditional anticoagulants include heparin and warfarin. Heparin is a glycosaminoglycan that exerts its anticoagulant effects through binding with antithrombin, greatly increasing its inactivation of thrombin and factor Xa of the coagulation cascade.⁶ Warfarin is a coumarin derivative that inhibits activation of vitamin K, subsequently limiting the function of vitamin K–dependent factors II, VII, IX, and X.^7,8 Watras et al⁹ noted that heparin and warfarin were implicated in alopecia as their clinical use became widespread throughout the mid-20th century. Onset of alopecia following the use of heparin or warfarin was reported at 3 weeks to 3 months following medication initiation, with most cases clinically consistent with TE.⁹ Heparin and warfarin both have alopecia reported as a potential adverse effect in their structured product labeling documents.^10,11

Heparin is further classified into unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH); the latter is a heterogeneous group of medications derived from chemical or enzymatic depolymerization of UFH.¹² In contrast to UFH, LMWH exerts its anticoagulant effects through inactivation of factor Xa without the ability to bind thrombin.¹² An animal study using anagen-induced mice demonstrated that intraperitoneal administration of heparin inhibited the development of anagen follicles, while in vitro studies showed that the addition of heparin inhibited mouse dermal papilla cell proliferation.¹³ Other animal and in vitro studies have examined the inhibitory effects of heparin on signaling pathways in tumor lymphangiogenesis, including the vascular endothelial growth factor C/vascular endothelial growth factor receptor 3 axis.^14,15 Clinically, it has been demonstrated that heparin, especially LMWHs, may be associated with a survival benefit among certain cancer patients,^16,17 with the impact of LMWHs attributed to antimitotic and antimetastatic effects of heparin on tumor growth.¹⁴ It is hypothesized that such antiangiogenic and antimitotic effects also are involved in the pathomechanisms of heparin-induced alopecia.¹⁸

More recently, the use of direct oral anticoagulants (DOACs) such as dabigatran, rivaroxaban, and apixaban has increased due to their more favorable adverse-effect profile and minimal monitoring requirements. Bonaldo et al¹⁹ conducted an analysis of reports submitted to the World Health Organization’s VigiBase database of alopecia associated with DOACs until May 2, 2018. They found 1316 nonduplicate DOAC-induced cases of alopecia, with rivaroxaban as the most reported drug associated with alopecia development (58.8% [774/1316]). Only 4 cases demonstrated alopecia with DOAC rechallenge, suggesting onset of alopecia may have been unrelated to DOAC use or caused by a different trigger. Among 243 cases with a documented time to onset of alopecia, the median was 28 days, with an interquartile range of 63 days. Because TE most commonly occurs 3 to 4 months after the inciting event or medication trigger, there is little evidence to suggest DOACs as the cause of TE, and the observed cases of alopecia may be attributable to another preceding medical event and/or medication exposure.¹⁹ More studies are needed to examine the impact of anticoagulant medications on the hair cycle.

Antihypertensives

Hypertension is a modifiable risk factor for several ­cardiovascular diseases.²⁰ According to the 2019 American College of Cardiology/American Heart Association Guideline on the Primary Prevention of Cardiovascular Disease,²¹ first-line medications include thiazide diuretics, calcium channel blockers, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor ­blockers (ARBs).

Angiotensin-converting enzyme inhibitors exert their antihypertensive effects by reducing conversion of angiotensin I to angiotensin II, thereby limiting the downstream effects of vasoconstriction as well as sodium and water retention. Given the proven mortality benefit of ACE inhibition in patients with congestive heart failure, ACE inhibitors are used as first-line therapy in these patients.^22,23 Alopecia associated with ACE inhibitors is rare and limited to case reports following their introduction and approval in 1981.^24-28 In one case, a woman in her 60s with congestive heart failure initiated captopril with development of an erythematous pruritic rash on the extremities and diffuse scalp hair loss 2 months later; spontaneous hair growth resumed 1 month following captopril discontinuation.²⁵ In this case, the hair loss may be secondary to the drug eruption rather than true medication-induced TE. Initiation of enalapril in a woman in her 30s with hypertension was associated with diffuse scalp alopecia 4 weeks later that resolved with cessation of the suspected culprit, enalapril; rechallenge with enalapril several months later reproduced the hair loss.²⁷ Given limited reports of ACE inhibitor–associated hair loss relative to their pervasive use, a direct causal role between ACE inhibition and TE is unlikely, or it has not been rigorously identified. The structured product labeling for captopril includes alopecia in its list of adverse effects reported in approximately 0.5% to 2% of patients but did not appear at increased frequency compared to placebo or other treatments used in controlled trials.²⁹ Alternative inciting causes of alopecia in patients prescribed ACE inhibitors may include use of other medications, hospitalization, or metabolic derangements related to their underlying cardiac disease.

Although not indicated as a primary treatment for hypertension, β-blockers have US Food and Drug Administration approval for the treatment of certain arrhythmias, hypertension, heart failure, myocardial infarction, hyperthyroidism, and other conditions.³⁰β-Blockers are competitive antagonists of β-adrenergic receptors that limit the production of intracellular cyclic adenosine monophosphate, but the mechanism of β-blockers as antihypertensives is unclear.³¹ Evidence supporting the role of β-adrenergic antagonists in TE is limited to case reports. Widespread alopecia across the scalp and arms was noted in a man in his 30s several months after starting propranolol.³² Biopsy of an affected area of the scalp demonstrated an increased number of telogen follicles with no other abnormalities. Near-complete resolution of alopecia was seen 4 months following cessation of propranolol, which recurred within 4 weeks of rechallenge.³² Although the histopathologic features are compatible with TE, the loss of body hair and rapid recurrence within 4 weeks of rechallenge are atypical for TE. As such, the use of propranolol and the reported alopecia may be coincidental or evidence of an atypical drug reaction distinct from medication-induced TE. Only a handful of other case reports have been published describing TE in patients treated with β-blockers, including metoprolol and propranolol.^33,34 Alopecia has been reported with the use of carvedilol in up to 0.1% of participants.³⁵ Although cases have been reported, TE appears to be an uncommon occurrence following β-blocker therapy.

Minoxidil—Oral minoxidil originally was approved for use in patients with resistant hypertension, defined as blood pressure elevated above goal despite concurrent use of the maximum dose of 3 classes of antihypertensives.³⁶ Unlike other antihypertensive medications, minoxidil appears to cause reversible hypertrichosis that affects nearly all patients using oral minoxidil for longer than 1 month.³⁷ This common adverse effect was a desired outcome in patients affected by hair loss, and a topical formulation of minoxidil was approved for androgenetic alopecia in men and women in 1988 and 1991, respectively.³⁸ Since its approval, topical minoxidil has been commonly prescribed in the treatment of several types of alopecia, though evidence of its efficacy in the treatment of TE is limited.^39,40 Low-dose oral minoxidil also has been reported to aid hair growth in androgenetic alopecia and TE.⁴¹ Taken orally, minoxidil is converted by sulfotransferases in the liver to minoxidil sulfate, which causes opening of plasma membrane adenosine ­triphosphate–sensitive potassium channels.^42-44 The subsequent membrane hyperpolarization reduces calcium ion influx, which also reduces cell excitability, and inhibits contraction in vascular smooth muscle cells, which results in the arteriolar vasodilatory and antihypertensive effects of minoxidil.^43,45 The potassium channel–opening effects of minoxidil may underly its hair growth stimulatory action. Unrelated potassium channel openers such as diazoxide and pinacidil also cause hypertrichosis.^46-48 An animal study showed that topical minoxidil, cromakalim (potassium channel opener), and P1075 (pinacidil analog) applied daily to the scalps of balding stump-tailed macaques led to significant increases in hair weight over a 20-week treatment period compared with the vehicle control group (P<.05 for minoxidil 100 mM and 250 mM, cromakalim 100 mM, and P1075 100 mM and 250 mM).⁵⁰ For minoxidil, this effect on hair growth appears to be dose dependent, as cumulative hair weights for the study period were significantly greater in the 250-mM concentration compared with 100-mM minoxidil (P<.05).⁴⁹ The potassium channel–opening activity of minoxidil may induce stimulation of microcirculation around hair follicles conducive to hair growth.⁵⁰ Other proposed mechanisms for hair growth with minoxidil include effects on keratinocyte and fibroblast cell proliferation,^51-53 collagen synthesis,^52,54 and prostaglandin activity.^44,55

Final Thoughts

Medication-induced TE is an undesired adverse effect of many commonly used medications, including retinoids, azole antifungals, mood stabilizers, anticoagulants, and antihypertensives. In part 1⁵⁶ of this 2-part series, we reviewed the existing literature on hair loss from retinoids, antifungals, and psychotropic medications. Herein, we focused on anticoagulant and antihypertensive medications as potential culprits of TE. Heparin and its derivatives have been associated with development of diffuse alopecia weeks to months after the start of treatment. Alopecia associated with ACE inhibitors and β-blockers has been described only in case reports, suggesting that they may be unlikely causes of TE. In contrast, minoxidil is an antihypertensive that can result in hypertrichosis and is used in the treatment of androgenetic alopecia. It should not be assumed that medications that share an indication or are part of the same medication class would similarly induce TE. The development of diffuse nonscarring alopecia should prompt suspicion for TE and thorough investigation of medications initiated 1 to 6 months prior to onset of clinically apparent alopecia. Suspected culprit medications should be carefully assessed for their likelihood of inducing TE.

The Diagnosis: Cutaneous Rosai-Dorfman Disease

Rosai-Dorfman disease is a rare benign non- Langerhans cell histiocytopathy that can manifest initially with lymph node involvement—classically, massive painless cervical lymphadenopathy.¹ Cutaneous Rosai-Dorfman disease (CRDD) is a variant that can be associated with lymph node and internal involvement, but more than 80% of cases lack extracutaneous involvement.^2,3 In cases with extracutaneous involvement, lymph node disease is most frequent.3 Cutaneous Rosai-Dorfman disease unassociated with extracutaneous disease is a benign self-limiting histiocytopathy that manifests as painless red-brown, yellow, or fleshcolored nodules, plaques, or papules that may become tender or ulcerated.⁴

Cutaneous Rosai-Dorfman disease represents a benign histiocytopathy of resident dendritic cell derivation.³ A characteristic immunohistochemical finding is S-100 positivity, which might suggest a Langerhans cell transdifferentiation phenotype, but other markers corroborative of a Langerhans cell phenotype—namely CD1a and langerin—will be negative. Biopsies typically show a mid to deep dermal histiocytic infiltration in a variably dense polymorphous inflammatory cell background comprised of a mixture of lymphocytes, plasma cells, and neutrophils.³ At times the extent of lymphocytic infiltration can be to a magnitude that resembles a lymphoma on histopathology. In our patient, lymphoma was excluded based on clinical presentation, as this patient lacked the typical symptoms of lymphadenopathy or B symptoms that come with B-cell lymphoma.⁵

The histiocytes in CRDD are characteristically large mononuclear cells exhibiting a low nuclear to cytoplasmic ratio reflective of the voluminous, nonvacuolated, watery cytoplasm. They have ill-defined cytoplasmic membranes resulting in a seemingly syncytial growth pattern. A hallmark of the histiocytes is emperipolesis characterized by intracytoplasmic localization of intact inflammatory cells including neutrophils, lymphocytes, and plasma cells.³

The differential diagnosis of CRDD includes Langerhans cell histiocytosis (LCH), indeterminate cell histiocytosis, xanthogranuloma, and reticulohistiocytoma. All of these conditions can be differentiated by their unique histopathologic and phenotypic characteristics.

Langerhans cell histiocytosis is a distinct clonal histiocytopathy that has a varied presentation ranging from cutaneous confined cases manifesting as a solitary lesion to one of disseminated cutaneous disease with the potential for multiorgan involvement. Regardless of the variant of LCH, the hallmark cell is one showing an eccentrically disposed, reniform nucleus with an open chromatin and abundant eosinophilic cytoplasm (Figure 1).⁶ Both LCH and CRDD stain positive for S-100. However, unlike the histiocytes in CRDD, those seen in LCH stain positive for CD1a and langerin and would not express factor XIIIA. Additionally, the neoplastic cells would not exhibit the same extent of CD68 positivity seen in CRDD.⁶ Treatment of LCH depends on the extent of disease, especially for the presence or absence of extracutaneous disease.⁷

A variant of LCH is indeterminate cell histiocytosis, which can be seen in neonates or adults. It represents a neoplastic proliferation of Langerhans cells that are devoid of Birbeck granules, reflective of an immature early phase of differentiation in the skin prior to the cells acquiring the Birbeck granule (as would be seen in neonates) or a later phase of differentiation after the mature Langerhans cell has encountered antigen and is en route to the lymph node (typically seen in adults).⁸ The phenotypic profile is identical to conventional LCH except the cells do not express langerin. Microscopically, the infiltrates are composed of Langerhans cells that are morphologically indistinguishable from classic LCH but without epidermotropism and exhibit a dominant localization in the dermis typically unassociated with other inflammatory cell elements (Figure 2).⁹

Xanthogranuloma is seen in young children (juvenile xanthogranuloma) as a solitary lesion, though a multifocal cutaneous variant and extracutaneous presentations have been described. Similar lesions can be seen in adults.¹⁰ These lesions are evolutionary in their morphology. In the inception of a juvenile xanthogranuloma, the lesions are highly cellular, and the histiocytes typically are poorly lipidized; there may be a dearth of other inflammatory cell elements. As the lesions mature, the histiocytes become lipidized, and characteristic Touton giant cells that exhibit a wreath of nuclei with peripheral lipidization may develop (Figure 3). In the later stages, there is considerable hyalinizing fibrosis, and the cells can acquire a spindled appearance. The absence of emperipolesis and the presence of notable lipidization are useful light microscopy features differentiating xanthogranuloma from CRDD.¹¹ Treatment of xanthogranuloma can range from a conservative monitoring approach to an aggressive approach combining various antineoplastic therapies with immunosuppressive agents.¹²

Solitary and multicentric reticulohistiocytoma is another form of resident dendritic cell histiocytopathy that can resemble Rosai-Dorfman disease. It is a dermal histiocytic infiltrate accompanied by a polymorphous inflammatory cell infiltrate (Figure 4) and can show variable fibrosis.¹³ One of the hallmarks is the distinct amphophilic cytoplasms, possibly attributable to nuclear DNA released into the cytoplasm from effete nuclei.¹³ The solitary form is unassociated with systemic disease, whereas the multicentric variant can be a paraneoplastic syndrome in the setting of solid and hematologic malignancies.¹⁴ In addition, in the multicentric variant, similar lesions can affect any organ but there can be a proclivity to involve the hand and knee joints, leading to a crippling arthritis.¹⁵ We presented a case of CRDD, a benign resident dendritic cell histiocytopathy that can manifest as a cutaneous confined process in the skin where the clinical course is characteristically benign. It potentially can be confused with LCH, indeterminate cell histiocytosis, xanthogranuloma, and reticulohistiocytoma. For a solitary lesion, intralesional triamcinolone injection and excision are options. Multifocal cutaneous disease or CRDD with notable extracutaneous disease may require systemic treatment.16 In our patient, one intralesional triamcinolone injection was performed with notable resolution.

The Diagnosis: Cutaneous Rosai-Dorfman Disease

Rosai-Dorfman disease is a rare benign non- Langerhans cell histiocytopathy that can manifest initially with lymph node involvement—classically, massive painless cervical lymphadenopathy.¹ Cutaneous Rosai-Dorfman disease (CRDD) is a variant that can be associated with lymph node and internal involvement, but more than 80% of cases lack extracutaneous involvement.^2,3 In cases with extracutaneous involvement, lymph node disease is most frequent.3 Cutaneous Rosai-Dorfman disease unassociated with extracutaneous disease is a benign self-limiting histiocytopathy that manifests as painless red-brown, yellow, or fleshcolored nodules, plaques, or papules that may become tender or ulcerated.⁴

Cutaneous Rosai-Dorfman disease represents a benign histiocytopathy of resident dendritic cell derivation.³ A characteristic immunohistochemical finding is S-100 positivity, which might suggest a Langerhans cell transdifferentiation phenotype, but other markers corroborative of a Langerhans cell phenotype—namely CD1a and langerin—will be negative. Biopsies typically show a mid to deep dermal histiocytic infiltration in a variably dense polymorphous inflammatory cell background comprised of a mixture of lymphocytes, plasma cells, and neutrophils.³ At times the extent of lymphocytic infiltration can be to a magnitude that resembles a lymphoma on histopathology. In our patient, lymphoma was excluded based on clinical presentation, as this patient lacked the typical symptoms of lymphadenopathy or B symptoms that come with B-cell lymphoma.⁵

The histiocytes in CRDD are characteristically large mononuclear cells exhibiting a low nuclear to cytoplasmic ratio reflective of the voluminous, nonvacuolated, watery cytoplasm. They have ill-defined cytoplasmic membranes resulting in a seemingly syncytial growth pattern. A hallmark of the histiocytes is emperipolesis characterized by intracytoplasmic localization of intact inflammatory cells including neutrophils, lymphocytes, and plasma cells.³

The differential diagnosis of CRDD includes Langerhans cell histiocytosis (LCH), indeterminate cell histiocytosis, xanthogranuloma, and reticulohistiocytoma. All of these conditions can be differentiated by their unique histopathologic and phenotypic characteristics.

Langerhans cell histiocytosis is a distinct clonal histiocytopathy that has a varied presentation ranging from cutaneous confined cases manifesting as a solitary lesion to one of disseminated cutaneous disease with the potential for multiorgan involvement. Regardless of the variant of LCH, the hallmark cell is one showing an eccentrically disposed, reniform nucleus with an open chromatin and abundant eosinophilic cytoplasm (Figure 1).⁶ Both LCH and CRDD stain positive for S-100. However, unlike the histiocytes in CRDD, those seen in LCH stain positive for CD1a and langerin and would not express factor XIIIA. Additionally, the neoplastic cells would not exhibit the same extent of CD68 positivity seen in CRDD.⁶ Treatment of LCH depends on the extent of disease, especially for the presence or absence of extracutaneous disease.⁷

A variant of LCH is indeterminate cell histiocytosis, which can be seen in neonates or adults. It represents a neoplastic proliferation of Langerhans cells that are devoid of Birbeck granules, reflective of an immature early phase of differentiation in the skin prior to the cells acquiring the Birbeck granule (as would be seen in neonates) or a later phase of differentiation after the mature Langerhans cell has encountered antigen and is en route to the lymph node (typically seen in adults).⁸ The phenotypic profile is identical to conventional LCH except the cells do not express langerin. Microscopically, the infiltrates are composed of Langerhans cells that are morphologically indistinguishable from classic LCH but without epidermotropism and exhibit a dominant localization in the dermis typically unassociated with other inflammatory cell elements (Figure 2).⁹

Xanthogranuloma is seen in young children (juvenile xanthogranuloma) as a solitary lesion, though a multifocal cutaneous variant and extracutaneous presentations have been described. Similar lesions can be seen in adults.¹⁰ These lesions are evolutionary in their morphology. In the inception of a juvenile xanthogranuloma, the lesions are highly cellular, and the histiocytes typically are poorly lipidized; there may be a dearth of other inflammatory cell elements. As the lesions mature, the histiocytes become lipidized, and characteristic Touton giant cells that exhibit a wreath of nuclei with peripheral lipidization may develop (Figure 3). In the later stages, there is considerable hyalinizing fibrosis, and the cells can acquire a spindled appearance. The absence of emperipolesis and the presence of notable lipidization are useful light microscopy features differentiating xanthogranuloma from CRDD.¹¹ Treatment of xanthogranuloma can range from a conservative monitoring approach to an aggressive approach combining various antineoplastic therapies with immunosuppressive agents.¹²

Solitary and multicentric reticulohistiocytoma is another form of resident dendritic cell histiocytopathy that can resemble Rosai-Dorfman disease. It is a dermal histiocytic infiltrate accompanied by a polymorphous inflammatory cell infiltrate (Figure 4) and can show variable fibrosis.¹³ One of the hallmarks is the distinct amphophilic cytoplasms, possibly attributable to nuclear DNA released into the cytoplasm from effete nuclei.¹³ The solitary form is unassociated with systemic disease, whereas the multicentric variant can be a paraneoplastic syndrome in the setting of solid and hematologic malignancies.¹⁴ In addition, in the multicentric variant, similar lesions can affect any organ but there can be a proclivity to involve the hand and knee joints, leading to a crippling arthritis.¹⁵ We presented a case of CRDD, a benign resident dendritic cell histiocytopathy that can manifest as a cutaneous confined process in the skin where the clinical course is characteristically benign. It potentially can be confused with LCH, indeterminate cell histiocytosis, xanthogranuloma, and reticulohistiocytoma. For a solitary lesion, intralesional triamcinolone injection and excision are options. Multifocal cutaneous disease or CRDD with notable extracutaneous disease may require systemic treatment.16 In our patient, one intralesional triamcinolone injection was performed with notable resolution.

The Diagnosis: Cutaneous Rosai-Dorfman Disease

Rosai-Dorfman disease is a rare benign non- Langerhans cell histiocytopathy that can manifest initially with lymph node involvement—classically, massive painless cervical lymphadenopathy.¹ Cutaneous Rosai-Dorfman disease (CRDD) is a variant that can be associated with lymph node and internal involvement, but more than 80% of cases lack extracutaneous involvement.^2,3 In cases with extracutaneous involvement, lymph node disease is most frequent.3 Cutaneous Rosai-Dorfman disease unassociated with extracutaneous disease is a benign self-limiting histiocytopathy that manifests as painless red-brown, yellow, or fleshcolored nodules, plaques, or papules that may become tender or ulcerated.⁴

Cutaneous Rosai-Dorfman disease represents a benign histiocytopathy of resident dendritic cell derivation.³ A characteristic immunohistochemical finding is S-100 positivity, which might suggest a Langerhans cell transdifferentiation phenotype, but other markers corroborative of a Langerhans cell phenotype—namely CD1a and langerin—will be negative. Biopsies typically show a mid to deep dermal histiocytic infiltration in a variably dense polymorphous inflammatory cell background comprised of a mixture of lymphocytes, plasma cells, and neutrophils.³ At times the extent of lymphocytic infiltration can be to a magnitude that resembles a lymphoma on histopathology. In our patient, lymphoma was excluded based on clinical presentation, as this patient lacked the typical symptoms of lymphadenopathy or B symptoms that come with B-cell lymphoma.⁵

The histiocytes in CRDD are characteristically large mononuclear cells exhibiting a low nuclear to cytoplasmic ratio reflective of the voluminous, nonvacuolated, watery cytoplasm. They have ill-defined cytoplasmic membranes resulting in a seemingly syncytial growth pattern. A hallmark of the histiocytes is emperipolesis characterized by intracytoplasmic localization of intact inflammatory cells including neutrophils, lymphocytes, and plasma cells.³

The differential diagnosis of CRDD includes Langerhans cell histiocytosis (LCH), indeterminate cell histiocytosis, xanthogranuloma, and reticulohistiocytoma. All of these conditions can be differentiated by their unique histopathologic and phenotypic characteristics.

Langerhans cell histiocytosis is a distinct clonal histiocytopathy that has a varied presentation ranging from cutaneous confined cases manifesting as a solitary lesion to one of disseminated cutaneous disease with the potential for multiorgan involvement. Regardless of the variant of LCH, the hallmark cell is one showing an eccentrically disposed, reniform nucleus with an open chromatin and abundant eosinophilic cytoplasm (Figure 1).⁶ Both LCH and CRDD stain positive for S-100. However, unlike the histiocytes in CRDD, those seen in LCH stain positive for CD1a and langerin and would not express factor XIIIA. Additionally, the neoplastic cells would not exhibit the same extent of CD68 positivity seen in CRDD.⁶ Treatment of LCH depends on the extent of disease, especially for the presence or absence of extracutaneous disease.⁷

A variant of LCH is indeterminate cell histiocytosis, which can be seen in neonates or adults. It represents a neoplastic proliferation of Langerhans cells that are devoid of Birbeck granules, reflective of an immature early phase of differentiation in the skin prior to the cells acquiring the Birbeck granule (as would be seen in neonates) or a later phase of differentiation after the mature Langerhans cell has encountered antigen and is en route to the lymph node (typically seen in adults).⁸ The phenotypic profile is identical to conventional LCH except the cells do not express langerin. Microscopically, the infiltrates are composed of Langerhans cells that are morphologically indistinguishable from classic LCH but without epidermotropism and exhibit a dominant localization in the dermis typically unassociated with other inflammatory cell elements (Figure 2).⁹

Xanthogranuloma is seen in young children (juvenile xanthogranuloma) as a solitary lesion, though a multifocal cutaneous variant and extracutaneous presentations have been described. Similar lesions can be seen in adults.¹⁰ These lesions are evolutionary in their morphology. In the inception of a juvenile xanthogranuloma, the lesions are highly cellular, and the histiocytes typically are poorly lipidized; there may be a dearth of other inflammatory cell elements. As the lesions mature, the histiocytes become lipidized, and characteristic Touton giant cells that exhibit a wreath of nuclei with peripheral lipidization may develop (Figure 3). In the later stages, there is considerable hyalinizing fibrosis, and the cells can acquire a spindled appearance. The absence of emperipolesis and the presence of notable lipidization are useful light microscopy features differentiating xanthogranuloma from CRDD.¹¹ Treatment of xanthogranuloma can range from a conservative monitoring approach to an aggressive approach combining various antineoplastic therapies with immunosuppressive agents.¹²

Solitary and multicentric reticulohistiocytoma is another form of resident dendritic cell histiocytopathy that can resemble Rosai-Dorfman disease. It is a dermal histiocytic infiltrate accompanied by a polymorphous inflammatory cell infiltrate (Figure 4) and can show variable fibrosis.¹³ One of the hallmarks is the distinct amphophilic cytoplasms, possibly attributable to nuclear DNA released into the cytoplasm from effete nuclei.¹³ The solitary form is unassociated with systemic disease, whereas the multicentric variant can be a paraneoplastic syndrome in the setting of solid and hematologic malignancies.¹⁴ In addition, in the multicentric variant, similar lesions can affect any organ but there can be a proclivity to involve the hand and knee joints, leading to a crippling arthritis.¹⁵ We presented a case of CRDD, a benign resident dendritic cell histiocytopathy that can manifest as a cutaneous confined process in the skin where the clinical course is characteristically benign. It potentially can be confused with LCH, indeterminate cell histiocytosis, xanthogranuloma, and reticulohistiocytoma. For a solitary lesion, intralesional triamcinolone injection and excision are options. Multifocal cutaneous disease or CRDD with notable extracutaneous disease may require systemic treatment.16 In our patient, one intralesional triamcinolone injection was performed with notable resolution.

When it comes to selecting medical treatments for androgenetic alopecia (AGA), patients and practitioners alike want to know, “What works?” The ideal AGA treatment is one that meets 4 criteria: highly effective, safe, affordable, and easy to use. To date, there is no known treatment for AGA that meets all these criteria. Some therapies are more effective than others, but there are no treatments at present that are able to completely and permanently reverse the condition. Some treatments are safer, some are less expensive, and some are easier to use than others. In the end, the treatment that the patient chooses is influenced not only by its known effectiveness but also by the value that the patient places on the other 3 categories—safety, affordability, and ease of use. Therefore, shared decision-making between patient and practitioner is central to the selection of specific AGA treatments.

Effectiveness: Some Treatments Work Better Than Others

Of the nearly 2 dozen medical treatments for AGA, some have been found to be more effective than others. Whether a given treatment should be considered a bona fide AGA therapy—and then whether to position it as a first-line, second-line, or third-line agent—depends on the answers to 3 fundamental questions:

1. Does the treatment truly help patients with AGA?
2. How effective is this treatment?
3. How safe is it?

Does the Treatment Truly Help Patients?—Surprisingly, it is not always straightforward to confirm that a given treatment helps patients with AGA. Does oral finasteride help female AGA? Yes and no: Finasteride 1 mg is ineffective in the treatment of female AGA, but higher doses such as 2.5 or 5 mg likely have benefit.^1,2 Does topical minoxidil help AGA? Yes and no: Minoxidil 5% is ineffective in the treatment of a male with Hamilton-Norwood stage VII AGA but often is helpful in earlier stages of the condition.

One of the best ways to determine if a treatment really helps AGA is to evaluate how it performs in the setting of a well-conducted, randomized, double-blind, placebo-controlled trial. These types of clinical trials have been performed for many known AGA treatments and give us some of the best evidence that a treatment truly works. The AGA treatments with the highest-quality evidence (level 1) are topical minoxidil, oral finasteride, and oral dutasteride for male AGA and topical minoxidil for female AGA.

How Effective Is This Treatment?—Patients are particularly interested to know whether a given treatment has the potential to notably restore hair density. It is one thing to know that use of the treatment might slightly improve hair density and another to know that it could potentially lead to dramatic improvement. In addition, patients want to know whether a specific treatment they are considering is more (or less) likely to improve their hair density compared to another treatment.

Advanced statistical methods such as the network meta-analysis are increasingly being used to understand how individual treatments from different studies compare. Two recent studies have provided us with powerful data on the relative efficacy of minoxidil and 5α-reductase inhibitors in the treatment of both male and female AGA.^2,3 A 2022 network meta-analysis of male AGA ranked treatment efficacy from most to least effective: oral dutasteride 0.5 mg, oral finasteride 5 mg, oral minoxidil 5 mg, oral finasteride 1 mg, and topical minoxidil 5%.³ Similarly, a 2023 network meta-analysis of female AGA ranked treatment efficacy from most to least effective: oral 5 mg finasteride, minoxidil solution 5% twice daily, oral minoxidil 1 mg, and minoxidil foam 5% once daily.² We are not yet able to rank all known treatments for AGA.

Things We Tend to Ignore: Quality of Data, Long-term Results, Nonresponders, and Study Populations—There are a few caveats for anyone treating AGA. First, the quality of published AGA studies is highly variable and many are of low quality. The highest-quality evidence (level 1) for male AGA comes from studies of minoxidil solution/foam 5% twice daily, oral finasteride 1 mg, and oral dutasteride 0.5 mg. For female AGA, the highest-quality evidence is for topical minoxidil—either 5% foam once daily or 2% solution twice daily. Lower-quality studies limit conclusions and the ability to properly compare treatments.

Second, long-term data are nonexistent for most of our AGA treatments. The exceptions include finasteride, dutasteride, and topical minoxidil, which have reasonably adequate long-term studies.^4-6 However, most other treatments have been evaluated only through short-term studies. It is tempting to assume that results from a 24-week study can be used to infer how a patient might respond when using the same treatment over the course of many decades; however, making these assumptions would be unwise.

Third, most AGA treatments help improve hair density in only a proportion of patients who decide to use the given treatment. There usually is one subgroup of patients for whom the treatment does not seem to help much at all and one subgroup for whom the treatment halts further hair loss but does not regrow hair. For example, in the case of finasteride treatment of male AGA, approximately 10% of patients do not seem to respond to treatment at all, and another 50% seem to be able to halt further loss but never achieve hair regrowth.⁷ In an analysis of 12 studies with 3927 male patients, Mella et al⁸ showed that 5.6 patients needed to be treated short term and 3.4 patients needed to be treated long term for 1 patient to perceive an improvement in the hair. It is clear that many males who use finasteride will not see evidence of hair regrowth. This same general concept applies for all available treatments and is important to remember if a patient with AGA decides to start 2 new treatments simultaneously. Consider the 34-year-old man who starts oral minoxidil and platelet-rich plasma (PRP) for AGA. At his follow-up appointment 9 months later, the patient reports improved hair density and wants to know what contributed to the improvement: the oral minoxidil, the PRP, or both? Many practitioners would believe that both treatments likely provided some degree of benefit—but in reality, that represents a flaw in logic. If 2 hair loss treatments are started at exactly the same time, it is impossible to know the relative benefit of each treatment and whether one might not be helping at all. Combination therapies are still common in my practice and highly encouraged, but my personal preference is to stagger start dates whenever possible so I can determine each treatment’s contribution to the patient’s final outcome.

Finally, when evaluating what works for AGA, we need to define the specific patient subpopulation, as the available data are less robust for some patient groups than others. We have limited data in children and adolescents with AGA, as well as limited comparative data across different racial backgrounds, body mass indices, and underlying health issues. For example, data on the most effective strategies to treat female AGA in the setting of polycystic ovary syndrome, premature menopause, and other endocrine disorders are lacking.

Which Treatments Also Have Good Safety?—The treatment that a patient ultimately selects also depends on its actual or perceived safety. Patients have vastly different levels of risk tolerance. Some patients would much rather start a less effective treatment if they believe that the chances of experiencing treatment-related adverse effects would be lower. In general, topical and injectable treatments tend to have fewer adverse effects than oral therapies. Long-term safety data generally are lacking for many hair-loss therapies. A limited number of studies of topical minoxidil include data up to 5 years,⁴ and some studies of oral finasteride and oral dutasteride include patients who used these medications for up to 10 years.^5,6

So Then, What Works?

The Table shows treatments for AGA and how I prioritize starting them in my own clinic. First-line treatment options often include those with level 1 evidence but also may include those with less-robust evidence plus a good history (over many years) of safety, affordability, ease of use, and effectiveness (eg, spironolactone and finasteride for female-pattern hair loss).

• Male AGA: I consider topical minoxidil, oral finasteride, and oral dutasteride as first-line agents, and low-level laser, PRP, oral minoxidil, and topical finasteride as second-line agents. Only topical minoxidil and oral finasteride are approved by the US Food and Drug Administration (FDA) for AGA in males; laser devices are FDA cleared.

• Premenopausal females with AGA: I use topical minoxidil and spironolactone as first-line agents. Low-level laser, PRP, oral minoxidil, and oral contraceptives are helpful second-line agents. Only topical minoxidil is FDA approved in women. I consider all treatments, with the exception of low-level laser, to be contraindicated in pregnancy.

• Postmenopausal females with AGA: I consider topical minoxidil, spironolactone, and oral finasteride as first-line agents. Low-level laser, PRP, oral minoxidil, and oral dutasteride are helpful second-line agents.

When choosing an initial treatment plan, I generally will start with one or more first-line options. I will then add or replace with remaining first-line options or a second-line option after 6 to 12 months depending on how well the patient responds to the first-line options. Patients who do not wish to use first-line options or have contraindications begin with second-line options. Third-line options are best reserved for patients who do not respond to or do not wish to use first- and second-line options.

Experts differ in opinion as to what constitutes a first-line treatment option and what constitutes a second- or third-line option. For example, some increasingly consider oral minoxidil to be a first-line option for AGA.⁹ In my opinion, the lack of high-quality comparative, randomized, controlled trials and long-term safety data keep oral minoxidil reserved as a respectable second-line option. Similarly, some experts reserve oral dutasteride as a second-line option for AGA.¹⁰ In my opinion, the data now are of the highest-quality evidence (level 1)⁹ to support placing oral dutasteride in the tier of first-line treatments.

Shared decision-making using an evidence-based approach is ultimately what connects patients with treatment plans that offer a good chance of helping to improve hair loss.

When it comes to selecting medical treatments for androgenetic alopecia (AGA), patients and practitioners alike want to know, “What works?” The ideal AGA treatment is one that meets 4 criteria: highly effective, safe, affordable, and easy to use. To date, there is no known treatment for AGA that meets all these criteria. Some therapies are more effective than others, but there are no treatments at present that are able to completely and permanently reverse the condition. Some treatments are safer, some are less expensive, and some are easier to use than others. In the end, the treatment that the patient chooses is influenced not only by its known effectiveness but also by the value that the patient places on the other 3 categories—safety, affordability, and ease of use. Therefore, shared decision-making between patient and practitioner is central to the selection of specific AGA treatments.

Effectiveness: Some Treatments Work Better Than Others

Of the nearly 2 dozen medical treatments for AGA, some have been found to be more effective than others. Whether a given treatment should be considered a bona fide AGA therapy—and then whether to position it as a first-line, second-line, or third-line agent—depends on the answers to 3 fundamental questions:

1. Does the treatment truly help patients with AGA?
2. How effective is this treatment?
3. How safe is it?

Does the Treatment Truly Help Patients?—Surprisingly, it is not always straightforward to confirm that a given treatment helps patients with AGA. Does oral finasteride help female AGA? Yes and no: Finasteride 1 mg is ineffective in the treatment of female AGA, but higher doses such as 2.5 or 5 mg likely have benefit.^1,2 Does topical minoxidil help AGA? Yes and no: Minoxidil 5% is ineffective in the treatment of a male with Hamilton-Norwood stage VII AGA but often is helpful in earlier stages of the condition.

One of the best ways to determine if a treatment really helps AGA is to evaluate how it performs in the setting of a well-conducted, randomized, double-blind, placebo-controlled trial. These types of clinical trials have been performed for many known AGA treatments and give us some of the best evidence that a treatment truly works. The AGA treatments with the highest-quality evidence (level 1) are topical minoxidil, oral finasteride, and oral dutasteride for male AGA and topical minoxidil for female AGA.

How Effective Is This Treatment?—Patients are particularly interested to know whether a given treatment has the potential to notably restore hair density. It is one thing to know that use of the treatment might slightly improve hair density and another to know that it could potentially lead to dramatic improvement. In addition, patients want to know whether a specific treatment they are considering is more (or less) likely to improve their hair density compared to another treatment.

Advanced statistical methods such as the network meta-analysis are increasingly being used to understand how individual treatments from different studies compare. Two recent studies have provided us with powerful data on the relative efficacy of minoxidil and 5α-reductase inhibitors in the treatment of both male and female AGA.^2,3 A 2022 network meta-analysis of male AGA ranked treatment efficacy from most to least effective: oral dutasteride 0.5 mg, oral finasteride 5 mg, oral minoxidil 5 mg, oral finasteride 1 mg, and topical minoxidil 5%.³ Similarly, a 2023 network meta-analysis of female AGA ranked treatment efficacy from most to least effective: oral 5 mg finasteride, minoxidil solution 5% twice daily, oral minoxidil 1 mg, and minoxidil foam 5% once daily.² We are not yet able to rank all known treatments for AGA.

Things We Tend to Ignore: Quality of Data, Long-term Results, Nonresponders, and Study Populations—There are a few caveats for anyone treating AGA. First, the quality of published AGA studies is highly variable and many are of low quality. The highest-quality evidence (level 1) for male AGA comes from studies of minoxidil solution/foam 5% twice daily, oral finasteride 1 mg, and oral dutasteride 0.5 mg. For female AGA, the highest-quality evidence is for topical minoxidil—either 5% foam once daily or 2% solution twice daily. Lower-quality studies limit conclusions and the ability to properly compare treatments.

Second, long-term data are nonexistent for most of our AGA treatments. The exceptions include finasteride, dutasteride, and topical minoxidil, which have reasonably adequate long-term studies.^4-6 However, most other treatments have been evaluated only through short-term studies. It is tempting to assume that results from a 24-week study can be used to infer how a patient might respond when using the same treatment over the course of many decades; however, making these assumptions would be unwise.

Third, most AGA treatments help improve hair density in only a proportion of patients who decide to use the given treatment. There usually is one subgroup of patients for whom the treatment does not seem to help much at all and one subgroup for whom the treatment halts further hair loss but does not regrow hair. For example, in the case of finasteride treatment of male AGA, approximately 10% of patients do not seem to respond to treatment at all, and another 50% seem to be able to halt further loss but never achieve hair regrowth.⁷ In an analysis of 12 studies with 3927 male patients, Mella et al⁸ showed that 5.6 patients needed to be treated short term and 3.4 patients needed to be treated long term for 1 patient to perceive an improvement in the hair. It is clear that many males who use finasteride will not see evidence of hair regrowth. This same general concept applies for all available treatments and is important to remember if a patient with AGA decides to start 2 new treatments simultaneously. Consider the 34-year-old man who starts oral minoxidil and platelet-rich plasma (PRP) for AGA. At his follow-up appointment 9 months later, the patient reports improved hair density and wants to know what contributed to the improvement: the oral minoxidil, the PRP, or both? Many practitioners would believe that both treatments likely provided some degree of benefit—but in reality, that represents a flaw in logic. If 2 hair loss treatments are started at exactly the same time, it is impossible to know the relative benefit of each treatment and whether one might not be helping at all. Combination therapies are still common in my practice and highly encouraged, but my personal preference is to stagger start dates whenever possible so I can determine each treatment’s contribution to the patient’s final outcome.

Finally, when evaluating what works for AGA, we need to define the specific patient subpopulation, as the available data are less robust for some patient groups than others. We have limited data in children and adolescents with AGA, as well as limited comparative data across different racial backgrounds, body mass indices, and underlying health issues. For example, data on the most effective strategies to treat female AGA in the setting of polycystic ovary syndrome, premature menopause, and other endocrine disorders are lacking.

Which Treatments Also Have Good Safety?—The treatment that a patient ultimately selects also depends on its actual or perceived safety. Patients have vastly different levels of risk tolerance. Some patients would much rather start a less effective treatment if they believe that the chances of experiencing treatment-related adverse effects would be lower. In general, topical and injectable treatments tend to have fewer adverse effects than oral therapies. Long-term safety data generally are lacking for many hair-loss therapies. A limited number of studies of topical minoxidil include data up to 5 years,⁴ and some studies of oral finasteride and oral dutasteride include patients who used these medications for up to 10 years.^5,6

So Then, What Works?

The Table shows treatments for AGA and how I prioritize starting them in my own clinic. First-line treatment options often include those with level 1 evidence but also may include those with less-robust evidence plus a good history (over many years) of safety, affordability, ease of use, and effectiveness (eg, spironolactone and finasteride for female-pattern hair loss).

• Male AGA: I consider topical minoxidil, oral finasteride, and oral dutasteride as first-line agents, and low-level laser, PRP, oral minoxidil, and topical finasteride as second-line agents. Only topical minoxidil and oral finasteride are approved by the US Food and Drug Administration (FDA) for AGA in males; laser devices are FDA cleared.

• Premenopausal females with AGA: I use topical minoxidil and spironolactone as first-line agents. Low-level laser, PRP, oral minoxidil, and oral contraceptives are helpful second-line agents. Only topical minoxidil is FDA approved in women. I consider all treatments, with the exception of low-level laser, to be contraindicated in pregnancy.

• Postmenopausal females with AGA: I consider topical minoxidil, spironolactone, and oral finasteride as first-line agents. Low-level laser, PRP, oral minoxidil, and oral dutasteride are helpful second-line agents.

When choosing an initial treatment plan, I generally will start with one or more first-line options. I will then add or replace with remaining first-line options or a second-line option after 6 to 12 months depending on how well the patient responds to the first-line options. Patients who do not wish to use first-line options or have contraindications begin with second-line options. Third-line options are best reserved for patients who do not respond to or do not wish to use first- and second-line options.

Experts differ in opinion as to what constitutes a first-line treatment option and what constitutes a second- or third-line option. For example, some increasingly consider oral minoxidil to be a first-line option for AGA.⁹ In my opinion, the lack of high-quality comparative, randomized, controlled trials and long-term safety data keep oral minoxidil reserved as a respectable second-line option. Similarly, some experts reserve oral dutasteride as a second-line option for AGA.¹⁰ In my opinion, the data now are of the highest-quality evidence (level 1)⁹ to support placing oral dutasteride in the tier of first-line treatments.

Shared decision-making using an evidence-based approach is ultimately what connects patients with treatment plans that offer a good chance of helping to improve hair loss.

When it comes to selecting medical treatments for androgenetic alopecia (AGA), patients and practitioners alike want to know, “What works?” The ideal AGA treatment is one that meets 4 criteria: highly effective, safe, affordable, and easy to use. To date, there is no known treatment for AGA that meets all these criteria. Some therapies are more effective than others, but there are no treatments at present that are able to completely and permanently reverse the condition. Some treatments are safer, some are less expensive, and some are easier to use than others. In the end, the treatment that the patient chooses is influenced not only by its known effectiveness but also by the value that the patient places on the other 3 categories—safety, affordability, and ease of use. Therefore, shared decision-making between patient and practitioner is central to the selection of specific AGA treatments.

Effectiveness: Some Treatments Work Better Than Others

Of the nearly 2 dozen medical treatments for AGA, some have been found to be more effective than others. Whether a given treatment should be considered a bona fide AGA therapy—and then whether to position it as a first-line, second-line, or third-line agent—depends on the answers to 3 fundamental questions:

1. Does the treatment truly help patients with AGA?
2. How effective is this treatment?
3. How safe is it?

Does the Treatment Truly Help Patients?—Surprisingly, it is not always straightforward to confirm that a given treatment helps patients with AGA. Does oral finasteride help female AGA? Yes and no: Finasteride 1 mg is ineffective in the treatment of female AGA, but higher doses such as 2.5 or 5 mg likely have benefit.^1,2 Does topical minoxidil help AGA? Yes and no: Minoxidil 5% is ineffective in the treatment of a male with Hamilton-Norwood stage VII AGA but often is helpful in earlier stages of the condition.

One of the best ways to determine if a treatment really helps AGA is to evaluate how it performs in the setting of a well-conducted, randomized, double-blind, placebo-controlled trial. These types of clinical trials have been performed for many known AGA treatments and give us some of the best evidence that a treatment truly works. The AGA treatments with the highest-quality evidence (level 1) are topical minoxidil, oral finasteride, and oral dutasteride for male AGA and topical minoxidil for female AGA.

How Effective Is This Treatment?—Patients are particularly interested to know whether a given treatment has the potential to notably restore hair density. It is one thing to know that use of the treatment might slightly improve hair density and another to know that it could potentially lead to dramatic improvement. In addition, patients want to know whether a specific treatment they are considering is more (or less) likely to improve their hair density compared to another treatment.

Advanced statistical methods such as the network meta-analysis are increasingly being used to understand how individual treatments from different studies compare. Two recent studies have provided us with powerful data on the relative efficacy of minoxidil and 5α-reductase inhibitors in the treatment of both male and female AGA.^2,3 A 2022 network meta-analysis of male AGA ranked treatment efficacy from most to least effective: oral dutasteride 0.5 mg, oral finasteride 5 mg, oral minoxidil 5 mg, oral finasteride 1 mg, and topical minoxidil 5%.³ Similarly, a 2023 network meta-analysis of female AGA ranked treatment efficacy from most to least effective: oral 5 mg finasteride, minoxidil solution 5% twice daily, oral minoxidil 1 mg, and minoxidil foam 5% once daily.² We are not yet able to rank all known treatments for AGA.

Things We Tend to Ignore: Quality of Data, Long-term Results, Nonresponders, and Study Populations—There are a few caveats for anyone treating AGA. First, the quality of published AGA studies is highly variable and many are of low quality. The highest-quality evidence (level 1) for male AGA comes from studies of minoxidil solution/foam 5% twice daily, oral finasteride 1 mg, and oral dutasteride 0.5 mg. For female AGA, the highest-quality evidence is for topical minoxidil—either 5% foam once daily or 2% solution twice daily. Lower-quality studies limit conclusions and the ability to properly compare treatments.

Second, long-term data are nonexistent for most of our AGA treatments. The exceptions include finasteride, dutasteride, and topical minoxidil, which have reasonably adequate long-term studies.^4-6 However, most other treatments have been evaluated only through short-term studies. It is tempting to assume that results from a 24-week study can be used to infer how a patient might respond when using the same treatment over the course of many decades; however, making these assumptions would be unwise.

Third, most AGA treatments help improve hair density in only a proportion of patients who decide to use the given treatment. There usually is one subgroup of patients for whom the treatment does not seem to help much at all and one subgroup for whom the treatment halts further hair loss but does not regrow hair. For example, in the case of finasteride treatment of male AGA, approximately 10% of patients do not seem to respond to treatment at all, and another 50% seem to be able to halt further loss but never achieve hair regrowth.⁷ In an analysis of 12 studies with 3927 male patients, Mella et al⁸ showed that 5.6 patients needed to be treated short term and 3.4 patients needed to be treated long term for 1 patient to perceive an improvement in the hair. It is clear that many males who use finasteride will not see evidence of hair regrowth. This same general concept applies for all available treatments and is important to remember if a patient with AGA decides to start 2 new treatments simultaneously. Consider the 34-year-old man who starts oral minoxidil and platelet-rich plasma (PRP) for AGA. At his follow-up appointment 9 months later, the patient reports improved hair density and wants to know what contributed to the improvement: the oral minoxidil, the PRP, or both? Many practitioners would believe that both treatments likely provided some degree of benefit—but in reality, that represents a flaw in logic. If 2 hair loss treatments are started at exactly the same time, it is impossible to know the relative benefit of each treatment and whether one might not be helping at all. Combination therapies are still common in my practice and highly encouraged, but my personal preference is to stagger start dates whenever possible so I can determine each treatment’s contribution to the patient’s final outcome.

Finally, when evaluating what works for AGA, we need to define the specific patient subpopulation, as the available data are less robust for some patient groups than others. We have limited data in children and adolescents with AGA, as well as limited comparative data across different racial backgrounds, body mass indices, and underlying health issues. For example, data on the most effective strategies to treat female AGA in the setting of polycystic ovary syndrome, premature menopause, and other endocrine disorders are lacking.

Which Treatments Also Have Good Safety?—The treatment that a patient ultimately selects also depends on its actual or perceived safety. Patients have vastly different levels of risk tolerance. Some patients would much rather start a less effective treatment if they believe that the chances of experiencing treatment-related adverse effects would be lower. In general, topical and injectable treatments tend to have fewer adverse effects than oral therapies. Long-term safety data generally are lacking for many hair-loss therapies. A limited number of studies of topical minoxidil include data up to 5 years,⁴ and some studies of oral finasteride and oral dutasteride include patients who used these medications for up to 10 years.^5,6

So Then, What Works?

The Table shows treatments for AGA and how I prioritize starting them in my own clinic. First-line treatment options often include those with level 1 evidence but also may include those with less-robust evidence plus a good history (over many years) of safety, affordability, ease of use, and effectiveness (eg, spironolactone and finasteride for female-pattern hair loss).

• Male AGA: I consider topical minoxidil, oral finasteride, and oral dutasteride as first-line agents, and low-level laser, PRP, oral minoxidil, and topical finasteride as second-line agents. Only topical minoxidil and oral finasteride are approved by the US Food and Drug Administration (FDA) for AGA in males; laser devices are FDA cleared.

• Premenopausal females with AGA: I use topical minoxidil and spironolactone as first-line agents. Low-level laser, PRP, oral minoxidil, and oral contraceptives are helpful second-line agents. Only topical minoxidil is FDA approved in women. I consider all treatments, with the exception of low-level laser, to be contraindicated in pregnancy.

• Postmenopausal females with AGA: I consider topical minoxidil, spironolactone, and oral finasteride as first-line agents. Low-level laser, PRP, oral minoxidil, and oral dutasteride are helpful second-line agents.

When choosing an initial treatment plan, I generally will start with one or more first-line options. I will then add or replace with remaining first-line options or a second-line option after 6 to 12 months depending on how well the patient responds to the first-line options. Patients who do not wish to use first-line options or have contraindications begin with second-line options. Third-line options are best reserved for patients who do not respond to or do not wish to use first- and second-line options.

Experts differ in opinion as to what constitutes a first-line treatment option and what constitutes a second- or third-line option. For example, some increasingly consider oral minoxidil to be a first-line option for AGA.⁹ In my opinion, the lack of high-quality comparative, randomized, controlled trials and long-term safety data keep oral minoxidil reserved as a respectable second-line option. Similarly, some experts reserve oral dutasteride as a second-line option for AGA.¹⁰ In my opinion, the data now are of the highest-quality evidence (level 1)⁹ to support placing oral dutasteride in the tier of first-line treatments.

Shared decision-making using an evidence-based approach is ultimately what connects patients with treatment plans that offer a good chance of helping to improve hair loss.

Pediatrician Michelle Collins-Ogle, MD, already has a busy practice helping young people address questions about their gender identity. She has treated more than 230 patients over the past 2 years at Children’s Hospital at Montefiore in the Bronx, New York.

Dr. Collins-Ogle specializes in adolescent medicine in New York, a state without the restrictions on such care that have been enacted in roughly half the country.

On December 13, 2023, Ohio lawmakers passed a bill banning gender-affirming medical care to minors which Gov. Mike DeWine vetoed on December 29. Another 26 states have similar restrictions in place, according to a tally provided to this news organization by the Human Rights Campaign, which tracks this issue.

Clinicians like Dr. Collins-Ogle are feeling the impact. In her practice, Dr. Collins-Ogle met a couple that moved from Texas to New York to allow their child to access gender-affirming medical care.

“They wanted their child to be able to receive medical care, but they also were afraid for their own safety, of having their child taken from them, and being locked up,” Dr. Collins-Ogle told this news organization. 

With patients have also come protestors and harassment. In fact, many physicians are reluctant to speak on this topic amid a recent spate of threats. Psychiatric News reported that conservative pundits and high-profile social media accounts have targeted physicians who provide gender-affirming medical care, spurring harassment campaigns against clinics in cities such as Akron, Boston, and Nashville. “The attackers asserted that the clinics were mutilating children and giving them ‘chemical castration drugs,’ among other claims,” the Psychiatric News reported.

This news organization contacted more than a half dozen organizations that provide gender-affirming care for adolescents and teens seeking interviews about the effects of these restrictions.

All but Montefiore’s Dr. Collins-Ogle turned down the request.

“If my kids are brave enough to come see me, I can’t cower,” Dr. Collins-Ogle said. 

But Dr. Collins-Ogle emphasized she understands why many fellow physicians are concerned about speaking publicly about gender-affirming medical care. 
 

Dissenters Spread Misinformation and Threats

Recent years have seen increasing politicization of this issue, often due to inaccurate depictions of gender-affirming medical care circulating on social media. 

In 2022, the American Medical Association (AMA), the American Academy of Pediatrics (AAP), and the Children’s Hospital Association asked the Justice Department to investigate what they called “increasing threats of violence against physicians, hospitals, and families of children for providing and seeking evidence-based gender-affirming care.” 

The three organizations also called on X (formerly known as Twitter), TikTok, and Meta, which owns Facebook and Instagram, to do more to address coordinated campaigns of disinformation. 

“We cannot stand by as threats of violence against our members and their patients proliferate with little consequence,” said Moira Szilagyi, MD, PhD, then AAP president in a statement. 
 

Medical Groups Defend Care to Prevent Suicide

The AAP, AMA, and other influential medical associations are banding together to fight new legal restrictions on gender-affirming medical care for teens and adolescents. (These briefs do not discuss surgeries typically available for adults.) 

Since 2022, these medical organizations have filed amicus briefs in cases challenging new restrictions put in place in Arkansas, Alabama, Florida, Georgia, Idaho, Indiana, Kentucky, North Dakota, Oklahoma, Tennessee, and Texas. 

Other signers to the amicus briefs: 

• Academic Pediatric Association
• American Academy of Child & Adolescent Psychiatry
• American Academy of Family Physicians
• American Academy of Nursing
• GLMA: Health Professionals Advancing LGBTQ+ Equality
• American College of Obstetricians and Gynecologists
• American College of Osteopathic Pediatricians
• The American College of Physicians
• American Pediatric Society
• Association of Medical School Pediatric Department Chairs, Inc.
• Endocrine Society
• National Association of Pediatric Nurse Practitioners
• The Pediatric Endocrine Society, Societies for Pediatric Urology
• Society for Adolescent Health and Medicine
• Society for Pediatric Research
• The Society of Pediatric Nurses
• World Professional Association for Transgender Health

In these amicus briefs, the medical groups argue that evidence-based guidelines support the use of medication in treating gender dysphoria. The amicus briefs in particular cite an Endocrine Society guideline and the standards of care developed by the World Professional Association for Transgender Health (WPATH).

Research shows that adolescents with gender dysphoria who receive puberty blockers and other medications experience less depression, anxiety, and suicidal ideation, the groups have said.

“In light of this evidence supporting the connection between lack of access to gender-affirming care and lifetime suicide risk, banning such care can put patients’ lives at risk,” the AAP and other groups said.
 

Debate Over Source of Gender Identity Concerns 

Having doubts and concerns about one’s gender remains a relatively rare phenomena, although it appears more common among younger people. 

Among US adults, 0.5% or about 1.3 million people identify as transgender whereas about 1.4% or about 300,000 people in the 13-17–year-old group do so, according to a report issued in 2022 by the Williams Institute of the UCLA School of Law. 
 

Questionable Diagnosis Drives Bans on Care

The term “rapid-onset gender dysphoria,” referring to young people who suddenly question their gender as part of peer group dynamics, persists in political debates. The conservative Heritage Foundation has used the term as well as “social contagion” in its effort to seek restrictions on gender-affirming care for young people. 

Ohio Rep. Gary Click, a Republican, said at an April 2023 hearing that his Save Adolescents from Experimentation (SAFE) bill would prevent teens from being harmed due to “social contagion” or “ rapid-onset gender dysphoria.” 

The bill, which the Ohio legislature cleared in December, would block physicians from starting new patients on puberty blockers. (It also bars surgeries as part of gender-affirming medical care, although hospital officials and physicians told lawmakers these are not done in Ohio.) 

Among the groups opposing Click’s bill were the Ohio chapter of the AAP, the Ohio State Medical Association and several hospitals and hospital groups as well as physicians speaking independently. 

Gender-Affirming Care ‘Buys Time’ to Avoid Impulsive Decisions

Kate Krueck, MD, a pediatrician with a practice in the Columbus area, testified about her experience as the mother of a transgender child who once attempted suicide. 

“It wasn’t always easy to reconstruct my vision of a baby with a vagina into the adolescent before me with a new name and changed pronouns, but they were still the same incredible person,” Krueck said. 

She urged lawmakers to understand how puberty blockers can “buy time” for teens to cope with a body at odds with their vision of themselves, noting that many of the effects of these medications are largely reversible. The side effects that are not reversible, such as facial hair growth and the growth of Adam’s Apple, are certainly outweighed by the risks of withholding treatment, she said. 
 

Bad Patient Experience Drives Detractor Activist

Arguing against that point was Chloe Cole, a detransitioner activist who had returned to a female identity. At the Ohio legislative hearings, Ms. Cole spoke of her experience in California as a teen treated for gender dysphoria.

“I was fast-tracked by medical butchers starting at 13 when I was given cross sex hormones, and they took my breasts away from me at 15 years old,” she said.

Ms. Cole appears frequently to testify in favor of bans on gender-affirming medical care. In 2022, she told the Ohio lawmakers about her experience of attending a class with about a dozen other young people in the midst of female-to-male transitions. She now sees that class as having inadvertently helped reinforce her decision to have her breasts removed.

“Despite all these consultations and classes, I don’t feel like I understood all the ramifications that came with any of the medical decisions I was making,” Ms. Cole said. “I didn’t realize how traumatic the recovery would be, and it wasn’t until I was almost a year post-op that I realized I may want to breastfeed my future children; I will never be able to do that.”

Ms. Cole also spoke in July before the US House subcommittee on the Constitution and Limited Government.

“I look in the mirror sometimes, and I feel like a monster,” Ms. Cole said at the House hearing, which was titled “ The Dangers and Due Process Violations of ‘Gender-Affirming Care’.” 

During the hearing, Shannon Minter, legal director of the National Center for Lesbian Rights (NCLR), who also made a gender transition, thanked Ms. Cole but noted that her case is an exception.

A 2022 Lancet Child and Adolescent Health article reported that 704 (98%) people in the Netherlands who had started gender-affirming medical treatment in adolescence continued to use gender-affirming hormones at follow-up. Ms. Minter credits this high rate of continuation to clinicians taking their duties to adolescents seriously. 

State legislatures and medical boards oversee the regulation of medical practice in the US. But a few Republicans in both chambers of the US Congress have shown an interest in enacting a federal ban restricting physicians’ ability to provide gender-affirming medical care. 

They include Rep. Mike Johnson of Louisiana, who in October 2023 became Speaker of the House. He chaired the July hearing at which Ms. Cole spoke. He’s also a sponsor of a House bill introduced by Rep. Marjorie Taylor Greene (R-GA). 

This measure, which has the support of 45 House Republicans, would make it a felony to perform any gender-affirming care on a minor, and it permits a minor on whom such care is performed to bring a civil action against each individual who provided the care. Sen. JD Vance (R-OH) introduced the companion Senate measure.
 

Reality of Gender-Affirming Care

The drive to pass laws like those in Ohio and Arkansas stem from a lack of knowledge about gender-affirming treatments, including a false idea that doctors prescribe medications at teens’ requests, Montefiore’s Dr. Collins-Ogle said. 

“There’s a misperception that young people will say ‘I’m transgender’ and that those of us who provide care are just giving them hormones or whatever they want. It’s not true, and it doesn’t happen that way,” Dr. Collins-Ogle said. 

At the Children’s Hospital at Montefiore, Dr. Collins-Ogle said her work with patients wrestling with gender identity issues begins with questions. 

“What’s your understanding of dysphoria? Where’s the incongruence between the gender you were assigned at birth and what you’re feeling now? You have to be able to verbalize that” before the treatment proceeds, she said. 

Sometimes teens leave after an initial conversation and then return later when they have a more clearly defined sense of what dysphoria means. 

“There are other kids who clearly, clearly understand that the gender they were assigned at birth is not who they are,” she said. 

Children now wrestle with added concerns that their parents could be put at risk for trying to help them, she said. 

“These kids go through so much. And we have these people in powerful positions telling them that they don’t matter and telling them, ‘We’re going to cut off your access to healthcare, Medicaid; if your parents tried to seek out this care for you, we’re going to put them in jail,’” she said. 

“It’s the biggest factor in fear mongering,” she said. 

Dr. Collins-Ogle said she wonders why legislators who lack medical training are trying to dictate how physicians can practice. 

“I took a Hippocratic oath to do no harm. I have a medical board that I answer to,” she said. “I don’t understand how legislators can get away with legislating about something they know nothing about.”

A version of this article appeared on Medscape.com.

Pediatrician Michelle Collins-Ogle, MD, already has a busy practice helping young people address questions about their gender identity. She has treated more than 230 patients over the past 2 years at Children’s Hospital at Montefiore in the Bronx, New York.

Dr. Collins-Ogle specializes in adolescent medicine in New York, a state without the restrictions on such care that have been enacted in roughly half the country.

On December 13, 2023, Ohio lawmakers passed a bill banning gender-affirming medical care to minors which Gov. Mike DeWine vetoed on December 29. Another 26 states have similar restrictions in place, according to a tally provided to this news organization by the Human Rights Campaign, which tracks this issue.

Clinicians like Dr. Collins-Ogle are feeling the impact. In her practice, Dr. Collins-Ogle met a couple that moved from Texas to New York to allow their child to access gender-affirming medical care.

“They wanted their child to be able to receive medical care, but they also were afraid for their own safety, of having their child taken from them, and being locked up,” Dr. Collins-Ogle told this news organization. 

With patients have also come protestors and harassment. In fact, many physicians are reluctant to speak on this topic amid a recent spate of threats. Psychiatric News reported that conservative pundits and high-profile social media accounts have targeted physicians who provide gender-affirming medical care, spurring harassment campaigns against clinics in cities such as Akron, Boston, and Nashville. “The attackers asserted that the clinics were mutilating children and giving them ‘chemical castration drugs,’ among other claims,” the Psychiatric News reported.

This news organization contacted more than a half dozen organizations that provide gender-affirming care for adolescents and teens seeking interviews about the effects of these restrictions.

All but Montefiore’s Dr. Collins-Ogle turned down the request.

“If my kids are brave enough to come see me, I can’t cower,” Dr. Collins-Ogle said. 

But Dr. Collins-Ogle emphasized she understands why many fellow physicians are concerned about speaking publicly about gender-affirming medical care. 
 

Dissenters Spread Misinformation and Threats

Recent years have seen increasing politicization of this issue, often due to inaccurate depictions of gender-affirming medical care circulating on social media. 

In 2022, the American Medical Association (AMA), the American Academy of Pediatrics (AAP), and the Children’s Hospital Association asked the Justice Department to investigate what they called “increasing threats of violence against physicians, hospitals, and families of children for providing and seeking evidence-based gender-affirming care.” 

The three organizations also called on X (formerly known as Twitter), TikTok, and Meta, which owns Facebook and Instagram, to do more to address coordinated campaigns of disinformation. 

“We cannot stand by as threats of violence against our members and their patients proliferate with little consequence,” said Moira Szilagyi, MD, PhD, then AAP president in a statement. 
 

Medical Groups Defend Care to Prevent Suicide

The AAP, AMA, and other influential medical associations are banding together to fight new legal restrictions on gender-affirming medical care for teens and adolescents. (These briefs do not discuss surgeries typically available for adults.) 

Since 2022, these medical organizations have filed amicus briefs in cases challenging new restrictions put in place in Arkansas, Alabama, Florida, Georgia, Idaho, Indiana, Kentucky, North Dakota, Oklahoma, Tennessee, and Texas. 

Other signers to the amicus briefs: 

• Academic Pediatric Association
• American Academy of Child & Adolescent Psychiatry
• American Academy of Family Physicians
• American Academy of Nursing
• GLMA: Health Professionals Advancing LGBTQ+ Equality
• American College of Obstetricians and Gynecologists
• American College of Osteopathic Pediatricians
• The American College of Physicians
• American Pediatric Society
• Association of Medical School Pediatric Department Chairs, Inc.
• Endocrine Society
• National Association of Pediatric Nurse Practitioners
• The Pediatric Endocrine Society, Societies for Pediatric Urology
• Society for Adolescent Health and Medicine
• Society for Pediatric Research
• The Society of Pediatric Nurses
• World Professional Association for Transgender Health

In these amicus briefs, the medical groups argue that evidence-based guidelines support the use of medication in treating gender dysphoria. The amicus briefs in particular cite an Endocrine Society guideline and the standards of care developed by the World Professional Association for Transgender Health (WPATH).

Research shows that adolescents with gender dysphoria who receive puberty blockers and other medications experience less depression, anxiety, and suicidal ideation, the groups have said.

“In light of this evidence supporting the connection between lack of access to gender-affirming care and lifetime suicide risk, banning such care can put patients’ lives at risk,” the AAP and other groups said.
 

Debate Over Source of Gender Identity Concerns 

Having doubts and concerns about one’s gender remains a relatively rare phenomena, although it appears more common among younger people. 

Among US adults, 0.5% or about 1.3 million people identify as transgender whereas about 1.4% or about 300,000 people in the 13-17–year-old group do so, according to a report issued in 2022 by the Williams Institute of the UCLA School of Law. 
 

Questionable Diagnosis Drives Bans on Care

The term “rapid-onset gender dysphoria,” referring to young people who suddenly question their gender as part of peer group dynamics, persists in political debates. The conservative Heritage Foundation has used the term as well as “social contagion” in its effort to seek restrictions on gender-affirming care for young people. 

Ohio Rep. Gary Click, a Republican, said at an April 2023 hearing that his Save Adolescents from Experimentation (SAFE) bill would prevent teens from being harmed due to “social contagion” or “ rapid-onset gender dysphoria.” 

The bill, which the Ohio legislature cleared in December, would block physicians from starting new patients on puberty blockers. (It also bars surgeries as part of gender-affirming medical care, although hospital officials and physicians told lawmakers these are not done in Ohio.) 

Among the groups opposing Click’s bill were the Ohio chapter of the AAP, the Ohio State Medical Association and several hospitals and hospital groups as well as physicians speaking independently. 

Gender-Affirming Care ‘Buys Time’ to Avoid Impulsive Decisions

Kate Krueck, MD, a pediatrician with a practice in the Columbus area, testified about her experience as the mother of a transgender child who once attempted suicide. 

“It wasn’t always easy to reconstruct my vision of a baby with a vagina into the adolescent before me with a new name and changed pronouns, but they were still the same incredible person,” Krueck said. 

She urged lawmakers to understand how puberty blockers can “buy time” for teens to cope with a body at odds with their vision of themselves, noting that many of the effects of these medications are largely reversible. The side effects that are not reversible, such as facial hair growth and the growth of Adam’s Apple, are certainly outweighed by the risks of withholding treatment, she said. 
 

Bad Patient Experience Drives Detractor Activist

Arguing against that point was Chloe Cole, a detransitioner activist who had returned to a female identity. At the Ohio legislative hearings, Ms. Cole spoke of her experience in California as a teen treated for gender dysphoria.

“I was fast-tracked by medical butchers starting at 13 when I was given cross sex hormones, and they took my breasts away from me at 15 years old,” she said.

Ms. Cole appears frequently to testify in favor of bans on gender-affirming medical care. In 2022, she told the Ohio lawmakers about her experience of attending a class with about a dozen other young people in the midst of female-to-male transitions. She now sees that class as having inadvertently helped reinforce her decision to have her breasts removed.

“Despite all these consultations and classes, I don’t feel like I understood all the ramifications that came with any of the medical decisions I was making,” Ms. Cole said. “I didn’t realize how traumatic the recovery would be, and it wasn’t until I was almost a year post-op that I realized I may want to breastfeed my future children; I will never be able to do that.”

Ms. Cole also spoke in July before the US House subcommittee on the Constitution and Limited Government.

“I look in the mirror sometimes, and I feel like a monster,” Ms. Cole said at the House hearing, which was titled “ The Dangers and Due Process Violations of ‘Gender-Affirming Care’.” 

During the hearing, Shannon Minter, legal director of the National Center for Lesbian Rights (NCLR), who also made a gender transition, thanked Ms. Cole but noted that her case is an exception.

A 2022 Lancet Child and Adolescent Health article reported that 704 (98%) people in the Netherlands who had started gender-affirming medical treatment in adolescence continued to use gender-affirming hormones at follow-up. Ms. Minter credits this high rate of continuation to clinicians taking their duties to adolescents seriously. 

State legislatures and medical boards oversee the regulation of medical practice in the US. But a few Republicans in both chambers of the US Congress have shown an interest in enacting a federal ban restricting physicians’ ability to provide gender-affirming medical care. 

They include Rep. Mike Johnson of Louisiana, who in October 2023 became Speaker of the House. He chaired the July hearing at which Ms. Cole spoke. He’s also a sponsor of a House bill introduced by Rep. Marjorie Taylor Greene (R-GA). 

This measure, which has the support of 45 House Republicans, would make it a felony to perform any gender-affirming care on a minor, and it permits a minor on whom such care is performed to bring a civil action against each individual who provided the care. Sen. JD Vance (R-OH) introduced the companion Senate measure.
 

Reality of Gender-Affirming Care

The drive to pass laws like those in Ohio and Arkansas stem from a lack of knowledge about gender-affirming treatments, including a false idea that doctors prescribe medications at teens’ requests, Montefiore’s Dr. Collins-Ogle said. 

“There’s a misperception that young people will say ‘I’m transgender’ and that those of us who provide care are just giving them hormones or whatever they want. It’s not true, and it doesn’t happen that way,” Dr. Collins-Ogle said. 

At the Children’s Hospital at Montefiore, Dr. Collins-Ogle said her work with patients wrestling with gender identity issues begins with questions. 

“What’s your understanding of dysphoria? Where’s the incongruence between the gender you were assigned at birth and what you’re feeling now? You have to be able to verbalize that” before the treatment proceeds, she said. 

Sometimes teens leave after an initial conversation and then return later when they have a more clearly defined sense of what dysphoria means. 

“There are other kids who clearly, clearly understand that the gender they were assigned at birth is not who they are,” she said. 

Children now wrestle with added concerns that their parents could be put at risk for trying to help them, she said. 

“These kids go through so much. And we have these people in powerful positions telling them that they don’t matter and telling them, ‘We’re going to cut off your access to healthcare, Medicaid; if your parents tried to seek out this care for you, we’re going to put them in jail,’” she said. 

“It’s the biggest factor in fear mongering,” she said. 

Dr. Collins-Ogle said she wonders why legislators who lack medical training are trying to dictate how physicians can practice. 

“I took a Hippocratic oath to do no harm. I have a medical board that I answer to,” she said. “I don’t understand how legislators can get away with legislating about something they know nothing about.”

A version of this article appeared on Medscape.com.

Pediatrician Michelle Collins-Ogle, MD, already has a busy practice helping young people address questions about their gender identity. She has treated more than 230 patients over the past 2 years at Children’s Hospital at Montefiore in the Bronx, New York.

Dr. Collins-Ogle specializes in adolescent medicine in New York, a state without the restrictions on such care that have been enacted in roughly half the country.

On December 13, 2023, Ohio lawmakers passed a bill banning gender-affirming medical care to minors which Gov. Mike DeWine vetoed on December 29. Another 26 states have similar restrictions in place, according to a tally provided to this news organization by the Human Rights Campaign, which tracks this issue.

Clinicians like Dr. Collins-Ogle are feeling the impact. In her practice, Dr. Collins-Ogle met a couple that moved from Texas to New York to allow their child to access gender-affirming medical care.

“They wanted their child to be able to receive medical care, but they also were afraid for their own safety, of having their child taken from them, and being locked up,” Dr. Collins-Ogle told this news organization. 

With patients have also come protestors and harassment. In fact, many physicians are reluctant to speak on this topic amid a recent spate of threats. Psychiatric News reported that conservative pundits and high-profile social media accounts have targeted physicians who provide gender-affirming medical care, spurring harassment campaigns against clinics in cities such as Akron, Boston, and Nashville. “The attackers asserted that the clinics were mutilating children and giving them ‘chemical castration drugs,’ among other claims,” the Psychiatric News reported.

This news organization contacted more than a half dozen organizations that provide gender-affirming care for adolescents and teens seeking interviews about the effects of these restrictions.

All but Montefiore’s Dr. Collins-Ogle turned down the request.

“If my kids are brave enough to come see me, I can’t cower,” Dr. Collins-Ogle said. 

But Dr. Collins-Ogle emphasized she understands why many fellow physicians are concerned about speaking publicly about gender-affirming medical care. 
 

Dissenters Spread Misinformation and Threats

Recent years have seen increasing politicization of this issue, often due to inaccurate depictions of gender-affirming medical care circulating on social media. 

In 2022, the American Medical Association (AMA), the American Academy of Pediatrics (AAP), and the Children’s Hospital Association asked the Justice Department to investigate what they called “increasing threats of violence against physicians, hospitals, and families of children for providing and seeking evidence-based gender-affirming care.” 

The three organizations also called on X (formerly known as Twitter), TikTok, and Meta, which owns Facebook and Instagram, to do more to address coordinated campaigns of disinformation. 

“We cannot stand by as threats of violence against our members and their patients proliferate with little consequence,” said Moira Szilagyi, MD, PhD, then AAP president in a statement. 
 

Medical Groups Defend Care to Prevent Suicide

The AAP, AMA, and other influential medical associations are banding together to fight new legal restrictions on gender-affirming medical care for teens and adolescents. (These briefs do not discuss surgeries typically available for adults.) 

Since 2022, these medical organizations have filed amicus briefs in cases challenging new restrictions put in place in Arkansas, Alabama, Florida, Georgia, Idaho, Indiana, Kentucky, North Dakota, Oklahoma, Tennessee, and Texas. 

Other signers to the amicus briefs: 

• Academic Pediatric Association
• American Academy of Child & Adolescent Psychiatry
• American Academy of Family Physicians
• American Academy of Nursing
• GLMA: Health Professionals Advancing LGBTQ+ Equality
• American College of Obstetricians and Gynecologists
• American College of Osteopathic Pediatricians
• The American College of Physicians
• American Pediatric Society
• Association of Medical School Pediatric Department Chairs, Inc.
• Endocrine Society
• National Association of Pediatric Nurse Practitioners
• The Pediatric Endocrine Society, Societies for Pediatric Urology
• Society for Adolescent Health and Medicine
• Society for Pediatric Research
• The Society of Pediatric Nurses
• World Professional Association for Transgender Health

In these amicus briefs, the medical groups argue that evidence-based guidelines support the use of medication in treating gender dysphoria. The amicus briefs in particular cite an Endocrine Society guideline and the standards of care developed by the World Professional Association for Transgender Health (WPATH).

Research shows that adolescents with gender dysphoria who receive puberty blockers and other medications experience less depression, anxiety, and suicidal ideation, the groups have said.

“In light of this evidence supporting the connection between lack of access to gender-affirming care and lifetime suicide risk, banning such care can put patients’ lives at risk,” the AAP and other groups said.
 

Debate Over Source of Gender Identity Concerns 

Having doubts and concerns about one’s gender remains a relatively rare phenomena, although it appears more common among younger people. 

Among US adults, 0.5% or about 1.3 million people identify as transgender whereas about 1.4% or about 300,000 people in the 13-17–year-old group do so, according to a report issued in 2022 by the Williams Institute of the UCLA School of Law. 
 

Questionable Diagnosis Drives Bans on Care

The term “rapid-onset gender dysphoria,” referring to young people who suddenly question their gender as part of peer group dynamics, persists in political debates. The conservative Heritage Foundation has used the term as well as “social contagion” in its effort to seek restrictions on gender-affirming care for young people. 

Ohio Rep. Gary Click, a Republican, said at an April 2023 hearing that his Save Adolescents from Experimentation (SAFE) bill would prevent teens from being harmed due to “social contagion” or “ rapid-onset gender dysphoria.” 

The bill, which the Ohio legislature cleared in December, would block physicians from starting new patients on puberty blockers. (It also bars surgeries as part of gender-affirming medical care, although hospital officials and physicians told lawmakers these are not done in Ohio.) 

Among the groups opposing Click’s bill were the Ohio chapter of the AAP, the Ohio State Medical Association and several hospitals and hospital groups as well as physicians speaking independently. 

Gender-Affirming Care ‘Buys Time’ to Avoid Impulsive Decisions

Kate Krueck, MD, a pediatrician with a practice in the Columbus area, testified about her experience as the mother of a transgender child who once attempted suicide. 

“It wasn’t always easy to reconstruct my vision of a baby with a vagina into the adolescent before me with a new name and changed pronouns, but they were still the same incredible person,” Krueck said. 

She urged lawmakers to understand how puberty blockers can “buy time” for teens to cope with a body at odds with their vision of themselves, noting that many of the effects of these medications are largely reversible. The side effects that are not reversible, such as facial hair growth and the growth of Adam’s Apple, are certainly outweighed by the risks of withholding treatment, she said. 
 

Bad Patient Experience Drives Detractor Activist

Arguing against that point was Chloe Cole, a detransitioner activist who had returned to a female identity. At the Ohio legislative hearings, Ms. Cole spoke of her experience in California as a teen treated for gender dysphoria.

“I was fast-tracked by medical butchers starting at 13 when I was given cross sex hormones, and they took my breasts away from me at 15 years old,” she said.

Ms. Cole appears frequently to testify in favor of bans on gender-affirming medical care. In 2022, she told the Ohio lawmakers about her experience of attending a class with about a dozen other young people in the midst of female-to-male transitions. She now sees that class as having inadvertently helped reinforce her decision to have her breasts removed.

“Despite all these consultations and classes, I don’t feel like I understood all the ramifications that came with any of the medical decisions I was making,” Ms. Cole said. “I didn’t realize how traumatic the recovery would be, and it wasn’t until I was almost a year post-op that I realized I may want to breastfeed my future children; I will never be able to do that.”

Ms. Cole also spoke in July before the US House subcommittee on the Constitution and Limited Government.

“I look in the mirror sometimes, and I feel like a monster,” Ms. Cole said at the House hearing, which was titled “ The Dangers and Due Process Violations of ‘Gender-Affirming Care’.” 

During the hearing, Shannon Minter, legal director of the National Center for Lesbian Rights (NCLR), who also made a gender transition, thanked Ms. Cole but noted that her case is an exception.

A 2022 Lancet Child and Adolescent Health article reported that 704 (98%) people in the Netherlands who had started gender-affirming medical treatment in adolescence continued to use gender-affirming hormones at follow-up. Ms. Minter credits this high rate of continuation to clinicians taking their duties to adolescents seriously. 

State legislatures and medical boards oversee the regulation of medical practice in the US. But a few Republicans in both chambers of the US Congress have shown an interest in enacting a federal ban restricting physicians’ ability to provide gender-affirming medical care. 

They include Rep. Mike Johnson of Louisiana, who in October 2023 became Speaker of the House. He chaired the July hearing at which Ms. Cole spoke. He’s also a sponsor of a House bill introduced by Rep. Marjorie Taylor Greene (R-GA). 

This measure, which has the support of 45 House Republicans, would make it a felony to perform any gender-affirming care on a minor, and it permits a minor on whom such care is performed to bring a civil action against each individual who provided the care. Sen. JD Vance (R-OH) introduced the companion Senate measure.
 

Reality of Gender-Affirming Care

The drive to pass laws like those in Ohio and Arkansas stem from a lack of knowledge about gender-affirming treatments, including a false idea that doctors prescribe medications at teens’ requests, Montefiore’s Dr. Collins-Ogle said. 

“There’s a misperception that young people will say ‘I’m transgender’ and that those of us who provide care are just giving them hormones or whatever they want. It’s not true, and it doesn’t happen that way,” Dr. Collins-Ogle said. 

At the Children’s Hospital at Montefiore, Dr. Collins-Ogle said her work with patients wrestling with gender identity issues begins with questions. 

“What’s your understanding of dysphoria? Where’s the incongruence between the gender you were assigned at birth and what you’re feeling now? You have to be able to verbalize that” before the treatment proceeds, she said. 

Sometimes teens leave after an initial conversation and then return later when they have a more clearly defined sense of what dysphoria means. 

“There are other kids who clearly, clearly understand that the gender they were assigned at birth is not who they are,” she said. 

Children now wrestle with added concerns that their parents could be put at risk for trying to help them, she said. 

“These kids go through so much. And we have these people in powerful positions telling them that they don’t matter and telling them, ‘We’re going to cut off your access to healthcare, Medicaid; if your parents tried to seek out this care for you, we’re going to put them in jail,’” she said. 

“It’s the biggest factor in fear mongering,” she said. 

Dr. Collins-Ogle said she wonders why legislators who lack medical training are trying to dictate how physicians can practice. 

“I took a Hippocratic oath to do no harm. I have a medical board that I answer to,” she said. “I don’t understand how legislators can get away with legislating about something they know nothing about.”

A version of this article appeared on Medscape.com.

Practice Gap

In light of inflation, rising costs of procedures, and decreased reimbursements,¹ there is an increased need to identify and utilize inexpensive multitasking tools that can serve the dermatologic surgeon from preoperative to postoperative care. The 70% isopropyl alcohol swab may be the dermatologist’s most cost-effective and versatile surgical tool.

The Technique

When assessing a lesion, alcohol swabs can remove scale, crust, or residue from personal care products to help reveal primary morphology. They aid in the diagnosis of porokeratosis by highlighting the cornoid lamella when used following application of gentian violet.² The alcohol swab also can lay down a liquid interface to facilitate contact dermoscopy and improve visualization while also reducing the transmission of pathogens by the dermatoscope.³ Rubbing an area with an alcohol swab can induce vasodilation of scar tissue, which also may help localize a prior biopsy or surgical site (Figure).

Before a surgical site is marked, an initial cleanse with an alcohol swab serves to both remove debris and provide antisepsis ahead of the procedure. Additionally, the swab may improve adherence of skin markers by clearing excess lipid from the skin surface. Assessing the amount of debris and oil removed in the process can help determine a patient’s baseline level of hygiene, which can aid postoperative wound care planning. In extreme cases, use of an alcohol swab may help diagnose dermatitis neglecta or terra firma-forme dermatosis by completely removing any pigmentation.⁴ 

After surgery, the alcohol swab can remove skin marker(s) and blood and prepare the site for the surgical dressing. There also is some evidence to suggest that cleansing the surgical site with an alcohol swab as part of routine postoperative wound care may decrease incidence of surgical-site infection.⁵ At follow-up, the swab can remove crust and clean the skin before suture removal. If infection is suspected, the swab can cleanse skin before a wound culture is obtained to remove skin commensals and flora on the outer surface of the wound.

Practice Implications

The 70% isopropyl alcohol swab can assist the dermatologist in numerous tasks related to everyday procedures. It is readily available in every clinic and costs only a few cents.

Practice Gap

In light of inflation, rising costs of procedures, and decreased reimbursements,¹ there is an increased need to identify and utilize inexpensive multitasking tools that can serve the dermatologic surgeon from preoperative to postoperative care. The 70% isopropyl alcohol swab may be the dermatologist’s most cost-effective and versatile surgical tool.

The Technique

When assessing a lesion, alcohol swabs can remove scale, crust, or residue from personal care products to help reveal primary morphology. They aid in the diagnosis of porokeratosis by highlighting the cornoid lamella when used following application of gentian violet.² The alcohol swab also can lay down a liquid interface to facilitate contact dermoscopy and improve visualization while also reducing the transmission of pathogens by the dermatoscope.³ Rubbing an area with an alcohol swab can induce vasodilation of scar tissue, which also may help localize a prior biopsy or surgical site (Figure).

Before a surgical site is marked, an initial cleanse with an alcohol swab serves to both remove debris and provide antisepsis ahead of the procedure. Additionally, the swab may improve adherence of skin markers by clearing excess lipid from the skin surface. Assessing the amount of debris and oil removed in the process can help determine a patient’s baseline level of hygiene, which can aid postoperative wound care planning. In extreme cases, use of an alcohol swab may help diagnose dermatitis neglecta or terra firma-forme dermatosis by completely removing any pigmentation.⁴ 

After surgery, the alcohol swab can remove skin marker(s) and blood and prepare the site for the surgical dressing. There also is some evidence to suggest that cleansing the surgical site with an alcohol swab as part of routine postoperative wound care may decrease incidence of surgical-site infection.⁵ At follow-up, the swab can remove crust and clean the skin before suture removal. If infection is suspected, the swab can cleanse skin before a wound culture is obtained to remove skin commensals and flora on the outer surface of the wound.

Practice Implications

The 70% isopropyl alcohol swab can assist the dermatologist in numerous tasks related to everyday procedures. It is readily available in every clinic and costs only a few cents.

Practice Gap

In light of inflation, rising costs of procedures, and decreased reimbursements,¹ there is an increased need to identify and utilize inexpensive multitasking tools that can serve the dermatologic surgeon from preoperative to postoperative care. The 70% isopropyl alcohol swab may be the dermatologist’s most cost-effective and versatile surgical tool.

The Technique

When assessing a lesion, alcohol swabs can remove scale, crust, or residue from personal care products to help reveal primary morphology. They aid in the diagnosis of porokeratosis by highlighting the cornoid lamella when used following application of gentian violet.² The alcohol swab also can lay down a liquid interface to facilitate contact dermoscopy and improve visualization while also reducing the transmission of pathogens by the dermatoscope.³ Rubbing an area with an alcohol swab can induce vasodilation of scar tissue, which also may help localize a prior biopsy or surgical site (Figure).

Before a surgical site is marked, an initial cleanse with an alcohol swab serves to both remove debris and provide antisepsis ahead of the procedure. Additionally, the swab may improve adherence of skin markers by clearing excess lipid from the skin surface. Assessing the amount of debris and oil removed in the process can help determine a patient’s baseline level of hygiene, which can aid postoperative wound care planning. In extreme cases, use of an alcohol swab may help diagnose dermatitis neglecta or terra firma-forme dermatosis by completely removing any pigmentation.⁴ 

After surgery, the alcohol swab can remove skin marker(s) and blood and prepare the site for the surgical dressing. There also is some evidence to suggest that cleansing the surgical site with an alcohol swab as part of routine postoperative wound care may decrease incidence of surgical-site infection.⁵ At follow-up, the swab can remove crust and clean the skin before suture removal. If infection is suspected, the swab can cleanse skin before a wound culture is obtained to remove skin commensals and flora on the outer surface of the wound.

Practice Implications

The 70% isopropyl alcohol swab can assist the dermatologist in numerous tasks related to everyday procedures. It is readily available in every clinic and costs only a few cents.

Evidence-based guidelines for managing atopic dermatitis (AD) issued by The American Academy of Allergy, Asthma and Immunology/American College of Allergy, Asthma and Immunology Joint Task Force on Practice Parameters (JTFPP) incorporate a decade of new treatments and new methodological standards for making recommendations. The new guidelines update 2012 recommendations.

The JTFPP AD guidelines represent “an evolution” in trustworthy allergy guidelines and provide systematic reviews of the evidence with multidisciplinary panelist engagement, adherence to a rigorous guideline development process, the involvement of the patient and caregiver voice from start to finish, clear translation of evidence to clinically actionable and contextual recommendations, and novel approaches to facilitate knowledge translation, task force cochair Derek K. Chu, MD, PhD, said in an interview. Dr. Chu, director of the Evidence in Allergy research group at McMaster University, Hamilton, Ontario, Canada, cochaired the task force with Lynda Schneider, MD, section chief of the allergy and asthma program at Boston Children’s Hospital.

The new guidelines were published online on December 17, 2023, in Annals of Allergy, Asthma, & Immunology. They include 25 recommendations and address optimal use of topical treatments, such as topical corticosteroids, topical calcineurin inhibitors, topical JAK inhibitors, topical crisaborole, and topical antimicrobials; dilute bleach baths; dietary elimination; allergen immunotherapy by subcutaneous (SCIT) and sublingual (SLIT) routes; and systemic treatments with dupilumab and tralokinumab, cyclosporine, azathioprine, methotrexate, mycophenolate, oral JAK inhibitors, systemic corticosteroids; and phototherapy.

“There’s something in here for all clinicians — from primary care to AD experts— and patients may benefit as well, so the key individual recommendations will vary,” Dr. Chu told this news organization.

“Throughout the guideline, we emphasize shared decision-making, key factors to consider for each recommendation, and the specific evidence behind each recommendation,” he said. “There is a major focus on addressing equity, diversity, inclusiveness; and addressing health disparities, and key gaps to address in future research.”

Among the changes to the 2012 JTFPP guidelines, the 2023 update suggests using dilute bleach baths for patients with AD with moderate to severe disease as an additive therapy and suggests using allergen immunotherapy (AIT) for moderate to severe AD.

In other changes, the 2023 update suggests against using elimination diets for AD; recommends against very low dose baricitinib (1 mg); suggests against azathioprine, methotrexate, and mycophenolate mofetil; and suggests against adding topical JAK inhibitors, such as ruxolitinib, for patients with mild to moderate AD refractory to moisturization alone.

The 38-page guidelines include an infographic that summarizes comparative effects of systemic treatments on patient-important outcomes for AD that are important to patients, and includes other key summary tables that can be used at the point of care.

In addition to addressing evidence underlying each recommendation, the guideline’s eAppendix contains 1- to 2-page handouts that address practical issues for each treatment and can be used to facilitate shared decision making.

Dr. Chu said that the updated guidelines “provide important changes to almost all aspects of AD care — my own and my colleagues’ — and I strongly recommend all clinicians treating AD to read the full guidelines and use them in clinical practice. We’re grateful to all our contributors, especially our patient and caregiver partners, for helping make these guidelines. We will continue to periodically update the guidelines as part of maintaining them as living guidelines.”

The guidelines incorporate the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach for assessing the certainty of the evidence.

The work was funded by the AAAAI/ACAAI JTFPP. Dr. Chu disclosed that he has received a faculty development award from the AAAAI Foundation and research grants to McMaster from the Canadian Institutes of Health Research, the Ontario Ministry of Health, and the Ontario Medical Association.

Evidence-based guidelines for managing atopic dermatitis (AD) issued by The American Academy of Allergy, Asthma and Immunology/American College of Allergy, Asthma and Immunology Joint Task Force on Practice Parameters (JTFPP) incorporate a decade of new treatments and new methodological standards for making recommendations. The new guidelines update 2012 recommendations.

The JTFPP AD guidelines represent “an evolution” in trustworthy allergy guidelines and provide systematic reviews of the evidence with multidisciplinary panelist engagement, adherence to a rigorous guideline development process, the involvement of the patient and caregiver voice from start to finish, clear translation of evidence to clinically actionable and contextual recommendations, and novel approaches to facilitate knowledge translation, task force cochair Derek K. Chu, MD, PhD, said in an interview. Dr. Chu, director of the Evidence in Allergy research group at McMaster University, Hamilton, Ontario, Canada, cochaired the task force with Lynda Schneider, MD, section chief of the allergy and asthma program at Boston Children’s Hospital.

The new guidelines were published online on December 17, 2023, in Annals of Allergy, Asthma, & Immunology. They include 25 recommendations and address optimal use of topical treatments, such as topical corticosteroids, topical calcineurin inhibitors, topical JAK inhibitors, topical crisaborole, and topical antimicrobials; dilute bleach baths; dietary elimination; allergen immunotherapy by subcutaneous (SCIT) and sublingual (SLIT) routes; and systemic treatments with dupilumab and tralokinumab, cyclosporine, azathioprine, methotrexate, mycophenolate, oral JAK inhibitors, systemic corticosteroids; and phototherapy.

“There’s something in here for all clinicians — from primary care to AD experts— and patients may benefit as well, so the key individual recommendations will vary,” Dr. Chu told this news organization.

“Throughout the guideline, we emphasize shared decision-making, key factors to consider for each recommendation, and the specific evidence behind each recommendation,” he said. “There is a major focus on addressing equity, diversity, inclusiveness; and addressing health disparities, and key gaps to address in future research.”

Among the changes to the 2012 JTFPP guidelines, the 2023 update suggests using dilute bleach baths for patients with AD with moderate to severe disease as an additive therapy and suggests using allergen immunotherapy (AIT) for moderate to severe AD.

In other changes, the 2023 update suggests against using elimination diets for AD; recommends against very low dose baricitinib (1 mg); suggests against azathioprine, methotrexate, and mycophenolate mofetil; and suggests against adding topical JAK inhibitors, such as ruxolitinib, for patients with mild to moderate AD refractory to moisturization alone.

The 38-page guidelines include an infographic that summarizes comparative effects of systemic treatments on patient-important outcomes for AD that are important to patients, and includes other key summary tables that can be used at the point of care.

In addition to addressing evidence underlying each recommendation, the guideline’s eAppendix contains 1- to 2-page handouts that address practical issues for each treatment and can be used to facilitate shared decision making.

Dr. Chu said that the updated guidelines “provide important changes to almost all aspects of AD care — my own and my colleagues’ — and I strongly recommend all clinicians treating AD to read the full guidelines and use them in clinical practice. We’re grateful to all our contributors, especially our patient and caregiver partners, for helping make these guidelines. We will continue to periodically update the guidelines as part of maintaining them as living guidelines.”

The guidelines incorporate the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach for assessing the certainty of the evidence.

The work was funded by the AAAAI/ACAAI JTFPP. Dr. Chu disclosed that he has received a faculty development award from the AAAAI Foundation and research grants to McMaster from the Canadian Institutes of Health Research, the Ontario Ministry of Health, and the Ontario Medical Association.

Evidence-based guidelines for managing atopic dermatitis (AD) issued by The American Academy of Allergy, Asthma and Immunology/American College of Allergy, Asthma and Immunology Joint Task Force on Practice Parameters (JTFPP) incorporate a decade of new treatments and new methodological standards for making recommendations. The new guidelines update 2012 recommendations.

The JTFPP AD guidelines represent “an evolution” in trustworthy allergy guidelines and provide systematic reviews of the evidence with multidisciplinary panelist engagement, adherence to a rigorous guideline development process, the involvement of the patient and caregiver voice from start to finish, clear translation of evidence to clinically actionable and contextual recommendations, and novel approaches to facilitate knowledge translation, task force cochair Derek K. Chu, MD, PhD, said in an interview. Dr. Chu, director of the Evidence in Allergy research group at McMaster University, Hamilton, Ontario, Canada, cochaired the task force with Lynda Schneider, MD, section chief of the allergy and asthma program at Boston Children’s Hospital.

The new guidelines were published online on December 17, 2023, in Annals of Allergy, Asthma, & Immunology. They include 25 recommendations and address optimal use of topical treatments, such as topical corticosteroids, topical calcineurin inhibitors, topical JAK inhibitors, topical crisaborole, and topical antimicrobials; dilute bleach baths; dietary elimination; allergen immunotherapy by subcutaneous (SCIT) and sublingual (SLIT) routes; and systemic treatments with dupilumab and tralokinumab, cyclosporine, azathioprine, methotrexate, mycophenolate, oral JAK inhibitors, systemic corticosteroids; and phototherapy.

“There’s something in here for all clinicians — from primary care to AD experts— and patients may benefit as well, so the key individual recommendations will vary,” Dr. Chu told this news organization.

“Throughout the guideline, we emphasize shared decision-making, key factors to consider for each recommendation, and the specific evidence behind each recommendation,” he said. “There is a major focus on addressing equity, diversity, inclusiveness; and addressing health disparities, and key gaps to address in future research.”

Among the changes to the 2012 JTFPP guidelines, the 2023 update suggests using dilute bleach baths for patients with AD with moderate to severe disease as an additive therapy and suggests using allergen immunotherapy (AIT) for moderate to severe AD.

In other changes, the 2023 update suggests against using elimination diets for AD; recommends against very low dose baricitinib (1 mg); suggests against azathioprine, methotrexate, and mycophenolate mofetil; and suggests against adding topical JAK inhibitors, such as ruxolitinib, for patients with mild to moderate AD refractory to moisturization alone.

The 38-page guidelines include an infographic that summarizes comparative effects of systemic treatments on patient-important outcomes for AD that are important to patients, and includes other key summary tables that can be used at the point of care.

In addition to addressing evidence underlying each recommendation, the guideline’s eAppendix contains 1- to 2-page handouts that address practical issues for each treatment and can be used to facilitate shared decision making.

Dr. Chu said that the updated guidelines “provide important changes to almost all aspects of AD care — my own and my colleagues’ — and I strongly recommend all clinicians treating AD to read the full guidelines and use them in clinical practice. We’re grateful to all our contributors, especially our patient and caregiver partners, for helping make these guidelines. We will continue to periodically update the guidelines as part of maintaining them as living guidelines.”

The guidelines incorporate the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach for assessing the certainty of the evidence.

The work was funded by the AAAAI/ACAAI JTFPP. Dr. Chu disclosed that he has received a faculty development award from the AAAAI Foundation and research grants to McMaster from the Canadian Institutes of Health Research, the Ontario Ministry of Health, and the Ontario Medical Association.

The assessment and diagnosis of melanocytic lesions can present a formidable challenge to even a seasoned pathologist, which is especially true when dealing with the subset of nevi occurring at special sites—where baseline variations inherent to particular locations on the body can preclude the use of features routinely used to diagnose malignancy elsewhere. These so-called special-site nevi previously have been described in the literature along with suggested criteria for differentiating malignant lesions from their benign counterparts.¹ Locations generally considered to be special sites include the acral skin, anogenital region, breast, ear, and flexural regions.^1,2

When evaluating non–special-site melanocytic lesions, general characteristics associated with a malignant diagnosis include confluence or pagetoid spread of melanocytes, nuclear pleomorphism, cytologic atypia, and irregular architecture³; however, these features can be compatible with a benign diagnosis in special-site nevi depending on their extent and the site in question. Although they can be atypical, special-site nevi tend to have the bulk of their architectural distortion and cytologic atypia in the center of the lesion as opposed to the edges.¹ If a given lesion is from a special site but lacks this reassuring feature, special care should be taken to rule out malignancy.

Preferentially expressed antigen in melanoma (PRAME) is an antigen first identified in tumor-reactive T-cell populations in patients with malignant melanoma. It is the product of an oncogene that frequently is overexpressed in melanomas, lung squamous cell carcinomas, sarcomas, and acute leukemias.⁴ It functions as an antagonist of the retinoic acid signaling pathway, which normally serves to induce further cell differentiation, senescence, or apoptosis.⁵ PRAME inhibits retinoid signaling by forming a complex with both the ligand-bound retinoic acid holoreceptor and the polycomb protein EZH2, which blocks retinoid-dependent gene expression by encouraging chromatin condensation at the RARβ promoter site⁵; therefore, expressing PRAME allows lesional cells a substantial growth advantage.

PRAME expression has been extensively characterized in non–special-site nevi and has filled the need for a rather specific marker of melanoma.^6-10 Although PRAME has been studied in acral nevi,¹¹ the expression pattern in nevi of special sites has yet to be elucidated. Herein, we present a dataset characterizing PRAME expression in these challenging lesions.

Methods

We performed a retrospective case review at the University of Virginia (Charlottesville, Virginia) and collected a panel of 36 special-site nevi that previously were diagnosed as benign by a trained dermatopathologist from January 2020 through December 2022. Special-site nevi were identified using a natural language filter for the following terms: acral, palm, sole, ear, auricular, lip, axilla, armpit, breast, groin, labia, vulva, umbilicus, and penis. This study was approved by the University of Virginia institutional review board.

The original hematoxylin and eosin slides used for primary diagnosis were re-examined to verify the prior diagnosis of benign nevus at a special site. We performed a detailed microscopic examination of all benign nevi in our cohort to determine the frequency of various characteristics at each special site. Sections were prepared from the formalin-fixed and paraffin-embedded tissue blocks and stained with a commercial PRAME antibody (#219650 [Abcam] at a 1:50 dilution) and counterstain. A trained dermatopathologist (S.S.R.) examined the stained sections and recorded the percentage of tumor cells with nuclear PRAME staining. We reported our results using previously established criteria for scoring PRAME immunohistochemistry⁷: 0 for no expression, 1+ for 1% to 25% expression, 2+ for 26% to 50% expression, 3+ for 51% to 75% expression, and 4+ for diffuse or 76% to 100% expression. Only strong clonal expression within a population of cells was graded.

Data handling and statistical testing were performed using the R Project for Statistical Computing (https://www.r-project.org/). Significance testing was performed using the Fisher exact test. Plot construction was performed using ggplot2 (https://ggplot2.tidyverse.org/).

Our study cohort included 36 special-site nevi, and the control cohort comprised 25 melanoma in situ (MIS) or invasive melanoma (IM) lesions occurring at special sites. Table 1 provides a breakdown of the study and control cohorts by lesion site. Table 2 details the results of our microscopic examination, describing frequency of various characteristics of special-site nevi stratified by site.

Of the 36 special-site nevi in our cohort, 20 (56%) had no staining (0) for PRAME, 11 (31%) demonstrated 1+ PRAME expression, 3 (8%) demonstrated 2+ PRAME expression, and 2 (6%) demonstrated 3+ PRAME expression. No nevi showed 4+ expression. In the control cohort, 24 of 25 (96%) MIS and IM showed 3+ or 4+ expression, with 21 (84%) demonstrating ­diffuse/4+ expression. One control case (4%) demonstrated 0 PRAME expression. These data are summarized in Table 3 and Figure 1. There is a significant difference in diffuse (4+) PRAME expression between special-site nevi and MIS/IM occurring at special sites (P=1.039×10^-12).

Based on our cohort, a positivity threshold of 3+ for PRAME expression for the diagnosis of melanoma in a special-site lesion would have a sensitivity of 96% and a specificity of 94%, while a positivity threshold of 4+ for PRAME expression would have a sensitivity of 84% and a specificity of 100%. Figures 2 through 4 show photomicrographs of a special-site nevus of the breast, which appropriately does not stain for PRAME; Figures 5 and 6 show an MIS at a special site that appropriately stains for PRAME.

Comment

The distinction between benign and malignant pigmented lesions at special sites presents a fair challenge for pathologists due to the larger degree of leniency for architectural distortion and cytologic atypia in benign lesions at these sites. The presence of architectural distortion or cytologic atypia at the lesion’s edge makes rendering a benign diagnosis especially difficult, and the need for a validated immunohistochemical stain is apparent. In our cohort, strong clonal PRAME expression provided a reliable immunohistochemical marker, allowing for the distinction of malignant lesions from benign nevi at special sites. Diffuse faint PRAME expression was present in several benign nevi within our cohort, and these lesions were considered negative (0) in our analysis.

Given the described test characteristics, we support the implementation of PRAME immunohistochemistry with a positivity threshold of 4+ expression as an ancillary test supporting the diagnosis of IM or MIS in special sites, which would allow clinicians to leverage the high specificity of 4+ PRAME expression to distinguish an IM or MIS from a benign nevus occurring at a special site. We do not recommend the use of 4+ PRAME expression as a screening test for melanoma or MIS among special-site nevi due to its comparatively low sensitivity; however, no one marker is always reliable, and we recommend continued clinicopathologic correlation for all cases. Although PRAME can assist in the delineation of malignant lesions from benign ones, microscopic examination of hematoxylin and eosin–stained section remains the gold standard for diagnosing malignant melanoma and MIS.

Although our case series included nevi and MIS/IM from all special sites, we were limited in the number of acrogenital and ear nevi included due to a relative paucity of biopsied benign nevi from these locations at the University of Virginia. Additionally, although the magnitude of the difference in PRAME expression between the study and control groups is sufficient to demonstrate statistical significance, the overall strength of our argument would be increased with a larger study group. We were limited by the number of cases available at our institution, which did not utilize PRAME during the initial diagnosis of the case; including these cases in the study group would have undermined the integrity of our argument because the differentiation of benign vs malignant initially was made using PRAME immunohistochemistry.

Conclusion

Due to their atypical features, special-site nevi can be challenging to assess. In this study, we showed that PRAME expression can be a reliable marker to distinguish benign from malignant lesions. Our results showed that 100% of benign special-site nevi demonstrated 3+ expression or less, with 56% (20/36) demonstrating no expression at all. The presence of diffuse PRAME expression (4+ PRAME staining) appears to be a specific indicator of a malignant lesion, but results should always be interpreted with respect to the patient’s clinical history and the lesion’s histomorphologic features. Further study of a larger sample size would allow refinement of the sensitivity and specificity of diffuse PRAME expression in the determination of malignancy for special-site lesions.

Acknowledgment—The authors thank the pathologistsat the University of Virginia Biorepository and Tissue Research Facility (Charlottesville, Virginia) for their skill and expertise in performing immunohistochemical staining for this study.

The assessment and diagnosis of melanocytic lesions can present a formidable challenge to even a seasoned pathologist, which is especially true when dealing with the subset of nevi occurring at special sites—where baseline variations inherent to particular locations on the body can preclude the use of features routinely used to diagnose malignancy elsewhere. These so-called special-site nevi previously have been described in the literature along with suggested criteria for differentiating malignant lesions from their benign counterparts.¹ Locations generally considered to be special sites include the acral skin, anogenital region, breast, ear, and flexural regions.^1,2

When evaluating non–special-site melanocytic lesions, general characteristics associated with a malignant diagnosis include confluence or pagetoid spread of melanocytes, nuclear pleomorphism, cytologic atypia, and irregular architecture³; however, these features can be compatible with a benign diagnosis in special-site nevi depending on their extent and the site in question. Although they can be atypical, special-site nevi tend to have the bulk of their architectural distortion and cytologic atypia in the center of the lesion as opposed to the edges.¹ If a given lesion is from a special site but lacks this reassuring feature, special care should be taken to rule out malignancy.

Preferentially expressed antigen in melanoma (PRAME) is an antigen first identified in tumor-reactive T-cell populations in patients with malignant melanoma. It is the product of an oncogene that frequently is overexpressed in melanomas, lung squamous cell carcinomas, sarcomas, and acute leukemias.⁴ It functions as an antagonist of the retinoic acid signaling pathway, which normally serves to induce further cell differentiation, senescence, or apoptosis.⁵ PRAME inhibits retinoid signaling by forming a complex with both the ligand-bound retinoic acid holoreceptor and the polycomb protein EZH2, which blocks retinoid-dependent gene expression by encouraging chromatin condensation at the RARβ promoter site⁵; therefore, expressing PRAME allows lesional cells a substantial growth advantage.

PRAME expression has been extensively characterized in non–special-site nevi and has filled the need for a rather specific marker of melanoma.^6-10 Although PRAME has been studied in acral nevi,¹¹ the expression pattern in nevi of special sites has yet to be elucidated. Herein, we present a dataset characterizing PRAME expression in these challenging lesions.

Methods

We performed a retrospective case review at the University of Virginia (Charlottesville, Virginia) and collected a panel of 36 special-site nevi that previously were diagnosed as benign by a trained dermatopathologist from January 2020 through December 2022. Special-site nevi were identified using a natural language filter for the following terms: acral, palm, sole, ear, auricular, lip, axilla, armpit, breast, groin, labia, vulva, umbilicus, and penis. This study was approved by the University of Virginia institutional review board.

The original hematoxylin and eosin slides used for primary diagnosis were re-examined to verify the prior diagnosis of benign nevus at a special site. We performed a detailed microscopic examination of all benign nevi in our cohort to determine the frequency of various characteristics at each special site. Sections were prepared from the formalin-fixed and paraffin-embedded tissue blocks and stained with a commercial PRAME antibody (#219650 [Abcam] at a 1:50 dilution) and counterstain. A trained dermatopathologist (S.S.R.) examined the stained sections and recorded the percentage of tumor cells with nuclear PRAME staining. We reported our results using previously established criteria for scoring PRAME immunohistochemistry⁷: 0 for no expression, 1+ for 1% to 25% expression, 2+ for 26% to 50% expression, 3+ for 51% to 75% expression, and 4+ for diffuse or 76% to 100% expression. Only strong clonal expression within a population of cells was graded.

Data handling and statistical testing were performed using the R Project for Statistical Computing (https://www.r-project.org/). Significance testing was performed using the Fisher exact test. Plot construction was performed using ggplot2 (https://ggplot2.tidyverse.org/).

Our study cohort included 36 special-site nevi, and the control cohort comprised 25 melanoma in situ (MIS) or invasive melanoma (IM) lesions occurring at special sites. Table 1 provides a breakdown of the study and control cohorts by lesion site. Table 2 details the results of our microscopic examination, describing frequency of various characteristics of special-site nevi stratified by site.

Of the 36 special-site nevi in our cohort, 20 (56%) had no staining (0) for PRAME, 11 (31%) demonstrated 1+ PRAME expression, 3 (8%) demonstrated 2+ PRAME expression, and 2 (6%) demonstrated 3+ PRAME expression. No nevi showed 4+ expression. In the control cohort, 24 of 25 (96%) MIS and IM showed 3+ or 4+ expression, with 21 (84%) demonstrating ­diffuse/4+ expression. One control case (4%) demonstrated 0 PRAME expression. These data are summarized in Table 3 and Figure 1. There is a significant difference in diffuse (4+) PRAME expression between special-site nevi and MIS/IM occurring at special sites (P=1.039×10^-12).

Based on our cohort, a positivity threshold of 3+ for PRAME expression for the diagnosis of melanoma in a special-site lesion would have a sensitivity of 96% and a specificity of 94%, while a positivity threshold of 4+ for PRAME expression would have a sensitivity of 84% and a specificity of 100%. Figures 2 through 4 show photomicrographs of a special-site nevus of the breast, which appropriately does not stain for PRAME; Figures 5 and 6 show an MIS at a special site that appropriately stains for PRAME.

Comment

The distinction between benign and malignant pigmented lesions at special sites presents a fair challenge for pathologists due to the larger degree of leniency for architectural distortion and cytologic atypia in benign lesions at these sites. The presence of architectural distortion or cytologic atypia at the lesion’s edge makes rendering a benign diagnosis especially difficult, and the need for a validated immunohistochemical stain is apparent. In our cohort, strong clonal PRAME expression provided a reliable immunohistochemical marker, allowing for the distinction of malignant lesions from benign nevi at special sites. Diffuse faint PRAME expression was present in several benign nevi within our cohort, and these lesions were considered negative (0) in our analysis.

Given the described test characteristics, we support the implementation of PRAME immunohistochemistry with a positivity threshold of 4+ expression as an ancillary test supporting the diagnosis of IM or MIS in special sites, which would allow clinicians to leverage the high specificity of 4+ PRAME expression to distinguish an IM or MIS from a benign nevus occurring at a special site. We do not recommend the use of 4+ PRAME expression as a screening test for melanoma or MIS among special-site nevi due to its comparatively low sensitivity; however, no one marker is always reliable, and we recommend continued clinicopathologic correlation for all cases. Although PRAME can assist in the delineation of malignant lesions from benign ones, microscopic examination of hematoxylin and eosin–stained section remains the gold standard for diagnosing malignant melanoma and MIS.

Although our case series included nevi and MIS/IM from all special sites, we were limited in the number of acrogenital and ear nevi included due to a relative paucity of biopsied benign nevi from these locations at the University of Virginia. Additionally, although the magnitude of the difference in PRAME expression between the study and control groups is sufficient to demonstrate statistical significance, the overall strength of our argument would be increased with a larger study group. We were limited by the number of cases available at our institution, which did not utilize PRAME during the initial diagnosis of the case; including these cases in the study group would have undermined the integrity of our argument because the differentiation of benign vs malignant initially was made using PRAME immunohistochemistry.

Conclusion

Due to their atypical features, special-site nevi can be challenging to assess. In this study, we showed that PRAME expression can be a reliable marker to distinguish benign from malignant lesions. Our results showed that 100% of benign special-site nevi demonstrated 3+ expression or less, with 56% (20/36) demonstrating no expression at all. The presence of diffuse PRAME expression (4+ PRAME staining) appears to be a specific indicator of a malignant lesion, but results should always be interpreted with respect to the patient’s clinical history and the lesion’s histomorphologic features. Further study of a larger sample size would allow refinement of the sensitivity and specificity of diffuse PRAME expression in the determination of malignancy for special-site lesions.

Acknowledgment—The authors thank the pathologistsat the University of Virginia Biorepository and Tissue Research Facility (Charlottesville, Virginia) for their skill and expertise in performing immunohistochemical staining for this study.

The assessment and diagnosis of melanocytic lesions can present a formidable challenge to even a seasoned pathologist, which is especially true when dealing with the subset of nevi occurring at special sites—where baseline variations inherent to particular locations on the body can preclude the use of features routinely used to diagnose malignancy elsewhere. These so-called special-site nevi previously have been described in the literature along with suggested criteria for differentiating malignant lesions from their benign counterparts.¹ Locations generally considered to be special sites include the acral skin, anogenital region, breast, ear, and flexural regions.^1,2

When evaluating non–special-site melanocytic lesions, general characteristics associated with a malignant diagnosis include confluence or pagetoid spread of melanocytes, nuclear pleomorphism, cytologic atypia, and irregular architecture³; however, these features can be compatible with a benign diagnosis in special-site nevi depending on their extent and the site in question. Although they can be atypical, special-site nevi tend to have the bulk of their architectural distortion and cytologic atypia in the center of the lesion as opposed to the edges.¹ If a given lesion is from a special site but lacks this reassuring feature, special care should be taken to rule out malignancy.

Preferentially expressed antigen in melanoma (PRAME) is an antigen first identified in tumor-reactive T-cell populations in patients with malignant melanoma. It is the product of an oncogene that frequently is overexpressed in melanomas, lung squamous cell carcinomas, sarcomas, and acute leukemias.⁴ It functions as an antagonist of the retinoic acid signaling pathway, which normally serves to induce further cell differentiation, senescence, or apoptosis.⁵ PRAME inhibits retinoid signaling by forming a complex with both the ligand-bound retinoic acid holoreceptor and the polycomb protein EZH2, which blocks retinoid-dependent gene expression by encouraging chromatin condensation at the RARβ promoter site⁵; therefore, expressing PRAME allows lesional cells a substantial growth advantage.

PRAME expression has been extensively characterized in non–special-site nevi and has filled the need for a rather specific marker of melanoma.^6-10 Although PRAME has been studied in acral nevi,¹¹ the expression pattern in nevi of special sites has yet to be elucidated. Herein, we present a dataset characterizing PRAME expression in these challenging lesions.

Methods

We performed a retrospective case review at the University of Virginia (Charlottesville, Virginia) and collected a panel of 36 special-site nevi that previously were diagnosed as benign by a trained dermatopathologist from January 2020 through December 2022. Special-site nevi were identified using a natural language filter for the following terms: acral, palm, sole, ear, auricular, lip, axilla, armpit, breast, groin, labia, vulva, umbilicus, and penis. This study was approved by the University of Virginia institutional review board.

The original hematoxylin and eosin slides used for primary diagnosis were re-examined to verify the prior diagnosis of benign nevus at a special site. We performed a detailed microscopic examination of all benign nevi in our cohort to determine the frequency of various characteristics at each special site. Sections were prepared from the formalin-fixed and paraffin-embedded tissue blocks and stained with a commercial PRAME antibody (#219650 [Abcam] at a 1:50 dilution) and counterstain. A trained dermatopathologist (S.S.R.) examined the stained sections and recorded the percentage of tumor cells with nuclear PRAME staining. We reported our results using previously established criteria for scoring PRAME immunohistochemistry⁷: 0 for no expression, 1+ for 1% to 25% expression, 2+ for 26% to 50% expression, 3+ for 51% to 75% expression, and 4+ for diffuse or 76% to 100% expression. Only strong clonal expression within a population of cells was graded.

Data handling and statistical testing were performed using the R Project for Statistical Computing (https://www.r-project.org/). Significance testing was performed using the Fisher exact test. Plot construction was performed using ggplot2 (https://ggplot2.tidyverse.org/).

Our study cohort included 36 special-site nevi, and the control cohort comprised 25 melanoma in situ (MIS) or invasive melanoma (IM) lesions occurring at special sites. Table 1 provides a breakdown of the study and control cohorts by lesion site. Table 2 details the results of our microscopic examination, describing frequency of various characteristics of special-site nevi stratified by site.

Of the 36 special-site nevi in our cohort, 20 (56%) had no staining (0) for PRAME, 11 (31%) demonstrated 1+ PRAME expression, 3 (8%) demonstrated 2+ PRAME expression, and 2 (6%) demonstrated 3+ PRAME expression. No nevi showed 4+ expression. In the control cohort, 24 of 25 (96%) MIS and IM showed 3+ or 4+ expression, with 21 (84%) demonstrating ­diffuse/4+ expression. One control case (4%) demonstrated 0 PRAME expression. These data are summarized in Table 3 and Figure 1. There is a significant difference in diffuse (4+) PRAME expression between special-site nevi and MIS/IM occurring at special sites (P=1.039×10^-12).

Based on our cohort, a positivity threshold of 3+ for PRAME expression for the diagnosis of melanoma in a special-site lesion would have a sensitivity of 96% and a specificity of 94%, while a positivity threshold of 4+ for PRAME expression would have a sensitivity of 84% and a specificity of 100%. Figures 2 through 4 show photomicrographs of a special-site nevus of the breast, which appropriately does not stain for PRAME; Figures 5 and 6 show an MIS at a special site that appropriately stains for PRAME.

Comment

The distinction between benign and malignant pigmented lesions at special sites presents a fair challenge for pathologists due to the larger degree of leniency for architectural distortion and cytologic atypia in benign lesions at these sites. The presence of architectural distortion or cytologic atypia at the lesion’s edge makes rendering a benign diagnosis especially difficult, and the need for a validated immunohistochemical stain is apparent. In our cohort, strong clonal PRAME expression provided a reliable immunohistochemical marker, allowing for the distinction of malignant lesions from benign nevi at special sites. Diffuse faint PRAME expression was present in several benign nevi within our cohort, and these lesions were considered negative (0) in our analysis.

Given the described test characteristics, we support the implementation of PRAME immunohistochemistry with a positivity threshold of 4+ expression as an ancillary test supporting the diagnosis of IM or MIS in special sites, which would allow clinicians to leverage the high specificity of 4+ PRAME expression to distinguish an IM or MIS from a benign nevus occurring at a special site. We do not recommend the use of 4+ PRAME expression as a screening test for melanoma or MIS among special-site nevi due to its comparatively low sensitivity; however, no one marker is always reliable, and we recommend continued clinicopathologic correlation for all cases. Although PRAME can assist in the delineation of malignant lesions from benign ones, microscopic examination of hematoxylin and eosin–stained section remains the gold standard for diagnosing malignant melanoma and MIS.

Although our case series included nevi and MIS/IM from all special sites, we were limited in the number of acrogenital and ear nevi included due to a relative paucity of biopsied benign nevi from these locations at the University of Virginia. Additionally, although the magnitude of the difference in PRAME expression between the study and control groups is sufficient to demonstrate statistical significance, the overall strength of our argument would be increased with a larger study group. We were limited by the number of cases available at our institution, which did not utilize PRAME during the initial diagnosis of the case; including these cases in the study group would have undermined the integrity of our argument because the differentiation of benign vs malignant initially was made using PRAME immunohistochemistry.

Conclusion

Due to their atypical features, special-site nevi can be challenging to assess. In this study, we showed that PRAME expression can be a reliable marker to distinguish benign from malignant lesions. Our results showed that 100% of benign special-site nevi demonstrated 3+ expression or less, with 56% (20/36) demonstrating no expression at all. The presence of diffuse PRAME expression (4+ PRAME staining) appears to be a specific indicator of a malignant lesion, but results should always be interpreted with respect to the patient’s clinical history and the lesion’s histomorphologic features. Further study of a larger sample size would allow refinement of the sensitivity and specificity of diffuse PRAME expression in the determination of malignancy for special-site lesions.

Acknowledgment—The authors thank the pathologistsat the University of Virginia Biorepository and Tissue Research Facility (Charlottesville, Virginia) for their skill and expertise in performing immunohistochemical staining for this study.

Approximately 20% of the general population has a contact allergy.¹ Allergic contact dermatitis (ACD) is a delayed type IV hypersensitivity reaction mediated by T lymphocytes.² Axillary ACD presentation is variable but typically includes an eczematous eruption with erythematous scaly patches or plaques. Common products in contact with the axillae include deodorants, antiperspirants, razors, bodywash, and clothing.

Axillary skin is distinct from skin elsewhere on the body due to both anatomical characteristics and unique human self-care practices. Axillary skin has reduced barrier function, faster stratum corneum turnover, and altered lipid levels.^3-5 Moreover, the axillae often are subject to shaving or other hair removal practices that alter the local environment, as layers of stratum corneum and hair are mechanically removed, which causes irritation and predisposes the skin to enhanced sensitivity to topical exposures.^6,7 With the abundance of apocrine and eccrine glands, the axillae are prone to sweat, which also can accentuate contact allergy.^2,3 Other factors, such as occlusion and friction, contribute to axillary contact allergy.^8,9

Patch testing is the gold standard for the diagnosis of ACD and aids in identification of culprit allergens. A thorough patient history and examination of the rash distribution may provide further clues; for example, dermatitis due to a deodorant typically affects the vault, whereas textile dye dermatitis tends to spare the vault.^10,11 Baseline-limited patch testing detects up to two-thirds of clinically relevant allergens.¹² Therefore, patients may require subsequent testing with supplemental allergens.

The differential diagnosis for axillary lesions is broad—including inflammatory diseases such as irritant contact dermatitis and hidradenitis suppurativa, genetic disorders such as Hailey-Hailey disease, and infectious causes such as erythrasma—but may be narrowed with a thorough physical examination and patient history, histopathology, bedside diagnostic techniques (eg, scrapings and Wood lamp examination), and patch testing. Systemic contact dermatitis (SCD) or symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) also may be suspected in cases of intertriginous dermatoses.

We review the potential allergens in products used on the axillae as well as the management of axillary ACD. We also discuss axillary dermatitis as a manifestation of SCD and SDRIFE.

Top Allergens in Products Used on the Axillae

Fragrance—A 1982 North American Contact Dermatitis Group study on cosmetic products identified fragrances as the most common cause of ACD,¹³ and this trend continues to hold true with more recent data.¹⁴ The incidence of fragrance allergy may be increasing, with positive patch tests to a fragrance chemical in 10% of patch test clinic populations.¹⁵ Fragrances are a ubiquitous ingredient in deodorants and antiperspirants, which are important sources implicated in the development and elicitation of fragrance ACD.¹⁶ One study found that fragrance was present in 97 of 107 (90%) deodorants available at Walgreens pharmacies.¹¹

In a study of patients with a history of an axillary rash caused by a deodorant spray, Johansen et al¹⁷ reported that the likelihood of fragrance allergy is increased by a factor of 2.4. This risk of developing a fragrance allergy may be exacerbated in those who shave; Edman¹⁸ reported that the odds ratio of developing a fragrance allergy among men who shave their beards was 2.9. Although there are no specific data on the effects of shaving on ACD, shaving in general can induce localized irritation and increase percutaneous absorption.¹⁹

The individual fragrance components in deodorants most likely to cause ACD include hydroxycitronellal, eugenol, and geraniol—all constituent ingredients in patch test formulations of fragrance mixture I.^11,20 Other common fragrance allergens associated with ACD include hydroxymethylpentylcyclohexenecarboxaldehyde, farnesol, and balsam of Peru.^21-27 Hydroperoxides of limonene and linalool, common fragrances in detergents and personal care products, are increasingly recognized as contact allergens and have been reported to cause axillary ACD from deodorants.^28-30

Dermatitis involving the bilateral axillary vaults wherever deodorant or antiperspirant was directly applied is the most common presentation of ACD due to fragrance (Figure 1).¹⁷ An eczematous eruption is common, though scale may be less apparent than in nonflexural regions. Axillary ACD secondary to fragrances also may result from use of fragranced laundry detergents, fabric softeners, soaps, and perfumes, and may spare the vaults.^10,29,31,32 Less common presentations of axillary ACD due to fragrance include pigmented dermatoses; for example, ACD from an antiperspirant containing hydroperoxide of limonene presented as hyperpigmented patches with minimal erythema and scaling in the edges of the axillary folds.^33,34

Diagnosis of a fragrance ACD typically is made with a standard patch test series including fragrance mixture I and balsam of Peru, which may detect 75% and 50% of fragrance sensitivities, respectively.³⁵ Patch testing may be followed with a repeated open application test of the product in question.³⁶ Additionally, it may be appropriate to test for other fragrance allergens including balsam of Tolu, fragrance mixture II, lichen acid mix, and hydroxyperoxides of linalool and limonene (among other botanicals) if standard patch testing is negative and suspicion of fragrance ACD remains elevated.¹¹

Propylene Glycol—Propylene glycol (PG)—a versatile substance that functions as a solvent, humectant, emulsifier, stabilizer, and antimicrobial—is the second most common contact allergen present in deodorants.¹¹ It is prevalent in both personal care and household products, including deodorants, cosmetics, foods, toothpaste, cleaning agents, and detergents.^11,37 Propylene glycol is both an allergen and an irritant. Among deodorants/antiperspirants, PG is both a common irritant and allergen, as its concentration may be particularly high (as much as 73%).³⁸ One commonly reported example of PG contact dermatitis is from the topical medicament minoxidil.^39,40

Patch testing data have demonstrated a positivity rate for PG ranging between 0.1% to 3.8%. The variability in these findings likely is due to differences in the tested concentrations of PG, as higher concentrations sometimes required to elicit an allergic reaction also may create a stronger irritation effect.⁴¹ Propylene glycol irritancy and the occlusive nature of the axillae may enhance sensitization to other allergens, as demonstrated by Agren-Jonsson and Magnusson,⁴² who reported sensitization to propantheline bromide and trichlorocarbanilide in patients who used a lotion with 90% PG. Many PG-containing products beyond deodorants/antiperspirants may be applied to the axillae, including steroid creams, lotions, shaving creams, and bodywashes.^38,43

The diagnosis of PG allergy via patch testing is challenging and at times controversial given its irritant nature. False-positive irritant reactions have been documented, characterized by a weak reaction at 48 hours that is absent by 96 hours (decrescendo reaction). A reaction may not appear until 96 hours (crescendo reaction), which typically indicates a true contact allergy but in the case of PG also may be the substance acting as a “late irritant.”⁴⁴ Fast (<24 hours) and well-demarcated reactions suggest irritation.⁴⁵ Regardless, reactions to PG on patch testing, even those regarded as weak, may be considered relevant in consideration of the clinical context.³⁷

Aluminum—Aluminum is the active ingredient in most antiperspirants, typically in the form of aluminum chloride, aluminum chlorohydrate, aluminum zirconium trichlorohydrex gly, or aluminum zirconium tetrachlorohydrex gly.⁴⁶ Aluminum mechanically obstructs the eccrine glands to reduce sweat.⁴⁷ Although aluminum is an uncommon allergen, a possible presentation of aluminum allergy is axillary vault dermatitis secondary to antiperspirant use.⁴⁶ Another potential manifestation is a ringlike reaction to the Finn Chambers (SmartPractice) used in patch testing.⁴⁶ In one case of aluminum-induced axillary dermatitis, a 28-year-old woman presented with eczema of the axillae, and subsequent patch testing revealed an allergy to aluminum chloride. The rash resolved upon cessation of use of an aluminum-containing deodorant.⁴⁸

Aluminum has been reported to cause granulomatous dermatitis in the axillae. This reaction typically presents as red-brown, pruritic papules limited to the area in which deodorant was applied, with histopathology revealing epithelioid granulomas.^49-51

Alum deodorants—considered a natural alternative—contain aluminum bound to potassium or ammonium in the form of a crystal or powder. Alum crystal deodorants have been reported to cause both a typical erythematous pruritic dermatitis as well as a granulomatous dermatitis with red-brown papules.^52,53 The granulomatous dermatitis caused by either form of aluminum resolves with avoidance and use of topical steroids or topical tacrolimus.^49,50,52,53

The diagnosis of aluminum ACD via patch testing may be identified with empty Finn Chambers, which are metallic aluminum, or with patch placement of aluminum chloride hexahydrate, though the former is only positive in patients with a strong allergy.^54,55 In 2022, aluminum was named Allergen of the Year by the American Contact Dermatitis Society, with recommendations to conduct patch testing with aluminum chloride hexahydrate 10% rather than the traditional 2% to increase diagnostic yield.⁵⁵ Additionally, it is recommended that aluminum be included in baseline patch testing for children due to the high prevalence of aluminum allergy in children and early exposure via childhood vaccines.^54-56 In patients with aluminum allergy, providers may suggest purchasing aluminum-free deodorants or provide recipes for homemade deodorant that includes ingredients such as arrowroot powder, cornstarch, and diatomaceous earth.⁴⁶

Nickel—Nickel is the most commonly identified contact allergen on patch testing yet an infrequent cause of axillary dermatitis. A case report from 2014 described axillary dermatitis in a woman that worsened during a positive patch test to nickel. Improvement was noted when the patient switched to titanium shaving razors.⁵⁷ Nickel allergy also may present in the form of SCD. In one report, a woman developed dermatitis of the flexural areas, including the axillae, 3 months after undergoing a sterilization procedure in which nickel-containing tubal implants were placed.⁵⁸ Patch testing revealed a positive reaction to nickel. The patient experienced complete resolution of the steroid-resistant dermatitis following removal of the implants via salpingectomy.⁵⁸

Textile Dye—In contrast to dermatitis caused by deodorants/antiperspirants, contact allergy to textile dyes presents as dermatitis involving the axillary borders but sparing the axillary vaults (Figures 2 and 3).¹⁰ Other potential presentations of textile dye dermatitis include erythema multiforme–like eruptions and erythematous wheal–type reactions.⁵⁹ Textile dyes are classified as disperse vs nondisperse, with the majority of contact dermatoses caused by disperse dyes, specifically Disperse Orange 1, blue 106, and blue 124.^60-62 Ryberg et al⁶¹ found that the axilla is one of the more common locations to be affected by textile dye allergy, particularly in women, which was further supported by Seidenari et al,⁶³ who found that skin folds were affected in 27% of study participants allergic to textile dyes (N=437), a finding that is likely due to friction, sweat, and occlusion.⁶² In one case report of a patient with dermatitis caused by reactive dyes, the garment required 3 washes before the patient experienced resolution of dermatitis.⁶⁴ For patients with textile dye dermatitis, mitigation strategies include washing clothing before wearing, especially for darkly dyed items; avoiding tight clothing; wearing garments made of cotton, wool, silk, or linen; and choosing light-colored garments.^9,64,65

Axillary Dermatitis as a Manifestation of SCD and SDRIFE

Systemic contact dermatitis occurs when an individual who was previously sensitized to a particular allergen develops ACD of the skin with systemic exposure to that allergen or immunochemically related allergens. Exposure may occur via ingestion, inhalation, intravenous, intramuscular, and transepidermal routes.⁶⁶ Systemic contact dermatitis manifests in a variety of ways, including focal flares at sites of prior contact dermatitis (recall reaction), vesicular hand dermatitis, intertriginous eruptions including axillary dermatitis, and generalized eruptions.⁶⁷

Systemic contact dermatitis rarely involves systemic symptoms, and onset typically is within days of exposure. The 3 most common groups of allergens causing SCD are metals, medications, and plants and herbals.⁶⁸ These allergens have all been reported to cause axillary dermatitis via SCD.^58,69,70 Foods containing balsam of Peru that may lead to SCD include citrus, chocolate, tomato, and certain alcohols.^70,71 Patients with a positive patch test to balsam of Peru may experience improvement of their dermatitis after reduction of balsam of Peru–rich foods from their diet.⁷⁰ Metals implicated in SCD include mercury, nickel, and gold.^72-74 Finally, PG ingestion also has been implicated in cases of SCD.³⁷

Symmetrical drug-related intertriginous and flexural exanthema is another condition that presents as intertriginous dermatitis and differs from SCD in that the eruption does not require presensitization; there may be no known prior exposure to the agent causing dermatitis. Historically, SDRIFE was described as baboon syndrome because of its frequent involvement of the buttocks with diffuse, well-demarcated, erythematous dermatitis resembling that of a baboon. This term is no longer used due to its insensitive nature and incomplete depiction of SDRIFE, which can affect body sites other than the buttocks.^68,75,76 Specific criteria to make this diagnosis include sharply demarcated and/or V-shaped erythema of the gluteal/perianal area, involvement of at least 1 other intertriginous or flexural region, symmetry of affected areas, and an absence of systemic symptoms.⁷⁶ There also may be papules, pustules, and vesicles present in affected areas. Symmetrical drug-related intertriginous and flexural exanthema most often is caused by β-lactam antibiotics, but other associated drugs include chemotherapeutic agents, such as mitomycin C.⁷⁶

Histopathology of both SCD and SDRIFE is variable and typically nonspecific, often revealing epidermal spongiosis and a perivascular mononuclear cell infiltrate with occasional neutrophils and eosinophils.⁷⁶ A case of SCD to mercury presenting as intertriginous dermatitis demonstrated a leukocytoclastic vasculitis pattern on biopsy.⁷⁷

Systemic contact dermatitis is diagnosed via a patch test, while SDRIFE typically has a negative patch test result and requires oral rechallenge testing, which reproduces the rash within hours.^78,79

Additional Allergens Causing Axillary ACD

Although fragrance is the most common allergen in deodorants, other ingredients have been shown to cause axillary ACD (Table).^80-90 In addition to these ingredients, allergens not previously mentioned that may be present in deodorants include lanolin, essential oils, and parabens.¹¹ Methylisothiazolinone in laundry detergent also has been found to instigate ACD.⁹¹ Fragrances and preservatives in laundry detergents also may contribute to dermatitis.⁹²

Other products that have caused axillary contact dermatitis include topical exposure to medicaments including clindamycin,⁹³ ethylenediamine in nystatin cream,⁹⁴ methylprednisolone acetate⁹⁵ and dipropylene glycol in a hydrocortisone lotion,⁹⁶ wood dusts from tropical hardwoods,⁹⁷ and tobacco.⁹⁸

Management of ACD

The most effective strategy in the management of patients with contact dermatitis is avoidance of the offending agent. Additionally, clinicians may recommend the use of topical steroids and/or calcineurin inhibitors to hasten resolution.²

For patients with contact dermatitis, a clinician may recommend product substitutions with few potential allergens to use prior to patch testing. Patients with a fragrance allergy should look for products specifically labeled as “fragrance free” rather than “hypoallergenic” or “unscented,” as the latter two may still contain minimal amounts of fragrance.³⁵ Patients should be educated on the functions of the allergens to which they are allergic so they may adequately avoid potential sources of contact.⁹⁹ For suspected textile dye dermatitis, instructing patients to wash clothing before wearing and to avoid synthetic fabrics, dark dyes, and tightly fitted clothing may help.^9,64,65

The differential diagnosis for axillary lesions is broad, including infectious, inflammatory, and autoimmune etiologies. Irritant contact dermatitis (ICD) presents similar to ACD, though it is more immediate in onsetand typically demonstrates symptoms of burning and stinging rather than pruritus. Although histopathology is not reliable in differentiating ICD and ACD, it has been shown that focal parakeratosis is associated with ACD, whereas necrotic epidermal keratinocytes are found in ICD.¹⁰⁰

Intertrigo presents as large, erythematous, opposing patches or plaques confined to inguinal, submammary, axillary, and/or abdominal folds. Findings of beefy red erythema and peripheral satellite pustules may implicate presence of Candida, which can be identified with potassium hydroxide preparations.

Inverse psoriasis presents as sharply demarcated, erythematous, moist, smooth plaques or patches with minimal scale. The most common area of involvement is the inguinal folds, followed by the axillae, inframammary folds, perianal area, umbilicus, and retroauricular areas. Involvement of the elbows and knees or a positive family history of psoriasis may be useful knowledge in establishing the diagnosis. A biopsy may show dermal eosinophils, epidermal spongiosis, and focal serum in the scale, in addition to features of typical psoriasis plaques.¹⁰¹

Seborrheic dermatitis typically is an erythematous eruption, often with yellowish greasy scale. Simultaneous involvement of the face and scalp may be noted. Although typically a clinical diagnosis, biopsy demonstrates shoulder parakeratosis with follicular plugging and lymphocytic exocytosis.

Hailey-Hailey disease (also called benign familial pemphigus) is an autosomal-dominant genetic condition presenting as moist, malodorous, painful, vegetative plaques, patches, or scaly pustules in flexural areas, frequently with flaccid blisters. Lesions are provoked by traumatic stimuli. Onset occurs in the second to fourth decades and may improve with age. The diagnosis is confirmed by biopsy, which demonstrates acantholysis of the epidermis. The moist superficial patches of Hailey-Hailey disease help distinguish it from comparably drier Darier disease, the other acantholytic disease of the axillae.

Granular parakeratosis (also called hyperkeratotic flexural erythema) is an uncommon dermatosis most often observed in middle-aged women. It presents as red-brown keratotic papules coalescing into plaques, often with overlying scale in intertriginous areas. This disorder may be related to exposure to aluminum, a key component of antiperspirants.¹⁰² Diagnosis with a skin biopsy demonstrates granular parakeratosis.

Infections most commonly include erythrasma, tinea, and candidiasis. Erythrasma caused by Corynebacterium minutissimum may present in the axillae and/or groin with sharply demarcated, red-brown patches. Wood lamp examination reveals coral red fluorescence. Tinea corporis, a dermatophyte infection, may present as scaly erythematous plaques with advancing borders and central clearing. Fungal cultures and potassium hydroxide preparations are useful to confirm the diagnosis.

Pseudofolliculitis barbae most often is thought of as a condition affecting the beard in Black men, but it also may present in individuals of all races who shave the axillary and inguinal regions. Typical features include pruritic inflammatory papules and pustules with surrounding erythema and hyperpigmentation.

Fox-Fordyce disease is a disorder of the apocrine sweat glands that presents as several flesh-colored, perifollicular, monomorphic papules in the axillae. It typically is a disease of young females and also can involve the areola and vulva. Histopathology may show hyperkeratosis, irregular acanthosis, and dilated sweat glands.

Hidradenitis suppurativa is a chronic inflammatory condition that presents with multiple cysts; nodules; abscesses; sinus tract formation; and suppuration of the axillary, anogenital, and sometimes inframammary areas, typically at the onset of puberty. The diagnosis is best supported by history and physical examination, which may be notable for recurrent abscesses, draining tracts, double comedones, and ropelike scarring.

Extramammary Paget disease is a rare malignancy affecting apocrine gland–bearing areas, including axillary and genital regions. It most commonly presents as a unilateral or asymmetric, scaly, erythematous plaque. Histopathology demonstrates Paget cells with abundant clear cytoplasm and pleomorphic nuclei, typically grouped in the lower portion of the epidermis.

Final Thoughts

Axillary dermatoses often can be challenging to diagnose given the range of pathologies that can present in intertriginous areas. Allergic contact dermatitis is a common culprit due to unique anatomical considerations and self-care practices, including shaving/hair removal; use of deodorants, antiperspirants, bodywashes, and clothing; and frictional and moisture influences. The most likely offender among contact allergens is fragrance, but other possibilities to consider include PG, preservatives, aluminum, nickel, and textile dyes. Albeit less common, systemic exposure to allergens may result in SCD and SDRIFE with a rash in intertriginous zones, including the axillae. Additionally, other infectious, inflammatory, and autoimmune etiologies should be considered and ruled out.

Patch testing is the most reliable method to diagnose suspected ACD. Once confirmed, management includes the use of topical steroids and avoidance of the causative agent. Additionally, patients should be informed of the American Contact Dermatitis Society Contact Allergen Management Program (https://www.contactderm.org/patient-support/camp-access), which provides patients with useful information on products that are safe to use based on their patch testing results.

Approximately 20% of the general population has a contact allergy.¹ Allergic contact dermatitis (ACD) is a delayed type IV hypersensitivity reaction mediated by T lymphocytes.² Axillary ACD presentation is variable but typically includes an eczematous eruption with erythematous scaly patches or plaques. Common products in contact with the axillae include deodorants, antiperspirants, razors, bodywash, and clothing.

Axillary skin is distinct from skin elsewhere on the body due to both anatomical characteristics and unique human self-care practices. Axillary skin has reduced barrier function, faster stratum corneum turnover, and altered lipid levels.^3-5 Moreover, the axillae often are subject to shaving or other hair removal practices that alter the local environment, as layers of stratum corneum and hair are mechanically removed, which causes irritation and predisposes the skin to enhanced sensitivity to topical exposures.^6,7 With the abundance of apocrine and eccrine glands, the axillae are prone to sweat, which also can accentuate contact allergy.^2,3 Other factors, such as occlusion and friction, contribute to axillary contact allergy.^8,9

Patch testing is the gold standard for the diagnosis of ACD and aids in identification of culprit allergens. A thorough patient history and examination of the rash distribution may provide further clues; for example, dermatitis due to a deodorant typically affects the vault, whereas textile dye dermatitis tends to spare the vault.^10,11 Baseline-limited patch testing detects up to two-thirds of clinically relevant allergens.¹² Therefore, patients may require subsequent testing with supplemental allergens.

The differential diagnosis for axillary lesions is broad—including inflammatory diseases such as irritant contact dermatitis and hidradenitis suppurativa, genetic disorders such as Hailey-Hailey disease, and infectious causes such as erythrasma—but may be narrowed with a thorough physical examination and patient history, histopathology, bedside diagnostic techniques (eg, scrapings and Wood lamp examination), and patch testing. Systemic contact dermatitis (SCD) or symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) also may be suspected in cases of intertriginous dermatoses.

We review the potential allergens in products used on the axillae as well as the management of axillary ACD. We also discuss axillary dermatitis as a manifestation of SCD and SDRIFE.

Top Allergens in Products Used on the Axillae

Fragrance—A 1982 North American Contact Dermatitis Group study on cosmetic products identified fragrances as the most common cause of ACD,¹³ and this trend continues to hold true with more recent data.¹⁴ The incidence of fragrance allergy may be increasing, with positive patch tests to a fragrance chemical in 10% of patch test clinic populations.¹⁵ Fragrances are a ubiquitous ingredient in deodorants and antiperspirants, which are important sources implicated in the development and elicitation of fragrance ACD.¹⁶ One study found that fragrance was present in 97 of 107 (90%) deodorants available at Walgreens pharmacies.¹¹

In a study of patients with a history of an axillary rash caused by a deodorant spray, Johansen et al¹⁷ reported that the likelihood of fragrance allergy is increased by a factor of 2.4. This risk of developing a fragrance allergy may be exacerbated in those who shave; Edman¹⁸ reported that the odds ratio of developing a fragrance allergy among men who shave their beards was 2.9. Although there are no specific data on the effects of shaving on ACD, shaving in general can induce localized irritation and increase percutaneous absorption.¹⁹

The individual fragrance components in deodorants most likely to cause ACD include hydroxycitronellal, eugenol, and geraniol—all constituent ingredients in patch test formulations of fragrance mixture I.^11,20 Other common fragrance allergens associated with ACD include hydroxymethylpentylcyclohexenecarboxaldehyde, farnesol, and balsam of Peru.^21-27 Hydroperoxides of limonene and linalool, common fragrances in detergents and personal care products, are increasingly recognized as contact allergens and have been reported to cause axillary ACD from deodorants.^28-30

Dermatitis involving the bilateral axillary vaults wherever deodorant or antiperspirant was directly applied is the most common presentation of ACD due to fragrance (Figure 1).¹⁷ An eczematous eruption is common, though scale may be less apparent than in nonflexural regions. Axillary ACD secondary to fragrances also may result from use of fragranced laundry detergents, fabric softeners, soaps, and perfumes, and may spare the vaults.^10,29,31,32 Less common presentations of axillary ACD due to fragrance include pigmented dermatoses; for example, ACD from an antiperspirant containing hydroperoxide of limonene presented as hyperpigmented patches with minimal erythema and scaling in the edges of the axillary folds.^33,34

Diagnosis of a fragrance ACD typically is made with a standard patch test series including fragrance mixture I and balsam of Peru, which may detect 75% and 50% of fragrance sensitivities, respectively.³⁵ Patch testing may be followed with a repeated open application test of the product in question.³⁶ Additionally, it may be appropriate to test for other fragrance allergens including balsam of Tolu, fragrance mixture II, lichen acid mix, and hydroxyperoxides of linalool and limonene (among other botanicals) if standard patch testing is negative and suspicion of fragrance ACD remains elevated.¹¹

Propylene Glycol—Propylene glycol (PG)—a versatile substance that functions as a solvent, humectant, emulsifier, stabilizer, and antimicrobial—is the second most common contact allergen present in deodorants.¹¹ It is prevalent in both personal care and household products, including deodorants, cosmetics, foods, toothpaste, cleaning agents, and detergents.^11,37 Propylene glycol is both an allergen and an irritant. Among deodorants/antiperspirants, PG is both a common irritant and allergen, as its concentration may be particularly high (as much as 73%).³⁸ One commonly reported example of PG contact dermatitis is from the topical medicament minoxidil.^39,40

Patch testing data have demonstrated a positivity rate for PG ranging between 0.1% to 3.8%. The variability in these findings likely is due to differences in the tested concentrations of PG, as higher concentrations sometimes required to elicit an allergic reaction also may create a stronger irritation effect.⁴¹ Propylene glycol irritancy and the occlusive nature of the axillae may enhance sensitization to other allergens, as demonstrated by Agren-Jonsson and Magnusson,⁴² who reported sensitization to propantheline bromide and trichlorocarbanilide in patients who used a lotion with 90% PG. Many PG-containing products beyond deodorants/antiperspirants may be applied to the axillae, including steroid creams, lotions, shaving creams, and bodywashes.^38,43

The diagnosis of PG allergy via patch testing is challenging and at times controversial given its irritant nature. False-positive irritant reactions have been documented, characterized by a weak reaction at 48 hours that is absent by 96 hours (decrescendo reaction). A reaction may not appear until 96 hours (crescendo reaction), which typically indicates a true contact allergy but in the case of PG also may be the substance acting as a “late irritant.”⁴⁴ Fast (<24 hours) and well-demarcated reactions suggest irritation.⁴⁵ Regardless, reactions to PG on patch testing, even those regarded as weak, may be considered relevant in consideration of the clinical context.³⁷

Aluminum—Aluminum is the active ingredient in most antiperspirants, typically in the form of aluminum chloride, aluminum chlorohydrate, aluminum zirconium trichlorohydrex gly, or aluminum zirconium tetrachlorohydrex gly.⁴⁶ Aluminum mechanically obstructs the eccrine glands to reduce sweat.⁴⁷ Although aluminum is an uncommon allergen, a possible presentation of aluminum allergy is axillary vault dermatitis secondary to antiperspirant use.⁴⁶ Another potential manifestation is a ringlike reaction to the Finn Chambers (SmartPractice) used in patch testing.⁴⁶ In one case of aluminum-induced axillary dermatitis, a 28-year-old woman presented with eczema of the axillae, and subsequent patch testing revealed an allergy to aluminum chloride. The rash resolved upon cessation of use of an aluminum-containing deodorant.⁴⁸

Aluminum has been reported to cause granulomatous dermatitis in the axillae. This reaction typically presents as red-brown, pruritic papules limited to the area in which deodorant was applied, with histopathology revealing epithelioid granulomas.^49-51

Alum deodorants—considered a natural alternative—contain aluminum bound to potassium or ammonium in the form of a crystal or powder. Alum crystal deodorants have been reported to cause both a typical erythematous pruritic dermatitis as well as a granulomatous dermatitis with red-brown papules.^52,53 The granulomatous dermatitis caused by either form of aluminum resolves with avoidance and use of topical steroids or topical tacrolimus.^49,50,52,53

The diagnosis of aluminum ACD via patch testing may be identified with empty Finn Chambers, which are metallic aluminum, or with patch placement of aluminum chloride hexahydrate, though the former is only positive in patients with a strong allergy.^54,55 In 2022, aluminum was named Allergen of the Year by the American Contact Dermatitis Society, with recommendations to conduct patch testing with aluminum chloride hexahydrate 10% rather than the traditional 2% to increase diagnostic yield.⁵⁵ Additionally, it is recommended that aluminum be included in baseline patch testing for children due to the high prevalence of aluminum allergy in children and early exposure via childhood vaccines.^54-56 In patients with aluminum allergy, providers may suggest purchasing aluminum-free deodorants or provide recipes for homemade deodorant that includes ingredients such as arrowroot powder, cornstarch, and diatomaceous earth.⁴⁶

Nickel—Nickel is the most commonly identified contact allergen on patch testing yet an infrequent cause of axillary dermatitis. A case report from 2014 described axillary dermatitis in a woman that worsened during a positive patch test to nickel. Improvement was noted when the patient switched to titanium shaving razors.⁵⁷ Nickel allergy also may present in the form of SCD. In one report, a woman developed dermatitis of the flexural areas, including the axillae, 3 months after undergoing a sterilization procedure in which nickel-containing tubal implants were placed.⁵⁸ Patch testing revealed a positive reaction to nickel. The patient experienced complete resolution of the steroid-resistant dermatitis following removal of the implants via salpingectomy.⁵⁸

Textile Dye—In contrast to dermatitis caused by deodorants/antiperspirants, contact allergy to textile dyes presents as dermatitis involving the axillary borders but sparing the axillary vaults (Figures 2 and 3).¹⁰ Other potential presentations of textile dye dermatitis include erythema multiforme–like eruptions and erythematous wheal–type reactions.⁵⁹ Textile dyes are classified as disperse vs nondisperse, with the majority of contact dermatoses caused by disperse dyes, specifically Disperse Orange 1, blue 106, and blue 124.^60-62 Ryberg et al⁶¹ found that the axilla is one of the more common locations to be affected by textile dye allergy, particularly in women, which was further supported by Seidenari et al,⁶³ who found that skin folds were affected in 27% of study participants allergic to textile dyes (N=437), a finding that is likely due to friction, sweat, and occlusion.⁶² In one case report of a patient with dermatitis caused by reactive dyes, the garment required 3 washes before the patient experienced resolution of dermatitis.⁶⁴ For patients with textile dye dermatitis, mitigation strategies include washing clothing before wearing, especially for darkly dyed items; avoiding tight clothing; wearing garments made of cotton, wool, silk, or linen; and choosing light-colored garments.^9,64,65

Axillary Dermatitis as a Manifestation of SCD and SDRIFE

Systemic contact dermatitis occurs when an individual who was previously sensitized to a particular allergen develops ACD of the skin with systemic exposure to that allergen or immunochemically related allergens. Exposure may occur via ingestion, inhalation, intravenous, intramuscular, and transepidermal routes.⁶⁶ Systemic contact dermatitis manifests in a variety of ways, including focal flares at sites of prior contact dermatitis (recall reaction), vesicular hand dermatitis, intertriginous eruptions including axillary dermatitis, and generalized eruptions.⁶⁷

Systemic contact dermatitis rarely involves systemic symptoms, and onset typically is within days of exposure. The 3 most common groups of allergens causing SCD are metals, medications, and plants and herbals.⁶⁸ These allergens have all been reported to cause axillary dermatitis via SCD.^58,69,70 Foods containing balsam of Peru that may lead to SCD include citrus, chocolate, tomato, and certain alcohols.^70,71 Patients with a positive patch test to balsam of Peru may experience improvement of their dermatitis after reduction of balsam of Peru–rich foods from their diet.⁷⁰ Metals implicated in SCD include mercury, nickel, and gold.^72-74 Finally, PG ingestion also has been implicated in cases of SCD.³⁷

Symmetrical drug-related intertriginous and flexural exanthema is another condition that presents as intertriginous dermatitis and differs from SCD in that the eruption does not require presensitization; there may be no known prior exposure to the agent causing dermatitis. Historically, SDRIFE was described as baboon syndrome because of its frequent involvement of the buttocks with diffuse, well-demarcated, erythematous dermatitis resembling that of a baboon. This term is no longer used due to its insensitive nature and incomplete depiction of SDRIFE, which can affect body sites other than the buttocks.^68,75,76 Specific criteria to make this diagnosis include sharply demarcated and/or V-shaped erythema of the gluteal/perianal area, involvement of at least 1 other intertriginous or flexural region, symmetry of affected areas, and an absence of systemic symptoms.⁷⁶ There also may be papules, pustules, and vesicles present in affected areas. Symmetrical drug-related intertriginous and flexural exanthema most often is caused by β-lactam antibiotics, but other associated drugs include chemotherapeutic agents, such as mitomycin C.⁷⁶

Histopathology of both SCD and SDRIFE is variable and typically nonspecific, often revealing epidermal spongiosis and a perivascular mononuclear cell infiltrate with occasional neutrophils and eosinophils.⁷⁶ A case of SCD to mercury presenting as intertriginous dermatitis demonstrated a leukocytoclastic vasculitis pattern on biopsy.⁷⁷

Systemic contact dermatitis is diagnosed via a patch test, while SDRIFE typically has a negative patch test result and requires oral rechallenge testing, which reproduces the rash within hours.^78,79

Additional Allergens Causing Axillary ACD

Although fragrance is the most common allergen in deodorants, other ingredients have been shown to cause axillary ACD (Table).^80-90 In addition to these ingredients, allergens not previously mentioned that may be present in deodorants include lanolin, essential oils, and parabens.¹¹ Methylisothiazolinone in laundry detergent also has been found to instigate ACD.⁹¹ Fragrances and preservatives in laundry detergents also may contribute to dermatitis.⁹²

Other products that have caused axillary contact dermatitis include topical exposure to medicaments including clindamycin,⁹³ ethylenediamine in nystatin cream,⁹⁴ methylprednisolone acetate⁹⁵ and dipropylene glycol in a hydrocortisone lotion,⁹⁶ wood dusts from tropical hardwoods,⁹⁷ and tobacco.⁹⁸

Management of ACD

The most effective strategy in the management of patients with contact dermatitis is avoidance of the offending agent. Additionally, clinicians may recommend the use of topical steroids and/or calcineurin inhibitors to hasten resolution.²

For patients with contact dermatitis, a clinician may recommend product substitutions with few potential allergens to use prior to patch testing. Patients with a fragrance allergy should look for products specifically labeled as “fragrance free” rather than “hypoallergenic” or “unscented,” as the latter two may still contain minimal amounts of fragrance.³⁵ Patients should be educated on the functions of the allergens to which they are allergic so they may adequately avoid potential sources of contact.⁹⁹ For suspected textile dye dermatitis, instructing patients to wash clothing before wearing and to avoid synthetic fabrics, dark dyes, and tightly fitted clothing may help.^9,64,65

The differential diagnosis for axillary lesions is broad, including infectious, inflammatory, and autoimmune etiologies. Irritant contact dermatitis (ICD) presents similar to ACD, though it is more immediate in onsetand typically demonstrates symptoms of burning and stinging rather than pruritus. Although histopathology is not reliable in differentiating ICD and ACD, it has been shown that focal parakeratosis is associated with ACD, whereas necrotic epidermal keratinocytes are found in ICD.¹⁰⁰

Intertrigo presents as large, erythematous, opposing patches or plaques confined to inguinal, submammary, axillary, and/or abdominal folds. Findings of beefy red erythema and peripheral satellite pustules may implicate presence of Candida, which can be identified with potassium hydroxide preparations.

Inverse psoriasis presents as sharply demarcated, erythematous, moist, smooth plaques or patches with minimal scale. The most common area of involvement is the inguinal folds, followed by the axillae, inframammary folds, perianal area, umbilicus, and retroauricular areas. Involvement of the elbows and knees or a positive family history of psoriasis may be useful knowledge in establishing the diagnosis. A biopsy may show dermal eosinophils, epidermal spongiosis, and focal serum in the scale, in addition to features of typical psoriasis plaques.¹⁰¹

Seborrheic dermatitis typically is an erythematous eruption, often with yellowish greasy scale. Simultaneous involvement of the face and scalp may be noted. Although typically a clinical diagnosis, biopsy demonstrates shoulder parakeratosis with follicular plugging and lymphocytic exocytosis.

Hailey-Hailey disease (also called benign familial pemphigus) is an autosomal-dominant genetic condition presenting as moist, malodorous, painful, vegetative plaques, patches, or scaly pustules in flexural areas, frequently with flaccid blisters. Lesions are provoked by traumatic stimuli. Onset occurs in the second to fourth decades and may improve with age. The diagnosis is confirmed by biopsy, which demonstrates acantholysis of the epidermis. The moist superficial patches of Hailey-Hailey disease help distinguish it from comparably drier Darier disease, the other acantholytic disease of the axillae.

Granular parakeratosis (also called hyperkeratotic flexural erythema) is an uncommon dermatosis most often observed in middle-aged women. It presents as red-brown keratotic papules coalescing into plaques, often with overlying scale in intertriginous areas. This disorder may be related to exposure to aluminum, a key component of antiperspirants.¹⁰² Diagnosis with a skin biopsy demonstrates granular parakeratosis.

Infections most commonly include erythrasma, tinea, and candidiasis. Erythrasma caused by Corynebacterium minutissimum may present in the axillae and/or groin with sharply demarcated, red-brown patches. Wood lamp examination reveals coral red fluorescence. Tinea corporis, a dermatophyte infection, may present as scaly erythematous plaques with advancing borders and central clearing. Fungal cultures and potassium hydroxide preparations are useful to confirm the diagnosis.

Pseudofolliculitis barbae most often is thought of as a condition affecting the beard in Black men, but it also may present in individuals of all races who shave the axillary and inguinal regions. Typical features include pruritic inflammatory papules and pustules with surrounding erythema and hyperpigmentation.

Fox-Fordyce disease is a disorder of the apocrine sweat glands that presents as several flesh-colored, perifollicular, monomorphic papules in the axillae. It typically is a disease of young females and also can involve the areola and vulva. Histopathology may show hyperkeratosis, irregular acanthosis, and dilated sweat glands.

Hidradenitis suppurativa is a chronic inflammatory condition that presents with multiple cysts; nodules; abscesses; sinus tract formation; and suppuration of the axillary, anogenital, and sometimes inframammary areas, typically at the onset of puberty. The diagnosis is best supported by history and physical examination, which may be notable for recurrent abscesses, draining tracts, double comedones, and ropelike scarring.

Extramammary Paget disease is a rare malignancy affecting apocrine gland–bearing areas, including axillary and genital regions. It most commonly presents as a unilateral or asymmetric, scaly, erythematous plaque. Histopathology demonstrates Paget cells with abundant clear cytoplasm and pleomorphic nuclei, typically grouped in the lower portion of the epidermis.

Final Thoughts

Axillary dermatoses often can be challenging to diagnose given the range of pathologies that can present in intertriginous areas. Allergic contact dermatitis is a common culprit due to unique anatomical considerations and self-care practices, including shaving/hair removal; use of deodorants, antiperspirants, bodywashes, and clothing; and frictional and moisture influences. The most likely offender among contact allergens is fragrance, but other possibilities to consider include PG, preservatives, aluminum, nickel, and textile dyes. Albeit less common, systemic exposure to allergens may result in SCD and SDRIFE with a rash in intertriginous zones, including the axillae. Additionally, other infectious, inflammatory, and autoimmune etiologies should be considered and ruled out.

Patch testing is the most reliable method to diagnose suspected ACD. Once confirmed, management includes the use of topical steroids and avoidance of the causative agent. Additionally, patients should be informed of the American Contact Dermatitis Society Contact Allergen Management Program (https://www.contactderm.org/patient-support/camp-access), which provides patients with useful information on products that are safe to use based on their patch testing results.

Approximately 20% of the general population has a contact allergy.¹ Allergic contact dermatitis (ACD) is a delayed type IV hypersensitivity reaction mediated by T lymphocytes.² Axillary ACD presentation is variable but typically includes an eczematous eruption with erythematous scaly patches or plaques. Common products in contact with the axillae include deodorants, antiperspirants, razors, bodywash, and clothing.

Axillary skin is distinct from skin elsewhere on the body due to both anatomical characteristics and unique human self-care practices. Axillary skin has reduced barrier function, faster stratum corneum turnover, and altered lipid levels.^3-5 Moreover, the axillae often are subject to shaving or other hair removal practices that alter the local environment, as layers of stratum corneum and hair are mechanically removed, which causes irritation and predisposes the skin to enhanced sensitivity to topical exposures.^6,7 With the abundance of apocrine and eccrine glands, the axillae are prone to sweat, which also can accentuate contact allergy.^2,3 Other factors, such as occlusion and friction, contribute to axillary contact allergy.^8,9

Patch testing is the gold standard for the diagnosis of ACD and aids in identification of culprit allergens. A thorough patient history and examination of the rash distribution may provide further clues; for example, dermatitis due to a deodorant typically affects the vault, whereas textile dye dermatitis tends to spare the vault.^10,11 Baseline-limited patch testing detects up to two-thirds of clinically relevant allergens.¹² Therefore, patients may require subsequent testing with supplemental allergens.

The differential diagnosis for axillary lesions is broad—including inflammatory diseases such as irritant contact dermatitis and hidradenitis suppurativa, genetic disorders such as Hailey-Hailey disease, and infectious causes such as erythrasma—but may be narrowed with a thorough physical examination and patient history, histopathology, bedside diagnostic techniques (eg, scrapings and Wood lamp examination), and patch testing. Systemic contact dermatitis (SCD) or symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) also may be suspected in cases of intertriginous dermatoses.

We review the potential allergens in products used on the axillae as well as the management of axillary ACD. We also discuss axillary dermatitis as a manifestation of SCD and SDRIFE.

Top Allergens in Products Used on the Axillae

Fragrance—A 1982 North American Contact Dermatitis Group study on cosmetic products identified fragrances as the most common cause of ACD,¹³ and this trend continues to hold true with more recent data.¹⁴ The incidence of fragrance allergy may be increasing, with positive patch tests to a fragrance chemical in 10% of patch test clinic populations.¹⁵ Fragrances are a ubiquitous ingredient in deodorants and antiperspirants, which are important sources implicated in the development and elicitation of fragrance ACD.¹⁶ One study found that fragrance was present in 97 of 107 (90%) deodorants available at Walgreens pharmacies.¹¹

In a study of patients with a history of an axillary rash caused by a deodorant spray, Johansen et al¹⁷ reported that the likelihood of fragrance allergy is increased by a factor of 2.4. This risk of developing a fragrance allergy may be exacerbated in those who shave; Edman¹⁸ reported that the odds ratio of developing a fragrance allergy among men who shave their beards was 2.9. Although there are no specific data on the effects of shaving on ACD, shaving in general can induce localized irritation and increase percutaneous absorption.¹⁹

The individual fragrance components in deodorants most likely to cause ACD include hydroxycitronellal, eugenol, and geraniol—all constituent ingredients in patch test formulations of fragrance mixture I.^11,20 Other common fragrance allergens associated with ACD include hydroxymethylpentylcyclohexenecarboxaldehyde, farnesol, and balsam of Peru.^21-27 Hydroperoxides of limonene and linalool, common fragrances in detergents and personal care products, are increasingly recognized as contact allergens and have been reported to cause axillary ACD from deodorants.^28-30

Dermatitis involving the bilateral axillary vaults wherever deodorant or antiperspirant was directly applied is the most common presentation of ACD due to fragrance (Figure 1).¹⁷ An eczematous eruption is common, though scale may be less apparent than in nonflexural regions. Axillary ACD secondary to fragrances also may result from use of fragranced laundry detergents, fabric softeners, soaps, and perfumes, and may spare the vaults.^10,29,31,32 Less common presentations of axillary ACD due to fragrance include pigmented dermatoses; for example, ACD from an antiperspirant containing hydroperoxide of limonene presented as hyperpigmented patches with minimal erythema and scaling in the edges of the axillary folds.^33,34

Diagnosis of a fragrance ACD typically is made with a standard patch test series including fragrance mixture I and balsam of Peru, which may detect 75% and 50% of fragrance sensitivities, respectively.³⁵ Patch testing may be followed with a repeated open application test of the product in question.³⁶ Additionally, it may be appropriate to test for other fragrance allergens including balsam of Tolu, fragrance mixture II, lichen acid mix, and hydroxyperoxides of linalool and limonene (among other botanicals) if standard patch testing is negative and suspicion of fragrance ACD remains elevated.¹¹

Propylene Glycol—Propylene glycol (PG)—a versatile substance that functions as a solvent, humectant, emulsifier, stabilizer, and antimicrobial—is the second most common contact allergen present in deodorants.¹¹ It is prevalent in both personal care and household products, including deodorants, cosmetics, foods, toothpaste, cleaning agents, and detergents.^11,37 Propylene glycol is both an allergen and an irritant. Among deodorants/antiperspirants, PG is both a common irritant and allergen, as its concentration may be particularly high (as much as 73%).³⁸ One commonly reported example of PG contact dermatitis is from the topical medicament minoxidil.^39,40

Patch testing data have demonstrated a positivity rate for PG ranging between 0.1% to 3.8%. The variability in these findings likely is due to differences in the tested concentrations of PG, as higher concentrations sometimes required to elicit an allergic reaction also may create a stronger irritation effect.⁴¹ Propylene glycol irritancy and the occlusive nature of the axillae may enhance sensitization to other allergens, as demonstrated by Agren-Jonsson and Magnusson,⁴² who reported sensitization to propantheline bromide and trichlorocarbanilide in patients who used a lotion with 90% PG. Many PG-containing products beyond deodorants/antiperspirants may be applied to the axillae, including steroid creams, lotions, shaving creams, and bodywashes.^38,43

The diagnosis of PG allergy via patch testing is challenging and at times controversial given its irritant nature. False-positive irritant reactions have been documented, characterized by a weak reaction at 48 hours that is absent by 96 hours (decrescendo reaction). A reaction may not appear until 96 hours (crescendo reaction), which typically indicates a true contact allergy but in the case of PG also may be the substance acting as a “late irritant.”⁴⁴ Fast (<24 hours) and well-demarcated reactions suggest irritation.⁴⁵ Regardless, reactions to PG on patch testing, even those regarded as weak, may be considered relevant in consideration of the clinical context.³⁷

Aluminum—Aluminum is the active ingredient in most antiperspirants, typically in the form of aluminum chloride, aluminum chlorohydrate, aluminum zirconium trichlorohydrex gly, or aluminum zirconium tetrachlorohydrex gly.⁴⁶ Aluminum mechanically obstructs the eccrine glands to reduce sweat.⁴⁷ Although aluminum is an uncommon allergen, a possible presentation of aluminum allergy is axillary vault dermatitis secondary to antiperspirant use.⁴⁶ Another potential manifestation is a ringlike reaction to the Finn Chambers (SmartPractice) used in patch testing.⁴⁶ In one case of aluminum-induced axillary dermatitis, a 28-year-old woman presented with eczema of the axillae, and subsequent patch testing revealed an allergy to aluminum chloride. The rash resolved upon cessation of use of an aluminum-containing deodorant.⁴⁸

Aluminum has been reported to cause granulomatous dermatitis in the axillae. This reaction typically presents as red-brown, pruritic papules limited to the area in which deodorant was applied, with histopathology revealing epithelioid granulomas.^49-51

Alum deodorants—considered a natural alternative—contain aluminum bound to potassium or ammonium in the form of a crystal or powder. Alum crystal deodorants have been reported to cause both a typical erythematous pruritic dermatitis as well as a granulomatous dermatitis with red-brown papules.^52,53 The granulomatous dermatitis caused by either form of aluminum resolves with avoidance and use of topical steroids or topical tacrolimus.^49,50,52,53

The diagnosis of aluminum ACD via patch testing may be identified with empty Finn Chambers, which are metallic aluminum, or with patch placement of aluminum chloride hexahydrate, though the former is only positive in patients with a strong allergy.^54,55 In 2022, aluminum was named Allergen of the Year by the American Contact Dermatitis Society, with recommendations to conduct patch testing with aluminum chloride hexahydrate 10% rather than the traditional 2% to increase diagnostic yield.⁵⁵ Additionally, it is recommended that aluminum be included in baseline patch testing for children due to the high prevalence of aluminum allergy in children and early exposure via childhood vaccines.^54-56 In patients with aluminum allergy, providers may suggest purchasing aluminum-free deodorants or provide recipes for homemade deodorant that includes ingredients such as arrowroot powder, cornstarch, and diatomaceous earth.⁴⁶

Nickel—Nickel is the most commonly identified contact allergen on patch testing yet an infrequent cause of axillary dermatitis. A case report from 2014 described axillary dermatitis in a woman that worsened during a positive patch test to nickel. Improvement was noted when the patient switched to titanium shaving razors.⁵⁷ Nickel allergy also may present in the form of SCD. In one report, a woman developed dermatitis of the flexural areas, including the axillae, 3 months after undergoing a sterilization procedure in which nickel-containing tubal implants were placed.⁵⁸ Patch testing revealed a positive reaction to nickel. The patient experienced complete resolution of the steroid-resistant dermatitis following removal of the implants via salpingectomy.⁵⁸

Textile Dye—In contrast to dermatitis caused by deodorants/antiperspirants, contact allergy to textile dyes presents as dermatitis involving the axillary borders but sparing the axillary vaults (Figures 2 and 3).¹⁰ Other potential presentations of textile dye dermatitis include erythema multiforme–like eruptions and erythematous wheal–type reactions.⁵⁹ Textile dyes are classified as disperse vs nondisperse, with the majority of contact dermatoses caused by disperse dyes, specifically Disperse Orange 1, blue 106, and blue 124.^60-62 Ryberg et al⁶¹ found that the axilla is one of the more common locations to be affected by textile dye allergy, particularly in women, which was further supported by Seidenari et al,⁶³ who found that skin folds were affected in 27% of study participants allergic to textile dyes (N=437), a finding that is likely due to friction, sweat, and occlusion.⁶² In one case report of a patient with dermatitis caused by reactive dyes, the garment required 3 washes before the patient experienced resolution of dermatitis.⁶⁴ For patients with textile dye dermatitis, mitigation strategies include washing clothing before wearing, especially for darkly dyed items; avoiding tight clothing; wearing garments made of cotton, wool, silk, or linen; and choosing light-colored garments.^9,64,65

Axillary Dermatitis as a Manifestation of SCD and SDRIFE

Systemic contact dermatitis occurs when an individual who was previously sensitized to a particular allergen develops ACD of the skin with systemic exposure to that allergen or immunochemically related allergens. Exposure may occur via ingestion, inhalation, intravenous, intramuscular, and transepidermal routes.⁶⁶ Systemic contact dermatitis manifests in a variety of ways, including focal flares at sites of prior contact dermatitis (recall reaction), vesicular hand dermatitis, intertriginous eruptions including axillary dermatitis, and generalized eruptions.⁶⁷

Systemic contact dermatitis rarely involves systemic symptoms, and onset typically is within days of exposure. The 3 most common groups of allergens causing SCD are metals, medications, and plants and herbals.⁶⁸ These allergens have all been reported to cause axillary dermatitis via SCD.^58,69,70 Foods containing balsam of Peru that may lead to SCD include citrus, chocolate, tomato, and certain alcohols.^70,71 Patients with a positive patch test to balsam of Peru may experience improvement of their dermatitis after reduction of balsam of Peru–rich foods from their diet.⁷⁰ Metals implicated in SCD include mercury, nickel, and gold.^72-74 Finally, PG ingestion also has been implicated in cases of SCD.³⁷

Symmetrical drug-related intertriginous and flexural exanthema is another condition that presents as intertriginous dermatitis and differs from SCD in that the eruption does not require presensitization; there may be no known prior exposure to the agent causing dermatitis. Historically, SDRIFE was described as baboon syndrome because of its frequent involvement of the buttocks with diffuse, well-demarcated, erythematous dermatitis resembling that of a baboon. This term is no longer used due to its insensitive nature and incomplete depiction of SDRIFE, which can affect body sites other than the buttocks.^68,75,76 Specific criteria to make this diagnosis include sharply demarcated and/or V-shaped erythema of the gluteal/perianal area, involvement of at least 1 other intertriginous or flexural region, symmetry of affected areas, and an absence of systemic symptoms.⁷⁶ There also may be papules, pustules, and vesicles present in affected areas. Symmetrical drug-related intertriginous and flexural exanthema most often is caused by β-lactam antibiotics, but other associated drugs include chemotherapeutic agents, such as mitomycin C.⁷⁶

Histopathology of both SCD and SDRIFE is variable and typically nonspecific, often revealing epidermal spongiosis and a perivascular mononuclear cell infiltrate with occasional neutrophils and eosinophils.⁷⁶ A case of SCD to mercury presenting as intertriginous dermatitis demonstrated a leukocytoclastic vasculitis pattern on biopsy.⁷⁷

Systemic contact dermatitis is diagnosed via a patch test, while SDRIFE typically has a negative patch test result and requires oral rechallenge testing, which reproduces the rash within hours.^78,79

Additional Allergens Causing Axillary ACD

Although fragrance is the most common allergen in deodorants, other ingredients have been shown to cause axillary ACD (Table).^80-90 In addition to these ingredients, allergens not previously mentioned that may be present in deodorants include lanolin, essential oils, and parabens.¹¹ Methylisothiazolinone in laundry detergent also has been found to instigate ACD.⁹¹ Fragrances and preservatives in laundry detergents also may contribute to dermatitis.⁹²

Other products that have caused axillary contact dermatitis include topical exposure to medicaments including clindamycin,⁹³ ethylenediamine in nystatin cream,⁹⁴ methylprednisolone acetate⁹⁵ and dipropylene glycol in a hydrocortisone lotion,⁹⁶ wood dusts from tropical hardwoods,⁹⁷ and tobacco.⁹⁸

Management of ACD

The most effective strategy in the management of patients with contact dermatitis is avoidance of the offending agent. Additionally, clinicians may recommend the use of topical steroids and/or calcineurin inhibitors to hasten resolution.²

For patients with contact dermatitis, a clinician may recommend product substitutions with few potential allergens to use prior to patch testing. Patients with a fragrance allergy should look for products specifically labeled as “fragrance free” rather than “hypoallergenic” or “unscented,” as the latter two may still contain minimal amounts of fragrance.³⁵ Patients should be educated on the functions of the allergens to which they are allergic so they may adequately avoid potential sources of contact.⁹⁹ For suspected textile dye dermatitis, instructing patients to wash clothing before wearing and to avoid synthetic fabrics, dark dyes, and tightly fitted clothing may help.^9,64,65

The differential diagnosis for axillary lesions is broad, including infectious, inflammatory, and autoimmune etiologies. Irritant contact dermatitis (ICD) presents similar to ACD, though it is more immediate in onsetand typically demonstrates symptoms of burning and stinging rather than pruritus. Although histopathology is not reliable in differentiating ICD and ACD, it has been shown that focal parakeratosis is associated with ACD, whereas necrotic epidermal keratinocytes are found in ICD.¹⁰⁰

Intertrigo presents as large, erythematous, opposing patches or plaques confined to inguinal, submammary, axillary, and/or abdominal folds. Findings of beefy red erythema and peripheral satellite pustules may implicate presence of Candida, which can be identified with potassium hydroxide preparations.

Inverse psoriasis presents as sharply demarcated, erythematous, moist, smooth plaques or patches with minimal scale. The most common area of involvement is the inguinal folds, followed by the axillae, inframammary folds, perianal area, umbilicus, and retroauricular areas. Involvement of the elbows and knees or a positive family history of psoriasis may be useful knowledge in establishing the diagnosis. A biopsy may show dermal eosinophils, epidermal spongiosis, and focal serum in the scale, in addition to features of typical psoriasis plaques.¹⁰¹

Seborrheic dermatitis typically is an erythematous eruption, often with yellowish greasy scale. Simultaneous involvement of the face and scalp may be noted. Although typically a clinical diagnosis, biopsy demonstrates shoulder parakeratosis with follicular plugging and lymphocytic exocytosis.

Hailey-Hailey disease (also called benign familial pemphigus) is an autosomal-dominant genetic condition presenting as moist, malodorous, painful, vegetative plaques, patches, or scaly pustules in flexural areas, frequently with flaccid blisters. Lesions are provoked by traumatic stimuli. Onset occurs in the second to fourth decades and may improve with age. The diagnosis is confirmed by biopsy, which demonstrates acantholysis of the epidermis. The moist superficial patches of Hailey-Hailey disease help distinguish it from comparably drier Darier disease, the other acantholytic disease of the axillae.

Granular parakeratosis (also called hyperkeratotic flexural erythema) is an uncommon dermatosis most often observed in middle-aged women. It presents as red-brown keratotic papules coalescing into plaques, often with overlying scale in intertriginous areas. This disorder may be related to exposure to aluminum, a key component of antiperspirants.¹⁰² Diagnosis with a skin biopsy demonstrates granular parakeratosis.

Infections most commonly include erythrasma, tinea, and candidiasis. Erythrasma caused by Corynebacterium minutissimum may present in the axillae and/or groin with sharply demarcated, red-brown patches. Wood lamp examination reveals coral red fluorescence. Tinea corporis, a dermatophyte infection, may present as scaly erythematous plaques with advancing borders and central clearing. Fungal cultures and potassium hydroxide preparations are useful to confirm the diagnosis.

Pseudofolliculitis barbae most often is thought of as a condition affecting the beard in Black men, but it also may present in individuals of all races who shave the axillary and inguinal regions. Typical features include pruritic inflammatory papules and pustules with surrounding erythema and hyperpigmentation.

Fox-Fordyce disease is a disorder of the apocrine sweat glands that presents as several flesh-colored, perifollicular, monomorphic papules in the axillae. It typically is a disease of young females and also can involve the areola and vulva. Histopathology may show hyperkeratosis, irregular acanthosis, and dilated sweat glands.

Hidradenitis suppurativa is a chronic inflammatory condition that presents with multiple cysts; nodules; abscesses; sinus tract formation; and suppuration of the axillary, anogenital, and sometimes inframammary areas, typically at the onset of puberty. The diagnosis is best supported by history and physical examination, which may be notable for recurrent abscesses, draining tracts, double comedones, and ropelike scarring.

Extramammary Paget disease is a rare malignancy affecting apocrine gland–bearing areas, including axillary and genital regions. It most commonly presents as a unilateral or asymmetric, scaly, erythematous plaque. Histopathology demonstrates Paget cells with abundant clear cytoplasm and pleomorphic nuclei, typically grouped in the lower portion of the epidermis.

Final Thoughts

Axillary dermatoses often can be challenging to diagnose given the range of pathologies that can present in intertriginous areas. Allergic contact dermatitis is a common culprit due to unique anatomical considerations and self-care practices, including shaving/hair removal; use of deodorants, antiperspirants, bodywashes, and clothing; and frictional and moisture influences. The most likely offender among contact allergens is fragrance, but other possibilities to consider include PG, preservatives, aluminum, nickel, and textile dyes. Albeit less common, systemic exposure to allergens may result in SCD and SDRIFE with a rash in intertriginous zones, including the axillae. Additionally, other infectious, inflammatory, and autoimmune etiologies should be considered and ruled out.

Patch testing is the most reliable method to diagnose suspected ACD. Once confirmed, management includes the use of topical steroids and avoidance of the causative agent. Additionally, patients should be informed of the American Contact Dermatitis Society Contact Allergen Management Program (https://www.contactderm.org/patient-support/camp-access), which provides patients with useful information on products that are safe to use based on their patch testing results.