Cutis

Approximately 108 million individuals have been forcibly displaced across the globe as of 2022, 35 million of whom are formally designated as refugees.^1,2 The United States has coordinated resettlement of more refugee populations than any other country; the most common countries of origin are the Democratic Republic of the Congo, Syria, Afghanistan, and Myanmar.³ In 2021, policy to increase the number of refugees resettled in the United States by more than 700% (from 15,000 up to 125,000) was established; since enactment, the United States has seen more than double the refugee arrivals in 2023 than the prior year, making medical care for this population increasingly relevant for the dermatologist.⁴

Understanding how to care for this population begins with an accurate understanding of the term refugee. The United Nations defines a refugee as a person who is unwilling or unable to return to their country of nationality because of persecution or well-founded fear of persecution due to race, religion, nationality, membership in a particular social group, or political opinion. This term grants a protected status under international law and encompasses access to travel assistance, housing, cultural orientation, and medical evaluation upon resettlement.^5,6

The burden of treatable dermatologic conditions in refugee populations ranges from 19% to 96% in the literature^7,8 and varies from inflammatory disorders to infectious and parasitic diseases.⁹ In one study of 6899 displaced individuals in Greece, the prevalence of dermatologic conditions was higher than traumatic injury, cardiac disease, psychological conditions, and dental disease.¹⁰

When outlining differential diagnoses for parasitic infestations of the skin that affect refugee populations, helpful considerations include the individual’s country of origin, route traveled, and method of travel.¹¹ Parasitic infestations specifically are more common in refugee populations when there are barriers to basic hygiene, crowded living or travel conditions, or lack of access to health care, which they may experience at any point in their home country, during travel, or in resettlement housing.⁸

Even with limited examination and diagnostic resources, the skin is the most accessible first indication of patients’ overall well-being and often provides simple diagnostic clues—in combination with contextualization of the patient’s unique circumstances—necessary for successful diagnosis and treatment of scabies and pediculosis.¹² The dermatologist working with refugee populations may be the first set of eyes available and trained to discern skin infestations and therefore has the potential to improve overall outcomes.

Some parasitic infestations in refugee populations may fall under the category of neglected tropical diseases, including scabies, ascariasis, trypanosomiasis, leishmaniasis, and schistosomiasis; they affect an estimated 1 billion individuals across the globe but historically have been underrepresented in the literature and in health policy due in part to limited access to care.¹³ This review will focus on infestations by the scabies mite (Sarcoptes scabiei var hominis) and the human louse, as these frequently are encountered, easily diagnosed, and treatable by trained clinicians, even in resource-limited settings.

Scabies

Scabies is a parasitic skin infestation caused by the 8-legged mite Sarcoptes scabiei var hominis. The female mite begins the infestation process via penetration of the epidermis, particularly the stratum corneum, and commences laying eggs (Figure 1). The subsequent larvae emerge 48 to 72 hours later and remain burrowed in the epidermis. The larvae mature over the next 10 to 14 days and continue the reproductive cycle.^14,15 Symptoms of infestation occurs due to a hypersensitivity reaction to the mite and its by-products.¹⁶ Transmission of the mite primarily occurs via direct (skin-to-skin) contact with infected individuals or environmental surfaces for 24 to36 hours in specific conditions, though the latter source has been debated in the literature.

CT113004016_fig1.jpg

The method of transmission is particularly important when considering care for refugee populations. Scabies is found most often in those living in or traveling from tropical regions including East Asia, Southeast Asia, Oceania, and Latin America.¹⁷ In displaced or refugee populations, a lack of access to basic hygiene, extended travel in close quarters, and suboptimal health care access all may lead to an increased incidence of untreated scabies infestations.¹⁸ Scabies is more prevalent in children, with increased potential for secondary bacterial infections with Streptococcus and Staphylococcus species due to excoriation in unsanitary conditions. Secondary infection with Streptococcus pyogenes can lead to acute poststreptococcal glomerulonephritis, which accounts for a large burden of chronic kidney disease in affected populations.¹⁹ However, scabies may be found in any population, regardless of hygiene or health care access. Treating health care providers should keep a broad differential.

Presentation—The latency of scabies symptoms is 2 to 6 weeks in a primary outbreak and may be as short as 1 to 3 days with re-infestation, following the course of delayed-type hypersensitivity.²⁰ The initial hallmark symptom is pruritus with increased severity in the evening. Visible lesions, excoriations, and burrows associated with scattered vesicles or pustules may be seen over the web spaces of the hands and feet, volar surfaces of the wrists, axillae, waist, genitalia, inner thighs, or buttocks.¹⁹ Chronic infestation often manifests with genital nodules. In populations with limited access to health care, there are reports of a sensitization phenomenon in which the individual may become less symptomatic after 4 to 6 weeks and yet be a potential carrier of the mite.²¹

Those with compromised immune function, such as individuals living with HIV or severe malnutrition, may present with crusted scabies, a variant that manifests as widespread hyperkeratotic scaling with more pronounced involvement of the head, neck, and acral areas. In contrast to classic scabies, crusted scabies is associated with minimal pruritus.²²

Diagnosis—The diagnosis of scabies is largely clinical with confirmation through skin scrapings. The International Alliance for Control of Scabies has established diagnostic criteria that include a combination of clinical findings, history, and visualization of mites.²³ A dermatologist working with refugee populations may employ any combination of history (eg, nocturnal itch, exposure to an affected individual) or clinical findings along with a high degree of suspicion in those with elevated risk. Visualization of mites is helpful to confirm the diagnosis and may be completed with the application of mineral oil at the terminal end of a burrow, skin scraping with a surgical blade or needle, and examination under light microscopy.

Treatment—First-line treatment for scabies consists of application of permethrin cream 5% on the skin of the neck to the soles of the feet, which is to be left on for 8 to 14 hours followed by rinsing. Re-application is recommended in 1 to 2 weeks. Oral ivermectin is a reasonable alternative to permethrin cream due to its low cost and easy administration in large affected groups. It is not labeled for use in pregnant women or children weighing less than 15 kg but has no selective fetal toxicity. Treatment of scabies with ivermectin has the benefit of treating many other parasitic infections. Both medications are on the World Health Organization Model List of Essential Medications and are widely available for treating providers, even in resource-limited settings.²⁴

Much of the world still uses benzyl benzoate or precipitated sulfur ointment to treat scabies, and some botanicals used in folk medicine have genuine antiscabetic properties. Pruritus may persist for 1 to 4 weeks following treatment and does not indicate treatment failure. Topical camphor and menthol preparations, low-potency topical corticosteroids, or emollients all may be employed for relief.²⁵Sarna is a Spanish term for scabies and has become the proprietary name for topical antipruritic agents. Additional methods of treatment and prevention include washing clothes and linens in hot water and drying on high heat. If machine washing is not available, clothing and linens may be sealed in a plastic bag for 72 hours.

Pediculosis

Pediculosis is an infestation caused by the ectoparasite Pediculus humanus, an obligate, sesame seed–sized louse that feeds exclusively on the blood of its host (Figure 2).²⁶ Of the lice species, 2 require humans as hosts; one is P humanus and the other is Pthirus pubis (pubic lice). Pediculus humanus may be further classified into morphologies based largely on the affected area: body (P humanus corporis) or head (P humanus capitis), both of which will be discussed.²⁷

CT113004016_fig2.jpg

Lice primarily attach to clothing and hair shafts, then transfer to the skin for blood feeds. Females lay eggs that hatch 6 to 10 days later, subsequently maturing into adults. The lifespan of these parasites with regular access to a host is 1 to 3 months for head lice and 18 days for body lice vs only 3 to 5 days without a host.²⁸ Transmission of P humanus capitis primarily occurs via direct contact with affected individuals, either head-to-head contact or sharing of items such as brushes and headscarves; P humanus corporis also may be transmitted via direct contact with affected individuals or clothing.

Pediculosis is an important infestation to consider when providing care for refugee populations. Risk factors include lack of access to basic hygiene, including regular bathing or laundering of clothing, and crowded conditions that make direct person-to-person contact with affected individuals more likely.²⁹ Body lice are associated more often with domestic turbulence and displaced populations³⁰ in comparison to head lice, which have broad demographic variables, most often affecting females and children.²⁸ Fatty acids in adult male sebum make the scalp less hospitable to lice.

Presentation—The most common clinical manifestation of pediculosis is pruritus. Cutaneous findings can include papules, wheals, or hemorrhagic puncta secondary to the louse bite. Due to the Tyndall effect of deep hemosiderin pigment, blue-grey macules termed maculae ceruleae (Figure 3) also may be present in chronic infestations of pediculosis pubis, in contrast to pediculosis capitis or corporis.³¹ Body louse infestation is associated with a general pruritus concentrated on the neck, shoulders, and waist—areas where clothing makes the most direct contact. Lesions may be visible and include eczematous patches with excoriation and possible secondary bacterial infection. Chronic infestation may exhibit lichenification or hyperpigmentation in associated areas. Head lice most often manifest with localized scalp pruritus and associated excoriation and cervical or occipital lymphadenopathy.³²

CT113004016_fig3.jpg

Diagnosis—The diagnosis of pediculosis is clinical, with confirmation requiring direct examination of the insect or nits (the egg case of the parasite)(Figure 4). Body lice and associated nits can be visualized on clothing seams near areas of highest body temperature, particularly the waistband. Head lice may be visualized crawling on hair shafts or on a louse comb. Nits are firmly attached to hair shafts and are visible to the naked eye, whereas pseudonits slide freely along the hair shaft and are not a manifestation of louse infestation (Figure 5).³¹

CT113004016_fig4.jpg

Treatment—Treatment varies by affected area. Pediculosis corporis may be treated with permethrin cream 5% applied to the entire body and left on for 8 to 10 hours, but this may not be necessary if facilities are available to wash and dry clothing.³³ The use of oral ivermectin and permethrin-impregnated underwear both have been proposed.^34,35 Treatment of pediculosis capitis may be accomplished with a variety of topical pediculicides including permethrin, pyrethrum with piperonyl butoxide, dimethicone, malathion, benzyl alcohol, spinosad, and topical ivermectin.²² Topical corticosteroids or emollients may be employed for residual pruritus.

CT113004016_fig5.jpg

Equally important is environmental elimination of infestation. Clothing should be discarded if possible or washed and dried using high heat. If neither approach is possible or appropriate, clothing may be sealed in a plastic bag for 2 weeks or treated with a pediculicide. Nit combing is an important adjunct in the treatment of pediculosis capitis.³⁶ It is important to encourage return to work and/or school immediately after treatment. “No nit” policies are more harmful to education than helpful for prevention of investation.³⁷

Pediculosis corporis may transmit infectious agents including Bartonella quintana, (trench fever, endocarditis, bacillary angiomatosis), Borrelia recurrentis (louse-borne relapsing fever), and Rickettsia prowazekii (epidemic typhus).^31,38,39 Additionally, severe pediculosis infestations have the potential to cause chronic blood loss in affected populations. In a study of patients with active pediculosis infestation, mean hemoglobin values were found to be 2.5 g/dL lower than a matched population without infestation.⁴⁰ It is important to consider pediculosis as a risk for iron-deficiency anemia in populations who are known to lack access to regular medical evaluation.⁴¹

Future Considerations

Increased access to tools and education for clinicians treating refugee populations is key to reducing the burden of parasitic skin disease and related morbidity and mortality in vulnerable groups both domestically and globally. One such tool, the Skin NTDs App, was launched by the World Health Organization in 2020. It is available for free for Android and iOS devices to assist clinicians in the field with the diagnosis and treatment of neglected tropical diseases—including scabies—that may affect refugee populations.⁴²

Additionally, to both improve access and limit preventable sequelae, future investigations into appropriate models of community-based care are paramount. The model of community-based care is centered on the idea of care provision that prioritizes safety, accessibility, affordability, and acceptability in an environment closest to vulnerable populations. The largest dermatologic society, the International League of Dermatological Societies, formed a Migrant Health Dermatology Working Group that prioritizes understanding and improving care for refugee and migrant populations; this group hosted a summit in 2022, bringing together international subject matter leaders to discuss such models of care and set goals for the creation of tool kits for patients, frontline health care workers, and dermatologists.⁴³

Conclusion

Improvement in dermatologic care of refugee populations includes provision of culturally and linguistically appropriate care by trained clinicians, adequate access to the most essential medications, and basic physical or legal access to health care systems in general.^8,11,44 Parasitic infestations have the potential to remain asymptomatic for extended periods of time and result in spread to potentially nonendemic regions of resettlement.⁴⁵ Additionally, the psychosocial well-being of refugee populations upon resettlement may be negatively affected by stigma of disease processes such as scabies and pediculosis, leading to additional barriers to successful re-entry into the patient’s new environment.⁴⁶ Therefore, proper screening, diagnosis, and treatment of the most common parasitic infestations in this population have great potential to improve outcomes for large groups across the globe.

Approximately 108 million individuals have been forcibly displaced across the globe as of 2022, 35 million of whom are formally designated as refugees.^1,2 The United States has coordinated resettlement of more refugee populations than any other country; the most common countries of origin are the Democratic Republic of the Congo, Syria, Afghanistan, and Myanmar.³ In 2021, policy to increase the number of refugees resettled in the United States by more than 700% (from 15,000 up to 125,000) was established; since enactment, the United States has seen more than double the refugee arrivals in 2023 than the prior year, making medical care for this population increasingly relevant for the dermatologist.⁴

Understanding how to care for this population begins with an accurate understanding of the term refugee. The United Nations defines a refugee as a person who is unwilling or unable to return to their country of nationality because of persecution or well-founded fear of persecution due to race, religion, nationality, membership in a particular social group, or political opinion. This term grants a protected status under international law and encompasses access to travel assistance, housing, cultural orientation, and medical evaluation upon resettlement.^5,6

The burden of treatable dermatologic conditions in refugee populations ranges from 19% to 96% in the literature^7,8 and varies from inflammatory disorders to infectious and parasitic diseases.⁹ In one study of 6899 displaced individuals in Greece, the prevalence of dermatologic conditions was higher than traumatic injury, cardiac disease, psychological conditions, and dental disease.¹⁰

When outlining differential diagnoses for parasitic infestations of the skin that affect refugee populations, helpful considerations include the individual’s country of origin, route traveled, and method of travel.¹¹ Parasitic infestations specifically are more common in refugee populations when there are barriers to basic hygiene, crowded living or travel conditions, or lack of access to health care, which they may experience at any point in their home country, during travel, or in resettlement housing.⁸

Even with limited examination and diagnostic resources, the skin is the most accessible first indication of patients’ overall well-being and often provides simple diagnostic clues—in combination with contextualization of the patient’s unique circumstances—necessary for successful diagnosis and treatment of scabies and pediculosis.¹² The dermatologist working with refugee populations may be the first set of eyes available and trained to discern skin infestations and therefore has the potential to improve overall outcomes.

Some parasitic infestations in refugee populations may fall under the category of neglected tropical diseases, including scabies, ascariasis, trypanosomiasis, leishmaniasis, and schistosomiasis; they affect an estimated 1 billion individuals across the globe but historically have been underrepresented in the literature and in health policy due in part to limited access to care.¹³ This review will focus on infestations by the scabies mite (Sarcoptes scabiei var hominis) and the human louse, as these frequently are encountered, easily diagnosed, and treatable by trained clinicians, even in resource-limited settings.

Scabies

Scabies is a parasitic skin infestation caused by the 8-legged mite Sarcoptes scabiei var hominis. The female mite begins the infestation process via penetration of the epidermis, particularly the stratum corneum, and commences laying eggs (Figure 1). The subsequent larvae emerge 48 to 72 hours later and remain burrowed in the epidermis. The larvae mature over the next 10 to 14 days and continue the reproductive cycle.^14,15 Symptoms of infestation occurs due to a hypersensitivity reaction to the mite and its by-products.¹⁶ Transmission of the mite primarily occurs via direct (skin-to-skin) contact with infected individuals or environmental surfaces for 24 to36 hours in specific conditions, though the latter source has been debated in the literature.

CT113004016_fig1.jpg

The method of transmission is particularly important when considering care for refugee populations. Scabies is found most often in those living in or traveling from tropical regions including East Asia, Southeast Asia, Oceania, and Latin America.¹⁷ In displaced or refugee populations, a lack of access to basic hygiene, extended travel in close quarters, and suboptimal health care access all may lead to an increased incidence of untreated scabies infestations.¹⁸ Scabies is more prevalent in children, with increased potential for secondary bacterial infections with Streptococcus and Staphylococcus species due to excoriation in unsanitary conditions. Secondary infection with Streptococcus pyogenes can lead to acute poststreptococcal glomerulonephritis, which accounts for a large burden of chronic kidney disease in affected populations.¹⁹ However, scabies may be found in any population, regardless of hygiene or health care access. Treating health care providers should keep a broad differential.

Presentation—The latency of scabies symptoms is 2 to 6 weeks in a primary outbreak and may be as short as 1 to 3 days with re-infestation, following the course of delayed-type hypersensitivity.²⁰ The initial hallmark symptom is pruritus with increased severity in the evening. Visible lesions, excoriations, and burrows associated with scattered vesicles or pustules may be seen over the web spaces of the hands and feet, volar surfaces of the wrists, axillae, waist, genitalia, inner thighs, or buttocks.¹⁹ Chronic infestation often manifests with genital nodules. In populations with limited access to health care, there are reports of a sensitization phenomenon in which the individual may become less symptomatic after 4 to 6 weeks and yet be a potential carrier of the mite.²¹

Those with compromised immune function, such as individuals living with HIV or severe malnutrition, may present with crusted scabies, a variant that manifests as widespread hyperkeratotic scaling with more pronounced involvement of the head, neck, and acral areas. In contrast to classic scabies, crusted scabies is associated with minimal pruritus.²²

Diagnosis—The diagnosis of scabies is largely clinical with confirmation through skin scrapings. The International Alliance for Control of Scabies has established diagnostic criteria that include a combination of clinical findings, history, and visualization of mites.²³ A dermatologist working with refugee populations may employ any combination of history (eg, nocturnal itch, exposure to an affected individual) or clinical findings along with a high degree of suspicion in those with elevated risk. Visualization of mites is helpful to confirm the diagnosis and may be completed with the application of mineral oil at the terminal end of a burrow, skin scraping with a surgical blade or needle, and examination under light microscopy.

Treatment—First-line treatment for scabies consists of application of permethrin cream 5% on the skin of the neck to the soles of the feet, which is to be left on for 8 to 14 hours followed by rinsing. Re-application is recommended in 1 to 2 weeks. Oral ivermectin is a reasonable alternative to permethrin cream due to its low cost and easy administration in large affected groups. It is not labeled for use in pregnant women or children weighing less than 15 kg but has no selective fetal toxicity. Treatment of scabies with ivermectin has the benefit of treating many other parasitic infections. Both medications are on the World Health Organization Model List of Essential Medications and are widely available for treating providers, even in resource-limited settings.²⁴

Much of the world still uses benzyl benzoate or precipitated sulfur ointment to treat scabies, and some botanicals used in folk medicine have genuine antiscabetic properties. Pruritus may persist for 1 to 4 weeks following treatment and does not indicate treatment failure. Topical camphor and menthol preparations, low-potency topical corticosteroids, or emollients all may be employed for relief.²⁵Sarna is a Spanish term for scabies and has become the proprietary name for topical antipruritic agents. Additional methods of treatment and prevention include washing clothes and linens in hot water and drying on high heat. If machine washing is not available, clothing and linens may be sealed in a plastic bag for 72 hours.

Pediculosis

Pediculosis is an infestation caused by the ectoparasite Pediculus humanus, an obligate, sesame seed–sized louse that feeds exclusively on the blood of its host (Figure 2).²⁶ Of the lice species, 2 require humans as hosts; one is P humanus and the other is Pthirus pubis (pubic lice). Pediculus humanus may be further classified into morphologies based largely on the affected area: body (P humanus corporis) or head (P humanus capitis), both of which will be discussed.²⁷

CT113004016_fig2.jpg

Lice primarily attach to clothing and hair shafts, then transfer to the skin for blood feeds. Females lay eggs that hatch 6 to 10 days later, subsequently maturing into adults. The lifespan of these parasites with regular access to a host is 1 to 3 months for head lice and 18 days for body lice vs only 3 to 5 days without a host.²⁸ Transmission of P humanus capitis primarily occurs via direct contact with affected individuals, either head-to-head contact or sharing of items such as brushes and headscarves; P humanus corporis also may be transmitted via direct contact with affected individuals or clothing.

Pediculosis is an important infestation to consider when providing care for refugee populations. Risk factors include lack of access to basic hygiene, including regular bathing or laundering of clothing, and crowded conditions that make direct person-to-person contact with affected individuals more likely.²⁹ Body lice are associated more often with domestic turbulence and displaced populations³⁰ in comparison to head lice, which have broad demographic variables, most often affecting females and children.²⁸ Fatty acids in adult male sebum make the scalp less hospitable to lice.

Presentation—The most common clinical manifestation of pediculosis is pruritus. Cutaneous findings can include papules, wheals, or hemorrhagic puncta secondary to the louse bite. Due to the Tyndall effect of deep hemosiderin pigment, blue-grey macules termed maculae ceruleae (Figure 3) also may be present in chronic infestations of pediculosis pubis, in contrast to pediculosis capitis or corporis.³¹ Body louse infestation is associated with a general pruritus concentrated on the neck, shoulders, and waist—areas where clothing makes the most direct contact. Lesions may be visible and include eczematous patches with excoriation and possible secondary bacterial infection. Chronic infestation may exhibit lichenification or hyperpigmentation in associated areas. Head lice most often manifest with localized scalp pruritus and associated excoriation and cervical or occipital lymphadenopathy.³²

CT113004016_fig3.jpg

Diagnosis—The diagnosis of pediculosis is clinical, with confirmation requiring direct examination of the insect or nits (the egg case of the parasite)(Figure 4). Body lice and associated nits can be visualized on clothing seams near areas of highest body temperature, particularly the waistband. Head lice may be visualized crawling on hair shafts or on a louse comb. Nits are firmly attached to hair shafts and are visible to the naked eye, whereas pseudonits slide freely along the hair shaft and are not a manifestation of louse infestation (Figure 5).³¹

CT113004016_fig4.jpg

Treatment—Treatment varies by affected area. Pediculosis corporis may be treated with permethrin cream 5% applied to the entire body and left on for 8 to 10 hours, but this may not be necessary if facilities are available to wash and dry clothing.³³ The use of oral ivermectin and permethrin-impregnated underwear both have been proposed.^34,35 Treatment of pediculosis capitis may be accomplished with a variety of topical pediculicides including permethrin, pyrethrum with piperonyl butoxide, dimethicone, malathion, benzyl alcohol, spinosad, and topical ivermectin.²² Topical corticosteroids or emollients may be employed for residual pruritus.

CT113004016_fig5.jpg

Equally important is environmental elimination of infestation. Clothing should be discarded if possible or washed and dried using high heat. If neither approach is possible or appropriate, clothing may be sealed in a plastic bag for 2 weeks or treated with a pediculicide. Nit combing is an important adjunct in the treatment of pediculosis capitis.³⁶ It is important to encourage return to work and/or school immediately after treatment. “No nit” policies are more harmful to education than helpful for prevention of investation.³⁷

Pediculosis corporis may transmit infectious agents including Bartonella quintana, (trench fever, endocarditis, bacillary angiomatosis), Borrelia recurrentis (louse-borne relapsing fever), and Rickettsia prowazekii (epidemic typhus).^31,38,39 Additionally, severe pediculosis infestations have the potential to cause chronic blood loss in affected populations. In a study of patients with active pediculosis infestation, mean hemoglobin values were found to be 2.5 g/dL lower than a matched population without infestation.⁴⁰ It is important to consider pediculosis as a risk for iron-deficiency anemia in populations who are known to lack access to regular medical evaluation.⁴¹

Future Considerations

Increased access to tools and education for clinicians treating refugee populations is key to reducing the burden of parasitic skin disease and related morbidity and mortality in vulnerable groups both domestically and globally. One such tool, the Skin NTDs App, was launched by the World Health Organization in 2020. It is available for free for Android and iOS devices to assist clinicians in the field with the diagnosis and treatment of neglected tropical diseases—including scabies—that may affect refugee populations.⁴²

Additionally, to both improve access and limit preventable sequelae, future investigations into appropriate models of community-based care are paramount. The model of community-based care is centered on the idea of care provision that prioritizes safety, accessibility, affordability, and acceptability in an environment closest to vulnerable populations. The largest dermatologic society, the International League of Dermatological Societies, formed a Migrant Health Dermatology Working Group that prioritizes understanding and improving care for refugee and migrant populations; this group hosted a summit in 2022, bringing together international subject matter leaders to discuss such models of care and set goals for the creation of tool kits for patients, frontline health care workers, and dermatologists.⁴³

Conclusion

Improvement in dermatologic care of refugee populations includes provision of culturally and linguistically appropriate care by trained clinicians, adequate access to the most essential medications, and basic physical or legal access to health care systems in general.^8,11,44 Parasitic infestations have the potential to remain asymptomatic for extended periods of time and result in spread to potentially nonendemic regions of resettlement.⁴⁵ Additionally, the psychosocial well-being of refugee populations upon resettlement may be negatively affected by stigma of disease processes such as scabies and pediculosis, leading to additional barriers to successful re-entry into the patient’s new environment.⁴⁶ Therefore, proper screening, diagnosis, and treatment of the most common parasitic infestations in this population have great potential to improve outcomes for large groups across the globe.

Approximately 108 million individuals have been forcibly displaced across the globe as of 2022, 35 million of whom are formally designated as refugees.^1,2 The United States has coordinated resettlement of more refugee populations than any other country; the most common countries of origin are the Democratic Republic of the Congo, Syria, Afghanistan, and Myanmar.³ In 2021, policy to increase the number of refugees resettled in the United States by more than 700% (from 15,000 up to 125,000) was established; since enactment, the United States has seen more than double the refugee arrivals in 2023 than the prior year, making medical care for this population increasingly relevant for the dermatologist.⁴

Understanding how to care for this population begins with an accurate understanding of the term refugee. The United Nations defines a refugee as a person who is unwilling or unable to return to their country of nationality because of persecution or well-founded fear of persecution due to race, religion, nationality, membership in a particular social group, or political opinion. This term grants a protected status under international law and encompasses access to travel assistance, housing, cultural orientation, and medical evaluation upon resettlement.^5,6

The burden of treatable dermatologic conditions in refugee populations ranges from 19% to 96% in the literature^7,8 and varies from inflammatory disorders to infectious and parasitic diseases.⁹ In one study of 6899 displaced individuals in Greece, the prevalence of dermatologic conditions was higher than traumatic injury, cardiac disease, psychological conditions, and dental disease.¹⁰

When outlining differential diagnoses for parasitic infestations of the skin that affect refugee populations, helpful considerations include the individual’s country of origin, route traveled, and method of travel.¹¹ Parasitic infestations specifically are more common in refugee populations when there are barriers to basic hygiene, crowded living or travel conditions, or lack of access to health care, which they may experience at any point in their home country, during travel, or in resettlement housing.⁸

Even with limited examination and diagnostic resources, the skin is the most accessible first indication of patients’ overall well-being and often provides simple diagnostic clues—in combination with contextualization of the patient’s unique circumstances—necessary for successful diagnosis and treatment of scabies and pediculosis.¹² The dermatologist working with refugee populations may be the first set of eyes available and trained to discern skin infestations and therefore has the potential to improve overall outcomes.

Some parasitic infestations in refugee populations may fall under the category of neglected tropical diseases, including scabies, ascariasis, trypanosomiasis, leishmaniasis, and schistosomiasis; they affect an estimated 1 billion individuals across the globe but historically have been underrepresented in the literature and in health policy due in part to limited access to care.¹³ This review will focus on infestations by the scabies mite (Sarcoptes scabiei var hominis) and the human louse, as these frequently are encountered, easily diagnosed, and treatable by trained clinicians, even in resource-limited settings.

Scabies

Scabies is a parasitic skin infestation caused by the 8-legged mite Sarcoptes scabiei var hominis. The female mite begins the infestation process via penetration of the epidermis, particularly the stratum corneum, and commences laying eggs (Figure 1). The subsequent larvae emerge 48 to 72 hours later and remain burrowed in the epidermis. The larvae mature over the next 10 to 14 days and continue the reproductive cycle.^14,15 Symptoms of infestation occurs due to a hypersensitivity reaction to the mite and its by-products.¹⁶ Transmission of the mite primarily occurs via direct (skin-to-skin) contact with infected individuals or environmental surfaces for 24 to36 hours in specific conditions, though the latter source has been debated in the literature.

CT113004016_fig1.jpg

The method of transmission is particularly important when considering care for refugee populations. Scabies is found most often in those living in or traveling from tropical regions including East Asia, Southeast Asia, Oceania, and Latin America.¹⁷ In displaced or refugee populations, a lack of access to basic hygiene, extended travel in close quarters, and suboptimal health care access all may lead to an increased incidence of untreated scabies infestations.¹⁸ Scabies is more prevalent in children, with increased potential for secondary bacterial infections with Streptococcus and Staphylococcus species due to excoriation in unsanitary conditions. Secondary infection with Streptococcus pyogenes can lead to acute poststreptococcal glomerulonephritis, which accounts for a large burden of chronic kidney disease in affected populations.¹⁹ However, scabies may be found in any population, regardless of hygiene or health care access. Treating health care providers should keep a broad differential.

Presentation—The latency of scabies symptoms is 2 to 6 weeks in a primary outbreak and may be as short as 1 to 3 days with re-infestation, following the course of delayed-type hypersensitivity.²⁰ The initial hallmark symptom is pruritus with increased severity in the evening. Visible lesions, excoriations, and burrows associated with scattered vesicles or pustules may be seen over the web spaces of the hands and feet, volar surfaces of the wrists, axillae, waist, genitalia, inner thighs, or buttocks.¹⁹ Chronic infestation often manifests with genital nodules. In populations with limited access to health care, there are reports of a sensitization phenomenon in which the individual may become less symptomatic after 4 to 6 weeks and yet be a potential carrier of the mite.²¹

Those with compromised immune function, such as individuals living with HIV or severe malnutrition, may present with crusted scabies, a variant that manifests as widespread hyperkeratotic scaling with more pronounced involvement of the head, neck, and acral areas. In contrast to classic scabies, crusted scabies is associated with minimal pruritus.²²

Diagnosis—The diagnosis of scabies is largely clinical with confirmation through skin scrapings. The International Alliance for Control of Scabies has established diagnostic criteria that include a combination of clinical findings, history, and visualization of mites.²³ A dermatologist working with refugee populations may employ any combination of history (eg, nocturnal itch, exposure to an affected individual) or clinical findings along with a high degree of suspicion in those with elevated risk. Visualization of mites is helpful to confirm the diagnosis and may be completed with the application of mineral oil at the terminal end of a burrow, skin scraping with a surgical blade or needle, and examination under light microscopy.

Treatment—First-line treatment for scabies consists of application of permethrin cream 5% on the skin of the neck to the soles of the feet, which is to be left on for 8 to 14 hours followed by rinsing. Re-application is recommended in 1 to 2 weeks. Oral ivermectin is a reasonable alternative to permethrin cream due to its low cost and easy administration in large affected groups. It is not labeled for use in pregnant women or children weighing less than 15 kg but has no selective fetal toxicity. Treatment of scabies with ivermectin has the benefit of treating many other parasitic infections. Both medications are on the World Health Organization Model List of Essential Medications and are widely available for treating providers, even in resource-limited settings.²⁴

Much of the world still uses benzyl benzoate or precipitated sulfur ointment to treat scabies, and some botanicals used in folk medicine have genuine antiscabetic properties. Pruritus may persist for 1 to 4 weeks following treatment and does not indicate treatment failure. Topical camphor and menthol preparations, low-potency topical corticosteroids, or emollients all may be employed for relief.²⁵Sarna is a Spanish term for scabies and has become the proprietary name for topical antipruritic agents. Additional methods of treatment and prevention include washing clothes and linens in hot water and drying on high heat. If machine washing is not available, clothing and linens may be sealed in a plastic bag for 72 hours.

Pediculosis

Pediculosis is an infestation caused by the ectoparasite Pediculus humanus, an obligate, sesame seed–sized louse that feeds exclusively on the blood of its host (Figure 2).²⁶ Of the lice species, 2 require humans as hosts; one is P humanus and the other is Pthirus pubis (pubic lice). Pediculus humanus may be further classified into morphologies based largely on the affected area: body (P humanus corporis) or head (P humanus capitis), both of which will be discussed.²⁷

CT113004016_fig2.jpg

Lice primarily attach to clothing and hair shafts, then transfer to the skin for blood feeds. Females lay eggs that hatch 6 to 10 days later, subsequently maturing into adults. The lifespan of these parasites with regular access to a host is 1 to 3 months for head lice and 18 days for body lice vs only 3 to 5 days without a host.²⁸ Transmission of P humanus capitis primarily occurs via direct contact with affected individuals, either head-to-head contact or sharing of items such as brushes and headscarves; P humanus corporis also may be transmitted via direct contact with affected individuals or clothing.

Pediculosis is an important infestation to consider when providing care for refugee populations. Risk factors include lack of access to basic hygiene, including regular bathing or laundering of clothing, and crowded conditions that make direct person-to-person contact with affected individuals more likely.²⁹ Body lice are associated more often with domestic turbulence and displaced populations³⁰ in comparison to head lice, which have broad demographic variables, most often affecting females and children.²⁸ Fatty acids in adult male sebum make the scalp less hospitable to lice.

Presentation—The most common clinical manifestation of pediculosis is pruritus. Cutaneous findings can include papules, wheals, or hemorrhagic puncta secondary to the louse bite. Due to the Tyndall effect of deep hemosiderin pigment, blue-grey macules termed maculae ceruleae (Figure 3) also may be present in chronic infestations of pediculosis pubis, in contrast to pediculosis capitis or corporis.³¹ Body louse infestation is associated with a general pruritus concentrated on the neck, shoulders, and waist—areas where clothing makes the most direct contact. Lesions may be visible and include eczematous patches with excoriation and possible secondary bacterial infection. Chronic infestation may exhibit lichenification or hyperpigmentation in associated areas. Head lice most often manifest with localized scalp pruritus and associated excoriation and cervical or occipital lymphadenopathy.³²

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Diagnosis—The diagnosis of pediculosis is clinical, with confirmation requiring direct examination of the insect or nits (the egg case of the parasite)(Figure 4). Body lice and associated nits can be visualized on clothing seams near areas of highest body temperature, particularly the waistband. Head lice may be visualized crawling on hair shafts or on a louse comb. Nits are firmly attached to hair shafts and are visible to the naked eye, whereas pseudonits slide freely along the hair shaft and are not a manifestation of louse infestation (Figure 5).³¹

CT113004016_fig4.jpg

Treatment—Treatment varies by affected area. Pediculosis corporis may be treated with permethrin cream 5% applied to the entire body and left on for 8 to 10 hours, but this may not be necessary if facilities are available to wash and dry clothing.³³ The use of oral ivermectin and permethrin-impregnated underwear both have been proposed.^34,35 Treatment of pediculosis capitis may be accomplished with a variety of topical pediculicides including permethrin, pyrethrum with piperonyl butoxide, dimethicone, malathion, benzyl alcohol, spinosad, and topical ivermectin.²² Topical corticosteroids or emollients may be employed for residual pruritus.

CT113004016_fig5.jpg

Equally important is environmental elimination of infestation. Clothing should be discarded if possible or washed and dried using high heat. If neither approach is possible or appropriate, clothing may be sealed in a plastic bag for 2 weeks or treated with a pediculicide. Nit combing is an important adjunct in the treatment of pediculosis capitis.³⁶ It is important to encourage return to work and/or school immediately after treatment. “No nit” policies are more harmful to education than helpful for prevention of investation.³⁷

Pediculosis corporis may transmit infectious agents including Bartonella quintana, (trench fever, endocarditis, bacillary angiomatosis), Borrelia recurrentis (louse-borne relapsing fever), and Rickettsia prowazekii (epidemic typhus).^31,38,39 Additionally, severe pediculosis infestations have the potential to cause chronic blood loss in affected populations. In a study of patients with active pediculosis infestation, mean hemoglobin values were found to be 2.5 g/dL lower than a matched population without infestation.⁴⁰ It is important to consider pediculosis as a risk for iron-deficiency anemia in populations who are known to lack access to regular medical evaluation.⁴¹

Future Considerations

Increased access to tools and education for clinicians treating refugee populations is key to reducing the burden of parasitic skin disease and related morbidity and mortality in vulnerable groups both domestically and globally. One such tool, the Skin NTDs App, was launched by the World Health Organization in 2020. It is available for free for Android and iOS devices to assist clinicians in the field with the diagnosis and treatment of neglected tropical diseases—including scabies—that may affect refugee populations.⁴²

Additionally, to both improve access and limit preventable sequelae, future investigations into appropriate models of community-based care are paramount. The model of community-based care is centered on the idea of care provision that prioritizes safety, accessibility, affordability, and acceptability in an environment closest to vulnerable populations. The largest dermatologic society, the International League of Dermatological Societies, formed a Migrant Health Dermatology Working Group that prioritizes understanding and improving care for refugee and migrant populations; this group hosted a summit in 2022, bringing together international subject matter leaders to discuss such models of care and set goals for the creation of tool kits for patients, frontline health care workers, and dermatologists.⁴³

Conclusion

Improvement in dermatologic care of refugee populations includes provision of culturally and linguistically appropriate care by trained clinicians, adequate access to the most essential medications, and basic physical or legal access to health care systems in general.^8,11,44 Parasitic infestations have the potential to remain asymptomatic for extended periods of time and result in spread to potentially nonendemic regions of resettlement.⁴⁵ Additionally, the psychosocial well-being of refugee populations upon resettlement may be negatively affected by stigma of disease processes such as scabies and pediculosis, leading to additional barriers to successful re-entry into the patient’s new environment.⁴⁶ Therefore, proper screening, diagnosis, and treatment of the most common parasitic infestations in this population have great potential to improve outcomes for large groups across the globe.

The Diagnosis: Subcutaneous Fat Necrosis

Histopathology revealed lobular panniculitis with lymphohistiocytic inflammation, lipid crystals, and calcifications in our patient (Figure). Subcutaneous fat necrosis (SCFN) was diagnosed based on these characteristic histopathologic findings. No further treatment was pursued.

CT113004027_figAB.jpg

Subcutaneous fat necrosis is a rare, self-limiting panniculitis that typically resolves within several weeks to months without scarring. It manifests as red or violaceous subcutaneous nodules or plaques most commonly on the buttocks, trunk, proximal arms and legs, and cheeks.¹ Histopathology reveals lobular panniculitis with dense granulomatous infiltrates of histiocytes, eosinophils, and multinucleated giant cells with needle-shaped crystals. Focal areas of fat necrosis with calcification also can be seen.²

The epidemiology of SCFN is unknown. Most cases occur in healthy full-term to postterm neonates who experience hypoxia, other prenatal stressors, or therapeutic hypothermia for the treatment of hypoxic-ischemic encephalopathy.³ Although the etiology is unclear, certain inciting factors such as local tissue hypoxia, cold exposure, meconium aspiration, maternal diabetes, preeclampsia, and mechanical pressure have been proposed. Our patient underwent hypothermic cooling protocol, and it has been suggested that the increased saturated to unsaturated fat concentration in the skin of newborns increases the melting point, thus predisposing them to fat crystalization.⁴ Cases of SCFN involving the scalp are rare; therefore, any newborns receiving hypothermic therapy for hypoxic-ischemic encephalopathy should have a thorough skin examination with possible biopsy of lesions that are characteristic of SCFN, such as red or violaceous subcutaneous nodules or plaques, for specific disease identification.

The main complication of SCFN is hypercalcemia, which occurs in approximately 50% of cases. Other serum abnormalities include hyperglycemia, hypertriglyceridemia, and thrombocytopenia, though these findings are not as well associated.⁴ Patients with associated hypercalcemia may be asymptomatic, as in our patient, but other presentations include irritability, weakness, anorexia, vomiting, renal failure, failure to thrive, and encephalopathy. Nephrocalcinosis is a common complication of severe hypercalcemia; however, there is little evidence of associated major renal dysfunction.⁵ The exact mechanism of hypercalcemia is poorly understood. A widely accepted theory postulates that a granulomatous inflammatory infiltrate upregulates 1-α-hydroxylase activity, which enzymatically converts 25-hydroxyvitamin D to its active form, 1,25-dihydroxycholecalciferol, which increases bone resorption and calcium absorption through the gastrointestinal tract and renal systems. Treatments for hypercalcemia include hyperhydration, calcium-wasting diuretics, and low calcium intake.⁶ Furthermore, calcium levels should be obtained at the time of diagnosis and 30, 45, and 60 days after the lesions resolve.⁴

Subcutaneous fat necrosis needs to be differentiated from the more severe panniculitis, sclerema neonatorum (SN), which typically affects critically ill, preterm, and small-for-gestational-age newborns. It is associated with a high mortality rate and is characterized by skin and subadjacent tissue structures. The process typically begins in the thighs, buttocks, or trunk and spreads diffusely, sparing the fat-free palms, soles, and genitalia.⁷ Although our patient was born preterm, the physical characteristics of the nodule and the lack of severe illness placed SN lower on our differential. Histopathologic differences between SCFN and SN involve the extent of tissue fibrosis and presence of inflammatory cells. Sclerema neonatorum typically manifests with thickened connective tissue with a sparse inflammatory infiltrate, including lymphocytes, histiocytes, and multinucleated giant cells.⁷ Conversely, SCFN manifests with fat necrosis with an extensive inflammatory infiltrate. It is important to be able to distinguish between these 2 conditions, as both have vastly different prognoses.

Cold panniculitis, sometimes called “popsicle panniculitis,” is a phenomenon in which cold contact with the skin causes eruption of firm, erythematous, indurated plaques at the site of exposure. This self-limiting condition typically appears hours to days after cold exposure and spontaneously resolves in a few weeks.⁸ Therapeutic hypothermic protocol treatment involves using cooling devices to lower the body temperature for a short duration. The temperature typically is lowered to approximately 32 °C to 36 °C. These temperatures are not low enough to induce cold panniculitis, which is more commonly seen in facial ice applications when managing supraventricular tachycardia in neonates.

Cephalohematoma is a birthing injury that causes blood accumulation within the subperiosteal space. During parturition, the compressive and sheering forces on the calvarium rupture the vessels passing through the periosteum, causing blood to pool slowly into the subperiostium; thus, a cephalohematoma usually manifests later at 1 to 3 days of life as localized head swelling.⁹ The bleeding typically does not cross suture lines and is primarily found in the occipital or parietal regions. The incidence has been reported to be 0.4% to 2.5% of all live births.¹⁰ Although the location of the nodule in our patient was in the occipital region, imaging and biopsy results did not show hemorrhagic findings consistent with cephalohematoma. Management of cephalohematoma mainly is observational, as the mass slowly regresses and the accumulated blood gradually is reabsorbed.

Fungal scalp infections (tinea capitis) are common in the pediatric population. The peak incidence of this infection has been reported in children aged 3 to 7 years, with Trichophyton tonsurans and Microsporum canis as the usual causative organisms.¹¹ Clinical features of tinea capitis include scaly patches with hair loss, hair loss with black pigmented dots at the follicular openings, diffuse scalp scaling with subtle hair loss, and cervical lymphadenopathy.¹² Although less common, tinea capitis can progress to a more severe form known as a kerion, which is characterized by a tender plaque with pustules and crusting. A kerion can result in permanent scarring and alopecia if left untreated.¹² In our patient, a nodule with scaling and faint erythema was observed, but no black pigmented dots at the follicular orifices were present. Therefore, a potassium hydroxide wet mount preparation used to diagnose tinea capitis was unnecessary. Systemic oral antifungal therapy such as fluconazole or terbinafine is the standard treatment for tinea capitis.

The Diagnosis: Subcutaneous Fat Necrosis

Histopathology revealed lobular panniculitis with lymphohistiocytic inflammation, lipid crystals, and calcifications in our patient (Figure). Subcutaneous fat necrosis (SCFN) was diagnosed based on these characteristic histopathologic findings. No further treatment was pursued.

CT113004027_figAB.jpg

Subcutaneous fat necrosis is a rare, self-limiting panniculitis that typically resolves within several weeks to months without scarring. It manifests as red or violaceous subcutaneous nodules or plaques most commonly on the buttocks, trunk, proximal arms and legs, and cheeks.¹ Histopathology reveals lobular panniculitis with dense granulomatous infiltrates of histiocytes, eosinophils, and multinucleated giant cells with needle-shaped crystals. Focal areas of fat necrosis with calcification also can be seen.²

The epidemiology of SCFN is unknown. Most cases occur in healthy full-term to postterm neonates who experience hypoxia, other prenatal stressors, or therapeutic hypothermia for the treatment of hypoxic-ischemic encephalopathy.³ Although the etiology is unclear, certain inciting factors such as local tissue hypoxia, cold exposure, meconium aspiration, maternal diabetes, preeclampsia, and mechanical pressure have been proposed. Our patient underwent hypothermic cooling protocol, and it has been suggested that the increased saturated to unsaturated fat concentration in the skin of newborns increases the melting point, thus predisposing them to fat crystalization.⁴ Cases of SCFN involving the scalp are rare; therefore, any newborns receiving hypothermic therapy for hypoxic-ischemic encephalopathy should have a thorough skin examination with possible biopsy of lesions that are characteristic of SCFN, such as red or violaceous subcutaneous nodules or plaques, for specific disease identification.

The main complication of SCFN is hypercalcemia, which occurs in approximately 50% of cases. Other serum abnormalities include hyperglycemia, hypertriglyceridemia, and thrombocytopenia, though these findings are not as well associated.⁴ Patients with associated hypercalcemia may be asymptomatic, as in our patient, but other presentations include irritability, weakness, anorexia, vomiting, renal failure, failure to thrive, and encephalopathy. Nephrocalcinosis is a common complication of severe hypercalcemia; however, there is little evidence of associated major renal dysfunction.⁵ The exact mechanism of hypercalcemia is poorly understood. A widely accepted theory postulates that a granulomatous inflammatory infiltrate upregulates 1-α-hydroxylase activity, which enzymatically converts 25-hydroxyvitamin D to its active form, 1,25-dihydroxycholecalciferol, which increases bone resorption and calcium absorption through the gastrointestinal tract and renal systems. Treatments for hypercalcemia include hyperhydration, calcium-wasting diuretics, and low calcium intake.⁶ Furthermore, calcium levels should be obtained at the time of diagnosis and 30, 45, and 60 days after the lesions resolve.⁴

Subcutaneous fat necrosis needs to be differentiated from the more severe panniculitis, sclerema neonatorum (SN), which typically affects critically ill, preterm, and small-for-gestational-age newborns. It is associated with a high mortality rate and is characterized by skin and subadjacent tissue structures. The process typically begins in the thighs, buttocks, or trunk and spreads diffusely, sparing the fat-free palms, soles, and genitalia.⁷ Although our patient was born preterm, the physical characteristics of the nodule and the lack of severe illness placed SN lower on our differential. Histopathologic differences between SCFN and SN involve the extent of tissue fibrosis and presence of inflammatory cells. Sclerema neonatorum typically manifests with thickened connective tissue with a sparse inflammatory infiltrate, including lymphocytes, histiocytes, and multinucleated giant cells.⁷ Conversely, SCFN manifests with fat necrosis with an extensive inflammatory infiltrate. It is important to be able to distinguish between these 2 conditions, as both have vastly different prognoses.

Cold panniculitis, sometimes called “popsicle panniculitis,” is a phenomenon in which cold contact with the skin causes eruption of firm, erythematous, indurated plaques at the site of exposure. This self-limiting condition typically appears hours to days after cold exposure and spontaneously resolves in a few weeks.⁸ Therapeutic hypothermic protocol treatment involves using cooling devices to lower the body temperature for a short duration. The temperature typically is lowered to approximately 32 °C to 36 °C. These temperatures are not low enough to induce cold panniculitis, which is more commonly seen in facial ice applications when managing supraventricular tachycardia in neonates.

Cephalohematoma is a birthing injury that causes blood accumulation within the subperiosteal space. During parturition, the compressive and sheering forces on the calvarium rupture the vessels passing through the periosteum, causing blood to pool slowly into the subperiostium; thus, a cephalohematoma usually manifests later at 1 to 3 days of life as localized head swelling.⁹ The bleeding typically does not cross suture lines and is primarily found in the occipital or parietal regions. The incidence has been reported to be 0.4% to 2.5% of all live births.¹⁰ Although the location of the nodule in our patient was in the occipital region, imaging and biopsy results did not show hemorrhagic findings consistent with cephalohematoma. Management of cephalohematoma mainly is observational, as the mass slowly regresses and the accumulated blood gradually is reabsorbed.

Fungal scalp infections (tinea capitis) are common in the pediatric population. The peak incidence of this infection has been reported in children aged 3 to 7 years, with Trichophyton tonsurans and Microsporum canis as the usual causative organisms.¹¹ Clinical features of tinea capitis include scaly patches with hair loss, hair loss with black pigmented dots at the follicular openings, diffuse scalp scaling with subtle hair loss, and cervical lymphadenopathy.¹² Although less common, tinea capitis can progress to a more severe form known as a kerion, which is characterized by a tender plaque with pustules and crusting. A kerion can result in permanent scarring and alopecia if left untreated.¹² In our patient, a nodule with scaling and faint erythema was observed, but no black pigmented dots at the follicular orifices were present. Therefore, a potassium hydroxide wet mount preparation used to diagnose tinea capitis was unnecessary. Systemic oral antifungal therapy such as fluconazole or terbinafine is the standard treatment for tinea capitis.

The Diagnosis: Subcutaneous Fat Necrosis

Histopathology revealed lobular panniculitis with lymphohistiocytic inflammation, lipid crystals, and calcifications in our patient (Figure). Subcutaneous fat necrosis (SCFN) was diagnosed based on these characteristic histopathologic findings. No further treatment was pursued.

CT113004027_figAB.jpg

Subcutaneous fat necrosis is a rare, self-limiting panniculitis that typically resolves within several weeks to months without scarring. It manifests as red or violaceous subcutaneous nodules or plaques most commonly on the buttocks, trunk, proximal arms and legs, and cheeks.¹ Histopathology reveals lobular panniculitis with dense granulomatous infiltrates of histiocytes, eosinophils, and multinucleated giant cells with needle-shaped crystals. Focal areas of fat necrosis with calcification also can be seen.²

The epidemiology of SCFN is unknown. Most cases occur in healthy full-term to postterm neonates who experience hypoxia, other prenatal stressors, or therapeutic hypothermia for the treatment of hypoxic-ischemic encephalopathy.³ Although the etiology is unclear, certain inciting factors such as local tissue hypoxia, cold exposure, meconium aspiration, maternal diabetes, preeclampsia, and mechanical pressure have been proposed. Our patient underwent hypothermic cooling protocol, and it has been suggested that the increased saturated to unsaturated fat concentration in the skin of newborns increases the melting point, thus predisposing them to fat crystalization.⁴ Cases of SCFN involving the scalp are rare; therefore, any newborns receiving hypothermic therapy for hypoxic-ischemic encephalopathy should have a thorough skin examination with possible biopsy of lesions that are characteristic of SCFN, such as red or violaceous subcutaneous nodules or plaques, for specific disease identification.

The main complication of SCFN is hypercalcemia, which occurs in approximately 50% of cases. Other serum abnormalities include hyperglycemia, hypertriglyceridemia, and thrombocytopenia, though these findings are not as well associated.⁴ Patients with associated hypercalcemia may be asymptomatic, as in our patient, but other presentations include irritability, weakness, anorexia, vomiting, renal failure, failure to thrive, and encephalopathy. Nephrocalcinosis is a common complication of severe hypercalcemia; however, there is little evidence of associated major renal dysfunction.⁵ The exact mechanism of hypercalcemia is poorly understood. A widely accepted theory postulates that a granulomatous inflammatory infiltrate upregulates 1-α-hydroxylase activity, which enzymatically converts 25-hydroxyvitamin D to its active form, 1,25-dihydroxycholecalciferol, which increases bone resorption and calcium absorption through the gastrointestinal tract and renal systems. Treatments for hypercalcemia include hyperhydration, calcium-wasting diuretics, and low calcium intake.⁶ Furthermore, calcium levels should be obtained at the time of diagnosis and 30, 45, and 60 days after the lesions resolve.⁴

Subcutaneous fat necrosis needs to be differentiated from the more severe panniculitis, sclerema neonatorum (SN), which typically affects critically ill, preterm, and small-for-gestational-age newborns. It is associated with a high mortality rate and is characterized by skin and subadjacent tissue structures. The process typically begins in the thighs, buttocks, or trunk and spreads diffusely, sparing the fat-free palms, soles, and genitalia.⁷ Although our patient was born preterm, the physical characteristics of the nodule and the lack of severe illness placed SN lower on our differential. Histopathologic differences between SCFN and SN involve the extent of tissue fibrosis and presence of inflammatory cells. Sclerema neonatorum typically manifests with thickened connective tissue with a sparse inflammatory infiltrate, including lymphocytes, histiocytes, and multinucleated giant cells.⁷ Conversely, SCFN manifests with fat necrosis with an extensive inflammatory infiltrate. It is important to be able to distinguish between these 2 conditions, as both have vastly different prognoses.

Cold panniculitis, sometimes called “popsicle panniculitis,” is a phenomenon in which cold contact with the skin causes eruption of firm, erythematous, indurated plaques at the site of exposure. This self-limiting condition typically appears hours to days after cold exposure and spontaneously resolves in a few weeks.⁸ Therapeutic hypothermic protocol treatment involves using cooling devices to lower the body temperature for a short duration. The temperature typically is lowered to approximately 32 °C to 36 °C. These temperatures are not low enough to induce cold panniculitis, which is more commonly seen in facial ice applications when managing supraventricular tachycardia in neonates.

Cephalohematoma is a birthing injury that causes blood accumulation within the subperiosteal space. During parturition, the compressive and sheering forces on the calvarium rupture the vessels passing through the periosteum, causing blood to pool slowly into the subperiostium; thus, a cephalohematoma usually manifests later at 1 to 3 days of life as localized head swelling.⁹ The bleeding typically does not cross suture lines and is primarily found in the occipital or parietal regions. The incidence has been reported to be 0.4% to 2.5% of all live births.¹⁰ Although the location of the nodule in our patient was in the occipital region, imaging and biopsy results did not show hemorrhagic findings consistent with cephalohematoma. Management of cephalohematoma mainly is observational, as the mass slowly regresses and the accumulated blood gradually is reabsorbed.

Fungal scalp infections (tinea capitis) are common in the pediatric population. The peak incidence of this infection has been reported in children aged 3 to 7 years, with Trichophyton tonsurans and Microsporum canis as the usual causative organisms.¹¹ Clinical features of tinea capitis include scaly patches with hair loss, hair loss with black pigmented dots at the follicular openings, diffuse scalp scaling with subtle hair loss, and cervical lymphadenopathy.¹² Although less common, tinea capitis can progress to a more severe form known as a kerion, which is characterized by a tender plaque with pustules and crusting. A kerion can result in permanent scarring and alopecia if left untreated.¹² In our patient, a nodule with scaling and faint erythema was observed, but no black pigmented dots at the follicular orifices were present. Therefore, a potassium hydroxide wet mount preparation used to diagnose tinea capitis was unnecessary. Systemic oral antifungal therapy such as fluconazole or terbinafine is the standard treatment for tinea capitis.

The Diagnosis: Erythrodermic Allergic Contact Dermatitis

The worsening symptoms in our patient prompted intervention rather than observation and reassurance. Contact allergy to lanolin was suspected given the worsening presentation after the addition of Minerin, which was immediately discontinued. The patient’s family applied betamethasone cream 0.1% twice daily to severe plaques, pimecrolimus cream 1% to the face, and triamcinolone cream 0.1% to the rest of the body. At follow-up 1 week later, he experienced complete resolution of symptoms, which supported the diagnosis of erythrodermic allergic contact dermatitis (ACD).

The prevalence of ACD caused by lanolin varies among the general population from 1.2% to 6.9%.¹ Lanolin recently was named Allergen of the Year in 2023 by the American Contact Dermatitis Society.² It can be found in various commercial products, including creams, soaps, and ointments. Atopic dermatitis (AD) is a common pediatric inflammatory skin disorder that typically is treated with these products.³ In a study analyzing 533 products, up to 6% of skin care products for babies and children contained lanolin.⁴ Therefore, exposure to lanolin-containing products may be fairly common in the pediatric population.

Lanolin is a fatlike substance derived from sheep sebaceous gland secretions and extracted from sheep’s wool. Its composition varies by sheep breed, location, and extraction and purification methods. The most common allergens involve the alcoholic fraction produced by hydrolysis of lanolin.⁴ In 1996, Wolf⁵ described the “lanolin paradox,” which argued the difficulty with identifying lanolin as an allergen (similar to Fisher’s “paraben paradox”) based on 4 principles: (1) lanolin-containing topical medicaments tend to be more sensitizing than lanolin-containing cosmetics; (2) patients with ACD after applying lanolin-containing topical medicaments to damaged or ulcerated skin often can apply lanolin-containing cosmetics to normal or unaffected skin without a reaction; (3) false-negative patch test results often occur in lanolin-sensitive patients; and (4) patch testing with a single lanolin-containing agent (lanolin alcohol [30% in petrolatum]) is an unreliable and inadequate method of detecting lanolin allergy.^6,7 This theory elucidates the challenge of diagnosing contact allergies, particularly lanolin contact allergies.

Clinical features of acute ACD vary by skin type. Lighter skin types may have well-demarcated, pruritic, eczematous patches and plaques affecting the flexor surfaces. Asian patients may present with psoriasiform plaques with more well-demarcated borders and increased scaling and lichenification. In patients with darker skin types, dermatitis may manifest as papulation, lichenification, and color changes (violet, gray, or darker brown) along extensor surfaces.8 Chronic dermatitis manifests as lichenified scaly plaques. Given the diversity in dermatitis manifestation and the challenges of identifying erythema, especially in skin of color, clinicians may misidentify disease severity. These features aid in diagnosing and treating patients presenting with diffuse erythroderma and worsening eczematous patches and plaques despite use of typical topical treatments.

The differential diagnosis includes irritant contact dermatitis, AD, seborrheic dermatitis, and chronic plaque psoriasis. Negative patch testing suggests contact dermatitis based on exposure to a product. A thorough medication and personal history helps distinguish ACD from AD. Atopic dermatitis classically appears on the flexural areas, face, eyelids, and hands of patients with a personal or family history of atopy. Greasy scaly plaques on the central part of the face, eyelids, and scalp commonly are found in seborrheic dermatitis. In chronic plaque psoriasis, lesions typically are described as welldemarcated, inflamed plaques with notable scale located primarily in the scalp and diaper area in newborns and children until the age of 2 years. Our patient presented with scaly plaques throughout most of the body. The history of Minerin use over the course of 3 to 5 months and worsening skin eruptions involving a majority of the skin surface suggested continued exposure.

Patch testing assists in the diagnosis of ACD, with varying results due to manufacturing and processing inconsistencies in the composition of various substances used in the standard test sets, often making it difficult to diagnose lanolin as an allergen. According to Lee and Warshaw,6 the lack of uniformity within testing of lanolin-containing products may cause false-positive results, poor patch-test reproducibility, and loss of allergic contact response. A 2019 study utilized a combination of Amerchol L101 and lanolin alcohol to improve the diagnosis of lanolin allergy, as standard testing may not identify patients with lanolin sensitivities.1 A study with the North American Contact Dermatitis Group from 2005 to 2012 demonstrated that positive patch testing among children was the most consistent method for diagnosing ACD, and results were clinically relevant.⁹ However, the different lanolin-containing products are not standardized in patch testing, which often causes mixed reactions and does not definitely demonstrate classic positive results, even with the use of repeated open application tests.² Although there has been an emphasis on refining the standardization of the lanolin used for patch testing, lanolin contact allergy remains a predominantly clinical diagnosis.

Both AD and ACD are common pediatric skin findings, and mixed positive and neutral associations between AD and allergy to lanolin have been described in a few studies.^1,3,9,10 A history of atopy is more notable in a pediatric patient vs an adult, as sensitivities tend to subside into adulthood.⁹ Further studies and more precise testing are needed to investigate the relationship between AD and ACD.

The Diagnosis: Erythrodermic Allergic Contact Dermatitis

The worsening symptoms in our patient prompted intervention rather than observation and reassurance. Contact allergy to lanolin was suspected given the worsening presentation after the addition of Minerin, which was immediately discontinued. The patient’s family applied betamethasone cream 0.1% twice daily to severe plaques, pimecrolimus cream 1% to the face, and triamcinolone cream 0.1% to the rest of the body. At follow-up 1 week later, he experienced complete resolution of symptoms, which supported the diagnosis of erythrodermic allergic contact dermatitis (ACD).

The prevalence of ACD caused by lanolin varies among the general population from 1.2% to 6.9%.¹ Lanolin recently was named Allergen of the Year in 2023 by the American Contact Dermatitis Society.² It can be found in various commercial products, including creams, soaps, and ointments. Atopic dermatitis (AD) is a common pediatric inflammatory skin disorder that typically is treated with these products.³ In a study analyzing 533 products, up to 6% of skin care products for babies and children contained lanolin.⁴ Therefore, exposure to lanolin-containing products may be fairly common in the pediatric population.

Lanolin is a fatlike substance derived from sheep sebaceous gland secretions and extracted from sheep’s wool. Its composition varies by sheep breed, location, and extraction and purification methods. The most common allergens involve the alcoholic fraction produced by hydrolysis of lanolin.⁴ In 1996, Wolf⁵ described the “lanolin paradox,” which argued the difficulty with identifying lanolin as an allergen (similar to Fisher’s “paraben paradox”) based on 4 principles: (1) lanolin-containing topical medicaments tend to be more sensitizing than lanolin-containing cosmetics; (2) patients with ACD after applying lanolin-containing topical medicaments to damaged or ulcerated skin often can apply lanolin-containing cosmetics to normal or unaffected skin without a reaction; (3) false-negative patch test results often occur in lanolin-sensitive patients; and (4) patch testing with a single lanolin-containing agent (lanolin alcohol [30% in petrolatum]) is an unreliable and inadequate method of detecting lanolin allergy.^6,7 This theory elucidates the challenge of diagnosing contact allergies, particularly lanolin contact allergies.

Clinical features of acute ACD vary by skin type. Lighter skin types may have well-demarcated, pruritic, eczematous patches and plaques affecting the flexor surfaces. Asian patients may present with psoriasiform plaques with more well-demarcated borders and increased scaling and lichenification. In patients with darker skin types, dermatitis may manifest as papulation, lichenification, and color changes (violet, gray, or darker brown) along extensor surfaces.8 Chronic dermatitis manifests as lichenified scaly plaques. Given the diversity in dermatitis manifestation and the challenges of identifying erythema, especially in skin of color, clinicians may misidentify disease severity. These features aid in diagnosing and treating patients presenting with diffuse erythroderma and worsening eczematous patches and plaques despite use of typical topical treatments.

The differential diagnosis includes irritant contact dermatitis, AD, seborrheic dermatitis, and chronic plaque psoriasis. Negative patch testing suggests contact dermatitis based on exposure to a product. A thorough medication and personal history helps distinguish ACD from AD. Atopic dermatitis classically appears on the flexural areas, face, eyelids, and hands of patients with a personal or family history of atopy. Greasy scaly plaques on the central part of the face, eyelids, and scalp commonly are found in seborrheic dermatitis. In chronic plaque psoriasis, lesions typically are described as welldemarcated, inflamed plaques with notable scale located primarily in the scalp and diaper area in newborns and children until the age of 2 years. Our patient presented with scaly plaques throughout most of the body. The history of Minerin use over the course of 3 to 5 months and worsening skin eruptions involving a majority of the skin surface suggested continued exposure.

Patch testing assists in the diagnosis of ACD, with varying results due to manufacturing and processing inconsistencies in the composition of various substances used in the standard test sets, often making it difficult to diagnose lanolin as an allergen. According to Lee and Warshaw,6 the lack of uniformity within testing of lanolin-containing products may cause false-positive results, poor patch-test reproducibility, and loss of allergic contact response. A 2019 study utilized a combination of Amerchol L101 and lanolin alcohol to improve the diagnosis of lanolin allergy, as standard testing may not identify patients with lanolin sensitivities.1 A study with the North American Contact Dermatitis Group from 2005 to 2012 demonstrated that positive patch testing among children was the most consistent method for diagnosing ACD, and results were clinically relevant.⁹ However, the different lanolin-containing products are not standardized in patch testing, which often causes mixed reactions and does not definitely demonstrate classic positive results, even with the use of repeated open application tests.² Although there has been an emphasis on refining the standardization of the lanolin used for patch testing, lanolin contact allergy remains a predominantly clinical diagnosis.

Both AD and ACD are common pediatric skin findings, and mixed positive and neutral associations between AD and allergy to lanolin have been described in a few studies.^1,3,9,10 A history of atopy is more notable in a pediatric patient vs an adult, as sensitivities tend to subside into adulthood.⁹ Further studies and more precise testing are needed to investigate the relationship between AD and ACD.

The Diagnosis: Erythrodermic Allergic Contact Dermatitis

The worsening symptoms in our patient prompted intervention rather than observation and reassurance. Contact allergy to lanolin was suspected given the worsening presentation after the addition of Minerin, which was immediately discontinued. The patient’s family applied betamethasone cream 0.1% twice daily to severe plaques, pimecrolimus cream 1% to the face, and triamcinolone cream 0.1% to the rest of the body. At follow-up 1 week later, he experienced complete resolution of symptoms, which supported the diagnosis of erythrodermic allergic contact dermatitis (ACD).

The prevalence of ACD caused by lanolin varies among the general population from 1.2% to 6.9%.¹ Lanolin recently was named Allergen of the Year in 2023 by the American Contact Dermatitis Society.² It can be found in various commercial products, including creams, soaps, and ointments. Atopic dermatitis (AD) is a common pediatric inflammatory skin disorder that typically is treated with these products.³ In a study analyzing 533 products, up to 6% of skin care products for babies and children contained lanolin.⁴ Therefore, exposure to lanolin-containing products may be fairly common in the pediatric population.

Lanolin is a fatlike substance derived from sheep sebaceous gland secretions and extracted from sheep’s wool. Its composition varies by sheep breed, location, and extraction and purification methods. The most common allergens involve the alcoholic fraction produced by hydrolysis of lanolin.⁴ In 1996, Wolf⁵ described the “lanolin paradox,” which argued the difficulty with identifying lanolin as an allergen (similar to Fisher’s “paraben paradox”) based on 4 principles: (1) lanolin-containing topical medicaments tend to be more sensitizing than lanolin-containing cosmetics; (2) patients with ACD after applying lanolin-containing topical medicaments to damaged or ulcerated skin often can apply lanolin-containing cosmetics to normal or unaffected skin without a reaction; (3) false-negative patch test results often occur in lanolin-sensitive patients; and (4) patch testing with a single lanolin-containing agent (lanolin alcohol [30% in petrolatum]) is an unreliable and inadequate method of detecting lanolin allergy.^6,7 This theory elucidates the challenge of diagnosing contact allergies, particularly lanolin contact allergies.

Clinical features of acute ACD vary by skin type. Lighter skin types may have well-demarcated, pruritic, eczematous patches and plaques affecting the flexor surfaces. Asian patients may present with psoriasiform plaques with more well-demarcated borders and increased scaling and lichenification. In patients with darker skin types, dermatitis may manifest as papulation, lichenification, and color changes (violet, gray, or darker brown) along extensor surfaces.8 Chronic dermatitis manifests as lichenified scaly plaques. Given the diversity in dermatitis manifestation and the challenges of identifying erythema, especially in skin of color, clinicians may misidentify disease severity. These features aid in diagnosing and treating patients presenting with diffuse erythroderma and worsening eczematous patches and plaques despite use of typical topical treatments.

The differential diagnosis includes irritant contact dermatitis, AD, seborrheic dermatitis, and chronic plaque psoriasis. Negative patch testing suggests contact dermatitis based on exposure to a product. A thorough medication and personal history helps distinguish ACD from AD. Atopic dermatitis classically appears on the flexural areas, face, eyelids, and hands of patients with a personal or family history of atopy. Greasy scaly plaques on the central part of the face, eyelids, and scalp commonly are found in seborrheic dermatitis. In chronic plaque psoriasis, lesions typically are described as welldemarcated, inflamed plaques with notable scale located primarily in the scalp and diaper area in newborns and children until the age of 2 years. Our patient presented with scaly plaques throughout most of the body. The history of Minerin use over the course of 3 to 5 months and worsening skin eruptions involving a majority of the skin surface suggested continued exposure.

Patch testing assists in the diagnosis of ACD, with varying results due to manufacturing and processing inconsistencies in the composition of various substances used in the standard test sets, often making it difficult to diagnose lanolin as an allergen. According to Lee and Warshaw,6 the lack of uniformity within testing of lanolin-containing products may cause false-positive results, poor patch-test reproducibility, and loss of allergic contact response. A 2019 study utilized a combination of Amerchol L101 and lanolin alcohol to improve the diagnosis of lanolin allergy, as standard testing may not identify patients with lanolin sensitivities.1 A study with the North American Contact Dermatitis Group from 2005 to 2012 demonstrated that positive patch testing among children was the most consistent method for diagnosing ACD, and results were clinically relevant.⁹ However, the different lanolin-containing products are not standardized in patch testing, which often causes mixed reactions and does not definitely demonstrate classic positive results, even with the use of repeated open application tests.² Although there has been an emphasis on refining the standardization of the lanolin used for patch testing, lanolin contact allergy remains a predominantly clinical diagnosis.

Both AD and ACD are common pediatric skin findings, and mixed positive and neutral associations between AD and allergy to lanolin have been described in a few studies.^1,3,9,10 A history of atopy is more notable in a pediatric patient vs an adult, as sensitivities tend to subside into adulthood.⁹ Further studies and more precise testing are needed to investigate the relationship between AD and ACD.

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The Diagnosis: Hypertrophic Lichen Planus

Two biopsies from the left lateral foot revealed hyperkeratosis, wedge-shaped hypergranulosis, irregular acanthosis, and a bandlike lymphocytic infiltrate in the superficial dermis with a classic sawtooth pattern of the rete ridges (Figure 1). Based on the clinical findings and histopathology, the patient was diagnosed with hypertrophic lichen planus (LP) and was treated with clobetasol ointment 0.05%, which resulted in progression of the symptoms. She experienced notable improvement 3 months after adding methotrexate 12.5 mg weekly (Figure 2).

Medina_1.jpg

Lichen planus is an idiopathic chronic inflammatory condition of the skin and mucous membranes that classically manifests as pruritic violaceous papules and plaques, which commonly are found on the wrists, lower back, and ankles.¹ The most common variants of LP are hypertrophic, linear, mucosal, actinic, follicular, pigmented, annular, atrophic, and guttate.² The clinical presentation and biopsy results in our patient were consistent with the hypertrophic variant of LP, which is a chronic condition that most often manifests on the lower legs, especially around the ankles, as hyperkeratotic papules, plaques, and nodules.^2,3 The exact pathophysiology of hypertrophic LP is unknown, but there is evidence that the immune system plays a role in its development and that the Koebner phenomenon may contribute to its exacerbation.⁴ There is a well-known association between LP and hepatitis. Patients with chronic LP may develop squamous cell carcinoma.⁴ The variants of LP can overlap and do not exist independent of one another. Recognizing the overlap in these variants allows for earlier diagnosis and therapeutic intervention of the disease process to limit disease progression and patient clinic visits and to improve patient quality of life.

CT113004010_e_Fig2_AB.jpg

The differential diagnosis for hyperkeratotic plaques of the feet and ankles can be broad and may include keratosis lichenoides chronica, palmoplantar keratoderma, palmoplantar psoriasis, or lichen amyloidosis. These conditions are classified based on various criteria that include extent of disease manifestations, morphology of palmoplantar skin involvement, inheritance patterns, and molecular pathogenesis.⁵ Keratosis lichenoides chronica is a rare dermatosis that presents as a distinctive seborrheic dermatitis–like facial eruption. The facial eruption is accompanied by violaceous papular and nodular lesions that appear on the extremities and trunk, typically arranged in a linear or reticular pattern.⁶ Palmoplantar keratoderma represents a group of acquired and hereditary conditions that are characterized by excessive thickening of the palms and soles.⁵ Palmoplantar psoriasis is a variant of psoriasis that affects the palms and soles and can manifest as hyperkeratosis, pustular, or mixed morphology.⁷ Lichen amyloidosis is a subtype of primary localized cutaneous amyloidosis that manifests as multiple pruritic, firm, hyperpigmented, hyperkeratotic papules on the shins that later coalesce in a rippled pattern.^8,9

The first-line treatment for hypertrophic LP is topical corticosteroids. Alternative therapies include mycophenolate mofetil, acitretin, and intralesional corticosteroid injections.⁴ Treatment is similar for all of the LP variants.

The Diagnosis: Hypertrophic Lichen Planus

Two biopsies from the left lateral foot revealed hyperkeratosis, wedge-shaped hypergranulosis, irregular acanthosis, and a bandlike lymphocytic infiltrate in the superficial dermis with a classic sawtooth pattern of the rete ridges (Figure 1). Based on the clinical findings and histopathology, the patient was diagnosed with hypertrophic lichen planus (LP) and was treated with clobetasol ointment 0.05%, which resulted in progression of the symptoms. She experienced notable improvement 3 months after adding methotrexate 12.5 mg weekly (Figure 2).

Medina_1.jpg

Lichen planus is an idiopathic chronic inflammatory condition of the skin and mucous membranes that classically manifests as pruritic violaceous papules and plaques, which commonly are found on the wrists, lower back, and ankles.¹ The most common variants of LP are hypertrophic, linear, mucosal, actinic, follicular, pigmented, annular, atrophic, and guttate.² The clinical presentation and biopsy results in our patient were consistent with the hypertrophic variant of LP, which is a chronic condition that most often manifests on the lower legs, especially around the ankles, as hyperkeratotic papules, plaques, and nodules.^2,3 The exact pathophysiology of hypertrophic LP is unknown, but there is evidence that the immune system plays a role in its development and that the Koebner phenomenon may contribute to its exacerbation.⁴ There is a well-known association between LP and hepatitis. Patients with chronic LP may develop squamous cell carcinoma.⁴ The variants of LP can overlap and do not exist independent of one another. Recognizing the overlap in these variants allows for earlier diagnosis and therapeutic intervention of the disease process to limit disease progression and patient clinic visits and to improve patient quality of life.

CT113004010_e_Fig2_AB.jpg

The differential diagnosis for hyperkeratotic plaques of the feet and ankles can be broad and may include keratosis lichenoides chronica, palmoplantar keratoderma, palmoplantar psoriasis, or lichen amyloidosis. These conditions are classified based on various criteria that include extent of disease manifestations, morphology of palmoplantar skin involvement, inheritance patterns, and molecular pathogenesis.⁵ Keratosis lichenoides chronica is a rare dermatosis that presents as a distinctive seborrheic dermatitis–like facial eruption. The facial eruption is accompanied by violaceous papular and nodular lesions that appear on the extremities and trunk, typically arranged in a linear or reticular pattern.⁶ Palmoplantar keratoderma represents a group of acquired and hereditary conditions that are characterized by excessive thickening of the palms and soles.⁵ Palmoplantar psoriasis is a variant of psoriasis that affects the palms and soles and can manifest as hyperkeratosis, pustular, or mixed morphology.⁷ Lichen amyloidosis is a subtype of primary localized cutaneous amyloidosis that manifests as multiple pruritic, firm, hyperpigmented, hyperkeratotic papules on the shins that later coalesce in a rippled pattern.^8,9

The first-line treatment for hypertrophic LP is topical corticosteroids. Alternative therapies include mycophenolate mofetil, acitretin, and intralesional corticosteroid injections.⁴ Treatment is similar for all of the LP variants.

The Diagnosis: Hypertrophic Lichen Planus

Two biopsies from the left lateral foot revealed hyperkeratosis, wedge-shaped hypergranulosis, irregular acanthosis, and a bandlike lymphocytic infiltrate in the superficial dermis with a classic sawtooth pattern of the rete ridges (Figure 1). Based on the clinical findings and histopathology, the patient was diagnosed with hypertrophic lichen planus (LP) and was treated with clobetasol ointment 0.05%, which resulted in progression of the symptoms. She experienced notable improvement 3 months after adding methotrexate 12.5 mg weekly (Figure 2).

Medina_1.jpg

Lichen planus is an idiopathic chronic inflammatory condition of the skin and mucous membranes that classically manifests as pruritic violaceous papules and plaques, which commonly are found on the wrists, lower back, and ankles.¹ The most common variants of LP are hypertrophic, linear, mucosal, actinic, follicular, pigmented, annular, atrophic, and guttate.² The clinical presentation and biopsy results in our patient were consistent with the hypertrophic variant of LP, which is a chronic condition that most often manifests on the lower legs, especially around the ankles, as hyperkeratotic papules, plaques, and nodules.^2,3 The exact pathophysiology of hypertrophic LP is unknown, but there is evidence that the immune system plays a role in its development and that the Koebner phenomenon may contribute to its exacerbation.⁴ There is a well-known association between LP and hepatitis. Patients with chronic LP may develop squamous cell carcinoma.⁴ The variants of LP can overlap and do not exist independent of one another. Recognizing the overlap in these variants allows for earlier diagnosis and therapeutic intervention of the disease process to limit disease progression and patient clinic visits and to improve patient quality of life.

CT113004010_e_Fig2_AB.jpg

The differential diagnosis for hyperkeratotic plaques of the feet and ankles can be broad and may include keratosis lichenoides chronica, palmoplantar keratoderma, palmoplantar psoriasis, or lichen amyloidosis. These conditions are classified based on various criteria that include extent of disease manifestations, morphology of palmoplantar skin involvement, inheritance patterns, and molecular pathogenesis.⁵ Keratosis lichenoides chronica is a rare dermatosis that presents as a distinctive seborrheic dermatitis–like facial eruption. The facial eruption is accompanied by violaceous papular and nodular lesions that appear on the extremities and trunk, typically arranged in a linear or reticular pattern.⁶ Palmoplantar keratoderma represents a group of acquired and hereditary conditions that are characterized by excessive thickening of the palms and soles.⁵ Palmoplantar psoriasis is a variant of psoriasis that affects the palms and soles and can manifest as hyperkeratosis, pustular, or mixed morphology.⁷ Lichen amyloidosis is a subtype of primary localized cutaneous amyloidosis that manifests as multiple pruritic, firm, hyperpigmented, hyperkeratotic papules on the shins that later coalesce in a rippled pattern.^8,9

The first-line treatment for hypertrophic LP is topical corticosteroids. Alternative therapies include mycophenolate mofetil, acitretin, and intralesional corticosteroid injections.⁴ Treatment is similar for all of the LP variants.

The Diagnosis: Lymphoepithelioma-like Carcinoma

Lymphoepithelioma-like carcinoma (LELC) is a rare, poorly differentiated, primary cutaneous neoplasm that occurs on sun-exposed skin, particularly on the head and neck of elderly individuals. It often manifests as an asymptomatic, slow-growing, flesh-colored or erythematous dermal nodule, though ulceration and tenderness have been reported.¹ Histopathologically, these neoplasms often are poorly circumscribed and can infiltrate surrounding subcutaneous and soft tissue. As a biphasic tumor, LELC is characterized by islands, nests, or trabeculae of epithelioid cells within the mid dermis surrounded by a dense lymphocytic infiltrate with plasma cells (Figure 1).¹ The epithelial component rarely communicates with the overlying epidermis and is composed of atypical polygonal cells with eosinophilic cytoplasm, vesicular nuclei, prominent nucleoli, and frequent mitosis.² These epithelial nests can be highlighted by pancytokeratin AE1/AE3 or other epithelial differentiation markers (eg, CAM 5.2, CK5/6, epithelial membrane antigen, high-molecular-weight cytokeratin), while the surrounding lymphocytic infiltrate consists of an admixture of T cells and B cells. Lymphoepithelioma-like carcinomas also can demonstrate sebaceous, eccrine, or follicular differentiations.³ The epithelial nests of LELC also are positive for p63 and epithelial membrane antigen.²

Chaiprasit_1.jpg

The usual treatment of LELC is wide local excision or Mohs micrographic surgery.¹ Despite the poorly differentiated morphology of the tumor, LELC has a generally good prognosis with low metastatic potential and few reports of local recurrence after incomplete excision.³ Patients who are not candidates for surgery as well as recalcitrant cases are managed with radiotherapy.¹

Cutaneous lymphadenoma (CL) is a benign adnexal neoplasm that manifests as a small, solitary, fleshcolored nodule usually in the head and neck region.⁴ Histologically, CL consists of well-circumscribed epithelial nests within the dermis that are peripherally outlined by palisading basaloid cells and filled with clear to eosinophilic epithelioid cells (Figure 2).5 The fibrotic tumor stroma often is infiltrated by numerous intralobular dendritic cells and lymphocytes that occasionally can be arranged in germinal center–like nodules.⁴ The lymphoepithelial nature of CL can be challenging to distinguish morphologically from LELC, and immunohistochemistry stains may be required. In CL, both the basaloid and epithelioid cells stain positive for pancytokeratin AE1/ AE3, but the peripheral palisaded basaloid cells also stain positive for BerEP4. Additionally, the fibrotic stroma can be highlighted by CD34 and the intralobular dendritic cells by S-100.⁴

Chaiprasit_2.jpg

Nasopharyngeal carcinoma (NPC), formerly known as lymphoepithelioma, refers to carcinoma arising within the epithelium of the nasopharynx.⁶ Endemic to China, NPC manifests as an enlarging nasopharyngeal mass, causing clinical symptoms such as nasal obstruction and epistaxis.⁷ Histologically, nonkeratinizing NPC exhibits a biphasic morphology consisting of epithelioid neoplastic cells and background lymphocytic infiltrates (Figure 3). The epithelial component consists of round to oval neoplastic cells with amphophilic to eosinophilic cytoplasm, vesicular nuclei, and prominent nucleoli.⁶ Nasopharyngeal carcinoma is associated strongly with the Epstein-Barr virus while LELC is not; thus, Epstein- Barr encoding region in situ hybridization can reliably distinguish these entities. Metastatic NPC is rare but has been reported; therefore, it is highly recommended to perform an otolaryngologic examination in addition to testing for Epstein-Barr virus reactivity as part of a complete evaluation.⁸

Chaiprasit_3.jpg

Cutaneous squamous cell carcinoma (SCC) is a common epidermal malignancy with multiple subtypes and variable morphology. The clinical presentation of SCC is similar to LELC—an enlarging hyperkeratotic papule or nodule on sun-exposed skin that often is ulcerated and tender.⁹ Histologically, poorly differentiated nonkeratinizing SCC can form nests and trabeculae of epithelioid cells that are stained by epithelial differentiation markers, resembling the epithelioid nests of LELC. Distinguishing between LELC and poorly differentiated SCC with robust inflammatory infiltrate can be challenging (Figure 4). In fact, some experts support LELC as an SCC variant rather than a separate entity.9 However, in contrast to LELC, the dermal nests of SCC usually maintain an epidermal connection and often are associated with an overlying area of SCC in situ or welldifferentiated SCC.³

Chaiprasit_4.jpg

Mycosis fungoides (MF) is a primary cutaneous T-cell lymphoma. It is the most common type of cutaneous lymphoma, accounting for almost 50% of all reported cases.¹⁰ Classic MF has an indolent course and progresses through several clinical stages. Patches and plaques characterize early stages; lymphadenopathy indicates progression to later stages in which erythroderma may develop with coalescence of patches, plaques, and tumors; and MF present in blood or lymph nodes characterizes the late stage. Each stage of MF is different histologically—from a superficial lichenoid infiltrate with exocytosis of malignant T cells in the patch stage, to more robust epidermotropism and dermal infiltrate in the plaque stage, and finally a dense dermal infiltrate in the late stage.¹¹ The rare syringotropic variant of MF clinically manifests as solitary or multiple erythematous lesions, often with overlying alopecia. Syringotropic MF uniquely exhibits folliculotropism and syringotropism along with syringometaplasia on histologic evaluation (Figure 5).¹² The syringometaplasia can be difficult to distinguish from the epithelial nests of LELC, particularly with the lymphocytic background. Immunohistochemical panels for T-cell markers can highlight aberrant T cells in syringotropic MF through their usual loss of CD5 and CD7, in comparison to normal T cells in LELC.¹¹ An elevated CD4:CD8 ratio of 4:1 and molecular analysis for T-cell receptor gene clonal rearrangements also can support the diagnosis of MF.¹²

Chaiprasit_5.jpg

The Diagnosis: Lymphoepithelioma-like Carcinoma

Lymphoepithelioma-like carcinoma (LELC) is a rare, poorly differentiated, primary cutaneous neoplasm that occurs on sun-exposed skin, particularly on the head and neck of elderly individuals. It often manifests as an asymptomatic, slow-growing, flesh-colored or erythematous dermal nodule, though ulceration and tenderness have been reported.¹ Histopathologically, these neoplasms often are poorly circumscribed and can infiltrate surrounding subcutaneous and soft tissue. As a biphasic tumor, LELC is characterized by islands, nests, or trabeculae of epithelioid cells within the mid dermis surrounded by a dense lymphocytic infiltrate with plasma cells (Figure 1).¹ The epithelial component rarely communicates with the overlying epidermis and is composed of atypical polygonal cells with eosinophilic cytoplasm, vesicular nuclei, prominent nucleoli, and frequent mitosis.² These epithelial nests can be highlighted by pancytokeratin AE1/AE3 or other epithelial differentiation markers (eg, CAM 5.2, CK5/6, epithelial membrane antigen, high-molecular-weight cytokeratin), while the surrounding lymphocytic infiltrate consists of an admixture of T cells and B cells. Lymphoepithelioma-like carcinomas also can demonstrate sebaceous, eccrine, or follicular differentiations.³ The epithelial nests of LELC also are positive for p63 and epithelial membrane antigen.²

Chaiprasit_1.jpg

The usual treatment of LELC is wide local excision or Mohs micrographic surgery.¹ Despite the poorly differentiated morphology of the tumor, LELC has a generally good prognosis with low metastatic potential and few reports of local recurrence after incomplete excision.³ Patients who are not candidates for surgery as well as recalcitrant cases are managed with radiotherapy.¹

Cutaneous lymphadenoma (CL) is a benign adnexal neoplasm that manifests as a small, solitary, fleshcolored nodule usually in the head and neck region.⁴ Histologically, CL consists of well-circumscribed epithelial nests within the dermis that are peripherally outlined by palisading basaloid cells and filled with clear to eosinophilic epithelioid cells (Figure 2).5 The fibrotic tumor stroma often is infiltrated by numerous intralobular dendritic cells and lymphocytes that occasionally can be arranged in germinal center–like nodules.⁴ The lymphoepithelial nature of CL can be challenging to distinguish morphologically from LELC, and immunohistochemistry stains may be required. In CL, both the basaloid and epithelioid cells stain positive for pancytokeratin AE1/ AE3, but the peripheral palisaded basaloid cells also stain positive for BerEP4. Additionally, the fibrotic stroma can be highlighted by CD34 and the intralobular dendritic cells by S-100.⁴

Chaiprasit_2.jpg

Nasopharyngeal carcinoma (NPC), formerly known as lymphoepithelioma, refers to carcinoma arising within the epithelium of the nasopharynx.⁶ Endemic to China, NPC manifests as an enlarging nasopharyngeal mass, causing clinical symptoms such as nasal obstruction and epistaxis.⁷ Histologically, nonkeratinizing NPC exhibits a biphasic morphology consisting of epithelioid neoplastic cells and background lymphocytic infiltrates (Figure 3). The epithelial component consists of round to oval neoplastic cells with amphophilic to eosinophilic cytoplasm, vesicular nuclei, and prominent nucleoli.⁶ Nasopharyngeal carcinoma is associated strongly with the Epstein-Barr virus while LELC is not; thus, Epstein- Barr encoding region in situ hybridization can reliably distinguish these entities. Metastatic NPC is rare but has been reported; therefore, it is highly recommended to perform an otolaryngologic examination in addition to testing for Epstein-Barr virus reactivity as part of a complete evaluation.⁸

Chaiprasit_3.jpg

Cutaneous squamous cell carcinoma (SCC) is a common epidermal malignancy with multiple subtypes and variable morphology. The clinical presentation of SCC is similar to LELC—an enlarging hyperkeratotic papule or nodule on sun-exposed skin that often is ulcerated and tender.⁹ Histologically, poorly differentiated nonkeratinizing SCC can form nests and trabeculae of epithelioid cells that are stained by epithelial differentiation markers, resembling the epithelioid nests of LELC. Distinguishing between LELC and poorly differentiated SCC with robust inflammatory infiltrate can be challenging (Figure 4). In fact, some experts support LELC as an SCC variant rather than a separate entity.9 However, in contrast to LELC, the dermal nests of SCC usually maintain an epidermal connection and often are associated with an overlying area of SCC in situ or welldifferentiated SCC.³

Chaiprasit_4.jpg

Mycosis fungoides (MF) is a primary cutaneous T-cell lymphoma. It is the most common type of cutaneous lymphoma, accounting for almost 50% of all reported cases.¹⁰ Classic MF has an indolent course and progresses through several clinical stages. Patches and plaques characterize early stages; lymphadenopathy indicates progression to later stages in which erythroderma may develop with coalescence of patches, plaques, and tumors; and MF present in blood or lymph nodes characterizes the late stage. Each stage of MF is different histologically—from a superficial lichenoid infiltrate with exocytosis of malignant T cells in the patch stage, to more robust epidermotropism and dermal infiltrate in the plaque stage, and finally a dense dermal infiltrate in the late stage.¹¹ The rare syringotropic variant of MF clinically manifests as solitary or multiple erythematous lesions, often with overlying alopecia. Syringotropic MF uniquely exhibits folliculotropism and syringotropism along with syringometaplasia on histologic evaluation (Figure 5).¹² The syringometaplasia can be difficult to distinguish from the epithelial nests of LELC, particularly with the lymphocytic background. Immunohistochemical panels for T-cell markers can highlight aberrant T cells in syringotropic MF through their usual loss of CD5 and CD7, in comparison to normal T cells in LELC.¹¹ An elevated CD4:CD8 ratio of 4:1 and molecular analysis for T-cell receptor gene clonal rearrangements also can support the diagnosis of MF.¹²

Chaiprasit_5.jpg

The Diagnosis: Lymphoepithelioma-like Carcinoma

Lymphoepithelioma-like carcinoma (LELC) is a rare, poorly differentiated, primary cutaneous neoplasm that occurs on sun-exposed skin, particularly on the head and neck of elderly individuals. It often manifests as an asymptomatic, slow-growing, flesh-colored or erythematous dermal nodule, though ulceration and tenderness have been reported.¹ Histopathologically, these neoplasms often are poorly circumscribed and can infiltrate surrounding subcutaneous and soft tissue. As a biphasic tumor, LELC is characterized by islands, nests, or trabeculae of epithelioid cells within the mid dermis surrounded by a dense lymphocytic infiltrate with plasma cells (Figure 1).¹ The epithelial component rarely communicates with the overlying epidermis and is composed of atypical polygonal cells with eosinophilic cytoplasm, vesicular nuclei, prominent nucleoli, and frequent mitosis.² These epithelial nests can be highlighted by pancytokeratin AE1/AE3 or other epithelial differentiation markers (eg, CAM 5.2, CK5/6, epithelial membrane antigen, high-molecular-weight cytokeratin), while the surrounding lymphocytic infiltrate consists of an admixture of T cells and B cells. Lymphoepithelioma-like carcinomas also can demonstrate sebaceous, eccrine, or follicular differentiations.³ The epithelial nests of LELC also are positive for p63 and epithelial membrane antigen.²

Chaiprasit_1.jpg

The usual treatment of LELC is wide local excision or Mohs micrographic surgery.¹ Despite the poorly differentiated morphology of the tumor, LELC has a generally good prognosis with low metastatic potential and few reports of local recurrence after incomplete excision.³ Patients who are not candidates for surgery as well as recalcitrant cases are managed with radiotherapy.¹

Cutaneous lymphadenoma (CL) is a benign adnexal neoplasm that manifests as a small, solitary, fleshcolored nodule usually in the head and neck region.⁴ Histologically, CL consists of well-circumscribed epithelial nests within the dermis that are peripherally outlined by palisading basaloid cells and filled with clear to eosinophilic epithelioid cells (Figure 2).5 The fibrotic tumor stroma often is infiltrated by numerous intralobular dendritic cells and lymphocytes that occasionally can be arranged in germinal center–like nodules.⁴ The lymphoepithelial nature of CL can be challenging to distinguish morphologically from LELC, and immunohistochemistry stains may be required. In CL, both the basaloid and epithelioid cells stain positive for pancytokeratin AE1/ AE3, but the peripheral palisaded basaloid cells also stain positive for BerEP4. Additionally, the fibrotic stroma can be highlighted by CD34 and the intralobular dendritic cells by S-100.⁴

Chaiprasit_2.jpg

Nasopharyngeal carcinoma (NPC), formerly known as lymphoepithelioma, refers to carcinoma arising within the epithelium of the nasopharynx.⁶ Endemic to China, NPC manifests as an enlarging nasopharyngeal mass, causing clinical symptoms such as nasal obstruction and epistaxis.⁷ Histologically, nonkeratinizing NPC exhibits a biphasic morphology consisting of epithelioid neoplastic cells and background lymphocytic infiltrates (Figure 3). The epithelial component consists of round to oval neoplastic cells with amphophilic to eosinophilic cytoplasm, vesicular nuclei, and prominent nucleoli.⁶ Nasopharyngeal carcinoma is associated strongly with the Epstein-Barr virus while LELC is not; thus, Epstein- Barr encoding region in situ hybridization can reliably distinguish these entities. Metastatic NPC is rare but has been reported; therefore, it is highly recommended to perform an otolaryngologic examination in addition to testing for Epstein-Barr virus reactivity as part of a complete evaluation.⁸

Chaiprasit_3.jpg

Cutaneous squamous cell carcinoma (SCC) is a common epidermal malignancy with multiple subtypes and variable morphology. The clinical presentation of SCC is similar to LELC—an enlarging hyperkeratotic papule or nodule on sun-exposed skin that often is ulcerated and tender.⁹ Histologically, poorly differentiated nonkeratinizing SCC can form nests and trabeculae of epithelioid cells that are stained by epithelial differentiation markers, resembling the epithelioid nests of LELC. Distinguishing between LELC and poorly differentiated SCC with robust inflammatory infiltrate can be challenging (Figure 4). In fact, some experts support LELC as an SCC variant rather than a separate entity.9 However, in contrast to LELC, the dermal nests of SCC usually maintain an epidermal connection and often are associated with an overlying area of SCC in situ or welldifferentiated SCC.³

Chaiprasit_4.jpg

Mycosis fungoides (MF) is a primary cutaneous T-cell lymphoma. It is the most common type of cutaneous lymphoma, accounting for almost 50% of all reported cases.¹⁰ Classic MF has an indolent course and progresses through several clinical stages. Patches and plaques characterize early stages; lymphadenopathy indicates progression to later stages in which erythroderma may develop with coalescence of patches, plaques, and tumors; and MF present in blood or lymph nodes characterizes the late stage. Each stage of MF is different histologically—from a superficial lichenoid infiltrate with exocytosis of malignant T cells in the patch stage, to more robust epidermotropism and dermal infiltrate in the plaque stage, and finally a dense dermal infiltrate in the late stage.¹¹ The rare syringotropic variant of MF clinically manifests as solitary or multiple erythematous lesions, often with overlying alopecia. Syringotropic MF uniquely exhibits folliculotropism and syringotropism along with syringometaplasia on histologic evaluation (Figure 5).¹² The syringometaplasia can be difficult to distinguish from the epithelial nests of LELC, particularly with the lymphocytic background. Immunohistochemical panels for T-cell markers can highlight aberrant T cells in syringotropic MF through their usual loss of CD5 and CD7, in comparison to normal T cells in LELC.¹¹ An elevated CD4:CD8 ratio of 4:1 and molecular analysis for T-cell receptor gene clonal rearrangements also can support the diagnosis of MF.¹²

Chaiprasit_5.jpg

Plant Parts and Nomenclature

Ficus carica (common fig) is a deciduous shrub or small tree with smooth gray bark that can grow up to 10 m in height (Figure 1). It is characterized by many spreading branches, but the trunk rarely grows beyond a diameter of 7 in. Its hairy leaves are coarse on the upper side and soft underneath with 3 to 7 deep lobes that can extend up to 25 cm in length or width; the leaves grow individually, alternating along the sides of the branches. Fig trees often can be seen adorning yards, gardens, and parks, especially in tropical and subtropical climates. Ficus carica should not be confused with Ficus benjamina (weeping fig), a common ornamental tree that also is used to provide shade in hot climates, though both can cause phototoxic skin eruptions.

Barker_0424_1.jpg

The common fig tree originated in the Mediterranean and western Asia¹ and has been cultivated by humans since the second and third millennia bc for its fruit, which commonly is used to sweeten cookies, cakes, and jams.² Figs are the most commonly mentioned food plant in the Bible, with at least 56 references in the Old and New Testaments.³ The “fruit” technically is a syconium—a hollow fleshy receptacle with a small opening at the apex partly closed by small scales. It can be obovoid, turbinate, or pear shaped; can be 1 to 4 inches long; and can vary in color from yellowish green to coppery, bronze, or dark purple (Figure 2).

Barker_0424_2.jpg

Ficus carica is a member of the Moraceae family (derived from the Latin name for the mulberry tree), which includes 53 genera and approximately 1400 species, of which about 850 belong to the genus Ficus (the Latin name for a fig tree). The term carica likely comes from the Latin word carricare (to load) to describe a tree loaded with figs. Family members include trees, shrubs, lianas, and herbs that usually contain laticifers with a milky latex.

Traditional Uses

For centuries, components of the fig tree have been used in herbal teas and pastes to treat ailments ranging from sore throats to diarrhea, though there is no evidence to support their efficacy.⁴ Ancient Indians and Egyptians used plants such as the common fig tree containing furocoumarins to induce hyperpigmentation in vitiligo.⁵

Phototoxic Components

The leaves and sap of the common fig tree contain psoralens, which are members of the furocoumarin group of chemical compounds and are the source of its phototoxicity. The fruit does not contain psoralens.^6-9 The tree also produces proteolytic enzymes such as protease, amylase, ficin, triterpenoids, and lipodiastase that enhance its phototoxic effects.⁸ Exposure to UV light between 320 and 400 nm following contact with these phototoxic components triggers a reaction in the skin over the course of 1 to 3 days.⁵ The psoralens bind in epidermal cells, cross-link the DNA, and cause cell-membrane destruction, leading to edema and necrosis.¹⁰ The delay in symptoms may be attributed to the time needed to synthesize acute-phase reaction proteins such as tumor necrosis factor α and IL-1.¹¹ In spring and summer months, an increased concentration of psoralens in the leaves and sap contribute to an increased incidence of phytophotodermatitis.⁹ Humidity and sweat also increase the percutaneous absorption of psoralens.^12,13

Allergens

Fig trees produce a latex protein that can cause cross-reactive hypersensitivity reactions in those allergic to F benjamina latex and rubber latex.⁶ The latex proteins in fig trees can act as airborne respiratory allergens. Ingestion of figs can produce anaphylactic reactions in those sensitized to rubber latex and F benjamina latex.⁷ Other plant families associated with phototoxic reactions include Rutaceae (lemon, lime, bitter orange), Apiaceae (formerly Umbelliferae)(carrot, parsnip, parsley, dill, celery, hogweed), and Fabaceae (prairie turnip).

Most cases of fig phytophotodermatitis begin with burning, pain, and/or itching within hours of sunlight exposure in areas of the skin that encountered components of the fig tree, often in a linear pattern. The affected areas become erythematous and edematous with formation of bullae and unilocular vesicles over the course of 1 to 3 days.^12,14,15 Lesions may extend beyond the region of contact with the fig tree as they spread across the skin due to sweat or friction, and pain may linger even after the lesions resolve.^12,13,16 Adults who handle fig trees (eg, pruning) are susceptible to phototoxic reactions, especially those using chain saws or other mechanisms that result in spray exposure, as the photosensitizing sap permeates the wood and bark of the entire tree.¹⁷ Similarly, children who handle fig leaves or sap during outdoor play can develop bullous eruptions. Severe cases have resulted in hospital admission after prolonged exposure.¹⁶ Additionally, irritant dermatitis may arise from contact with the trichomes or “hairs” on various parts of the plant.

Barker_0424_3.jpg

Patients who use natural remedies containing components of the fig tree without the supervision of a medical provider put themselves at risk for unsafe or unwanted adverse effects, such as phytophotodermatitis.^12,15,16,18 An entire family presented with burns after they applied fig leaf extract to the skin prior to tanning outside in the sun.¹⁹ A 42-year-old woman acquired a severe burn covering 81% of the body surface after topically applying fig leaf tea to the skin as a tanning agent.²⁰ A subset of patients ingesting or applying fig tree components for conditions such as vitiligo, dermatitis, onychomycosis, and motor retardation developed similar cutaneous reactions.^13,14,21,22 Lesions resembling finger marks can raise concerns for potential abuse or neglect in children.²²

The differential diagnosis for fig phytophotodermatitis includes sunburn, chemical burns, drug-related photosensitivity, infectious lesions (eg, herpes simplex, bullous impetigo, Lyme disease, superficial lymphangitis), connective tissue disease (eg, systemic lupus erythematosus), contact dermatitis, and nonaccidental trauma.^12,15,18 Compared to sunburn, phytophotodermatitis tends to increase in severity over days following exposure and heals with dramatic hyperpigmentation, which also prompts visits to dermatology.¹²

Treatment

Treatment of fig phytophotodermatitis chiefly is symptomatic, including analgesia, appropriate wound care, and infection prophylaxis. Topical and systemic corticosteroids may aid in the resolution of moderate to severe reactions.^15,23,24 Even severe injuries over small areas or mild injuries to a high percentage of the total body surface area may require treatment in a burn unit. Patients should be encouraged to use mineral-based sunscreens on the affected areas to reduce the risk for hyperpigmentation. Individuals who regularly handle fig trees should use contact barriers including gloves and protective clothing (eg, long-sleeved shirts, long pants).

Plant Parts and Nomenclature

Ficus carica (common fig) is a deciduous shrub or small tree with smooth gray bark that can grow up to 10 m in height (Figure 1). It is characterized by many spreading branches, but the trunk rarely grows beyond a diameter of 7 in. Its hairy leaves are coarse on the upper side and soft underneath with 3 to 7 deep lobes that can extend up to 25 cm in length or width; the leaves grow individually, alternating along the sides of the branches. Fig trees often can be seen adorning yards, gardens, and parks, especially in tropical and subtropical climates. Ficus carica should not be confused with Ficus benjamina (weeping fig), a common ornamental tree that also is used to provide shade in hot climates, though both can cause phototoxic skin eruptions.

Barker_0424_1.jpg

The common fig tree originated in the Mediterranean and western Asia¹ and has been cultivated by humans since the second and third millennia bc for its fruit, which commonly is used to sweeten cookies, cakes, and jams.² Figs are the most commonly mentioned food plant in the Bible, with at least 56 references in the Old and New Testaments.³ The “fruit” technically is a syconium—a hollow fleshy receptacle with a small opening at the apex partly closed by small scales. It can be obovoid, turbinate, or pear shaped; can be 1 to 4 inches long; and can vary in color from yellowish green to coppery, bronze, or dark purple (Figure 2).

Barker_0424_2.jpg

Ficus carica is a member of the Moraceae family (derived from the Latin name for the mulberry tree), which includes 53 genera and approximately 1400 species, of which about 850 belong to the genus Ficus (the Latin name for a fig tree). The term carica likely comes from the Latin word carricare (to load) to describe a tree loaded with figs. Family members include trees, shrubs, lianas, and herbs that usually contain laticifers with a milky latex.

Traditional Uses

For centuries, components of the fig tree have been used in herbal teas and pastes to treat ailments ranging from sore throats to diarrhea, though there is no evidence to support their efficacy.⁴ Ancient Indians and Egyptians used plants such as the common fig tree containing furocoumarins to induce hyperpigmentation in vitiligo.⁵

Phototoxic Components

The leaves and sap of the common fig tree contain psoralens, which are members of the furocoumarin group of chemical compounds and are the source of its phototoxicity. The fruit does not contain psoralens.^6-9 The tree also produces proteolytic enzymes such as protease, amylase, ficin, triterpenoids, and lipodiastase that enhance its phototoxic effects.⁸ Exposure to UV light between 320 and 400 nm following contact with these phototoxic components triggers a reaction in the skin over the course of 1 to 3 days.⁵ The psoralens bind in epidermal cells, cross-link the DNA, and cause cell-membrane destruction, leading to edema and necrosis.¹⁰ The delay in symptoms may be attributed to the time needed to synthesize acute-phase reaction proteins such as tumor necrosis factor α and IL-1.¹¹ In spring and summer months, an increased concentration of psoralens in the leaves and sap contribute to an increased incidence of phytophotodermatitis.⁹ Humidity and sweat also increase the percutaneous absorption of psoralens.^12,13

Allergens

Fig trees produce a latex protein that can cause cross-reactive hypersensitivity reactions in those allergic to F benjamina latex and rubber latex.⁶ The latex proteins in fig trees can act as airborne respiratory allergens. Ingestion of figs can produce anaphylactic reactions in those sensitized to rubber latex and F benjamina latex.⁷ Other plant families associated with phototoxic reactions include Rutaceae (lemon, lime, bitter orange), Apiaceae (formerly Umbelliferae)(carrot, parsnip, parsley, dill, celery, hogweed), and Fabaceae (prairie turnip).

Most cases of fig phytophotodermatitis begin with burning, pain, and/or itching within hours of sunlight exposure in areas of the skin that encountered components of the fig tree, often in a linear pattern. The affected areas become erythematous and edematous with formation of bullae and unilocular vesicles over the course of 1 to 3 days.^12,14,15 Lesions may extend beyond the region of contact with the fig tree as they spread across the skin due to sweat or friction, and pain may linger even after the lesions resolve.^12,13,16 Adults who handle fig trees (eg, pruning) are susceptible to phototoxic reactions, especially those using chain saws or other mechanisms that result in spray exposure, as the photosensitizing sap permeates the wood and bark of the entire tree.¹⁷ Similarly, children who handle fig leaves or sap during outdoor play can develop bullous eruptions. Severe cases have resulted in hospital admission after prolonged exposure.¹⁶ Additionally, irritant dermatitis may arise from contact with the trichomes or “hairs” on various parts of the plant.

Barker_0424_3.jpg

Patients who use natural remedies containing components of the fig tree without the supervision of a medical provider put themselves at risk for unsafe or unwanted adverse effects, such as phytophotodermatitis.^12,15,16,18 An entire family presented with burns after they applied fig leaf extract to the skin prior to tanning outside in the sun.¹⁹ A 42-year-old woman acquired a severe burn covering 81% of the body surface after topically applying fig leaf tea to the skin as a tanning agent.²⁰ A subset of patients ingesting or applying fig tree components for conditions such as vitiligo, dermatitis, onychomycosis, and motor retardation developed similar cutaneous reactions.^13,14,21,22 Lesions resembling finger marks can raise concerns for potential abuse or neglect in children.²²

The differential diagnosis for fig phytophotodermatitis includes sunburn, chemical burns, drug-related photosensitivity, infectious lesions (eg, herpes simplex, bullous impetigo, Lyme disease, superficial lymphangitis), connective tissue disease (eg, systemic lupus erythematosus), contact dermatitis, and nonaccidental trauma.^12,15,18 Compared to sunburn, phytophotodermatitis tends to increase in severity over days following exposure and heals with dramatic hyperpigmentation, which also prompts visits to dermatology.¹²

Treatment

Treatment of fig phytophotodermatitis chiefly is symptomatic, including analgesia, appropriate wound care, and infection prophylaxis. Topical and systemic corticosteroids may aid in the resolution of moderate to severe reactions.^15,23,24 Even severe injuries over small areas or mild injuries to a high percentage of the total body surface area may require treatment in a burn unit. Patients should be encouraged to use mineral-based sunscreens on the affected areas to reduce the risk for hyperpigmentation. Individuals who regularly handle fig trees should use contact barriers including gloves and protective clothing (eg, long-sleeved shirts, long pants).

Plant Parts and Nomenclature

Ficus carica (common fig) is a deciduous shrub or small tree with smooth gray bark that can grow up to 10 m in height (Figure 1). It is characterized by many spreading branches, but the trunk rarely grows beyond a diameter of 7 in. Its hairy leaves are coarse on the upper side and soft underneath with 3 to 7 deep lobes that can extend up to 25 cm in length or width; the leaves grow individually, alternating along the sides of the branches. Fig trees often can be seen adorning yards, gardens, and parks, especially in tropical and subtropical climates. Ficus carica should not be confused with Ficus benjamina (weeping fig), a common ornamental tree that also is used to provide shade in hot climates, though both can cause phototoxic skin eruptions.

Barker_0424_1.jpg

The common fig tree originated in the Mediterranean and western Asia¹ and has been cultivated by humans since the second and third millennia bc for its fruit, which commonly is used to sweeten cookies, cakes, and jams.² Figs are the most commonly mentioned food plant in the Bible, with at least 56 references in the Old and New Testaments.³ The “fruit” technically is a syconium—a hollow fleshy receptacle with a small opening at the apex partly closed by small scales. It can be obovoid, turbinate, or pear shaped; can be 1 to 4 inches long; and can vary in color from yellowish green to coppery, bronze, or dark purple (Figure 2).

Barker_0424_2.jpg

Ficus carica is a member of the Moraceae family (derived from the Latin name for the mulberry tree), which includes 53 genera and approximately 1400 species, of which about 850 belong to the genus Ficus (the Latin name for a fig tree). The term carica likely comes from the Latin word carricare (to load) to describe a tree loaded with figs. Family members include trees, shrubs, lianas, and herbs that usually contain laticifers with a milky latex.

Traditional Uses

For centuries, components of the fig tree have been used in herbal teas and pastes to treat ailments ranging from sore throats to diarrhea, though there is no evidence to support their efficacy.⁴ Ancient Indians and Egyptians used plants such as the common fig tree containing furocoumarins to induce hyperpigmentation in vitiligo.⁵

Phototoxic Components

The leaves and sap of the common fig tree contain psoralens, which are members of the furocoumarin group of chemical compounds and are the source of its phototoxicity. The fruit does not contain psoralens.^6-9 The tree also produces proteolytic enzymes such as protease, amylase, ficin, triterpenoids, and lipodiastase that enhance its phototoxic effects.⁸ Exposure to UV light between 320 and 400 nm following contact with these phototoxic components triggers a reaction in the skin over the course of 1 to 3 days.⁵ The psoralens bind in epidermal cells, cross-link the DNA, and cause cell-membrane destruction, leading to edema and necrosis.¹⁰ The delay in symptoms may be attributed to the time needed to synthesize acute-phase reaction proteins such as tumor necrosis factor α and IL-1.¹¹ In spring and summer months, an increased concentration of psoralens in the leaves and sap contribute to an increased incidence of phytophotodermatitis.⁹ Humidity and sweat also increase the percutaneous absorption of psoralens.^12,13

Allergens

Fig trees produce a latex protein that can cause cross-reactive hypersensitivity reactions in those allergic to F benjamina latex and rubber latex.⁶ The latex proteins in fig trees can act as airborne respiratory allergens. Ingestion of figs can produce anaphylactic reactions in those sensitized to rubber latex and F benjamina latex.⁷ Other plant families associated with phototoxic reactions include Rutaceae (lemon, lime, bitter orange), Apiaceae (formerly Umbelliferae)(carrot, parsnip, parsley, dill, celery, hogweed), and Fabaceae (prairie turnip).

Most cases of fig phytophotodermatitis begin with burning, pain, and/or itching within hours of sunlight exposure in areas of the skin that encountered components of the fig tree, often in a linear pattern. The affected areas become erythematous and edematous with formation of bullae and unilocular vesicles over the course of 1 to 3 days.^12,14,15 Lesions may extend beyond the region of contact with the fig tree as they spread across the skin due to sweat or friction, and pain may linger even after the lesions resolve.^12,13,16 Adults who handle fig trees (eg, pruning) are susceptible to phototoxic reactions, especially those using chain saws or other mechanisms that result in spray exposure, as the photosensitizing sap permeates the wood and bark of the entire tree.¹⁷ Similarly, children who handle fig leaves or sap during outdoor play can develop bullous eruptions. Severe cases have resulted in hospital admission after prolonged exposure.¹⁶ Additionally, irritant dermatitis may arise from contact with the trichomes or “hairs” on various parts of the plant.

Barker_0424_3.jpg

Patients who use natural remedies containing components of the fig tree without the supervision of a medical provider put themselves at risk for unsafe or unwanted adverse effects, such as phytophotodermatitis.^12,15,16,18 An entire family presented with burns after they applied fig leaf extract to the skin prior to tanning outside in the sun.¹⁹ A 42-year-old woman acquired a severe burn covering 81% of the body surface after topically applying fig leaf tea to the skin as a tanning agent.²⁰ A subset of patients ingesting or applying fig tree components for conditions such as vitiligo, dermatitis, onychomycosis, and motor retardation developed similar cutaneous reactions.^13,14,21,22 Lesions resembling finger marks can raise concerns for potential abuse or neglect in children.²²

The differential diagnosis for fig phytophotodermatitis includes sunburn, chemical burns, drug-related photosensitivity, infectious lesions (eg, herpes simplex, bullous impetigo, Lyme disease, superficial lymphangitis), connective tissue disease (eg, systemic lupus erythematosus), contact dermatitis, and nonaccidental trauma.^12,15,18 Compared to sunburn, phytophotodermatitis tends to increase in severity over days following exposure and heals with dramatic hyperpigmentation, which also prompts visits to dermatology.¹²

Treatment

Treatment of fig phytophotodermatitis chiefly is symptomatic, including analgesia, appropriate wound care, and infection prophylaxis. Topical and systemic corticosteroids may aid in the resolution of moderate to severe reactions.^15,23,24 Even severe injuries over small areas or mild injuries to a high percentage of the total body surface area may require treatment in a burn unit. Patients should be encouraged to use mineral-based sunscreens on the affected areas to reduce the risk for hyperpigmentation. Individuals who regularly handle fig trees should use contact barriers including gloves and protective clothing (eg, long-sleeved shirts, long pants).

In 2023, ESPEN (the European Society for Clinical Nutrition and Metabolism) published consensus recommendations highlighting the importance of regular monitoring and treatment of nutrient deficiencies in patients with inflammatory bowel disease (IBD) for improved prognosis, mortality, and quality of life.¹ Suboptimal nutrition in patients with IBD predominantly results from inflammation of the gastrointestinal (GI) tract leading to malabsorption; however, medications commonly used to manage IBD also can contribute to malnutrition.^2,3 Additionally, patients may develop nausea and food avoidance due to medication or the disease itself, leading to nutritional withdrawal and eventual deficiency.⁴ Even with the development of diets focused on balancing nutritional needs and decreasing inflammation,⁵ offsetting this aversion to food can be difficult to overcome.²

Cutaneous manifestations of IBD are multifaceted and can be secondary to the disease, reactive to or associated with IBD, or effects from nutritional deficiencies. The most common vitamin and nutrient deficiencies in patients with IBD include iron; zinc; calcium; vitamin D; and vitamins B₆ (pyridoxine), B₉ (folic acid), and B₁₂.⁶ Malnutrition may manifest with cutaneous disease, and dermatologists can be the first to identify and assess for nutritional deficiencies. In this article, we review the mechanisms of these micronutrient depletions in the context of IBD, their subsequent dermatologic manifestations (Table), and treatment and monitoring guidelines for each deficiency.

CT113004159_Table.jpg

Iron

A systematic review conducted from 2007 to 2012 in European patients with IBD (N=2192) found the overall prevalence of anemia in this population to be 24% (95% CI, 18%-31%), with 57% of patients with anemia experiencing iron deficiency.⁷ Anemia is observed more commonly in patients hospitalized with IBD and is common in patients with both Crohn disease and ulcerative colitis.⁸

Pathophysiology—Iron is critically important in oxygen transportation throughout the body as a major component of hemoglobin. Physiologically, the low pH of the duodenum and proximal jejunum allows divalent metal transporter 1 to transfer dietary Fe³⁺ into enterocytes, where it is reduced to the transportable Fe²⁺.^9,10 Distribution of Fe²⁺ ions from enterocytes relies on ferroportin, an iron-transporting protein, which is heavily regulated by the protein hepcidin.¹¹ Hepcidin, a known acute phase reactant, will increase in the setting of active IBD, causing a depletion of ferroportin and an inability of the body to utilize the stored iron in enterocytes.¹² This poor utilization of iron stores combined with blood loss caused by inflammation in the GI tract is the proposed primary mechanism of iron-deficiency anemia observed in patients with IBD.¹³

Cutaneous Manifestations—From a dermatologic perspective, iron-deficiency anemia can manifest with a wide range of symptoms including glossitis, koilonychia, xerosis and/or pruritus, and brittle hair or hair loss.^14,15 Although the underlying pathophysiology of these cutaneous manifestations is not fully understood, there are several theories assessing the mechanisms behind the skin findings of iron deficiency.

Atrophic glossitis has been observed in many patients with iron deficiency and is thought to manifest due to low iron concentrations in the blood, thereby decreasing oxygen delivery to the papillae of the dorsal tongue with resultant atrophy.^16,17 Similarly, decreased oxygen delivery to the nail bed capillaries may cause deformities in the nail called koilonychia (or “spoon nails”).¹⁸ Iron is a key co-factor in collagen lysyl hydroxylase that promotes collagen binding; iron deficiency may lead to disruptions in the epidermal barrier that can cause pruritus and xerosis.¹⁹ An observational study of 200 healthy patients with a primary concern of pruritus found a correlation between low serum ferritin and a higher degree of pruritus (r=−0.768; P<.00001).²⁰

Evidence for iron’s role in hair growth comes from a mouse model study with a mutation in the serine protease TMPRSS6—a protein that regulates hepcidin and iron absorption—which caused an increase in hepcidin production and subsequent systemic iron deficiency. Mice at 4 weeks of age were devoid of all body hair but had substantial regrowth after initiation of a 2-week iron-rich diet, which suggests a connection between iron repletion and hair growth in mice with iron deficiency.²¹ Additionally, a meta-analysis analyzing the comorbidities of patients with alopecia areata found them to have higher odds (odds ratio [OR]=2.78; 95% CI, 1.23-6.29) of iron-deficiency anemia but no association with IBD (OR=1.48; 95% CI, 0.32-6.82).²²

Diagnosis and Monitoring—The American Gastroenterological Association recommends a complete blood cell count (CBC), serum ferritin, transferrin saturation (TfS), and C-reactive protein (CRP) as standard evaluations for iron deficiency in patients with IBD. Patients with active IBD should be screened every 3 months,and patients with inactive disease should be screened every 6 to 12 months.²³

Although ferritin and TfS often are used as markers for iron status in healthy individuals, they are positive and negative acute phase reactants, respectively. Using them to assess iron status in patients with IBD may inaccurately represent iron status in the setting of inflammation from the disease.²⁴ The European Crohn’s and Colitis Organisation (ECCO) produced guidelines to define iron deficiency as a TfS less than 20% or a ferritin level less than 30 µg/L in patients without evidence of active IBD and a ferritin level less than 100 µg/L for patients with active inflammation.²⁵

A 2020 multicenter observational study of 202 patients with diagnosed IBD found that the ECCO guideline of ferritin less than 30 µg/L had an area under the receiver operating characteristic (AUROC) curve of 0.69, a sensitivity of 0.43, and a specificity of 0.95 in their population.²⁶ In a sensitivity analysis stratifying patients by CRP level (<10 or ≥10 mg/L), the authors found that for patients with ulcerative colitis and a CRP less than 10 mg/L, a cut-off value of ferritin less than 65 µg/L (AUROC=0.78) had a sensitivity of 0.78 and specificity of 0.76, and a TfS value of less than 16% (AUROC=0.88) had a sensitivity of 0.79 and a specificity of 0.9. In patients with a CRP of 10 mg/L or greater, a cut-off value of ferritin 80 µg/L (AUROC=0.76) had a sensitivity of 0.75 and a specificity of 0.82, and a TfS value of less than 11% (AUROC=0.69) had a sensitivity of 0.79 and a specificity of 0.88. There were no ferritin cut-off values associated with good diagnostic performance (defined as both sensitivity and specificity >0.70) for iron deficiency in patients with Crohn disease.²⁶

The authors recommended using an alternative iron measurement such as soluble transferrin receptor (sTfR)/log ferritin ratio (TfR-F) that is not influenced by active inflammation and has a good correlation with ferritin values (TfR-F: r=0.66; P<.001).²⁶ However, both sTfR and TfR-F have high costs and intermethod variability as well as differences in their reference ranges depending on which laboratory performs the analysis, limiting the accessibility and practicality of easily obtaining these tests.²⁷ Although there may be inaccuracies for standard ferritin or TfS under ECCO guidelines, proposed alternatives have their own limitations, which may make ferritin and TfS the most reasonable evaluations of iron status as long as disease activity status at the time of testing is taken into consideration.

Treatment—Treatment of underlying iron deficiency in patients with IBD requires reversing the cause of the deficiency and supplementing iron. In patients with IBD, the options to supplement iron may be limited by active disease, making oral intake less effective. Oral iron supplementation also is associated with notable GI adverse effects that may be exacerbated in patients with IBD. A systematic review of 43 randomized controlled trials (RCTs) evaluating GI adverse effects (eg, nausea, abdominal pain, diarrhea, constipation, and black or tarry stools) of oral ferrous sulfate compared with placebo or intravenous (IV) iron supplementation in healthy nonanemic individuals found a significant increase in GI adverse effects with oral supplementation (placebo: OR=2.32; P<.0001; IV: OR=3.05; P<.0001).²⁸

Therefore, IV iron repletion may be necessary in patients with IBD and may require numerous infusions depending on the formulation of iron. In an RCT conducted in 2011, patients with iron-deficiency anemia with quiescent or mild to moderate IBD were treated with either IV iron sulfate or ferric carboxymaltose.²⁹ With a primary end point of hemoglobin response greater than 2 g/dL, the authors found that 150 of 240 patients responded to ferric carboxymaltose vs 118 of 235 treated with iron sulfate (P=.004). The dosing for ferric carboxymaltose was 1 to 3 infusions of 500 to 1000 mg of iron and for iron sulfate up to 11 infusions of 200 mg of iron.²⁹

Zinc

A systematic review of zinc deficiency in patients with IBD identified 7 studies including 2413 patients and revealed those with Crohn disease had a higher prevalence of zinc deficiency compared with patients with ulcerative colitis (54% vs 41%).³⁰

Pathophysiology—Zinc serves as a catalytic cofactor for enzymatic activity within proteins and immune cells.³¹ The homeostasis of zinc is tightly regulated within the brush border of the small intestine by zinc transporters ZIP4 and ZIP1 from the lumen of enterocytes into the bloodstream.³² Inflammation in the small intestine due to Crohn disease can result in zinc malabsorption.

Ranaldi et al³³ exposed intestinal cells and zinc-depleted intestinal cells to tumor necrosis factor α media to simulate an inflammatory environment. They measured transepithelial electrical resistance as a surrogate for transmembrane permeability and found that zinc-depleted cells had a statistically significantly higher transepithelial electrical resistance percentage (60% reduction after 4 hours; P<1.10^–6) when exposed to tumor necrosis factor α signaling compared with normal intestinal cells. They concluded that zinc deficiency can increase intestinal permeability in the presence of inflammation, creating a cycle of further nutrient malabsorption and inflammation exacerbating IBD symptoms.³³

Cutaneous Manifestations—After absorption in the small intestine, approximately 5% of zinc resides in the skin, with the highest concentration in the stratum spinosum.³⁴ A cell study found that keratinocytes in zinc-deficient environments had higher rates of apoptosis compared with cells in normal media. The authors proposed that this higher rate of apoptosis and the resulting inflammation could be a mechanism for developing the desquamative or eczematous scaly plaques that are common cutaneous manifestations of zinc deficiency.³⁵

Other cutaneous findings may include angular cheilitis, stomatitis, glossitis, paronychia, onychodystrophy, generalized alopecia, and delayed wound healing.³⁶ The histopathology of these skin lesions is characterized by granular layer loss, epidermal pallor, confluent parakeratosis, spongiosis, dyskeratosis, and psoriasiform hyperplasia.³⁷

Diagnosis and Monitoring—Assessing serum zinc levels is challenging, as they may decrease during states of inflammation.³⁸ A mouse model study showed a 3.1-fold increase (P<.001) in ZIP14 expression in wild-type mice compared with an IL-6 -/- knock-down model after IL-6 exposure. The authors concluded that the upregulation of ZIP14 in the liver due to inflammatory cytokine upregulation decreases zinc availability in serum.³⁹ Additionally, serum zinc can overestimate the level of deficiency in IBD because approximately 75% of serum zinc is bound to albumin, which decreases in the setting of inflammation.^40-42

Alternatively, alkaline phosphatase (AP), a zinc-dependent metalloenzyme, may be a better evaluator of zinc status during periods of inflammation. A study in rats evaluated zinc through serum zinc levels and AP levels after a period of induced stress to mimic a short-term inflammatory state.⁴³ The researchers found that total body stores of zinc were unaffected throughout the experiment; only serum zinc declined throughout the experiment duration while AP did not. Because approximately 75% of serum zinc is bound to serum albumin,⁴² the researchers concluded the induced inflammatory state depleted serum albumin and redistributed zinc to the liver, causing the observed serum zinc changes, while total body zinc levels and AP were largely unaffected in comparison.⁴³ Comorbid conditions such as liver or bone disease can increase AP levels, which limits the utility of AP as a surrogate for zinc in patients with comorbidities.⁴⁴ However, even in the context of active IBD, serum zinc still is currently considered the best biomarker to evaluate zinc status.⁴⁵

Treatment—The recommended dose for zinc supplementation is 20 to 40 mg daily with higher doses (>50 mg/d) for patients with malabsorptive syndromes such as IBD.⁴⁶ It can be administered orally or parenterally. Although rare, zinc replacement therapy may be associated with diarrhea, nausea, vomiting, mild headaches, and fatigue.⁴⁶ Additional considerations should be taken when repleting other micronutrients with zinc, as calcium and folate can inhibit zinc reabsorption, while zinc itself can inhibit iron and copper reabsorption.⁴⁷

Vitamin D and Calcium

Low vitamin D levels (<50 nmol/L) and hypocalcemia (<8.8 mg/dL) are common in patients with IBD.^48,49

Pathophysiology—Vitamin D levels are maintained via 2 mechanisms. The first mechanism is through the skin, as keratinocytes produce 7-dehydrocholesterol after exposure to UV light, which is converted into previtamin D₃ and then thermally isomerizes into vitamin D₃. This vitamin D₃ is then transported to the liver on vitamin D–binding protein.⁵⁰ The second mechanism is through oral vitamin D₃ that is absorbed through vitamin D receptors in intestinal epithelium and transported to the liver, where it is hydroxylated into 25-hydroxyvitamin D (25[OH]D), then to the kidneys for hydroxylation to 1,25(OH)₂D for redistribution throughout the body.⁵⁰ This activated form of vitamin D regulates calcium absorption in the intestine, and optimal vitamin D levels are necessary to absorb calcium efficiently.⁵¹ Inflammation from IBD within the small intestine can downregulate vitamin D receptors, causing malabsorption and decreased serum vitamin D.⁵²

Vitamin D signaling also is vital to maintaining the tight junctions and adherens junctions of the intestinal epithelium. Weakening the permeability of the epithelium further exacerbates malabsorption and subsequent vitamin D deficiency.⁵² A meta-analysis of 27 studies including 8316 patients with IBD showed low vitamin D levels were associated with increased odds of disease activity (OR=1.53; 95% CI, 1.32-1.77), mucosal inflammation (OR=1.25; 95% CI, 1.06-1.47), and future clinical relapse (OR=1.23; 95% CI, 1.03-1.47) in patients with Crohn disease. The authors concluded that low levels of vitamin D could be used as a potential biomarker of inflammatory status in Crohn disease.⁵³

Vitamin D and calcium are further implicated in maintaining skeletal health,⁴⁷ while vitamin D specifically helps maintain intestinal homeostasis⁵⁴ and immune system modulation in the skin.⁵⁵

Cutaneous Manifestations—Vitamin D is thought to play crucial roles in skin differentiation and proliferation, cutaneous innate immunity, hair follicle cycling, photoprotection, and wound healing.⁵⁶ Vitamin D deficiency has been observed in a large range of cutaneous diseases including skin cancer, psoriasis, vitiligo, bullous pemphigoid, atopic dermatitis, and various types of alopecia.^56-59 It is unclear whether vitamin D deficiency facilitates these disease processes or is merely the consequence of a disrupted cutaneous surface with the inability to complete the first step in vitamin D processing. A 2014 meta-analysis of 290 prospective cohort studies and 172 randomized trials concluded that 25(OH)D deficiency was associated with ill health and did not find causal evidence for any specific disease, dermatologic or otherwise.⁶⁰ Calcium deficiency may cause epidermal changes including dry skin, coarse hair, and brittle nails.⁶¹

Diagnosis and Monitoring—The ECCO guidelines recommend obtaining serum 25(OH)D levels every 3 months in patients with IBD.⁶² Levels less than 75 nmol/L are considered deficient, and a value less than 30 nmol/L increases the risk for osteomalacia and nutritional rickets, constituting severe vitamin D deficiency.^63-65

An observational study of 325 patients with IBD showed a statistically significant negative correlation between serum vitamin D and fecal calprotectin (r=−0.19; P<.001), a stool-based marker for gut inflammation, supporting vitamin D as a potential biomarker in IBD.⁶⁶

Evaluation of calcium can be done through serum levels in patients with IBD.⁶⁷ Patients with IBD are at risk for hypoalbuminemia; therefore, consideration should be taken to ensure calcium levels are corrected, as approximately 50% of calcium is bound to albumin or other ions in the body,⁶⁸ which can be done by adjusting the calcium concentration by 0.02 mmol/L for every 1 g/L of albumin above or below 40 g/L. In the most critically ill patients, a direct ionized calcium blood level should be used instead because the previously mentioned correction calculations are inaccurate when albumin is critically low.⁶⁹

Treatment—The ECCO guidelines recommend calcium and vitamin D repletion of 500 to 1000 mg and 800 to 1000 U, respectively, in patients with IBD on systemic corticosteroids to prevent the negative effects of bone loss.⁶² Calcium repletion in patients with IBD who are not on systemic steroids are the same as for the general population.⁶⁵

Vitamin D repletion also may help decrease IBD activity. In a prospective study, 10,000 IU/d of vitamin D in 10 patients with IBD—adjusted over 12 weeks to a target of 100 to 125 nmol/L of serum 25(OH)D—showed a significant reduction in clinical Crohn activity (P=.019) over the study period.⁷⁰ In contrast, 2000 IU/d for 3 months in an RCT of 27 patients with Crohn disease found significantly lower CRP (P=.019) and significantly higher self-reported quality of life (P=.037) but nonsignificant decreases in Crohn activity (P=.082) in patients with 25(OH)D levels of 75 nmol/L or higher compared with those with 25(OH)D levels less than 75 nmol/L.⁷¹

These discrepancies illustrate the need for expanded clinical trials to elucidate the optimal vitamin D dosing for patients with IBD. Ultimately, assessing vitamin D and calcium status and considering repletion in patients with IBD, especially those with comorbid dermatologic diseases such as poor wound healing, psoriasis, or atopic dermatitis, is important.

Vitamin B₆ (Pyridoxine)

Pathophysiology—Pyridoxine is an important coenzyme for many functions including amino acid transamination, fatty acid metabolism, and conversion of tryptophan to niacin. It is absorbed in the jejunum and ileum and subsequently transported to the liver for rephosphorylation and release into its active form.³⁶ An observational study assessing the nutritional status of patients with IBD found that only 5.7% of 105 patients with food records had inadequate dietary intake of pyridoxine, but 29% of all patients with IBD had subnormal pyridoxine levels.⁷² Additionally, they found no significant difference in the prevalence of subnormal pyridoxine levels in patients with active IBD vs IBD in remission. The authors suggested that the subnormal pyridoxine levels in patients with IBD likely were multifactorial and resulted from malabsorption due to active disease, inflammation, and inadequate intake.⁷²

Cutaneous Manifestations—Cutaneous findings associated with pyridoxine deficiency include periorificial and perineal dermatitis,⁷³ angular stomatitis, and cheilitis with associated burning, redness, and tongue edema.³⁶ Additionally, pyridoxine is involved in the conversion of tryptophan to niacin, and its deficiency may manifest with pellagralike findings.⁷⁴

Because pyridoxine is critical to protein metabolism, its deficiency may disrupt key cellular structures that rely on protein concentrations to maintain structural integrity. One such structure in the skin that heavily relies on protein concentrations is the ground substance of the extracellular matrix—the amorphous gelatinous spaces that occupy the areas between the extracellular matrix, which consists of cross-linked glycosaminoglycans and proteins.⁷⁵ Without protein, ground substance increases in viscosity and can disrupt the epidermal barrier, leading to increased transepidermal water loss and ultimately inflammation.⁷⁶ Although this theory has yet to be validated fully, this is a potential mechanistic explanation for the inflammation in dermal papillae that leads to dermatitis observed in pyridoxine deficiency.

Diagnosis and Monitoring—Direct biomarkers of pyridoxine status are in serum, plasma, erythrocytes, and urine, with the most common measurement in plasma as pyridoxal 5′-phosphate (PLP).⁷⁷ Plasma PLP concentrations lower than 20 nmol/L are suggestive of deficiency.⁷⁸ Plasma PLP has shown inverse relationships with acute phase inflammatory markers CRP⁷⁹ and AP,⁷⁸ thereby raising concerns for its validity to assess pyridoxine status in patients with symptomatic IBD.⁸⁰

Alternative evaluations of pyridoxine include tryptophan and methionine loading tests,³⁶ which are measured via urinary excretion and require normal kidney function to be accurate. They should be considered in IBD if necessary, but routine testing, even in patients with symptomatic IBD, is not recommended in the ECCO guidelines. Additional considerations should be taken in patients with altered nutrient requirements such as those who have undergone bowel resection due to highly active disease or those who receive parenteral nutritional supplementation.⁸¹

Treatment—Recommendations for oral pyridoxine supplementation range from 25 to 600 mg daily,⁸² with symptoms typically improving on 100 mg daily.³⁶ Pyridoxine supplementation may have additional benefits for patients with IBD and potentially modulate disease severity. An IL-10 knockout mouse supplemented with pyridoxine had an approximately 60% reduction (P<.05) in inflammation compared to mice deficient in pyridoxine.⁸³ The authors suggest that PLP-dependent enzymes can inhibit further proinflammatory signaling and T-cell migration that can exacerbate IBD. Ultimately, more data is needed before determining the efficacy of pyridoxine supplementation for active IBD.

Vitamin B₁₂ and Vitamin B₉ (Folic Acid)

Pathophysiology—Vitamin B₁₂ is reabsorbed in the terminal ileum, the distal portion of the small intestine. The American Gastroenterological Association recommends that patients with a history of extensive ileal disease or prior ileal surgery, which is the case for many patients with Crohn disease, be monitored for vitamin B₁₂ deficiency.²³ Monitoring and rapid supplementation of vitamin B₁₂ can prevent pernicious anemia and irreversible neurologic damage that may result from deficiency.⁸⁴

Folic acid is primarily absorbed in the duodenum and jejunum of the small intestine. A meta-analysis performed in 2017 assessed studies observing folic acid and vitamin B₁₂ levels in 1086 patients with IBD compared with 1484 healthy controls and found an average difference in serum folate concentration of 0.46 nmol/L (P<.001).⁸⁴ Interestingly, this study did not find a significant difference in serum vitamin B₁₂ levels between patients with IBD and healthy controls, highlighting the mechanism of vitamin B₁₂ deficiency in IBD because only patients with terminal ileal involvement are at risk for malabsorption and subsequent deficiency.

Cutaneous Manifestations—Both vitamin B₁₂ and folic acid deficiency can manifest as cheilitis, glossitis, and/or generalized hyperpigmentation that is accentuated in the flexural areas, palms, soles, and oral cavity.^85,86 Systemic symptoms of patients with vitamin B₁₂ and folic acid deficiency include megaloblastic anemia, pallor, and fatigue. A potential mechanism for the hyperpigmentation observed from vitamin B₁₂ deficiency came from an electron microscope study that showed an increased concentration of melanosomes in a patient with deficiency.⁸⁷

Diagnosis and Monitoring—In patients with suspected vitamin B₁₂ and/or folic acid deficiency, initial evaluation should include a CBC with peripheral smear and serum vitamin B₁₂ and folate levels. In cases for which the diagnosis still is unclear after initial testing, methylmalonic acid and homocysteine levels can help differentiate between the 2 deficiencies. Methylmalonic acid classically is elevated (>260 nmol/L) in vitamin B₁₂ deficiency but not in folate deficiency.⁸⁸ Cut-off values for vitamin B₁₂ deficiency are less than 200 to 250 pg/mL forserum vitamin B₁₂ and/or an elevated level of methylmalonic acid (>0.271 µmol/L).⁸⁹ A serum folic acid value greater than 3 ng/mL and/or erythrocyte folate concentrations greater than 140 ng/mL are considered adequate, whereas an indicator of folic acid deficiency is a homocysteine level less than 10 µmol/L.⁹⁰ A CBC can screen for macrocytic megaloblastic anemias (mean corpuscular volume >100 fl), which are classic diagnostic signs of an underlying vitamin B₁₂ or folate deficiency.

Treatment—According to the Centers for Disease Control and Prevention, supplementation of vitamin B₁₂ can be done orally with 1000 µg daily in patients with deficiency. In patients with active IBD, oral reabsorption of vitamin B₁₂ can be less effective, making subcutaneous or intramuscular administration (1000 µg/wk for 8 weeks, then monthly for life) better options.⁸⁹

Patients with IBD managed with methotrexate should be screened carefully for folate deficiency. Methotrexate is a folate analog that sometimes is used for the treatment of IBD. Reversible competitive inhibition of dihydrofolate reductase can precipitate a systemic folic acid decrease.⁹¹ Typically, oral folic acid (1 to 5 mg/d) is sufficient to treat folate deficiency, with the ESPEN recommending 5 mg once weekly 24 to 72 hours after methotrexate treatment or 1 mg daily for 5 days per week in patients with IBD.¹ Alternative formulations—IV, subcutaneous, or intramuscular—are available for patients who cannot tolerate oral intake.⁹²

Final Thoughts

Dermatologists can be the first to observe the cutaneous manifestations of micronutrient deficiencies. Although the symptoms of each micronutrient deficiency discussed may overlap, attention to small clinical clues in patients with IBD can improve patient outcomes and quality of life. For example, koilonychia with glossitis and xerosis likely is due to iron deficiency, while zinc deficiency should be suspected in patients with scaly eczematous plaques in skin folds. A high level of suspicion for micronutrient deficiencies in patients with IBD should be followed by a complete patient history, review of systems, and thorough clinical examination. A thorough laboratory evaluation can pinpoint nutritional deficiencies in patients with IBD, keeping in mind that specific biomarkers such as ferritin and serum zinc also act as acute phase reactants and should be interpreted in this context. Co-management with gastroenterologists should be a priority in patients with IBD, as gaining control of inflammatory disease is crucial for the prevention of recurrent vitamin and micronutrient deficiencies in addition to long-term health in this population.

In 2023, ESPEN (the European Society for Clinical Nutrition and Metabolism) published consensus recommendations highlighting the importance of regular monitoring and treatment of nutrient deficiencies in patients with inflammatory bowel disease (IBD) for improved prognosis, mortality, and quality of life.¹ Suboptimal nutrition in patients with IBD predominantly results from inflammation of the gastrointestinal (GI) tract leading to malabsorption; however, medications commonly used to manage IBD also can contribute to malnutrition.^2,3 Additionally, patients may develop nausea and food avoidance due to medication or the disease itself, leading to nutritional withdrawal and eventual deficiency.⁴ Even with the development of diets focused on balancing nutritional needs and decreasing inflammation,⁵ offsetting this aversion to food can be difficult to overcome.²

Cutaneous manifestations of IBD are multifaceted and can be secondary to the disease, reactive to or associated with IBD, or effects from nutritional deficiencies. The most common vitamin and nutrient deficiencies in patients with IBD include iron; zinc; calcium; vitamin D; and vitamins B₆ (pyridoxine), B₉ (folic acid), and B₁₂.⁶ Malnutrition may manifest with cutaneous disease, and dermatologists can be the first to identify and assess for nutritional deficiencies. In this article, we review the mechanisms of these micronutrient depletions in the context of IBD, their subsequent dermatologic manifestations (Table), and treatment and monitoring guidelines for each deficiency.

CT113004159_Table.jpg

Iron

A systematic review conducted from 2007 to 2012 in European patients with IBD (N=2192) found the overall prevalence of anemia in this population to be 24% (95% CI, 18%-31%), with 57% of patients with anemia experiencing iron deficiency.⁷ Anemia is observed more commonly in patients hospitalized with IBD and is common in patients with both Crohn disease and ulcerative colitis.⁸

Pathophysiology—Iron is critically important in oxygen transportation throughout the body as a major component of hemoglobin. Physiologically, the low pH of the duodenum and proximal jejunum allows divalent metal transporter 1 to transfer dietary Fe³⁺ into enterocytes, where it is reduced to the transportable Fe²⁺.^9,10 Distribution of Fe²⁺ ions from enterocytes relies on ferroportin, an iron-transporting protein, which is heavily regulated by the protein hepcidin.¹¹ Hepcidin, a known acute phase reactant, will increase in the setting of active IBD, causing a depletion of ferroportin and an inability of the body to utilize the stored iron in enterocytes.¹² This poor utilization of iron stores combined with blood loss caused by inflammation in the GI tract is the proposed primary mechanism of iron-deficiency anemia observed in patients with IBD.¹³

Cutaneous Manifestations—From a dermatologic perspective, iron-deficiency anemia can manifest with a wide range of symptoms including glossitis, koilonychia, xerosis and/or pruritus, and brittle hair or hair loss.^14,15 Although the underlying pathophysiology of these cutaneous manifestations is not fully understood, there are several theories assessing the mechanisms behind the skin findings of iron deficiency.

Atrophic glossitis has been observed in many patients with iron deficiency and is thought to manifest due to low iron concentrations in the blood, thereby decreasing oxygen delivery to the papillae of the dorsal tongue with resultant atrophy.^16,17 Similarly, decreased oxygen delivery to the nail bed capillaries may cause deformities in the nail called koilonychia (or “spoon nails”).¹⁸ Iron is a key co-factor in collagen lysyl hydroxylase that promotes collagen binding; iron deficiency may lead to disruptions in the epidermal barrier that can cause pruritus and xerosis.¹⁹ An observational study of 200 healthy patients with a primary concern of pruritus found a correlation between low serum ferritin and a higher degree of pruritus (r=−0.768; P<.00001).²⁰

Evidence for iron’s role in hair growth comes from a mouse model study with a mutation in the serine protease TMPRSS6—a protein that regulates hepcidin and iron absorption—which caused an increase in hepcidin production and subsequent systemic iron deficiency. Mice at 4 weeks of age were devoid of all body hair but had substantial regrowth after initiation of a 2-week iron-rich diet, which suggests a connection between iron repletion and hair growth in mice with iron deficiency.²¹ Additionally, a meta-analysis analyzing the comorbidities of patients with alopecia areata found them to have higher odds (odds ratio [OR]=2.78; 95% CI, 1.23-6.29) of iron-deficiency anemia but no association with IBD (OR=1.48; 95% CI, 0.32-6.82).²²

Diagnosis and Monitoring—The American Gastroenterological Association recommends a complete blood cell count (CBC), serum ferritin, transferrin saturation (TfS), and C-reactive protein (CRP) as standard evaluations for iron deficiency in patients with IBD. Patients with active IBD should be screened every 3 months,and patients with inactive disease should be screened every 6 to 12 months.²³

Although ferritin and TfS often are used as markers for iron status in healthy individuals, they are positive and negative acute phase reactants, respectively. Using them to assess iron status in patients with IBD may inaccurately represent iron status in the setting of inflammation from the disease.²⁴ The European Crohn’s and Colitis Organisation (ECCO) produced guidelines to define iron deficiency as a TfS less than 20% or a ferritin level less than 30 µg/L in patients without evidence of active IBD and a ferritin level less than 100 µg/L for patients with active inflammation.²⁵

A 2020 multicenter observational study of 202 patients with diagnosed IBD found that the ECCO guideline of ferritin less than 30 µg/L had an area under the receiver operating characteristic (AUROC) curve of 0.69, a sensitivity of 0.43, and a specificity of 0.95 in their population.²⁶ In a sensitivity analysis stratifying patients by CRP level (<10 or ≥10 mg/L), the authors found that for patients with ulcerative colitis and a CRP less than 10 mg/L, a cut-off value of ferritin less than 65 µg/L (AUROC=0.78) had a sensitivity of 0.78 and specificity of 0.76, and a TfS value of less than 16% (AUROC=0.88) had a sensitivity of 0.79 and a specificity of 0.9. In patients with a CRP of 10 mg/L or greater, a cut-off value of ferritin 80 µg/L (AUROC=0.76) had a sensitivity of 0.75 and a specificity of 0.82, and a TfS value of less than 11% (AUROC=0.69) had a sensitivity of 0.79 and a specificity of 0.88. There were no ferritin cut-off values associated with good diagnostic performance (defined as both sensitivity and specificity >0.70) for iron deficiency in patients with Crohn disease.²⁶

The authors recommended using an alternative iron measurement such as soluble transferrin receptor (sTfR)/log ferritin ratio (TfR-F) that is not influenced by active inflammation and has a good correlation with ferritin values (TfR-F: r=0.66; P<.001).²⁶ However, both sTfR and TfR-F have high costs and intermethod variability as well as differences in their reference ranges depending on which laboratory performs the analysis, limiting the accessibility and practicality of easily obtaining these tests.²⁷ Although there may be inaccuracies for standard ferritin or TfS under ECCO guidelines, proposed alternatives have their own limitations, which may make ferritin and TfS the most reasonable evaluations of iron status as long as disease activity status at the time of testing is taken into consideration.

Treatment—Treatment of underlying iron deficiency in patients with IBD requires reversing the cause of the deficiency and supplementing iron. In patients with IBD, the options to supplement iron may be limited by active disease, making oral intake less effective. Oral iron supplementation also is associated with notable GI adverse effects that may be exacerbated in patients with IBD. A systematic review of 43 randomized controlled trials (RCTs) evaluating GI adverse effects (eg, nausea, abdominal pain, diarrhea, constipation, and black or tarry stools) of oral ferrous sulfate compared with placebo or intravenous (IV) iron supplementation in healthy nonanemic individuals found a significant increase in GI adverse effects with oral supplementation (placebo: OR=2.32; P<.0001; IV: OR=3.05; P<.0001).²⁸

Therefore, IV iron repletion may be necessary in patients with IBD and may require numerous infusions depending on the formulation of iron. In an RCT conducted in 2011, patients with iron-deficiency anemia with quiescent or mild to moderate IBD were treated with either IV iron sulfate or ferric carboxymaltose.²⁹ With a primary end point of hemoglobin response greater than 2 g/dL, the authors found that 150 of 240 patients responded to ferric carboxymaltose vs 118 of 235 treated with iron sulfate (P=.004). The dosing for ferric carboxymaltose was 1 to 3 infusions of 500 to 1000 mg of iron and for iron sulfate up to 11 infusions of 200 mg of iron.²⁹

Zinc

A systematic review of zinc deficiency in patients with IBD identified 7 studies including 2413 patients and revealed those with Crohn disease had a higher prevalence of zinc deficiency compared with patients with ulcerative colitis (54% vs 41%).³⁰

Pathophysiology—Zinc serves as a catalytic cofactor for enzymatic activity within proteins and immune cells.³¹ The homeostasis of zinc is tightly regulated within the brush border of the small intestine by zinc transporters ZIP4 and ZIP1 from the lumen of enterocytes into the bloodstream.³² Inflammation in the small intestine due to Crohn disease can result in zinc malabsorption.

Ranaldi et al³³ exposed intestinal cells and zinc-depleted intestinal cells to tumor necrosis factor α media to simulate an inflammatory environment. They measured transepithelial electrical resistance as a surrogate for transmembrane permeability and found that zinc-depleted cells had a statistically significantly higher transepithelial electrical resistance percentage (60% reduction after 4 hours; P<1.10^–6) when exposed to tumor necrosis factor α signaling compared with normal intestinal cells. They concluded that zinc deficiency can increase intestinal permeability in the presence of inflammation, creating a cycle of further nutrient malabsorption and inflammation exacerbating IBD symptoms.³³

Cutaneous Manifestations—After absorption in the small intestine, approximately 5% of zinc resides in the skin, with the highest concentration in the stratum spinosum.³⁴ A cell study found that keratinocytes in zinc-deficient environments had higher rates of apoptosis compared with cells in normal media. The authors proposed that this higher rate of apoptosis and the resulting inflammation could be a mechanism for developing the desquamative or eczematous scaly plaques that are common cutaneous manifestations of zinc deficiency.³⁵

Other cutaneous findings may include angular cheilitis, stomatitis, glossitis, paronychia, onychodystrophy, generalized alopecia, and delayed wound healing.³⁶ The histopathology of these skin lesions is characterized by granular layer loss, epidermal pallor, confluent parakeratosis, spongiosis, dyskeratosis, and psoriasiform hyperplasia.³⁷

Diagnosis and Monitoring—Assessing serum zinc levels is challenging, as they may decrease during states of inflammation.³⁸ A mouse model study showed a 3.1-fold increase (P<.001) in ZIP14 expression in wild-type mice compared with an IL-6 -/- knock-down model after IL-6 exposure. The authors concluded that the upregulation of ZIP14 in the liver due to inflammatory cytokine upregulation decreases zinc availability in serum.³⁹ Additionally, serum zinc can overestimate the level of deficiency in IBD because approximately 75% of serum zinc is bound to albumin, which decreases in the setting of inflammation.^40-42

Alternatively, alkaline phosphatase (AP), a zinc-dependent metalloenzyme, may be a better evaluator of zinc status during periods of inflammation. A study in rats evaluated zinc through serum zinc levels and AP levels after a period of induced stress to mimic a short-term inflammatory state.⁴³ The researchers found that total body stores of zinc were unaffected throughout the experiment; only serum zinc declined throughout the experiment duration while AP did not. Because approximately 75% of serum zinc is bound to serum albumin,⁴² the researchers concluded the induced inflammatory state depleted serum albumin and redistributed zinc to the liver, causing the observed serum zinc changes, while total body zinc levels and AP were largely unaffected in comparison.⁴³ Comorbid conditions such as liver or bone disease can increase AP levels, which limits the utility of AP as a surrogate for zinc in patients with comorbidities.⁴⁴ However, even in the context of active IBD, serum zinc still is currently considered the best biomarker to evaluate zinc status.⁴⁵

Treatment—The recommended dose for zinc supplementation is 20 to 40 mg daily with higher doses (>50 mg/d) for patients with malabsorptive syndromes such as IBD.⁴⁶ It can be administered orally or parenterally. Although rare, zinc replacement therapy may be associated with diarrhea, nausea, vomiting, mild headaches, and fatigue.⁴⁶ Additional considerations should be taken when repleting other micronutrients with zinc, as calcium and folate can inhibit zinc reabsorption, while zinc itself can inhibit iron and copper reabsorption.⁴⁷

Vitamin D and Calcium

Low vitamin D levels (<50 nmol/L) and hypocalcemia (<8.8 mg/dL) are common in patients with IBD.^48,49

Pathophysiology—Vitamin D levels are maintained via 2 mechanisms. The first mechanism is through the skin, as keratinocytes produce 7-dehydrocholesterol after exposure to UV light, which is converted into previtamin D₃ and then thermally isomerizes into vitamin D₃. This vitamin D₃ is then transported to the liver on vitamin D–binding protein.⁵⁰ The second mechanism is through oral vitamin D₃ that is absorbed through vitamin D receptors in intestinal epithelium and transported to the liver, where it is hydroxylated into 25-hydroxyvitamin D (25[OH]D), then to the kidneys for hydroxylation to 1,25(OH)₂D for redistribution throughout the body.⁵⁰ This activated form of vitamin D regulates calcium absorption in the intestine, and optimal vitamin D levels are necessary to absorb calcium efficiently.⁵¹ Inflammation from IBD within the small intestine can downregulate vitamin D receptors, causing malabsorption and decreased serum vitamin D.⁵²

Vitamin D signaling also is vital to maintaining the tight junctions and adherens junctions of the intestinal epithelium. Weakening the permeability of the epithelium further exacerbates malabsorption and subsequent vitamin D deficiency.⁵² A meta-analysis of 27 studies including 8316 patients with IBD showed low vitamin D levels were associated with increased odds of disease activity (OR=1.53; 95% CI, 1.32-1.77), mucosal inflammation (OR=1.25; 95% CI, 1.06-1.47), and future clinical relapse (OR=1.23; 95% CI, 1.03-1.47) in patients with Crohn disease. The authors concluded that low levels of vitamin D could be used as a potential biomarker of inflammatory status in Crohn disease.⁵³

Vitamin D and calcium are further implicated in maintaining skeletal health,⁴⁷ while vitamin D specifically helps maintain intestinal homeostasis⁵⁴ and immune system modulation in the skin.⁵⁵

Cutaneous Manifestations—Vitamin D is thought to play crucial roles in skin differentiation and proliferation, cutaneous innate immunity, hair follicle cycling, photoprotection, and wound healing.⁵⁶ Vitamin D deficiency has been observed in a large range of cutaneous diseases including skin cancer, psoriasis, vitiligo, bullous pemphigoid, atopic dermatitis, and various types of alopecia.^56-59 It is unclear whether vitamin D deficiency facilitates these disease processes or is merely the consequence of a disrupted cutaneous surface with the inability to complete the first step in vitamin D processing. A 2014 meta-analysis of 290 prospective cohort studies and 172 randomized trials concluded that 25(OH)D deficiency was associated with ill health and did not find causal evidence for any specific disease, dermatologic or otherwise.⁶⁰ Calcium deficiency may cause epidermal changes including dry skin, coarse hair, and brittle nails.⁶¹

Diagnosis and Monitoring—The ECCO guidelines recommend obtaining serum 25(OH)D levels every 3 months in patients with IBD.⁶² Levels less than 75 nmol/L are considered deficient, and a value less than 30 nmol/L increases the risk for osteomalacia and nutritional rickets, constituting severe vitamin D deficiency.^63-65

An observational study of 325 patients with IBD showed a statistically significant negative correlation between serum vitamin D and fecal calprotectin (r=−0.19; P<.001), a stool-based marker for gut inflammation, supporting vitamin D as a potential biomarker in IBD.⁶⁶

Evaluation of calcium can be done through serum levels in patients with IBD.⁶⁷ Patients with IBD are at risk for hypoalbuminemia; therefore, consideration should be taken to ensure calcium levels are corrected, as approximately 50% of calcium is bound to albumin or other ions in the body,⁶⁸ which can be done by adjusting the calcium concentration by 0.02 mmol/L for every 1 g/L of albumin above or below 40 g/L. In the most critically ill patients, a direct ionized calcium blood level should be used instead because the previously mentioned correction calculations are inaccurate when albumin is critically low.⁶⁹

Treatment—The ECCO guidelines recommend calcium and vitamin D repletion of 500 to 1000 mg and 800 to 1000 U, respectively, in patients with IBD on systemic corticosteroids to prevent the negative effects of bone loss.⁶² Calcium repletion in patients with IBD who are not on systemic steroids are the same as for the general population.⁶⁵

Vitamin D repletion also may help decrease IBD activity. In a prospective study, 10,000 IU/d of vitamin D in 10 patients with IBD—adjusted over 12 weeks to a target of 100 to 125 nmol/L of serum 25(OH)D—showed a significant reduction in clinical Crohn activity (P=.019) over the study period.⁷⁰ In contrast, 2000 IU/d for 3 months in an RCT of 27 patients with Crohn disease found significantly lower CRP (P=.019) and significantly higher self-reported quality of life (P=.037) but nonsignificant decreases in Crohn activity (P=.082) in patients with 25(OH)D levels of 75 nmol/L or higher compared with those with 25(OH)D levels less than 75 nmol/L.⁷¹

These discrepancies illustrate the need for expanded clinical trials to elucidate the optimal vitamin D dosing for patients with IBD. Ultimately, assessing vitamin D and calcium status and considering repletion in patients with IBD, especially those with comorbid dermatologic diseases such as poor wound healing, psoriasis, or atopic dermatitis, is important.

Vitamin B₆ (Pyridoxine)

Pathophysiology—Pyridoxine is an important coenzyme for many functions including amino acid transamination, fatty acid metabolism, and conversion of tryptophan to niacin. It is absorbed in the jejunum and ileum and subsequently transported to the liver for rephosphorylation and release into its active form.³⁶ An observational study assessing the nutritional status of patients with IBD found that only 5.7% of 105 patients with food records had inadequate dietary intake of pyridoxine, but 29% of all patients with IBD had subnormal pyridoxine levels.⁷² Additionally, they found no significant difference in the prevalence of subnormal pyridoxine levels in patients with active IBD vs IBD in remission. The authors suggested that the subnormal pyridoxine levels in patients with IBD likely were multifactorial and resulted from malabsorption due to active disease, inflammation, and inadequate intake.⁷²

Cutaneous Manifestations—Cutaneous findings associated with pyridoxine deficiency include periorificial and perineal dermatitis,⁷³ angular stomatitis, and cheilitis with associated burning, redness, and tongue edema.³⁶ Additionally, pyridoxine is involved in the conversion of tryptophan to niacin, and its deficiency may manifest with pellagralike findings.⁷⁴

Because pyridoxine is critical to protein metabolism, its deficiency may disrupt key cellular structures that rely on protein concentrations to maintain structural integrity. One such structure in the skin that heavily relies on protein concentrations is the ground substance of the extracellular matrix—the amorphous gelatinous spaces that occupy the areas between the extracellular matrix, which consists of cross-linked glycosaminoglycans and proteins.⁷⁵ Without protein, ground substance increases in viscosity and can disrupt the epidermal barrier, leading to increased transepidermal water loss and ultimately inflammation.⁷⁶ Although this theory has yet to be validated fully, this is a potential mechanistic explanation for the inflammation in dermal papillae that leads to dermatitis observed in pyridoxine deficiency.

Diagnosis and Monitoring—Direct biomarkers of pyridoxine status are in serum, plasma, erythrocytes, and urine, with the most common measurement in plasma as pyridoxal 5′-phosphate (PLP).⁷⁷ Plasma PLP concentrations lower than 20 nmol/L are suggestive of deficiency.⁷⁸ Plasma PLP has shown inverse relationships with acute phase inflammatory markers CRP⁷⁹ and AP,⁷⁸ thereby raising concerns for its validity to assess pyridoxine status in patients with symptomatic IBD.⁸⁰

Alternative evaluations of pyridoxine include tryptophan and methionine loading tests,³⁶ which are measured via urinary excretion and require normal kidney function to be accurate. They should be considered in IBD if necessary, but routine testing, even in patients with symptomatic IBD, is not recommended in the ECCO guidelines. Additional considerations should be taken in patients with altered nutrient requirements such as those who have undergone bowel resection due to highly active disease or those who receive parenteral nutritional supplementation.⁸¹

Treatment—Recommendations for oral pyridoxine supplementation range from 25 to 600 mg daily,⁸² with symptoms typically improving on 100 mg daily.³⁶ Pyridoxine supplementation may have additional benefits for patients with IBD and potentially modulate disease severity. An IL-10 knockout mouse supplemented with pyridoxine had an approximately 60% reduction (P<.05) in inflammation compared to mice deficient in pyridoxine.⁸³ The authors suggest that PLP-dependent enzymes can inhibit further proinflammatory signaling and T-cell migration that can exacerbate IBD. Ultimately, more data is needed before determining the efficacy of pyridoxine supplementation for active IBD.

Vitamin B₁₂ and Vitamin B₉ (Folic Acid)

Pathophysiology—Vitamin B₁₂ is reabsorbed in the terminal ileum, the distal portion of the small intestine. The American Gastroenterological Association recommends that patients with a history of extensive ileal disease or prior ileal surgery, which is the case for many patients with Crohn disease, be monitored for vitamin B₁₂ deficiency.²³ Monitoring and rapid supplementation of vitamin B₁₂ can prevent pernicious anemia and irreversible neurologic damage that may result from deficiency.⁸⁴

Folic acid is primarily absorbed in the duodenum and jejunum of the small intestine. A meta-analysis performed in 2017 assessed studies observing folic acid and vitamin B₁₂ levels in 1086 patients with IBD compared with 1484 healthy controls and found an average difference in serum folate concentration of 0.46 nmol/L (P<.001).⁸⁴ Interestingly, this study did not find a significant difference in serum vitamin B₁₂ levels between patients with IBD and healthy controls, highlighting the mechanism of vitamin B₁₂ deficiency in IBD because only patients with terminal ileal involvement are at risk for malabsorption and subsequent deficiency.

Cutaneous Manifestations—Both vitamin B₁₂ and folic acid deficiency can manifest as cheilitis, glossitis, and/or generalized hyperpigmentation that is accentuated in the flexural areas, palms, soles, and oral cavity.^85,86 Systemic symptoms of patients with vitamin B₁₂ and folic acid deficiency include megaloblastic anemia, pallor, and fatigue. A potential mechanism for the hyperpigmentation observed from vitamin B₁₂ deficiency came from an electron microscope study that showed an increased concentration of melanosomes in a patient with deficiency.⁸⁷

Diagnosis and Monitoring—In patients with suspected vitamin B₁₂ and/or folic acid deficiency, initial evaluation should include a CBC with peripheral smear and serum vitamin B₁₂ and folate levels. In cases for which the diagnosis still is unclear after initial testing, methylmalonic acid and homocysteine levels can help differentiate between the 2 deficiencies. Methylmalonic acid classically is elevated (>260 nmol/L) in vitamin B₁₂ deficiency but not in folate deficiency.⁸⁸ Cut-off values for vitamin B₁₂ deficiency are less than 200 to 250 pg/mL forserum vitamin B₁₂ and/or an elevated level of methylmalonic acid (>0.271 µmol/L).⁸⁹ A serum folic acid value greater than 3 ng/mL and/or erythrocyte folate concentrations greater than 140 ng/mL are considered adequate, whereas an indicator of folic acid deficiency is a homocysteine level less than 10 µmol/L.⁹⁰ A CBC can screen for macrocytic megaloblastic anemias (mean corpuscular volume >100 fl), which are classic diagnostic signs of an underlying vitamin B₁₂ or folate deficiency.

Treatment—According to the Centers for Disease Control and Prevention, supplementation of vitamin B₁₂ can be done orally with 1000 µg daily in patients with deficiency. In patients with active IBD, oral reabsorption of vitamin B₁₂ can be less effective, making subcutaneous or intramuscular administration (1000 µg/wk for 8 weeks, then monthly for life) better options.⁸⁹

Patients with IBD managed with methotrexate should be screened carefully for folate deficiency. Methotrexate is a folate analog that sometimes is used for the treatment of IBD. Reversible competitive inhibition of dihydrofolate reductase can precipitate a systemic folic acid decrease.⁹¹ Typically, oral folic acid (1 to 5 mg/d) is sufficient to treat folate deficiency, with the ESPEN recommending 5 mg once weekly 24 to 72 hours after methotrexate treatment or 1 mg daily for 5 days per week in patients with IBD.¹ Alternative formulations—IV, subcutaneous, or intramuscular—are available for patients who cannot tolerate oral intake.⁹²

Final Thoughts

Dermatologists can be the first to observe the cutaneous manifestations of micronutrient deficiencies. Although the symptoms of each micronutrient deficiency discussed may overlap, attention to small clinical clues in patients with IBD can improve patient outcomes and quality of life. For example, koilonychia with glossitis and xerosis likely is due to iron deficiency, while zinc deficiency should be suspected in patients with scaly eczematous plaques in skin folds. A high level of suspicion for micronutrient deficiencies in patients with IBD should be followed by a complete patient history, review of systems, and thorough clinical examination. A thorough laboratory evaluation can pinpoint nutritional deficiencies in patients with IBD, keeping in mind that specific biomarkers such as ferritin and serum zinc also act as acute phase reactants and should be interpreted in this context. Co-management with gastroenterologists should be a priority in patients with IBD, as gaining control of inflammatory disease is crucial for the prevention of recurrent vitamin and micronutrient deficiencies in addition to long-term health in this population.

In 2023, ESPEN (the European Society for Clinical Nutrition and Metabolism) published consensus recommendations highlighting the importance of regular monitoring and treatment of nutrient deficiencies in patients with inflammatory bowel disease (IBD) for improved prognosis, mortality, and quality of life.¹ Suboptimal nutrition in patients with IBD predominantly results from inflammation of the gastrointestinal (GI) tract leading to malabsorption; however, medications commonly used to manage IBD also can contribute to malnutrition.^2,3 Additionally, patients may develop nausea and food avoidance due to medication or the disease itself, leading to nutritional withdrawal and eventual deficiency.⁴ Even with the development of diets focused on balancing nutritional needs and decreasing inflammation,⁵ offsetting this aversion to food can be difficult to overcome.²

Cutaneous manifestations of IBD are multifaceted and can be secondary to the disease, reactive to or associated with IBD, or effects from nutritional deficiencies. The most common vitamin and nutrient deficiencies in patients with IBD include iron; zinc; calcium; vitamin D; and vitamins B₆ (pyridoxine), B₉ (folic acid), and B₁₂.⁶ Malnutrition may manifest with cutaneous disease, and dermatologists can be the first to identify and assess for nutritional deficiencies. In this article, we review the mechanisms of these micronutrient depletions in the context of IBD, their subsequent dermatologic manifestations (Table), and treatment and monitoring guidelines for each deficiency.

CT113004159_Table.jpg

Iron

A systematic review conducted from 2007 to 2012 in European patients with IBD (N=2192) found the overall prevalence of anemia in this population to be 24% (95% CI, 18%-31%), with 57% of patients with anemia experiencing iron deficiency.⁷ Anemia is observed more commonly in patients hospitalized with IBD and is common in patients with both Crohn disease and ulcerative colitis.⁸

Pathophysiology—Iron is critically important in oxygen transportation throughout the body as a major component of hemoglobin. Physiologically, the low pH of the duodenum and proximal jejunum allows divalent metal transporter 1 to transfer dietary Fe³⁺ into enterocytes, where it is reduced to the transportable Fe²⁺.^9,10 Distribution of Fe²⁺ ions from enterocytes relies on ferroportin, an iron-transporting protein, which is heavily regulated by the protein hepcidin.¹¹ Hepcidin, a known acute phase reactant, will increase in the setting of active IBD, causing a depletion of ferroportin and an inability of the body to utilize the stored iron in enterocytes.¹² This poor utilization of iron stores combined with blood loss caused by inflammation in the GI tract is the proposed primary mechanism of iron-deficiency anemia observed in patients with IBD.¹³

Cutaneous Manifestations—From a dermatologic perspective, iron-deficiency anemia can manifest with a wide range of symptoms including glossitis, koilonychia, xerosis and/or pruritus, and brittle hair or hair loss.^14,15 Although the underlying pathophysiology of these cutaneous manifestations is not fully understood, there are several theories assessing the mechanisms behind the skin findings of iron deficiency.

Atrophic glossitis has been observed in many patients with iron deficiency and is thought to manifest due to low iron concentrations in the blood, thereby decreasing oxygen delivery to the papillae of the dorsal tongue with resultant atrophy.^16,17 Similarly, decreased oxygen delivery to the nail bed capillaries may cause deformities in the nail called koilonychia (or “spoon nails”).¹⁸ Iron is a key co-factor in collagen lysyl hydroxylase that promotes collagen binding; iron deficiency may lead to disruptions in the epidermal barrier that can cause pruritus and xerosis.¹⁹ An observational study of 200 healthy patients with a primary concern of pruritus found a correlation between low serum ferritin and a higher degree of pruritus (r=−0.768; P<.00001).²⁰

Evidence for iron’s role in hair growth comes from a mouse model study with a mutation in the serine protease TMPRSS6—a protein that regulates hepcidin and iron absorption—which caused an increase in hepcidin production and subsequent systemic iron deficiency. Mice at 4 weeks of age were devoid of all body hair but had substantial regrowth after initiation of a 2-week iron-rich diet, which suggests a connection between iron repletion and hair growth in mice with iron deficiency.²¹ Additionally, a meta-analysis analyzing the comorbidities of patients with alopecia areata found them to have higher odds (odds ratio [OR]=2.78; 95% CI, 1.23-6.29) of iron-deficiency anemia but no association with IBD (OR=1.48; 95% CI, 0.32-6.82).²²

Diagnosis and Monitoring—The American Gastroenterological Association recommends a complete blood cell count (CBC), serum ferritin, transferrin saturation (TfS), and C-reactive protein (CRP) as standard evaluations for iron deficiency in patients with IBD. Patients with active IBD should be screened every 3 months,and patients with inactive disease should be screened every 6 to 12 months.²³

Although ferritin and TfS often are used as markers for iron status in healthy individuals, they are positive and negative acute phase reactants, respectively. Using them to assess iron status in patients with IBD may inaccurately represent iron status in the setting of inflammation from the disease.²⁴ The European Crohn’s and Colitis Organisation (ECCO) produced guidelines to define iron deficiency as a TfS less than 20% or a ferritin level less than 30 µg/L in patients without evidence of active IBD and a ferritin level less than 100 µg/L for patients with active inflammation.²⁵

A 2020 multicenter observational study of 202 patients with diagnosed IBD found that the ECCO guideline of ferritin less than 30 µg/L had an area under the receiver operating characteristic (AUROC) curve of 0.69, a sensitivity of 0.43, and a specificity of 0.95 in their population.²⁶ In a sensitivity analysis stratifying patients by CRP level (<10 or ≥10 mg/L), the authors found that for patients with ulcerative colitis and a CRP less than 10 mg/L, a cut-off value of ferritin less than 65 µg/L (AUROC=0.78) had a sensitivity of 0.78 and specificity of 0.76, and a TfS value of less than 16% (AUROC=0.88) had a sensitivity of 0.79 and a specificity of 0.9. In patients with a CRP of 10 mg/L or greater, a cut-off value of ferritin 80 µg/L (AUROC=0.76) had a sensitivity of 0.75 and a specificity of 0.82, and a TfS value of less than 11% (AUROC=0.69) had a sensitivity of 0.79 and a specificity of 0.88. There were no ferritin cut-off values associated with good diagnostic performance (defined as both sensitivity and specificity >0.70) for iron deficiency in patients with Crohn disease.²⁶

The authors recommended using an alternative iron measurement such as soluble transferrin receptor (sTfR)/log ferritin ratio (TfR-F) that is not influenced by active inflammation and has a good correlation with ferritin values (TfR-F: r=0.66; P<.001).²⁶ However, both sTfR and TfR-F have high costs and intermethod variability as well as differences in their reference ranges depending on which laboratory performs the analysis, limiting the accessibility and practicality of easily obtaining these tests.²⁷ Although there may be inaccuracies for standard ferritin or TfS under ECCO guidelines, proposed alternatives have their own limitations, which may make ferritin and TfS the most reasonable evaluations of iron status as long as disease activity status at the time of testing is taken into consideration.

Treatment—Treatment of underlying iron deficiency in patients with IBD requires reversing the cause of the deficiency and supplementing iron. In patients with IBD, the options to supplement iron may be limited by active disease, making oral intake less effective. Oral iron supplementation also is associated with notable GI adverse effects that may be exacerbated in patients with IBD. A systematic review of 43 randomized controlled trials (RCTs) evaluating GI adverse effects (eg, nausea, abdominal pain, diarrhea, constipation, and black or tarry stools) of oral ferrous sulfate compared with placebo or intravenous (IV) iron supplementation in healthy nonanemic individuals found a significant increase in GI adverse effects with oral supplementation (placebo: OR=2.32; P<.0001; IV: OR=3.05; P<.0001).²⁸

Therefore, IV iron repletion may be necessary in patients with IBD and may require numerous infusions depending on the formulation of iron. In an RCT conducted in 2011, patients with iron-deficiency anemia with quiescent or mild to moderate IBD were treated with either IV iron sulfate or ferric carboxymaltose.²⁹ With a primary end point of hemoglobin response greater than 2 g/dL, the authors found that 150 of 240 patients responded to ferric carboxymaltose vs 118 of 235 treated with iron sulfate (P=.004). The dosing for ferric carboxymaltose was 1 to 3 infusions of 500 to 1000 mg of iron and for iron sulfate up to 11 infusions of 200 mg of iron.²⁹

Zinc

A systematic review of zinc deficiency in patients with IBD identified 7 studies including 2413 patients and revealed those with Crohn disease had a higher prevalence of zinc deficiency compared with patients with ulcerative colitis (54% vs 41%).³⁰

Pathophysiology—Zinc serves as a catalytic cofactor for enzymatic activity within proteins and immune cells.³¹ The homeostasis of zinc is tightly regulated within the brush border of the small intestine by zinc transporters ZIP4 and ZIP1 from the lumen of enterocytes into the bloodstream.³² Inflammation in the small intestine due to Crohn disease can result in zinc malabsorption.

Ranaldi et al³³ exposed intestinal cells and zinc-depleted intestinal cells to tumor necrosis factor α media to simulate an inflammatory environment. They measured transepithelial electrical resistance as a surrogate for transmembrane permeability and found that zinc-depleted cells had a statistically significantly higher transepithelial electrical resistance percentage (60% reduction after 4 hours; P<1.10^–6) when exposed to tumor necrosis factor α signaling compared with normal intestinal cells. They concluded that zinc deficiency can increase intestinal permeability in the presence of inflammation, creating a cycle of further nutrient malabsorption and inflammation exacerbating IBD symptoms.³³

Cutaneous Manifestations—After absorption in the small intestine, approximately 5% of zinc resides in the skin, with the highest concentration in the stratum spinosum.³⁴ A cell study found that keratinocytes in zinc-deficient environments had higher rates of apoptosis compared with cells in normal media. The authors proposed that this higher rate of apoptosis and the resulting inflammation could be a mechanism for developing the desquamative or eczematous scaly plaques that are common cutaneous manifestations of zinc deficiency.³⁵

Other cutaneous findings may include angular cheilitis, stomatitis, glossitis, paronychia, onychodystrophy, generalized alopecia, and delayed wound healing.³⁶ The histopathology of these skin lesions is characterized by granular layer loss, epidermal pallor, confluent parakeratosis, spongiosis, dyskeratosis, and psoriasiform hyperplasia.³⁷

Diagnosis and Monitoring—Assessing serum zinc levels is challenging, as they may decrease during states of inflammation.³⁸ A mouse model study showed a 3.1-fold increase (P<.001) in ZIP14 expression in wild-type mice compared with an IL-6 -/- knock-down model after IL-6 exposure. The authors concluded that the upregulation of ZIP14 in the liver due to inflammatory cytokine upregulation decreases zinc availability in serum.³⁹ Additionally, serum zinc can overestimate the level of deficiency in IBD because approximately 75% of serum zinc is bound to albumin, which decreases in the setting of inflammation.^40-42

Alternatively, alkaline phosphatase (AP), a zinc-dependent metalloenzyme, may be a better evaluator of zinc status during periods of inflammation. A study in rats evaluated zinc through serum zinc levels and AP levels after a period of induced stress to mimic a short-term inflammatory state.⁴³ The researchers found that total body stores of zinc were unaffected throughout the experiment; only serum zinc declined throughout the experiment duration while AP did not. Because approximately 75% of serum zinc is bound to serum albumin,⁴² the researchers concluded the induced inflammatory state depleted serum albumin and redistributed zinc to the liver, causing the observed serum zinc changes, while total body zinc levels and AP were largely unaffected in comparison.⁴³ Comorbid conditions such as liver or bone disease can increase AP levels, which limits the utility of AP as a surrogate for zinc in patients with comorbidities.⁴⁴ However, even in the context of active IBD, serum zinc still is currently considered the best biomarker to evaluate zinc status.⁴⁵

Treatment—The recommended dose for zinc supplementation is 20 to 40 mg daily with higher doses (>50 mg/d) for patients with malabsorptive syndromes such as IBD.⁴⁶ It can be administered orally or parenterally. Although rare, zinc replacement therapy may be associated with diarrhea, nausea, vomiting, mild headaches, and fatigue.⁴⁶ Additional considerations should be taken when repleting other micronutrients with zinc, as calcium and folate can inhibit zinc reabsorption, while zinc itself can inhibit iron and copper reabsorption.⁴⁷

Vitamin D and Calcium

Low vitamin D levels (<50 nmol/L) and hypocalcemia (<8.8 mg/dL) are common in patients with IBD.^48,49

Pathophysiology—Vitamin D levels are maintained via 2 mechanisms. The first mechanism is through the skin, as keratinocytes produce 7-dehydrocholesterol after exposure to UV light, which is converted into previtamin D₃ and then thermally isomerizes into vitamin D₃. This vitamin D₃ is then transported to the liver on vitamin D–binding protein.⁵⁰ The second mechanism is through oral vitamin D₃ that is absorbed through vitamin D receptors in intestinal epithelium and transported to the liver, where it is hydroxylated into 25-hydroxyvitamin D (25[OH]D), then to the kidneys for hydroxylation to 1,25(OH)₂D for redistribution throughout the body.⁵⁰ This activated form of vitamin D regulates calcium absorption in the intestine, and optimal vitamin D levels are necessary to absorb calcium efficiently.⁵¹ Inflammation from IBD within the small intestine can downregulate vitamin D receptors, causing malabsorption and decreased serum vitamin D.⁵²

Vitamin D signaling also is vital to maintaining the tight junctions and adherens junctions of the intestinal epithelium. Weakening the permeability of the epithelium further exacerbates malabsorption and subsequent vitamin D deficiency.⁵² A meta-analysis of 27 studies including 8316 patients with IBD showed low vitamin D levels were associated with increased odds of disease activity (OR=1.53; 95% CI, 1.32-1.77), mucosal inflammation (OR=1.25; 95% CI, 1.06-1.47), and future clinical relapse (OR=1.23; 95% CI, 1.03-1.47) in patients with Crohn disease. The authors concluded that low levels of vitamin D could be used as a potential biomarker of inflammatory status in Crohn disease.⁵³

Vitamin D and calcium are further implicated in maintaining skeletal health,⁴⁷ while vitamin D specifically helps maintain intestinal homeostasis⁵⁴ and immune system modulation in the skin.⁵⁵

Cutaneous Manifestations—Vitamin D is thought to play crucial roles in skin differentiation and proliferation, cutaneous innate immunity, hair follicle cycling, photoprotection, and wound healing.⁵⁶ Vitamin D deficiency has been observed in a large range of cutaneous diseases including skin cancer, psoriasis, vitiligo, bullous pemphigoid, atopic dermatitis, and various types of alopecia.^56-59 It is unclear whether vitamin D deficiency facilitates these disease processes or is merely the consequence of a disrupted cutaneous surface with the inability to complete the first step in vitamin D processing. A 2014 meta-analysis of 290 prospective cohort studies and 172 randomized trials concluded that 25(OH)D deficiency was associated with ill health and did not find causal evidence for any specific disease, dermatologic or otherwise.⁶⁰ Calcium deficiency may cause epidermal changes including dry skin, coarse hair, and brittle nails.⁶¹

Diagnosis and Monitoring—The ECCO guidelines recommend obtaining serum 25(OH)D levels every 3 months in patients with IBD.⁶² Levels less than 75 nmol/L are considered deficient, and a value less than 30 nmol/L increases the risk for osteomalacia and nutritional rickets, constituting severe vitamin D deficiency.^63-65

An observational study of 325 patients with IBD showed a statistically significant negative correlation between serum vitamin D and fecal calprotectin (r=−0.19; P<.001), a stool-based marker for gut inflammation, supporting vitamin D as a potential biomarker in IBD.⁶⁶

Evaluation of calcium can be done through serum levels in patients with IBD.⁶⁷ Patients with IBD are at risk for hypoalbuminemia; therefore, consideration should be taken to ensure calcium levels are corrected, as approximately 50% of calcium is bound to albumin or other ions in the body,⁶⁸ which can be done by adjusting the calcium concentration by 0.02 mmol/L for every 1 g/L of albumin above or below 40 g/L. In the most critically ill patients, a direct ionized calcium blood level should be used instead because the previously mentioned correction calculations are inaccurate when albumin is critically low.⁶⁹

Treatment—The ECCO guidelines recommend calcium and vitamin D repletion of 500 to 1000 mg and 800 to 1000 U, respectively, in patients with IBD on systemic corticosteroids to prevent the negative effects of bone loss.⁶² Calcium repletion in patients with IBD who are not on systemic steroids are the same as for the general population.⁶⁵

Vitamin D repletion also may help decrease IBD activity. In a prospective study, 10,000 IU/d of vitamin D in 10 patients with IBD—adjusted over 12 weeks to a target of 100 to 125 nmol/L of serum 25(OH)D—showed a significant reduction in clinical Crohn activity (P=.019) over the study period.⁷⁰ In contrast, 2000 IU/d for 3 months in an RCT of 27 patients with Crohn disease found significantly lower CRP (P=.019) and significantly higher self-reported quality of life (P=.037) but nonsignificant decreases in Crohn activity (P=.082) in patients with 25(OH)D levels of 75 nmol/L or higher compared with those with 25(OH)D levels less than 75 nmol/L.⁷¹

These discrepancies illustrate the need for expanded clinical trials to elucidate the optimal vitamin D dosing for patients with IBD. Ultimately, assessing vitamin D and calcium status and considering repletion in patients with IBD, especially those with comorbid dermatologic diseases such as poor wound healing, psoriasis, or atopic dermatitis, is important.

Vitamin B₆ (Pyridoxine)

Pathophysiology—Pyridoxine is an important coenzyme for many functions including amino acid transamination, fatty acid metabolism, and conversion of tryptophan to niacin. It is absorbed in the jejunum and ileum and subsequently transported to the liver for rephosphorylation and release into its active form.³⁶ An observational study assessing the nutritional status of patients with IBD found that only 5.7% of 105 patients with food records had inadequate dietary intake of pyridoxine, but 29% of all patients with IBD had subnormal pyridoxine levels.⁷² Additionally, they found no significant difference in the prevalence of subnormal pyridoxine levels in patients with active IBD vs IBD in remission. The authors suggested that the subnormal pyridoxine levels in patients with IBD likely were multifactorial and resulted from malabsorption due to active disease, inflammation, and inadequate intake.⁷²

Cutaneous Manifestations—Cutaneous findings associated with pyridoxine deficiency include periorificial and perineal dermatitis,⁷³ angular stomatitis, and cheilitis with associated burning, redness, and tongue edema.³⁶ Additionally, pyridoxine is involved in the conversion of tryptophan to niacin, and its deficiency may manifest with pellagralike findings.⁷⁴

Because pyridoxine is critical to protein metabolism, its deficiency may disrupt key cellular structures that rely on protein concentrations to maintain structural integrity. One such structure in the skin that heavily relies on protein concentrations is the ground substance of the extracellular matrix—the amorphous gelatinous spaces that occupy the areas between the extracellular matrix, which consists of cross-linked glycosaminoglycans and proteins.⁷⁵ Without protein, ground substance increases in viscosity and can disrupt the epidermal barrier, leading to increased transepidermal water loss and ultimately inflammation.⁷⁶ Although this theory has yet to be validated fully, this is a potential mechanistic explanation for the inflammation in dermal papillae that leads to dermatitis observed in pyridoxine deficiency.

Diagnosis and Monitoring—Direct biomarkers of pyridoxine status are in serum, plasma, erythrocytes, and urine, with the most common measurement in plasma as pyridoxal 5′-phosphate (PLP).⁷⁷ Plasma PLP concentrations lower than 20 nmol/L are suggestive of deficiency.⁷⁸ Plasma PLP has shown inverse relationships with acute phase inflammatory markers CRP⁷⁹ and AP,⁷⁸ thereby raising concerns for its validity to assess pyridoxine status in patients with symptomatic IBD.⁸⁰

Alternative evaluations of pyridoxine include tryptophan and methionine loading tests,³⁶ which are measured via urinary excretion and require normal kidney function to be accurate. They should be considered in IBD if necessary, but routine testing, even in patients with symptomatic IBD, is not recommended in the ECCO guidelines. Additional considerations should be taken in patients with altered nutrient requirements such as those who have undergone bowel resection due to highly active disease or those who receive parenteral nutritional supplementation.⁸¹

Treatment—Recommendations for oral pyridoxine supplementation range from 25 to 600 mg daily,⁸² with symptoms typically improving on 100 mg daily.³⁶ Pyridoxine supplementation may have additional benefits for patients with IBD and potentially modulate disease severity. An IL-10 knockout mouse supplemented with pyridoxine had an approximately 60% reduction (P<.05) in inflammation compared to mice deficient in pyridoxine.⁸³ The authors suggest that PLP-dependent enzymes can inhibit further proinflammatory signaling and T-cell migration that can exacerbate IBD. Ultimately, more data is needed before determining the efficacy of pyridoxine supplementation for active IBD.

Vitamin B₁₂ and Vitamin B₉ (Folic Acid)

Pathophysiology—Vitamin B₁₂ is reabsorbed in the terminal ileum, the distal portion of the small intestine. The American Gastroenterological Association recommends that patients with a history of extensive ileal disease or prior ileal surgery, which is the case for many patients with Crohn disease, be monitored for vitamin B₁₂ deficiency.²³ Monitoring and rapid supplementation of vitamin B₁₂ can prevent pernicious anemia and irreversible neurologic damage that may result from deficiency.⁸⁴

Folic acid is primarily absorbed in the duodenum and jejunum of the small intestine. A meta-analysis performed in 2017 assessed studies observing folic acid and vitamin B₁₂ levels in 1086 patients with IBD compared with 1484 healthy controls and found an average difference in serum folate concentration of 0.46 nmol/L (P<.001).⁸⁴ Interestingly, this study did not find a significant difference in serum vitamin B₁₂ levels between patients with IBD and healthy controls, highlighting the mechanism of vitamin B₁₂ deficiency in IBD because only patients with terminal ileal involvement are at risk for malabsorption and subsequent deficiency.

Cutaneous Manifestations—Both vitamin B₁₂ and folic acid deficiency can manifest as cheilitis, glossitis, and/or generalized hyperpigmentation that is accentuated in the flexural areas, palms, soles, and oral cavity.^85,86 Systemic symptoms of patients with vitamin B₁₂ and folic acid deficiency include megaloblastic anemia, pallor, and fatigue. A potential mechanism for the hyperpigmentation observed from vitamin B₁₂ deficiency came from an electron microscope study that showed an increased concentration of melanosomes in a patient with deficiency.⁸⁷

Diagnosis and Monitoring—In patients with suspected vitamin B₁₂ and/or folic acid deficiency, initial evaluation should include a CBC with peripheral smear and serum vitamin B₁₂ and folate levels. In cases for which the diagnosis still is unclear after initial testing, methylmalonic acid and homocysteine levels can help differentiate between the 2 deficiencies. Methylmalonic acid classically is elevated (>260 nmol/L) in vitamin B₁₂ deficiency but not in folate deficiency.⁸⁸ Cut-off values for vitamin B₁₂ deficiency are less than 200 to 250 pg/mL forserum vitamin B₁₂ and/or an elevated level of methylmalonic acid (>0.271 µmol/L).⁸⁹ A serum folic acid value greater than 3 ng/mL and/or erythrocyte folate concentrations greater than 140 ng/mL are considered adequate, whereas an indicator of folic acid deficiency is a homocysteine level less than 10 µmol/L.⁹⁰ A CBC can screen for macrocytic megaloblastic anemias (mean corpuscular volume >100 fl), which are classic diagnostic signs of an underlying vitamin B₁₂ or folate deficiency.

Treatment—According to the Centers for Disease Control and Prevention, supplementation of vitamin B₁₂ can be done orally with 1000 µg daily in patients with deficiency. In patients with active IBD, oral reabsorption of vitamin B₁₂ can be less effective, making subcutaneous or intramuscular administration (1000 µg/wk for 8 weeks, then monthly for life) better options.⁸⁹

Patients with IBD managed with methotrexate should be screened carefully for folate deficiency. Methotrexate is a folate analog that sometimes is used for the treatment of IBD. Reversible competitive inhibition of dihydrofolate reductase can precipitate a systemic folic acid decrease.⁹¹ Typically, oral folic acid (1 to 5 mg/d) is sufficient to treat folate deficiency, with the ESPEN recommending 5 mg once weekly 24 to 72 hours after methotrexate treatment or 1 mg daily for 5 days per week in patients with IBD.¹ Alternative formulations—IV, subcutaneous, or intramuscular—are available for patients who cannot tolerate oral intake.⁹²

Final Thoughts

Dermatologists can be the first to observe the cutaneous manifestations of micronutrient deficiencies. Although the symptoms of each micronutrient deficiency discussed may overlap, attention to small clinical clues in patients with IBD can improve patient outcomes and quality of life. For example, koilonychia with glossitis and xerosis likely is due to iron deficiency, while zinc deficiency should be suspected in patients with scaly eczematous plaques in skin folds. A high level of suspicion for micronutrient deficiencies in patients with IBD should be followed by a complete patient history, review of systems, and thorough clinical examination. A thorough laboratory evaluation can pinpoint nutritional deficiencies in patients with IBD, keeping in mind that specific biomarkers such as ferritin and serum zinc also act as acute phase reactants and should be interpreted in this context. Co-management with gastroenterologists should be a priority in patients with IBD, as gaining control of inflammatory disease is crucial for the prevention of recurrent vitamin and micronutrient deficiencies in addition to long-term health in this population.

To the Editor:

Recurrent aphthous stomatitis (RAS) is a mucocutaneous condition characterized by single or multiple, painful,^1,2 round ulcerations of variable sizes with a tendency for recurrence, most commonly located in nonkeratinized areas of the oral mucosa. Pathergy commonly is observed.³ Although many authors consider the terms RAS andaphtha to be synonymous,^4,5 differentiating the clinical lesion (aphthous ulceration) from the disease (aphtha or RAS) can be useful, as several other diseases can at times manifest with similar ulcers (called aphthoid lesions), such as pemphigus vulgaris, mucous membrane pemphigoid, and erythema multiforme.⁶

It is estimated that approximately 20% of individuals worldwide have at least one episode of aphtha during their lifetime,⁷ and it is considered the most common disease of the oral mucosa.^8,9 However, only patients presenting with severe acute outbreaks or frequent relapses typically seek medical treatment. Clinically, aphthous ulcers are classified as aphtha minor (small number of small lesions), aphtha major (large deep lesions that also can affect the minor salivary glands with intense necrosis, difficulty in healing, and mucosal scarring), and aphtha herpetiformis (innumerous tiny lesions that reappear in recurring outbreaks).^1-3 The term complex aphthosis was introduced in 1985¹⁰ and is defined as recurrent oral and genital aphthous ulcerations or recurring multiple oral aphthous ulcers in the absence of systemic manifestations or Behçet disease^11,12; however, complex aphthosis also has been reported as frequent episodes of ulcerations that may be associated with systemic diseases including Behçet disease.^13,14

Currently, RAS is considered an immunologically mediated alteration in cutaneous mucosal reactivity with a multifactorial systemic cause. Underlying conditions such as Behçet disease, inflammatory bowel disease (IBD), iatrogenic immunosuppression (eg, following solid organ transplantation), AIDS, and cyclic neutropenia may or may not be detected.^11-13

Our retrospective study explored the systemic nature of RAS. We reviewed patient records to evaluate underlying systemic conditions associated with the diagnosis of RAS and the use of oral medications in managing the disease. Medical records from the Department of Dermatology of the University of São Paulo, Brazil, from 2003 to 2017 were reviewed to identify patients with a diagnosis of RAS. Clinical classification of RAS—minor, major, or herpetiform—as well as the presence of aphthous lesions in other locations and the presence of other associated inflammatory cutaneous manifestations also were noted. Associated systemic diseases and treatments for RAS were recorded. Patients for whom the diagnosis of RAS was changed during follow-up were excluded. Because this was a retrospective analysis of medical records and without any patient risk, informed consent was not needed.

Medical records for 125 patients were reviewed; 63 were male (50.4%), and 62 were female (49.6%). The age at onset of symptoms, which ranged from a few months after birth to 74 years, was reported in only 92 (73.6%) patient medical records. Of these, 30 (32.6%) reported onset before 20 years of age, 39 (42.4%) between 20 and 39 years, 17 (18.5%) between 40 and 59 years, and 6 (6.5%) at 60 years or older. Morphologically, 72 (57.6%) had minor, 42 (33.6%) had major, and 11 (8.8%) had herpetiform aphthous ulcers. None of the patients presented with sporadic lesions; the disease was long-standing and persistent in all cases (complex aphthosis).

Regarding the location of the ulcers, 92 (73.6%) patients had lesions on the oral mucosa only. Some patients had lesions in more than one site in addition to the oral mucosa: 32 (25.6%) had aphthae in the genital/groin region and 4 (3.2%) presented with perianal/anal aphthae. Nineteen patients (19.2%) presented other cutaneous manifestations in addition to aphthae: 11 (45.8%) had folliculitis/pseudofolliculitis, and 8 (33.3%) had erythema nodosum (EN). Eight patients (33.3%) presented with uveitis, and 6 (25%) presented with concomitant arthralgia/arthritis. Fifty-four patients (43.2%) had confirmed or suspected associated disease: Behçet disease (21 [38.9%]), IBD (10 [18.5%]), solid organ transplantation (7 [13.0%])(kidney, 4 [57.1%]; heart, 2 [28.6%]; liver, 1 [14.3%]), HIV infection (6 [11.1%]), lymphoma (1 [1.9%]), aplastic anemia (1 [1.9%]), or myelodysplastic syndrome (1 [1.9%]). Ten patients (18.5%) presented with other diseases under investigation (eg, unidentified rheumatologic disease, unexplained neutropenia, undiagnosed immunodeficiencies, autoinflammatory syndromes, possible cyclic neutropenia).

Biopsies of the oral mucosa were performed in 31 patients. Histopathologic findings will be discussed in a future publication (unpublished data).

Five patients (4.0%) were lost to follow-up and did not receive treatment; 10 (8.0%) received only topical treatment (analgesics and/or corticosteroids). All 9 (7.2%) patients undergoing intralesional corticosteroid injections also were on a systemic treatment. One hundred ten (88.0%) patients were treated systemically—with colchicine (84/110 [76.4%]), thalidomide (43/110 [39.1%]), small pulses of oral corticosteroids (26 [23.6%]), dapsone (12/110 [10.9%]), or pentoxifylline (3 [2.7%]). Furthermore, in patients with associated diseases, treatment of the underlying condition was conducted when available, and follow-up was carried out in conjunction with the appropriate specialists. For treatment of the associated disease, patients received other medications such as methotrexate, azathioprine, cyclophosphamide, intravenous corticosteroid pulse, and immunobiologics.

The prevalence of RAS between sexes in our study population was similar (50.4% male; 49.6% female). Results from prior studies have been mixed; some reported a higher prevalence in females,^15-18 while others found no predilection for sex among patients diagnosed with RAS.^19,20 In our analysis, 75% of patients experienced symptoms of RAS before 40 years of age; in prior studies, up to 56% of patients experienced symptoms between the ages of 20 and 40 years.^21,22

In our study, 26.4% of patients had extraoral aphthae. Genital lesions have been described as infrequent,²³ and lesions manifesting in other mucous membranes or on the skin are rare.²⁴ A study reported genital involvement in 8% to 13% of patients with oral aphtha.²⁵ We observed genital involvement in 25.6% of patients. Likewise, this higher value may be due to our study population of patients referred to our university hospital. In our study, 19.2% of patients presented with other inflammatory manifestations in addition to aphthous ulcerations (eg, folliculitis, EN, uveitis, arthritis). As dermatologists in a tertiary reference hospital, we actively look for such associations in every aphtha patient, which may not be the case in many nondermatologic oral care services.

In our study population, 43.2% of patients were diagnosed with or were under investigation for systemic diseases known to be associated with RAS. We found associations with Behçet disease most frequently, followed by IBD,²⁶ solid organ transplantation, and HIV. In this group of patients, the respective systemic disease was active or poorly controlled. In transplant recipients, aphtha major was the most common type, similar to other studies.²⁷ We observed no notable difference in the clinical picture of the oral ulcers in patients with a well-established systemic disease vs those without.

Most of our cases did not present findings other than aphtha, indicating that the intrinsic defect that predisposes to RAS is always systemic. Even mild and sporadic cases may be attributable to a systemic disorder of cutaneous-mucosal reactivity. The predisposition to RAS never originates in the oral cavity, hence the confusion caused and the uselessness of studies that relate aphthae to factors such as local food allergies, pH changes, or local infection with microorganisms.^5,28 The disease course (reducing the frequency of lesion appearance and accelerating the healing of extensive lesions) is only modified with systemic treatment, with local measures proving to be only moderately useful to relieve pain. We believe that RAS can in many ways be compared to EN and pyoderma gangrenosum (PG): some systemic conditions that predispose patients to EN and PG also may predispose them to RAS (eg, IBD, hematologic disorders). Similar to RAS, many cases of EN and PG are idiopathic. In addition, pathergy also occurs in PG.^11,13

We were unable to observe or establish any predictive clinical element that could indicate a better or worse response to the prescribed treatments, which also has been noted by other authors.^3,4 Treatment of RAS is empiric, generally starting with drugs that are easier to prescribe and with fewer adverse effects, then progressing to more complex drugs when a good response is not obtained. Colchicine was the most commonly prescribed medication (76.4% [84/110]). It has been proposed by several authors^3,4 as a first-line systemic medication for the treatment of recurrent aphthae, as it has been shown to be effective and safe. The dosage ranged from 0.5 mg twice daily to 0.5 mg 4 times daily. Dapsone is an established drug for aphtha^29,30 and was used in 12 of our patients. The dosage used in our patients ranged from 50 to 100 mg/d. Adverse effects such as hemolytic anemia frequently are seen, and one of the patients in our study developed DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome in response to dapsone. In 7 cases, colchicine and dapsone were used together, which is believed to potentiate the therapeutic effects. This combination may be useful in patients for whom thalidomide cannot be used or those who have not improved with monotherapy.²⁹ Thalidomide is considered one of the most effective drugs for RAS.^30,31 Forty-three patients in our analysis were treated with thalidomide,usually as a first choice. The dosage ranged from 100 to 200 mg/d. It was mainly chosen in disabling pediatric cases, adult men with aphthous major, and women with no risk for pregnancy. Due to its potential adverse effects, thalidomide has been recommended when there is no response with other medications that are dose dependent; severe adverse effects such as thromboembolism and peripheral neuropathy are rare.³¹ Oral corticosteroids were used in 26 patients, aiming at rapid improvement in very symptomatic cases; however, due to the potential for long-term adverse effects, in all cases they were prescribed in combination with another medication that was maintained after the corticosteroid was discontinued.

We highlight the systemic nature of RAS as well as its frequent association with systemic diseases and other correlated manifestations (pustules, EN, arthralgia). We also emphasize the importance of using oral medications to adequately control the disease and do not recommend topical medications aimed at treating local causes. Dermatologists should be consulted in managing severe cases of RAS.

To the Editor:

Recurrent aphthous stomatitis (RAS) is a mucocutaneous condition characterized by single or multiple, painful,^1,2 round ulcerations of variable sizes with a tendency for recurrence, most commonly located in nonkeratinized areas of the oral mucosa. Pathergy commonly is observed.³ Although many authors consider the terms RAS andaphtha to be synonymous,^4,5 differentiating the clinical lesion (aphthous ulceration) from the disease (aphtha or RAS) can be useful, as several other diseases can at times manifest with similar ulcers (called aphthoid lesions), such as pemphigus vulgaris, mucous membrane pemphigoid, and erythema multiforme.⁶

It is estimated that approximately 20% of individuals worldwide have at least one episode of aphtha during their lifetime,⁷ and it is considered the most common disease of the oral mucosa.^8,9 However, only patients presenting with severe acute outbreaks or frequent relapses typically seek medical treatment. Clinically, aphthous ulcers are classified as aphtha minor (small number of small lesions), aphtha major (large deep lesions that also can affect the minor salivary glands with intense necrosis, difficulty in healing, and mucosal scarring), and aphtha herpetiformis (innumerous tiny lesions that reappear in recurring outbreaks).^1-3 The term complex aphthosis was introduced in 1985¹⁰ and is defined as recurrent oral and genital aphthous ulcerations or recurring multiple oral aphthous ulcers in the absence of systemic manifestations or Behçet disease^11,12; however, complex aphthosis also has been reported as frequent episodes of ulcerations that may be associated with systemic diseases including Behçet disease.^13,14

Currently, RAS is considered an immunologically mediated alteration in cutaneous mucosal reactivity with a multifactorial systemic cause. Underlying conditions such as Behçet disease, inflammatory bowel disease (IBD), iatrogenic immunosuppression (eg, following solid organ transplantation), AIDS, and cyclic neutropenia may or may not be detected.^11-13

Our retrospective study explored the systemic nature of RAS. We reviewed patient records to evaluate underlying systemic conditions associated with the diagnosis of RAS and the use of oral medications in managing the disease. Medical records from the Department of Dermatology of the University of São Paulo, Brazil, from 2003 to 2017 were reviewed to identify patients with a diagnosis of RAS. Clinical classification of RAS—minor, major, or herpetiform—as well as the presence of aphthous lesions in other locations and the presence of other associated inflammatory cutaneous manifestations also were noted. Associated systemic diseases and treatments for RAS were recorded. Patients for whom the diagnosis of RAS was changed during follow-up were excluded. Because this was a retrospective analysis of medical records and without any patient risk, informed consent was not needed.

Medical records for 125 patients were reviewed; 63 were male (50.4%), and 62 were female (49.6%). The age at onset of symptoms, which ranged from a few months after birth to 74 years, was reported in only 92 (73.6%) patient medical records. Of these, 30 (32.6%) reported onset before 20 years of age, 39 (42.4%) between 20 and 39 years, 17 (18.5%) between 40 and 59 years, and 6 (6.5%) at 60 years or older. Morphologically, 72 (57.6%) had minor, 42 (33.6%) had major, and 11 (8.8%) had herpetiform aphthous ulcers. None of the patients presented with sporadic lesions; the disease was long-standing and persistent in all cases (complex aphthosis).

Regarding the location of the ulcers, 92 (73.6%) patients had lesions on the oral mucosa only. Some patients had lesions in more than one site in addition to the oral mucosa: 32 (25.6%) had aphthae in the genital/groin region and 4 (3.2%) presented with perianal/anal aphthae. Nineteen patients (19.2%) presented other cutaneous manifestations in addition to aphthae: 11 (45.8%) had folliculitis/pseudofolliculitis, and 8 (33.3%) had erythema nodosum (EN). Eight patients (33.3%) presented with uveitis, and 6 (25%) presented with concomitant arthralgia/arthritis. Fifty-four patients (43.2%) had confirmed or suspected associated disease: Behçet disease (21 [38.9%]), IBD (10 [18.5%]), solid organ transplantation (7 [13.0%])(kidney, 4 [57.1%]; heart, 2 [28.6%]; liver, 1 [14.3%]), HIV infection (6 [11.1%]), lymphoma (1 [1.9%]), aplastic anemia (1 [1.9%]), or myelodysplastic syndrome (1 [1.9%]). Ten patients (18.5%) presented with other diseases under investigation (eg, unidentified rheumatologic disease, unexplained neutropenia, undiagnosed immunodeficiencies, autoinflammatory syndromes, possible cyclic neutropenia).

Biopsies of the oral mucosa were performed in 31 patients. Histopathologic findings will be discussed in a future publication (unpublished data).

Five patients (4.0%) were lost to follow-up and did not receive treatment; 10 (8.0%) received only topical treatment (analgesics and/or corticosteroids). All 9 (7.2%) patients undergoing intralesional corticosteroid injections also were on a systemic treatment. One hundred ten (88.0%) patients were treated systemically—with colchicine (84/110 [76.4%]), thalidomide (43/110 [39.1%]), small pulses of oral corticosteroids (26 [23.6%]), dapsone (12/110 [10.9%]), or pentoxifylline (3 [2.7%]). Furthermore, in patients with associated diseases, treatment of the underlying condition was conducted when available, and follow-up was carried out in conjunction with the appropriate specialists. For treatment of the associated disease, patients received other medications such as methotrexate, azathioprine, cyclophosphamide, intravenous corticosteroid pulse, and immunobiologics.

The prevalence of RAS between sexes in our study population was similar (50.4% male; 49.6% female). Results from prior studies have been mixed; some reported a higher prevalence in females,^15-18 while others found no predilection for sex among patients diagnosed with RAS.^19,20 In our analysis, 75% of patients experienced symptoms of RAS before 40 years of age; in prior studies, up to 56% of patients experienced symptoms between the ages of 20 and 40 years.^21,22

In our study, 26.4% of patients had extraoral aphthae. Genital lesions have been described as infrequent,²³ and lesions manifesting in other mucous membranes or on the skin are rare.²⁴ A study reported genital involvement in 8% to 13% of patients with oral aphtha.²⁵ We observed genital involvement in 25.6% of patients. Likewise, this higher value may be due to our study population of patients referred to our university hospital. In our study, 19.2% of patients presented with other inflammatory manifestations in addition to aphthous ulcerations (eg, folliculitis, EN, uveitis, arthritis). As dermatologists in a tertiary reference hospital, we actively look for such associations in every aphtha patient, which may not be the case in many nondermatologic oral care services.

In our study population, 43.2% of patients were diagnosed with or were under investigation for systemic diseases known to be associated with RAS. We found associations with Behçet disease most frequently, followed by IBD,²⁶ solid organ transplantation, and HIV. In this group of patients, the respective systemic disease was active or poorly controlled. In transplant recipients, aphtha major was the most common type, similar to other studies.²⁷ We observed no notable difference in the clinical picture of the oral ulcers in patients with a well-established systemic disease vs those without.

Most of our cases did not present findings other than aphtha, indicating that the intrinsic defect that predisposes to RAS is always systemic. Even mild and sporadic cases may be attributable to a systemic disorder of cutaneous-mucosal reactivity. The predisposition to RAS never originates in the oral cavity, hence the confusion caused and the uselessness of studies that relate aphthae to factors such as local food allergies, pH changes, or local infection with microorganisms.^5,28 The disease course (reducing the frequency of lesion appearance and accelerating the healing of extensive lesions) is only modified with systemic treatment, with local measures proving to be only moderately useful to relieve pain. We believe that RAS can in many ways be compared to EN and pyoderma gangrenosum (PG): some systemic conditions that predispose patients to EN and PG also may predispose them to RAS (eg, IBD, hematologic disorders). Similar to RAS, many cases of EN and PG are idiopathic. In addition, pathergy also occurs in PG.^11,13

We were unable to observe or establish any predictive clinical element that could indicate a better or worse response to the prescribed treatments, which also has been noted by other authors.^3,4 Treatment of RAS is empiric, generally starting with drugs that are easier to prescribe and with fewer adverse effects, then progressing to more complex drugs when a good response is not obtained. Colchicine was the most commonly prescribed medication (76.4% [84/110]). It has been proposed by several authors^3,4 as a first-line systemic medication for the treatment of recurrent aphthae, as it has been shown to be effective and safe. The dosage ranged from 0.5 mg twice daily to 0.5 mg 4 times daily. Dapsone is an established drug for aphtha^29,30 and was used in 12 of our patients. The dosage used in our patients ranged from 50 to 100 mg/d. Adverse effects such as hemolytic anemia frequently are seen, and one of the patients in our study developed DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome in response to dapsone. In 7 cases, colchicine and dapsone were used together, which is believed to potentiate the therapeutic effects. This combination may be useful in patients for whom thalidomide cannot be used or those who have not improved with monotherapy.²⁹ Thalidomide is considered one of the most effective drugs for RAS.^30,31 Forty-three patients in our analysis were treated with thalidomide,usually as a first choice. The dosage ranged from 100 to 200 mg/d. It was mainly chosen in disabling pediatric cases, adult men with aphthous major, and women with no risk for pregnancy. Due to its potential adverse effects, thalidomide has been recommended when there is no response with other medications that are dose dependent; severe adverse effects such as thromboembolism and peripheral neuropathy are rare.³¹ Oral corticosteroids were used in 26 patients, aiming at rapid improvement in very symptomatic cases; however, due to the potential for long-term adverse effects, in all cases they were prescribed in combination with another medication that was maintained after the corticosteroid was discontinued.

We highlight the systemic nature of RAS as well as its frequent association with systemic diseases and other correlated manifestations (pustules, EN, arthralgia). We also emphasize the importance of using oral medications to adequately control the disease and do not recommend topical medications aimed at treating local causes. Dermatologists should be consulted in managing severe cases of RAS.

To the Editor:

Recurrent aphthous stomatitis (RAS) is a mucocutaneous condition characterized by single or multiple, painful,^1,2 round ulcerations of variable sizes with a tendency for recurrence, most commonly located in nonkeratinized areas of the oral mucosa. Pathergy commonly is observed.³ Although many authors consider the terms RAS andaphtha to be synonymous,^4,5 differentiating the clinical lesion (aphthous ulceration) from the disease (aphtha or RAS) can be useful, as several other diseases can at times manifest with similar ulcers (called aphthoid lesions), such as pemphigus vulgaris, mucous membrane pemphigoid, and erythema multiforme.⁶

It is estimated that approximately 20% of individuals worldwide have at least one episode of aphtha during their lifetime,⁷ and it is considered the most common disease of the oral mucosa.^8,9 However, only patients presenting with severe acute outbreaks or frequent relapses typically seek medical treatment. Clinically, aphthous ulcers are classified as aphtha minor (small number of small lesions), aphtha major (large deep lesions that also can affect the minor salivary glands with intense necrosis, difficulty in healing, and mucosal scarring), and aphtha herpetiformis (innumerous tiny lesions that reappear in recurring outbreaks).^1-3 The term complex aphthosis was introduced in 1985¹⁰ and is defined as recurrent oral and genital aphthous ulcerations or recurring multiple oral aphthous ulcers in the absence of systemic manifestations or Behçet disease^11,12; however, complex aphthosis also has been reported as frequent episodes of ulcerations that may be associated with systemic diseases including Behçet disease.^13,14

Currently, RAS is considered an immunologically mediated alteration in cutaneous mucosal reactivity with a multifactorial systemic cause. Underlying conditions such as Behçet disease, inflammatory bowel disease (IBD), iatrogenic immunosuppression (eg, following solid organ transplantation), AIDS, and cyclic neutropenia may or may not be detected.^11-13

Our retrospective study explored the systemic nature of RAS. We reviewed patient records to evaluate underlying systemic conditions associated with the diagnosis of RAS and the use of oral medications in managing the disease. Medical records from the Department of Dermatology of the University of São Paulo, Brazil, from 2003 to 2017 were reviewed to identify patients with a diagnosis of RAS. Clinical classification of RAS—minor, major, or herpetiform—as well as the presence of aphthous lesions in other locations and the presence of other associated inflammatory cutaneous manifestations also were noted. Associated systemic diseases and treatments for RAS were recorded. Patients for whom the diagnosis of RAS was changed during follow-up were excluded. Because this was a retrospective analysis of medical records and without any patient risk, informed consent was not needed.

Medical records for 125 patients were reviewed; 63 were male (50.4%), and 62 were female (49.6%). The age at onset of symptoms, which ranged from a few months after birth to 74 years, was reported in only 92 (73.6%) patient medical records. Of these, 30 (32.6%) reported onset before 20 years of age, 39 (42.4%) between 20 and 39 years, 17 (18.5%) between 40 and 59 years, and 6 (6.5%) at 60 years or older. Morphologically, 72 (57.6%) had minor, 42 (33.6%) had major, and 11 (8.8%) had herpetiform aphthous ulcers. None of the patients presented with sporadic lesions; the disease was long-standing and persistent in all cases (complex aphthosis).

Regarding the location of the ulcers, 92 (73.6%) patients had lesions on the oral mucosa only. Some patients had lesions in more than one site in addition to the oral mucosa: 32 (25.6%) had aphthae in the genital/groin region and 4 (3.2%) presented with perianal/anal aphthae. Nineteen patients (19.2%) presented other cutaneous manifestations in addition to aphthae: 11 (45.8%) had folliculitis/pseudofolliculitis, and 8 (33.3%) had erythema nodosum (EN). Eight patients (33.3%) presented with uveitis, and 6 (25%) presented with concomitant arthralgia/arthritis. Fifty-four patients (43.2%) had confirmed or suspected associated disease: Behçet disease (21 [38.9%]), IBD (10 [18.5%]), solid organ transplantation (7 [13.0%])(kidney, 4 [57.1%]; heart, 2 [28.6%]; liver, 1 [14.3%]), HIV infection (6 [11.1%]), lymphoma (1 [1.9%]), aplastic anemia (1 [1.9%]), or myelodysplastic syndrome (1 [1.9%]). Ten patients (18.5%) presented with other diseases under investigation (eg, unidentified rheumatologic disease, unexplained neutropenia, undiagnosed immunodeficiencies, autoinflammatory syndromes, possible cyclic neutropenia).

Biopsies of the oral mucosa were performed in 31 patients. Histopathologic findings will be discussed in a future publication (unpublished data).

Five patients (4.0%) were lost to follow-up and did not receive treatment; 10 (8.0%) received only topical treatment (analgesics and/or corticosteroids). All 9 (7.2%) patients undergoing intralesional corticosteroid injections also were on a systemic treatment. One hundred ten (88.0%) patients were treated systemically—with colchicine (84/110 [76.4%]), thalidomide (43/110 [39.1%]), small pulses of oral corticosteroids (26 [23.6%]), dapsone (12/110 [10.9%]), or pentoxifylline (3 [2.7%]). Furthermore, in patients with associated diseases, treatment of the underlying condition was conducted when available, and follow-up was carried out in conjunction with the appropriate specialists. For treatment of the associated disease, patients received other medications such as methotrexate, azathioprine, cyclophosphamide, intravenous corticosteroid pulse, and immunobiologics.

The prevalence of RAS between sexes in our study population was similar (50.4% male; 49.6% female). Results from prior studies have been mixed; some reported a higher prevalence in females,^15-18 while others found no predilection for sex among patients diagnosed with RAS.^19,20 In our analysis, 75% of patients experienced symptoms of RAS before 40 years of age; in prior studies, up to 56% of patients experienced symptoms between the ages of 20 and 40 years.^21,22

In our study, 26.4% of patients had extraoral aphthae. Genital lesions have been described as infrequent,²³ and lesions manifesting in other mucous membranes or on the skin are rare.²⁴ A study reported genital involvement in 8% to 13% of patients with oral aphtha.²⁵ We observed genital involvement in 25.6% of patients. Likewise, this higher value may be due to our study population of patients referred to our university hospital. In our study, 19.2% of patients presented with other inflammatory manifestations in addition to aphthous ulcerations (eg, folliculitis, EN, uveitis, arthritis). As dermatologists in a tertiary reference hospital, we actively look for such associations in every aphtha patient, which may not be the case in many nondermatologic oral care services.

In our study population, 43.2% of patients were diagnosed with or were under investigation for systemic diseases known to be associated with RAS. We found associations with Behçet disease most frequently, followed by IBD,²⁶ solid organ transplantation, and HIV. In this group of patients, the respective systemic disease was active or poorly controlled. In transplant recipients, aphtha major was the most common type, similar to other studies.²⁷ We observed no notable difference in the clinical picture of the oral ulcers in patients with a well-established systemic disease vs those without.

Most of our cases did not present findings other than aphtha, indicating that the intrinsic defect that predisposes to RAS is always systemic. Even mild and sporadic cases may be attributable to a systemic disorder of cutaneous-mucosal reactivity. The predisposition to RAS never originates in the oral cavity, hence the confusion caused and the uselessness of studies that relate aphthae to factors such as local food allergies, pH changes, or local infection with microorganisms.^5,28 The disease course (reducing the frequency of lesion appearance and accelerating the healing of extensive lesions) is only modified with systemic treatment, with local measures proving to be only moderately useful to relieve pain. We believe that RAS can in many ways be compared to EN and pyoderma gangrenosum (PG): some systemic conditions that predispose patients to EN and PG also may predispose them to RAS (eg, IBD, hematologic disorders). Similar to RAS, many cases of EN and PG are idiopathic. In addition, pathergy also occurs in PG.^11,13

We were unable to observe or establish any predictive clinical element that could indicate a better or worse response to the prescribed treatments, which also has been noted by other authors.^3,4 Treatment of RAS is empiric, generally starting with drugs that are easier to prescribe and with fewer adverse effects, then progressing to more complex drugs when a good response is not obtained. Colchicine was the most commonly prescribed medication (76.4% [84/110]). It has been proposed by several authors^3,4 as a first-line systemic medication for the treatment of recurrent aphthae, as it has been shown to be effective and safe. The dosage ranged from 0.5 mg twice daily to 0.5 mg 4 times daily. Dapsone is an established drug for aphtha^29,30 and was used in 12 of our patients. The dosage used in our patients ranged from 50 to 100 mg/d. Adverse effects such as hemolytic anemia frequently are seen, and one of the patients in our study developed DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome in response to dapsone. In 7 cases, colchicine and dapsone were used together, which is believed to potentiate the therapeutic effects. This combination may be useful in patients for whom thalidomide cannot be used or those who have not improved with monotherapy.²⁹ Thalidomide is considered one of the most effective drugs for RAS.^30,31 Forty-three patients in our analysis were treated with thalidomide,usually as a first choice. The dosage ranged from 100 to 200 mg/d. It was mainly chosen in disabling pediatric cases, adult men with aphthous major, and women with no risk for pregnancy. Due to its potential adverse effects, thalidomide has been recommended when there is no response with other medications that are dose dependent; severe adverse effects such as thromboembolism and peripheral neuropathy are rare.³¹ Oral corticosteroids were used in 26 patients, aiming at rapid improvement in very symptomatic cases; however, due to the potential for long-term adverse effects, in all cases they were prescribed in combination with another medication that was maintained after the corticosteroid was discontinued.

We highlight the systemic nature of RAS as well as its frequent association with systemic diseases and other correlated manifestations (pustules, EN, arthralgia). We also emphasize the importance of using oral medications to adequately control the disease and do not recommend topical medications aimed at treating local causes. Dermatologists should be consulted in managing severe cases of RAS.

Vitiligo is a common acquired autoimmune disease that causes depigmented patches to develop throughout the skin , with descriptions dating back more than 3000 years to the earliest known Indian and Egyptian texts. Approximately 1.4% of the worldwide population has vitiligo,¹ and onset follows a bimodal age distribution with an early-onset population (mean age at onset, 10.3 years) as well as an adult-onset population (mean age at onset, 34 years).² Vitiligo manifests as well-defined, irregular, depigmented macules and patches surrounded by normal skin. The patches can vary in size from a few millimeters to several centimeters. There may be signs of inflammation, and the lesions can be itchy, but in most cases vitiligo is asymptomatic. In nonsegmental vitiligo, the depigmented patches are ymmetrical, can appear in any area of the body, and commonly progress slowly. In segmental vitiligo, the patches are unilateral, rarely cross the midline of the body, and are localized to one area. Segmental vitiligo commonly appears in childhood and progresses rapidly but stops abruptly within 6 to 12 months and remains stable, usually for life.³ Although the condition may be more apparent in patients with skin of color, vitiligo manifests at a similar rate in individuals of all races and ethnicities.⁴

Similar to most autoimmune diseases, vitiligo has a strong genetic predisposition. Although the overall prevalence of vitiligo is less than 2%, having a family history of vitiligo (ie, a first-degree relative with vitiligo) increases an individual’s risk to 6%, while concordance in identical twins is 23%.⁵ Beyond genetic predisposition, there is strong evidence that environmental exposures, such as hair dyes, contribute to risk for disease.⁶ Interestingly, vitiligo is associated with polyautoimmunity—the presence of multiple autoimmune diseases in a single patient,⁷ such as type 1 diabetes mellitus, rheumatoid arthritis, autoimmune thyroid disease, pernicious anemia, and Addison disease. Similar to vitiligo itself, polyautoimmunity likely is driven by a combination of genetic and environmental factors.⁵

We provide a brief overview of clinical trial results of Janus kinase (JAK) inhibitors for treating vitiligo and discuss the trial cohorts, with an emphasis on the impact of cohort demographic composition for individuals with skin of color. We recommend factors that investigators should consider to ensure equitable representation of individuals with skin of color in future clinical trials.

Autoimmune Pathogenesis and Treatment With JAK Inhibitors

Vitiligo is driven by autoreactive CD8⁺ T cells that target melanocytes and secrete IFN-g. Signaling of IFN-g occurs through the JAK–signal transducer and activator of transcription (JAK-STAT) pathway, leading to transcriptional changes that activate proinflammatory genes such as the chemokine CXCL10, which is required for the directed accumulation of melanocyte-specific CD8⁺ T cells at the epidermis where melanocytes reside.⁸ Once vitiligo has been initiated, the disease persists due to the presence of resident memory T cells that remain in the skin and destroy new melanocytes.^9,10

Given the central role of IFN-g signaling in the pathogenesis of vitiligo, drugs that inhibit JAK signaling are appealing to treat the disease. These JAK inhibitors bind to the kinase domain of JAK to prevent its activation, thus preventing downstream signaling events including STAT phosphorylation and its translocation to the nucleus, which ultimately stops the upregulation of inflammatory gene transcription. This process attenuates the autoimmune response in the skin and results in repigmentation of vitiligo lesions. In 2022, the US Food and Drug Administration approved the topical JAK inhibitor ruxolitinib for the treatment of vitiligo. Additional clinical trials have been initiated to test oral JAK inhibitors—ritlecitinib (ClinicalTrials.gov identifiers NCT06163326, NCT06072183, NCT05583526), povorcitinib (NCT04818346, NCT06113445, NCT06113471), and upadacitinib (NCT04927975, NCT06118411)—with strong results reported so far.¹¹

The effects of JAK inhibitors can be striking, as shown in the Figure. A patient of one of the authors (J.E.H.) used topical ruxolitinib on only the left arm for approximately 36 weeks and results were as expected—strong repigmentation of only the treated area, which is possible with JAK inhibitors. Indeed, 2 phase 3 studies—Topical Ruxolitinib Evaluation in Vitiligo (TRuE-V1 and TRuE-V2)—showed that approximately 30% of participants in TRuE-V1 (N=330) and 30.9% of participants in TRuE-V2 (N=344) achieved at least 75% improvement over baseline in the facial vitiligo area scoring index (VASI).¹² In the oral ritlecitinib phase 2b study, 12.1% of the 187 participants on the highest tested dose of ritlecitinib (loading dose of 200 mg/d for 28 days, followed by 50 mg/d maintenance dose) achieved at least 75% improvement over baseline in the VASI at 24 weeks.¹¹ Although this rate is lower than for topical ruxolitinib, this trial required all participants to have active disease (unlike the TRuE-V trials of ruxolitinib), which likely created a higher bar for repigmentation and thus resulted in fewer participants achieving the primary outcome at the early 6-month end point. Extension of treatment through 48 weeks demonstrated continued improvement over baseline without any evidence of plateau.¹¹ Although treatment with JAK inhibitors can result in dramatic repigmentation of vitiligo patches, it falls short of providing a permanent cure, as stopping treatment results in relapse (ie, the return of depigmented lesions).

Delva_Figure.jpg

Racial Disparities in Clinical Trials

Even though vitiligo affects all skin types and races/ethnicities with similar prevalence and severity, the proportion of individuals with darker skin types enrolled in these clinical trials fails to match their representation in the population as a whole. A study examining the prevalence of vitiligo in the United States reported that Black or African American individuals represented 15.8% of vitiligo diagnoses in the United States⁴ even though they are only 12.7% of the total US population. However, Black or African American individuals comprised only 5% of the combined participants in the TRuE-V clinical trials for topical ruxolitinib¹² and 2.7% of the participants in the phase 2b study of oral ritlecitinib.¹¹ This lack of appropriate representation is not unique to JAK inhibitors or other vitiligo trials. Indeed, the US Food and Drug Administration reported that Black or African American individuals comprised only 8% of participants for all clinical trials in 2020.¹³

Efficacy Metrics Beyond Repigmentation

Disparities in quality-of-life (QOL) metrics in diseases affecting individuals with skin of color also exist. In vitiligo, the contrast between affected and unaffected skin is greater in patients with skin of color, which means that for a given VASI score, the visibility of depigmentation as well as repigmentation may be variable among patients. Additionally, there is evidence that QOL concerns vary between patients with skin of color and those with lighter skin types. Ezzedine et al¹⁴ found that QOL concerns in vitiligo patients with darker skin focused more on appearance, while concerns in vitiligo patients with lighter skin focused more on skin cancer risk. In addition to QOL differences among individuals with different skin types, there also are well-documented differences in attitudes to vitiligo among certain ethnic or cultural groups.¹⁵ For example, the Rigveda (an ancient Hindu text) indicates that individuals with vitiligo and their progeny are disqualified from marriage. Although the JAK inhibitor clinical trials for vitiligo did not appear to show differences in the degree of repigmentation among different skin types or races/ethnicities, QOL measures were not collected as a secondary end point in these studies—despite the fact that at least 1 study had documented that QOL measures were not uniform across patients when stratified by age and extent of disease.^1,11,12 This same study also presented limited data suggestive of lower QOL in patients with the darkest skin phototype.¹

Considerations for Future Clinical Trials

It is logical to assume that every clinical trialist in dermatology seeks equitable representation among a diverse set of races, ethnicities, and skin types, but achieving this goal remains elusive. Two recent publications^16,17 outlined the challenges and examined solutions to address enrollment disparities, including several barriers to diversity among clinical trial participants: awareness of the clinical trials among minority populations; easy access to clinical trial sites; reluctance to participate because of prior experiences of discrimination, even if unrelated to clinical trials; and a lack of workforce diversity among the clinical trialist teams. To overcome these barriers, a multifaceted approach is needed that requires action at the level of the patient, provider, community, and institution. Once diverse representation is achieved, investigators should consider the need for QOL metrics as a secondary outcome in their trials, which will ensure that the intended clinical effect is matched by patient expectations across different races and ethnicities based on the potential differential impact that diseases such as vitiligo can have on patients with skin of color.

Vitiligo is a common acquired autoimmune disease that causes depigmented patches to develop throughout the skin , with descriptions dating back more than 3000 years to the earliest known Indian and Egyptian texts. Approximately 1.4% of the worldwide population has vitiligo,¹ and onset follows a bimodal age distribution with an early-onset population (mean age at onset, 10.3 years) as well as an adult-onset population (mean age at onset, 34 years).² Vitiligo manifests as well-defined, irregular, depigmented macules and patches surrounded by normal skin. The patches can vary in size from a few millimeters to several centimeters. There may be signs of inflammation, and the lesions can be itchy, but in most cases vitiligo is asymptomatic. In nonsegmental vitiligo, the depigmented patches are ymmetrical, can appear in any area of the body, and commonly progress slowly. In segmental vitiligo, the patches are unilateral, rarely cross the midline of the body, and are localized to one area. Segmental vitiligo commonly appears in childhood and progresses rapidly but stops abruptly within 6 to 12 months and remains stable, usually for life.³ Although the condition may be more apparent in patients with skin of color, vitiligo manifests at a similar rate in individuals of all races and ethnicities.⁴

Similar to most autoimmune diseases, vitiligo has a strong genetic predisposition. Although the overall prevalence of vitiligo is less than 2%, having a family history of vitiligo (ie, a first-degree relative with vitiligo) increases an individual’s risk to 6%, while concordance in identical twins is 23%.⁵ Beyond genetic predisposition, there is strong evidence that environmental exposures, such as hair dyes, contribute to risk for disease.⁶ Interestingly, vitiligo is associated with polyautoimmunity—the presence of multiple autoimmune diseases in a single patient,⁷ such as type 1 diabetes mellitus, rheumatoid arthritis, autoimmune thyroid disease, pernicious anemia, and Addison disease. Similar to vitiligo itself, polyautoimmunity likely is driven by a combination of genetic and environmental factors.⁵

We provide a brief overview of clinical trial results of Janus kinase (JAK) inhibitors for treating vitiligo and discuss the trial cohorts, with an emphasis on the impact of cohort demographic composition for individuals with skin of color. We recommend factors that investigators should consider to ensure equitable representation of individuals with skin of color in future clinical trials.

Autoimmune Pathogenesis and Treatment With JAK Inhibitors

Vitiligo is driven by autoreactive CD8⁺ T cells that target melanocytes and secrete IFN-g. Signaling of IFN-g occurs through the JAK–signal transducer and activator of transcription (JAK-STAT) pathway, leading to transcriptional changes that activate proinflammatory genes such as the chemokine CXCL10, which is required for the directed accumulation of melanocyte-specific CD8⁺ T cells at the epidermis where melanocytes reside.⁸ Once vitiligo has been initiated, the disease persists due to the presence of resident memory T cells that remain in the skin and destroy new melanocytes.^9,10

Given the central role of IFN-g signaling in the pathogenesis of vitiligo, drugs that inhibit JAK signaling are appealing to treat the disease. These JAK inhibitors bind to the kinase domain of JAK to prevent its activation, thus preventing downstream signaling events including STAT phosphorylation and its translocation to the nucleus, which ultimately stops the upregulation of inflammatory gene transcription. This process attenuates the autoimmune response in the skin and results in repigmentation of vitiligo lesions. In 2022, the US Food and Drug Administration approved the topical JAK inhibitor ruxolitinib for the treatment of vitiligo. Additional clinical trials have been initiated to test oral JAK inhibitors—ritlecitinib (ClinicalTrials.gov identifiers NCT06163326, NCT06072183, NCT05583526), povorcitinib (NCT04818346, NCT06113445, NCT06113471), and upadacitinib (NCT04927975, NCT06118411)—with strong results reported so far.¹¹

The effects of JAK inhibitors can be striking, as shown in the Figure. A patient of one of the authors (J.E.H.) used topical ruxolitinib on only the left arm for approximately 36 weeks and results were as expected—strong repigmentation of only the treated area, which is possible with JAK inhibitors. Indeed, 2 phase 3 studies—Topical Ruxolitinib Evaluation in Vitiligo (TRuE-V1 and TRuE-V2)—showed that approximately 30% of participants in TRuE-V1 (N=330) and 30.9% of participants in TRuE-V2 (N=344) achieved at least 75% improvement over baseline in the facial vitiligo area scoring index (VASI).¹² In the oral ritlecitinib phase 2b study, 12.1% of the 187 participants on the highest tested dose of ritlecitinib (loading dose of 200 mg/d for 28 days, followed by 50 mg/d maintenance dose) achieved at least 75% improvement over baseline in the VASI at 24 weeks.¹¹ Although this rate is lower than for topical ruxolitinib, this trial required all participants to have active disease (unlike the TRuE-V trials of ruxolitinib), which likely created a higher bar for repigmentation and thus resulted in fewer participants achieving the primary outcome at the early 6-month end point. Extension of treatment through 48 weeks demonstrated continued improvement over baseline without any evidence of plateau.¹¹ Although treatment with JAK inhibitors can result in dramatic repigmentation of vitiligo patches, it falls short of providing a permanent cure, as stopping treatment results in relapse (ie, the return of depigmented lesions).

Delva_Figure.jpg

Racial Disparities in Clinical Trials

Even though vitiligo affects all skin types and races/ethnicities with similar prevalence and severity, the proportion of individuals with darker skin types enrolled in these clinical trials fails to match their representation in the population as a whole. A study examining the prevalence of vitiligo in the United States reported that Black or African American individuals represented 15.8% of vitiligo diagnoses in the United States⁴ even though they are only 12.7% of the total US population. However, Black or African American individuals comprised only 5% of the combined participants in the TRuE-V clinical trials for topical ruxolitinib¹² and 2.7% of the participants in the phase 2b study of oral ritlecitinib.¹¹ This lack of appropriate representation is not unique to JAK inhibitors or other vitiligo trials. Indeed, the US Food and Drug Administration reported that Black or African American individuals comprised only 8% of participants for all clinical trials in 2020.¹³

Efficacy Metrics Beyond Repigmentation

Disparities in quality-of-life (QOL) metrics in diseases affecting individuals with skin of color also exist. In vitiligo, the contrast between affected and unaffected skin is greater in patients with skin of color, which means that for a given VASI score, the visibility of depigmentation as well as repigmentation may be variable among patients. Additionally, there is evidence that QOL concerns vary between patients with skin of color and those with lighter skin types. Ezzedine et al¹⁴ found that QOL concerns in vitiligo patients with darker skin focused more on appearance, while concerns in vitiligo patients with lighter skin focused more on skin cancer risk. In addition to QOL differences among individuals with different skin types, there also are well-documented differences in attitudes to vitiligo among certain ethnic or cultural groups.¹⁵ For example, the Rigveda (an ancient Hindu text) indicates that individuals with vitiligo and their progeny are disqualified from marriage. Although the JAK inhibitor clinical trials for vitiligo did not appear to show differences in the degree of repigmentation among different skin types or races/ethnicities, QOL measures were not collected as a secondary end point in these studies—despite the fact that at least 1 study had documented that QOL measures were not uniform across patients when stratified by age and extent of disease.^1,11,12 This same study also presented limited data suggestive of lower QOL in patients with the darkest skin phototype.¹

Considerations for Future Clinical Trials

It is logical to assume that every clinical trialist in dermatology seeks equitable representation among a diverse set of races, ethnicities, and skin types, but achieving this goal remains elusive. Two recent publications^16,17 outlined the challenges and examined solutions to address enrollment disparities, including several barriers to diversity among clinical trial participants: awareness of the clinical trials among minority populations; easy access to clinical trial sites; reluctance to participate because of prior experiences of discrimination, even if unrelated to clinical trials; and a lack of workforce diversity among the clinical trialist teams. To overcome these barriers, a multifaceted approach is needed that requires action at the level of the patient, provider, community, and institution. Once diverse representation is achieved, investigators should consider the need for QOL metrics as a secondary outcome in their trials, which will ensure that the intended clinical effect is matched by patient expectations across different races and ethnicities based on the potential differential impact that diseases such as vitiligo can have on patients with skin of color.

Vitiligo is a common acquired autoimmune disease that causes depigmented patches to develop throughout the skin , with descriptions dating back more than 3000 years to the earliest known Indian and Egyptian texts. Approximately 1.4% of the worldwide population has vitiligo,¹ and onset follows a bimodal age distribution with an early-onset population (mean age at onset, 10.3 years) as well as an adult-onset population (mean age at onset, 34 years).² Vitiligo manifests as well-defined, irregular, depigmented macules and patches surrounded by normal skin. The patches can vary in size from a few millimeters to several centimeters. There may be signs of inflammation, and the lesions can be itchy, but in most cases vitiligo is asymptomatic. In nonsegmental vitiligo, the depigmented patches are ymmetrical, can appear in any area of the body, and commonly progress slowly. In segmental vitiligo, the patches are unilateral, rarely cross the midline of the body, and are localized to one area. Segmental vitiligo commonly appears in childhood and progresses rapidly but stops abruptly within 6 to 12 months and remains stable, usually for life.³ Although the condition may be more apparent in patients with skin of color, vitiligo manifests at a similar rate in individuals of all races and ethnicities.⁴

Similar to most autoimmune diseases, vitiligo has a strong genetic predisposition. Although the overall prevalence of vitiligo is less than 2%, having a family history of vitiligo (ie, a first-degree relative with vitiligo) increases an individual’s risk to 6%, while concordance in identical twins is 23%.⁵ Beyond genetic predisposition, there is strong evidence that environmental exposures, such as hair dyes, contribute to risk for disease.⁶ Interestingly, vitiligo is associated with polyautoimmunity—the presence of multiple autoimmune diseases in a single patient,⁷ such as type 1 diabetes mellitus, rheumatoid arthritis, autoimmune thyroid disease, pernicious anemia, and Addison disease. Similar to vitiligo itself, polyautoimmunity likely is driven by a combination of genetic and environmental factors.⁵

We provide a brief overview of clinical trial results of Janus kinase (JAK) inhibitors for treating vitiligo and discuss the trial cohorts, with an emphasis on the impact of cohort demographic composition for individuals with skin of color. We recommend factors that investigators should consider to ensure equitable representation of individuals with skin of color in future clinical trials.

Autoimmune Pathogenesis and Treatment With JAK Inhibitors

Vitiligo is driven by autoreactive CD8⁺ T cells that target melanocytes and secrete IFN-g. Signaling of IFN-g occurs through the JAK–signal transducer and activator of transcription (JAK-STAT) pathway, leading to transcriptional changes that activate proinflammatory genes such as the chemokine CXCL10, which is required for the directed accumulation of melanocyte-specific CD8⁺ T cells at the epidermis where melanocytes reside.⁸ Once vitiligo has been initiated, the disease persists due to the presence of resident memory T cells that remain in the skin and destroy new melanocytes.^9,10

Given the central role of IFN-g signaling in the pathogenesis of vitiligo, drugs that inhibit JAK signaling are appealing to treat the disease. These JAK inhibitors bind to the kinase domain of JAK to prevent its activation, thus preventing downstream signaling events including STAT phosphorylation and its translocation to the nucleus, which ultimately stops the upregulation of inflammatory gene transcription. This process attenuates the autoimmune response in the skin and results in repigmentation of vitiligo lesions. In 2022, the US Food and Drug Administration approved the topical JAK inhibitor ruxolitinib for the treatment of vitiligo. Additional clinical trials have been initiated to test oral JAK inhibitors—ritlecitinib (ClinicalTrials.gov identifiers NCT06163326, NCT06072183, NCT05583526), povorcitinib (NCT04818346, NCT06113445, NCT06113471), and upadacitinib (NCT04927975, NCT06118411)—with strong results reported so far.¹¹

The effects of JAK inhibitors can be striking, as shown in the Figure. A patient of one of the authors (J.E.H.) used topical ruxolitinib on only the left arm for approximately 36 weeks and results were as expected—strong repigmentation of only the treated area, which is possible with JAK inhibitors. Indeed, 2 phase 3 studies—Topical Ruxolitinib Evaluation in Vitiligo (TRuE-V1 and TRuE-V2)—showed that approximately 30% of participants in TRuE-V1 (N=330) and 30.9% of participants in TRuE-V2 (N=344) achieved at least 75% improvement over baseline in the facial vitiligo area scoring index (VASI).¹² In the oral ritlecitinib phase 2b study, 12.1% of the 187 participants on the highest tested dose of ritlecitinib (loading dose of 200 mg/d for 28 days, followed by 50 mg/d maintenance dose) achieved at least 75% improvement over baseline in the VASI at 24 weeks.¹¹ Although this rate is lower than for topical ruxolitinib, this trial required all participants to have active disease (unlike the TRuE-V trials of ruxolitinib), which likely created a higher bar for repigmentation and thus resulted in fewer participants achieving the primary outcome at the early 6-month end point. Extension of treatment through 48 weeks demonstrated continued improvement over baseline without any evidence of plateau.¹¹ Although treatment with JAK inhibitors can result in dramatic repigmentation of vitiligo patches, it falls short of providing a permanent cure, as stopping treatment results in relapse (ie, the return of depigmented lesions).

Delva_Figure.jpg

Racial Disparities in Clinical Trials

Even though vitiligo affects all skin types and races/ethnicities with similar prevalence and severity, the proportion of individuals with darker skin types enrolled in these clinical trials fails to match their representation in the population as a whole. A study examining the prevalence of vitiligo in the United States reported that Black or African American individuals represented 15.8% of vitiligo diagnoses in the United States⁴ even though they are only 12.7% of the total US population. However, Black or African American individuals comprised only 5% of the combined participants in the TRuE-V clinical trials for topical ruxolitinib¹² and 2.7% of the participants in the phase 2b study of oral ritlecitinib.¹¹ This lack of appropriate representation is not unique to JAK inhibitors or other vitiligo trials. Indeed, the US Food and Drug Administration reported that Black or African American individuals comprised only 8% of participants for all clinical trials in 2020.¹³

Efficacy Metrics Beyond Repigmentation

Disparities in quality-of-life (QOL) metrics in diseases affecting individuals with skin of color also exist. In vitiligo, the contrast between affected and unaffected skin is greater in patients with skin of color, which means that for a given VASI score, the visibility of depigmentation as well as repigmentation may be variable among patients. Additionally, there is evidence that QOL concerns vary between patients with skin of color and those with lighter skin types. Ezzedine et al¹⁴ found that QOL concerns in vitiligo patients with darker skin focused more on appearance, while concerns in vitiligo patients with lighter skin focused more on skin cancer risk. In addition to QOL differences among individuals with different skin types, there also are well-documented differences in attitudes to vitiligo among certain ethnic or cultural groups.¹⁵ For example, the Rigveda (an ancient Hindu text) indicates that individuals with vitiligo and their progeny are disqualified from marriage. Although the JAK inhibitor clinical trials for vitiligo did not appear to show differences in the degree of repigmentation among different skin types or races/ethnicities, QOL measures were not collected as a secondary end point in these studies—despite the fact that at least 1 study had documented that QOL measures were not uniform across patients when stratified by age and extent of disease.^1,11,12 This same study also presented limited data suggestive of lower QOL in patients with the darkest skin phototype.¹

Considerations for Future Clinical Trials

It is logical to assume that every clinical trialist in dermatology seeks equitable representation among a diverse set of races, ethnicities, and skin types, but achieving this goal remains elusive. Two recent publications^16,17 outlined the challenges and examined solutions to address enrollment disparities, including several barriers to diversity among clinical trial participants: awareness of the clinical trials among minority populations; easy access to clinical trial sites; reluctance to participate because of prior experiences of discrimination, even if unrelated to clinical trials; and a lack of workforce diversity among the clinical trialist teams. To overcome these barriers, a multifaceted approach is needed that requires action at the level of the patient, provider, community, and institution. Once diverse representation is achieved, investigators should consider the need for QOL metrics as a secondary outcome in their trials, which will ensure that the intended clinical effect is matched by patient expectations across different races and ethnicities based on the potential differential impact that diseases such as vitiligo can have on patients with skin of color.