Cutis

Autoeczematization (AE), or id reaction, is a disseminated eczematous reaction that occurs days or weeks after exposure to a primary stimulus, resulting from a release of antigen(s). Whitfield¹ first described AE in 1921, when he postulated that the id reaction was due to sensitization of the skin after a primary stimulus. He called it “a form of auto-intoxication derived from changes in the patient’s own tissues.”¹ The exact prevalence of id reactions is unknown; one study showed that 17% of patients with dermatophyte infections developed an id reaction, typically tinea pedis linked with vesicles on the palms.² Tinea capitis is one of the most common causes of AE in children, which is frequently misdiagnosed as a drug reaction. Approximately 37% of patients diagnosed with stasis dermatitis develop an id reaction (Figure 1). A history of contact dermatitis is common in patients presenting with AE.^2-6

Pathophysiology of Id Reactions

An abnormal immune response against autologous skin antigens may be responsible for the development of AE. Shelley⁵ postulated that hair follicles play an important role in id reactions, as Sharquie et al⁶ recently emphasized for many skin disorders. The pathogenesis of AE is uncertain, but circulating T lymphocytes play a role in this reaction. Normally, T cells are activated by a release of antigens after a primary exposure to a stimulus. However, overactivation of these T cells induces autoimmune reactions such as AE.⁷ Activated T lymphocytes express HLA-DR and IL-2 receptor, markers elevated in the peripheral blood of patients undergoing id reactions. After treatment, the levels of activated T lymphocytes decline. An increase in the number of CD25⁺ T cells and a decrease in the number of suppressor T cells in the blood may occur during an id reaction.^7-9 Keratinocytes produce proinflammatory cytokines, such as thymic stromal erythropoietin, IL-25, and IL-33, that activate T cells.^10-12 Therefore, the most likely pathogenesis of an id reaction is that T lymphocytes are activated at the primary reaction site due to proinflammatory cytokines released by keratinocytes. These activated T cells then travel systemically via hematogenous dissemination. The spread of activated T lymphocytes produces an eczematous reaction at secondary locations distant to the primary site.⁹

Clinical and Histopathological Features of Id Reactions

Clinically, AE is first evident as a vesicular dissemination that groups to form papules or nummular patches and usually is present on the legs, feet, arms, and/or trunk (Figure 2). The primary dermatitis is localized to the area that was the site of contact to the offending stimuli. This localized eczematous eruption begins with an acute or subacute onset. It has the appearance of small crusted vesicles with erythema (Figure 1). The first sign of AE is vesicles presenting near the primary site on flexural surfaces or on the hands and feet. A classic example is tinea pedis linked with vesicles on the palms and sides of the fingers, resembling dyshidrotic eczema. Sites of prior cutaneous trauma, such as dermatoses, scars, and burns, are common locations for early AE. In later stages, vesicles disseminate to the legs, arms, and trunk, where they group to form papules and nummular patches in a symmetrical pattern.^5,13-15 These lesions may be extremely pruritic. The pruritus may be so intense that it interrupts daily activities and disrupts the ability to fall or stay asleep.¹⁶

Histologically, biopsy specimens show psoriasiform spongiotic dermatitis with mononuclear cells contained in the vesicles. Interstitial edema and perivascular lymphohistiocytic infiltrates are evident. Eosinophils also may be present. This pattern is not unique toid reactions.^17-19 Although AE is a reaction pattern that may be due to a fungal or bacterial infection, the etiologic agent is not evident microscopically within the eczema itself.

Etiology of Id Reactions

Id reactions most commonly occur from either stasis dermatitis or tinea pedis, although a wide variety of other causes should be considered. Evaluation of the primary site rather than the id reaction may identify an infectious or parasitic agent. Sometimes the AE reaction is specifically named: dermatophytid with dermatophytosis, bacterid with a bacterial infectious process, and tuberculid with tuberculosis. Similarly, there may be reactions to underlying candidiasis, sporotrichosis, histoplasmosis, and other fungal infections that can cause a cutaneous id reaction.^18,20-22Mycobacterium species, Pseudomonas, Staphylococcus, and Streptococcus are bacterial causes of AE.^15,23-26 Viral infections that can cause an id reaction are herpes simplex virus and molluscum contagiosum.^27-29 Scabies, leishmaniasis, and pediculosis capitis are parasitic infections that may be etiologic.^14,30,31 In addition, noninfectious stimuli besides stasis dermatitis that can produce id reactions include medications, topical creams, tattoo ink, sutures, radiotherapy, and dyshidrotic eczema. The primary reaction to these agents is a localized dermatitis followed by the immunological response that induces a secondary reaction distant from the primary site.^17,18,32-38

Differential Diagnoses

Differential diagnoses include other types of eczema and some vesicular eruptions. Irritant contact dermatitis is another dermatosis that presents as a widespread vesicular eruption due to repetitive exposure to toxic irritants. The rash is erythematous with pustules, blisters, and crusts. It is only found in areas directly exposed to irritants, as opposed to AE, which spreads to areas distant to the primary reaction site. Irritant contact dermatitis presents with more of a burning sensation, whereas AE is more pruritic.^39,40 Allergic contact dermatitis presents with erythematous vesicles and papules and sometimes with bullae. There is edema and crust formation, which often can spread past the point of contact in later stages. Similar to AE, there is intense pruritus. However, allergic contact dermatitis most commonly is caused by exposure to metals, cosmetics, and fragrances, whereas infectious agents and stasis dermatitis are the most common causes of AE.^40,41 It may be challenging to distinguish AE from other causes of widespread eczematous dissemination. Vesicular eruptions sometimes require distinction from AE, including herpetic infections, insect bite reactions, and drug eruptions.^18,42

Treatment

The underlying condition should be treated to mitigate the inflammatory response causing the id reaction. If not skillfully orchestrated, the id reaction can reoccur. For infectious causes of AE, an antifungal, antibacterial, antiviral, or antiparasitic should be given. If stasis dermatitis is responsible for the id reaction, compression stockings and leg elevation are indicated. The id reaction itself is treated with systemic or topical corticosteroids and wet compresses if acute. The goal of these treatments is to reduce patient discomfort caused by the inflammation and pruritus.^18,43

Conclusion

Id reactions are an unusual phenomenon that commonly occurs after fungal skin infections and stasis dermatitis. T lymphocytes and keratinocytes may play a key role in this reaction, with newer research further delineating the process and possibly providing enhanced treatment options. Therapy focuses on treating the underlying condition, supplemented with corticosteroids for the autoeczema.

Autoeczematization (AE), or id reaction, is a disseminated eczematous reaction that occurs days or weeks after exposure to a primary stimulus, resulting from a release of antigen(s). Whitfield¹ first described AE in 1921, when he postulated that the id reaction was due to sensitization of the skin after a primary stimulus. He called it “a form of auto-intoxication derived from changes in the patient’s own tissues.”¹ The exact prevalence of id reactions is unknown; one study showed that 17% of patients with dermatophyte infections developed an id reaction, typically tinea pedis linked with vesicles on the palms.² Tinea capitis is one of the most common causes of AE in children, which is frequently misdiagnosed as a drug reaction. Approximately 37% of patients diagnosed with stasis dermatitis develop an id reaction (Figure 1). A history of contact dermatitis is common in patients presenting with AE.^2-6

Pathophysiology of Id Reactions

An abnormal immune response against autologous skin antigens may be responsible for the development of AE. Shelley⁵ postulated that hair follicles play an important role in id reactions, as Sharquie et al⁶ recently emphasized for many skin disorders. The pathogenesis of AE is uncertain, but circulating T lymphocytes play a role in this reaction. Normally, T cells are activated by a release of antigens after a primary exposure to a stimulus. However, overactivation of these T cells induces autoimmune reactions such as AE.⁷ Activated T lymphocytes express HLA-DR and IL-2 receptor, markers elevated in the peripheral blood of patients undergoing id reactions. After treatment, the levels of activated T lymphocytes decline. An increase in the number of CD25⁺ T cells and a decrease in the number of suppressor T cells in the blood may occur during an id reaction.^7-9 Keratinocytes produce proinflammatory cytokines, such as thymic stromal erythropoietin, IL-25, and IL-33, that activate T cells.^10-12 Therefore, the most likely pathogenesis of an id reaction is that T lymphocytes are activated at the primary reaction site due to proinflammatory cytokines released by keratinocytes. These activated T cells then travel systemically via hematogenous dissemination. The spread of activated T lymphocytes produces an eczematous reaction at secondary locations distant to the primary site.⁹

Clinical and Histopathological Features of Id Reactions

Clinically, AE is first evident as a vesicular dissemination that groups to form papules or nummular patches and usually is present on the legs, feet, arms, and/or trunk (Figure 2). The primary dermatitis is localized to the area that was the site of contact to the offending stimuli. This localized eczematous eruption begins with an acute or subacute onset. It has the appearance of small crusted vesicles with erythema (Figure 1). The first sign of AE is vesicles presenting near the primary site on flexural surfaces or on the hands and feet. A classic example is tinea pedis linked with vesicles on the palms and sides of the fingers, resembling dyshidrotic eczema. Sites of prior cutaneous trauma, such as dermatoses, scars, and burns, are common locations for early AE. In later stages, vesicles disseminate to the legs, arms, and trunk, where they group to form papules and nummular patches in a symmetrical pattern.^5,13-15 These lesions may be extremely pruritic. The pruritus may be so intense that it interrupts daily activities and disrupts the ability to fall or stay asleep.¹⁶

Histologically, biopsy specimens show psoriasiform spongiotic dermatitis with mononuclear cells contained in the vesicles. Interstitial edema and perivascular lymphohistiocytic infiltrates are evident. Eosinophils also may be present. This pattern is not unique toid reactions.^17-19 Although AE is a reaction pattern that may be due to a fungal or bacterial infection, the etiologic agent is not evident microscopically within the eczema itself.

Etiology of Id Reactions

Id reactions most commonly occur from either stasis dermatitis or tinea pedis, although a wide variety of other causes should be considered. Evaluation of the primary site rather than the id reaction may identify an infectious or parasitic agent. Sometimes the AE reaction is specifically named: dermatophytid with dermatophytosis, bacterid with a bacterial infectious process, and tuberculid with tuberculosis. Similarly, there may be reactions to underlying candidiasis, sporotrichosis, histoplasmosis, and other fungal infections that can cause a cutaneous id reaction.^18,20-22Mycobacterium species, Pseudomonas, Staphylococcus, and Streptococcus are bacterial causes of AE.^15,23-26 Viral infections that can cause an id reaction are herpes simplex virus and molluscum contagiosum.^27-29 Scabies, leishmaniasis, and pediculosis capitis are parasitic infections that may be etiologic.^14,30,31 In addition, noninfectious stimuli besides stasis dermatitis that can produce id reactions include medications, topical creams, tattoo ink, sutures, radiotherapy, and dyshidrotic eczema. The primary reaction to these agents is a localized dermatitis followed by the immunological response that induces a secondary reaction distant from the primary site.^17,18,32-38

Differential Diagnoses

Differential diagnoses include other types of eczema and some vesicular eruptions. Irritant contact dermatitis is another dermatosis that presents as a widespread vesicular eruption due to repetitive exposure to toxic irritants. The rash is erythematous with pustules, blisters, and crusts. It is only found in areas directly exposed to irritants, as opposed to AE, which spreads to areas distant to the primary reaction site. Irritant contact dermatitis presents with more of a burning sensation, whereas AE is more pruritic.^39,40 Allergic contact dermatitis presents with erythematous vesicles and papules and sometimes with bullae. There is edema and crust formation, which often can spread past the point of contact in later stages. Similar to AE, there is intense pruritus. However, allergic contact dermatitis most commonly is caused by exposure to metals, cosmetics, and fragrances, whereas infectious agents and stasis dermatitis are the most common causes of AE.^40,41 It may be challenging to distinguish AE from other causes of widespread eczematous dissemination. Vesicular eruptions sometimes require distinction from AE, including herpetic infections, insect bite reactions, and drug eruptions.^18,42

Treatment

The underlying condition should be treated to mitigate the inflammatory response causing the id reaction. If not skillfully orchestrated, the id reaction can reoccur. For infectious causes of AE, an antifungal, antibacterial, antiviral, or antiparasitic should be given. If stasis dermatitis is responsible for the id reaction, compression stockings and leg elevation are indicated. The id reaction itself is treated with systemic or topical corticosteroids and wet compresses if acute. The goal of these treatments is to reduce patient discomfort caused by the inflammation and pruritus.^18,43

Conclusion

Id reactions are an unusual phenomenon that commonly occurs after fungal skin infections and stasis dermatitis. T lymphocytes and keratinocytes may play a key role in this reaction, with newer research further delineating the process and possibly providing enhanced treatment options. Therapy focuses on treating the underlying condition, supplemented with corticosteroids for the autoeczema.

Autoeczematization (AE), or id reaction, is a disseminated eczematous reaction that occurs days or weeks after exposure to a primary stimulus, resulting from a release of antigen(s). Whitfield¹ first described AE in 1921, when he postulated that the id reaction was due to sensitization of the skin after a primary stimulus. He called it “a form of auto-intoxication derived from changes in the patient’s own tissues.”¹ The exact prevalence of id reactions is unknown; one study showed that 17% of patients with dermatophyte infections developed an id reaction, typically tinea pedis linked with vesicles on the palms.² Tinea capitis is one of the most common causes of AE in children, which is frequently misdiagnosed as a drug reaction. Approximately 37% of patients diagnosed with stasis dermatitis develop an id reaction (Figure 1). A history of contact dermatitis is common in patients presenting with AE.^2-6

Pathophysiology of Id Reactions

An abnormal immune response against autologous skin antigens may be responsible for the development of AE. Shelley⁵ postulated that hair follicles play an important role in id reactions, as Sharquie et al⁶ recently emphasized for many skin disorders. The pathogenesis of AE is uncertain, but circulating T lymphocytes play a role in this reaction. Normally, T cells are activated by a release of antigens after a primary exposure to a stimulus. However, overactivation of these T cells induces autoimmune reactions such as AE.⁷ Activated T lymphocytes express HLA-DR and IL-2 receptor, markers elevated in the peripheral blood of patients undergoing id reactions. After treatment, the levels of activated T lymphocytes decline. An increase in the number of CD25⁺ T cells and a decrease in the number of suppressor T cells in the blood may occur during an id reaction.^7-9 Keratinocytes produce proinflammatory cytokines, such as thymic stromal erythropoietin, IL-25, and IL-33, that activate T cells.^10-12 Therefore, the most likely pathogenesis of an id reaction is that T lymphocytes are activated at the primary reaction site due to proinflammatory cytokines released by keratinocytes. These activated T cells then travel systemically via hematogenous dissemination. The spread of activated T lymphocytes produces an eczematous reaction at secondary locations distant to the primary site.⁹

Clinical and Histopathological Features of Id Reactions

Clinically, AE is first evident as a vesicular dissemination that groups to form papules or nummular patches and usually is present on the legs, feet, arms, and/or trunk (Figure 2). The primary dermatitis is localized to the area that was the site of contact to the offending stimuli. This localized eczematous eruption begins with an acute or subacute onset. It has the appearance of small crusted vesicles with erythema (Figure 1). The first sign of AE is vesicles presenting near the primary site on flexural surfaces or on the hands and feet. A classic example is tinea pedis linked with vesicles on the palms and sides of the fingers, resembling dyshidrotic eczema. Sites of prior cutaneous trauma, such as dermatoses, scars, and burns, are common locations for early AE. In later stages, vesicles disseminate to the legs, arms, and trunk, where they group to form papules and nummular patches in a symmetrical pattern.^5,13-15 These lesions may be extremely pruritic. The pruritus may be so intense that it interrupts daily activities and disrupts the ability to fall or stay asleep.¹⁶

Histologically, biopsy specimens show psoriasiform spongiotic dermatitis with mononuclear cells contained in the vesicles. Interstitial edema and perivascular lymphohistiocytic infiltrates are evident. Eosinophils also may be present. This pattern is not unique toid reactions.^17-19 Although AE is a reaction pattern that may be due to a fungal or bacterial infection, the etiologic agent is not evident microscopically within the eczema itself.

Etiology of Id Reactions

Id reactions most commonly occur from either stasis dermatitis or tinea pedis, although a wide variety of other causes should be considered. Evaluation of the primary site rather than the id reaction may identify an infectious or parasitic agent. Sometimes the AE reaction is specifically named: dermatophytid with dermatophytosis, bacterid with a bacterial infectious process, and tuberculid with tuberculosis. Similarly, there may be reactions to underlying candidiasis, sporotrichosis, histoplasmosis, and other fungal infections that can cause a cutaneous id reaction.^18,20-22Mycobacterium species, Pseudomonas, Staphylococcus, and Streptococcus are bacterial causes of AE.^15,23-26 Viral infections that can cause an id reaction are herpes simplex virus and molluscum contagiosum.^27-29 Scabies, leishmaniasis, and pediculosis capitis are parasitic infections that may be etiologic.^14,30,31 In addition, noninfectious stimuli besides stasis dermatitis that can produce id reactions include medications, topical creams, tattoo ink, sutures, radiotherapy, and dyshidrotic eczema. The primary reaction to these agents is a localized dermatitis followed by the immunological response that induces a secondary reaction distant from the primary site.^17,18,32-38

Differential Diagnoses

Differential diagnoses include other types of eczema and some vesicular eruptions. Irritant contact dermatitis is another dermatosis that presents as a widespread vesicular eruption due to repetitive exposure to toxic irritants. The rash is erythematous with pustules, blisters, and crusts. It is only found in areas directly exposed to irritants, as opposed to AE, which spreads to areas distant to the primary reaction site. Irritant contact dermatitis presents with more of a burning sensation, whereas AE is more pruritic.^39,40 Allergic contact dermatitis presents with erythematous vesicles and papules and sometimes with bullae. There is edema and crust formation, which often can spread past the point of contact in later stages. Similar to AE, there is intense pruritus. However, allergic contact dermatitis most commonly is caused by exposure to metals, cosmetics, and fragrances, whereas infectious agents and stasis dermatitis are the most common causes of AE.^40,41 It may be challenging to distinguish AE from other causes of widespread eczematous dissemination. Vesicular eruptions sometimes require distinction from AE, including herpetic infections, insect bite reactions, and drug eruptions.^18,42

Treatment

The underlying condition should be treated to mitigate the inflammatory response causing the id reaction. If not skillfully orchestrated, the id reaction can reoccur. For infectious causes of AE, an antifungal, antibacterial, antiviral, or antiparasitic should be given. If stasis dermatitis is responsible for the id reaction, compression stockings and leg elevation are indicated. The id reaction itself is treated with systemic or topical corticosteroids and wet compresses if acute. The goal of these treatments is to reduce patient discomfort caused by the inflammation and pruritus.^18,43

Conclusion

Id reactions are an unusual phenomenon that commonly occurs after fungal skin infections and stasis dermatitis. T lymphocytes and keratinocytes may play a key role in this reaction, with newer research further delineating the process and possibly providing enhanced treatment options. Therapy focuses on treating the underlying condition, supplemented with corticosteroids for the autoeczema.

To the Editor:

Oral immunosuppressive therapies are prescribed for moderate to severe atopic dermatitis. Patients often consult YouTube to make informed decisions about these therapies. In the United States, most health-related online searches are initiated through a search engine, which frequently leads to social media sites such as YouTube. Recent studies have examined the reasons why users turn to the Internet for health-related information, indicating that users typically seek specific information regarding health concerns.^1,2 Furthermore, social media platforms such as YouTube are a popular means of sharing health information with the public.^3-5 Currently, YouTube has more than 1 billion registered users, and 30 million health-related videos are watched each day.⁶ Almost one-third of US consumers use YouTube, Facebook, and Twitter to obtain medical information.⁷ YouTube is a versatile tool because of its video-discovery mechanisms such as a keyword-based search engine, video-recommendation system, highlight feature for videos on home pages, and the capacity to embed YouTube videos on various web pages.⁸ Searchers use videos that are short, fast paced, emotion evoking, from credible sources, recently uploaded, and relevant to the searcher for aiding in health decisions.⁹ Furthermore, studies have demonstrated YouTube’s capacity to support a change in attitude and increase users’ knowledge. In fact, YouTube had higher impact on recall, attitudes, and behaviors when compared with written materials on other social media platforms, such as Facebook and Twitter.⁹ We conducted a cross-sectional study to examine the quality of YouTube videos on oral therapies for atopic dermatitis, such as cyclosporine, methotrexate, azathioprine, and mycophenolate mofetil.

On April 23, 2020, we performed 8 searches using a private browser with default filters on YouTube (Figure). Injectables were not included in the analysis, as the YouTube experience on dupilumab previously has been investigated.¹⁰ The top 40 videos from each search were screened by 3 researchers. Duplicates, non–English-language videos, and videos that did not discuss atopic dermatitis or oral therapies were excluded, resulting in 73 videos included in this analysis. Testimonials generated by patients made up 39 of 73 (53.4%) videos. Health care professionals created 23 of 73 (31.5%) videos, and educators with financial interest created 11 of 73 (15.1%) videos. The dates of production for the videos spanned from 2008 to 2020.

Importantly, this analysis is limited by its lack of quality-assessment tools for video-based resources such as JAMA score and DISCERN score.^14,15 However, these metrics have limited ability to evaluate audiovisual elements, indicating the need for novel tools to score their validity.

To the Editor:

Oral immunosuppressive therapies are prescribed for moderate to severe atopic dermatitis. Patients often consult YouTube to make informed decisions about these therapies. In the United States, most health-related online searches are initiated through a search engine, which frequently leads to social media sites such as YouTube. Recent studies have examined the reasons why users turn to the Internet for health-related information, indicating that users typically seek specific information regarding health concerns.^1,2 Furthermore, social media platforms such as YouTube are a popular means of sharing health information with the public.^3-5 Currently, YouTube has more than 1 billion registered users, and 30 million health-related videos are watched each day.⁶ Almost one-third of US consumers use YouTube, Facebook, and Twitter to obtain medical information.⁷ YouTube is a versatile tool because of its video-discovery mechanisms such as a keyword-based search engine, video-recommendation system, highlight feature for videos on home pages, and the capacity to embed YouTube videos on various web pages.⁸ Searchers use videos that are short, fast paced, emotion evoking, from credible sources, recently uploaded, and relevant to the searcher for aiding in health decisions.⁹ Furthermore, studies have demonstrated YouTube’s capacity to support a change in attitude and increase users’ knowledge. In fact, YouTube had higher impact on recall, attitudes, and behaviors when compared with written materials on other social media platforms, such as Facebook and Twitter.⁹ We conducted a cross-sectional study to examine the quality of YouTube videos on oral therapies for atopic dermatitis, such as cyclosporine, methotrexate, azathioprine, and mycophenolate mofetil.

On April 23, 2020, we performed 8 searches using a private browser with default filters on YouTube (Figure). Injectables were not included in the analysis, as the YouTube experience on dupilumab previously has been investigated.¹⁰ The top 40 videos from each search were screened by 3 researchers. Duplicates, non–English-language videos, and videos that did not discuss atopic dermatitis or oral therapies were excluded, resulting in 73 videos included in this analysis. Testimonials generated by patients made up 39 of 73 (53.4%) videos. Health care professionals created 23 of 73 (31.5%) videos, and educators with financial interest created 11 of 73 (15.1%) videos. The dates of production for the videos spanned from 2008 to 2020.

Importantly, this analysis is limited by its lack of quality-assessment tools for video-based resources such as JAMA score and DISCERN score.^14,15 However, these metrics have limited ability to evaluate audiovisual elements, indicating the need for novel tools to score their validity.

To the Editor:

Oral immunosuppressive therapies are prescribed for moderate to severe atopic dermatitis. Patients often consult YouTube to make informed decisions about these therapies. In the United States, most health-related online searches are initiated through a search engine, which frequently leads to social media sites such as YouTube. Recent studies have examined the reasons why users turn to the Internet for health-related information, indicating that users typically seek specific information regarding health concerns.^1,2 Furthermore, social media platforms such as YouTube are a popular means of sharing health information with the public.^3-5 Currently, YouTube has more than 1 billion registered users, and 30 million health-related videos are watched each day.⁶ Almost one-third of US consumers use YouTube, Facebook, and Twitter to obtain medical information.⁷ YouTube is a versatile tool because of its video-discovery mechanisms such as a keyword-based search engine, video-recommendation system, highlight feature for videos on home pages, and the capacity to embed YouTube videos on various web pages.⁸ Searchers use videos that are short, fast paced, emotion evoking, from credible sources, recently uploaded, and relevant to the searcher for aiding in health decisions.⁹ Furthermore, studies have demonstrated YouTube’s capacity to support a change in attitude and increase users’ knowledge. In fact, YouTube had higher impact on recall, attitudes, and behaviors when compared with written materials on other social media platforms, such as Facebook and Twitter.⁹ We conducted a cross-sectional study to examine the quality of YouTube videos on oral therapies for atopic dermatitis, such as cyclosporine, methotrexate, azathioprine, and mycophenolate mofetil.

On April 23, 2020, we performed 8 searches using a private browser with default filters on YouTube (Figure). Injectables were not included in the analysis, as the YouTube experience on dupilumab previously has been investigated.¹⁰ The top 40 videos from each search were screened by 3 researchers. Duplicates, non–English-language videos, and videos that did not discuss atopic dermatitis or oral therapies were excluded, resulting in 73 videos included in this analysis. Testimonials generated by patients made up 39 of 73 (53.4%) videos. Health care professionals created 23 of 73 (31.5%) videos, and educators with financial interest created 11 of 73 (15.1%) videos. The dates of production for the videos spanned from 2008 to 2020.

Importantly, this analysis is limited by its lack of quality-assessment tools for video-based resources such as JAMA score and DISCERN score.^14,15 However, these metrics have limited ability to evaluate audiovisual elements, indicating the need for novel tools to score their validity.

To the Editor:

Atopic dermatitis (eczema) affects approximately 20% of children worldwide.¹ In atopic dermatitis management, patient education is crucial for optimal outcomes.² The COVID-19 pandemic has impacted patient-physician interactions. To ensure safety of patients and physicians, visits may have been canceled, postponed, or conducted virtually, leaving less time for discussion and questions.³ As a consequence, patients may seek information about atopic dermatitis from alternative sources, including YouTube videos. We performed a cross-sectional study to analyze YouTube videos about topical treatments for atopic dermatitis.

During the week of July 16, 2020, we performed 4 private browser YouTube searches with default filters using the following terms: eczema topicals, eczema topical treatments, atopic dermatitis topicals, and atopic dermatitis topical treatments. For video selection, we defined topical treatments as topical corticosteroids, topical calcineurin inhibitors, crisaborole, emollients, wet wraps, and any prospective treatment topically administered. For each of the 4 searches, 2 researchers (A.M. and A.T.) independently examined the top 75 videos, yielding a total of 300 videos. Of them, 98 videos were duplicates, 19 videos were not about atopic dermatitis, and 91 videos were not about topical treatments, leaving a total of 92 videos for analysis (Figure 1).

Although less popular, professional source videos had a significantly higher DISCERN overall quality rating score (question 16) compared to those categorized as nonprofessional source (3.92 vs 1.53; P<.001). In contrast, nonprofessional source videos scored significantly higher on the quality-of-life question (question 13) compared to professional source videos (3.90 vs 2.56; P<.001)(eTable). (Three professional source videos were removed from YouTube before DISCERN scores could be assigned.)

To the Editor:

Atopic dermatitis (eczema) affects approximately 20% of children worldwide.¹ In atopic dermatitis management, patient education is crucial for optimal outcomes.² The COVID-19 pandemic has impacted patient-physician interactions. To ensure safety of patients and physicians, visits may have been canceled, postponed, or conducted virtually, leaving less time for discussion and questions.³ As a consequence, patients may seek information about atopic dermatitis from alternative sources, including YouTube videos. We performed a cross-sectional study to analyze YouTube videos about topical treatments for atopic dermatitis.

During the week of July 16, 2020, we performed 4 private browser YouTube searches with default filters using the following terms: eczema topicals, eczema topical treatments, atopic dermatitis topicals, and atopic dermatitis topical treatments. For video selection, we defined topical treatments as topical corticosteroids, topical calcineurin inhibitors, crisaborole, emollients, wet wraps, and any prospective treatment topically administered. For each of the 4 searches, 2 researchers (A.M. and A.T.) independently examined the top 75 videos, yielding a total of 300 videos. Of them, 98 videos were duplicates, 19 videos were not about atopic dermatitis, and 91 videos were not about topical treatments, leaving a total of 92 videos for analysis (Figure 1).

Although less popular, professional source videos had a significantly higher DISCERN overall quality rating score (question 16) compared to those categorized as nonprofessional source (3.92 vs 1.53; P<.001). In contrast, nonprofessional source videos scored significantly higher on the quality-of-life question (question 13) compared to professional source videos (3.90 vs 2.56; P<.001)(eTable). (Three professional source videos were removed from YouTube before DISCERN scores could be assigned.)

To the Editor:

Atopic dermatitis (eczema) affects approximately 20% of children worldwide.¹ In atopic dermatitis management, patient education is crucial for optimal outcomes.² The COVID-19 pandemic has impacted patient-physician interactions. To ensure safety of patients and physicians, visits may have been canceled, postponed, or conducted virtually, leaving less time for discussion and questions.³ As a consequence, patients may seek information about atopic dermatitis from alternative sources, including YouTube videos. We performed a cross-sectional study to analyze YouTube videos about topical treatments for atopic dermatitis.

During the week of July 16, 2020, we performed 4 private browser YouTube searches with default filters using the following terms: eczema topicals, eczema topical treatments, atopic dermatitis topicals, and atopic dermatitis topical treatments. For video selection, we defined topical treatments as topical corticosteroids, topical calcineurin inhibitors, crisaborole, emollients, wet wraps, and any prospective treatment topically administered. For each of the 4 searches, 2 researchers (A.M. and A.T.) independently examined the top 75 videos, yielding a total of 300 videos. Of them, 98 videos were duplicates, 19 videos were not about atopic dermatitis, and 91 videos were not about topical treatments, leaving a total of 92 videos for analysis (Figure 1).

Although less popular, professional source videos had a significantly higher DISCERN overall quality rating score (question 16) compared to those categorized as nonprofessional source (3.92 vs 1.53; P<.001). In contrast, nonprofessional source videos scored significantly higher on the quality-of-life question (question 13) compared to professional source videos (3.90 vs 2.56; P<.001)(eTable). (Three professional source videos were removed from YouTube before DISCERN scores could be assigned.)

Plants can contribute to a variety of dermatoses. The Toxicodendron genus, which includes poison ivy, poison oak, and poison sumac, is a well-known and common cause of allergic contact dermatitis (ACD), but many other plants can cause direct or airborne contact dermatitis, especially in gardeners, florists, and farmers. This article provides an overview of different plant-related dermatoses and culprit plants as well as how these dermatoses should be diagnosed and treated.

Epidemiology

Plant dermatoses affect more than 50 million individuals each year.^1,2 In the United States, the Toxicodendron genus causes ACD in more than 70% of exposed individuals, leading to medical visits.³ An urgent care visit for a plant-related dermatitis is estimated to cost $168, while an emergency department visit can cost 3 times as much.⁴ Although less common, Compositae plants are another important culprit of plant dermatitis, particularly in gardeners, florists, and farmers. Data from the 2017-2018 North American Contact Dermatitis Group screening series (N=4947) showed sesquiterpene lactones and Compositae to be positive in 0.5% of patch-tested patients.⁵

Plant Dermatitis Classifications

Plant dermatitis can be classified into 5 main categories: ACD, mechanical irritant contact dermatitis, chemical irritant contact dermatitis, light-mediated dermatitis, and pseudophytodermatitis.⁶

Allergic contact dermatitis is an immune-mediated type IV delayed hypersensitivity reaction. The common molecular allergens in plants include phenols, α-methylene-γ-butyrolactones, quinones, terpenes, disulfides, isothiocyanates, and polyacetylenic derivatives.⁶

Plant contact dermatitis due to mechanical and chemical irritants is precipitated by multiple mechanisms, including disruption of the epidermal barrier and subsequent cytokine release from keratinocytes.⁷ Nonimmunologic contact urticaria from plants is thought to be a type of irritant reaction precipitated by mechanical or chemical trauma.⁸

Light-mediated dermatitis includes phytophotodermatitis and photoallergic contact dermatitis. Phytophotodermatitis is a phototoxic reaction triggered by exposure to both plant-derived furanocoumarin and UVA light.⁹ By contrast, photoallergic contact dermatitis is a delayed hypersensitivity reaction from prior sensitization to a light-activated antigen.¹⁰

Pseudophytodermatitis, as its name implies, is not truly mediated by an allergen or irritant intrinsic to the plant but rather by dyes, waxes, insecticides, or arthropods that inhabit the plant or are secondarily applied.⁶

Common Plant Allergens

Anacardiaceae Family
Most of the allergenic plants within the Anacardiaceae family belong to the Toxicodendron genus, which encompasses poison ivy (Toxicodendron radicans), poison oak (Toxicodendron pubescens,Toxicodendron quercifolium, Toxicodendron diversiloum), and poison sumac (Toxicodendron vernix). Poison ivy is the celebrity of the Anacardiaceae family and contributes to most cases of plant-related ACD. It is found in every state in the continental United States. Poison oak is another common culprit found in the western and southeastern United States.¹¹ Plants within the Anacardiaceae family contain an oleoresin called urushiol, which is the primary sensitizing substance. Although poison ivy and poison oak grow well in full sun to partial shade, poison sumac typically is found in damp swampy areas east of the Rocky Mountains. Most cases of ACD related to Anacardiaceae species are due to direct contact with urushiol from a Toxicodendron plant, but burning of brush containing Toxicodendron can cause airborne exposure when urushiol oil is carried by smoke particles.¹² Sensitization to Toxicodendron can cause ACD to other Anacardiaceae species such as the Japanese lacquer tree (Toxicodendron vernicifluum), mango tree (Mangifera indica), cashew tree (Anacardium occidentale), and Indian marking nut tree (Semecarpus anacardium).⁶ Cross-reactions to components of the ginkgo tree (Ginkgo biloba) also are possible.

Toxicodendron plants can be more easily identified and avoided with knowledge of their characteristic leaf patterns. The most dependable way to identify poison ivy and poison oak species is to look for plants with 3 leaves, giving rise to the common saying, “Leaves of three, leave them be.” Poison sumac plants have groups of 7 to 13 leaves arranged as pairs along a central rib. Another helpful finding is a black deposit that Toxicodendron species leave behind following trauma to the leaves. Urushiol oxidizes when exposed to air and turns into a black deposit that can be seen on damaged leaves themselves or can be demonstrated in a black spot test to verify if a plant is a Toxicodendron species. The test is performed by gathering (carefully, without direct contact) a few leaves in a paper towel and crushing them to release sap. Within minutes, the sap will turn black if the plant is indeed a Toxicodendron species.¹³Pruritic, edematous, erythematous papules, plaques, and eventual vesicles in a linear distribution are suspicious for Toxicodendron exposure. Although your pet will not develop Toxicodendron ACD, oleoresin-contaminated pets can transfer the oils to their owners after coming into contact with these plants. Toxicodendron dermatitis also can be acquired from oleoresin-contaminated fomites such as clothing and shoes worn in the garden or when hiking. Toxicodendron dermatitis can appear at different sites on the body at different times depending on the amount of oleoresin exposure as well as epidermal thickness. For example, the oleoresin can be transferred from the hands to body areas with a thinner stratum corneum (eg, genitalia) and cause subsequent dermatitis.¹

Compositae Family
The Compositae family (also known as Asteraceae) is a large plant family with more than 20,000 species, including numerous weeds, wildflowers, and vegetables. The flowers, leaves, stems, and pollens of the Compositae family are coated by cyclic esters called sesquiterpene lactones. Mitchell and Dupuis¹⁴ showed that sesquiterpene lactones are the allergens responsible for ACD to various Compositae plants, including ragweed (Ambrosia), sneezeweed (Helenium), and chrysanthemums (Chrysanthemum). Common Compositae vegetables such as lettuce (Lactuca sativa) have been reported to cause ACD in chefs, grocery store produce handlers, gardeners, and even owners of lettuce-eating pet guinea pigs and turtles.¹⁵ Similarly, artichokes (Cynara scolymus) can cause ACD in gardeners.¹⁶ Exposure to Compositae species also has been implicated in photoallergic reactions, and studies have demonstrated that some patients with chronic actinic dermatitis also have positive patch test reactions to Compositae species and/or sesquiterpene lactones.^17,18

In addition to direct contact with Compositae plants, airborne exposure to sesquiterpene lactones can cause ACD.¹⁴ The pattern of airborne contact dermatitis typically involves exposed areas such as the eyelids, central face, and/or neck. The beak sign also can be a clue to airborne contact dermatitis, which involves dermatitis of the face that spares the nasal tip and/or nasal ridge. It is thought that the beak sign may result from increased sebaceous gland concentration on the nose, which prevents penetration of allergens and irritants.¹⁹ Unlike photoallergic contact dermatitis, which also can involve the face, airborne ACD frequently involves photoprotected areas such as the submandibular chin and the upper lip. Davies and Kersey²⁰ reported the case of a groundsman who was cutting grass with dandelions (Taraxacum officinale) and was found to have associated airborne ACD of the face, neck, and forearms due to Compositae allergy. In a different setting, the aromas of chamomile (Matricaria chamomilla) have been reported to cause airborne ACD in a tea drinker.²¹ Paulsen²² found that ingestion of chamomile tea can induce systemic ACD in sensitized individuals.

Alstroemeriaceae, Liliaceae, and Primulaceae
Florists are exposed to many plant species and have a high prevalence of ACD. Thiboutot et al²³ found that 15 of 57 (26%) floral workers experienced hand dermatitis that cleared with time away from work. The Peruvian lily (Alstroemeria, Alstroemeriaceae family), which contains tuliposide A, was found to be the leading cause of sensitization.²³ Tulips (Tulipa, Liliaceae family), as the flower name suggests, also contain tuliposide A, which along with mechanical irritation from the course tecta fibers on the bulbs lead to a dermatitis known as tulip fingers.^24,25 Poison primrose (Primula obconica, Primulaceae family), cultivated for its highly colorful flowers, contains the contact allergen primin.⁶ A common clinical presentation of ACD for any of these culprit flowers is localized dermatitis of the thumb and index finger in a florist or gardener.

Plants That Cause Irritant Reactions

Cactuses
Although the long spines of the Cactaceae family of cactuses is a warning for passersby, it is the small and nearly invisible barbed hairs (glochids) that inflict a more dramatic cutaneous reaction. The prickly pear cactus (Opuntia species) is a good example of such a plant, as its glochids cause mechanical irritation but also can become embedded in the skin and result in subcutaneous granulomas known as sabra dermatitis.²⁶

Stinging Nettle
The dermatologic term urticaria owes its namesake to the stinging nettle plant, which comes from the family Urticaceae. The stinging nettle has small hairs on its leaves, referred to as stinging trichomes, which have needlelike tips that pierce the skin and inject a mix of histamine, formic acid, and acetylcholine, causing a pruritic dermatitis that may last up to 12 hours.²⁷ The plant is found worldwide and is a common weed in North America.

Phytophotodermatitis

Lemons and limes (Rutaceae family) are common culprits of phytophotodermatitis, often causing what is known as a margarita burn after outdoor consumption or preparation of this tasty citrus beverage.²⁸ An accidental spray of lime juice on the skin while adding it to a beer, guacamole, salsa, or any other food or beverage also can cause phytophotodermatitis.^29-31 Although the juice of lemons and limes contains psoralens, the rind can contain a 6- to 186-fold increased concentration.³² Psoralen is the photoactive agent in Rutaceae plants that intercalates in double-stranded DNA and promotes intrastrand cross-links when exposed to UVA light, which ultimately leads to dermatitis.⁹ Phytophotodermatitis commonly causes erythema, edema, and painful bullae on sun-exposed areas and classically heals with hyperpigmentation.

Pseudophytodermatitis can occur in grain farmers and harvesters who handle wheat and/or barley and incidentally come in contact with insects and chemicals on the plant material. Pseudophytodermatitis from mites in the wheat and/or barley plant can occur at harvest time when contact with the plant material is high. Insects such as the North American itch mite (Pediculoides ventricosus) can cause petechiae, wheals, and pustules. In addition, insecticides such as malathion and arsenical sprays that are applied to plant leaves can cause pseudophytodermatitis, which may be initially diagnosed as dermatitis to the plant itself.⁶

Patch Testing to Plants

When a patient presents with recurrent or persistent dermatitis and a plant contact allergen is suspected, patch testing is indicated. Most comprehensive patch test series contain various plant allergens, such as sesquiterpene lactones, Compositae mix, and limonene hydroperoxides, and patch testing to a specialized plant series may be necessary. Poison ivy/oak/sumac allergens typically are not included in patch test series because of the high prevalence of allergic reactions to these chemicals and the likelihood of sensitization when patch testing with urushiol. Compositae contact sensitization can be difficult to diagnose because neither sesquiterpene lactone mix 0.1% nor parthenolide 0.1% are sensitive enough to pick up all Compositae allergies.^33,34 Paulsen and Andersen³⁴ proposed that if Compositae sensitization is suspected, testing should include sesquiterpene lactone, parthenolide, and Compositae mix II 2.5%, as well as other potential Compositae allergens based on the patient’s history.³⁴

Because plants can have geographic variability and contain potentially unknown allergens,³⁵ testing to plant components may increase the diagnostic yield of patch testing. Dividing the plant into component parts (ie, stem, bulb, leaf, flower) is helpful, as different components have different allergen concentrations. It is important to consult expert resources before proceeding with plant component patch testing because irritant reactions are frequent and may confound the testing.³⁶

Prevention and Treatment

For all plant dermatoses, the mainstay of prevention is to avoid contact with the offending plant material. Gloves can be an important protective tool for plant dermatitis prevention; the correct material depends on the plant species being handled. Rubber gloves should not be worn to protect against Toxicodendron plants since the catechols in urushiol are soluble in rubber; vinyl gloves should be worn instead.⁶ Marks³⁷ found that tuliposide A, the allergen in the Peruvian lily (Alstroemeria), penetrates both vinyl and latex gloves; it does not penetrate nitrile gloves. If exposed, the risk of dermatitis can be decreased if the allergen is washed away with soap and water as soon as possible. Some allergens such as Toxicodendron are absorbed quickly and need to be washed off within 10 minutes of exposure.⁶ Importantly, exposed gardening gloves may continue to perpetuate ACD if the allergen is not also washed off the gloves themselves.

For light-mediated dermatoses, sun avoidance or use of an effective sunscreen can reduce symptoms in an individual who has already been exposed.¹⁰ UVA light activates psoralen-mediated dermatitis but not until 30 to 120 minutes after absorption into the skin.³⁸

Barrier creams are thought to be protective against plant ACD through a variety of mechanisms. The cream itself is meant to reduce skin contact to an allergen or irritant. Additionally, barrier creams contain active ingredients such as silicone, hydrocarbons, and aluminum chlorohydrate, which are thought to trap or transform offending agents before contacting the skin. When contact with a Toxicodendron species is anticipated, Marks et al³⁹ found that dermatitis was absent or significantly reduced when 144 patients were pretreated with quaternium-18 bentonite lotion 5% (P<.0001).

Although allergen avoidance and use of gloves and barrier creams are the mainstays of preventing plant dermatoses, treatment often is required to control postexposure symptoms. For all plant dermatoses, topical corticosteroids can be used to reduce inflammation and pruritus. In some cases, systemic steroids may be necessary. To prevent rebound of dermatitis, patients often require a 3-week or longer course of oral steroids to quell the reaction, particularly if the dermatitis is vigorous or an id reaction is present.⁴⁰ Antihistamines and cold compresses also can provide symptomatic relief.

Final Interpretation

Plants can cause a variety of dermatoses. Although Toxicodendron plants are the most frequent cause of ACD, it is important to keep in mind that florists, gardeners, and farmers are exposed to a large variety of allergens, irritants, and phototoxic agents that cause dermatoses as well. Confirmation of plant-induced ACD involves patch testing against suspected species. Prevention involves use of appropriate barriers and avoidance of implicated plants. Treatment includes topical steroids, antihistamines, and prednisone.

Plants can contribute to a variety of dermatoses. The Toxicodendron genus, which includes poison ivy, poison oak, and poison sumac, is a well-known and common cause of allergic contact dermatitis (ACD), but many other plants can cause direct or airborne contact dermatitis, especially in gardeners, florists, and farmers. This article provides an overview of different plant-related dermatoses and culprit plants as well as how these dermatoses should be diagnosed and treated.

Epidemiology

Plant dermatoses affect more than 50 million individuals each year.^1,2 In the United States, the Toxicodendron genus causes ACD in more than 70% of exposed individuals, leading to medical visits.³ An urgent care visit for a plant-related dermatitis is estimated to cost $168, while an emergency department visit can cost 3 times as much.⁴ Although less common, Compositae plants are another important culprit of plant dermatitis, particularly in gardeners, florists, and farmers. Data from the 2017-2018 North American Contact Dermatitis Group screening series (N=4947) showed sesquiterpene lactones and Compositae to be positive in 0.5% of patch-tested patients.⁵

Plant Dermatitis Classifications

Plant dermatitis can be classified into 5 main categories: ACD, mechanical irritant contact dermatitis, chemical irritant contact dermatitis, light-mediated dermatitis, and pseudophytodermatitis.⁶

Allergic contact dermatitis is an immune-mediated type IV delayed hypersensitivity reaction. The common molecular allergens in plants include phenols, α-methylene-γ-butyrolactones, quinones, terpenes, disulfides, isothiocyanates, and polyacetylenic derivatives.⁶

Plant contact dermatitis due to mechanical and chemical irritants is precipitated by multiple mechanisms, including disruption of the epidermal barrier and subsequent cytokine release from keratinocytes.⁷ Nonimmunologic contact urticaria from plants is thought to be a type of irritant reaction precipitated by mechanical or chemical trauma.⁸

Light-mediated dermatitis includes phytophotodermatitis and photoallergic contact dermatitis. Phytophotodermatitis is a phototoxic reaction triggered by exposure to both plant-derived furanocoumarin and UVA light.⁹ By contrast, photoallergic contact dermatitis is a delayed hypersensitivity reaction from prior sensitization to a light-activated antigen.¹⁰

Pseudophytodermatitis, as its name implies, is not truly mediated by an allergen or irritant intrinsic to the plant but rather by dyes, waxes, insecticides, or arthropods that inhabit the plant or are secondarily applied.⁶

Common Plant Allergens

Anacardiaceae Family
Most of the allergenic plants within the Anacardiaceae family belong to the Toxicodendron genus, which encompasses poison ivy (Toxicodendron radicans), poison oak (Toxicodendron pubescens,Toxicodendron quercifolium, Toxicodendron diversiloum), and poison sumac (Toxicodendron vernix). Poison ivy is the celebrity of the Anacardiaceae family and contributes to most cases of plant-related ACD. It is found in every state in the continental United States. Poison oak is another common culprit found in the western and southeastern United States.¹¹ Plants within the Anacardiaceae family contain an oleoresin called urushiol, which is the primary sensitizing substance. Although poison ivy and poison oak grow well in full sun to partial shade, poison sumac typically is found in damp swampy areas east of the Rocky Mountains. Most cases of ACD related to Anacardiaceae species are due to direct contact with urushiol from a Toxicodendron plant, but burning of brush containing Toxicodendron can cause airborne exposure when urushiol oil is carried by smoke particles.¹² Sensitization to Toxicodendron can cause ACD to other Anacardiaceae species such as the Japanese lacquer tree (Toxicodendron vernicifluum), mango tree (Mangifera indica), cashew tree (Anacardium occidentale), and Indian marking nut tree (Semecarpus anacardium).⁶ Cross-reactions to components of the ginkgo tree (Ginkgo biloba) also are possible.

Toxicodendron plants can be more easily identified and avoided with knowledge of their characteristic leaf patterns. The most dependable way to identify poison ivy and poison oak species is to look for plants with 3 leaves, giving rise to the common saying, “Leaves of three, leave them be.” Poison sumac plants have groups of 7 to 13 leaves arranged as pairs along a central rib. Another helpful finding is a black deposit that Toxicodendron species leave behind following trauma to the leaves. Urushiol oxidizes when exposed to air and turns into a black deposit that can be seen on damaged leaves themselves or can be demonstrated in a black spot test to verify if a plant is a Toxicodendron species. The test is performed by gathering (carefully, without direct contact) a few leaves in a paper towel and crushing them to release sap. Within minutes, the sap will turn black if the plant is indeed a Toxicodendron species.¹³Pruritic, edematous, erythematous papules, plaques, and eventual vesicles in a linear distribution are suspicious for Toxicodendron exposure. Although your pet will not develop Toxicodendron ACD, oleoresin-contaminated pets can transfer the oils to their owners after coming into contact with these plants. Toxicodendron dermatitis also can be acquired from oleoresin-contaminated fomites such as clothing and shoes worn in the garden or when hiking. Toxicodendron dermatitis can appear at different sites on the body at different times depending on the amount of oleoresin exposure as well as epidermal thickness. For example, the oleoresin can be transferred from the hands to body areas with a thinner stratum corneum (eg, genitalia) and cause subsequent dermatitis.¹

Compositae Family
The Compositae family (also known as Asteraceae) is a large plant family with more than 20,000 species, including numerous weeds, wildflowers, and vegetables. The flowers, leaves, stems, and pollens of the Compositae family are coated by cyclic esters called sesquiterpene lactones. Mitchell and Dupuis¹⁴ showed that sesquiterpene lactones are the allergens responsible for ACD to various Compositae plants, including ragweed (Ambrosia), sneezeweed (Helenium), and chrysanthemums (Chrysanthemum). Common Compositae vegetables such as lettuce (Lactuca sativa) have been reported to cause ACD in chefs, grocery store produce handlers, gardeners, and even owners of lettuce-eating pet guinea pigs and turtles.¹⁵ Similarly, artichokes (Cynara scolymus) can cause ACD in gardeners.¹⁶ Exposure to Compositae species also has been implicated in photoallergic reactions, and studies have demonstrated that some patients with chronic actinic dermatitis also have positive patch test reactions to Compositae species and/or sesquiterpene lactones.^17,18

In addition to direct contact with Compositae plants, airborne exposure to sesquiterpene lactones can cause ACD.¹⁴ The pattern of airborne contact dermatitis typically involves exposed areas such as the eyelids, central face, and/or neck. The beak sign also can be a clue to airborne contact dermatitis, which involves dermatitis of the face that spares the nasal tip and/or nasal ridge. It is thought that the beak sign may result from increased sebaceous gland concentration on the nose, which prevents penetration of allergens and irritants.¹⁹ Unlike photoallergic contact dermatitis, which also can involve the face, airborne ACD frequently involves photoprotected areas such as the submandibular chin and the upper lip. Davies and Kersey²⁰ reported the case of a groundsman who was cutting grass with dandelions (Taraxacum officinale) and was found to have associated airborne ACD of the face, neck, and forearms due to Compositae allergy. In a different setting, the aromas of chamomile (Matricaria chamomilla) have been reported to cause airborne ACD in a tea drinker.²¹ Paulsen²² found that ingestion of chamomile tea can induce systemic ACD in sensitized individuals.

Alstroemeriaceae, Liliaceae, and Primulaceae
Florists are exposed to many plant species and have a high prevalence of ACD. Thiboutot et al²³ found that 15 of 57 (26%) floral workers experienced hand dermatitis that cleared with time away from work. The Peruvian lily (Alstroemeria, Alstroemeriaceae family), which contains tuliposide A, was found to be the leading cause of sensitization.²³ Tulips (Tulipa, Liliaceae family), as the flower name suggests, also contain tuliposide A, which along with mechanical irritation from the course tecta fibers on the bulbs lead to a dermatitis known as tulip fingers.^24,25 Poison primrose (Primula obconica, Primulaceae family), cultivated for its highly colorful flowers, contains the contact allergen primin.⁶ A common clinical presentation of ACD for any of these culprit flowers is localized dermatitis of the thumb and index finger in a florist or gardener.

Plants That Cause Irritant Reactions

Cactuses
Although the long spines of the Cactaceae family of cactuses is a warning for passersby, it is the small and nearly invisible barbed hairs (glochids) that inflict a more dramatic cutaneous reaction. The prickly pear cactus (Opuntia species) is a good example of such a plant, as its glochids cause mechanical irritation but also can become embedded in the skin and result in subcutaneous granulomas known as sabra dermatitis.²⁶

Stinging Nettle
The dermatologic term urticaria owes its namesake to the stinging nettle plant, which comes from the family Urticaceae. The stinging nettle has small hairs on its leaves, referred to as stinging trichomes, which have needlelike tips that pierce the skin and inject a mix of histamine, formic acid, and acetylcholine, causing a pruritic dermatitis that may last up to 12 hours.²⁷ The plant is found worldwide and is a common weed in North America.

Phytophotodermatitis

Lemons and limes (Rutaceae family) are common culprits of phytophotodermatitis, often causing what is known as a margarita burn after outdoor consumption or preparation of this tasty citrus beverage.²⁸ An accidental spray of lime juice on the skin while adding it to a beer, guacamole, salsa, or any other food or beverage also can cause phytophotodermatitis.^29-31 Although the juice of lemons and limes contains psoralens, the rind can contain a 6- to 186-fold increased concentration.³² Psoralen is the photoactive agent in Rutaceae plants that intercalates in double-stranded DNA and promotes intrastrand cross-links when exposed to UVA light, which ultimately leads to dermatitis.⁹ Phytophotodermatitis commonly causes erythema, edema, and painful bullae on sun-exposed areas and classically heals with hyperpigmentation.

Pseudophytodermatitis can occur in grain farmers and harvesters who handle wheat and/or barley and incidentally come in contact with insects and chemicals on the plant material. Pseudophytodermatitis from mites in the wheat and/or barley plant can occur at harvest time when contact with the plant material is high. Insects such as the North American itch mite (Pediculoides ventricosus) can cause petechiae, wheals, and pustules. In addition, insecticides such as malathion and arsenical sprays that are applied to plant leaves can cause pseudophytodermatitis, which may be initially diagnosed as dermatitis to the plant itself.⁶

Patch Testing to Plants

When a patient presents with recurrent or persistent dermatitis and a plant contact allergen is suspected, patch testing is indicated. Most comprehensive patch test series contain various plant allergens, such as sesquiterpene lactones, Compositae mix, and limonene hydroperoxides, and patch testing to a specialized plant series may be necessary. Poison ivy/oak/sumac allergens typically are not included in patch test series because of the high prevalence of allergic reactions to these chemicals and the likelihood of sensitization when patch testing with urushiol. Compositae contact sensitization can be difficult to diagnose because neither sesquiterpene lactone mix 0.1% nor parthenolide 0.1% are sensitive enough to pick up all Compositae allergies.^33,34 Paulsen and Andersen³⁴ proposed that if Compositae sensitization is suspected, testing should include sesquiterpene lactone, parthenolide, and Compositae mix II 2.5%, as well as other potential Compositae allergens based on the patient’s history.³⁴

Because plants can have geographic variability and contain potentially unknown allergens,³⁵ testing to plant components may increase the diagnostic yield of patch testing. Dividing the plant into component parts (ie, stem, bulb, leaf, flower) is helpful, as different components have different allergen concentrations. It is important to consult expert resources before proceeding with plant component patch testing because irritant reactions are frequent and may confound the testing.³⁶

Prevention and Treatment

For all plant dermatoses, the mainstay of prevention is to avoid contact with the offending plant material. Gloves can be an important protective tool for plant dermatitis prevention; the correct material depends on the plant species being handled. Rubber gloves should not be worn to protect against Toxicodendron plants since the catechols in urushiol are soluble in rubber; vinyl gloves should be worn instead.⁶ Marks³⁷ found that tuliposide A, the allergen in the Peruvian lily (Alstroemeria), penetrates both vinyl and latex gloves; it does not penetrate nitrile gloves. If exposed, the risk of dermatitis can be decreased if the allergen is washed away with soap and water as soon as possible. Some allergens such as Toxicodendron are absorbed quickly and need to be washed off within 10 minutes of exposure.⁶ Importantly, exposed gardening gloves may continue to perpetuate ACD if the allergen is not also washed off the gloves themselves.

For light-mediated dermatoses, sun avoidance or use of an effective sunscreen can reduce symptoms in an individual who has already been exposed.¹⁰ UVA light activates psoralen-mediated dermatitis but not until 30 to 120 minutes after absorption into the skin.³⁸

Barrier creams are thought to be protective against plant ACD through a variety of mechanisms. The cream itself is meant to reduce skin contact to an allergen or irritant. Additionally, barrier creams contain active ingredients such as silicone, hydrocarbons, and aluminum chlorohydrate, which are thought to trap or transform offending agents before contacting the skin. When contact with a Toxicodendron species is anticipated, Marks et al³⁹ found that dermatitis was absent or significantly reduced when 144 patients were pretreated with quaternium-18 bentonite lotion 5% (P<.0001).

Although allergen avoidance and use of gloves and barrier creams are the mainstays of preventing plant dermatoses, treatment often is required to control postexposure symptoms. For all plant dermatoses, topical corticosteroids can be used to reduce inflammation and pruritus. In some cases, systemic steroids may be necessary. To prevent rebound of dermatitis, patients often require a 3-week or longer course of oral steroids to quell the reaction, particularly if the dermatitis is vigorous or an id reaction is present.⁴⁰ Antihistamines and cold compresses also can provide symptomatic relief.

Final Interpretation

Plants can cause a variety of dermatoses. Although Toxicodendron plants are the most frequent cause of ACD, it is important to keep in mind that florists, gardeners, and farmers are exposed to a large variety of allergens, irritants, and phototoxic agents that cause dermatoses as well. Confirmation of plant-induced ACD involves patch testing against suspected species. Prevention involves use of appropriate barriers and avoidance of implicated plants. Treatment includes topical steroids, antihistamines, and prednisone.

Plants can contribute to a variety of dermatoses. The Toxicodendron genus, which includes poison ivy, poison oak, and poison sumac, is a well-known and common cause of allergic contact dermatitis (ACD), but many other plants can cause direct or airborne contact dermatitis, especially in gardeners, florists, and farmers. This article provides an overview of different plant-related dermatoses and culprit plants as well as how these dermatoses should be diagnosed and treated.

Epidemiology

Plant dermatoses affect more than 50 million individuals each year.^1,2 In the United States, the Toxicodendron genus causes ACD in more than 70% of exposed individuals, leading to medical visits.³ An urgent care visit for a plant-related dermatitis is estimated to cost $168, while an emergency department visit can cost 3 times as much.⁴ Although less common, Compositae plants are another important culprit of plant dermatitis, particularly in gardeners, florists, and farmers. Data from the 2017-2018 North American Contact Dermatitis Group screening series (N=4947) showed sesquiterpene lactones and Compositae to be positive in 0.5% of patch-tested patients.⁵

Plant Dermatitis Classifications

Plant dermatitis can be classified into 5 main categories: ACD, mechanical irritant contact dermatitis, chemical irritant contact dermatitis, light-mediated dermatitis, and pseudophytodermatitis.⁶

Allergic contact dermatitis is an immune-mediated type IV delayed hypersensitivity reaction. The common molecular allergens in plants include phenols, α-methylene-γ-butyrolactones, quinones, terpenes, disulfides, isothiocyanates, and polyacetylenic derivatives.⁶

Plant contact dermatitis due to mechanical and chemical irritants is precipitated by multiple mechanisms, including disruption of the epidermal barrier and subsequent cytokine release from keratinocytes.⁷ Nonimmunologic contact urticaria from plants is thought to be a type of irritant reaction precipitated by mechanical or chemical trauma.⁸

Light-mediated dermatitis includes phytophotodermatitis and photoallergic contact dermatitis. Phytophotodermatitis is a phototoxic reaction triggered by exposure to both plant-derived furanocoumarin and UVA light.⁹ By contrast, photoallergic contact dermatitis is a delayed hypersensitivity reaction from prior sensitization to a light-activated antigen.¹⁰

Pseudophytodermatitis, as its name implies, is not truly mediated by an allergen or irritant intrinsic to the plant but rather by dyes, waxes, insecticides, or arthropods that inhabit the plant or are secondarily applied.⁶

Common Plant Allergens

Anacardiaceae Family
Most of the allergenic plants within the Anacardiaceae family belong to the Toxicodendron genus, which encompasses poison ivy (Toxicodendron radicans), poison oak (Toxicodendron pubescens,Toxicodendron quercifolium, Toxicodendron diversiloum), and poison sumac (Toxicodendron vernix). Poison ivy is the celebrity of the Anacardiaceae family and contributes to most cases of plant-related ACD. It is found in every state in the continental United States. Poison oak is another common culprit found in the western and southeastern United States.¹¹ Plants within the Anacardiaceae family contain an oleoresin called urushiol, which is the primary sensitizing substance. Although poison ivy and poison oak grow well in full sun to partial shade, poison sumac typically is found in damp swampy areas east of the Rocky Mountains. Most cases of ACD related to Anacardiaceae species are due to direct contact with urushiol from a Toxicodendron plant, but burning of brush containing Toxicodendron can cause airborne exposure when urushiol oil is carried by smoke particles.¹² Sensitization to Toxicodendron can cause ACD to other Anacardiaceae species such as the Japanese lacquer tree (Toxicodendron vernicifluum), mango tree (Mangifera indica), cashew tree (Anacardium occidentale), and Indian marking nut tree (Semecarpus anacardium).⁶ Cross-reactions to components of the ginkgo tree (Ginkgo biloba) also are possible.

Toxicodendron plants can be more easily identified and avoided with knowledge of their characteristic leaf patterns. The most dependable way to identify poison ivy and poison oak species is to look for plants with 3 leaves, giving rise to the common saying, “Leaves of three, leave them be.” Poison sumac plants have groups of 7 to 13 leaves arranged as pairs along a central rib. Another helpful finding is a black deposit that Toxicodendron species leave behind following trauma to the leaves. Urushiol oxidizes when exposed to air and turns into a black deposit that can be seen on damaged leaves themselves or can be demonstrated in a black spot test to verify if a plant is a Toxicodendron species. The test is performed by gathering (carefully, without direct contact) a few leaves in a paper towel and crushing them to release sap. Within minutes, the sap will turn black if the plant is indeed a Toxicodendron species.¹³Pruritic, edematous, erythematous papules, plaques, and eventual vesicles in a linear distribution are suspicious for Toxicodendron exposure. Although your pet will not develop Toxicodendron ACD, oleoresin-contaminated pets can transfer the oils to their owners after coming into contact with these plants. Toxicodendron dermatitis also can be acquired from oleoresin-contaminated fomites such as clothing and shoes worn in the garden or when hiking. Toxicodendron dermatitis can appear at different sites on the body at different times depending on the amount of oleoresin exposure as well as epidermal thickness. For example, the oleoresin can be transferred from the hands to body areas with a thinner stratum corneum (eg, genitalia) and cause subsequent dermatitis.¹

Compositae Family
The Compositae family (also known as Asteraceae) is a large plant family with more than 20,000 species, including numerous weeds, wildflowers, and vegetables. The flowers, leaves, stems, and pollens of the Compositae family are coated by cyclic esters called sesquiterpene lactones. Mitchell and Dupuis¹⁴ showed that sesquiterpene lactones are the allergens responsible for ACD to various Compositae plants, including ragweed (Ambrosia), sneezeweed (Helenium), and chrysanthemums (Chrysanthemum). Common Compositae vegetables such as lettuce (Lactuca sativa) have been reported to cause ACD in chefs, grocery store produce handlers, gardeners, and even owners of lettuce-eating pet guinea pigs and turtles.¹⁵ Similarly, artichokes (Cynara scolymus) can cause ACD in gardeners.¹⁶ Exposure to Compositae species also has been implicated in photoallergic reactions, and studies have demonstrated that some patients with chronic actinic dermatitis also have positive patch test reactions to Compositae species and/or sesquiterpene lactones.^17,18

In addition to direct contact with Compositae plants, airborne exposure to sesquiterpene lactones can cause ACD.¹⁴ The pattern of airborne contact dermatitis typically involves exposed areas such as the eyelids, central face, and/or neck. The beak sign also can be a clue to airborne contact dermatitis, which involves dermatitis of the face that spares the nasal tip and/or nasal ridge. It is thought that the beak sign may result from increased sebaceous gland concentration on the nose, which prevents penetration of allergens and irritants.¹⁹ Unlike photoallergic contact dermatitis, which also can involve the face, airborne ACD frequently involves photoprotected areas such as the submandibular chin and the upper lip. Davies and Kersey²⁰ reported the case of a groundsman who was cutting grass with dandelions (Taraxacum officinale) and was found to have associated airborne ACD of the face, neck, and forearms due to Compositae allergy. In a different setting, the aromas of chamomile (Matricaria chamomilla) have been reported to cause airborne ACD in a tea drinker.²¹ Paulsen²² found that ingestion of chamomile tea can induce systemic ACD in sensitized individuals.

Alstroemeriaceae, Liliaceae, and Primulaceae
Florists are exposed to many plant species and have a high prevalence of ACD. Thiboutot et al²³ found that 15 of 57 (26%) floral workers experienced hand dermatitis that cleared with time away from work. The Peruvian lily (Alstroemeria, Alstroemeriaceae family), which contains tuliposide A, was found to be the leading cause of sensitization.²³ Tulips (Tulipa, Liliaceae family), as the flower name suggests, also contain tuliposide A, which along with mechanical irritation from the course tecta fibers on the bulbs lead to a dermatitis known as tulip fingers.^24,25 Poison primrose (Primula obconica, Primulaceae family), cultivated for its highly colorful flowers, contains the contact allergen primin.⁶ A common clinical presentation of ACD for any of these culprit flowers is localized dermatitis of the thumb and index finger in a florist or gardener.

Plants That Cause Irritant Reactions

Cactuses
Although the long spines of the Cactaceae family of cactuses is a warning for passersby, it is the small and nearly invisible barbed hairs (glochids) that inflict a more dramatic cutaneous reaction. The prickly pear cactus (Opuntia species) is a good example of such a plant, as its glochids cause mechanical irritation but also can become embedded in the skin and result in subcutaneous granulomas known as sabra dermatitis.²⁶

Stinging Nettle
The dermatologic term urticaria owes its namesake to the stinging nettle plant, which comes from the family Urticaceae. The stinging nettle has small hairs on its leaves, referred to as stinging trichomes, which have needlelike tips that pierce the skin and inject a mix of histamine, formic acid, and acetylcholine, causing a pruritic dermatitis that may last up to 12 hours.²⁷ The plant is found worldwide and is a common weed in North America.

Phytophotodermatitis

Lemons and limes (Rutaceae family) are common culprits of phytophotodermatitis, often causing what is known as a margarita burn after outdoor consumption or preparation of this tasty citrus beverage.²⁸ An accidental spray of lime juice on the skin while adding it to a beer, guacamole, salsa, or any other food or beverage also can cause phytophotodermatitis.^29-31 Although the juice of lemons and limes contains psoralens, the rind can contain a 6- to 186-fold increased concentration.³² Psoralen is the photoactive agent in Rutaceae plants that intercalates in double-stranded DNA and promotes intrastrand cross-links when exposed to UVA light, which ultimately leads to dermatitis.⁹ Phytophotodermatitis commonly causes erythema, edema, and painful bullae on sun-exposed areas and classically heals with hyperpigmentation.

Pseudophytodermatitis can occur in grain farmers and harvesters who handle wheat and/or barley and incidentally come in contact with insects and chemicals on the plant material. Pseudophytodermatitis from mites in the wheat and/or barley plant can occur at harvest time when contact with the plant material is high. Insects such as the North American itch mite (Pediculoides ventricosus) can cause petechiae, wheals, and pustules. In addition, insecticides such as malathion and arsenical sprays that are applied to plant leaves can cause pseudophytodermatitis, which may be initially diagnosed as dermatitis to the plant itself.⁶

Patch Testing to Plants

When a patient presents with recurrent or persistent dermatitis and a plant contact allergen is suspected, patch testing is indicated. Most comprehensive patch test series contain various plant allergens, such as sesquiterpene lactones, Compositae mix, and limonene hydroperoxides, and patch testing to a specialized plant series may be necessary. Poison ivy/oak/sumac allergens typically are not included in patch test series because of the high prevalence of allergic reactions to these chemicals and the likelihood of sensitization when patch testing with urushiol. Compositae contact sensitization can be difficult to diagnose because neither sesquiterpene lactone mix 0.1% nor parthenolide 0.1% are sensitive enough to pick up all Compositae allergies.^33,34 Paulsen and Andersen³⁴ proposed that if Compositae sensitization is suspected, testing should include sesquiterpene lactone, parthenolide, and Compositae mix II 2.5%, as well as other potential Compositae allergens based on the patient’s history.³⁴

Because plants can have geographic variability and contain potentially unknown allergens,³⁵ testing to plant components may increase the diagnostic yield of patch testing. Dividing the plant into component parts (ie, stem, bulb, leaf, flower) is helpful, as different components have different allergen concentrations. It is important to consult expert resources before proceeding with plant component patch testing because irritant reactions are frequent and may confound the testing.³⁶

Prevention and Treatment

For all plant dermatoses, the mainstay of prevention is to avoid contact with the offending plant material. Gloves can be an important protective tool for plant dermatitis prevention; the correct material depends on the plant species being handled. Rubber gloves should not be worn to protect against Toxicodendron plants since the catechols in urushiol are soluble in rubber; vinyl gloves should be worn instead.⁶ Marks³⁷ found that tuliposide A, the allergen in the Peruvian lily (Alstroemeria), penetrates both vinyl and latex gloves; it does not penetrate nitrile gloves. If exposed, the risk of dermatitis can be decreased if the allergen is washed away with soap and water as soon as possible. Some allergens such as Toxicodendron are absorbed quickly and need to be washed off within 10 minutes of exposure.⁶ Importantly, exposed gardening gloves may continue to perpetuate ACD if the allergen is not also washed off the gloves themselves.

For light-mediated dermatoses, sun avoidance or use of an effective sunscreen can reduce symptoms in an individual who has already been exposed.¹⁰ UVA light activates psoralen-mediated dermatitis but not until 30 to 120 minutes after absorption into the skin.³⁸

Barrier creams are thought to be protective against plant ACD through a variety of mechanisms. The cream itself is meant to reduce skin contact to an allergen or irritant. Additionally, barrier creams contain active ingredients such as silicone, hydrocarbons, and aluminum chlorohydrate, which are thought to trap or transform offending agents before contacting the skin. When contact with a Toxicodendron species is anticipated, Marks et al³⁹ found that dermatitis was absent or significantly reduced when 144 patients were pretreated with quaternium-18 bentonite lotion 5% (P<.0001).

Although allergen avoidance and use of gloves and barrier creams are the mainstays of preventing plant dermatoses, treatment often is required to control postexposure symptoms. For all plant dermatoses, topical corticosteroids can be used to reduce inflammation and pruritus. In some cases, systemic steroids may be necessary. To prevent rebound of dermatitis, patients often require a 3-week or longer course of oral steroids to quell the reaction, particularly if the dermatitis is vigorous or an id reaction is present.⁴⁰ Antihistamines and cold compresses also can provide symptomatic relief.

Final Interpretation

Plants can cause a variety of dermatoses. Although Toxicodendron plants are the most frequent cause of ACD, it is important to keep in mind that florists, gardeners, and farmers are exposed to a large variety of allergens, irritants, and phototoxic agents that cause dermatoses as well. Confirmation of plant-induced ACD involves patch testing against suspected species. Prevention involves use of appropriate barriers and avoidance of implicated plants. Treatment includes topical steroids, antihistamines, and prednisone.

Atopic dermatitis (AD) is an incredibly common chronic skin disease, affecting up to 25% of children and 7% of adults in the United States.^1,2 Despite the prevalence of this disease and its impact on patient quality of life, research and scholarly work in AD has been limited until recent years. A PubMed search of articles indexed for MEDLINE using the term atopic dermatitis showed that there were fewer than 500 articles published in 2000 and 965 in 2010; with our more recent acceleration in research, there were 2168 articles published in 2020 and more than 1300 published in just the first half of 2021 (through June). This new research includes insights into the pathogenesis of AD and study of the disease impact and comorbidities as well as an extensive amount of drug development and clinical trial work for new topical and systemic therapies.

New Agents to Treat AD

The 2016 approval of crisaborole,³ a phosphodiesterase 4 inhibitor, followed by the approval of dupilumab, an IL-4 and IL-13 pathway inhibitor and the first biologic agent approved for AD,⁴ ushered in a new age of therapy. We currently are awaiting the incorporation of a new set of topical nonsteroidal agents, oral Janus kinase (JAK) inhibitors, and new biologic agents for AD, several of which have completed phase 3 trials and extended safety evaluations. How these new drugs will impact our standard treatment across the spectrum of care for AD is not yet known.

The emergence of new systemic therapies is timely, as the most used systemic medications previously were oral corticosteroids, despite their use being advised against in standard practice guidelines. Other agents such as methotrexate, cyclosporine, azathioprine, and mycophenolate are discussed in the literature and AD treatment guidelines as being potentially useful, though absence of US Food and Drug Administration (FDA) approval and the need for frequent laboratory monitoring, as well as drug-specific side effects and an increased risk of infection, limit their use in the United States, especially in pediatric and adolescent populations.⁵

The approval of dupilumab as a systemic therapy—initially for adults and subsequently for teenagers (12–17 years of age) and then children (6–11 years of age)—has markedly influenced the standard of care for moderate to severe AD. This agent has been shown to have a considerable impact on disease severity and quality of life, with a good safety profile and the added benefit of not requiring continuous (or any) laboratory monitoring.^6-8 Ongoing studies of dupilumab in children (ClinicalTrials.gov identifiers NCT02612454, NCT03346434), including those younger than 1 year,⁹ raise the question of how commonly this medication might be incorporated into care across the entire age spectrum of patients with AD. What standards will there be for assessment of severity, disease impact, and persistence to warrant use in younger ages? Will early treatment with novel systemic agents change the overall course of the disease and minimize the development of comorbidities? The answers to these questions remain to be seen.

JAK Inhibitors for AD
Additional novel therapeutics currently are undergoing studies for treatment of AD, most notably the oral JAK inhibitors upadacitinib,¹⁰ baricitinib,¹¹ and abrocitinib.¹² Each of these agents has completed phase 3 trials for AD. Two of these agents—upadacitinib and baricitinib—have prior FDA approval for use in other disease states. Of note, baricitinib is already approved for treatment of moderate to severe AD in adults in more than 40 countries¹³; however, the use of these agents in other diseases brings about concerns of malignancy, severe infection, and thrombosis. In the clinical trials for AD, many of these events have not been seen, but the number of patients treated is limited, and longer-term safety assessment is important.^10,11

How will the oral JAK inhibitors be incorporated into care compared to biologic agents such as dupilumab? Tolerance and more serious potential adverse events are concerns, with nausea, headaches, and acneform eruptions being associated with some of the medications, in addition to potential issues with herpes simplex and zoster infections. However, oral JAK inhibitors have the benefit of not requiring injections, something that many patients may prefer, and data show that these drugs generally are associated with a rapid reduction in pruritus and, depending on the drug, very quick and profound effects on objective signs of AD.^10-12 Two head-to-head studies have been completed comparing dupilumab to oral JAK inhibitors in adults: the JADE COMPARE trial examining dupilumab vs abrocitinib¹² and the Heads UP trial comparing dupilumab vs upadacitinib.¹⁴ Compared to dupilumab, higher-dose abrocitinib showed more rapid responses, superiority in itch response, and similarity or superiority in other outcomes depending on the time point of the evaluation. Adverse event profiles differed; for example, abrocitinib was associated with more nausea, acneform eruptions, and herpes zoster, while dupilumab had higher rates of conjunctivitis.¹² Upadacitinib, which was only studied at higher dosing (30 mg daily), showed superiority to dupilumab in itch response and in improvement in AD severity in multiple outcome measures; however, there were increases in serious infections, eczema herpeticum, herpes zoster, and laboratory-related adverse events.¹⁴ Dupilumab has the advantage of studies of extended use along with real-world experience, generally with excellent safety and tolerance other than injection-site reactions and conjunctivitis.⁸ Biologics targeting IL-13—tralokinumab and lebrikizumab—also are to be added to our armamentarium.^15,16 The addition of these agents and JAK inhibitors as new systemic treatment options points to the quickly evolving future of AD treatment for patients with extensive disease.

New topical therapies in development provide even more treatment options. New nonsteroidal topicals include topical JAK inhibitors such as ruxolitinib¹⁷; tapinarof,¹⁸ an aryl hydrocarbon receptor modulator; and phosphodiesterase 4 inhibitors. These agents may be useful either as monotherapy, as studied, potentially without the regional limitations associated with stronger topical corticosteroids, but also should be useful in clinical practice as part of therapeutic regimens with other topical steroid and nonsteroidal agents.

The Microbiome and AD

In addition, research looking at topical microbes as specific interventions that may mediate the microbiome and inflammation of AD are intriguing. A recent phase 1 trial from the University of California San Diego¹⁹ indicated that topical bacteriotherapy directed at decreasing Staphylococcus aureus may provide an impact in AD. Observations by Kong et al²⁰ showed that gram-negative microbiome differences are seen in AD patients compared to unaffected individuals, which has fueled studies showing that Roseomonas mucosa, a gram-negative skin commensal, when applied as a topical live biotherapeutic agent has improved disease severity in children and adults with AD.²¹ Although further studies are underway, these initial data suggest a role for microbiome-modifying therapies as AD treatment.

Chronic Hand Eczema

Chronic hand eczema (CHE), which has considerable overlap with AD in many patients, especially children and adolescents,^22-24 is another area of interesting research. This high-prevalence condition is associated with allergic and irritant contact dermatitis^24-26—conditions that are both considered alternative diagnoses for and exacerbators of AD²⁷—and is a disease process currently being targeted for new therapies. Delgocitinib (NCT04872101, NCT04871711), the novel JAK inhibitor ARQ-252 (NCT04378569), among other topical agents, as well as systemic therapeutics such as gusacitinib (NCT03728504), are in active trials for CHE. Given CHE’s impact on quality of life²⁸ and its overlap with AD, investigation into this disorder can help drive future AD research as well as lead to better knowledge and treatment of CHE.

Final Thoughts

Despite the promising results of these myriad new therapies in AD, there are many factors that influence how and when we use these drugs, including their approval status, FDA labeling, and the ability of patients to access and afford treatment. Additionally, continued study is needed to evaluate the long-term safety and extended efficacy of newer drugs, such as the oral JAK inhibitors. Despite these hurdles, the current landscape of research and development is rapidly evolving. Compared to the many years when only one main group of therapies was a reasonable option for patients, the future of AD treatment looks bright.

Atopic dermatitis (AD) is an incredibly common chronic skin disease, affecting up to 25% of children and 7% of adults in the United States.^1,2 Despite the prevalence of this disease and its impact on patient quality of life, research and scholarly work in AD has been limited until recent years. A PubMed search of articles indexed for MEDLINE using the term atopic dermatitis showed that there were fewer than 500 articles published in 2000 and 965 in 2010; with our more recent acceleration in research, there were 2168 articles published in 2020 and more than 1300 published in just the first half of 2021 (through June). This new research includes insights into the pathogenesis of AD and study of the disease impact and comorbidities as well as an extensive amount of drug development and clinical trial work for new topical and systemic therapies.

New Agents to Treat AD

The 2016 approval of crisaborole,³ a phosphodiesterase 4 inhibitor, followed by the approval of dupilumab, an IL-4 and IL-13 pathway inhibitor and the first biologic agent approved for AD,⁴ ushered in a new age of therapy. We currently are awaiting the incorporation of a new set of topical nonsteroidal agents, oral Janus kinase (JAK) inhibitors, and new biologic agents for AD, several of which have completed phase 3 trials and extended safety evaluations. How these new drugs will impact our standard treatment across the spectrum of care for AD is not yet known.

The emergence of new systemic therapies is timely, as the most used systemic medications previously were oral corticosteroids, despite their use being advised against in standard practice guidelines. Other agents such as methotrexate, cyclosporine, azathioprine, and mycophenolate are discussed in the literature and AD treatment guidelines as being potentially useful, though absence of US Food and Drug Administration (FDA) approval and the need for frequent laboratory monitoring, as well as drug-specific side effects and an increased risk of infection, limit their use in the United States, especially in pediatric and adolescent populations.⁵

The approval of dupilumab as a systemic therapy—initially for adults and subsequently for teenagers (12–17 years of age) and then children (6–11 years of age)—has markedly influenced the standard of care for moderate to severe AD. This agent has been shown to have a considerable impact on disease severity and quality of life, with a good safety profile and the added benefit of not requiring continuous (or any) laboratory monitoring.^6-8 Ongoing studies of dupilumab in children (ClinicalTrials.gov identifiers NCT02612454, NCT03346434), including those younger than 1 year,⁹ raise the question of how commonly this medication might be incorporated into care across the entire age spectrum of patients with AD. What standards will there be for assessment of severity, disease impact, and persistence to warrant use in younger ages? Will early treatment with novel systemic agents change the overall course of the disease and minimize the development of comorbidities? The answers to these questions remain to be seen.

JAK Inhibitors for AD
Additional novel therapeutics currently are undergoing studies for treatment of AD, most notably the oral JAK inhibitors upadacitinib,¹⁰ baricitinib,¹¹ and abrocitinib.¹² Each of these agents has completed phase 3 trials for AD. Two of these agents—upadacitinib and baricitinib—have prior FDA approval for use in other disease states. Of note, baricitinib is already approved for treatment of moderate to severe AD in adults in more than 40 countries¹³; however, the use of these agents in other diseases brings about concerns of malignancy, severe infection, and thrombosis. In the clinical trials for AD, many of these events have not been seen, but the number of patients treated is limited, and longer-term safety assessment is important.^10,11

How will the oral JAK inhibitors be incorporated into care compared to biologic agents such as dupilumab? Tolerance and more serious potential adverse events are concerns, with nausea, headaches, and acneform eruptions being associated with some of the medications, in addition to potential issues with herpes simplex and zoster infections. However, oral JAK inhibitors have the benefit of not requiring injections, something that many patients may prefer, and data show that these drugs generally are associated with a rapid reduction in pruritus and, depending on the drug, very quick and profound effects on objective signs of AD.^10-12 Two head-to-head studies have been completed comparing dupilumab to oral JAK inhibitors in adults: the JADE COMPARE trial examining dupilumab vs abrocitinib¹² and the Heads UP trial comparing dupilumab vs upadacitinib.¹⁴ Compared to dupilumab, higher-dose abrocitinib showed more rapid responses, superiority in itch response, and similarity or superiority in other outcomes depending on the time point of the evaluation. Adverse event profiles differed; for example, abrocitinib was associated with more nausea, acneform eruptions, and herpes zoster, while dupilumab had higher rates of conjunctivitis.¹² Upadacitinib, which was only studied at higher dosing (30 mg daily), showed superiority to dupilumab in itch response and in improvement in AD severity in multiple outcome measures; however, there were increases in serious infections, eczema herpeticum, herpes zoster, and laboratory-related adverse events.¹⁴ Dupilumab has the advantage of studies of extended use along with real-world experience, generally with excellent safety and tolerance other than injection-site reactions and conjunctivitis.⁸ Biologics targeting IL-13—tralokinumab and lebrikizumab—also are to be added to our armamentarium.^15,16 The addition of these agents and JAK inhibitors as new systemic treatment options points to the quickly evolving future of AD treatment for patients with extensive disease.

New topical therapies in development provide even more treatment options. New nonsteroidal topicals include topical JAK inhibitors such as ruxolitinib¹⁷; tapinarof,¹⁸ an aryl hydrocarbon receptor modulator; and phosphodiesterase 4 inhibitors. These agents may be useful either as monotherapy, as studied, potentially without the regional limitations associated with stronger topical corticosteroids, but also should be useful in clinical practice as part of therapeutic regimens with other topical steroid and nonsteroidal agents.

The Microbiome and AD

In addition, research looking at topical microbes as specific interventions that may mediate the microbiome and inflammation of AD are intriguing. A recent phase 1 trial from the University of California San Diego¹⁹ indicated that topical bacteriotherapy directed at decreasing Staphylococcus aureus may provide an impact in AD. Observations by Kong et al²⁰ showed that gram-negative microbiome differences are seen in AD patients compared to unaffected individuals, which has fueled studies showing that Roseomonas mucosa, a gram-negative skin commensal, when applied as a topical live biotherapeutic agent has improved disease severity in children and adults with AD.²¹ Although further studies are underway, these initial data suggest a role for microbiome-modifying therapies as AD treatment.

Chronic Hand Eczema

Chronic hand eczema (CHE), which has considerable overlap with AD in many patients, especially children and adolescents,^22-24 is another area of interesting research. This high-prevalence condition is associated with allergic and irritant contact dermatitis^24-26—conditions that are both considered alternative diagnoses for and exacerbators of AD²⁷—and is a disease process currently being targeted for new therapies. Delgocitinib (NCT04872101, NCT04871711), the novel JAK inhibitor ARQ-252 (NCT04378569), among other topical agents, as well as systemic therapeutics such as gusacitinib (NCT03728504), are in active trials for CHE. Given CHE’s impact on quality of life²⁸ and its overlap with AD, investigation into this disorder can help drive future AD research as well as lead to better knowledge and treatment of CHE.

Final Thoughts

Despite the promising results of these myriad new therapies in AD, there are many factors that influence how and when we use these drugs, including their approval status, FDA labeling, and the ability of patients to access and afford treatment. Additionally, continued study is needed to evaluate the long-term safety and extended efficacy of newer drugs, such as the oral JAK inhibitors. Despite these hurdles, the current landscape of research and development is rapidly evolving. Compared to the many years when only one main group of therapies was a reasonable option for patients, the future of AD treatment looks bright.

Atopic dermatitis (AD) is an incredibly common chronic skin disease, affecting up to 25% of children and 7% of adults in the United States.^1,2 Despite the prevalence of this disease and its impact on patient quality of life, research and scholarly work in AD has been limited until recent years. A PubMed search of articles indexed for MEDLINE using the term atopic dermatitis showed that there were fewer than 500 articles published in 2000 and 965 in 2010; with our more recent acceleration in research, there were 2168 articles published in 2020 and more than 1300 published in just the first half of 2021 (through June). This new research includes insights into the pathogenesis of AD and study of the disease impact and comorbidities as well as an extensive amount of drug development and clinical trial work for new topical and systemic therapies.

New Agents to Treat AD

The 2016 approval of crisaborole,³ a phosphodiesterase 4 inhibitor, followed by the approval of dupilumab, an IL-4 and IL-13 pathway inhibitor and the first biologic agent approved for AD,⁴ ushered in a new age of therapy. We currently are awaiting the incorporation of a new set of topical nonsteroidal agents, oral Janus kinase (JAK) inhibitors, and new biologic agents for AD, several of which have completed phase 3 trials and extended safety evaluations. How these new drugs will impact our standard treatment across the spectrum of care for AD is not yet known.

The emergence of new systemic therapies is timely, as the most used systemic medications previously were oral corticosteroids, despite their use being advised against in standard practice guidelines. Other agents such as methotrexate, cyclosporine, azathioprine, and mycophenolate are discussed in the literature and AD treatment guidelines as being potentially useful, though absence of US Food and Drug Administration (FDA) approval and the need for frequent laboratory monitoring, as well as drug-specific side effects and an increased risk of infection, limit their use in the United States, especially in pediatric and adolescent populations.⁵

The approval of dupilumab as a systemic therapy—initially for adults and subsequently for teenagers (12–17 years of age) and then children (6–11 years of age)—has markedly influenced the standard of care for moderate to severe AD. This agent has been shown to have a considerable impact on disease severity and quality of life, with a good safety profile and the added benefit of not requiring continuous (or any) laboratory monitoring.^6-8 Ongoing studies of dupilumab in children (ClinicalTrials.gov identifiers NCT02612454, NCT03346434), including those younger than 1 year,⁹ raise the question of how commonly this medication might be incorporated into care across the entire age spectrum of patients with AD. What standards will there be for assessment of severity, disease impact, and persistence to warrant use in younger ages? Will early treatment with novel systemic agents change the overall course of the disease and minimize the development of comorbidities? The answers to these questions remain to be seen.

JAK Inhibitors for AD
Additional novel therapeutics currently are undergoing studies for treatment of AD, most notably the oral JAK inhibitors upadacitinib,¹⁰ baricitinib,¹¹ and abrocitinib.¹² Each of these agents has completed phase 3 trials for AD. Two of these agents—upadacitinib and baricitinib—have prior FDA approval for use in other disease states. Of note, baricitinib is already approved for treatment of moderate to severe AD in adults in more than 40 countries¹³; however, the use of these agents in other diseases brings about concerns of malignancy, severe infection, and thrombosis. In the clinical trials for AD, many of these events have not been seen, but the number of patients treated is limited, and longer-term safety assessment is important.^10,11

How will the oral JAK inhibitors be incorporated into care compared to biologic agents such as dupilumab? Tolerance and more serious potential adverse events are concerns, with nausea, headaches, and acneform eruptions being associated with some of the medications, in addition to potential issues with herpes simplex and zoster infections. However, oral JAK inhibitors have the benefit of not requiring injections, something that many patients may prefer, and data show that these drugs generally are associated with a rapid reduction in pruritus and, depending on the drug, very quick and profound effects on objective signs of AD.^10-12 Two head-to-head studies have been completed comparing dupilumab to oral JAK inhibitors in adults: the JADE COMPARE trial examining dupilumab vs abrocitinib¹² and the Heads UP trial comparing dupilumab vs upadacitinib.¹⁴ Compared to dupilumab, higher-dose abrocitinib showed more rapid responses, superiority in itch response, and similarity or superiority in other outcomes depending on the time point of the evaluation. Adverse event profiles differed; for example, abrocitinib was associated with more nausea, acneform eruptions, and herpes zoster, while dupilumab had higher rates of conjunctivitis.¹² Upadacitinib, which was only studied at higher dosing (30 mg daily), showed superiority to dupilumab in itch response and in improvement in AD severity in multiple outcome measures; however, there were increases in serious infections, eczema herpeticum, herpes zoster, and laboratory-related adverse events.¹⁴ Dupilumab has the advantage of studies of extended use along with real-world experience, generally with excellent safety and tolerance other than injection-site reactions and conjunctivitis.⁸ Biologics targeting IL-13—tralokinumab and lebrikizumab—also are to be added to our armamentarium.^15,16 The addition of these agents and JAK inhibitors as new systemic treatment options points to the quickly evolving future of AD treatment for patients with extensive disease.

New topical therapies in development provide even more treatment options. New nonsteroidal topicals include topical JAK inhibitors such as ruxolitinib¹⁷; tapinarof,¹⁸ an aryl hydrocarbon receptor modulator; and phosphodiesterase 4 inhibitors. These agents may be useful either as monotherapy, as studied, potentially without the regional limitations associated with stronger topical corticosteroids, but also should be useful in clinical practice as part of therapeutic regimens with other topical steroid and nonsteroidal agents.

The Microbiome and AD

In addition, research looking at topical microbes as specific interventions that may mediate the microbiome and inflammation of AD are intriguing. A recent phase 1 trial from the University of California San Diego¹⁹ indicated that topical bacteriotherapy directed at decreasing Staphylococcus aureus may provide an impact in AD. Observations by Kong et al²⁰ showed that gram-negative microbiome differences are seen in AD patients compared to unaffected individuals, which has fueled studies showing that Roseomonas mucosa, a gram-negative skin commensal, when applied as a topical live biotherapeutic agent has improved disease severity in children and adults with AD.²¹ Although further studies are underway, these initial data suggest a role for microbiome-modifying therapies as AD treatment.

Chronic Hand Eczema

Chronic hand eczema (CHE), which has considerable overlap with AD in many patients, especially children and adolescents,^22-24 is another area of interesting research. This high-prevalence condition is associated with allergic and irritant contact dermatitis^24-26—conditions that are both considered alternative diagnoses for and exacerbators of AD²⁷—and is a disease process currently being targeted for new therapies. Delgocitinib (NCT04872101, NCT04871711), the novel JAK inhibitor ARQ-252 (NCT04378569), among other topical agents, as well as systemic therapeutics such as gusacitinib (NCT03728504), are in active trials for CHE. Given CHE’s impact on quality of life²⁸ and its overlap with AD, investigation into this disorder can help drive future AD research as well as lead to better knowledge and treatment of CHE.

Final Thoughts

Despite the promising results of these myriad new therapies in AD, there are many factors that influence how and when we use these drugs, including their approval status, FDA labeling, and the ability of patients to access and afford treatment. Additionally, continued study is needed to evaluate the long-term safety and extended efficacy of newer drugs, such as the oral JAK inhibitors. Despite these hurdles, the current landscape of research and development is rapidly evolving. Compared to the many years when only one main group of therapies was a reasonable option for patients, the future of AD treatment looks bright.

The Diagnosis: Microcystic Lymphatic Malformation 

The shave biopsy demonstrated numerous thin-walled vascular spaces filled with lymphatic fluid within the dermis (Figure), consistent with a diagnosis of microcystic lymphatic malformation (LM). Lymphatic malformations represent a class of benign vascular lesions consisting of anomalous or dilated lymphatic vessels, which can be broadly categorized as macrocystic (formerly cavernous lymphangioma or cystic hygroma), microcystic (formerly lymphangioma circumscriptum), or mixed.¹ Patients often will present with pruritus, crusting, secondary infection, edema, or oozing.² The superficial blebs of microcystic LMs resemble frog spawn and range in color from clear to pink, brawny, or deep maroon.³ Although the lymphatic vessels involved in microcystic LMs appear disconnected from the major lymphatic circulation,³ systemic fluid overload could plausibly promote lesional swelling and tenderness; we attributed our patient's worsening symptoms to the cumulative ^7.8 L of intravenous fluid he received intraoperatively during his cardiac transplant. The excess fluid allowed communication between lymphatic cisterns and thin-walled vesicles on the skin surface through dilated channels. Overall, LMs represent roughly 26% of pediatric benign vascular tumors and approximately 4% of all vascular tumors.⁴  

Although microcystic LMs may appear especially vascular or verrucous, the differential diagnosis for our patient's LM included condyloma acuminatum,^5,6 condyloma lata,⁷ epidermal nevus, and lymphangiosarcoma. Epidermal nevi are congenital lesions, varying in appearance from velvety to verrucous patches and plaques that often evolve during puberty and become thicker, more verrucous, and hyperpigmented. Keratinocytic epidermal nevus syndromes and other entities such as nevus sebaceous have been associated with somatic mutations affecting proteins in the fibroblast growth factor receptor signaling pathway (eg, FGFR3, HRAS).⁸ Although the clinical appearance alone may be similar, lymphangiosarcoma can be distinguished from LM via biopsy.  

There are several methods to diagnose LM. Duplex sonography is possibly the best noninvasive method to identify the flow between venous valves. Magnetic resonance imaging can detect larger occurrences of LM, and lymphangiography can be utilized to confirm a normal or abnormal lymphatic network.⁴ Treatment options are broad, including surgical excision, laser ablation, and topical sirolimus. Hypertonic saline sclerotherapy can be injected into the afflicted lymphatic channels to decrease inflammation, erythema, and hyperpigmentation without further treatment or major side effects.⁴

However, the benefits of sclerotherapy alone in the treatment of LM often come gradually, and radiofrequency ablation may need to be utilized to achieve more immediate results.² Overall, outcomes are highly variable, but favorable outcomes often can be difficult to obtain due to a high recurrence rate.^2,8 Our patient's symptoms improved during his postoperative recovery, and he declined further intervention.  

The Diagnosis: Microcystic Lymphatic Malformation 

The shave biopsy demonstrated numerous thin-walled vascular spaces filled with lymphatic fluid within the dermis (Figure), consistent with a diagnosis of microcystic lymphatic malformation (LM). Lymphatic malformations represent a class of benign vascular lesions consisting of anomalous or dilated lymphatic vessels, which can be broadly categorized as macrocystic (formerly cavernous lymphangioma or cystic hygroma), microcystic (formerly lymphangioma circumscriptum), or mixed.¹ Patients often will present with pruritus, crusting, secondary infection, edema, or oozing.² The superficial blebs of microcystic LMs resemble frog spawn and range in color from clear to pink, brawny, or deep maroon.³ Although the lymphatic vessels involved in microcystic LMs appear disconnected from the major lymphatic circulation,³ systemic fluid overload could plausibly promote lesional swelling and tenderness; we attributed our patient's worsening symptoms to the cumulative ^7.8 L of intravenous fluid he received intraoperatively during his cardiac transplant. The excess fluid allowed communication between lymphatic cisterns and thin-walled vesicles on the skin surface through dilated channels. Overall, LMs represent roughly 26% of pediatric benign vascular tumors and approximately 4% of all vascular tumors.⁴  

Although microcystic LMs may appear especially vascular or verrucous, the differential diagnosis for our patient's LM included condyloma acuminatum,^5,6 condyloma lata,⁷ epidermal nevus, and lymphangiosarcoma. Epidermal nevi are congenital lesions, varying in appearance from velvety to verrucous patches and plaques that often evolve during puberty and become thicker, more verrucous, and hyperpigmented. Keratinocytic epidermal nevus syndromes and other entities such as nevus sebaceous have been associated with somatic mutations affecting proteins in the fibroblast growth factor receptor signaling pathway (eg, FGFR3, HRAS).⁸ Although the clinical appearance alone may be similar, lymphangiosarcoma can be distinguished from LM via biopsy.  

There are several methods to diagnose LM. Duplex sonography is possibly the best noninvasive method to identify the flow between venous valves. Magnetic resonance imaging can detect larger occurrences of LM, and lymphangiography can be utilized to confirm a normal or abnormal lymphatic network.⁴ Treatment options are broad, including surgical excision, laser ablation, and topical sirolimus. Hypertonic saline sclerotherapy can be injected into the afflicted lymphatic channels to decrease inflammation, erythema, and hyperpigmentation without further treatment or major side effects.⁴

However, the benefits of sclerotherapy alone in the treatment of LM often come gradually, and radiofrequency ablation may need to be utilized to achieve more immediate results.² Overall, outcomes are highly variable, but favorable outcomes often can be difficult to obtain due to a high recurrence rate.^2,8 Our patient's symptoms improved during his postoperative recovery, and he declined further intervention.  

The Diagnosis: Microcystic Lymphatic Malformation 

The shave biopsy demonstrated numerous thin-walled vascular spaces filled with lymphatic fluid within the dermis (Figure), consistent with a diagnosis of microcystic lymphatic malformation (LM). Lymphatic malformations represent a class of benign vascular lesions consisting of anomalous or dilated lymphatic vessels, which can be broadly categorized as macrocystic (formerly cavernous lymphangioma or cystic hygroma), microcystic (formerly lymphangioma circumscriptum), or mixed.¹ Patients often will present with pruritus, crusting, secondary infection, edema, or oozing.² The superficial blebs of microcystic LMs resemble frog spawn and range in color from clear to pink, brawny, or deep maroon.³ Although the lymphatic vessels involved in microcystic LMs appear disconnected from the major lymphatic circulation,³ systemic fluid overload could plausibly promote lesional swelling and tenderness; we attributed our patient's worsening symptoms to the cumulative ^7.8 L of intravenous fluid he received intraoperatively during his cardiac transplant. The excess fluid allowed communication between lymphatic cisterns and thin-walled vesicles on the skin surface through dilated channels. Overall, LMs represent roughly 26% of pediatric benign vascular tumors and approximately 4% of all vascular tumors.⁴  

Although microcystic LMs may appear especially vascular or verrucous, the differential diagnosis for our patient's LM included condyloma acuminatum,^5,6 condyloma lata,⁷ epidermal nevus, and lymphangiosarcoma. Epidermal nevi are congenital lesions, varying in appearance from velvety to verrucous patches and plaques that often evolve during puberty and become thicker, more verrucous, and hyperpigmented. Keratinocytic epidermal nevus syndromes and other entities such as nevus sebaceous have been associated with somatic mutations affecting proteins in the fibroblast growth factor receptor signaling pathway (eg, FGFR3, HRAS).⁸ Although the clinical appearance alone may be similar, lymphangiosarcoma can be distinguished from LM via biopsy.  

There are several methods to diagnose LM. Duplex sonography is possibly the best noninvasive method to identify the flow between venous valves. Magnetic resonance imaging can detect larger occurrences of LM, and lymphangiography can be utilized to confirm a normal or abnormal lymphatic network.⁴ Treatment options are broad, including surgical excision, laser ablation, and topical sirolimus. Hypertonic saline sclerotherapy can be injected into the afflicted lymphatic channels to decrease inflammation, erythema, and hyperpigmentation without further treatment or major side effects.⁴

However, the benefits of sclerotherapy alone in the treatment of LM often come gradually, and radiofrequency ablation may need to be utilized to achieve more immediate results.² Overall, outcomes are highly variable, but favorable outcomes often can be difficult to obtain due to a high recurrence rate.^2,8 Our patient's symptoms improved during his postoperative recovery, and he declined further intervention.  

Plasma cell cheilitis (PCC), also known as plasmocytosis circumorificialis and plasmocytosis mucosae,¹ is a poorly understood, uncommon inflammatory condition characterized by dense infiltration of mature plasma cells in the mucosal dermis of the lip.^2-5 The etiology of PCC is unknown but is thought to be a reactive immune process triggered by infection, mechanical friction, trauma, or solar damage.^1,5,6

The most common presentation of PCC is a slowly evolving, red-brown patch or plaque on the lower lip in older individuals.^2,3,5,7 Secondary changes with disease progression can include erosion, ulceration, fissures, edema, bleeding, or crusting.⁵ The diagnosis of PCC is challenging because it can mimic neoplastic, infectious, and inflammatory conditions.^8,9

Treatment strategies for PCC described in the literature vary, as does therapeutic response. Resolution of PCC has been documented after systemic steroids, intralesional steroids, systemic griseofulvin, and topical calcineurin inhibitors, among other agents.^6,7,10-16

We present the case of a patient with a lip lesion who ultimately was diagnosed with PCC after it progressed to an advanced necrotic stage.

Case Report

An 80-year-old male veteran of the Armed Services initially presented to our institution via teledermatology with redness and crusting of the lower lip (Figure 1). He had a history of myelodysplastic syndrome and anemia requiring iron transfusion. The process appeared to be consistent with actinic cheilitis vs squamous cell carcinoma. In-person dermatology consultation was recommended; however, the patient did not follow through with that appointment.

Five months later, additional photographs of the lesion were taken by the patient's primary care physician and sent through teledermatology, revealing progression to an erythematous, yellow-crusted erosion (Figure 2). The medical record indicated that a punch biopsy performed by the patient’s primary care physician showed hyperkeratosis and fungal organisms on periodic acid–Schiff staining. He subsequently applied ketoconazole and terbinafine cream to the lower lip without improvement. Prompt in-person evaluation by dermatology was again recommended.

Comment

The diagnosis and management of PCC is difficult because the condition is uncommon (though its true incidence is unknown) and the presentation is nonspecific, invoking a wide differential diagnosis. In the literature, PCC presents as a slowly progressive, red-brown patch or plaque on the lower lip in older individuals.^2,3,5,7 The lesion can progress to become eroded, ulcerated, fissured, or edematous.⁵

Differential Diagnosis
The clinical differential diagnosis of PCC is broad and includes inflammatory, infectious, and neoplastic causes, such as actinic cheilitis, allergic contact cheilitis, exfoliative cheilitis, granulomatous cheilitis, lichen planus, candidiasis, syphilis, and squamous cell carcinoma of the lip.^7,9 The histologic differential diagnosis includes allergic contact cheilitis, secondary syphilis, actinic cheilitis, squamous cell carcinoma, cheilitis granulomatosa, and plasmacytoma.^17-19

Histopathology
On biopsy, PCC usually is characterized by plasma cells in a bandlike pattern in the upper submucosa or even more diffusely throughout the submucosa.²⁰ In earlier studies, polyclonality of plasma cells with kappa and lambda light chains has been demonstrated⁵; in this case, such polyclonality militated against a plasma cell dyscrasia. There have been reports of a various number of eosinophils in PCC,^5,20 but eosinophils were not a prominent feature in our case.

Treatment
As reported in the literature, treatment of PCC has been attempted using a broad range of strategies; however, the optimal regimen has yet to be elucidated.¹⁵ Numerous therapies, including excision, radiation, electrocauterization, cryotherapy, steroids, systemic griseofulvin, topical fusidic acid, and topical calcineurin inhibitors, have yielded variable success.^6,7,10-16

The success of topical corticosteroids, as demonstrated in our case, has been unpredictable; the reported response has ranged from complete resolution to failure.⁹ This variability is thought to be related to epithelial width and the degree of acanthosis, with ulcerative lesions demonstrating a superior response to topical corticosteroids.⁹

Conclusion

Our case highlights the challenges of diagnosing and managing PCC, especially through teledermatology. Initial photographs of the lesion (Figure 1) that were submitted demonstrated a nonspecific erosion, which was concerning for any of several infectious, inflammatory, and malignant causes. Prompt in-person evaluation was warranted; regrettably, the patient’s condition worsened rapidly in the 10 days it took for him to be seen in-person by dermatology.

Furthermore, this case necessitated 3 separate biopsies because the pathology on the first 2 biopsies initially was equivocal, demonstrating ulceration and granulation tissue. The diagnosis was finally made after a third biopsy was recommended by a dermatopathologist, who eventually identified a bandlike distribution of polyclonal plasma cells in the upper submucosa, consistent with a diagnosis of PCC. Our patient’s final disease presentation (Figure 3) was exuberant and may represent the end point of untreated PCC.

Plasma cell cheilitis (PCC), also known as plasmocytosis circumorificialis and plasmocytosis mucosae,¹ is a poorly understood, uncommon inflammatory condition characterized by dense infiltration of mature plasma cells in the mucosal dermis of the lip.^2-5 The etiology of PCC is unknown but is thought to be a reactive immune process triggered by infection, mechanical friction, trauma, or solar damage.^1,5,6

The most common presentation of PCC is a slowly evolving, red-brown patch or plaque on the lower lip in older individuals.^2,3,5,7 Secondary changes with disease progression can include erosion, ulceration, fissures, edema, bleeding, or crusting.⁵ The diagnosis of PCC is challenging because it can mimic neoplastic, infectious, and inflammatory conditions.^8,9

Treatment strategies for PCC described in the literature vary, as does therapeutic response. Resolution of PCC has been documented after systemic steroids, intralesional steroids, systemic griseofulvin, and topical calcineurin inhibitors, among other agents.^6,7,10-16

We present the case of a patient with a lip lesion who ultimately was diagnosed with PCC after it progressed to an advanced necrotic stage.

Case Report

An 80-year-old male veteran of the Armed Services initially presented to our institution via teledermatology with redness and crusting of the lower lip (Figure 1). He had a history of myelodysplastic syndrome and anemia requiring iron transfusion. The process appeared to be consistent with actinic cheilitis vs squamous cell carcinoma. In-person dermatology consultation was recommended; however, the patient did not follow through with that appointment.

Five months later, additional photographs of the lesion were taken by the patient's primary care physician and sent through teledermatology, revealing progression to an erythematous, yellow-crusted erosion (Figure 2). The medical record indicated that a punch biopsy performed by the patient’s primary care physician showed hyperkeratosis and fungal organisms on periodic acid–Schiff staining. He subsequently applied ketoconazole and terbinafine cream to the lower lip without improvement. Prompt in-person evaluation by dermatology was again recommended.

Comment

The diagnosis and management of PCC is difficult because the condition is uncommon (though its true incidence is unknown) and the presentation is nonspecific, invoking a wide differential diagnosis. In the literature, PCC presents as a slowly progressive, red-brown patch or plaque on the lower lip in older individuals.^2,3,5,7 The lesion can progress to become eroded, ulcerated, fissured, or edematous.⁵

Differential Diagnosis
The clinical differential diagnosis of PCC is broad and includes inflammatory, infectious, and neoplastic causes, such as actinic cheilitis, allergic contact cheilitis, exfoliative cheilitis, granulomatous cheilitis, lichen planus, candidiasis, syphilis, and squamous cell carcinoma of the lip.^7,9 The histologic differential diagnosis includes allergic contact cheilitis, secondary syphilis, actinic cheilitis, squamous cell carcinoma, cheilitis granulomatosa, and plasmacytoma.^17-19

Histopathology
On biopsy, PCC usually is characterized by plasma cells in a bandlike pattern in the upper submucosa or even more diffusely throughout the submucosa.²⁰ In earlier studies, polyclonality of plasma cells with kappa and lambda light chains has been demonstrated⁵; in this case, such polyclonality militated against a plasma cell dyscrasia. There have been reports of a various number of eosinophils in PCC,^5,20 but eosinophils were not a prominent feature in our case.

Treatment
As reported in the literature, treatment of PCC has been attempted using a broad range of strategies; however, the optimal regimen has yet to be elucidated.¹⁵ Numerous therapies, including excision, radiation, electrocauterization, cryotherapy, steroids, systemic griseofulvin, topical fusidic acid, and topical calcineurin inhibitors, have yielded variable success.^6,7,10-16

The success of topical corticosteroids, as demonstrated in our case, has been unpredictable; the reported response has ranged from complete resolution to failure.⁹ This variability is thought to be related to epithelial width and the degree of acanthosis, with ulcerative lesions demonstrating a superior response to topical corticosteroids.⁹

Conclusion

Our case highlights the challenges of diagnosing and managing PCC, especially through teledermatology. Initial photographs of the lesion (Figure 1) that were submitted demonstrated a nonspecific erosion, which was concerning for any of several infectious, inflammatory, and malignant causes. Prompt in-person evaluation was warranted; regrettably, the patient’s condition worsened rapidly in the 10 days it took for him to be seen in-person by dermatology.

Furthermore, this case necessitated 3 separate biopsies because the pathology on the first 2 biopsies initially was equivocal, demonstrating ulceration and granulation tissue. The diagnosis was finally made after a third biopsy was recommended by a dermatopathologist, who eventually identified a bandlike distribution of polyclonal plasma cells in the upper submucosa, consistent with a diagnosis of PCC. Our patient’s final disease presentation (Figure 3) was exuberant and may represent the end point of untreated PCC.

Plasma cell cheilitis (PCC), also known as plasmocytosis circumorificialis and plasmocytosis mucosae,¹ is a poorly understood, uncommon inflammatory condition characterized by dense infiltration of mature plasma cells in the mucosal dermis of the lip.^2-5 The etiology of PCC is unknown but is thought to be a reactive immune process triggered by infection, mechanical friction, trauma, or solar damage.^1,5,6

The most common presentation of PCC is a slowly evolving, red-brown patch or plaque on the lower lip in older individuals.^2,3,5,7 Secondary changes with disease progression can include erosion, ulceration, fissures, edema, bleeding, or crusting.⁵ The diagnosis of PCC is challenging because it can mimic neoplastic, infectious, and inflammatory conditions.^8,9

Treatment strategies for PCC described in the literature vary, as does therapeutic response. Resolution of PCC has been documented after systemic steroids, intralesional steroids, systemic griseofulvin, and topical calcineurin inhibitors, among other agents.^6,7,10-16

We present the case of a patient with a lip lesion who ultimately was diagnosed with PCC after it progressed to an advanced necrotic stage.

Case Report

An 80-year-old male veteran of the Armed Services initially presented to our institution via teledermatology with redness and crusting of the lower lip (Figure 1). He had a history of myelodysplastic syndrome and anemia requiring iron transfusion. The process appeared to be consistent with actinic cheilitis vs squamous cell carcinoma. In-person dermatology consultation was recommended; however, the patient did not follow through with that appointment.

Five months later, additional photographs of the lesion were taken by the patient's primary care physician and sent through teledermatology, revealing progression to an erythematous, yellow-crusted erosion (Figure 2). The medical record indicated that a punch biopsy performed by the patient’s primary care physician showed hyperkeratosis and fungal organisms on periodic acid–Schiff staining. He subsequently applied ketoconazole and terbinafine cream to the lower lip without improvement. Prompt in-person evaluation by dermatology was again recommended.

Comment

The diagnosis and management of PCC is difficult because the condition is uncommon (though its true incidence is unknown) and the presentation is nonspecific, invoking a wide differential diagnosis. In the literature, PCC presents as a slowly progressive, red-brown patch or plaque on the lower lip in older individuals.^2,3,5,7 The lesion can progress to become eroded, ulcerated, fissured, or edematous.⁵

Differential Diagnosis
The clinical differential diagnosis of PCC is broad and includes inflammatory, infectious, and neoplastic causes, such as actinic cheilitis, allergic contact cheilitis, exfoliative cheilitis, granulomatous cheilitis, lichen planus, candidiasis, syphilis, and squamous cell carcinoma of the lip.^7,9 The histologic differential diagnosis includes allergic contact cheilitis, secondary syphilis, actinic cheilitis, squamous cell carcinoma, cheilitis granulomatosa, and plasmacytoma.^17-19

Histopathology
On biopsy, PCC usually is characterized by plasma cells in a bandlike pattern in the upper submucosa or even more diffusely throughout the submucosa.²⁰ In earlier studies, polyclonality of plasma cells with kappa and lambda light chains has been demonstrated⁵; in this case, such polyclonality militated against a plasma cell dyscrasia. There have been reports of a various number of eosinophils in PCC,^5,20 but eosinophils were not a prominent feature in our case.

Treatment
As reported in the literature, treatment of PCC has been attempted using a broad range of strategies; however, the optimal regimen has yet to be elucidated.¹⁵ Numerous therapies, including excision, radiation, electrocauterization, cryotherapy, steroids, systemic griseofulvin, topical fusidic acid, and topical calcineurin inhibitors, have yielded variable success.^6,7,10-16

The success of topical corticosteroids, as demonstrated in our case, has been unpredictable; the reported response has ranged from complete resolution to failure.⁹ This variability is thought to be related to epithelial width and the degree of acanthosis, with ulcerative lesions demonstrating a superior response to topical corticosteroids.⁹

Conclusion

Our case highlights the challenges of diagnosing and managing PCC, especially through teledermatology. Initial photographs of the lesion (Figure 1) that were submitted demonstrated a nonspecific erosion, which was concerning for any of several infectious, inflammatory, and malignant causes. Prompt in-person evaluation was warranted; regrettably, the patient’s condition worsened rapidly in the 10 days it took for him to be seen in-person by dermatology.

Furthermore, this case necessitated 3 separate biopsies because the pathology on the first 2 biopsies initially was equivocal, demonstrating ulceration and granulation tissue. The diagnosis was finally made after a third biopsy was recommended by a dermatopathologist, who eventually identified a bandlike distribution of polyclonal plasma cells in the upper submucosa, consistent with a diagnosis of PCC. Our patient’s final disease presentation (Figure 3) was exuberant and may represent the end point of untreated PCC.

To the Editor:

The art of tattooing continues to gain popularity in the 21st century, albeit with accompanying hazards.¹ Reported adverse reactions to tattoos include infections, tumors, and hypersensitivity and granulomatous reactions.² Various infectious agents may involve tattoos, including human papillomavirus (HPV), molluscum contagiosum, herpes simplex virus, hepatitis C virus, tuberculoid and nontuberculoid mycobacteria, and Staphylococcus aureus.² Verruca vulgaris infrequently has been reported to develop in tattoos.^3,4 Previously reported cases of verruca in tattoos suggest a predilection for blue or black pigment.^1-5 We report a case of verruca vulgaris occurring within the red-inked areas of a tattoo that first appeared approximately 18 years after the initial tattoo placement.

A 44-year-old woman presented with erythema, induration, and irritation of a tattoo on the left leg of 2 years’ duration. The tattoo initially was inscribed more than 20 years prior. The patient had a history of type 2 diabetes mellitus and chronic obstructive pulmonary disease. She reported no prior trauma to the area, prior rash or irritation, or similar changes to her other tattoos, including those with red ink. The affected tattoo was inscribed at a separate time from the other tattoos. Physical examination of the irritated tattoo revealed hyperkeratotic papules with firm scaling in the zone of dermal red pigment (Figure 1). Notable nodularity or deep induration was not present. The clinical differential diagnosis included a hypersensitivity reaction to red tattoo ink, sarcoidosis, and an infectious process, such as an atypical mycobacterial infection. A punch biopsy demonstrated papillomatous epidermal hyperplasia with hyperkeratosis, focal parakeratosis, and frequent vacuolization of keratinocytes with enlarged keratohyalin granules, diagnostic of verruca vulgaris (Figure 2). Of note, the patient did not have clinically apparent viral warts elsewhere on physical examination. The patient was successfully managedwith a combination of 2 treatments of intralesional Candida antigen and 3 treatments of cryotherapy with resolution of most lesions over the course of 8 months. Over the following several months, the patient applied topical salicylic acid, which led to the resolution of the remaining lesions. The verrucae had not recurred 19 months after the initial presentation.

The development of verruca vulgaris within a tattoo may occur secondary to various mechanisms of HPV inoculation, including introduction of the virus through contaminated ink, the tattoo artist’s saliva, autoinoculation, or koebnerization of a pre-existing verruca vulgaris.⁴ Local immune system dysregulation secondary to tattoo ink also has been proposed as a mechanism for HPV infection in this setting.^1,5 The contents of darker tattoo pigments may promote formation of reactive oxygen species inducing local immunocompromise.⁵

The pathogenic mechanism was elusive in our patient. Although the localization of verruca vulgaris to the zones of red pigment may be merely coincidental, this phenomenon raised suspicion for direct inoculation via contaminated red ink. The patient’s other red ink–containing tattoos that were inscribed separately were spared, compatible with contamination of the red ink used for the affected tattoo. However, the delayed onset of nearly 2 decades was exceptional, given the shorter previously reported latencies ranging from months to 10 years.⁴ Autoinoculation or koebnerization is plausible, though greater involvement of nonred pigments would be expected as well as a briefer latency. Finally, the possibility of local immune dysregulation seemed feasible, given the slow evolution of the lesions largely restricted to one pigment type.

We report a case of verruca vulgaris within the red area of a multicolored tattoo that occurred approximately 18 years after tattoo placement. This case highlights a rare presentation of an infectious agent that may complicate tattoos. Both predilection for red pigment rather than black or blue pigment and the long latency period raised interesting questions regarding pathogenesis. Confirmatory biopsy enables effective management of this tattoo complication.

To the Editor:

The art of tattooing continues to gain popularity in the 21st century, albeit with accompanying hazards.¹ Reported adverse reactions to tattoos include infections, tumors, and hypersensitivity and granulomatous reactions.² Various infectious agents may involve tattoos, including human papillomavirus (HPV), molluscum contagiosum, herpes simplex virus, hepatitis C virus, tuberculoid and nontuberculoid mycobacteria, and Staphylococcus aureus.² Verruca vulgaris infrequently has been reported to develop in tattoos.^3,4 Previously reported cases of verruca in tattoos suggest a predilection for blue or black pigment.^1-5 We report a case of verruca vulgaris occurring within the red-inked areas of a tattoo that first appeared approximately 18 years after the initial tattoo placement.

A 44-year-old woman presented with erythema, induration, and irritation of a tattoo on the left leg of 2 years’ duration. The tattoo initially was inscribed more than 20 years prior. The patient had a history of type 2 diabetes mellitus and chronic obstructive pulmonary disease. She reported no prior trauma to the area, prior rash or irritation, or similar changes to her other tattoos, including those with red ink. The affected tattoo was inscribed at a separate time from the other tattoos. Physical examination of the irritated tattoo revealed hyperkeratotic papules with firm scaling in the zone of dermal red pigment (Figure 1). Notable nodularity or deep induration was not present. The clinical differential diagnosis included a hypersensitivity reaction to red tattoo ink, sarcoidosis, and an infectious process, such as an atypical mycobacterial infection. A punch biopsy demonstrated papillomatous epidermal hyperplasia with hyperkeratosis, focal parakeratosis, and frequent vacuolization of keratinocytes with enlarged keratohyalin granules, diagnostic of verruca vulgaris (Figure 2). Of note, the patient did not have clinically apparent viral warts elsewhere on physical examination. The patient was successfully managedwith a combination of 2 treatments of intralesional Candida antigen and 3 treatments of cryotherapy with resolution of most lesions over the course of 8 months. Over the following several months, the patient applied topical salicylic acid, which led to the resolution of the remaining lesions. The verrucae had not recurred 19 months after the initial presentation.

The development of verruca vulgaris within a tattoo may occur secondary to various mechanisms of HPV inoculation, including introduction of the virus through contaminated ink, the tattoo artist’s saliva, autoinoculation, or koebnerization of a pre-existing verruca vulgaris.⁴ Local immune system dysregulation secondary to tattoo ink also has been proposed as a mechanism for HPV infection in this setting.^1,5 The contents of darker tattoo pigments may promote formation of reactive oxygen species inducing local immunocompromise.⁵

The pathogenic mechanism was elusive in our patient. Although the localization of verruca vulgaris to the zones of red pigment may be merely coincidental, this phenomenon raised suspicion for direct inoculation via contaminated red ink. The patient’s other red ink–containing tattoos that were inscribed separately were spared, compatible with contamination of the red ink used for the affected tattoo. However, the delayed onset of nearly 2 decades was exceptional, given the shorter previously reported latencies ranging from months to 10 years.⁴ Autoinoculation or koebnerization is plausible, though greater involvement of nonred pigments would be expected as well as a briefer latency. Finally, the possibility of local immune dysregulation seemed feasible, given the slow evolution of the lesions largely restricted to one pigment type.

We report a case of verruca vulgaris within the red area of a multicolored tattoo that occurred approximately 18 years after tattoo placement. This case highlights a rare presentation of an infectious agent that may complicate tattoos. Both predilection for red pigment rather than black or blue pigment and the long latency period raised interesting questions regarding pathogenesis. Confirmatory biopsy enables effective management of this tattoo complication.

To the Editor:

The art of tattooing continues to gain popularity in the 21st century, albeit with accompanying hazards.¹ Reported adverse reactions to tattoos include infections, tumors, and hypersensitivity and granulomatous reactions.² Various infectious agents may involve tattoos, including human papillomavirus (HPV), molluscum contagiosum, herpes simplex virus, hepatitis C virus, tuberculoid and nontuberculoid mycobacteria, and Staphylococcus aureus.² Verruca vulgaris infrequently has been reported to develop in tattoos.^3,4 Previously reported cases of verruca in tattoos suggest a predilection for blue or black pigment.^1-5 We report a case of verruca vulgaris occurring within the red-inked areas of a tattoo that first appeared approximately 18 years after the initial tattoo placement.

A 44-year-old woman presented with erythema, induration, and irritation of a tattoo on the left leg of 2 years’ duration. The tattoo initially was inscribed more than 20 years prior. The patient had a history of type 2 diabetes mellitus and chronic obstructive pulmonary disease. She reported no prior trauma to the area, prior rash or irritation, or similar changes to her other tattoos, including those with red ink. The affected tattoo was inscribed at a separate time from the other tattoos. Physical examination of the irritated tattoo revealed hyperkeratotic papules with firm scaling in the zone of dermal red pigment (Figure 1). Notable nodularity or deep induration was not present. The clinical differential diagnosis included a hypersensitivity reaction to red tattoo ink, sarcoidosis, and an infectious process, such as an atypical mycobacterial infection. A punch biopsy demonstrated papillomatous epidermal hyperplasia with hyperkeratosis, focal parakeratosis, and frequent vacuolization of keratinocytes with enlarged keratohyalin granules, diagnostic of verruca vulgaris (Figure 2). Of note, the patient did not have clinically apparent viral warts elsewhere on physical examination. The patient was successfully managedwith a combination of 2 treatments of intralesional Candida antigen and 3 treatments of cryotherapy with resolution of most lesions over the course of 8 months. Over the following several months, the patient applied topical salicylic acid, which led to the resolution of the remaining lesions. The verrucae had not recurred 19 months after the initial presentation.

The development of verruca vulgaris within a tattoo may occur secondary to various mechanisms of HPV inoculation, including introduction of the virus through contaminated ink, the tattoo artist’s saliva, autoinoculation, or koebnerization of a pre-existing verruca vulgaris.⁴ Local immune system dysregulation secondary to tattoo ink also has been proposed as a mechanism for HPV infection in this setting.^1,5 The contents of darker tattoo pigments may promote formation of reactive oxygen species inducing local immunocompromise.⁵

The pathogenic mechanism was elusive in our patient. Although the localization of verruca vulgaris to the zones of red pigment may be merely coincidental, this phenomenon raised suspicion for direct inoculation via contaminated red ink. The patient’s other red ink–containing tattoos that were inscribed separately were spared, compatible with contamination of the red ink used for the affected tattoo. However, the delayed onset of nearly 2 decades was exceptional, given the shorter previously reported latencies ranging from months to 10 years.⁴ Autoinoculation or koebnerization is plausible, though greater involvement of nonred pigments would be expected as well as a briefer latency. Finally, the possibility of local immune dysregulation seemed feasible, given the slow evolution of the lesions largely restricted to one pigment type.

We report a case of verruca vulgaris within the red area of a multicolored tattoo that occurred approximately 18 years after tattoo placement. This case highlights a rare presentation of an infectious agent that may complicate tattoos. Both predilection for red pigment rather than black or blue pigment and the long latency period raised interesting questions regarding pathogenesis. Confirmatory biopsy enables effective management of this tattoo complication.

To the Editor:

Lupus erythematosus panniculitis (LEP) is rare in the pediatric population. It can be difficult to manage, as patients may not respond to conventional treatments including hydroxychloroquine and prednisone. We report the use of rituximab in the treatment of a 20-year-old woman with LEP of the face, legs, and arms that was refractory to standard treatments. She also had a history of hemophagocytic lymphohistiocytosis (HLH). Further studies are warranted to determine the role of rituximab in the treatment of pediatric patients with LEP.

A 20-year-old woman with history of LEP and HLH initially presented with migratory violaceous nodules on the face 16 years prior to the current presentation. A skin biopsy 3 years after that initial presentation suggested a diagnosis of cutaneous lupus erythematosus. Six years later, numerous asymptomatic lesions appeared on the legs, predominantly on the calves; she was successfully treated with hydroxychloroquine and high-dose prednisone. Four years prior to the current presentation, a febrile illness prompted discontinuation of hydroxychloroquine and hospitalization, where she was first was diagnosed with HLH; she achieved remission with cyclosporine. At the current presentation, she continued to have persistent violaceous lesions on the face, lower arms, and legs with underlying nodularity (Figure 1). Skin biopsies revealed LEP and were less suggestive of HLH. She was restarted on hydroxychloroquine, which did not adequately control the disease. Rheumatologic workup was only notable for an antinuclear antibody titer of 1:80 (reference range, <1:80) in a speckled pattern.

Rituximab, a chimeric monoclonal antibody targeting B-cell surface marker CD20, results in depletion of mature B cells. Use of rituximab for LEP has been described in multiple case reports involving an 8-year-old boy, 22-year-old girl, and 2 middle-aged women.^2-4 In addition, a recently published case series of 4 patients with childhood-onset refractory LEP described improvement of disease activity with rituximab.⁵ It is important to rule out subcutaneous T-cell lymphoma before treatment with rituximab, as its histopathology can closely resemble that seen in LEP and HLH-associated cytophagic histiocytic panniculitis.^1,6

Rituximab may be an effective treatment option in pediatric patients with refractory LEP. Larger studies on the use of rituximab in the pediatric population are necessary.

To the Editor:

Lupus erythematosus panniculitis (LEP) is rare in the pediatric population. It can be difficult to manage, as patients may not respond to conventional treatments including hydroxychloroquine and prednisone. We report the use of rituximab in the treatment of a 20-year-old woman with LEP of the face, legs, and arms that was refractory to standard treatments. She also had a history of hemophagocytic lymphohistiocytosis (HLH). Further studies are warranted to determine the role of rituximab in the treatment of pediatric patients with LEP.

A 20-year-old woman with history of LEP and HLH initially presented with migratory violaceous nodules on the face 16 years prior to the current presentation. A skin biopsy 3 years after that initial presentation suggested a diagnosis of cutaneous lupus erythematosus. Six years later, numerous asymptomatic lesions appeared on the legs, predominantly on the calves; she was successfully treated with hydroxychloroquine and high-dose prednisone. Four years prior to the current presentation, a febrile illness prompted discontinuation of hydroxychloroquine and hospitalization, where she was first was diagnosed with HLH; she achieved remission with cyclosporine. At the current presentation, she continued to have persistent violaceous lesions on the face, lower arms, and legs with underlying nodularity (Figure 1). Skin biopsies revealed LEP and were less suggestive of HLH. She was restarted on hydroxychloroquine, which did not adequately control the disease. Rheumatologic workup was only notable for an antinuclear antibody titer of 1:80 (reference range, <1:80) in a speckled pattern.

Rituximab, a chimeric monoclonal antibody targeting B-cell surface marker CD20, results in depletion of mature B cells. Use of rituximab for LEP has been described in multiple case reports involving an 8-year-old boy, 22-year-old girl, and 2 middle-aged women.^2-4 In addition, a recently published case series of 4 patients with childhood-onset refractory LEP described improvement of disease activity with rituximab.⁵ It is important to rule out subcutaneous T-cell lymphoma before treatment with rituximab, as its histopathology can closely resemble that seen in LEP and HLH-associated cytophagic histiocytic panniculitis.^1,6

Rituximab may be an effective treatment option in pediatric patients with refractory LEP. Larger studies on the use of rituximab in the pediatric population are necessary.

To the Editor:

Lupus erythematosus panniculitis (LEP) is rare in the pediatric population. It can be difficult to manage, as patients may not respond to conventional treatments including hydroxychloroquine and prednisone. We report the use of rituximab in the treatment of a 20-year-old woman with LEP of the face, legs, and arms that was refractory to standard treatments. She also had a history of hemophagocytic lymphohistiocytosis (HLH). Further studies are warranted to determine the role of rituximab in the treatment of pediatric patients with LEP.

A 20-year-old woman with history of LEP and HLH initially presented with migratory violaceous nodules on the face 16 years prior to the current presentation. A skin biopsy 3 years after that initial presentation suggested a diagnosis of cutaneous lupus erythematosus. Six years later, numerous asymptomatic lesions appeared on the legs, predominantly on the calves; she was successfully treated with hydroxychloroquine and high-dose prednisone. Four years prior to the current presentation, a febrile illness prompted discontinuation of hydroxychloroquine and hospitalization, where she was first was diagnosed with HLH; she achieved remission with cyclosporine. At the current presentation, she continued to have persistent violaceous lesions on the face, lower arms, and legs with underlying nodularity (Figure 1). Skin biopsies revealed LEP and were less suggestive of HLH. She was restarted on hydroxychloroquine, which did not adequately control the disease. Rheumatologic workup was only notable for an antinuclear antibody titer of 1:80 (reference range, <1:80) in a speckled pattern.

Rituximab, a chimeric monoclonal antibody targeting B-cell surface marker CD20, results in depletion of mature B cells. Use of rituximab for LEP has been described in multiple case reports involving an 8-year-old boy, 22-year-old girl, and 2 middle-aged women.^2-4 In addition, a recently published case series of 4 patients with childhood-onset refractory LEP described improvement of disease activity with rituximab.⁵ It is important to rule out subcutaneous T-cell lymphoma before treatment with rituximab, as its histopathology can closely resemble that seen in LEP and HLH-associated cytophagic histiocytic panniculitis.^1,6

Rituximab may be an effective treatment option in pediatric patients with refractory LEP. Larger studies on the use of rituximab in the pediatric population are necessary.