Clinical Review

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

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.

Alopecia areata (AA) affects 4.5 million individuals in the United States, with 66% younger than 30 years.^1,2 Inflammation causes hair loss in well-circumscribed, nonscarring patches on the body with a predilection for the scalp.^3-6 The disease can devastate a patient’s self-esteem, in turn reducing quality of life.^1,7 Alopecia areata is an autoimmune T-cell–mediated disease in which hair follicles lose their immune privilege.^8-10 Several specific mechanisms in the cytokine interactions between T cells and the hair follicle have been discovered, revealing the Janus kinase–signal transducer and activator of transcription (JAK-STAT) pathway as pivotal in the pathogenesis of the disease and leading to the use of JAK inhibitors for treatment.¹¹

There is no cure for AA, and the condition is managed with prolonged medical treatments and cosmetic therapies.² Although some patients may be able to manage the annual cost, the cumulative cost of AA treatment can be burdensome.¹² This cumulative cost may increase if newer, potentially expensive treatments become the standard of care. Patients with AA report dipping into their savings (41.3%) and cutting back on food or clothing expenses (33.9%) to account for the cost of alopecia treatment. Although prior estimates of the annual out-of-pocket cost of AA treatments range from $1354 to $2685, the cost burden of individual therapies is poorly understood.^12-14

Patients who must juggle expensive medical bills with basic living expenses may be lost to follow-up or fall into treatment nonadherence.¹⁵ Other patients’ out-of-pocket costs may be manageable, but the costs to the health care system may compromise care in other ways. We conducted a literature review of the recommended therapies for AA based on American Academy of Dermatology (AAD) guidelines to identify the costs of alopecia treatment and consolidate the available data for the practicing dermatologist.

Methods

We conducted a PubMed search of articles indexed for MEDLINE through September 15, 2022, using the terms alopecia and cost plus one of the treatments (n=21) identified by the AAD² for the treatment of AA (Figure). The reference lists of included articles were reviewed to identify other potentially relevant studies. Forty-five articles were identified.

Patel_Figure.jpg

Given the dearth of cost research in alopecia and the paucity of large prospective studies, we excluded articles that were not available in their full-text form or were not in English (n=3), articles whose primary study topic was not AA or an expert-approved alopecia treatment (n=15), and articles with no concrete cost data (n=17), which yielded 10 relevant articles that we studied using qualitative analysis.

Due to substantial differences in study methods and outcome measures, we did not compare the costs of alopecia among studies and did not perform statistical analysis. The quality of each study was investigated and assigned a level of evidence per the 2009 criteria from the Centre for Evidence-Based Medicine.¹⁶

All cost data were converted into US dollars ($) using the conversion rate from the time of the original article’s publication.

Results

Total and Out-of-pocket Costs of AA—Li et al¹³ studied out-of-pocket health care costs for AA patients (N=675). Of these participants, 56.9% said their AA was moderately to seriously financially burdensome, and 41.3% reported using their savings to manage these expenses. Participants reported median out-of-pocket spending of $1354 (interquartile range, $537–$3300) annually. The most common categories of expenses were hair appointments (81.8%) and vitamins/supplements (67.7%).¹³

Mesinkovska et al¹⁴ studied the qualitative and quantitative financial burdens of moderate to severe AA (N=216). Fifty-seven percent of patients reported the financial impact of AA as moderately to severely burdensome with a willingness to borrow money or use savings to cover out-of-pocket costs. Patients without insurance cited cost as a major barrier to obtaining reatment. In addition to direct treatment-related expenses, AA patients spent a mean of $1961 per year on therapy to cope with the disease’s psychological burden. Lost work hours represented another source of financial burden; 61% of patients were employed, and 45% of them reported missing time from their job because of AA.¹⁴

Mostaghimi et al¹² studied health care resource utilization and all-cause direct health care costs in privately insured AA patients with or without alopecia totalis (AT) or alopecia universalis (AU)(n=14,972) matched with non-AA controls (n=44,916)(1:3 ratio). Mean total all-cause medical and pharmacy costs were higher in both AA groups compared with controls (AT/AU, $18,988 vs $11,030; non-AT/AU, $13,686 vs $9336; P<.001 for both). Out-of-pocket costs were higher for AA vs controls (AT/AU, $2685 vs $1457; non-AT/AU, $2223 vs $1341; P<.001 for both). Medical costs in the AT/AU and non-AT/AU groups largely were driven by outpatient costs (AT/AU, $10,277 vs $5713; non-AT/AU, $8078 vs $4672; P<.001 for both).¹²

Costs of Concealment—When studying the out-of-pocket costs of AA (N=675), Li et al¹³ discovered that the median yearly spending was highest on headwear or cosmetic items such as hats, wigs, and makeup ($450; interquartile range, $50–$1500). Mesinkovska et al¹⁴ reported that 49% of patients had insurance that covered AA treatment. However, 75% of patients reported that their insurance would not cover costs of concealment (eg, weave, wig, hair piece). Patients (N=112) spent a mean of $2211 per year and 10.3 hours per week on concealment.¹⁴

Minoxidil—Minoxidil solution is available over-the-counter, and its ease of access makes it a popular treatment for AA.¹⁷ Because manufacturers can sell directly to the public, minoxidil is marketed with bold claims and convincing packaging. Shrank¹⁸ noted that the product can take 4 months to work, meaning customers must incur a substantial cost burden before realizing the treatment’s benefit, which is not always obvious when purchasing minoxidil products, leaving customers—who were marketed a miracle drug—disappointed. Per Shrank,¹⁸ patients who did not experience hair regrowth after 4 months were advised to continue treatment for a year, leading them to spend hundreds of dollars for uncertain results. Those who did experience hair regrowth were advised to continue using the product twice daily 7 days per week indefinitely.¹⁸

Wehner et al¹⁹ studied the association between gender and drug cost for over-the-counter minoxidil. The price that women paid for 2% regular-strength minoxidil solutions was similar to the price that men paid for 5% extra-strength minoxidil solutions (women’s 2%, $7.63/30 mL; men’s 5%, $7.61/30 mL; P=.67). Minoxidil 5% foams with identical ingredients were priced significantly more per volume of the same product when sold as a product directed at women vs a product directed at men (men’s 5%, $8.05/30 mL; women’s 5%, $11.27/30 mL; P<.001).¹⁹

Beach²⁰ compared the cost of oral minoxidil to topical minoxidil. At $28.60 for a 3-month supply, oral minoxidil demonstrated cost savings compared to topical minoxidil ($48.30).²⁰

Diphencyprone—Bhat et al²¹ studied the cost-efficiency of diphencyprone (DPC) in patients with AA resistant to at least 2 conventional treatments (N=29). After initial sensitization with 2% DPC, patients received weekly or fortnightly treatments. Most of the annual cost burden of DPC treatment was due to staff time and overhead rather than the cost of the DPC itself: $258 for the DPC, $978 in staff time and overhead for the department, and $1233 directly charged to the patient.²¹

Lekhavat et al²² studied the economic impact of home-use vs office-use DPC in extensive AA (N=82). Both groups received weekly treatments in the hospital until DPC concentrations had been adjusted. Afterward, the home group was given training on self-applying DPC at home. The home group had monthly office visits for DPC concentration evaluation and refills, while the office group had weekly appointments for DPC treatment at the hospital. Calculated costs included those to the health care provider (ie, material, labor, capital costs) and the patient’s final out-of-pocket expense. The total cost to the health care provider was higher for the office group than the home group at 48 weeks (office, $683.52; home, $303.67; P<.001). Median out-of-pocket costs did not vary significantly between groups, which may have been due to small sample size affecting the range (office, $418.07; home, $189.69; P=.101). There was no significant difference between groups in the proportion of patients who responded favorably to the DPC.²²

JAK Inhibitors—Chen et al²³ studied the efficacy of low-dose (5 mg) tofacitinib to treat severe AA (N=6). Compared to prior studies,^24-27 this analysis reported the efficacy of low-dose tofacitinib was not inferior to higher doses (10–20 mg), and low-dose tofacitinib reduced treatment costs by more than 50%.²³

Per the GlobalData Healthcare database, the estimated annual cost of therapy for JAK inhibitors following US Food and Drug Administration approval was $50,000. At the time of their reporting, the next most expensive immunomodulatory drug for AA was cyclosporine, with an annual cost of therapy of $1400.²⁸ Dillon²⁹ reviewed the use of JAK inhibitors for the treatment of AA. The cost estimates by Dillon²⁹ prior to FDA approval aligned with the pricing of Eli Lilly and Company for the now-approved JAK inhibitor baricitinib.³⁰ The list price of baricitinib is $2739.99 for a 30-day supply of 2-mg tablets or $5479.98 for a 30-day supply of 4-mg tablets. This amounts to $32,879.88 for an annual supply of 2-mg tablets and $65,759.76 for an annual supply for 4-mg tablets, though the out-of-pocket costs will vary.³⁰

Comment

We reviewed the global and treatment-specific costs of AA, consolidating the available data for the practicing dermatologist. Ten studies of approximately 16,000 patients with AA across a range of levels of evidence (1a to 4) were included (Table). Three of 10 articles studied global costs of AA, 1 studied costs of concealment, 3 studied costs of minoxidil, 2 studied costs of DPC, and 2 studied costs of JAK inhibitors. Only 2 studies achieved level of evidence 1a: the first assessed the economic impact of home-use vs office-use DPC,²² and the second researched the efficacy and outcomes of JAK inhibitors.²⁹

CT113004185_Table_part1.jpg

CT113004185_Table_part2.jpg

Hair-loss treatments and concealment techniques cost the average patient thousands of dollars. Spending was highest on headwear or cosmetic items, which were rarely covered by insurance.¹³ Psychosocial sequelae further increased cost via therapy charges and lost time at work.¹⁴ Patients with AA had greater all-cause medical costs than those without AA, with most of the cost driven by outpatient visits. Patients with AA also paid nearly twice as much as non-AA patients on out-of-pocket health care expenses.¹⁴ Despite the high costs and limited efficacy of many AA therapies, patients reported willingness to incur debt or use savings to manage their AA. This willingness to pay reflects AA’s impact on quality of life and puts these patients at high risk for financial distress.¹³

Minoxidil solution does not require physician office visits and is available over-the-counter.¹⁷ Despite identical ingredients, minoxidil is priced more per volume when marketed to women compared with men, which reflects the larger issue of gender-based pricing that does not exist for other AAD-approved alopecia therapies but may exist for cosmetic treatments and nonapproved therapies (eg, vitamins/supplements) that are popular in the treatment of AA.¹⁹ Oral minoxidil was more cost-effective than the topical form, and gender-based pricing was a nonissue.²⁰ However, oral minoxidil requires a prescription, mandating patients incur the cost of an office visit. Patients should be wary of gender- or marketing-related surcharges for minoxidil solutions, and oral minoxidil may be a cost-effective choice.

Diphencyprone is a relatively affordable drug for AA, but the regular office visits traditionally required for its administration increase associated cost.²¹ Self-administration of DPC at home was more cost- and time-effective than in-office DPC administration and did not decrease efficacy. A regimen combining office visits for initial DPC titration, at-home DPC administration, and periodic office follow-up could minimize costs while preserving outcomes and safety.²²

Janus kinase inhibitors are cutting-edge and expensive therapies for AA. The annual cost of these medications poses a tremendous burden on the payer (list price of annual supply ritlecitinib is $49,000),³¹ be that the patient or the insurance company. Low-dose tofacitinib may be similarly efficacious and could substantially reduce treatment costs.²³ The true utility of these medications, specifically considering their steep costs, remains to be determined.

Conclusion

Alopecia areata poses a substantial and recurring cost burden on patients that is multifactorial including treatment, office visits, concealment, alternative therapies, psychosocial costs, and missed time at work. Although several treatment options exist, none of them are definitive. Oral minoxidil and at-home DPC administration can be cost-effective, though the cumulative cost is still high. The cost utility of JAK inhibitors remains unclear. When JAK inhibitors are prescribed, low-dose therapy may be used as maintenance to curb treatment costs. Concealment and therapy costs pose an additional, largely out-of-pocket financial burden. Despite the limited efficacy of many AA therapies, patients incur substantial expenses to manage their AA. This willingness to pay reflects AA’s impact on quality of life and puts these patients at high risk for financial distress. There are no head-to-head studies comparing the cost-effectiveness of the different AA therapies; thus, it is unclear if one treatment is most efficacious. This topic remains an avenue for future investigation. Much of the cost burden of AA treatment falls directly on patients. Increasing coverage of AA-associated expenses, such as minoxidil therapy or wigs, could decrease the cost burden on patients. Providers also can inform patients about cost-saving tactics, such as purchasing minoxidil based on concentration and vehicle rather than marketing directed at men vs women. Finally, some patients may have insurance plans that at least partially cover the costs of wigs but may not be aware of this benefit. Querying a patient’s insurance provider can further minimize costs.

Alopecia areata (AA) affects 4.5 million individuals in the United States, with 66% younger than 30 years.^1,2 Inflammation causes hair loss in well-circumscribed, nonscarring patches on the body with a predilection for the scalp.^3-6 The disease can devastate a patient’s self-esteem, in turn reducing quality of life.^1,7 Alopecia areata is an autoimmune T-cell–mediated disease in which hair follicles lose their immune privilege.^8-10 Several specific mechanisms in the cytokine interactions between T cells and the hair follicle have been discovered, revealing the Janus kinase–signal transducer and activator of transcription (JAK-STAT) pathway as pivotal in the pathogenesis of the disease and leading to the use of JAK inhibitors for treatment.¹¹

There is no cure for AA, and the condition is managed with prolonged medical treatments and cosmetic therapies.² Although some patients may be able to manage the annual cost, the cumulative cost of AA treatment can be burdensome.¹² This cumulative cost may increase if newer, potentially expensive treatments become the standard of care. Patients with AA report dipping into their savings (41.3%) and cutting back on food or clothing expenses (33.9%) to account for the cost of alopecia treatment. Although prior estimates of the annual out-of-pocket cost of AA treatments range from $1354 to $2685, the cost burden of individual therapies is poorly understood.^12-14

Patients who must juggle expensive medical bills with basic living expenses may be lost to follow-up or fall into treatment nonadherence.¹⁵ Other patients’ out-of-pocket costs may be manageable, but the costs to the health care system may compromise care in other ways. We conducted a literature review of the recommended therapies for AA based on American Academy of Dermatology (AAD) guidelines to identify the costs of alopecia treatment and consolidate the available data for the practicing dermatologist.

Methods

We conducted a PubMed search of articles indexed for MEDLINE through September 15, 2022, using the terms alopecia and cost plus one of the treatments (n=21) identified by the AAD² for the treatment of AA (Figure). The reference lists of included articles were reviewed to identify other potentially relevant studies. Forty-five articles were identified.

Patel_Figure.jpg

Given the dearth of cost research in alopecia and the paucity of large prospective studies, we excluded articles that were not available in their full-text form or were not in English (n=3), articles whose primary study topic was not AA or an expert-approved alopecia treatment (n=15), and articles with no concrete cost data (n=17), which yielded 10 relevant articles that we studied using qualitative analysis.

Due to substantial differences in study methods and outcome measures, we did not compare the costs of alopecia among studies and did not perform statistical analysis. The quality of each study was investigated and assigned a level of evidence per the 2009 criteria from the Centre for Evidence-Based Medicine.¹⁶

All cost data were converted into US dollars ($) using the conversion rate from the time of the original article’s publication.

Results

Total and Out-of-pocket Costs of AA—Li et al¹³ studied out-of-pocket health care costs for AA patients (N=675). Of these participants, 56.9% said their AA was moderately to seriously financially burdensome, and 41.3% reported using their savings to manage these expenses. Participants reported median out-of-pocket spending of $1354 (interquartile range, $537–$3300) annually. The most common categories of expenses were hair appointments (81.8%) and vitamins/supplements (67.7%).¹³

Mesinkovska et al¹⁴ studied the qualitative and quantitative financial burdens of moderate to severe AA (N=216). Fifty-seven percent of patients reported the financial impact of AA as moderately to severely burdensome with a willingness to borrow money or use savings to cover out-of-pocket costs. Patients without insurance cited cost as a major barrier to obtaining reatment. In addition to direct treatment-related expenses, AA patients spent a mean of $1961 per year on therapy to cope with the disease’s psychological burden. Lost work hours represented another source of financial burden; 61% of patients were employed, and 45% of them reported missing time from their job because of AA.¹⁴

Mostaghimi et al¹² studied health care resource utilization and all-cause direct health care costs in privately insured AA patients with or without alopecia totalis (AT) or alopecia universalis (AU)(n=14,972) matched with non-AA controls (n=44,916)(1:3 ratio). Mean total all-cause medical and pharmacy costs were higher in both AA groups compared with controls (AT/AU, $18,988 vs $11,030; non-AT/AU, $13,686 vs $9336; P<.001 for both). Out-of-pocket costs were higher for AA vs controls (AT/AU, $2685 vs $1457; non-AT/AU, $2223 vs $1341; P<.001 for both). Medical costs in the AT/AU and non-AT/AU groups largely were driven by outpatient costs (AT/AU, $10,277 vs $5713; non-AT/AU, $8078 vs $4672; P<.001 for both).¹²

Costs of Concealment—When studying the out-of-pocket costs of AA (N=675), Li et al¹³ discovered that the median yearly spending was highest on headwear or cosmetic items such as hats, wigs, and makeup ($450; interquartile range, $50–$1500). Mesinkovska et al¹⁴ reported that 49% of patients had insurance that covered AA treatment. However, 75% of patients reported that their insurance would not cover costs of concealment (eg, weave, wig, hair piece). Patients (N=112) spent a mean of $2211 per year and 10.3 hours per week on concealment.¹⁴

Minoxidil—Minoxidil solution is available over-the-counter, and its ease of access makes it a popular treatment for AA.¹⁷ Because manufacturers can sell directly to the public, minoxidil is marketed with bold claims and convincing packaging. Shrank¹⁸ noted that the product can take 4 months to work, meaning customers must incur a substantial cost burden before realizing the treatment’s benefit, which is not always obvious when purchasing minoxidil products, leaving customers—who were marketed a miracle drug—disappointed. Per Shrank,¹⁸ patients who did not experience hair regrowth after 4 months were advised to continue treatment for a year, leading them to spend hundreds of dollars for uncertain results. Those who did experience hair regrowth were advised to continue using the product twice daily 7 days per week indefinitely.¹⁸

Wehner et al¹⁹ studied the association between gender and drug cost for over-the-counter minoxidil. The price that women paid for 2% regular-strength minoxidil solutions was similar to the price that men paid for 5% extra-strength minoxidil solutions (women’s 2%, $7.63/30 mL; men’s 5%, $7.61/30 mL; P=.67). Minoxidil 5% foams with identical ingredients were priced significantly more per volume of the same product when sold as a product directed at women vs a product directed at men (men’s 5%, $8.05/30 mL; women’s 5%, $11.27/30 mL; P<.001).¹⁹

Beach²⁰ compared the cost of oral minoxidil to topical minoxidil. At $28.60 for a 3-month supply, oral minoxidil demonstrated cost savings compared to topical minoxidil ($48.30).²⁰

Diphencyprone—Bhat et al²¹ studied the cost-efficiency of diphencyprone (DPC) in patients with AA resistant to at least 2 conventional treatments (N=29). After initial sensitization with 2% DPC, patients received weekly or fortnightly treatments. Most of the annual cost burden of DPC treatment was due to staff time and overhead rather than the cost of the DPC itself: $258 for the DPC, $978 in staff time and overhead for the department, and $1233 directly charged to the patient.²¹

Lekhavat et al²² studied the economic impact of home-use vs office-use DPC in extensive AA (N=82). Both groups received weekly treatments in the hospital until DPC concentrations had been adjusted. Afterward, the home group was given training on self-applying DPC at home. The home group had monthly office visits for DPC concentration evaluation and refills, while the office group had weekly appointments for DPC treatment at the hospital. Calculated costs included those to the health care provider (ie, material, labor, capital costs) and the patient’s final out-of-pocket expense. The total cost to the health care provider was higher for the office group than the home group at 48 weeks (office, $683.52; home, $303.67; P<.001). Median out-of-pocket costs did not vary significantly between groups, which may have been due to small sample size affecting the range (office, $418.07; home, $189.69; P=.101). There was no significant difference between groups in the proportion of patients who responded favorably to the DPC.²²

JAK Inhibitors—Chen et al²³ studied the efficacy of low-dose (5 mg) tofacitinib to treat severe AA (N=6). Compared to prior studies,^24-27 this analysis reported the efficacy of low-dose tofacitinib was not inferior to higher doses (10–20 mg), and low-dose tofacitinib reduced treatment costs by more than 50%.²³

Per the GlobalData Healthcare database, the estimated annual cost of therapy for JAK inhibitors following US Food and Drug Administration approval was $50,000. At the time of their reporting, the next most expensive immunomodulatory drug for AA was cyclosporine, with an annual cost of therapy of $1400.²⁸ Dillon²⁹ reviewed the use of JAK inhibitors for the treatment of AA. The cost estimates by Dillon²⁹ prior to FDA approval aligned with the pricing of Eli Lilly and Company for the now-approved JAK inhibitor baricitinib.³⁰ The list price of baricitinib is $2739.99 for a 30-day supply of 2-mg tablets or $5479.98 for a 30-day supply of 4-mg tablets. This amounts to $32,879.88 for an annual supply of 2-mg tablets and $65,759.76 for an annual supply for 4-mg tablets, though the out-of-pocket costs will vary.³⁰

Comment

We reviewed the global and treatment-specific costs of AA, consolidating the available data for the practicing dermatologist. Ten studies of approximately 16,000 patients with AA across a range of levels of evidence (1a to 4) were included (Table). Three of 10 articles studied global costs of AA, 1 studied costs of concealment, 3 studied costs of minoxidil, 2 studied costs of DPC, and 2 studied costs of JAK inhibitors. Only 2 studies achieved level of evidence 1a: the first assessed the economic impact of home-use vs office-use DPC,²² and the second researched the efficacy and outcomes of JAK inhibitors.²⁹

CT113004185_Table_part1.jpg

CT113004185_Table_part2.jpg

Hair-loss treatments and concealment techniques cost the average patient thousands of dollars. Spending was highest on headwear or cosmetic items, which were rarely covered by insurance.¹³ Psychosocial sequelae further increased cost via therapy charges and lost time at work.¹⁴ Patients with AA had greater all-cause medical costs than those without AA, with most of the cost driven by outpatient visits. Patients with AA also paid nearly twice as much as non-AA patients on out-of-pocket health care expenses.¹⁴ Despite the high costs and limited efficacy of many AA therapies, patients reported willingness to incur debt or use savings to manage their AA. This willingness to pay reflects AA’s impact on quality of life and puts these patients at high risk for financial distress.¹³

Minoxidil solution does not require physician office visits and is available over-the-counter.¹⁷ Despite identical ingredients, minoxidil is priced more per volume when marketed to women compared with men, which reflects the larger issue of gender-based pricing that does not exist for other AAD-approved alopecia therapies but may exist for cosmetic treatments and nonapproved therapies (eg, vitamins/supplements) that are popular in the treatment of AA.¹⁹ Oral minoxidil was more cost-effective than the topical form, and gender-based pricing was a nonissue.²⁰ However, oral minoxidil requires a prescription, mandating patients incur the cost of an office visit. Patients should be wary of gender- or marketing-related surcharges for minoxidil solutions, and oral minoxidil may be a cost-effective choice.

Diphencyprone is a relatively affordable drug for AA, but the regular office visits traditionally required for its administration increase associated cost.²¹ Self-administration of DPC at home was more cost- and time-effective than in-office DPC administration and did not decrease efficacy. A regimen combining office visits for initial DPC titration, at-home DPC administration, and periodic office follow-up could minimize costs while preserving outcomes and safety.²²

Janus kinase inhibitors are cutting-edge and expensive therapies for AA. The annual cost of these medications poses a tremendous burden on the payer (list price of annual supply ritlecitinib is $49,000),³¹ be that the patient or the insurance company. Low-dose tofacitinib may be similarly efficacious and could substantially reduce treatment costs.²³ The true utility of these medications, specifically considering their steep costs, remains to be determined.

Conclusion

Alopecia areata poses a substantial and recurring cost burden on patients that is multifactorial including treatment, office visits, concealment, alternative therapies, psychosocial costs, and missed time at work. Although several treatment options exist, none of them are definitive. Oral minoxidil and at-home DPC administration can be cost-effective, though the cumulative cost is still high. The cost utility of JAK inhibitors remains unclear. When JAK inhibitors are prescribed, low-dose therapy may be used as maintenance to curb treatment costs. Concealment and therapy costs pose an additional, largely out-of-pocket financial burden. Despite the limited efficacy of many AA therapies, patients incur substantial expenses to manage their AA. This willingness to pay reflects AA’s impact on quality of life and puts these patients at high risk for financial distress. There are no head-to-head studies comparing the cost-effectiveness of the different AA therapies; thus, it is unclear if one treatment is most efficacious. This topic remains an avenue for future investigation. Much of the cost burden of AA treatment falls directly on patients. Increasing coverage of AA-associated expenses, such as minoxidil therapy or wigs, could decrease the cost burden on patients. Providers also can inform patients about cost-saving tactics, such as purchasing minoxidil based on concentration and vehicle rather than marketing directed at men vs women. Finally, some patients may have insurance plans that at least partially cover the costs of wigs but may not be aware of this benefit. Querying a patient’s insurance provider can further minimize costs.

Alopecia areata (AA) affects 4.5 million individuals in the United States, with 66% younger than 30 years.^1,2 Inflammation causes hair loss in well-circumscribed, nonscarring patches on the body with a predilection for the scalp.^3-6 The disease can devastate a patient’s self-esteem, in turn reducing quality of life.^1,7 Alopecia areata is an autoimmune T-cell–mediated disease in which hair follicles lose their immune privilege.^8-10 Several specific mechanisms in the cytokine interactions between T cells and the hair follicle have been discovered, revealing the Janus kinase–signal transducer and activator of transcription (JAK-STAT) pathway as pivotal in the pathogenesis of the disease and leading to the use of JAK inhibitors for treatment.¹¹

There is no cure for AA, and the condition is managed with prolonged medical treatments and cosmetic therapies.² Although some patients may be able to manage the annual cost, the cumulative cost of AA treatment can be burdensome.¹² This cumulative cost may increase if newer, potentially expensive treatments become the standard of care. Patients with AA report dipping into their savings (41.3%) and cutting back on food or clothing expenses (33.9%) to account for the cost of alopecia treatment. Although prior estimates of the annual out-of-pocket cost of AA treatments range from $1354 to $2685, the cost burden of individual therapies is poorly understood.^12-14

Patients who must juggle expensive medical bills with basic living expenses may be lost to follow-up or fall into treatment nonadherence.¹⁵ Other patients’ out-of-pocket costs may be manageable, but the costs to the health care system may compromise care in other ways. We conducted a literature review of the recommended therapies for AA based on American Academy of Dermatology (AAD) guidelines to identify the costs of alopecia treatment and consolidate the available data for the practicing dermatologist.

Methods

We conducted a PubMed search of articles indexed for MEDLINE through September 15, 2022, using the terms alopecia and cost plus one of the treatments (n=21) identified by the AAD² for the treatment of AA (Figure). The reference lists of included articles were reviewed to identify other potentially relevant studies. Forty-five articles were identified.

Patel_Figure.jpg

Given the dearth of cost research in alopecia and the paucity of large prospective studies, we excluded articles that were not available in their full-text form or were not in English (n=3), articles whose primary study topic was not AA or an expert-approved alopecia treatment (n=15), and articles with no concrete cost data (n=17), which yielded 10 relevant articles that we studied using qualitative analysis.

Due to substantial differences in study methods and outcome measures, we did not compare the costs of alopecia among studies and did not perform statistical analysis. The quality of each study was investigated and assigned a level of evidence per the 2009 criteria from the Centre for Evidence-Based Medicine.¹⁶

All cost data were converted into US dollars ($) using the conversion rate from the time of the original article’s publication.

Results

Total and Out-of-pocket Costs of AA—Li et al¹³ studied out-of-pocket health care costs for AA patients (N=675). Of these participants, 56.9% said their AA was moderately to seriously financially burdensome, and 41.3% reported using their savings to manage these expenses. Participants reported median out-of-pocket spending of $1354 (interquartile range, $537–$3300) annually. The most common categories of expenses were hair appointments (81.8%) and vitamins/supplements (67.7%).¹³

Mesinkovska et al¹⁴ studied the qualitative and quantitative financial burdens of moderate to severe AA (N=216). Fifty-seven percent of patients reported the financial impact of AA as moderately to severely burdensome with a willingness to borrow money or use savings to cover out-of-pocket costs. Patients without insurance cited cost as a major barrier to obtaining reatment. In addition to direct treatment-related expenses, AA patients spent a mean of $1961 per year on therapy to cope with the disease’s psychological burden. Lost work hours represented another source of financial burden; 61% of patients were employed, and 45% of them reported missing time from their job because of AA.¹⁴

Mostaghimi et al¹² studied health care resource utilization and all-cause direct health care costs in privately insured AA patients with or without alopecia totalis (AT) or alopecia universalis (AU)(n=14,972) matched with non-AA controls (n=44,916)(1:3 ratio). Mean total all-cause medical and pharmacy costs were higher in both AA groups compared with controls (AT/AU, $18,988 vs $11,030; non-AT/AU, $13,686 vs $9336; P<.001 for both). Out-of-pocket costs were higher for AA vs controls (AT/AU, $2685 vs $1457; non-AT/AU, $2223 vs $1341; P<.001 for both). Medical costs in the AT/AU and non-AT/AU groups largely were driven by outpatient costs (AT/AU, $10,277 vs $5713; non-AT/AU, $8078 vs $4672; P<.001 for both).¹²

Costs of Concealment—When studying the out-of-pocket costs of AA (N=675), Li et al¹³ discovered that the median yearly spending was highest on headwear or cosmetic items such as hats, wigs, and makeup ($450; interquartile range, $50–$1500). Mesinkovska et al¹⁴ reported that 49% of patients had insurance that covered AA treatment. However, 75% of patients reported that their insurance would not cover costs of concealment (eg, weave, wig, hair piece). Patients (N=112) spent a mean of $2211 per year and 10.3 hours per week on concealment.¹⁴

Minoxidil—Minoxidil solution is available over-the-counter, and its ease of access makes it a popular treatment for AA.¹⁷ Because manufacturers can sell directly to the public, minoxidil is marketed with bold claims and convincing packaging. Shrank¹⁸ noted that the product can take 4 months to work, meaning customers must incur a substantial cost burden before realizing the treatment’s benefit, which is not always obvious when purchasing minoxidil products, leaving customers—who were marketed a miracle drug—disappointed. Per Shrank,¹⁸ patients who did not experience hair regrowth after 4 months were advised to continue treatment for a year, leading them to spend hundreds of dollars for uncertain results. Those who did experience hair regrowth were advised to continue using the product twice daily 7 days per week indefinitely.¹⁸

Wehner et al¹⁹ studied the association between gender and drug cost for over-the-counter minoxidil. The price that women paid for 2% regular-strength minoxidil solutions was similar to the price that men paid for 5% extra-strength minoxidil solutions (women’s 2%, $7.63/30 mL; men’s 5%, $7.61/30 mL; P=.67). Minoxidil 5% foams with identical ingredients were priced significantly more per volume of the same product when sold as a product directed at women vs a product directed at men (men’s 5%, $8.05/30 mL; women’s 5%, $11.27/30 mL; P<.001).¹⁹

Beach²⁰ compared the cost of oral minoxidil to topical minoxidil. At $28.60 for a 3-month supply, oral minoxidil demonstrated cost savings compared to topical minoxidil ($48.30).²⁰

Diphencyprone—Bhat et al²¹ studied the cost-efficiency of diphencyprone (DPC) in patients with AA resistant to at least 2 conventional treatments (N=29). After initial sensitization with 2% DPC, patients received weekly or fortnightly treatments. Most of the annual cost burden of DPC treatment was due to staff time and overhead rather than the cost of the DPC itself: $258 for the DPC, $978 in staff time and overhead for the department, and $1233 directly charged to the patient.²¹

Lekhavat et al²² studied the economic impact of home-use vs office-use DPC in extensive AA (N=82). Both groups received weekly treatments in the hospital until DPC concentrations had been adjusted. Afterward, the home group was given training on self-applying DPC at home. The home group had monthly office visits for DPC concentration evaluation and refills, while the office group had weekly appointments for DPC treatment at the hospital. Calculated costs included those to the health care provider (ie, material, labor, capital costs) and the patient’s final out-of-pocket expense. The total cost to the health care provider was higher for the office group than the home group at 48 weeks (office, $683.52; home, $303.67; P<.001). Median out-of-pocket costs did not vary significantly between groups, which may have been due to small sample size affecting the range (office, $418.07; home, $189.69; P=.101). There was no significant difference between groups in the proportion of patients who responded favorably to the DPC.²²

JAK Inhibitors—Chen et al²³ studied the efficacy of low-dose (5 mg) tofacitinib to treat severe AA (N=6). Compared to prior studies,^24-27 this analysis reported the efficacy of low-dose tofacitinib was not inferior to higher doses (10–20 mg), and low-dose tofacitinib reduced treatment costs by more than 50%.²³

Per the GlobalData Healthcare database, the estimated annual cost of therapy for JAK inhibitors following US Food and Drug Administration approval was $50,000. At the time of their reporting, the next most expensive immunomodulatory drug for AA was cyclosporine, with an annual cost of therapy of $1400.²⁸ Dillon²⁹ reviewed the use of JAK inhibitors for the treatment of AA. The cost estimates by Dillon²⁹ prior to FDA approval aligned with the pricing of Eli Lilly and Company for the now-approved JAK inhibitor baricitinib.³⁰ The list price of baricitinib is $2739.99 for a 30-day supply of 2-mg tablets or $5479.98 for a 30-day supply of 4-mg tablets. This amounts to $32,879.88 for an annual supply of 2-mg tablets and $65,759.76 for an annual supply for 4-mg tablets, though the out-of-pocket costs will vary.³⁰

Comment

We reviewed the global and treatment-specific costs of AA, consolidating the available data for the practicing dermatologist. Ten studies of approximately 16,000 patients with AA across a range of levels of evidence (1a to 4) were included (Table). Three of 10 articles studied global costs of AA, 1 studied costs of concealment, 3 studied costs of minoxidil, 2 studied costs of DPC, and 2 studied costs of JAK inhibitors. Only 2 studies achieved level of evidence 1a: the first assessed the economic impact of home-use vs office-use DPC,²² and the second researched the efficacy and outcomes of JAK inhibitors.²⁹

CT113004185_Table_part1.jpg

CT113004185_Table_part2.jpg

Hair-loss treatments and concealment techniques cost the average patient thousands of dollars. Spending was highest on headwear or cosmetic items, which were rarely covered by insurance.¹³ Psychosocial sequelae further increased cost via therapy charges and lost time at work.¹⁴ Patients with AA had greater all-cause medical costs than those without AA, with most of the cost driven by outpatient visits. Patients with AA also paid nearly twice as much as non-AA patients on out-of-pocket health care expenses.¹⁴ Despite the high costs and limited efficacy of many AA therapies, patients reported willingness to incur debt or use savings to manage their AA. This willingness to pay reflects AA’s impact on quality of life and puts these patients at high risk for financial distress.¹³

Minoxidil solution does not require physician office visits and is available over-the-counter.¹⁷ Despite identical ingredients, minoxidil is priced more per volume when marketed to women compared with men, which reflects the larger issue of gender-based pricing that does not exist for other AAD-approved alopecia therapies but may exist for cosmetic treatments and nonapproved therapies (eg, vitamins/supplements) that are popular in the treatment of AA.¹⁹ Oral minoxidil was more cost-effective than the topical form, and gender-based pricing was a nonissue.²⁰ However, oral minoxidil requires a prescription, mandating patients incur the cost of an office visit. Patients should be wary of gender- or marketing-related surcharges for minoxidil solutions, and oral minoxidil may be a cost-effective choice.

Diphencyprone is a relatively affordable drug for AA, but the regular office visits traditionally required for its administration increase associated cost.²¹ Self-administration of DPC at home was more cost- and time-effective than in-office DPC administration and did not decrease efficacy. A regimen combining office visits for initial DPC titration, at-home DPC administration, and periodic office follow-up could minimize costs while preserving outcomes and safety.²²

Janus kinase inhibitors are cutting-edge and expensive therapies for AA. The annual cost of these medications poses a tremendous burden on the payer (list price of annual supply ritlecitinib is $49,000),³¹ be that the patient or the insurance company. Low-dose tofacitinib may be similarly efficacious and could substantially reduce treatment costs.²³ The true utility of these medications, specifically considering their steep costs, remains to be determined.

Conclusion

Alopecia areata poses a substantial and recurring cost burden on patients that is multifactorial including treatment, office visits, concealment, alternative therapies, psychosocial costs, and missed time at work. Although several treatment options exist, none of them are definitive. Oral minoxidil and at-home DPC administration can be cost-effective, though the cumulative cost is still high. The cost utility of JAK inhibitors remains unclear. When JAK inhibitors are prescribed, low-dose therapy may be used as maintenance to curb treatment costs. Concealment and therapy costs pose an additional, largely out-of-pocket financial burden. Despite the limited efficacy of many AA therapies, patients incur substantial expenses to manage their AA. This willingness to pay reflects AA’s impact on quality of life and puts these patients at high risk for financial distress. There are no head-to-head studies comparing the cost-effectiveness of the different AA therapies; thus, it is unclear if one treatment is most efficacious. This topic remains an avenue for future investigation. Much of the cost burden of AA treatment falls directly on patients. Increasing coverage of AA-associated expenses, such as minoxidil therapy or wigs, could decrease the cost burden on patients. Providers also can inform patients about cost-saving tactics, such as purchasing minoxidil based on concentration and vehicle rather than marketing directed at men vs women. Finally, some patients may have insurance plans that at least partially cover the costs of wigs but may not be aware of this benefit. Querying a patient’s insurance provider can further minimize costs.

Hidradenitis suppurativa (HS)—a chronic, relapsing, inflammatory disorder involving terminal hair follicles in apocrine gland–rich skin—manifests as tender inflamed nodules that transform into abscesses, sinus tracts, and scarring.^1,2 The etiology of HS is multifactorial, encompassing lifestyle, microbiota, hormonal status, and genetic and environmental factors. These factors activate the immune system around the terminal hair follicles and lead to hyperkeratosis of the infundibulum of the hair follicles in intertriginous regions. This progresses to follicular occlusion, stasis, and eventual rupture. Bacterial multiplication within the plugged pilosebaceous units further boosts immune activation. Resident and migrated cells of the innate and adaptive immune system then release proinflammatory cytokines such as tumor necrosis factor, IL-1β, and IL-17, which further enhance immune cell influx and inflammation.^3,4 This aberrant immune response propagates the production of deep-seated inflammatory nodules and abscesses.^3-8

The estimated prevalence of HS is 1% worldwide.⁹ It is more prevalent in female and Black patients (0.30%) than White patients (0.09%) and is intermediate in prevalence in the biracial population (0.22%).¹⁰ Hidradenitis suppurativa is thought to be associated with lower socioeconomic status (SES). In a retrospective analysis of HS patients (N=375), approximately one-third of patients were Black, had advanced disease, and had a notably lower SES.¹¹ Furthermore, HS has been reported to be associated with systemic inflammation and comorbidities such as morbid obesity (38.3%) and hypertension (39.6%) as well as other metabolic syndrome–related disorders and depression (48.1%).¹

Hidradenitis suppurativa may contribute to the risk for depression through its substantial impact on health-related quality of life, which culminates in social withdrawal, unemployment, and suicidal thoughts.¹² The high prevalence of depression in individuals with HS¹ and its association with systemic inflammation¹³ increases the likelihood that a common genetic predisposition also may exist between both conditions. Because depression frequently has been discovered as a concomitant diagnosis in patients with HS, we hypothesize that a shared genetic susceptibility also may exist between the 2 disorders. Our study sought to explore data on the co-occurrence of depression with HS, including its demographics and racial data.

Methods

We conducted a PubMed search of articles indexed for MEDLINE as well as Google Scholar using the terms depression and hidradenitis suppurativa to obtain all research articles published from 2000 to 2022. Articles were selected based on relevance to the topic of exploration. English-language articles that directly addressed the epidemiology, etiology, pathophysiology, and co-occurrence of both depression and HS with numerical data were included. Articles were excluded if they did not explore the information of interest on these 2 disorders or did not contain clear statistical data of patients with the 2 concurrent medical conditions.

Results

Twenty-two cross-sectional, prospective, and retrospective studies that fit the search criteria were identified and included in the analysis (eTable).^1,14-34 Sixteen (72.7%) studies were cross-sectional, 5 (22.7%) were retrospective, and only 1 (4.5%) was a prospective study. Only 6 of the studies provided racial data,^{1,14,17,26,28,32} and of them, 4 had predominately White patients,^1,14,26,32 whereas the other 2 had predominantly Black patients.^17,28

CT113003137_eTable_part1.jpg

CT113003137_eTable_part2.jpg

Hidradenitis suppurativa was found to coexist with depression in all the studies, with a prevalence of 1.2% to 48.1%. There also was a higher prevalence of depression in HS patients than in the control patients without HS. Furthermore, a recent study by Wright and colleagues¹⁴ stratified the depression prevalence data by age and found a higher prevalence of depression in adults vs children with HS (30% vs 12%).

Comment

Major depression—a chronic and debilitating illness—is the chief cause of disability globally and in the United States alone and has a global lifetime prevalence of 17%.³⁵ In a study of 388 patients diagnosed with depression and 404 community-matched controls who were observed for 10 years, depressed patients had a two-thirds higher likelihood of developing a serious physical illness than controls. The depression-associated elevated risk for serious physical illness persisted after controlling for confounding variables such as alcohol abuse, smoking, and level of physical activity.³⁶ Studies also have demonstrated that HS is more prevalent in Black individuals¹⁰ and in individuals of low SES,³⁷ who are mostly the Black and Hispanic populations that experience the highest burden of racial microaggression³⁸ and disparities in health access and outcomes.^39,40 The severity and chronicity of major depressive disorder also is higher in Black patients compared with White patients (57% vs 39%).⁴¹ Because major depression and HS are most common among Black patients who experience the highest-burden negative financial and health disparities, there may be a shared genetic disposition to both medical conditions.

Moreover, the common detrimental lifestyle choices associated with patients with depression and HS also suggest the possibility of a collective genetic susceptibility. Patients with depression also report increased consumption of alcohol, tobacco, and illicit substances; sedentary lifestyle leading to obesity; and poor compliance with prescribed medical treatment.⁴² Smoking and obesity are known contributors to the pathogenesis of HS, and their modification also is known to positively impact the disease course. In a retrospective single-cohort study, 50% of obese HS patients (n=35) reported a substantial decrease in disease severity after a reduction of more than 15% in body mass index over 2 years following bariatric surgery (n=35).⁴³ Patients with HS also have reported disease remission following extensive weight loss.⁴⁴ In addition, evidence has supported smoking cessation in improving the disease course of HS.⁴³ Because these detrimental lifestyle choices are prevalent in both patients with HS and those with depression, a co-genetic susceptibility also may exist.

Furthermore, depression is characterized by a persistent inflammatory state,^13,45 similar to HS.⁴⁶ Elevated levels of a variety of inflammatory markers, such as C-reactive protein (CRP), IL-6, and soluble intercellular adhesion molecule 1, have been reported in patients with depression compared with healthy controls.^13,45 Further analysis found a positive correlation and a strong association between depression and these inflammatory markers.⁴⁷ Moreover, adipokines regulate inflammatory responses, and adipokines play a role in the pathogenesis of HS. Adipokine levels such as elevated omentin-1 (a recently identified adipokine) were found to be altered in patients with HS compared with controls.⁴⁸ Results from clinical studies and meta-analyses of patients with depression also have demonstrated that adipokines are dysregulated in this population,^49,50 which may be another potential genetic link between depression and HS.

In addition, genetic susceptibility to depression and HS may be shared because the inflammatory markers that have a strong association with depression also have been found to play an important role in HS treatment and disease severity prediction. In a retrospective cohort study of 404 patients, CRP or IL-6 levels were found to be reliable predictors of HS disease severity, which may explain why anti–tumor necrosis factor antibody regimens such as adalimumab and infliximab have clinically ameliorated disease activity in several cases of HS.⁵¹ In a study evaluating these drugs, high baseline levels of high-sensitivity CRP and IL-6 were predictive of patient response to infliximab.⁵² In a meta-analysis evaluating 20,791 participants, an association was found between concurrent depression and CRP. Furthermore, inflammation measured by high levels of CRP or IL-6 was observed to predict future depression.⁵³ If the same inflammatory markers—CRP and IL-6—both play a major role in the disease activity of depression and HS, then a concurrent genetic predisposition may exist.

Conclusion

Understanding the comorbidities, etiologies, and risk factors for the development and progression of HS is an important step toward improved disease management. Available studies on comorbid depression in HS largely involve White patients, and more studies are needed in patients with skin of color, particularly the Black population, who have the highest prevalence of HS.¹⁰ Given the evidence for an association between depression and HS, we suggest a large-scale investigation of this patient population that includes a complete medical history, onset of HS in comparison to the onset of depression, and specific measures of disease progress and lifetime management of depression, which may help to increase knowledge about the role of depression in HS and encourage more research in this area. If shared genetic susceptibility is established, aggressive management of depression in patients at risk for HS may reduce disease incidence and severity as well as the psychological burden on patients.

Hidradenitis suppurativa (HS)—a chronic, relapsing, inflammatory disorder involving terminal hair follicles in apocrine gland–rich skin—manifests as tender inflamed nodules that transform into abscesses, sinus tracts, and scarring.^1,2 The etiology of HS is multifactorial, encompassing lifestyle, microbiota, hormonal status, and genetic and environmental factors. These factors activate the immune system around the terminal hair follicles and lead to hyperkeratosis of the infundibulum of the hair follicles in intertriginous regions. This progresses to follicular occlusion, stasis, and eventual rupture. Bacterial multiplication within the plugged pilosebaceous units further boosts immune activation. Resident and migrated cells of the innate and adaptive immune system then release proinflammatory cytokines such as tumor necrosis factor, IL-1β, and IL-17, which further enhance immune cell influx and inflammation.^3,4 This aberrant immune response propagates the production of deep-seated inflammatory nodules and abscesses.^3-8

The estimated prevalence of HS is 1% worldwide.⁹ It is more prevalent in female and Black patients (0.30%) than White patients (0.09%) and is intermediate in prevalence in the biracial population (0.22%).¹⁰ Hidradenitis suppurativa is thought to be associated with lower socioeconomic status (SES). In a retrospective analysis of HS patients (N=375), approximately one-third of patients were Black, had advanced disease, and had a notably lower SES.¹¹ Furthermore, HS has been reported to be associated with systemic inflammation and comorbidities such as morbid obesity (38.3%) and hypertension (39.6%) as well as other metabolic syndrome–related disorders and depression (48.1%).¹

Hidradenitis suppurativa may contribute to the risk for depression through its substantial impact on health-related quality of life, which culminates in social withdrawal, unemployment, and suicidal thoughts.¹² The high prevalence of depression in individuals with HS¹ and its association with systemic inflammation¹³ increases the likelihood that a common genetic predisposition also may exist between both conditions. Because depression frequently has been discovered as a concomitant diagnosis in patients with HS, we hypothesize that a shared genetic susceptibility also may exist between the 2 disorders. Our study sought to explore data on the co-occurrence of depression with HS, including its demographics and racial data.

Methods

We conducted a PubMed search of articles indexed for MEDLINE as well as Google Scholar using the terms depression and hidradenitis suppurativa to obtain all research articles published from 2000 to 2022. Articles were selected based on relevance to the topic of exploration. English-language articles that directly addressed the epidemiology, etiology, pathophysiology, and co-occurrence of both depression and HS with numerical data were included. Articles were excluded if they did not explore the information of interest on these 2 disorders or did not contain clear statistical data of patients with the 2 concurrent medical conditions.

Results

Twenty-two cross-sectional, prospective, and retrospective studies that fit the search criteria were identified and included in the analysis (eTable).^1,14-34 Sixteen (72.7%) studies were cross-sectional, 5 (22.7%) were retrospective, and only 1 (4.5%) was a prospective study. Only 6 of the studies provided racial data,^{1,14,17,26,28,32} and of them, 4 had predominately White patients,^1,14,26,32 whereas the other 2 had predominantly Black patients.^17,28

CT113003137_eTable_part1.jpg

CT113003137_eTable_part2.jpg

Hidradenitis suppurativa was found to coexist with depression in all the studies, with a prevalence of 1.2% to 48.1%. There also was a higher prevalence of depression in HS patients than in the control patients without HS. Furthermore, a recent study by Wright and colleagues¹⁴ stratified the depression prevalence data by age and found a higher prevalence of depression in adults vs children with HS (30% vs 12%).

Comment

Major depression—a chronic and debilitating illness—is the chief cause of disability globally and in the United States alone and has a global lifetime prevalence of 17%.³⁵ In a study of 388 patients diagnosed with depression and 404 community-matched controls who were observed for 10 years, depressed patients had a two-thirds higher likelihood of developing a serious physical illness than controls. The depression-associated elevated risk for serious physical illness persisted after controlling for confounding variables such as alcohol abuse, smoking, and level of physical activity.³⁶ Studies also have demonstrated that HS is more prevalent in Black individuals¹⁰ and in individuals of low SES,³⁷ who are mostly the Black and Hispanic populations that experience the highest burden of racial microaggression³⁸ and disparities in health access and outcomes.^39,40 The severity and chronicity of major depressive disorder also is higher in Black patients compared with White patients (57% vs 39%).⁴¹ Because major depression and HS are most common among Black patients who experience the highest-burden negative financial and health disparities, there may be a shared genetic disposition to both medical conditions.

Moreover, the common detrimental lifestyle choices associated with patients with depression and HS also suggest the possibility of a collective genetic susceptibility. Patients with depression also report increased consumption of alcohol, tobacco, and illicit substances; sedentary lifestyle leading to obesity; and poor compliance with prescribed medical treatment.⁴² Smoking and obesity are known contributors to the pathogenesis of HS, and their modification also is known to positively impact the disease course. In a retrospective single-cohort study, 50% of obese HS patients (n=35) reported a substantial decrease in disease severity after a reduction of more than 15% in body mass index over 2 years following bariatric surgery (n=35).⁴³ Patients with HS also have reported disease remission following extensive weight loss.⁴⁴ In addition, evidence has supported smoking cessation in improving the disease course of HS.⁴³ Because these detrimental lifestyle choices are prevalent in both patients with HS and those with depression, a co-genetic susceptibility also may exist.

Furthermore, depression is characterized by a persistent inflammatory state,^13,45 similar to HS.⁴⁶ Elevated levels of a variety of inflammatory markers, such as C-reactive protein (CRP), IL-6, and soluble intercellular adhesion molecule 1, have been reported in patients with depression compared with healthy controls.^13,45 Further analysis found a positive correlation and a strong association between depression and these inflammatory markers.⁴⁷ Moreover, adipokines regulate inflammatory responses, and adipokines play a role in the pathogenesis of HS. Adipokine levels such as elevated omentin-1 (a recently identified adipokine) were found to be altered in patients with HS compared with controls.⁴⁸ Results from clinical studies and meta-analyses of patients with depression also have demonstrated that adipokines are dysregulated in this population,^49,50 which may be another potential genetic link between depression and HS.

In addition, genetic susceptibility to depression and HS may be shared because the inflammatory markers that have a strong association with depression also have been found to play an important role in HS treatment and disease severity prediction. In a retrospective cohort study of 404 patients, CRP or IL-6 levels were found to be reliable predictors of HS disease severity, which may explain why anti–tumor necrosis factor antibody regimens such as adalimumab and infliximab have clinically ameliorated disease activity in several cases of HS.⁵¹ In a study evaluating these drugs, high baseline levels of high-sensitivity CRP and IL-6 were predictive of patient response to infliximab.⁵² In a meta-analysis evaluating 20,791 participants, an association was found between concurrent depression and CRP. Furthermore, inflammation measured by high levels of CRP or IL-6 was observed to predict future depression.⁵³ If the same inflammatory markers—CRP and IL-6—both play a major role in the disease activity of depression and HS, then a concurrent genetic predisposition may exist.

Conclusion

Understanding the comorbidities, etiologies, and risk factors for the development and progression of HS is an important step toward improved disease management. Available studies on comorbid depression in HS largely involve White patients, and more studies are needed in patients with skin of color, particularly the Black population, who have the highest prevalence of HS.¹⁰ Given the evidence for an association between depression and HS, we suggest a large-scale investigation of this patient population that includes a complete medical history, onset of HS in comparison to the onset of depression, and specific measures of disease progress and lifetime management of depression, which may help to increase knowledge about the role of depression in HS and encourage more research in this area. If shared genetic susceptibility is established, aggressive management of depression in patients at risk for HS may reduce disease incidence and severity as well as the psychological burden on patients.

Hidradenitis suppurativa (HS)—a chronic, relapsing, inflammatory disorder involving terminal hair follicles in apocrine gland–rich skin—manifests as tender inflamed nodules that transform into abscesses, sinus tracts, and scarring.^1,2 The etiology of HS is multifactorial, encompassing lifestyle, microbiota, hormonal status, and genetic and environmental factors. These factors activate the immune system around the terminal hair follicles and lead to hyperkeratosis of the infundibulum of the hair follicles in intertriginous regions. This progresses to follicular occlusion, stasis, and eventual rupture. Bacterial multiplication within the plugged pilosebaceous units further boosts immune activation. Resident and migrated cells of the innate and adaptive immune system then release proinflammatory cytokines such as tumor necrosis factor, IL-1β, and IL-17, which further enhance immune cell influx and inflammation.^3,4 This aberrant immune response propagates the production of deep-seated inflammatory nodules and abscesses.^3-8

The estimated prevalence of HS is 1% worldwide.⁹ It is more prevalent in female and Black patients (0.30%) than White patients (0.09%) and is intermediate in prevalence in the biracial population (0.22%).¹⁰ Hidradenitis suppurativa is thought to be associated with lower socioeconomic status (SES). In a retrospective analysis of HS patients (N=375), approximately one-third of patients were Black, had advanced disease, and had a notably lower SES.¹¹ Furthermore, HS has been reported to be associated with systemic inflammation and comorbidities such as morbid obesity (38.3%) and hypertension (39.6%) as well as other metabolic syndrome–related disorders and depression (48.1%).¹

Hidradenitis suppurativa may contribute to the risk for depression through its substantial impact on health-related quality of life, which culminates in social withdrawal, unemployment, and suicidal thoughts.¹² The high prevalence of depression in individuals with HS¹ and its association with systemic inflammation¹³ increases the likelihood that a common genetic predisposition also may exist between both conditions. Because depression frequently has been discovered as a concomitant diagnosis in patients with HS, we hypothesize that a shared genetic susceptibility also may exist between the 2 disorders. Our study sought to explore data on the co-occurrence of depression with HS, including its demographics and racial data.

Methods

We conducted a PubMed search of articles indexed for MEDLINE as well as Google Scholar using the terms depression and hidradenitis suppurativa to obtain all research articles published from 2000 to 2022. Articles were selected based on relevance to the topic of exploration. English-language articles that directly addressed the epidemiology, etiology, pathophysiology, and co-occurrence of both depression and HS with numerical data were included. Articles were excluded if they did not explore the information of interest on these 2 disorders or did not contain clear statistical data of patients with the 2 concurrent medical conditions.

Results

Twenty-two cross-sectional, prospective, and retrospective studies that fit the search criteria were identified and included in the analysis (eTable).^1,14-34 Sixteen (72.7%) studies were cross-sectional, 5 (22.7%) were retrospective, and only 1 (4.5%) was a prospective study. Only 6 of the studies provided racial data,^{1,14,17,26,28,32} and of them, 4 had predominately White patients,^1,14,26,32 whereas the other 2 had predominantly Black patients.^17,28

CT113003137_eTable_part1.jpg

CT113003137_eTable_part2.jpg

Hidradenitis suppurativa was found to coexist with depression in all the studies, with a prevalence of 1.2% to 48.1%. There also was a higher prevalence of depression in HS patients than in the control patients without HS. Furthermore, a recent study by Wright and colleagues¹⁴ stratified the depression prevalence data by age and found a higher prevalence of depression in adults vs children with HS (30% vs 12%).

Comment

Major depression—a chronic and debilitating illness—is the chief cause of disability globally and in the United States alone and has a global lifetime prevalence of 17%.³⁵ In a study of 388 patients diagnosed with depression and 404 community-matched controls who were observed for 10 years, depressed patients had a two-thirds higher likelihood of developing a serious physical illness than controls. The depression-associated elevated risk for serious physical illness persisted after controlling for confounding variables such as alcohol abuse, smoking, and level of physical activity.³⁶ Studies also have demonstrated that HS is more prevalent in Black individuals¹⁰ and in individuals of low SES,³⁷ who are mostly the Black and Hispanic populations that experience the highest burden of racial microaggression³⁸ and disparities in health access and outcomes.^39,40 The severity and chronicity of major depressive disorder also is higher in Black patients compared with White patients (57% vs 39%).⁴¹ Because major depression and HS are most common among Black patients who experience the highest-burden negative financial and health disparities, there may be a shared genetic disposition to both medical conditions.

Moreover, the common detrimental lifestyle choices associated with patients with depression and HS also suggest the possibility of a collective genetic susceptibility. Patients with depression also report increased consumption of alcohol, tobacco, and illicit substances; sedentary lifestyle leading to obesity; and poor compliance with prescribed medical treatment.⁴² Smoking and obesity are known contributors to the pathogenesis of HS, and their modification also is known to positively impact the disease course. In a retrospective single-cohort study, 50% of obese HS patients (n=35) reported a substantial decrease in disease severity after a reduction of more than 15% in body mass index over 2 years following bariatric surgery (n=35).⁴³ Patients with HS also have reported disease remission following extensive weight loss.⁴⁴ In addition, evidence has supported smoking cessation in improving the disease course of HS.⁴³ Because these detrimental lifestyle choices are prevalent in both patients with HS and those with depression, a co-genetic susceptibility also may exist.

Furthermore, depression is characterized by a persistent inflammatory state,^13,45 similar to HS.⁴⁶ Elevated levels of a variety of inflammatory markers, such as C-reactive protein (CRP), IL-6, and soluble intercellular adhesion molecule 1, have been reported in patients with depression compared with healthy controls.^13,45 Further analysis found a positive correlation and a strong association between depression and these inflammatory markers.⁴⁷ Moreover, adipokines regulate inflammatory responses, and adipokines play a role in the pathogenesis of HS. Adipokine levels such as elevated omentin-1 (a recently identified adipokine) were found to be altered in patients with HS compared with controls.⁴⁸ Results from clinical studies and meta-analyses of patients with depression also have demonstrated that adipokines are dysregulated in this population,^49,50 which may be another potential genetic link between depression and HS.

In addition, genetic susceptibility to depression and HS may be shared because the inflammatory markers that have a strong association with depression also have been found to play an important role in HS treatment and disease severity prediction. In a retrospective cohort study of 404 patients, CRP or IL-6 levels were found to be reliable predictors of HS disease severity, which may explain why anti–tumor necrosis factor antibody regimens such as adalimumab and infliximab have clinically ameliorated disease activity in several cases of HS.⁵¹ In a study evaluating these drugs, high baseline levels of high-sensitivity CRP and IL-6 were predictive of patient response to infliximab.⁵² In a meta-analysis evaluating 20,791 participants, an association was found between concurrent depression and CRP. Furthermore, inflammation measured by high levels of CRP or IL-6 was observed to predict future depression.⁵³ If the same inflammatory markers—CRP and IL-6—both play a major role in the disease activity of depression and HS, then a concurrent genetic predisposition may exist.

Conclusion

Understanding the comorbidities, etiologies, and risk factors for the development and progression of HS is an important step toward improved disease management. Available studies on comorbid depression in HS largely involve White patients, and more studies are needed in patients with skin of color, particularly the Black population, who have the highest prevalence of HS.¹⁰ Given the evidence for an association between depression and HS, we suggest a large-scale investigation of this patient population that includes a complete medical history, onset of HS in comparison to the onset of depression, and specific measures of disease progress and lifetime management of depression, which may help to increase knowledge about the role of depression in HS and encourage more research in this area. If shared genetic susceptibility is established, aggressive management of depression in patients at risk for HS may reduce disease incidence and severity as well as the psychological burden on patients.

Inflammatory skin conditions often have a relapsing and remitting course and represent a large proportion of chronic skin diseases. Common inflammatory skin disorders include acne, psoriasis, hidradenitis suppurativa (HS), atopic dermatitis (AD), and seborrheic dermatitis (SD).¹ Although each of these conditions has a unique pathogenesis, they all are driven by a background of chronic inflammation. It has been reported that diets with high levels of refined carbohydrates and saturated or trans-fatty acids may exacerbate existing inflammation.² Consequently, dietary interventions, such as the ketogenic and low-glycemic diets, have potential anti-inflammatory and metabolic effects that are being assessed as stand-alone or adjunctive therapies for dermatologic diseases.

Diet may partially influence systemic inflammation through its effect on weight. Higher body mass index and obesity are linked to a low-grade inflammatory state and higher levels of circulating inflammatory markers. Therefore, weight loss leads to decreases in inflammatory cytokines, including C-reactive protein, tumor necrosis factor α, and IL-6.³ These cytokines and metabolic effects overlap with inflammatory skin condition pathways. It also is posited that decreased insulin release associated with weight loss results in decreased sebaceous lipogenesis and androgens, which drive keratinocyte proliferation and acne development.^4,5 For instance, in a 2015 meta-analysis of 5 randomized controlled trials on psoriasis, patients in the weight loss intervention group had more substantial reductions in psoriasis area and severity index (PASI) scores compared with controls receiving usual care (P=.004).⁶ However, in a systematic review of 35 studies on acne vulgaris, overweight and obese patients (defined by a body mass index of ≥23 kg/m²) had similar odds of having acne compared with normal-weight individuals (P=.671).⁷

Similar to weight loss, ketogenesis acts as a negative feedback mechanism to reduce insulin release, leading to decreased inflammation and androgens that often exacerbate inflammatory skin diseases.⁸ Ketogenesis ensues when daily carbohydrate intake is limited to less than 50 g, and long-term adherence to a ketogenic diet results in metabolic reliance on ketone bodies such as acetoacetate, β-hydroxybutyrate, and acetone.⁹ These metabolites may decrease free radical damage and consequently improve signs and symptoms of acne, psoriasis, and other inflammatory skin diseases.^10-12 Similarly, increased ketones also may decrease activation of the NLRP3 (NOD-, LRR-, and Pyrin domain-containing protein 3) inflammasome and therefore reduce inflammatory markers such as IL-1β and IL-1.^4,13 Several proposed mechanisms are outlined in the Table.

CT11302075_Table.jpg

Collectively, low-glycemic and ketogenic diets have been proposed as potential interventions for reducing inflammatory skin conditions. These dietary approaches are hypothesized to exert their effects by facilitating weight loss, elevating ketone levels, and reducing systemic inflammation. The current review summarizes the existing evidence on ketogenic and low-glycemic diets as treatments for inflammatory skin conditions and evaluates the potential benefits of these dietary interventions in managing and improving outcomes for individuals with inflammatory skin conditions.

Methods

Using PubMed for articles indexed for MEDLINE and Google Scholar, a review of the literature was conducted with a combination of the following search terms: low-glycemic diet, inflammatory, dermatologic, ketogenic diet, inflammation, dermatology, acne, psoriasis, eczema, seborrheic dermatitis, and hidradenitis suppurativa. Reference citations in identified works also were reviewed. Interventional (experimental studies or clinical trials), survey-based, and observational studies that investigated the effects of low-glycemic or ketogenic diets for the treatment of inflammatory skin conditions were included. Inclusion criteria were studies assessing acne, psoriasis, SD, AD, and HS. Exclusion criteria were studies published before 1965; those written in languages other than English; and those analyzing other diets, such as the Mediterranean or low-fat diets. The search yielded a total of 11 observational studies and 4 controlled studies published between 1966 and January 2023. Because this analysis utilized publicly available data and did not qualify as human subject research, institutional review board approval was not required.

Results

Acne Vulgaris—Acne vulgaris is a disease of chronic pilosebaceous inflammation and follicular epithelial proliferation associated with Propionibacterium acnes. The association between acne and low-glycemic diets has been examined in several studies. Diet quality is measured and assessed using the glycemic index (GI), which is the effect of a single food on postprandial blood glucose, and the glycemic load, which is the GI adjusted for carbohydrates per serving.¹⁴ High levels of GI and glycemic load are associated with hyperinsulinemia and an increase in insulinlike growth factor 1 concentration that promotes mechanistic target of rapamycin (mTOR) complex 1–mediated follicular lipogenesis, sebum fatty acid production, and androgen synthesis.¹⁵Propionibacterium acnes directly activates toll-like receptor 2 on monocytes through damage-associated molecular patterns and indirectly through products of triglyceride catalysis, causing release of IL-12, IL-6, tumor necrosis factor α, and other proinflammatory cytokines.¹⁶ Therefore, lifestyle modifications focused on strict glucose control have been postulated to reduce acne severity via modulation of lipogenesis, androgen concentration, and inflammation.

Six survey-based studies evaluated sugar intake in patients with acne compared to healthy matched controls (eTable). Among these studies, 5 reported higher glycemic loads or daily sugar intake in acne patients compared to individuals without acne.^{12,19,20,26,28} The remaining study was conducted in 1967 and enrolled 16 acne patients and 32 matched controls. It reported no significant difference in sugar intake between the groups (P>.05).¹⁷

CT11302075_eTable_part1.jpg

CT11302075_eTable_part2.jpg

Smith et al¹⁸ randomized 43 male patients aged 15 to 25 years with facial acne into 2 cohorts for 12 weeks, each consuming either a low-glycemic diet (25% protein, 45% low-glycemic food [fruits, whole grains], and 30% fat) or a carbohydrate-dense diet of foods with medium to high GI based on prior documentation of the original diet. Patients were instructed to use a noncomedogenic cleanser as their only acne treatment. At 12 weeks, patients consuming the low-glycemic diet had an average of 23.5 fewer inflammatory lesions, while those in the intervention group had 12.0 fewer lesions (P=.03).¹⁸

In another controlled study by Kwon et al,²¹ 32 male and female acne patients were randomized to a low-glycemic diet (25% protein, 45% low-glycemic food, and 30% fat) or a standard diet for 10 weeks. Patients on the low-glycemic diet experienced a 70.9% reduction in inflammatory lesions (P<.05). Hematoxylin and eosin staining and image analysis were performed to measure sebaceous gland surface area in the low-glycemic diet group, which decreased from 0.32 to 0.24 mm² (P=.03). The sebaceous gland surface area in the control group was not reported. Moreover, patients on the low-glycemic diet had reduced IL-8 immunohistochemical staining (decreasing from 2.9 to 1.7 [P=.03]) and sterol regulatory element-binding protein 1 levels (decreasing from 2.6 to 1.3 [P=.03]), suggesting suppression of ongoing inflammation. Patients on the low-glycemic diet had no significant difference in transforming growth factor β1(P=.83). In the control group, there was no difference in IL-8, sterol regulatory element binding protein 1, or transforming growth factor β1 (P>.05) on immunohistochemical staining.²¹

Psoriasis—Psoriasis is a systemic inflammatory disease characterized by hyperproliferation and aberrant keratinocyte plaque formation. The innate immune response of keratinocytes in response to epidermal damage or infection begins with neutrophil recruitment and dendritic cell activation. Dendritic cell secretion of IL-23 promotes T-cell differentiation into helper T cells (T_H1) that subsequently secrete IL-17 and IL-22, thereby stimulating keratinocyte proliferation and eventual plaque formation. The relationship between diet and psoriasis is poorly understood; however, hyperinsulinemia is associated with greater severity of psoriasis.³¹ 

Four observational studies examined sugar intake in psoriasis patients. Barrea et al²³ conducted a survey-based study of 82 male participants (41 with psoriasis and 41 healthy controls), reporting that PASI score was correlated with intake of simple carbohydrates (percentage of total kilocalorie)(r=0.564, P<.001). Another study by Yamashita et al²⁷ found higher sugar intake in psoriasis patients than controls (P=.003) based on surveys from 70 patients with psoriasis and 70 matched healthy controls.

These findings contrast with 2 survey-based studies by Johnson et al²² and Afifi et al²⁵ of sugar intake in psoriasis patients using the National Health and Nutrition Examination Survey. Johnson et al²² reported reduced sugar intake among 156 psoriasis patients compared with 6104 unmatched controls (odds ratio, 0.998; CI, 0.996-1 [P=.04]) from 2003 to 2006. Similarly, Afifi et al²⁵ reported decreased sugar intake in 1206 psoriasis patients compared with sex- and age-matched controls (P<.0001) in 2009 and 2010. When patients were asked about dietary triggers, 13.8% of psoriasis patients reported sugar as the most common trigger, which was more frequent than alcohol (13.6%), gluten (7.2%), and dairy (6%).²⁵

Castaldo et al^29,30 published 2 nonrandomized clinical intervention studies in 2020 and 2021 evaluating the impact of the ketogenic diet on psoriasis. In the first study, 37 psoriasis patients followed a 10-week diet consisting of 4 weeks on a ketogenic diet (500 kcal/d) followed by 6 weeks on a low-caloric Mediterranean diet.²⁹ At the end of the intervention, there was a 17.4% reduction in PASI score, a 33.2-point reduction in itch severity score, and a 13.4-point reduction in the dermatology life quality index score; however, this study did not include a control diet group for comparison.²⁹ The second study included 30 psoriasis patients on a ketogenic diet and 30 control patients without psoriasis on a regular diet.³⁰ The ketogenic diet consisted of 400 to 500 g of vegetables, 20 to 30 g of fat, and a proportion of protein based on body weight with at least 12 g of whey protein and various amino acids. Patients on the ketogenic diet had significant reduction in PASI scores (value relative to clinical features, 1.4916 [P=.007]). Furthermore, concentrations of cytokines IL-2 (P=.04) and IL-1β (P=.006) decreased following the ketogenic diet but were not measured in the control group.³⁰

Seborrheic Dermatitis—Seborrheic dermatitis is associated with overcolonization of Malassezia species near lipid-rich sebaceous glands. Malassezia hydrolyzes free fatty acids, yielding oleic acids and leading to T-cell release of IL-8 and IL-17.³² Literature is sparse regarding how dietary modifications may play a role in disease severity. In a survey study, Bett et al¹⁷ compared 16 SD patients to 1:2 matched controls (N=29) to investigate the relationship between sugar consumption and presence of disease. Two control cohorts were selected, 1 from clinic patients diagnosed with verruca and 1 matched by age and sex from a survey-based study at a facility in London, England. Sugar intake was measured both in total grams per day and in “beverage sugar” per day, defined as sugar taken in tea and coffee. There was higher total sugar and higher beverage sugar intake among the SD group compared with both control groups (P<.05).¹⁷

Atopic Dermatitis—Atopic dermatitis is a disease of epidermal barrier dysfunction and IgE-mediated allergic sensitization.³³ There are several mechanisms by which skin structure may be disrupted. It is well established that filaggrin mutations inhibit stratum corneum maturation and lamellar matrix deposition.³⁴ Upregulation of IL-4–, IL-13–, and IL-17–secreting T_H2 cells also is associated with disruption of tight junctions and reduction of filaggrin.^35,36 Given that a T cell–mediated inflammatory response is involved in disease pathogenesis, glycemic control is hypothesized to have therapeutic potential.

Nosrati et al²⁴ surveyed 169 AD patients about their perceived dietary triggers through a 61-question survey based on the National Health and Nutrition Examination Survey. Respondents were queried about their perceptions and dietary changes, such as removal or addition of specific food groups and trial of specific diets. Overall, 16.5% of patients reported sugar being a trigger, making it the fourth most common among those surveyed and less common than dairy (24.8%), gluten (18.3%), and alcohol (17.1%).²⁴

Hidradenitis Suppurativa—Hidradenitis suppurativa is driven by hyperkeratosis, dilatation, and occlusion of pilosebaceous follicular ducts, whose eventual rupture evokes a local acute inflammatory response.³⁷ The inciting event for both acne and HS involves mTOR complex–mediated follicular hyperproliferation andinsulinlike growth factor 1 stimulation of androgen receptors in pilosebaceous glands. Given the similarities between the pathogenesis of acne and HS, it is hypothesized that lifestyle changes, including diet modification, may have a beneficial effect on HS.^38-40

Comment

Acne—Overall, there is strong evidence supporting the efficacy of a low-glycemic diet in the treatment of acne. Notably, among the 6 observational studies identified, there was 1 conflicting study by Bett et al¹⁷ that did not find a statistically significant difference in glucose intake between acne and control patients. However, this study included only 16 acne patients, whereas the other 5 observational studies included 32 to 2255 patients.¹⁷ The strongest evidence supporting low-glycemic dietary interventions in acne treatment is from 2 rigorous randomized clinical trials by Kwon et al²¹ and Smith et al.¹⁸ These trials used intention-to-treat models and maintained consistency in gender, age, and acne treatment protocols across both control and treatment groups. To ensure compliance with dietary interventions, daily telephone calls, food logs, and 24-hour urea sampling were utilized. Acne outcomes were assessed by a dermatologist who remained blinded with well-defined outcome measures. An important limitation of these studies is the difficulty in attributing the observed results solely to reduced glucose intake, as low-glycemic diets often lead to other dietary changes, including reduced fat intake and increased nutrient consumption.^18,21

A 2022 systematic review of acne by Meixiong et al⁴¹ further reinforced the beneficial effects of low-glycemic diets in the management of acne patients. The group reviewed 6 interventional studies and 28 observational studies to investigate the relationship among acne, dairy, and glycemic content and found an association between decreased glucose and dairy on reduction of acne.⁴¹

It is likely that the ketogenic diet, which limits glucose, would be beneficial for acne patients. There may be added benefit through elevated ketone bodies and substantially reduced insulin secretion. However, because there are no observational or interventional studies, further research is needed to draw firm conclusions regarding diet for acne treatment. A randomized clinical trial investigating the effects of the ketogenic diet compared to the low-glycemic diet compared to a regular diet would be valuable.

Psoriasis—Among psoriasis studies, there was a lack of consensus regarding glucose intake and correlation with disease. Among the 4 observational studies, 2 reported increased glucose intake among psoriasis patients and 2 reported decreased glucose intake. It is plausible that the variability in studies is due to differences in sample size and diet heterogeneity among study populations. More specifically, Johnson et al²² and Afifi et al²⁵ analyzed large sample sizes of 6260 and 2412 US participants, respectively, and found decreased sugar intake among psoriasis patients compared to controls. In comparison, Barrea et al²³ and Yamashita et al²⁷ analyzed substantially smaller and more specific populations consisting of 82 Italian and 140 Japanese participants, respectively; both reported increased glucose intake among psoriasis patients compared to controls. These seemingly antithetical results may be explained by regional dietary differences, with varying proportions of meats, vegetables, antioxidants, and vitamins.

Moreover, the variation among studies may be further explained by the high prevalence of comorbidities among psoriasis patients. In the study by Barrea et al,²³ psoriasis patients had higher fasting glucose (P=.004) and insulin (P=.022) levels than healthy patients. After adjusting for body mass index and metabolic syndrome, the correlation coefficient measuring the relationship between the PASI score and intake of simple carbohydrates changed from r=0.564 (P<.001) to r=0.352 (P=.028). The confounding impact of these comorbidities was further highlighted by Yamashita et al,²⁷ who found statistically significant differences in glucose intake between psoriasis and healthy patients (P=.003). However, they reported diminished significance on additional subgroup analysis accounting for potential comorbidities (P=.994).²⁷ Johnson et al²² and Afifi et al²⁵ did not account for comorbidities; therefore, the 4 observational study results must be interpreted cautiously.

The 2 randomized clinical trials by Castaldo et al^29,30 weakly suggest that a ketogenic diet may be beneficial for psoriasis patients. The studies have several notable limitations, including insufficient sample sizes and control groups. Thus, the decreased PASI scores reported in psoriasis patients on the ketogenic diets are challenging to interpret. Additionally, both studies placed patients on highly restrictive diets of 500 kcal/d for 4 weeks. The feasibility of recommending such a diet to patients in clinical practice is questionable. Diets of less than 500 kcal/d may be dangerous for patients with underlying comorbidities and are unlikely to serve as long-term solutions.²³ To contextualize our findings, a 2022 review by Chung et al⁴² examined the impact of various diets—low-caloric, gluten-free, Mediterranean, Western, and ketogenic—on psoriasis and reported insufficient evidence to suggest a benefit to the ketogenic diet for psoriasis patients, though the Mediterranean diet may be well suited for psoriasis patients because of improved cardiovascular health and reduced mortality.

Seborrheic Dermatitis—Sanders et al⁴³ found that patients with a high-fruit diet had lower odds of having SD, while those on a Western diet had higher odds of having SD. Although the study did not measure glycemic load, it is conceivable that the high glycemic load characteristic of the Western diet contributed to these findings.⁴³ However, no studies have investigated the direct link between low-glycemic or ketogenic diets and SD, leaving this area open for further study.

Atopic Dermatitis—It has been hypothesized that mitigating T cell–mediated inflammation via glucose control may contribute to the improvement in AD.^35,36 However, in one study, 16.5% of AD patients self-identified sugar as a dietary trigger, ranking fourth among other dietary triggers.²⁴ Thus, the connection between glucose levels and AD warrants further exploration.

Hidradenitis Suppurativa—Given the role of metabolic and hormonal influence in HS as well as the overlapping pathophysiology with acne, it is possible that low-glycemic and ketogenic diets may have a role in improving HS.^38-40 However, there is a gap in observation and controlled studies investigating the link between low-glycemic or ketogenic diets and HS.

Conclusion

Our analysis focused on interventional and observational research exploring the effects of low-glycemic and ketogenic diets on associations and treatment of inflammatory skin conditions. There is sufficient evidence to counsel acne patients on the benefits of a low-glycemic diet as an adjunctive treatment for acne. Currently, there is insufficient evidence to recommend a low-glycemic or ketogenic diet as a treatment for patients with any other inflammatory skin disease. Prospective and controlled clinical trials are needed to clarify the utility of dietary interventions for treating inflammatory skin conditions.

Inflammatory skin conditions often have a relapsing and remitting course and represent a large proportion of chronic skin diseases. Common inflammatory skin disorders include acne, psoriasis, hidradenitis suppurativa (HS), atopic dermatitis (AD), and seborrheic dermatitis (SD).¹ Although each of these conditions has a unique pathogenesis, they all are driven by a background of chronic inflammation. It has been reported that diets with high levels of refined carbohydrates and saturated or trans-fatty acids may exacerbate existing inflammation.² Consequently, dietary interventions, such as the ketogenic and low-glycemic diets, have potential anti-inflammatory and metabolic effects that are being assessed as stand-alone or adjunctive therapies for dermatologic diseases.

Diet may partially influence systemic inflammation through its effect on weight. Higher body mass index and obesity are linked to a low-grade inflammatory state and higher levels of circulating inflammatory markers. Therefore, weight loss leads to decreases in inflammatory cytokines, including C-reactive protein, tumor necrosis factor α, and IL-6.³ These cytokines and metabolic effects overlap with inflammatory skin condition pathways. It also is posited that decreased insulin release associated with weight loss results in decreased sebaceous lipogenesis and androgens, which drive keratinocyte proliferation and acne development.^4,5 For instance, in a 2015 meta-analysis of 5 randomized controlled trials on psoriasis, patients in the weight loss intervention group had more substantial reductions in psoriasis area and severity index (PASI) scores compared with controls receiving usual care (P=.004).⁶ However, in a systematic review of 35 studies on acne vulgaris, overweight and obese patients (defined by a body mass index of ≥23 kg/m²) had similar odds of having acne compared with normal-weight individuals (P=.671).⁷

Similar to weight loss, ketogenesis acts as a negative feedback mechanism to reduce insulin release, leading to decreased inflammation and androgens that often exacerbate inflammatory skin diseases.⁸ Ketogenesis ensues when daily carbohydrate intake is limited to less than 50 g, and long-term adherence to a ketogenic diet results in metabolic reliance on ketone bodies such as acetoacetate, β-hydroxybutyrate, and acetone.⁹ These metabolites may decrease free radical damage and consequently improve signs and symptoms of acne, psoriasis, and other inflammatory skin diseases.^10-12 Similarly, increased ketones also may decrease activation of the NLRP3 (NOD-, LRR-, and Pyrin domain-containing protein 3) inflammasome and therefore reduce inflammatory markers such as IL-1β and IL-1.^4,13 Several proposed mechanisms are outlined in the Table.

CT11302075_Table.jpg

Collectively, low-glycemic and ketogenic diets have been proposed as potential interventions for reducing inflammatory skin conditions. These dietary approaches are hypothesized to exert their effects by facilitating weight loss, elevating ketone levels, and reducing systemic inflammation. The current review summarizes the existing evidence on ketogenic and low-glycemic diets as treatments for inflammatory skin conditions and evaluates the potential benefits of these dietary interventions in managing and improving outcomes for individuals with inflammatory skin conditions.

Methods

Using PubMed for articles indexed for MEDLINE and Google Scholar, a review of the literature was conducted with a combination of the following search terms: low-glycemic diet, inflammatory, dermatologic, ketogenic diet, inflammation, dermatology, acne, psoriasis, eczema, seborrheic dermatitis, and hidradenitis suppurativa. Reference citations in identified works also were reviewed. Interventional (experimental studies or clinical trials), survey-based, and observational studies that investigated the effects of low-glycemic or ketogenic diets for the treatment of inflammatory skin conditions were included. Inclusion criteria were studies assessing acne, psoriasis, SD, AD, and HS. Exclusion criteria were studies published before 1965; those written in languages other than English; and those analyzing other diets, such as the Mediterranean or low-fat diets. The search yielded a total of 11 observational studies and 4 controlled studies published between 1966 and January 2023. Because this analysis utilized publicly available data and did not qualify as human subject research, institutional review board approval was not required.

Results

Acne Vulgaris—Acne vulgaris is a disease of chronic pilosebaceous inflammation and follicular epithelial proliferation associated with Propionibacterium acnes. The association between acne and low-glycemic diets has been examined in several studies. Diet quality is measured and assessed using the glycemic index (GI), which is the effect of a single food on postprandial blood glucose, and the glycemic load, which is the GI adjusted for carbohydrates per serving.¹⁴ High levels of GI and glycemic load are associated with hyperinsulinemia and an increase in insulinlike growth factor 1 concentration that promotes mechanistic target of rapamycin (mTOR) complex 1–mediated follicular lipogenesis, sebum fatty acid production, and androgen synthesis.¹⁵Propionibacterium acnes directly activates toll-like receptor 2 on monocytes through damage-associated molecular patterns and indirectly through products of triglyceride catalysis, causing release of IL-12, IL-6, tumor necrosis factor α, and other proinflammatory cytokines.¹⁶ Therefore, lifestyle modifications focused on strict glucose control have been postulated to reduce acne severity via modulation of lipogenesis, androgen concentration, and inflammation.

Six survey-based studies evaluated sugar intake in patients with acne compared to healthy matched controls (eTable). Among these studies, 5 reported higher glycemic loads or daily sugar intake in acne patients compared to individuals without acne.^{12,19,20,26,28} The remaining study was conducted in 1967 and enrolled 16 acne patients and 32 matched controls. It reported no significant difference in sugar intake between the groups (P>.05).¹⁷

CT11302075_eTable_part1.jpg

CT11302075_eTable_part2.jpg

Smith et al¹⁸ randomized 43 male patients aged 15 to 25 years with facial acne into 2 cohorts for 12 weeks, each consuming either a low-glycemic diet (25% protein, 45% low-glycemic food [fruits, whole grains], and 30% fat) or a carbohydrate-dense diet of foods with medium to high GI based on prior documentation of the original diet. Patients were instructed to use a noncomedogenic cleanser as their only acne treatment. At 12 weeks, patients consuming the low-glycemic diet had an average of 23.5 fewer inflammatory lesions, while those in the intervention group had 12.0 fewer lesions (P=.03).¹⁸

In another controlled study by Kwon et al,²¹ 32 male and female acne patients were randomized to a low-glycemic diet (25% protein, 45% low-glycemic food, and 30% fat) or a standard diet for 10 weeks. Patients on the low-glycemic diet experienced a 70.9% reduction in inflammatory lesions (P<.05). Hematoxylin and eosin staining and image analysis were performed to measure sebaceous gland surface area in the low-glycemic diet group, which decreased from 0.32 to 0.24 mm² (P=.03). The sebaceous gland surface area in the control group was not reported. Moreover, patients on the low-glycemic diet had reduced IL-8 immunohistochemical staining (decreasing from 2.9 to 1.7 [P=.03]) and sterol regulatory element-binding protein 1 levels (decreasing from 2.6 to 1.3 [P=.03]), suggesting suppression of ongoing inflammation. Patients on the low-glycemic diet had no significant difference in transforming growth factor β1(P=.83). In the control group, there was no difference in IL-8, sterol regulatory element binding protein 1, or transforming growth factor β1 (P>.05) on immunohistochemical staining.²¹

Psoriasis—Psoriasis is a systemic inflammatory disease characterized by hyperproliferation and aberrant keratinocyte plaque formation. The innate immune response of keratinocytes in response to epidermal damage or infection begins with neutrophil recruitment and dendritic cell activation. Dendritic cell secretion of IL-23 promotes T-cell differentiation into helper T cells (T_H1) that subsequently secrete IL-17 and IL-22, thereby stimulating keratinocyte proliferation and eventual plaque formation. The relationship between diet and psoriasis is poorly understood; however, hyperinsulinemia is associated with greater severity of psoriasis.³¹ 

Four observational studies examined sugar intake in psoriasis patients. Barrea et al²³ conducted a survey-based study of 82 male participants (41 with psoriasis and 41 healthy controls), reporting that PASI score was correlated with intake of simple carbohydrates (percentage of total kilocalorie)(r=0.564, P<.001). Another study by Yamashita et al²⁷ found higher sugar intake in psoriasis patients than controls (P=.003) based on surveys from 70 patients with psoriasis and 70 matched healthy controls.

These findings contrast with 2 survey-based studies by Johnson et al²² and Afifi et al²⁵ of sugar intake in psoriasis patients using the National Health and Nutrition Examination Survey. Johnson et al²² reported reduced sugar intake among 156 psoriasis patients compared with 6104 unmatched controls (odds ratio, 0.998; CI, 0.996-1 [P=.04]) from 2003 to 2006. Similarly, Afifi et al²⁵ reported decreased sugar intake in 1206 psoriasis patients compared with sex- and age-matched controls (P<.0001) in 2009 and 2010. When patients were asked about dietary triggers, 13.8% of psoriasis patients reported sugar as the most common trigger, which was more frequent than alcohol (13.6%), gluten (7.2%), and dairy (6%).²⁵

Castaldo et al^29,30 published 2 nonrandomized clinical intervention studies in 2020 and 2021 evaluating the impact of the ketogenic diet on psoriasis. In the first study, 37 psoriasis patients followed a 10-week diet consisting of 4 weeks on a ketogenic diet (500 kcal/d) followed by 6 weeks on a low-caloric Mediterranean diet.²⁹ At the end of the intervention, there was a 17.4% reduction in PASI score, a 33.2-point reduction in itch severity score, and a 13.4-point reduction in the dermatology life quality index score; however, this study did not include a control diet group for comparison.²⁹ The second study included 30 psoriasis patients on a ketogenic diet and 30 control patients without psoriasis on a regular diet.³⁰ The ketogenic diet consisted of 400 to 500 g of vegetables, 20 to 30 g of fat, and a proportion of protein based on body weight with at least 12 g of whey protein and various amino acids. Patients on the ketogenic diet had significant reduction in PASI scores (value relative to clinical features, 1.4916 [P=.007]). Furthermore, concentrations of cytokines IL-2 (P=.04) and IL-1β (P=.006) decreased following the ketogenic diet but were not measured in the control group.³⁰

Seborrheic Dermatitis—Seborrheic dermatitis is associated with overcolonization of Malassezia species near lipid-rich sebaceous glands. Malassezia hydrolyzes free fatty acids, yielding oleic acids and leading to T-cell release of IL-8 and IL-17.³² Literature is sparse regarding how dietary modifications may play a role in disease severity. In a survey study, Bett et al¹⁷ compared 16 SD patients to 1:2 matched controls (N=29) to investigate the relationship between sugar consumption and presence of disease. Two control cohorts were selected, 1 from clinic patients diagnosed with verruca and 1 matched by age and sex from a survey-based study at a facility in London, England. Sugar intake was measured both in total grams per day and in “beverage sugar” per day, defined as sugar taken in tea and coffee. There was higher total sugar and higher beverage sugar intake among the SD group compared with both control groups (P<.05).¹⁷

Atopic Dermatitis—Atopic dermatitis is a disease of epidermal barrier dysfunction and IgE-mediated allergic sensitization.³³ There are several mechanisms by which skin structure may be disrupted. It is well established that filaggrin mutations inhibit stratum corneum maturation and lamellar matrix deposition.³⁴ Upregulation of IL-4–, IL-13–, and IL-17–secreting T_H2 cells also is associated with disruption of tight junctions and reduction of filaggrin.^35,36 Given that a T cell–mediated inflammatory response is involved in disease pathogenesis, glycemic control is hypothesized to have therapeutic potential.

Nosrati et al²⁴ surveyed 169 AD patients about their perceived dietary triggers through a 61-question survey based on the National Health and Nutrition Examination Survey. Respondents were queried about their perceptions and dietary changes, such as removal or addition of specific food groups and trial of specific diets. Overall, 16.5% of patients reported sugar being a trigger, making it the fourth most common among those surveyed and less common than dairy (24.8%), gluten (18.3%), and alcohol (17.1%).²⁴

Hidradenitis Suppurativa—Hidradenitis suppurativa is driven by hyperkeratosis, dilatation, and occlusion of pilosebaceous follicular ducts, whose eventual rupture evokes a local acute inflammatory response.³⁷ The inciting event for both acne and HS involves mTOR complex–mediated follicular hyperproliferation andinsulinlike growth factor 1 stimulation of androgen receptors in pilosebaceous glands. Given the similarities between the pathogenesis of acne and HS, it is hypothesized that lifestyle changes, including diet modification, may have a beneficial effect on HS.^38-40

Comment

Acne—Overall, there is strong evidence supporting the efficacy of a low-glycemic diet in the treatment of acne. Notably, among the 6 observational studies identified, there was 1 conflicting study by Bett et al¹⁷ that did not find a statistically significant difference in glucose intake between acne and control patients. However, this study included only 16 acne patients, whereas the other 5 observational studies included 32 to 2255 patients.¹⁷ The strongest evidence supporting low-glycemic dietary interventions in acne treatment is from 2 rigorous randomized clinical trials by Kwon et al²¹ and Smith et al.¹⁸ These trials used intention-to-treat models and maintained consistency in gender, age, and acne treatment protocols across both control and treatment groups. To ensure compliance with dietary interventions, daily telephone calls, food logs, and 24-hour urea sampling were utilized. Acne outcomes were assessed by a dermatologist who remained blinded with well-defined outcome measures. An important limitation of these studies is the difficulty in attributing the observed results solely to reduced glucose intake, as low-glycemic diets often lead to other dietary changes, including reduced fat intake and increased nutrient consumption.^18,21

A 2022 systematic review of acne by Meixiong et al⁴¹ further reinforced the beneficial effects of low-glycemic diets in the management of acne patients. The group reviewed 6 interventional studies and 28 observational studies to investigate the relationship among acne, dairy, and glycemic content and found an association between decreased glucose and dairy on reduction of acne.⁴¹

It is likely that the ketogenic diet, which limits glucose, would be beneficial for acne patients. There may be added benefit through elevated ketone bodies and substantially reduced insulin secretion. However, because there are no observational or interventional studies, further research is needed to draw firm conclusions regarding diet for acne treatment. A randomized clinical trial investigating the effects of the ketogenic diet compared to the low-glycemic diet compared to a regular diet would be valuable.

Psoriasis—Among psoriasis studies, there was a lack of consensus regarding glucose intake and correlation with disease. Among the 4 observational studies, 2 reported increased glucose intake among psoriasis patients and 2 reported decreased glucose intake. It is plausible that the variability in studies is due to differences in sample size and diet heterogeneity among study populations. More specifically, Johnson et al²² and Afifi et al²⁵ analyzed large sample sizes of 6260 and 2412 US participants, respectively, and found decreased sugar intake among psoriasis patients compared to controls. In comparison, Barrea et al²³ and Yamashita et al²⁷ analyzed substantially smaller and more specific populations consisting of 82 Italian and 140 Japanese participants, respectively; both reported increased glucose intake among psoriasis patients compared to controls. These seemingly antithetical results may be explained by regional dietary differences, with varying proportions of meats, vegetables, antioxidants, and vitamins.

Moreover, the variation among studies may be further explained by the high prevalence of comorbidities among psoriasis patients. In the study by Barrea et al,²³ psoriasis patients had higher fasting glucose (P=.004) and insulin (P=.022) levels than healthy patients. After adjusting for body mass index and metabolic syndrome, the correlation coefficient measuring the relationship between the PASI score and intake of simple carbohydrates changed from r=0.564 (P<.001) to r=0.352 (P=.028). The confounding impact of these comorbidities was further highlighted by Yamashita et al,²⁷ who found statistically significant differences in glucose intake between psoriasis and healthy patients (P=.003). However, they reported diminished significance on additional subgroup analysis accounting for potential comorbidities (P=.994).²⁷ Johnson et al²² and Afifi et al²⁵ did not account for comorbidities; therefore, the 4 observational study results must be interpreted cautiously.

The 2 randomized clinical trials by Castaldo et al^29,30 weakly suggest that a ketogenic diet may be beneficial for psoriasis patients. The studies have several notable limitations, including insufficient sample sizes and control groups. Thus, the decreased PASI scores reported in psoriasis patients on the ketogenic diets are challenging to interpret. Additionally, both studies placed patients on highly restrictive diets of 500 kcal/d for 4 weeks. The feasibility of recommending such a diet to patients in clinical practice is questionable. Diets of less than 500 kcal/d may be dangerous for patients with underlying comorbidities and are unlikely to serve as long-term solutions.²³ To contextualize our findings, a 2022 review by Chung et al⁴² examined the impact of various diets—low-caloric, gluten-free, Mediterranean, Western, and ketogenic—on psoriasis and reported insufficient evidence to suggest a benefit to the ketogenic diet for psoriasis patients, though the Mediterranean diet may be well suited for psoriasis patients because of improved cardiovascular health and reduced mortality.

Seborrheic Dermatitis—Sanders et al⁴³ found that patients with a high-fruit diet had lower odds of having SD, while those on a Western diet had higher odds of having SD. Although the study did not measure glycemic load, it is conceivable that the high glycemic load characteristic of the Western diet contributed to these findings.⁴³ However, no studies have investigated the direct link between low-glycemic or ketogenic diets and SD, leaving this area open for further study.

Atopic Dermatitis—It has been hypothesized that mitigating T cell–mediated inflammation via glucose control may contribute to the improvement in AD.^35,36 However, in one study, 16.5% of AD patients self-identified sugar as a dietary trigger, ranking fourth among other dietary triggers.²⁴ Thus, the connection between glucose levels and AD warrants further exploration.

Hidradenitis Suppurativa—Given the role of metabolic and hormonal influence in HS as well as the overlapping pathophysiology with acne, it is possible that low-glycemic and ketogenic diets may have a role in improving HS.^38-40 However, there is a gap in observation and controlled studies investigating the link between low-glycemic or ketogenic diets and HS.

Conclusion

Our analysis focused on interventional and observational research exploring the effects of low-glycemic and ketogenic diets on associations and treatment of inflammatory skin conditions. There is sufficient evidence to counsel acne patients on the benefits of a low-glycemic diet as an adjunctive treatment for acne. Currently, there is insufficient evidence to recommend a low-glycemic or ketogenic diet as a treatment for patients with any other inflammatory skin disease. Prospective and controlled clinical trials are needed to clarify the utility of dietary interventions for treating inflammatory skin conditions.

Inflammatory skin conditions often have a relapsing and remitting course and represent a large proportion of chronic skin diseases. Common inflammatory skin disorders include acne, psoriasis, hidradenitis suppurativa (HS), atopic dermatitis (AD), and seborrheic dermatitis (SD).¹ Although each of these conditions has a unique pathogenesis, they all are driven by a background of chronic inflammation. It has been reported that diets with high levels of refined carbohydrates and saturated or trans-fatty acids may exacerbate existing inflammation.² Consequently, dietary interventions, such as the ketogenic and low-glycemic diets, have potential anti-inflammatory and metabolic effects that are being assessed as stand-alone or adjunctive therapies for dermatologic diseases.

Diet may partially influence systemic inflammation through its effect on weight. Higher body mass index and obesity are linked to a low-grade inflammatory state and higher levels of circulating inflammatory markers. Therefore, weight loss leads to decreases in inflammatory cytokines, including C-reactive protein, tumor necrosis factor α, and IL-6.³ These cytokines and metabolic effects overlap with inflammatory skin condition pathways. It also is posited that decreased insulin release associated with weight loss results in decreased sebaceous lipogenesis and androgens, which drive keratinocyte proliferation and acne development.^4,5 For instance, in a 2015 meta-analysis of 5 randomized controlled trials on psoriasis, patients in the weight loss intervention group had more substantial reductions in psoriasis area and severity index (PASI) scores compared with controls receiving usual care (P=.004).⁶ However, in a systematic review of 35 studies on acne vulgaris, overweight and obese patients (defined by a body mass index of ≥23 kg/m²) had similar odds of having acne compared with normal-weight individuals (P=.671).⁷

Similar to weight loss, ketogenesis acts as a negative feedback mechanism to reduce insulin release, leading to decreased inflammation and androgens that often exacerbate inflammatory skin diseases.⁸ Ketogenesis ensues when daily carbohydrate intake is limited to less than 50 g, and long-term adherence to a ketogenic diet results in metabolic reliance on ketone bodies such as acetoacetate, β-hydroxybutyrate, and acetone.⁹ These metabolites may decrease free radical damage and consequently improve signs and symptoms of acne, psoriasis, and other inflammatory skin diseases.^10-12 Similarly, increased ketones also may decrease activation of the NLRP3 (NOD-, LRR-, and Pyrin domain-containing protein 3) inflammasome and therefore reduce inflammatory markers such as IL-1β and IL-1.^4,13 Several proposed mechanisms are outlined in the Table.

CT11302075_Table.jpg

Collectively, low-glycemic and ketogenic diets have been proposed as potential interventions for reducing inflammatory skin conditions. These dietary approaches are hypothesized to exert their effects by facilitating weight loss, elevating ketone levels, and reducing systemic inflammation. The current review summarizes the existing evidence on ketogenic and low-glycemic diets as treatments for inflammatory skin conditions and evaluates the potential benefits of these dietary interventions in managing and improving outcomes for individuals with inflammatory skin conditions.

Methods

Using PubMed for articles indexed for MEDLINE and Google Scholar, a review of the literature was conducted with a combination of the following search terms: low-glycemic diet, inflammatory, dermatologic, ketogenic diet, inflammation, dermatology, acne, psoriasis, eczema, seborrheic dermatitis, and hidradenitis suppurativa. Reference citations in identified works also were reviewed. Interventional (experimental studies or clinical trials), survey-based, and observational studies that investigated the effects of low-glycemic or ketogenic diets for the treatment of inflammatory skin conditions were included. Inclusion criteria were studies assessing acne, psoriasis, SD, AD, and HS. Exclusion criteria were studies published before 1965; those written in languages other than English; and those analyzing other diets, such as the Mediterranean or low-fat diets. The search yielded a total of 11 observational studies and 4 controlled studies published between 1966 and January 2023. Because this analysis utilized publicly available data and did not qualify as human subject research, institutional review board approval was not required.

Results

Acne Vulgaris—Acne vulgaris is a disease of chronic pilosebaceous inflammation and follicular epithelial proliferation associated with Propionibacterium acnes. The association between acne and low-glycemic diets has been examined in several studies. Diet quality is measured and assessed using the glycemic index (GI), which is the effect of a single food on postprandial blood glucose, and the glycemic load, which is the GI adjusted for carbohydrates per serving.¹⁴ High levels of GI and glycemic load are associated with hyperinsulinemia and an increase in insulinlike growth factor 1 concentration that promotes mechanistic target of rapamycin (mTOR) complex 1–mediated follicular lipogenesis, sebum fatty acid production, and androgen synthesis.¹⁵Propionibacterium acnes directly activates toll-like receptor 2 on monocytes through damage-associated molecular patterns and indirectly through products of triglyceride catalysis, causing release of IL-12, IL-6, tumor necrosis factor α, and other proinflammatory cytokines.¹⁶ Therefore, lifestyle modifications focused on strict glucose control have been postulated to reduce acne severity via modulation of lipogenesis, androgen concentration, and inflammation.

Six survey-based studies evaluated sugar intake in patients with acne compared to healthy matched controls (eTable). Among these studies, 5 reported higher glycemic loads or daily sugar intake in acne patients compared to individuals without acne.^{12,19,20,26,28} The remaining study was conducted in 1967 and enrolled 16 acne patients and 32 matched controls. It reported no significant difference in sugar intake between the groups (P>.05).¹⁷

CT11302075_eTable_part1.jpg

CT11302075_eTable_part2.jpg

Smith et al¹⁸ randomized 43 male patients aged 15 to 25 years with facial acne into 2 cohorts for 12 weeks, each consuming either a low-glycemic diet (25% protein, 45% low-glycemic food [fruits, whole grains], and 30% fat) or a carbohydrate-dense diet of foods with medium to high GI based on prior documentation of the original diet. Patients were instructed to use a noncomedogenic cleanser as their only acne treatment. At 12 weeks, patients consuming the low-glycemic diet had an average of 23.5 fewer inflammatory lesions, while those in the intervention group had 12.0 fewer lesions (P=.03).¹⁸

In another controlled study by Kwon et al,²¹ 32 male and female acne patients were randomized to a low-glycemic diet (25% protein, 45% low-glycemic food, and 30% fat) or a standard diet for 10 weeks. Patients on the low-glycemic diet experienced a 70.9% reduction in inflammatory lesions (P<.05). Hematoxylin and eosin staining and image analysis were performed to measure sebaceous gland surface area in the low-glycemic diet group, which decreased from 0.32 to 0.24 mm² (P=.03). The sebaceous gland surface area in the control group was not reported. Moreover, patients on the low-glycemic diet had reduced IL-8 immunohistochemical staining (decreasing from 2.9 to 1.7 [P=.03]) and sterol regulatory element-binding protein 1 levels (decreasing from 2.6 to 1.3 [P=.03]), suggesting suppression of ongoing inflammation. Patients on the low-glycemic diet had no significant difference in transforming growth factor β1(P=.83). In the control group, there was no difference in IL-8, sterol regulatory element binding protein 1, or transforming growth factor β1 (P>.05) on immunohistochemical staining.²¹

Psoriasis—Psoriasis is a systemic inflammatory disease characterized by hyperproliferation and aberrant keratinocyte plaque formation. The innate immune response of keratinocytes in response to epidermal damage or infection begins with neutrophil recruitment and dendritic cell activation. Dendritic cell secretion of IL-23 promotes T-cell differentiation into helper T cells (T_H1) that subsequently secrete IL-17 and IL-22, thereby stimulating keratinocyte proliferation and eventual plaque formation. The relationship between diet and psoriasis is poorly understood; however, hyperinsulinemia is associated with greater severity of psoriasis.³¹ 

Four observational studies examined sugar intake in psoriasis patients. Barrea et al²³ conducted a survey-based study of 82 male participants (41 with psoriasis and 41 healthy controls), reporting that PASI score was correlated with intake of simple carbohydrates (percentage of total kilocalorie)(r=0.564, P<.001). Another study by Yamashita et al²⁷ found higher sugar intake in psoriasis patients than controls (P=.003) based on surveys from 70 patients with psoriasis and 70 matched healthy controls.

These findings contrast with 2 survey-based studies by Johnson et al²² and Afifi et al²⁵ of sugar intake in psoriasis patients using the National Health and Nutrition Examination Survey. Johnson et al²² reported reduced sugar intake among 156 psoriasis patients compared with 6104 unmatched controls (odds ratio, 0.998; CI, 0.996-1 [P=.04]) from 2003 to 2006. Similarly, Afifi et al²⁵ reported decreased sugar intake in 1206 psoriasis patients compared with sex- and age-matched controls (P<.0001) in 2009 and 2010. When patients were asked about dietary triggers, 13.8% of psoriasis patients reported sugar as the most common trigger, which was more frequent than alcohol (13.6%), gluten (7.2%), and dairy (6%).²⁵

Castaldo et al^29,30 published 2 nonrandomized clinical intervention studies in 2020 and 2021 evaluating the impact of the ketogenic diet on psoriasis. In the first study, 37 psoriasis patients followed a 10-week diet consisting of 4 weeks on a ketogenic diet (500 kcal/d) followed by 6 weeks on a low-caloric Mediterranean diet.²⁹ At the end of the intervention, there was a 17.4% reduction in PASI score, a 33.2-point reduction in itch severity score, and a 13.4-point reduction in the dermatology life quality index score; however, this study did not include a control diet group for comparison.²⁹ The second study included 30 psoriasis patients on a ketogenic diet and 30 control patients without psoriasis on a regular diet.³⁰ The ketogenic diet consisted of 400 to 500 g of vegetables, 20 to 30 g of fat, and a proportion of protein based on body weight with at least 12 g of whey protein and various amino acids. Patients on the ketogenic diet had significant reduction in PASI scores (value relative to clinical features, 1.4916 [P=.007]). Furthermore, concentrations of cytokines IL-2 (P=.04) and IL-1β (P=.006) decreased following the ketogenic diet but were not measured in the control group.³⁰

Seborrheic Dermatitis—Seborrheic dermatitis is associated with overcolonization of Malassezia species near lipid-rich sebaceous glands. Malassezia hydrolyzes free fatty acids, yielding oleic acids and leading to T-cell release of IL-8 and IL-17.³² Literature is sparse regarding how dietary modifications may play a role in disease severity. In a survey study, Bett et al¹⁷ compared 16 SD patients to 1:2 matched controls (N=29) to investigate the relationship between sugar consumption and presence of disease. Two control cohorts were selected, 1 from clinic patients diagnosed with verruca and 1 matched by age and sex from a survey-based study at a facility in London, England. Sugar intake was measured both in total grams per day and in “beverage sugar” per day, defined as sugar taken in tea and coffee. There was higher total sugar and higher beverage sugar intake among the SD group compared with both control groups (P<.05).¹⁷

Atopic Dermatitis—Atopic dermatitis is a disease of epidermal barrier dysfunction and IgE-mediated allergic sensitization.³³ There are several mechanisms by which skin structure may be disrupted. It is well established that filaggrin mutations inhibit stratum corneum maturation and lamellar matrix deposition.³⁴ Upregulation of IL-4–, IL-13–, and IL-17–secreting T_H2 cells also is associated with disruption of tight junctions and reduction of filaggrin.^35,36 Given that a T cell–mediated inflammatory response is involved in disease pathogenesis, glycemic control is hypothesized to have therapeutic potential.

Nosrati et al²⁴ surveyed 169 AD patients about their perceived dietary triggers through a 61-question survey based on the National Health and Nutrition Examination Survey. Respondents were queried about their perceptions and dietary changes, such as removal or addition of specific food groups and trial of specific diets. Overall, 16.5% of patients reported sugar being a trigger, making it the fourth most common among those surveyed and less common than dairy (24.8%), gluten (18.3%), and alcohol (17.1%).²⁴

Hidradenitis Suppurativa—Hidradenitis suppurativa is driven by hyperkeratosis, dilatation, and occlusion of pilosebaceous follicular ducts, whose eventual rupture evokes a local acute inflammatory response.³⁷ The inciting event for both acne and HS involves mTOR complex–mediated follicular hyperproliferation andinsulinlike growth factor 1 stimulation of androgen receptors in pilosebaceous glands. Given the similarities between the pathogenesis of acne and HS, it is hypothesized that lifestyle changes, including diet modification, may have a beneficial effect on HS.^38-40

Comment

Acne—Overall, there is strong evidence supporting the efficacy of a low-glycemic diet in the treatment of acne. Notably, among the 6 observational studies identified, there was 1 conflicting study by Bett et al¹⁷ that did not find a statistically significant difference in glucose intake between acne and control patients. However, this study included only 16 acne patients, whereas the other 5 observational studies included 32 to 2255 patients.¹⁷ The strongest evidence supporting low-glycemic dietary interventions in acne treatment is from 2 rigorous randomized clinical trials by Kwon et al²¹ and Smith et al.¹⁸ These trials used intention-to-treat models and maintained consistency in gender, age, and acne treatment protocols across both control and treatment groups. To ensure compliance with dietary interventions, daily telephone calls, food logs, and 24-hour urea sampling were utilized. Acne outcomes were assessed by a dermatologist who remained blinded with well-defined outcome measures. An important limitation of these studies is the difficulty in attributing the observed results solely to reduced glucose intake, as low-glycemic diets often lead to other dietary changes, including reduced fat intake and increased nutrient consumption.^18,21

A 2022 systematic review of acne by Meixiong et al⁴¹ further reinforced the beneficial effects of low-glycemic diets in the management of acne patients. The group reviewed 6 interventional studies and 28 observational studies to investigate the relationship among acne, dairy, and glycemic content and found an association between decreased glucose and dairy on reduction of acne.⁴¹

It is likely that the ketogenic diet, which limits glucose, would be beneficial for acne patients. There may be added benefit through elevated ketone bodies and substantially reduced insulin secretion. However, because there are no observational or interventional studies, further research is needed to draw firm conclusions regarding diet for acne treatment. A randomized clinical trial investigating the effects of the ketogenic diet compared to the low-glycemic diet compared to a regular diet would be valuable.

Psoriasis—Among psoriasis studies, there was a lack of consensus regarding glucose intake and correlation with disease. Among the 4 observational studies, 2 reported increased glucose intake among psoriasis patients and 2 reported decreased glucose intake. It is plausible that the variability in studies is due to differences in sample size and diet heterogeneity among study populations. More specifically, Johnson et al²² and Afifi et al²⁵ analyzed large sample sizes of 6260 and 2412 US participants, respectively, and found decreased sugar intake among psoriasis patients compared to controls. In comparison, Barrea et al²³ and Yamashita et al²⁷ analyzed substantially smaller and more specific populations consisting of 82 Italian and 140 Japanese participants, respectively; both reported increased glucose intake among psoriasis patients compared to controls. These seemingly antithetical results may be explained by regional dietary differences, with varying proportions of meats, vegetables, antioxidants, and vitamins.

Moreover, the variation among studies may be further explained by the high prevalence of comorbidities among psoriasis patients. In the study by Barrea et al,²³ psoriasis patients had higher fasting glucose (P=.004) and insulin (P=.022) levels than healthy patients. After adjusting for body mass index and metabolic syndrome, the correlation coefficient measuring the relationship between the PASI score and intake of simple carbohydrates changed from r=0.564 (P<.001) to r=0.352 (P=.028). The confounding impact of these comorbidities was further highlighted by Yamashita et al,²⁷ who found statistically significant differences in glucose intake between psoriasis and healthy patients (P=.003). However, they reported diminished significance on additional subgroup analysis accounting for potential comorbidities (P=.994).²⁷ Johnson et al²² and Afifi et al²⁵ did not account for comorbidities; therefore, the 4 observational study results must be interpreted cautiously.

The 2 randomized clinical trials by Castaldo et al^29,30 weakly suggest that a ketogenic diet may be beneficial for psoriasis patients. The studies have several notable limitations, including insufficient sample sizes and control groups. Thus, the decreased PASI scores reported in psoriasis patients on the ketogenic diets are challenging to interpret. Additionally, both studies placed patients on highly restrictive diets of 500 kcal/d for 4 weeks. The feasibility of recommending such a diet to patients in clinical practice is questionable. Diets of less than 500 kcal/d may be dangerous for patients with underlying comorbidities and are unlikely to serve as long-term solutions.²³ To contextualize our findings, a 2022 review by Chung et al⁴² examined the impact of various diets—low-caloric, gluten-free, Mediterranean, Western, and ketogenic—on psoriasis and reported insufficient evidence to suggest a benefit to the ketogenic diet for psoriasis patients, though the Mediterranean diet may be well suited for psoriasis patients because of improved cardiovascular health and reduced mortality.

Seborrheic Dermatitis—Sanders et al⁴³ found that patients with a high-fruit diet had lower odds of having SD, while those on a Western diet had higher odds of having SD. Although the study did not measure glycemic load, it is conceivable that the high glycemic load characteristic of the Western diet contributed to these findings.⁴³ However, no studies have investigated the direct link between low-glycemic or ketogenic diets and SD, leaving this area open for further study.

Atopic Dermatitis—It has been hypothesized that mitigating T cell–mediated inflammation via glucose control may contribute to the improvement in AD.^35,36 However, in one study, 16.5% of AD patients self-identified sugar as a dietary trigger, ranking fourth among other dietary triggers.²⁴ Thus, the connection between glucose levels and AD warrants further exploration.

Hidradenitis Suppurativa—Given the role of metabolic and hormonal influence in HS as well as the overlapping pathophysiology with acne, it is possible that low-glycemic and ketogenic diets may have a role in improving HS.^38-40 However, there is a gap in observation and controlled studies investigating the link between low-glycemic or ketogenic diets and HS.

Conclusion

Our analysis focused on interventional and observational research exploring the effects of low-glycemic and ketogenic diets on associations and treatment of inflammatory skin conditions. There is sufficient evidence to counsel acne patients on the benefits of a low-glycemic diet as an adjunctive treatment for acne. Currently, there is insufficient evidence to recommend a low-glycemic or ketogenic diet as a treatment for patients with any other inflammatory skin disease. Prospective and controlled clinical trials are needed to clarify the utility of dietary interventions for treating inflammatory skin conditions.

Psoriasis is a chronic inflammatory disease that affects approximately 3% of the US population.¹ Plaque psoriasis comprises 80% to 90% of cases, while pustular, erythrodermic, guttate, inverse, and palmoplantar disease are less common variants (Figure 1). Psoriatic skin manifestations range from localized to widespread or generalized disease with recurrent flares. Body surface area or psoriasis area and severity index (PASI) measurements primarily focus on skin manifestations and are important for evaluating disease activity and response to treatment, but they have inherent limitations: they do not capture extracutaneous disease activity, systemic inflammation, comorbid conditions, quality of life impact, or the economic burden of psoriasis.

CT11302082_ABCD.jpg

A common manifestation of psoriasis is psoriatic arthritis (PsA), which can involve the nails, joints, ligaments, or tendons in 30% to 41% of affected individuals (Figure 2).^2,3 A growing number of psoriasis-associated comorbidities also have been reported including metabolic syndrome⁴; hyperlipidemia⁵; cardiovascular disease⁶; stroke⁷; hypertension⁸; obesity⁹; sleep disorders¹⁰; malignancy¹¹; infections¹²; inflammatory bowel disease¹³; and mental health disorders such as depression,¹⁴ anxiety,¹⁵ and suicidal ideation.¹⁵ Psoriatic disease also interferes with daily life activities and a patient’s overall quality of life, including interpersonal relationships, intimacy, employment, and work productivity.¹⁶ Finally, the total estimated cost of psoriasis-related health care is more than $35 billion annually,¹⁷ representing a substantial economic burden to our health care system and individual patients.

Nong_2.jpg

The overall burden of psoriatic disease has declined markedly in the last 2 decades due to revolutionary advances in our understanding of the immunopathogenesis of psoriasis and the subsequent development of improved therapies that predominantly interrupt IL-23/IL-17 cytokine signaling; however, critical knowledge and treatment gaps persist, underscoring the importance of ongoing clinical and research efforts in psoriatic disease. We review the working immune model of psoriasis, summarize related immune discoveries, and highlight recent therapeutic innovations that are shaping psoriatic disease management.

Current Immune Model of Psoriatic Disease

Psoriasis is an autoinflammatory T cell–mediated disease with negligible contributions from the humoral immune response. Early clinical observations reported increased inflammatory infiltrates in psoriatic skin lesions primarily consisting of both CD4⁺ and CD8⁺ T-cell populations.^18,19 Additionally, patients treated with broad-acting, systemic immunosuppressive medications (eg, cyclosporine, oral corticosteroids) experienced improvement of psoriatic lesions and normalization of the immune infiltrates observed in skin biopsy specimens.^20,21 These early clinical findings led to more sophisticated experimentation in xenotransplant models of psoriasis,^22,23 which explored the clinical efficacy of several less immunosuppressive (eg, methotrexate, anti–tumor necrosis factor [TNF] biologics)²⁴ or T cell–specific agents (eg, alefacept, abatacept, efalizumab).^25-27 The results of these translational studies provided indisputable evidence for the role of the dysregulated immune response as the primary pathogenic process driving plaque formation; they also led to a paradigm shift in how the immunopathogenesis of psoriatic disease was viewed and paved the way for the identification and targeting of other specific proinflammatory signals produced by activated dendritic cell (DC) and T-lymphocyte populations. Among the psoriasis-associated cytokines subsequently identified and studied, elevated IL-23 and IL-17 cytokine levels in psoriatic skin were most closely associated with disease activity, and rapid normalization of IL-23/IL-17 signaling in response to effective oral or injectable antipsoriatic treatments was the hallmark of skin clearance.²⁸ The predominant role of IL-23/IL-17 signaling in the development and maintenance of psoriatic disease is the central feature of all working immune models for this disease (Figure 3).

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Psoriasis-Associated Genetic and Environmental Risk Factors

The exact sequence of events that lead to the initiation and formation of plaque psoriasis in susceptible individuals is still poorly understood; however, several important risk factors and key immune events have been identified. First, decades of genetic research have reported more than 80 known psoriasis-associated susceptibility loci,²⁹ which explains approximately 50% of psoriasis heritability. The major genetic determinant of psoriasis, HLA-C*06:02 (formerly HLA-Cw6), resides in the major histocompatibility complex class I region on chromosome 6p21.3 (psoriasis susceptibility gene 1, PSORS1) and is most strongly associated with psoriatic disease.³⁰ Less common psoriasis-associated susceptibility genes also are known to directly or indirectly impact innate and adaptive immune functions that contribute to the pathogenesis of psoriasis.

Second, several nongenetic environmental risk factors for psoriasis have been reported across diverse patient populations, including skin trauma/injury, infections, alcohol/tobacco use, obesity, medication exposure (eg, lithium, antimalarials, beta-blockers), and stress.³¹ These genetic and/or environmental risk factors can trigger the onset of psoriatic disease at any stage of life, though most patients develop disease in early adulthood or later (age range, 50–60 years). Some patients never develop psoriasis despite exposure to environmental risk factors and/or a genetic makeup that is similar to affected first-degree relatives, which requires further study.

Prepsoriatic Skin and Initiation of Plaque Development

In response to environmental stimuli and/or other triggers of the immune system, DC and resident IL-17–producing T-cell (T17) populations become activated in predisposed individuals. Dendritic cell activation leads to the upregulation and increase of several proinflammatory cytokines, including TNF, interferon (IFN) α, IFN-γ, IL-12, and IL-23. Tumor necrosis factor and IL-23 play a vital role in psoriasis by helping to regulate the polarization and expansion of T22 and T17 cells in the skin, whereas IL-12 promotes a corresponding type 1 inflammatory response.³² Increased IL-17 and IL-22 result in alteration of the terminal differentiation and proliferative potential of epidermal keratinocytes, leading to the early clinical hallmarks of psoriatic plaques. The potential contribution of overexpressed psoriasis-related autoantigens, such as LL-37/cathelicidin, ADAMTSL5, and PLA2G4D,³³ in the initiation of psoriatic plaques has been suggested but is poorly characterized.³⁴ Whether these specific autoantigens or others presented by HLA-C variants found on antigen-presenting cells are required for the breakdown of immune tolerance and psoriatic disease initiation is highly relevant but requires further investigation and validation.

In response to the upstream production of IL-23 by dermal DCs, high levels of IL-17 cytokines can be found in mature psoriatic plaques. The IL-17 family consists of 6 dimeric cytokines (IL-17A through IL-17F) that provide innate cutaneous protection against bacterial, viral, and fungal infectious agents, such as Candida albicans. Unlike other IL-17 isoforms, IL-17A and IL-17F share the same receptor complex and have the highest structural homology of any pair (approximately 50% similar).³⁵ The relative expression of IL-17F is higher than IL-17A in psoriasis,³⁶ though IL-17A has been considered as the predominant IL-17 cytokine found in psoriatic skin lesions due to its higher potency.

Binding of IL-17A/F with the IL-17 receptor (IL-17R) on keratinocytes contributes to the development of psoriatic plaques by inducing epidermal hyperplasia via activation of CCAAT/enhancer-binding proteins β and δ, nuclear factor κB, and signal transducer and activator of transcription 1 gene (STAT1).^37,38 This also increases the expression of other keratinocyte-derived proteins (eg, human β-defensins, S-100 proteins, LL-37, other antimicrobial peptides, IL-19, IL-36, IL-17C) that act as reinforcing proinflammatory signals or chemotactic factors (eg, chemokine [C-C motif] ligand 20 [CCL20], chemokine [C-C motif] ligand 1/2/3/5 [CXCL1/2/3/5], CXCL8, IL-8) that facilitate the recruitment of additional immune cells to the skin including polymorphonuclear neutrophils (PMNs), macrophages, and DCs.^39-41 Routine immunohistochemical staining for these keratinocyte-derived proteins reveals a striking epidermal gene expression gradient wherein levels of IL-17–induced proteins are most highly expressed in the uppermost layers of keratinocytes and facilitate the recruitment of immune cells into the epidermis. Activated T17 cells also stimulate the production of keratinocyte-derived chemokines (eg, CXCL9/10/11), which recruit type 1 inflammatory T-cell populations into developing psoriatic plaques.^42,43 Finally, TNF, IL-36, and IL-17C cytokines act synergistically with IL-17A/F to amplify the proinflammatory effects of IL-17 signaling and further stimulate their production from T17 cell populations.⁴⁰ This inflammatory circuit in the skin creates and supports a self-amplifying or positive feedback loop between the skin and immune system that commonly is referred to as feed-forward inflammation (Figure 3).³⁴ The feed-forward inflammatory loop in psoriasis—predominantly driven by increased IL-23/IL-17 signaling—best characterizes the mature psoriatic plaque.

Several findings suggest that the influx of persistent, long-lived resident memory T cells (Trms) may contribute to the mature psoriatic plaque. It is believed that CD8⁺CD103⁺CD49a⁻ Trm cell populations may be responsible for the sharply demarcated borders of untreated psoriasis plaques or their recurrence at specific body sites such as the scalp, buttocks, extremity extensor surfaces, umbilicus, or acral skin following specific stimuli or trauma (Koebner phenomenon or isomorphic response).^44,45 It is not known if repeated stimuli or trauma induce disease formation via the activation of Trm cell populations; further study in large patient cohorts is needed, but this remains an intriguing area of study for durable treatment responses and potential cures for psoriasis.

Recent Discoveries in Psoriatic Disease

Remarkable treatment outcomes for psoriasis have been achieved with multiple selective IL-17 and IL-23 inhibitors (eTable). As demonstrated in several pivotal phase 3 clinical trials for members of these classes of medications, the majority of treated psoriasis patients achieved PASI90 clearance.⁴⁶ Due to their more favorable dosing schedule (ie, fewer injections) and ability to induce a durable remissionlike treatment response, IL-23 inhibitors have become the preferred treatment class for cutaneous disease, while IL-17 inhibitors may be preferred when treating patients with both plaque psoriasis and PsA.^47,48 Nevertheless, the complexity of this disease is punctuated by treated patients who do not adequately respond to selective IL-23/IL-17 blockade.⁴⁹ Recent and emerging treatments may shed light on these recalcitrant cases and will add to the rapidly growing arsenal of available psoriasis therapies.

The Role of IL-17F in Psoriasis and Other Inflammatory Skin Diseases

Dysregulation of IL-17A and IL-17F is associated with several chronic inflammatory conditions, such as psoriasis and PsA.^35,50 Both cytokines, either as homodimers or heterodimers, can selectively bind to the heterodimeric IL-17R formed by the IL-17RA and IL-17RC subunits.³⁵ IL-17F and IL-17C also can synergize with TNF and other cytokines to promote and support the self-sustaining inflammatory circuits in mature psoriatic plaques, though their inflammatory effects in the skin are more limited than IL-17A.^51,52 Therefore, incomplete blockade of IL-17 signaling (ie, unopposed IL-17F and IL-17C) represents a potential mechanism to explain the persistence of psoriasis in patients treated with selective IL-17A inhibitors. This hypothesis is supported by reports of psoriasis patients who have inadequate clinical responses to selective IL-17A inhibition but subsequently improve with IL-17R blockade, which results in disruption of IL-17A as well as IL-17C/E/F cytokine signaling. This formed the basis for further study into the specific role of IL-17F in psoriatic disease and any potential therapeutic benefits associated with its inhibition.

Recently approved in the European Union, Canada, Australia, Japan, the United Kingdom, and the United States for moderate to severe psoriasis, bimekizumab is a novel humanized IgG antibody that selectively inhibits both IL-17A and IL-17F cytokines.⁵³ Specifically, bimekizumab simultaneously prevents binding of IL-17A/A, IL-17A/F, and IL-17F/F dimers with the IL-17R. Compared to other IL-17 and IL-23 biologic therapies, bimekizumab (320 mg) achieved relatively higher response rates for PASI75, PASI90, and PASI100.⁴⁹ Neutralization of IL-17A and IL-17F by bimekizumab also resulted in more complete suppression of cytokine responses and PMN chemotaxis than either cytokine alone in treated PsA patients,⁵⁴ which is notable because of the incremental benefits of recent IL-23 and IL-17 inhibitors on inflammatory arthritis symptoms in contrast to the substantial improvements observed for cutaneous disease with those same agents.

The primary disadvantage of bimekizumab and its more complete blockade of the IL-17 signaling pathway is that treated patients have a substantially increased risk for oral candidiasis (>10%).⁵⁵ However, the precise link between candidiasis and IL-17 blockade is not yet fully understood because other targeted agents that also broadly suppress IL-17 signaling (ie, IL-17R, IL-23 inhibitors) are associated with much lower rates of candidiasis.^56-58 Bimekizumab also is being investigated as a novel therapy for hidradenitis suppurativa and will provide important reference information regarding the role for bispecific biologic agents in the treatment of chronic inflammatory skin diseases.⁵⁹

Recent genetic and clinical studies have expanded our understanding of the role of IL-36 signaling in the immunopathogenesis of pustular psoriasis variants. Generalized pustular psoriasis (GPP) is a rare distinct psoriasis subtype characterized by the recurrent development of widespread erythema, superficial sterile pustules, and desquamation. Systemic symptoms such as fever, malaise, itching, and skin pain accompany acute GPP flares.⁶⁰ Generalized pustular psoriasis is more common in female patients (in contrast with plaque psoriasis), and acute flares may be caused by multiple stimuli including infections, hypocalcemia, initiation or discontinuation of medications (eg, oral corticosteroids), pregnancy, or stress.^61,62 Flares of GPP often require emergency or in-patient care, as untreated symptoms increase the risk for severe health complications such as secondary infections, sepsis, or multisystem organ failure.⁶³ The prevalence of GPP is estimated to be approximately 1 in 10,000 individuals in the United States,^64-67 with mortality rates ranging from 0 to 3.3 deaths per 100 patient-years.⁶⁷

In contrast to plaque psoriasis, aberrant IL-36 signaling is the predominant driver of GPP. IL-36 is a member of the IL-1 cytokine family that includes three IL-36 agonists (IL-36α, IL-36β, IL-36γ) and 1 endogenous antagonist (IL-36Ra, encoded by IL36RN).⁶⁸ The immunopathogenesis of GPP involves dysregulation of the IL-36–chemokine–PMN axis, resulting in unopposed IL-36 signaling and the subsequent recruitment and influx of PMNs into the epidermis. IL36RN mutations are strongly associated with GPP and result in impaired function of the IL-36Ra protein, leading to unopposed IL-36 signaling.⁶⁹ However, approximately two-thirds of GPP patients lack identifiable gene mutations, suggesting other immune mechanisms or triggers causing upregulated IL-36 signaling.⁷⁰ In response to these triggers, increased IL-36 cytokines released by keratinocytes bind to the IL-36R, resulting in substantial keratinocyte hyperproliferation, increased IL-36 levels, and the expression of hundreds of additional inflammatory signals (eg, IL-17C, antimicrobial peptides, TNF, IL-6).⁷¹ Increased IL-36 levels also drive the production of PMN chemotactic proteins (eg, CXCL1/2/3/5/6/8 and CXCR1/2) and act synergistically with IL-17 cytokines to create an autoamplifying circuit that is analogous to the feed-forward inflammatory loop in plaque psoriasis.⁷² Biopsies of involved GPP skin reveal increased expression of IL-36 in the uppermost layers of the epidermis, which creates a gene expression gradient that acts as a strong attractant for PMNs and forms the basis for the hallmark pustular lesions observed in GPP patients.

Until recently, treatment strategies for GPP involved the off-label use of topical, oral, or biologic therapies approved for plaque psoriasis, which often was associated with variable or incomplete disease control. In September 2022, the US Food and Drug Administration (FDA) approved intravenous spesolimab as a first-in-class humanized monoclonal IgG1 antibody for the treatment of GPP flares in adults. Spesolimab binds to IL-36R and prevents its activation by its endogenous agonists. A phase 2, randomized, 12-week clinical trial (Effisayil-1) evaluated the efficacy and safety of a single 900-mg intravenous dose of spesolimab followed by an optional second dose 1 week later for inadequate treatment responses in 53 enrolled GPP patients (2:1 treatment to placebo randomization).⁷³ Remarkably, more than half (19/35 [54%]) of GPP patients experienced complete resolution of pustules (GPP physician global assessment subscore of 0 [range, 0–4]) and showed sustained efficacy out to week 12 after just 1 or 2 doses of spesolimab. Overall, the safety profile of spesolimab was good; asthenia, fatigue, nausea, vomiting, headache, pruritus, infusion-related reaction and symptoms, and mild infections (eg, urinary tract infection) were the most common adverse events reported.⁷³

Imsidolimab, a high-affinity humanized IgG4 monoclonal antibody that binds and blocks activation of IL-36R, also has completed phase 2 testing,⁷⁴ with phase 3 study results expected in early 2024. The rapid onset of action and overall safety of imsidolimab was in line with and similar to spesolimab. Future approval of imsidolimab would add to the limited treatment options available for GPP and has the additional convenience of being administered to patients subcutaneously. Overall, the development of selective IL-36R inhibitors offers a much-needed therapeutic option for GPP and illustrates the importance of translational research.

Role of Tyrosine Kinase in Psoriatic Disease

The Janus kinase (JAK) enzyme family consists of 4 enzymes—tyrosine kinase 2 (TYK2), JAK1, JAK2, and JAK3—that function as intracellular transduction signals that mediate the biologic response of most extracellular cytokines and growth factors.⁷⁵ Critical psoriasis-related cytokines are dependent on intact JAK-STAT signaling, including IL-23, IL-12, and type I IFNs. In 2010, a genome-wide association identified TYK2 as a psoriasis susceptibility locus,⁷⁶ and loss-of-function TYK2 mutations confer a reduced risk for psoriasis.⁷⁷ Unlike other JAK isoforms, TYK2 mediates biologic functions that are highly restricted to the immune responses associated with IL-23, IL-12, and type I IFN signaling.^78,79 For these reasons, blockade of TYK2 signaling is an attractive therapeutic target for the potential treatment of psoriatic disease.

In September 2022, the FDA approved deucravacitinib as a first-in-class, oral, selective TYK2 inhibitor for the treatment of adult patients with moderate to severe plaque psoriasis. It was the first FDA approval of an oral small-molecule treatment for plaque psoriasis in nearly a decade. Deucravacitinib inhibits TYK2 signaling via selective binding of its unique regulatory domain, resulting in a conformational (allosteric) change that interferes with its active domain.⁸⁰ This novel mechanism of action limits the unwanted blockade of other broad biologic processes mediated by JAK1/2/3. Of note, the FDA did not issue any boxed warnings for deucravacitinib as it did for other FDA-approved JAK inhibitors.

In a head-to-head, 52-week, double-blind, prospective, randomized, phase 3 study, deucravacitinib showed clear superiority over apremilast for PASI75 at week 16 (53.0% [271/511] vs 39.8% [101/254]) and week 24 (58.7% [296/504] vs 37.8% [96/254]).⁸¹ Clinical responses were sustained through week 52 and showed efficacy for difficult-to-treat areas such as the scalp, acral sites, and nails. Other advantages of deucravacitinib include once-daily dosing with no need for dose titration or adjustments for renal insufficiency as well as the absence of statistically significant differences in gastrointestinal tract symptoms compared to placebo. The most common adverse effects included nasopharyngitis, upper respiratory tract infections, headache, diarrhea, and herpes infections.⁸¹ The potential benefit of deucravacitinib for PsA and psoriasis comorbidities remains to be seen, but it is promising due to its simultaneous disruption of multiple psoriasis-related cytokine networks. Several other TYK2 inhibitors are being developed for psoriatic disease and related inflammatory conditions, underscoring the promise of targeting this intracellular pathway.

Topical steroids are the mainstay treatment option for localized or limited plaque psoriasis due to their potent immunosuppressive effect on the skin and relatively low cost. Combined with vitamin D analogs, topical steroids result in marked improvements in disease severity and improved tolerability.⁸² However, chronic use of topical steroids is limited by the need for twice-daily application, resulting in poor treatment compliance; loss of efficacy over time; risk for steroid-induced skin atrophy on special body sites; and patient concerns of potential systemic effects. The discovery of novel drug targets amenable to topical inhibition is needed.

Dysregulated aryl hydrocarbon receptor (AHR) levels have been reported in atopic dermatitis and psoriasis.⁸³ Aryl hydrocarbon receptors are ubiquitously expressed in many cell types and play an integral role in immune homeostasis within the skin, skin barrier function, protection against oxidative stressors, and regulation of proliferating melanocytes and keratinocytes.^84,85 They are widely expressed in multiple immune cell types (eg, antigen-presenting cells, T lymphocytes, fibroblasts) and modulate the differentiation of T17 and T22 cells as well as their balance with regulatory T-cell populations.⁸⁶ In keratinocytes, AHR helps to regulate terminal differentiation, enhance skin barrier integrity via AHR-dependent filaggrin (FLG) expression, and prevent transepidermal water loss.^87,88 The mechanisms by which AHR ligands lead to the upregulation or downregulation of specific genes is intricate and highly context dependent, such as the specific ligand and cell type involved. In preclinical studies, AHR-deficient mice develop psoriasiform skin inflammation, increased IL-17 and IL-22 expression, and abnormal skin barrier function.⁸⁹ Keratinocytes treated with AHR ligands in vitro modulated psoriasis-associated inflammatory cytokines, such as IL-6, IL-8, and type I and II IFNs.^89,90 The use of coal tar, one of the earliest historical treatments for psoriasis, is thought to activate AHRs in the skin via organic compound mixtures containing polyaromatic hydrocarbons that help normalize the proinflammatory environment in psoriatic skin.⁹¹

In June 2022, the FDA approved tapinarof as a first-in-class, topical, nonsteroidal AHR agonist for the treatment of plaque psoriasis in adults. Although the exact mechanism of action for tapinarof has not been fully elucidated, early studies suggest that its primary function is the activation of AHR, leading to reduced T-cell expansion and T17 cell differentiation. In the imiquimod mouse model, cytokine expression of IL-17A, IL-17F, IL-19, IL-22, IL-23A, and IL-lβ in psoriasiform skin lesions were downregulated following tapinarof treatment.⁹² In humans, tapinarof treatment is associated with a remittive effect, in which the average time for tapinarof-treated psoriasis lesions to remain clear was approximately 4 months.⁹³ Preliminary research investigating the mechanism by which tapinarof induces this remittive effect is ongoing and may involve the reduced activation and influx of T17 and Trm populations into the skin.⁹⁴ However, these preclinical studies were performed on healthy dermatome-derived skin tissue cultured in T17-skewing conditions and needs to be replicated in larger samples sizes using human-derived psoriatic tissue. Alternatively, a strong inhibitory effect on IL-23 cytokine signaling may, in part, explain the remittive effect of tapinarof, as an analogous response is observed in patients who start and discontinue treatment with selective IL-23 antagonists. Regardless, the once-daily dosing of tapinarof and sustained treatment response is appealing to psoriasis patients. Tapinarof generally is well tolerated with mild folliculitis (>20% of patients) and contact dermatitis (5% of patients) reported as the most common skin-related adverse events.

New Roles for Phosphodiesterase 4 Inhibition

Phosphodiesterases (PDEs) are enzymes that hydrolyze cyclic nucleotides (eg, cyclic adenosine monophosphate) to regulate intracellular secondary messengers involved in the inflammatory response. One of several enzymes in the PDE family, PDE4, has been shown to have greater activity in psoriatic skin compared to healthy skin.⁹⁵ Phosphodiesterase inhibitors decrease the degradation of cyclic adenosine monophosphate, which triggers protein kinase A to downregulate proinflammatory (eg, TNF-α, IL-6, IL-17, IL-12, IL-23) cytokines and increased expression of anti-inflammatory signals such as IL-10.^96,97 Apremilast, the first oral PDE4 inhibitor approved by the FDA for psoriasis, offered a safe alternative to traditional oral immunosuppressive agents that had extensive risks and potential end-organ adverse effects. Unfortunately, apremilast demonstrated modest efficacy for psoriatic disease (better efficacy in the skin vs joint manifestations) and was supplanted easily by next-generation targeted biologic agents that were more efficacious and lacked the troublesome gastrointestinal tract adverse effects of PDE4 inhibition.⁹⁸

Crisaborole became the first topical PDE4 inhibitor approved in the United States in December 2016 for twice-daily treatment of atopic dermatitis. Although phase 2 trial results were reported in psoriasis, this indication was never pursued, presumably due to similar improvements in primary outcome measures at week 12, compared to placebo (ClinicalTrials.gov Identifier NCT01300052).

In July 2022, the first topical PDE4 inhibitor indicated for plaque psoriasis was approved by the FDA—­roflumilast cream 0.3% for once-daily use in individuals 12 years and older. Roflumilast was found to be clinically efficacious as early as 2 weeks after its use in an early-phase clinical trial.⁹⁹ In 2 phase 3 clinical trials (DERMIS-1 and DERMIS-2), roflumilast significantly increased the proportion of patients achieving PASI75 at week 8 compared to vehicle (39%–41.6% vs 5.3%–7.6%, respectively)(P<.001).¹⁰⁰ Overall, this nonsteroidal topical therapy was found to be well tolerated, with infrequent reports of application site pain or irritation as adverse events. Similar to tapinarof, patients can apply roflumilast on all body surface areas including the face, external genitalia, and other intertriginous areas.¹⁰⁰ Importantly, the broad immune impact of PDE4 inhibition suggests that topical roflumilast likely will be an effective treatment for several additional inflammatory conditions, including seborrheic dermatitis and atopic dermatitis, which would expand the clinical utility of this specific medication.

Conclusion

In the last 2 decades, we have witnessed a translational revolution in our understanding of the underlying genetics and immunology of psoriatic disease. Psoriasis is widely considered one of the best-managed inflammatory conditions in all of medicine due to the development and availability of highly targeted, effective topical and systemic therapies that predominantly disrupt IL-23/IL-17 cytokine signaling in affected tissues. However, future clinical studies and laboratory research are necessary to elucidate the precise cause of psoriasis as well as the underlying genetic and immune signaling pathways driving less common clinical variants and recalcitrant disease.

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Psoriasis is a chronic inflammatory disease that affects approximately 3% of the US population.¹ Plaque psoriasis comprises 80% to 90% of cases, while pustular, erythrodermic, guttate, inverse, and palmoplantar disease are less common variants (Figure 1). Psoriatic skin manifestations range from localized to widespread or generalized disease with recurrent flares. Body surface area or psoriasis area and severity index (PASI) measurements primarily focus on skin manifestations and are important for evaluating disease activity and response to treatment, but they have inherent limitations: they do not capture extracutaneous disease activity, systemic inflammation, comorbid conditions, quality of life impact, or the economic burden of psoriasis.

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A common manifestation of psoriasis is psoriatic arthritis (PsA), which can involve the nails, joints, ligaments, or tendons in 30% to 41% of affected individuals (Figure 2).^2,3 A growing number of psoriasis-associated comorbidities also have been reported including metabolic syndrome⁴; hyperlipidemia⁵; cardiovascular disease⁶; stroke⁷; hypertension⁸; obesity⁹; sleep disorders¹⁰; malignancy¹¹; infections¹²; inflammatory bowel disease¹³; and mental health disorders such as depression,¹⁴ anxiety,¹⁵ and suicidal ideation.¹⁵ Psoriatic disease also interferes with daily life activities and a patient’s overall quality of life, including interpersonal relationships, intimacy, employment, and work productivity.¹⁶ Finally, the total estimated cost of psoriasis-related health care is more than $35 billion annually,¹⁷ representing a substantial economic burden to our health care system and individual patients.

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The overall burden of psoriatic disease has declined markedly in the last 2 decades due to revolutionary advances in our understanding of the immunopathogenesis of psoriasis and the subsequent development of improved therapies that predominantly interrupt IL-23/IL-17 cytokine signaling; however, critical knowledge and treatment gaps persist, underscoring the importance of ongoing clinical and research efforts in psoriatic disease. We review the working immune model of psoriasis, summarize related immune discoveries, and highlight recent therapeutic innovations that are shaping psoriatic disease management.

Current Immune Model of Psoriatic Disease

Psoriasis is an autoinflammatory T cell–mediated disease with negligible contributions from the humoral immune response. Early clinical observations reported increased inflammatory infiltrates in psoriatic skin lesions primarily consisting of both CD4⁺ and CD8⁺ T-cell populations.^18,19 Additionally, patients treated with broad-acting, systemic immunosuppressive medications (eg, cyclosporine, oral corticosteroids) experienced improvement of psoriatic lesions and normalization of the immune infiltrates observed in skin biopsy specimens.^20,21 These early clinical findings led to more sophisticated experimentation in xenotransplant models of psoriasis,^22,23 which explored the clinical efficacy of several less immunosuppressive (eg, methotrexate, anti–tumor necrosis factor [TNF] biologics)²⁴ or T cell–specific agents (eg, alefacept, abatacept, efalizumab).^25-27 The results of these translational studies provided indisputable evidence for the role of the dysregulated immune response as the primary pathogenic process driving plaque formation; they also led to a paradigm shift in how the immunopathogenesis of psoriatic disease was viewed and paved the way for the identification and targeting of other specific proinflammatory signals produced by activated dendritic cell (DC) and T-lymphocyte populations. Among the psoriasis-associated cytokines subsequently identified and studied, elevated IL-23 and IL-17 cytokine levels in psoriatic skin were most closely associated with disease activity, and rapid normalization of IL-23/IL-17 signaling in response to effective oral or injectable antipsoriatic treatments was the hallmark of skin clearance.²⁸ The predominant role of IL-23/IL-17 signaling in the development and maintenance of psoriatic disease is the central feature of all working immune models for this disease (Figure 3).

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Psoriasis-Associated Genetic and Environmental Risk Factors

The exact sequence of events that lead to the initiation and formation of plaque psoriasis in susceptible individuals is still poorly understood; however, several important risk factors and key immune events have been identified. First, decades of genetic research have reported more than 80 known psoriasis-associated susceptibility loci,²⁹ which explains approximately 50% of psoriasis heritability. The major genetic determinant of psoriasis, HLA-C*06:02 (formerly HLA-Cw6), resides in the major histocompatibility complex class I region on chromosome 6p21.3 (psoriasis susceptibility gene 1, PSORS1) and is most strongly associated with psoriatic disease.³⁰ Less common psoriasis-associated susceptibility genes also are known to directly or indirectly impact innate and adaptive immune functions that contribute to the pathogenesis of psoriasis.

Second, several nongenetic environmental risk factors for psoriasis have been reported across diverse patient populations, including skin trauma/injury, infections, alcohol/tobacco use, obesity, medication exposure (eg, lithium, antimalarials, beta-blockers), and stress.³¹ These genetic and/or environmental risk factors can trigger the onset of psoriatic disease at any stage of life, though most patients develop disease in early adulthood or later (age range, 50–60 years). Some patients never develop psoriasis despite exposure to environmental risk factors and/or a genetic makeup that is similar to affected first-degree relatives, which requires further study.

Prepsoriatic Skin and Initiation of Plaque Development

In response to environmental stimuli and/or other triggers of the immune system, DC and resident IL-17–producing T-cell (T17) populations become activated in predisposed individuals. Dendritic cell activation leads to the upregulation and increase of several proinflammatory cytokines, including TNF, interferon (IFN) α, IFN-γ, IL-12, and IL-23. Tumor necrosis factor and IL-23 play a vital role in psoriasis by helping to regulate the polarization and expansion of T22 and T17 cells in the skin, whereas IL-12 promotes a corresponding type 1 inflammatory response.³² Increased IL-17 and IL-22 result in alteration of the terminal differentiation and proliferative potential of epidermal keratinocytes, leading to the early clinical hallmarks of psoriatic plaques. The potential contribution of overexpressed psoriasis-related autoantigens, such as LL-37/cathelicidin, ADAMTSL5, and PLA2G4D,³³ in the initiation of psoriatic plaques has been suggested but is poorly characterized.³⁴ Whether these specific autoantigens or others presented by HLA-C variants found on antigen-presenting cells are required for the breakdown of immune tolerance and psoriatic disease initiation is highly relevant but requires further investigation and validation.

In response to the upstream production of IL-23 by dermal DCs, high levels of IL-17 cytokines can be found in mature psoriatic plaques. The IL-17 family consists of 6 dimeric cytokines (IL-17A through IL-17F) that provide innate cutaneous protection against bacterial, viral, and fungal infectious agents, such as Candida albicans. Unlike other IL-17 isoforms, IL-17A and IL-17F share the same receptor complex and have the highest structural homology of any pair (approximately 50% similar).³⁵ The relative expression of IL-17F is higher than IL-17A in psoriasis,³⁶ though IL-17A has been considered as the predominant IL-17 cytokine found in psoriatic skin lesions due to its higher potency.

Binding of IL-17A/F with the IL-17 receptor (IL-17R) on keratinocytes contributes to the development of psoriatic plaques by inducing epidermal hyperplasia via activation of CCAAT/enhancer-binding proteins β and δ, nuclear factor κB, and signal transducer and activator of transcription 1 gene (STAT1).^37,38 This also increases the expression of other keratinocyte-derived proteins (eg, human β-defensins, S-100 proteins, LL-37, other antimicrobial peptides, IL-19, IL-36, IL-17C) that act as reinforcing proinflammatory signals or chemotactic factors (eg, chemokine [C-C motif] ligand 20 [CCL20], chemokine [C-C motif] ligand 1/2/3/5 [CXCL1/2/3/5], CXCL8, IL-8) that facilitate the recruitment of additional immune cells to the skin including polymorphonuclear neutrophils (PMNs), macrophages, and DCs.^39-41 Routine immunohistochemical staining for these keratinocyte-derived proteins reveals a striking epidermal gene expression gradient wherein levels of IL-17–induced proteins are most highly expressed in the uppermost layers of keratinocytes and facilitate the recruitment of immune cells into the epidermis. Activated T17 cells also stimulate the production of keratinocyte-derived chemokines (eg, CXCL9/10/11), which recruit type 1 inflammatory T-cell populations into developing psoriatic plaques.^42,43 Finally, TNF, IL-36, and IL-17C cytokines act synergistically with IL-17A/F to amplify the proinflammatory effects of IL-17 signaling and further stimulate their production from T17 cell populations.⁴⁰ This inflammatory circuit in the skin creates and supports a self-amplifying or positive feedback loop between the skin and immune system that commonly is referred to as feed-forward inflammation (Figure 3).³⁴ The feed-forward inflammatory loop in psoriasis—predominantly driven by increased IL-23/IL-17 signaling—best characterizes the mature psoriatic plaque.

Several findings suggest that the influx of persistent, long-lived resident memory T cells (Trms) may contribute to the mature psoriatic plaque. It is believed that CD8⁺CD103⁺CD49a⁻ Trm cell populations may be responsible for the sharply demarcated borders of untreated psoriasis plaques or their recurrence at specific body sites such as the scalp, buttocks, extremity extensor surfaces, umbilicus, or acral skin following specific stimuli or trauma (Koebner phenomenon or isomorphic response).^44,45 It is not known if repeated stimuli or trauma induce disease formation via the activation of Trm cell populations; further study in large patient cohorts is needed, but this remains an intriguing area of study for durable treatment responses and potential cures for psoriasis.

Recent Discoveries in Psoriatic Disease

Remarkable treatment outcomes for psoriasis have been achieved with multiple selective IL-17 and IL-23 inhibitors (eTable). As demonstrated in several pivotal phase 3 clinical trials for members of these classes of medications, the majority of treated psoriasis patients achieved PASI90 clearance.⁴⁶ Due to their more favorable dosing schedule (ie, fewer injections) and ability to induce a durable remissionlike treatment response, IL-23 inhibitors have become the preferred treatment class for cutaneous disease, while IL-17 inhibitors may be preferred when treating patients with both plaque psoriasis and PsA.^47,48 Nevertheless, the complexity of this disease is punctuated by treated patients who do not adequately respond to selective IL-23/IL-17 blockade.⁴⁹ Recent and emerging treatments may shed light on these recalcitrant cases and will add to the rapidly growing arsenal of available psoriasis therapies.

The Role of IL-17F in Psoriasis and Other Inflammatory Skin Diseases

Dysregulation of IL-17A and IL-17F is associated with several chronic inflammatory conditions, such as psoriasis and PsA.^35,50 Both cytokines, either as homodimers or heterodimers, can selectively bind to the heterodimeric IL-17R formed by the IL-17RA and IL-17RC subunits.³⁵ IL-17F and IL-17C also can synergize with TNF and other cytokines to promote and support the self-sustaining inflammatory circuits in mature psoriatic plaques, though their inflammatory effects in the skin are more limited than IL-17A.^51,52 Therefore, incomplete blockade of IL-17 signaling (ie, unopposed IL-17F and IL-17C) represents a potential mechanism to explain the persistence of psoriasis in patients treated with selective IL-17A inhibitors. This hypothesis is supported by reports of psoriasis patients who have inadequate clinical responses to selective IL-17A inhibition but subsequently improve with IL-17R blockade, which results in disruption of IL-17A as well as IL-17C/E/F cytokine signaling. This formed the basis for further study into the specific role of IL-17F in psoriatic disease and any potential therapeutic benefits associated with its inhibition.

Recently approved in the European Union, Canada, Australia, Japan, the United Kingdom, and the United States for moderate to severe psoriasis, bimekizumab is a novel humanized IgG antibody that selectively inhibits both IL-17A and IL-17F cytokines.⁵³ Specifically, bimekizumab simultaneously prevents binding of IL-17A/A, IL-17A/F, and IL-17F/F dimers with the IL-17R. Compared to other IL-17 and IL-23 biologic therapies, bimekizumab (320 mg) achieved relatively higher response rates for PASI75, PASI90, and PASI100.⁴⁹ Neutralization of IL-17A and IL-17F by bimekizumab also resulted in more complete suppression of cytokine responses and PMN chemotaxis than either cytokine alone in treated PsA patients,⁵⁴ which is notable because of the incremental benefits of recent IL-23 and IL-17 inhibitors on inflammatory arthritis symptoms in contrast to the substantial improvements observed for cutaneous disease with those same agents.

The primary disadvantage of bimekizumab and its more complete blockade of the IL-17 signaling pathway is that treated patients have a substantially increased risk for oral candidiasis (>10%).⁵⁵ However, the precise link between candidiasis and IL-17 blockade is not yet fully understood because other targeted agents that also broadly suppress IL-17 signaling (ie, IL-17R, IL-23 inhibitors) are associated with much lower rates of candidiasis.^56-58 Bimekizumab also is being investigated as a novel therapy for hidradenitis suppurativa and will provide important reference information regarding the role for bispecific biologic agents in the treatment of chronic inflammatory skin diseases.⁵⁹

Recent genetic and clinical studies have expanded our understanding of the role of IL-36 signaling in the immunopathogenesis of pustular psoriasis variants. Generalized pustular psoriasis (GPP) is a rare distinct psoriasis subtype characterized by the recurrent development of widespread erythema, superficial sterile pustules, and desquamation. Systemic symptoms such as fever, malaise, itching, and skin pain accompany acute GPP flares.⁶⁰ Generalized pustular psoriasis is more common in female patients (in contrast with plaque psoriasis), and acute flares may be caused by multiple stimuli including infections, hypocalcemia, initiation or discontinuation of medications (eg, oral corticosteroids), pregnancy, or stress.^61,62 Flares of GPP often require emergency or in-patient care, as untreated symptoms increase the risk for severe health complications such as secondary infections, sepsis, or multisystem organ failure.⁶³ The prevalence of GPP is estimated to be approximately 1 in 10,000 individuals in the United States,^64-67 with mortality rates ranging from 0 to 3.3 deaths per 100 patient-years.⁶⁷

In contrast to plaque psoriasis, aberrant IL-36 signaling is the predominant driver of GPP. IL-36 is a member of the IL-1 cytokine family that includes three IL-36 agonists (IL-36α, IL-36β, IL-36γ) and 1 endogenous antagonist (IL-36Ra, encoded by IL36RN).⁶⁸ The immunopathogenesis of GPP involves dysregulation of the IL-36–chemokine–PMN axis, resulting in unopposed IL-36 signaling and the subsequent recruitment and influx of PMNs into the epidermis. IL36RN mutations are strongly associated with GPP and result in impaired function of the IL-36Ra protein, leading to unopposed IL-36 signaling.⁶⁹ However, approximately two-thirds of GPP patients lack identifiable gene mutations, suggesting other immune mechanisms or triggers causing upregulated IL-36 signaling.⁷⁰ In response to these triggers, increased IL-36 cytokines released by keratinocytes bind to the IL-36R, resulting in substantial keratinocyte hyperproliferation, increased IL-36 levels, and the expression of hundreds of additional inflammatory signals (eg, IL-17C, antimicrobial peptides, TNF, IL-6).⁷¹ Increased IL-36 levels also drive the production of PMN chemotactic proteins (eg, CXCL1/2/3/5/6/8 and CXCR1/2) and act synergistically with IL-17 cytokines to create an autoamplifying circuit that is analogous to the feed-forward inflammatory loop in plaque psoriasis.⁷² Biopsies of involved GPP skin reveal increased expression of IL-36 in the uppermost layers of the epidermis, which creates a gene expression gradient that acts as a strong attractant for PMNs and forms the basis for the hallmark pustular lesions observed in GPP patients.

Until recently, treatment strategies for GPP involved the off-label use of topical, oral, or biologic therapies approved for plaque psoriasis, which often was associated with variable or incomplete disease control. In September 2022, the US Food and Drug Administration (FDA) approved intravenous spesolimab as a first-in-class humanized monoclonal IgG1 antibody for the treatment of GPP flares in adults. Spesolimab binds to IL-36R and prevents its activation by its endogenous agonists. A phase 2, randomized, 12-week clinical trial (Effisayil-1) evaluated the efficacy and safety of a single 900-mg intravenous dose of spesolimab followed by an optional second dose 1 week later for inadequate treatment responses in 53 enrolled GPP patients (2:1 treatment to placebo randomization).⁷³ Remarkably, more than half (19/35 [54%]) of GPP patients experienced complete resolution of pustules (GPP physician global assessment subscore of 0 [range, 0–4]) and showed sustained efficacy out to week 12 after just 1 or 2 doses of spesolimab. Overall, the safety profile of spesolimab was good; asthenia, fatigue, nausea, vomiting, headache, pruritus, infusion-related reaction and symptoms, and mild infections (eg, urinary tract infection) were the most common adverse events reported.⁷³

Imsidolimab, a high-affinity humanized IgG4 monoclonal antibody that binds and blocks activation of IL-36R, also has completed phase 2 testing,⁷⁴ with phase 3 study results expected in early 2024. The rapid onset of action and overall safety of imsidolimab was in line with and similar to spesolimab. Future approval of imsidolimab would add to the limited treatment options available for GPP and has the additional convenience of being administered to patients subcutaneously. Overall, the development of selective IL-36R inhibitors offers a much-needed therapeutic option for GPP and illustrates the importance of translational research.

Role of Tyrosine Kinase in Psoriatic Disease

The Janus kinase (JAK) enzyme family consists of 4 enzymes—tyrosine kinase 2 (TYK2), JAK1, JAK2, and JAK3—that function as intracellular transduction signals that mediate the biologic response of most extracellular cytokines and growth factors.⁷⁵ Critical psoriasis-related cytokines are dependent on intact JAK-STAT signaling, including IL-23, IL-12, and type I IFNs. In 2010, a genome-wide association identified TYK2 as a psoriasis susceptibility locus,⁷⁶ and loss-of-function TYK2 mutations confer a reduced risk for psoriasis.⁷⁷ Unlike other JAK isoforms, TYK2 mediates biologic functions that are highly restricted to the immune responses associated with IL-23, IL-12, and type I IFN signaling.^78,79 For these reasons, blockade of TYK2 signaling is an attractive therapeutic target for the potential treatment of psoriatic disease.

In September 2022, the FDA approved deucravacitinib as a first-in-class, oral, selective TYK2 inhibitor for the treatment of adult patients with moderate to severe plaque psoriasis. It was the first FDA approval of an oral small-molecule treatment for plaque psoriasis in nearly a decade. Deucravacitinib inhibits TYK2 signaling via selective binding of its unique regulatory domain, resulting in a conformational (allosteric) change that interferes with its active domain.⁸⁰ This novel mechanism of action limits the unwanted blockade of other broad biologic processes mediated by JAK1/2/3. Of note, the FDA did not issue any boxed warnings for deucravacitinib as it did for other FDA-approved JAK inhibitors.

In a head-to-head, 52-week, double-blind, prospective, randomized, phase 3 study, deucravacitinib showed clear superiority over apremilast for PASI75 at week 16 (53.0% [271/511] vs 39.8% [101/254]) and week 24 (58.7% [296/504] vs 37.8% [96/254]).⁸¹ Clinical responses were sustained through week 52 and showed efficacy for difficult-to-treat areas such as the scalp, acral sites, and nails. Other advantages of deucravacitinib include once-daily dosing with no need for dose titration or adjustments for renal insufficiency as well as the absence of statistically significant differences in gastrointestinal tract symptoms compared to placebo. The most common adverse effects included nasopharyngitis, upper respiratory tract infections, headache, diarrhea, and herpes infections.⁸¹ The potential benefit of deucravacitinib for PsA and psoriasis comorbidities remains to be seen, but it is promising due to its simultaneous disruption of multiple psoriasis-related cytokine networks. Several other TYK2 inhibitors are being developed for psoriatic disease and related inflammatory conditions, underscoring the promise of targeting this intracellular pathway.

Topical steroids are the mainstay treatment option for localized or limited plaque psoriasis due to their potent immunosuppressive effect on the skin and relatively low cost. Combined with vitamin D analogs, topical steroids result in marked improvements in disease severity and improved tolerability.⁸² However, chronic use of topical steroids is limited by the need for twice-daily application, resulting in poor treatment compliance; loss of efficacy over time; risk for steroid-induced skin atrophy on special body sites; and patient concerns of potential systemic effects. The discovery of novel drug targets amenable to topical inhibition is needed.

Dysregulated aryl hydrocarbon receptor (AHR) levels have been reported in atopic dermatitis and psoriasis.⁸³ Aryl hydrocarbon receptors are ubiquitously expressed in many cell types and play an integral role in immune homeostasis within the skin, skin barrier function, protection against oxidative stressors, and regulation of proliferating melanocytes and keratinocytes.^84,85 They are widely expressed in multiple immune cell types (eg, antigen-presenting cells, T lymphocytes, fibroblasts) and modulate the differentiation of T17 and T22 cells as well as their balance with regulatory T-cell populations.⁸⁶ In keratinocytes, AHR helps to regulate terminal differentiation, enhance skin barrier integrity via AHR-dependent filaggrin (FLG) expression, and prevent transepidermal water loss.^87,88 The mechanisms by which AHR ligands lead to the upregulation or downregulation of specific genes is intricate and highly context dependent, such as the specific ligand and cell type involved. In preclinical studies, AHR-deficient mice develop psoriasiform skin inflammation, increased IL-17 and IL-22 expression, and abnormal skin barrier function.⁸⁹ Keratinocytes treated with AHR ligands in vitro modulated psoriasis-associated inflammatory cytokines, such as IL-6, IL-8, and type I and II IFNs.^89,90 The use of coal tar, one of the earliest historical treatments for psoriasis, is thought to activate AHRs in the skin via organic compound mixtures containing polyaromatic hydrocarbons that help normalize the proinflammatory environment in psoriatic skin.⁹¹

In June 2022, the FDA approved tapinarof as a first-in-class, topical, nonsteroidal AHR agonist for the treatment of plaque psoriasis in adults. Although the exact mechanism of action for tapinarof has not been fully elucidated, early studies suggest that its primary function is the activation of AHR, leading to reduced T-cell expansion and T17 cell differentiation. In the imiquimod mouse model, cytokine expression of IL-17A, IL-17F, IL-19, IL-22, IL-23A, and IL-lβ in psoriasiform skin lesions were downregulated following tapinarof treatment.⁹² In humans, tapinarof treatment is associated with a remittive effect, in which the average time for tapinarof-treated psoriasis lesions to remain clear was approximately 4 months.⁹³ Preliminary research investigating the mechanism by which tapinarof induces this remittive effect is ongoing and may involve the reduced activation and influx of T17 and Trm populations into the skin.⁹⁴ However, these preclinical studies were performed on healthy dermatome-derived skin tissue cultured in T17-skewing conditions and needs to be replicated in larger samples sizes using human-derived psoriatic tissue. Alternatively, a strong inhibitory effect on IL-23 cytokine signaling may, in part, explain the remittive effect of tapinarof, as an analogous response is observed in patients who start and discontinue treatment with selective IL-23 antagonists. Regardless, the once-daily dosing of tapinarof and sustained treatment response is appealing to psoriasis patients. Tapinarof generally is well tolerated with mild folliculitis (>20% of patients) and contact dermatitis (5% of patients) reported as the most common skin-related adverse events.

New Roles for Phosphodiesterase 4 Inhibition

Phosphodiesterases (PDEs) are enzymes that hydrolyze cyclic nucleotides (eg, cyclic adenosine monophosphate) to regulate intracellular secondary messengers involved in the inflammatory response. One of several enzymes in the PDE family, PDE4, has been shown to have greater activity in psoriatic skin compared to healthy skin.⁹⁵ Phosphodiesterase inhibitors decrease the degradation of cyclic adenosine monophosphate, which triggers protein kinase A to downregulate proinflammatory (eg, TNF-α, IL-6, IL-17, IL-12, IL-23) cytokines and increased expression of anti-inflammatory signals such as IL-10.^96,97 Apremilast, the first oral PDE4 inhibitor approved by the FDA for psoriasis, offered a safe alternative to traditional oral immunosuppressive agents that had extensive risks and potential end-organ adverse effects. Unfortunately, apremilast demonstrated modest efficacy for psoriatic disease (better efficacy in the skin vs joint manifestations) and was supplanted easily by next-generation targeted biologic agents that were more efficacious and lacked the troublesome gastrointestinal tract adverse effects of PDE4 inhibition.⁹⁸

Crisaborole became the first topical PDE4 inhibitor approved in the United States in December 2016 for twice-daily treatment of atopic dermatitis. Although phase 2 trial results were reported in psoriasis, this indication was never pursued, presumably due to similar improvements in primary outcome measures at week 12, compared to placebo (ClinicalTrials.gov Identifier NCT01300052).

In July 2022, the first topical PDE4 inhibitor indicated for plaque psoriasis was approved by the FDA—­roflumilast cream 0.3% for once-daily use in individuals 12 years and older. Roflumilast was found to be clinically efficacious as early as 2 weeks after its use in an early-phase clinical trial.⁹⁹ In 2 phase 3 clinical trials (DERMIS-1 and DERMIS-2), roflumilast significantly increased the proportion of patients achieving PASI75 at week 8 compared to vehicle (39%–41.6% vs 5.3%–7.6%, respectively)(P<.001).¹⁰⁰ Overall, this nonsteroidal topical therapy was found to be well tolerated, with infrequent reports of application site pain or irritation as adverse events. Similar to tapinarof, patients can apply roflumilast on all body surface areas including the face, external genitalia, and other intertriginous areas.¹⁰⁰ Importantly, the broad immune impact of PDE4 inhibition suggests that topical roflumilast likely will be an effective treatment for several additional inflammatory conditions, including seborrheic dermatitis and atopic dermatitis, which would expand the clinical utility of this specific medication.

Conclusion

In the last 2 decades, we have witnessed a translational revolution in our understanding of the underlying genetics and immunology of psoriatic disease. Psoriasis is widely considered one of the best-managed inflammatory conditions in all of medicine due to the development and availability of highly targeted, effective topical and systemic therapies that predominantly disrupt IL-23/IL-17 cytokine signaling in affected tissues. However, future clinical studies and laboratory research are necessary to elucidate the precise cause of psoriasis as well as the underlying genetic and immune signaling pathways driving less common clinical variants and recalcitrant disease.

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Psoriasis is a chronic inflammatory disease that affects approximately 3% of the US population.¹ Plaque psoriasis comprises 80% to 90% of cases, while pustular, erythrodermic, guttate, inverse, and palmoplantar disease are less common variants (Figure 1). Psoriatic skin manifestations range from localized to widespread or generalized disease with recurrent flares. Body surface area or psoriasis area and severity index (PASI) measurements primarily focus on skin manifestations and are important for evaluating disease activity and response to treatment, but they have inherent limitations: they do not capture extracutaneous disease activity, systemic inflammation, comorbid conditions, quality of life impact, or the economic burden of psoriasis.

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A common manifestation of psoriasis is psoriatic arthritis (PsA), which can involve the nails, joints, ligaments, or tendons in 30% to 41% of affected individuals (Figure 2).^2,3 A growing number of psoriasis-associated comorbidities also have been reported including metabolic syndrome⁴; hyperlipidemia⁵; cardiovascular disease⁶; stroke⁷; hypertension⁸; obesity⁹; sleep disorders¹⁰; malignancy¹¹; infections¹²; inflammatory bowel disease¹³; and mental health disorders such as depression,¹⁴ anxiety,¹⁵ and suicidal ideation.¹⁵ Psoriatic disease also interferes with daily life activities and a patient’s overall quality of life, including interpersonal relationships, intimacy, employment, and work productivity.¹⁶ Finally, the total estimated cost of psoriasis-related health care is more than $35 billion annually,¹⁷ representing a substantial economic burden to our health care system and individual patients.

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The overall burden of psoriatic disease has declined markedly in the last 2 decades due to revolutionary advances in our understanding of the immunopathogenesis of psoriasis and the subsequent development of improved therapies that predominantly interrupt IL-23/IL-17 cytokine signaling; however, critical knowledge and treatment gaps persist, underscoring the importance of ongoing clinical and research efforts in psoriatic disease. We review the working immune model of psoriasis, summarize related immune discoveries, and highlight recent therapeutic innovations that are shaping psoriatic disease management.

Current Immune Model of Psoriatic Disease

Psoriasis is an autoinflammatory T cell–mediated disease with negligible contributions from the humoral immune response. Early clinical observations reported increased inflammatory infiltrates in psoriatic skin lesions primarily consisting of both CD4⁺ and CD8⁺ T-cell populations.^18,19 Additionally, patients treated with broad-acting, systemic immunosuppressive medications (eg, cyclosporine, oral corticosteroids) experienced improvement of psoriatic lesions and normalization of the immune infiltrates observed in skin biopsy specimens.^20,21 These early clinical findings led to more sophisticated experimentation in xenotransplant models of psoriasis,^22,23 which explored the clinical efficacy of several less immunosuppressive (eg, methotrexate, anti–tumor necrosis factor [TNF] biologics)²⁴ or T cell–specific agents (eg, alefacept, abatacept, efalizumab).^25-27 The results of these translational studies provided indisputable evidence for the role of the dysregulated immune response as the primary pathogenic process driving plaque formation; they also led to a paradigm shift in how the immunopathogenesis of psoriatic disease was viewed and paved the way for the identification and targeting of other specific proinflammatory signals produced by activated dendritic cell (DC) and T-lymphocyte populations. Among the psoriasis-associated cytokines subsequently identified and studied, elevated IL-23 and IL-17 cytokine levels in psoriatic skin were most closely associated with disease activity, and rapid normalization of IL-23/IL-17 signaling in response to effective oral or injectable antipsoriatic treatments was the hallmark of skin clearance.²⁸ The predominant role of IL-23/IL-17 signaling in the development and maintenance of psoriatic disease is the central feature of all working immune models for this disease (Figure 3).

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Psoriasis-Associated Genetic and Environmental Risk Factors

The exact sequence of events that lead to the initiation and formation of plaque psoriasis in susceptible individuals is still poorly understood; however, several important risk factors and key immune events have been identified. First, decades of genetic research have reported more than 80 known psoriasis-associated susceptibility loci,²⁹ which explains approximately 50% of psoriasis heritability. The major genetic determinant of psoriasis, HLA-C*06:02 (formerly HLA-Cw6), resides in the major histocompatibility complex class I region on chromosome 6p21.3 (psoriasis susceptibility gene 1, PSORS1) and is most strongly associated with psoriatic disease.³⁰ Less common psoriasis-associated susceptibility genes also are known to directly or indirectly impact innate and adaptive immune functions that contribute to the pathogenesis of psoriasis.

Second, several nongenetic environmental risk factors for psoriasis have been reported across diverse patient populations, including skin trauma/injury, infections, alcohol/tobacco use, obesity, medication exposure (eg, lithium, antimalarials, beta-blockers), and stress.³¹ These genetic and/or environmental risk factors can trigger the onset of psoriatic disease at any stage of life, though most patients develop disease in early adulthood or later (age range, 50–60 years). Some patients never develop psoriasis despite exposure to environmental risk factors and/or a genetic makeup that is similar to affected first-degree relatives, which requires further study.

Prepsoriatic Skin and Initiation of Plaque Development

In response to environmental stimuli and/or other triggers of the immune system, DC and resident IL-17–producing T-cell (T17) populations become activated in predisposed individuals. Dendritic cell activation leads to the upregulation and increase of several proinflammatory cytokines, including TNF, interferon (IFN) α, IFN-γ, IL-12, and IL-23. Tumor necrosis factor and IL-23 play a vital role in psoriasis by helping to regulate the polarization and expansion of T22 and T17 cells in the skin, whereas IL-12 promotes a corresponding type 1 inflammatory response.³² Increased IL-17 and IL-22 result in alteration of the terminal differentiation and proliferative potential of epidermal keratinocytes, leading to the early clinical hallmarks of psoriatic plaques. The potential contribution of overexpressed psoriasis-related autoantigens, such as LL-37/cathelicidin, ADAMTSL5, and PLA2G4D,³³ in the initiation of psoriatic plaques has been suggested but is poorly characterized.³⁴ Whether these specific autoantigens or others presented by HLA-C variants found on antigen-presenting cells are required for the breakdown of immune tolerance and psoriatic disease initiation is highly relevant but requires further investigation and validation.

In response to the upstream production of IL-23 by dermal DCs, high levels of IL-17 cytokines can be found in mature psoriatic plaques. The IL-17 family consists of 6 dimeric cytokines (IL-17A through IL-17F) that provide innate cutaneous protection against bacterial, viral, and fungal infectious agents, such as Candida albicans. Unlike other IL-17 isoforms, IL-17A and IL-17F share the same receptor complex and have the highest structural homology of any pair (approximately 50% similar).³⁵ The relative expression of IL-17F is higher than IL-17A in psoriasis,³⁶ though IL-17A has been considered as the predominant IL-17 cytokine found in psoriatic skin lesions due to its higher potency.

Binding of IL-17A/F with the IL-17 receptor (IL-17R) on keratinocytes contributes to the development of psoriatic plaques by inducing epidermal hyperplasia via activation of CCAAT/enhancer-binding proteins β and δ, nuclear factor κB, and signal transducer and activator of transcription 1 gene (STAT1).^37,38 This also increases the expression of other keratinocyte-derived proteins (eg, human β-defensins, S-100 proteins, LL-37, other antimicrobial peptides, IL-19, IL-36, IL-17C) that act as reinforcing proinflammatory signals or chemotactic factors (eg, chemokine [C-C motif] ligand 20 [CCL20], chemokine [C-C motif] ligand 1/2/3/5 [CXCL1/2/3/5], CXCL8, IL-8) that facilitate the recruitment of additional immune cells to the skin including polymorphonuclear neutrophils (PMNs), macrophages, and DCs.^39-41 Routine immunohistochemical staining for these keratinocyte-derived proteins reveals a striking epidermal gene expression gradient wherein levels of IL-17–induced proteins are most highly expressed in the uppermost layers of keratinocytes and facilitate the recruitment of immune cells into the epidermis. Activated T17 cells also stimulate the production of keratinocyte-derived chemokines (eg, CXCL9/10/11), which recruit type 1 inflammatory T-cell populations into developing psoriatic plaques.^42,43 Finally, TNF, IL-36, and IL-17C cytokines act synergistically with IL-17A/F to amplify the proinflammatory effects of IL-17 signaling and further stimulate their production from T17 cell populations.⁴⁰ This inflammatory circuit in the skin creates and supports a self-amplifying or positive feedback loop between the skin and immune system that commonly is referred to as feed-forward inflammation (Figure 3).³⁴ The feed-forward inflammatory loop in psoriasis—predominantly driven by increased IL-23/IL-17 signaling—best characterizes the mature psoriatic plaque.

Several findings suggest that the influx of persistent, long-lived resident memory T cells (Trms) may contribute to the mature psoriatic plaque. It is believed that CD8⁺CD103⁺CD49a⁻ Trm cell populations may be responsible for the sharply demarcated borders of untreated psoriasis plaques or their recurrence at specific body sites such as the scalp, buttocks, extremity extensor surfaces, umbilicus, or acral skin following specific stimuli or trauma (Koebner phenomenon or isomorphic response).^44,45 It is not known if repeated stimuli or trauma induce disease formation via the activation of Trm cell populations; further study in large patient cohorts is needed, but this remains an intriguing area of study for durable treatment responses and potential cures for psoriasis.

Recent Discoveries in Psoriatic Disease

Remarkable treatment outcomes for psoriasis have been achieved with multiple selective IL-17 and IL-23 inhibitors (eTable). As demonstrated in several pivotal phase 3 clinical trials for members of these classes of medications, the majority of treated psoriasis patients achieved PASI90 clearance.⁴⁶ Due to their more favorable dosing schedule (ie, fewer injections) and ability to induce a durable remissionlike treatment response, IL-23 inhibitors have become the preferred treatment class for cutaneous disease, while IL-17 inhibitors may be preferred when treating patients with both plaque psoriasis and PsA.^47,48 Nevertheless, the complexity of this disease is punctuated by treated patients who do not adequately respond to selective IL-23/IL-17 blockade.⁴⁹ Recent and emerging treatments may shed light on these recalcitrant cases and will add to the rapidly growing arsenal of available psoriasis therapies.

The Role of IL-17F in Psoriasis and Other Inflammatory Skin Diseases

Dysregulation of IL-17A and IL-17F is associated with several chronic inflammatory conditions, such as psoriasis and PsA.^35,50 Both cytokines, either as homodimers or heterodimers, can selectively bind to the heterodimeric IL-17R formed by the IL-17RA and IL-17RC subunits.³⁵ IL-17F and IL-17C also can synergize with TNF and other cytokines to promote and support the self-sustaining inflammatory circuits in mature psoriatic plaques, though their inflammatory effects in the skin are more limited than IL-17A.^51,52 Therefore, incomplete blockade of IL-17 signaling (ie, unopposed IL-17F and IL-17C) represents a potential mechanism to explain the persistence of psoriasis in patients treated with selective IL-17A inhibitors. This hypothesis is supported by reports of psoriasis patients who have inadequate clinical responses to selective IL-17A inhibition but subsequently improve with IL-17R blockade, which results in disruption of IL-17A as well as IL-17C/E/F cytokine signaling. This formed the basis for further study into the specific role of IL-17F in psoriatic disease and any potential therapeutic benefits associated with its inhibition.

Recently approved in the European Union, Canada, Australia, Japan, the United Kingdom, and the United States for moderate to severe psoriasis, bimekizumab is a novel humanized IgG antibody that selectively inhibits both IL-17A and IL-17F cytokines.⁵³ Specifically, bimekizumab simultaneously prevents binding of IL-17A/A, IL-17A/F, and IL-17F/F dimers with the IL-17R. Compared to other IL-17 and IL-23 biologic therapies, bimekizumab (320 mg) achieved relatively higher response rates for PASI75, PASI90, and PASI100.⁴⁹ Neutralization of IL-17A and IL-17F by bimekizumab also resulted in more complete suppression of cytokine responses and PMN chemotaxis than either cytokine alone in treated PsA patients,⁵⁴ which is notable because of the incremental benefits of recent IL-23 and IL-17 inhibitors on inflammatory arthritis symptoms in contrast to the substantial improvements observed for cutaneous disease with those same agents.

The primary disadvantage of bimekizumab and its more complete blockade of the IL-17 signaling pathway is that treated patients have a substantially increased risk for oral candidiasis (>10%).⁵⁵ However, the precise link between candidiasis and IL-17 blockade is not yet fully understood because other targeted agents that also broadly suppress IL-17 signaling (ie, IL-17R, IL-23 inhibitors) are associated with much lower rates of candidiasis.^56-58 Bimekizumab also is being investigated as a novel therapy for hidradenitis suppurativa and will provide important reference information regarding the role for bispecific biologic agents in the treatment of chronic inflammatory skin diseases.⁵⁹

Recent genetic and clinical studies have expanded our understanding of the role of IL-36 signaling in the immunopathogenesis of pustular psoriasis variants. Generalized pustular psoriasis (GPP) is a rare distinct psoriasis subtype characterized by the recurrent development of widespread erythema, superficial sterile pustules, and desquamation. Systemic symptoms such as fever, malaise, itching, and skin pain accompany acute GPP flares.⁶⁰ Generalized pustular psoriasis is more common in female patients (in contrast with plaque psoriasis), and acute flares may be caused by multiple stimuli including infections, hypocalcemia, initiation or discontinuation of medications (eg, oral corticosteroids), pregnancy, or stress.^61,62 Flares of GPP often require emergency or in-patient care, as untreated symptoms increase the risk for severe health complications such as secondary infections, sepsis, or multisystem organ failure.⁶³ The prevalence of GPP is estimated to be approximately 1 in 10,000 individuals in the United States,^64-67 with mortality rates ranging from 0 to 3.3 deaths per 100 patient-years.⁶⁷

In contrast to plaque psoriasis, aberrant IL-36 signaling is the predominant driver of GPP. IL-36 is a member of the IL-1 cytokine family that includes three IL-36 agonists (IL-36α, IL-36β, IL-36γ) and 1 endogenous antagonist (IL-36Ra, encoded by IL36RN).⁶⁸ The immunopathogenesis of GPP involves dysregulation of the IL-36–chemokine–PMN axis, resulting in unopposed IL-36 signaling and the subsequent recruitment and influx of PMNs into the epidermis. IL36RN mutations are strongly associated with GPP and result in impaired function of the IL-36Ra protein, leading to unopposed IL-36 signaling.⁶⁹ However, approximately two-thirds of GPP patients lack identifiable gene mutations, suggesting other immune mechanisms or triggers causing upregulated IL-36 signaling.⁷⁰ In response to these triggers, increased IL-36 cytokines released by keratinocytes bind to the IL-36R, resulting in substantial keratinocyte hyperproliferation, increased IL-36 levels, and the expression of hundreds of additional inflammatory signals (eg, IL-17C, antimicrobial peptides, TNF, IL-6).⁷¹ Increased IL-36 levels also drive the production of PMN chemotactic proteins (eg, CXCL1/2/3/5/6/8 and CXCR1/2) and act synergistically with IL-17 cytokines to create an autoamplifying circuit that is analogous to the feed-forward inflammatory loop in plaque psoriasis.⁷² Biopsies of involved GPP skin reveal increased expression of IL-36 in the uppermost layers of the epidermis, which creates a gene expression gradient that acts as a strong attractant for PMNs and forms the basis for the hallmark pustular lesions observed in GPP patients.

Until recently, treatment strategies for GPP involved the off-label use of topical, oral, or biologic therapies approved for plaque psoriasis, which often was associated with variable or incomplete disease control. In September 2022, the US Food and Drug Administration (FDA) approved intravenous spesolimab as a first-in-class humanized monoclonal IgG1 antibody for the treatment of GPP flares in adults. Spesolimab binds to IL-36R and prevents its activation by its endogenous agonists. A phase 2, randomized, 12-week clinical trial (Effisayil-1) evaluated the efficacy and safety of a single 900-mg intravenous dose of spesolimab followed by an optional second dose 1 week later for inadequate treatment responses in 53 enrolled GPP patients (2:1 treatment to placebo randomization).⁷³ Remarkably, more than half (19/35 [54%]) of GPP patients experienced complete resolution of pustules (GPP physician global assessment subscore of 0 [range, 0–4]) and showed sustained efficacy out to week 12 after just 1 or 2 doses of spesolimab. Overall, the safety profile of spesolimab was good; asthenia, fatigue, nausea, vomiting, headache, pruritus, infusion-related reaction and symptoms, and mild infections (eg, urinary tract infection) were the most common adverse events reported.⁷³

Imsidolimab, a high-affinity humanized IgG4 monoclonal antibody that binds and blocks activation of IL-36R, also has completed phase 2 testing,⁷⁴ with phase 3 study results expected in early 2024. The rapid onset of action and overall safety of imsidolimab was in line with and similar to spesolimab. Future approval of imsidolimab would add to the limited treatment options available for GPP and has the additional convenience of being administered to patients subcutaneously. Overall, the development of selective IL-36R inhibitors offers a much-needed therapeutic option for GPP and illustrates the importance of translational research.

Role of Tyrosine Kinase in Psoriatic Disease

The Janus kinase (JAK) enzyme family consists of 4 enzymes—tyrosine kinase 2 (TYK2), JAK1, JAK2, and JAK3—that function as intracellular transduction signals that mediate the biologic response of most extracellular cytokines and growth factors.⁷⁵ Critical psoriasis-related cytokines are dependent on intact JAK-STAT signaling, including IL-23, IL-12, and type I IFNs. In 2010, a genome-wide association identified TYK2 as a psoriasis susceptibility locus,⁷⁶ and loss-of-function TYK2 mutations confer a reduced risk for psoriasis.⁷⁷ Unlike other JAK isoforms, TYK2 mediates biologic functions that are highly restricted to the immune responses associated with IL-23, IL-12, and type I IFN signaling.^78,79 For these reasons, blockade of TYK2 signaling is an attractive therapeutic target for the potential treatment of psoriatic disease.

In September 2022, the FDA approved deucravacitinib as a first-in-class, oral, selective TYK2 inhibitor for the treatment of adult patients with moderate to severe plaque psoriasis. It was the first FDA approval of an oral small-molecule treatment for plaque psoriasis in nearly a decade. Deucravacitinib inhibits TYK2 signaling via selective binding of its unique regulatory domain, resulting in a conformational (allosteric) change that interferes with its active domain.⁸⁰ This novel mechanism of action limits the unwanted blockade of other broad biologic processes mediated by JAK1/2/3. Of note, the FDA did not issue any boxed warnings for deucravacitinib as it did for other FDA-approved JAK inhibitors.

In a head-to-head, 52-week, double-blind, prospective, randomized, phase 3 study, deucravacitinib showed clear superiority over apremilast for PASI75 at week 16 (53.0% [271/511] vs 39.8% [101/254]) and week 24 (58.7% [296/504] vs 37.8% [96/254]).⁸¹ Clinical responses were sustained through week 52 and showed efficacy for difficult-to-treat areas such as the scalp, acral sites, and nails. Other advantages of deucravacitinib include once-daily dosing with no need for dose titration or adjustments for renal insufficiency as well as the absence of statistically significant differences in gastrointestinal tract symptoms compared to placebo. The most common adverse effects included nasopharyngitis, upper respiratory tract infections, headache, diarrhea, and herpes infections.⁸¹ The potential benefit of deucravacitinib for PsA and psoriasis comorbidities remains to be seen, but it is promising due to its simultaneous disruption of multiple psoriasis-related cytokine networks. Several other TYK2 inhibitors are being developed for psoriatic disease and related inflammatory conditions, underscoring the promise of targeting this intracellular pathway.

Topical steroids are the mainstay treatment option for localized or limited plaque psoriasis due to their potent immunosuppressive effect on the skin and relatively low cost. Combined with vitamin D analogs, topical steroids result in marked improvements in disease severity and improved tolerability.⁸² However, chronic use of topical steroids is limited by the need for twice-daily application, resulting in poor treatment compliance; loss of efficacy over time; risk for steroid-induced skin atrophy on special body sites; and patient concerns of potential systemic effects. The discovery of novel drug targets amenable to topical inhibition is needed.

Dysregulated aryl hydrocarbon receptor (AHR) levels have been reported in atopic dermatitis and psoriasis.⁸³ Aryl hydrocarbon receptors are ubiquitously expressed in many cell types and play an integral role in immune homeostasis within the skin, skin barrier function, protection against oxidative stressors, and regulation of proliferating melanocytes and keratinocytes.^84,85 They are widely expressed in multiple immune cell types (eg, antigen-presenting cells, T lymphocytes, fibroblasts) and modulate the differentiation of T17 and T22 cells as well as their balance with regulatory T-cell populations.⁸⁶ In keratinocytes, AHR helps to regulate terminal differentiation, enhance skin barrier integrity via AHR-dependent filaggrin (FLG) expression, and prevent transepidermal water loss.^87,88 The mechanisms by which AHR ligands lead to the upregulation or downregulation of specific genes is intricate and highly context dependent, such as the specific ligand and cell type involved. In preclinical studies, AHR-deficient mice develop psoriasiform skin inflammation, increased IL-17 and IL-22 expression, and abnormal skin barrier function.⁸⁹ Keratinocytes treated with AHR ligands in vitro modulated psoriasis-associated inflammatory cytokines, such as IL-6, IL-8, and type I and II IFNs.^89,90 The use of coal tar, one of the earliest historical treatments for psoriasis, is thought to activate AHRs in the skin via organic compound mixtures containing polyaromatic hydrocarbons that help normalize the proinflammatory environment in psoriatic skin.⁹¹

In June 2022, the FDA approved tapinarof as a first-in-class, topical, nonsteroidal AHR agonist for the treatment of plaque psoriasis in adults. Although the exact mechanism of action for tapinarof has not been fully elucidated, early studies suggest that its primary function is the activation of AHR, leading to reduced T-cell expansion and T17 cell differentiation. In the imiquimod mouse model, cytokine expression of IL-17A, IL-17F, IL-19, IL-22, IL-23A, and IL-lβ in psoriasiform skin lesions were downregulated following tapinarof treatment.⁹² In humans, tapinarof treatment is associated with a remittive effect, in which the average time for tapinarof-treated psoriasis lesions to remain clear was approximately 4 months.⁹³ Preliminary research investigating the mechanism by which tapinarof induces this remittive effect is ongoing and may involve the reduced activation and influx of T17 and Trm populations into the skin.⁹⁴ However, these preclinical studies were performed on healthy dermatome-derived skin tissue cultured in T17-skewing conditions and needs to be replicated in larger samples sizes using human-derived psoriatic tissue. Alternatively, a strong inhibitory effect on IL-23 cytokine signaling may, in part, explain the remittive effect of tapinarof, as an analogous response is observed in patients who start and discontinue treatment with selective IL-23 antagonists. Regardless, the once-daily dosing of tapinarof and sustained treatment response is appealing to psoriasis patients. Tapinarof generally is well tolerated with mild folliculitis (>20% of patients) and contact dermatitis (5% of patients) reported as the most common skin-related adverse events.

New Roles for Phosphodiesterase 4 Inhibition

Phosphodiesterases (PDEs) are enzymes that hydrolyze cyclic nucleotides (eg, cyclic adenosine monophosphate) to regulate intracellular secondary messengers involved in the inflammatory response. One of several enzymes in the PDE family, PDE4, has been shown to have greater activity in psoriatic skin compared to healthy skin.⁹⁵ Phosphodiesterase inhibitors decrease the degradation of cyclic adenosine monophosphate, which triggers protein kinase A to downregulate proinflammatory (eg, TNF-α, IL-6, IL-17, IL-12, IL-23) cytokines and increased expression of anti-inflammatory signals such as IL-10.^96,97 Apremilast, the first oral PDE4 inhibitor approved by the FDA for psoriasis, offered a safe alternative to traditional oral immunosuppressive agents that had extensive risks and potential end-organ adverse effects. Unfortunately, apremilast demonstrated modest efficacy for psoriatic disease (better efficacy in the skin vs joint manifestations) and was supplanted easily by next-generation targeted biologic agents that were more efficacious and lacked the troublesome gastrointestinal tract adverse effects of PDE4 inhibition.⁹⁸

Crisaborole became the first topical PDE4 inhibitor approved in the United States in December 2016 for twice-daily treatment of atopic dermatitis. Although phase 2 trial results were reported in psoriasis, this indication was never pursued, presumably due to similar improvements in primary outcome measures at week 12, compared to placebo (ClinicalTrials.gov Identifier NCT01300052).

In July 2022, the first topical PDE4 inhibitor indicated for plaque psoriasis was approved by the FDA—­roflumilast cream 0.3% for once-daily use in individuals 12 years and older. Roflumilast was found to be clinically efficacious as early as 2 weeks after its use in an early-phase clinical trial.⁹⁹ In 2 phase 3 clinical trials (DERMIS-1 and DERMIS-2), roflumilast significantly increased the proportion of patients achieving PASI75 at week 8 compared to vehicle (39%–41.6% vs 5.3%–7.6%, respectively)(P<.001).¹⁰⁰ Overall, this nonsteroidal topical therapy was found to be well tolerated, with infrequent reports of application site pain or irritation as adverse events. Similar to tapinarof, patients can apply roflumilast on all body surface areas including the face, external genitalia, and other intertriginous areas.¹⁰⁰ Importantly, the broad immune impact of PDE4 inhibition suggests that topical roflumilast likely will be an effective treatment for several additional inflammatory conditions, including seborrheic dermatitis and atopic dermatitis, which would expand the clinical utility of this specific medication.

Conclusion

In the last 2 decades, we have witnessed a translational revolution in our understanding of the underlying genetics and immunology of psoriatic disease. Psoriasis is widely considered one of the best-managed inflammatory conditions in all of medicine due to the development and availability of highly targeted, effective topical and systemic therapies that predominantly disrupt IL-23/IL-17 cytokine signaling in affected tissues. However, future clinical studies and laboratory research are necessary to elucidate the precise cause of psoriasis as well as the underlying genetic and immune signaling pathways driving less common clinical variants and recalcitrant disease.

CT11302082_eTable.jpg

Acne vulgaris, or acne, is a highly common inflammatory skin disorder affecting up to 85% of the population, and it constitutes the most commonly presenting chief concern in routine dermatology practice.¹ Older teenagers and young adults are most often affected by acne.² Although acne generally is more common in males, adult-onset acne occurs more frequently in women.^2,3 Black and Hispanic women are at higher risk for acne compared to those of Asian, White, or Continental Indian descent.⁴ As such, acne is a common concern in all women of childbearing age.

Concerns for maternal and fetal safety are important therapeutic considerations, especially because hormonal and physiologic changes in pregnancy can lead to onset of inflammatory acne lesions, particularly during the second and third trimesters.⁵ Female patients younger than 25 years; with a higher body mass index, prior irregular menstruation, or polycystic ovary syndrome; or those experiencing their first pregnancy are thought to be more commonly affected.^5-7 In fact, acne affects up to 43% of pregnant women, and lesions typically extend beyond the face to involve the trunk.^6,8-10 Importantly, one-third of women with a history of acne experience symptom relapse after disease-free periods, while two-thirds of those with ongoing disease experience symptom deterioration during pregnancy.¹⁰ Although acne is not a life-threatening condition, it has a well-documented, detrimental impact on social, emotional, and psychological well-being, namely self-perception, social interactions, quality-of-life scores, depression, and anxiety.¹¹

Therefore, safe and effective treatment of pregnant women is of paramount importance. Because pregnant women are not included in clinical trials, there is a paucity of medication safety data, further augmented by inefficient access to available information. The US Food and Drug Administration (FDA) pregnancy safety categories were updated in 2015, letting go of the traditional A, B, C, D, and X categories.¹² The Table reviews the current pregnancy classification system. In this narrative review, we summarize the most recent available data and recommendations on the safety and efficacy of acne treatment during pregnancy.

CT113001026_e_Table.jpg

Topical Treatments for Acne

Benzoyl Peroxide—Benzoyl peroxide commonly is used as first-line therapy alone or in combination with other agents for the treatment of mild to moderate acne.¹³ It is safe for use during pregnancy.¹⁴ Although the medication is systemically absorbed, it undergoes complete metabolism to benzoic acid, a commonly used food additive.^15,16 Benzoic acid has low bioavailability, as it gets rapidly metabolized by the kidneys; therefore, benzoyl peroxide is unlikely to reach clinically significant levels in the maternal circulation and consequently the fetal circulation. Additionally, it has a low risk for causing congenital malformations.¹⁷

Salicylic Acid—For mild to moderate acne, salicylic acid is a second-line agent that likely is safe for use by pregnant women at low concentrations and over limited body surface areas.^14,18,19 There is minimal systemic absorption of the drug.²⁰ Additionally, aspirin, which is broken down in the body into salicylic acid, is used in low doses for the treatment of pre-eclampsia during pregnancy.²¹

Dapsone—The use of dapsone gel 5% as a second-line agent has shown efficacy for mild to moderate acne.²² The oral formulation, commonly used for malaria and leprosy prophylaxis, has failed to show associated fetal toxicity or congenital anomalies.^23,24 It also has been used as a first-line treatment for dermatitis herpetiformis in pregnancy.²⁵ Although the medication likely is safe, it is better to minimize its use during the third trimester to reduce the theoretical risk for hyperbilirubinemia in the neonate.^17,26-29

Azelaic Acid—Azelaic acid effectively targets noninflammatory and inflammatory acne and generally is well tolerated, harboring a good safety profile.³⁰ Topical 20% azelaic acid has localized antibacterial and comedolytic effects and is safe for use during pregnancy.^31,32

Glycolic Acid—Limited data exist on the safety of glycolic acid during pregnancy. In vitro studies have shown up to 27% systemic absorption depending on pH, concentration, and duration of application.³³ Animal reproductive studies involving rats have shown fetal multisystem malformations and developmental abnormalities with oral administration of glycolic acid at doses far exceeding those used in humans.³⁴ Although no human reproductive studies exist, topical glycolic acid is unlikely to reach the developing fetus in notable amounts, and the medication is likely safe for use.^17,35

Clindamycin—Topical clindamycin phosphate is an effective and well-tolerated agent for the treatment of mild to moderate acne.³⁶ Its systemic absorption is minimal, and it is considered safe for use during all trimesters of pregnancy.^{14,17,26,27,35,37}

Erythromycin—Topical erythromycin is another commonly prescribed topical antibiotic used to target mild to moderate acne. However, its use recently has been associated with a decrease in efficacy secondary to the rise of antibacterial resistance in the community.^38-40 Nevertheless, it remains a safe treatment for use during all trimesters of pregnancy.^{14,17,26,27,35,37}

Topical Retinoids—Vitamin A derivatives (also known as retinoids) are the mainstay for the treatment of mild to moderate acne. Limited data exist regarding pregnancy outcomes after in utero exposure.⁴¹ A rare case report suggested topical tretinoin has been associated with fetal otocerebral anomalies.⁴² For tazarotene, teratogenic effects were seen in animal reproductive studies at doses exceeding maximum recommended human doses.^41,43 However, a large meta-analysis failed to find a clear risk for increased congenital malformations, spontaneous abortions, stillbirth, elective termination of pregnancy, low birthweight, or prematurity following first-trimester exposure to topical retinoids.⁴⁴ As the level of exposure that could lead to teratogenicity in humans is unknown, avoidance of both tretinoin and tazarotene is recommended in pregnant women.^41,45 Nevertheless, women inadvertently exposed should be reassured.⁴⁴

Conversely, adapalene has been associated with 1 case of anophthalmia and agenesis of the optic chiasma in a fetus following exposure until 13 weeks’ gestation.⁴⁶ However, a large, open-label trial prior to the patient transitioning from adapalene to over-the-counter treatment showed that the drug harbors a large and reassuring margin of safety and no risk for teratogenicity in a maximal usage trial and Pregnancy Safety Review.⁴⁷ Therefore, adapalene gel 0.1% is a safe and effective medication for the treatment of acne in a nonprescription environment and does not pose harm to the fetus.

Clascoterone—Clascoterone is a novel topical antiandrogenic drug approved for the treatment of hormonal and inflammatory moderate to severe acne.^48-51 Human reproductive data are limited to 1 case of pregnancy that occurred during phase 3 trial investigations, and no adverse outcomes were reported.⁵¹ Minimal systemic absorption follows topical use.⁵² Nonetheless, dose-independent malformations were reported in animal reproductive studies.⁵³ As such, it remains better to avoid the use of clascoterone during pregnancy pending further safety data.

Minocycline Foam—Minocycline foam 4% is approved to treat inflammatory lesions of nonnodular moderate to severe acne in patients 9 years and older.⁵⁴ Systemic absorption is minimal, and the drug has limited bioavailability with minimal systemic accumulation in the patient’s serum.⁵⁵ Given this information, it is unlikely that topical minocycline will reach notable levels in the fetal serum or harbor teratogenic effects, as seen with the oral formulation.⁵⁶ However, it may be best to avoid its use during the second and third trimesters given the potential risk for tooth discoloration in the fetus.^57,58

Systemic Treatments for Acne

Isotretinoin—Isotretinoin is the most effective treatment for moderate to severe acne with a well-documented potential for long-term clearance.⁵⁹ Its use during pregnancy is absolutely contraindicated, as the medication is a well-known teratogen. Associated congenital malformations include numerous craniofacial defects, cardiovascular and neurologic malformations, or thymic disorders that are estimated to affect 20% to 35% of infants exposed in utero.⁶⁰ Furthermore, strict contraception use during treatment is mandated for patients who can become pregnant. It is recommended to wait at least 1 month and 1 menstrual cycle after medication discontinuation before attempting to conceive.¹⁷ Pregnancy termination is recommended if conception occurs during treatment with isotretinoin.

Spironolactone—Spironolactone is an androgen-receptor antagonist commonly prescribed off label for mild to severe acne in females.^61,62 Spironolactone promotes the feminization of male fetuses and should be avoided in pregnancy.⁶³

Doxycycline/Minocycline—Tetracyclines are the most commonly prescribed oral antibiotics for moderate to severe acne.⁶⁴ Although highly effective at treating acne, tetracyclines generally should be avoided in pregnancy. First-trimester use of doxycycline is not absolutely contraindicated but should be reserved for severe illness and not employed for the treatment of acne. However, accidental exposure to doxycycline has not been associated with congenital malformations.⁶⁵ Nevertheless, after the 15th week of gestation, permanent tooth discoloration and bone growth inhibition in the fetus are serious and well-documented risks.^14,17 Additional adverse events following in utero exposure include infantile inguinal hernia, hypospadias, and limb hypoplasia.⁶³

Sarecycline—Sarecycline is a novel tetracycline-class antibiotic for the treatment of moderate to severe inflammatory acne. It has a narrower spectrum of activity compared to its counterparts within its class, which translates to an improved safety profile, namely when it comes to gastrointestinal tract microbiome disruption and potentially decreased likelihood of developing bacterial resistance.⁶⁶ Data on human reproductive studies are limited, but it is advisable to avoid sarecycline in pregnancy, as it may cause adverse developmental effects in the fetus, such as reduced bone growth, in addition to the well-known tetracycline-associated risk for permanent discoloration of the teeth if used during the second and third trimesters.^67,68

Erythromycin—Oral erythromycin targets moderate to severe inflammatory acne and is considered safe for use during pregnancy.^69,70 There has been 1 study reporting an increased risk for atrial and ventricular septal defects (1.8%) and pyloric stenosis (0.2%), but these risks are still uncertain, and erythromycin is considered compatible with pregnancy.⁷¹ However, erythromycin estolate formulations should be avoided given the associated 10% to 15% risk for reversible cholestatic liver injury.⁷² Erythromycin base or erythromycin ethylsuccinate formulations should be favored.

Systemic Steroids—Prednisone is indicated for severe acne with scarring and should only be used during pregnancy after clearance from the patient’s obstetrician. Doses of 0.5 mg/kg or less should be prescribed in combination with systemic antibiotics as well as agents for bone and gastrointestinal tract prophylaxis.²⁹

Zinc—The exact mechanism by which zinc exerts its effects to improve acne remains largely obscure. It has been found effective against inflammatory lesions of mild to moderate acne.⁷³ Generally recommended dosages range from 30 to 200 mg/d but may be associated with gastrointestinal tract disturbances. Dosages of 75 mg/d have shown no harm to the fetus.⁷⁴ When taking this supplement, patients should not exceed the recommended doses given the risk for hypocupremia associated with high-dose zinc supplementation.

Light-Based Therapies

Phototherapy—Narrowband UVB phototherapy is effective for the treatment of mild to moderate acne.⁷⁵ It has been proven to be a safe treatment option during pregnancy, but its use has been associated with decreased folic acid levels.^76-79 Therefore, in addition to attaining baseline folic acid serum levels, supplementation with folic acid prior to treatment, as per routine prenatal guidelines, should be sought.⁸⁰

AviClear—The AviClear (Cutera) laser is the first device cleared by the FDA for mild to severe acne in March 2022.⁸¹ The FDA clearance for the Accure (Accure Acne Inc) laser, also targeting mild to severe acne, followed soon after (November 2022). Both lasers harbor a wavelength of 1726 nm and target sebaceous glands with electrothermolysis.^82,83 Further research and long-term safety data are required before using them in pregnancy.

Other Therapies

Cosmetic Peels—Glycolic acid peels induce epidermolysis and desquamation.⁸⁴ Although data on use during pregnancy are limited, these peels have limited dermal penetration and are considered safe for use in pregnancy.^33,85,86 Similarly, keratolytic lactic acid peels harbor limited dermal penetration and can be safely used in pregnant women.^87-89 Salicylic acid peels also work through epidermolysis and desquamation⁸⁴; however, they tend to penetrate deeper into the skin, reaching down to the basal layer, if large areas are treated or when applied under occlusion.^86,90 Although their use is not contraindicated in pregnancy, they should be limited to small areas of coverage.⁹¹

Intralesional Triamcinolone—Acne cysts and inflammatory papules can be treated with intralesional triamcinolone injections to relieve acute symptoms such as pain.⁹² Low doses at concentrations of 2.5 mg/mL are considered compatible with pregnancy when indicated.²⁹

Approaching the Patient Clinical Encounter

In patients seeking treatment prior to conception, a few recommendations can be made to minimize the risk for acne recurrence or flares during pregnancy. For instance, because data show an association between increased acne severity in those with a higher body mass index and in pregnancy, weight loss may be recommended prior to pregnancy to help mitigate symptoms after conception.⁷ The Figure summarizes our recommendations for approaching and treating acne in pregnancy.

ret_Yaghi_figure.jpg

In all patients, grading the severity of the patient’s acne as mild, moderate, or severe is the first step. The presence of scarring is an additional consideration during the physical examination and should be documented. A careful discussion of treatment expectations and prognosis should be the focus before treatment initiation. Meticulous documentation of the physical examination and discussion with the patient should be prioritized.

To minimize toxicity and risks to the developing fetus, monotherapy is favored. Topical therapy should be considered first line. Safe regimens include mild nonabrasive washes, such as those containing benzoyl peroxide or glycolic acid, or topical azelaic acid or clindamycin phosphate for mild to moderate acne. More severe cases warrant the consideration of systemic medications as second line, as more severe acne is better treated with oral antibiotics such as the macrolides erythromycin or clindamycin or systemic corticosteroids when concern exists for severe scarring. The additional use of physical sunscreen also is recommended.

An important topic to address during the clinical encounter is cautious intake of oral supplements for acne during pregnancy, as they may contain harmful and teratogenic ingredients. A recent search focusing on acne supplements available online between March and May 2020 uncovered 49 different supplements, 26 (53%) of which contained vitamin A.⁹³ Importantly, 3 (6%) of these 49 supplements were likely teratogenic, 4 (8%) contained vitamin A doses exceeding the recommended daily nutritional intake level, and 15 (31%) harbored an unknown teratogenic risk. Furthermore, among the 6 (12%) supplements with vitamin A levels exceeding 10,000 IU, 2 lacked any mention of pregnancy warning, including the supplement with the highest vitamin A dose found in this study.⁹³ Because dietary supplements are not subject to the same stringent regulations by the FDA as drugs, inadvertent use by unaware patients ought to be prevented by careful counseling and education.

Finally, patients should be counseled to seek care following delivery for potentially updated medication management of acne, especially if they are breastfeeding. Co-management with a pediatrician may be indicated during lactation, particularly when newborns are born preterm or with other health conditions that may warrant additional caution with the use of certain agents.

Acne vulgaris, or acne, is a highly common inflammatory skin disorder affecting up to 85% of the population, and it constitutes the most commonly presenting chief concern in routine dermatology practice.¹ Older teenagers and young adults are most often affected by acne.² Although acne generally is more common in males, adult-onset acne occurs more frequently in women.^2,3 Black and Hispanic women are at higher risk for acne compared to those of Asian, White, or Continental Indian descent.⁴ As such, acne is a common concern in all women of childbearing age.

Concerns for maternal and fetal safety are important therapeutic considerations, especially because hormonal and physiologic changes in pregnancy can lead to onset of inflammatory acne lesions, particularly during the second and third trimesters.⁵ Female patients younger than 25 years; with a higher body mass index, prior irregular menstruation, or polycystic ovary syndrome; or those experiencing their first pregnancy are thought to be more commonly affected.^5-7 In fact, acne affects up to 43% of pregnant women, and lesions typically extend beyond the face to involve the trunk.^6,8-10 Importantly, one-third of women with a history of acne experience symptom relapse after disease-free periods, while two-thirds of those with ongoing disease experience symptom deterioration during pregnancy.¹⁰ Although acne is not a life-threatening condition, it has a well-documented, detrimental impact on social, emotional, and psychological well-being, namely self-perception, social interactions, quality-of-life scores, depression, and anxiety.¹¹

Therefore, safe and effective treatment of pregnant women is of paramount importance. Because pregnant women are not included in clinical trials, there is a paucity of medication safety data, further augmented by inefficient access to available information. The US Food and Drug Administration (FDA) pregnancy safety categories were updated in 2015, letting go of the traditional A, B, C, D, and X categories.¹² The Table reviews the current pregnancy classification system. In this narrative review, we summarize the most recent available data and recommendations on the safety and efficacy of acne treatment during pregnancy.

CT113001026_e_Table.jpg

Topical Treatments for Acne

Benzoyl Peroxide—Benzoyl peroxide commonly is used as first-line therapy alone or in combination with other agents for the treatment of mild to moderate acne.¹³ It is safe for use during pregnancy.¹⁴ Although the medication is systemically absorbed, it undergoes complete metabolism to benzoic acid, a commonly used food additive.^15,16 Benzoic acid has low bioavailability, as it gets rapidly metabolized by the kidneys; therefore, benzoyl peroxide is unlikely to reach clinically significant levels in the maternal circulation and consequently the fetal circulation. Additionally, it has a low risk for causing congenital malformations.¹⁷

Salicylic Acid—For mild to moderate acne, salicylic acid is a second-line agent that likely is safe for use by pregnant women at low concentrations and over limited body surface areas.^14,18,19 There is minimal systemic absorption of the drug.²⁰ Additionally, aspirin, which is broken down in the body into salicylic acid, is used in low doses for the treatment of pre-eclampsia during pregnancy.²¹

Dapsone—The use of dapsone gel 5% as a second-line agent has shown efficacy for mild to moderate acne.²² The oral formulation, commonly used for malaria and leprosy prophylaxis, has failed to show associated fetal toxicity or congenital anomalies.^23,24 It also has been used as a first-line treatment for dermatitis herpetiformis in pregnancy.²⁵ Although the medication likely is safe, it is better to minimize its use during the third trimester to reduce the theoretical risk for hyperbilirubinemia in the neonate.^17,26-29

Azelaic Acid—Azelaic acid effectively targets noninflammatory and inflammatory acne and generally is well tolerated, harboring a good safety profile.³⁰ Topical 20% azelaic acid has localized antibacterial and comedolytic effects and is safe for use during pregnancy.^31,32

Glycolic Acid—Limited data exist on the safety of glycolic acid during pregnancy. In vitro studies have shown up to 27% systemic absorption depending on pH, concentration, and duration of application.³³ Animal reproductive studies involving rats have shown fetal multisystem malformations and developmental abnormalities with oral administration of glycolic acid at doses far exceeding those used in humans.³⁴ Although no human reproductive studies exist, topical glycolic acid is unlikely to reach the developing fetus in notable amounts, and the medication is likely safe for use.^17,35

Clindamycin—Topical clindamycin phosphate is an effective and well-tolerated agent for the treatment of mild to moderate acne.³⁶ Its systemic absorption is minimal, and it is considered safe for use during all trimesters of pregnancy.^{14,17,26,27,35,37}

Erythromycin—Topical erythromycin is another commonly prescribed topical antibiotic used to target mild to moderate acne. However, its use recently has been associated with a decrease in efficacy secondary to the rise of antibacterial resistance in the community.^38-40 Nevertheless, it remains a safe treatment for use during all trimesters of pregnancy.^{14,17,26,27,35,37}

Topical Retinoids—Vitamin A derivatives (also known as retinoids) are the mainstay for the treatment of mild to moderate acne. Limited data exist regarding pregnancy outcomes after in utero exposure.⁴¹ A rare case report suggested topical tretinoin has been associated with fetal otocerebral anomalies.⁴² For tazarotene, teratogenic effects were seen in animal reproductive studies at doses exceeding maximum recommended human doses.^41,43 However, a large meta-analysis failed to find a clear risk for increased congenital malformations, spontaneous abortions, stillbirth, elective termination of pregnancy, low birthweight, or prematurity following first-trimester exposure to topical retinoids.⁴⁴ As the level of exposure that could lead to teratogenicity in humans is unknown, avoidance of both tretinoin and tazarotene is recommended in pregnant women.^41,45 Nevertheless, women inadvertently exposed should be reassured.⁴⁴

Conversely, adapalene has been associated with 1 case of anophthalmia and agenesis of the optic chiasma in a fetus following exposure until 13 weeks’ gestation.⁴⁶ However, a large, open-label trial prior to the patient transitioning from adapalene to over-the-counter treatment showed that the drug harbors a large and reassuring margin of safety and no risk for teratogenicity in a maximal usage trial and Pregnancy Safety Review.⁴⁷ Therefore, adapalene gel 0.1% is a safe and effective medication for the treatment of acne in a nonprescription environment and does not pose harm to the fetus.

Clascoterone—Clascoterone is a novel topical antiandrogenic drug approved for the treatment of hormonal and inflammatory moderate to severe acne.^48-51 Human reproductive data are limited to 1 case of pregnancy that occurred during phase 3 trial investigations, and no adverse outcomes were reported.⁵¹ Minimal systemic absorption follows topical use.⁵² Nonetheless, dose-independent malformations were reported in animal reproductive studies.⁵³ As such, it remains better to avoid the use of clascoterone during pregnancy pending further safety data.

Minocycline Foam—Minocycline foam 4% is approved to treat inflammatory lesions of nonnodular moderate to severe acne in patients 9 years and older.⁵⁴ Systemic absorption is minimal, and the drug has limited bioavailability with minimal systemic accumulation in the patient’s serum.⁵⁵ Given this information, it is unlikely that topical minocycline will reach notable levels in the fetal serum or harbor teratogenic effects, as seen with the oral formulation.⁵⁶ However, it may be best to avoid its use during the second and third trimesters given the potential risk for tooth discoloration in the fetus.^57,58

Systemic Treatments for Acne

Isotretinoin—Isotretinoin is the most effective treatment for moderate to severe acne with a well-documented potential for long-term clearance.⁵⁹ Its use during pregnancy is absolutely contraindicated, as the medication is a well-known teratogen. Associated congenital malformations include numerous craniofacial defects, cardiovascular and neurologic malformations, or thymic disorders that are estimated to affect 20% to 35% of infants exposed in utero.⁶⁰ Furthermore, strict contraception use during treatment is mandated for patients who can become pregnant. It is recommended to wait at least 1 month and 1 menstrual cycle after medication discontinuation before attempting to conceive.¹⁷ Pregnancy termination is recommended if conception occurs during treatment with isotretinoin.

Spironolactone—Spironolactone is an androgen-receptor antagonist commonly prescribed off label for mild to severe acne in females.^61,62 Spironolactone promotes the feminization of male fetuses and should be avoided in pregnancy.⁶³

Doxycycline/Minocycline—Tetracyclines are the most commonly prescribed oral antibiotics for moderate to severe acne.⁶⁴ Although highly effective at treating acne, tetracyclines generally should be avoided in pregnancy. First-trimester use of doxycycline is not absolutely contraindicated but should be reserved for severe illness and not employed for the treatment of acne. However, accidental exposure to doxycycline has not been associated with congenital malformations.⁶⁵ Nevertheless, after the 15th week of gestation, permanent tooth discoloration and bone growth inhibition in the fetus are serious and well-documented risks.^14,17 Additional adverse events following in utero exposure include infantile inguinal hernia, hypospadias, and limb hypoplasia.⁶³

Sarecycline—Sarecycline is a novel tetracycline-class antibiotic for the treatment of moderate to severe inflammatory acne. It has a narrower spectrum of activity compared to its counterparts within its class, which translates to an improved safety profile, namely when it comes to gastrointestinal tract microbiome disruption and potentially decreased likelihood of developing bacterial resistance.⁶⁶ Data on human reproductive studies are limited, but it is advisable to avoid sarecycline in pregnancy, as it may cause adverse developmental effects in the fetus, such as reduced bone growth, in addition to the well-known tetracycline-associated risk for permanent discoloration of the teeth if used during the second and third trimesters.^67,68

Erythromycin—Oral erythromycin targets moderate to severe inflammatory acne and is considered safe for use during pregnancy.^69,70 There has been 1 study reporting an increased risk for atrial and ventricular septal defects (1.8%) and pyloric stenosis (0.2%), but these risks are still uncertain, and erythromycin is considered compatible with pregnancy.⁷¹ However, erythromycin estolate formulations should be avoided given the associated 10% to 15% risk for reversible cholestatic liver injury.⁷² Erythromycin base or erythromycin ethylsuccinate formulations should be favored.

Systemic Steroids—Prednisone is indicated for severe acne with scarring and should only be used during pregnancy after clearance from the patient’s obstetrician. Doses of 0.5 mg/kg or less should be prescribed in combination with systemic antibiotics as well as agents for bone and gastrointestinal tract prophylaxis.²⁹

Zinc—The exact mechanism by which zinc exerts its effects to improve acne remains largely obscure. It has been found effective against inflammatory lesions of mild to moderate acne.⁷³ Generally recommended dosages range from 30 to 200 mg/d but may be associated with gastrointestinal tract disturbances. Dosages of 75 mg/d have shown no harm to the fetus.⁷⁴ When taking this supplement, patients should not exceed the recommended doses given the risk for hypocupremia associated with high-dose zinc supplementation.

Light-Based Therapies

Phototherapy—Narrowband UVB phototherapy is effective for the treatment of mild to moderate acne.⁷⁵ It has been proven to be a safe treatment option during pregnancy, but its use has been associated with decreased folic acid levels.^76-79 Therefore, in addition to attaining baseline folic acid serum levels, supplementation with folic acid prior to treatment, as per routine prenatal guidelines, should be sought.⁸⁰

AviClear—The AviClear (Cutera) laser is the first device cleared by the FDA for mild to severe acne in March 2022.⁸¹ The FDA clearance for the Accure (Accure Acne Inc) laser, also targeting mild to severe acne, followed soon after (November 2022). Both lasers harbor a wavelength of 1726 nm and target sebaceous glands with electrothermolysis.^82,83 Further research and long-term safety data are required before using them in pregnancy.

Other Therapies

Cosmetic Peels—Glycolic acid peels induce epidermolysis and desquamation.⁸⁴ Although data on use during pregnancy are limited, these peels have limited dermal penetration and are considered safe for use in pregnancy.^33,85,86 Similarly, keratolytic lactic acid peels harbor limited dermal penetration and can be safely used in pregnant women.^87-89 Salicylic acid peels also work through epidermolysis and desquamation⁸⁴; however, they tend to penetrate deeper into the skin, reaching down to the basal layer, if large areas are treated or when applied under occlusion.^86,90 Although their use is not contraindicated in pregnancy, they should be limited to small areas of coverage.⁹¹

Intralesional Triamcinolone—Acne cysts and inflammatory papules can be treated with intralesional triamcinolone injections to relieve acute symptoms such as pain.⁹² Low doses at concentrations of 2.5 mg/mL are considered compatible with pregnancy when indicated.²⁹

Approaching the Patient Clinical Encounter

In patients seeking treatment prior to conception, a few recommendations can be made to minimize the risk for acne recurrence or flares during pregnancy. For instance, because data show an association between increased acne severity in those with a higher body mass index and in pregnancy, weight loss may be recommended prior to pregnancy to help mitigate symptoms after conception.⁷ The Figure summarizes our recommendations for approaching and treating acne in pregnancy.

ret_Yaghi_figure.jpg

In all patients, grading the severity of the patient’s acne as mild, moderate, or severe is the first step. The presence of scarring is an additional consideration during the physical examination and should be documented. A careful discussion of treatment expectations and prognosis should be the focus before treatment initiation. Meticulous documentation of the physical examination and discussion with the patient should be prioritized.

To minimize toxicity and risks to the developing fetus, monotherapy is favored. Topical therapy should be considered first line. Safe regimens include mild nonabrasive washes, such as those containing benzoyl peroxide or glycolic acid, or topical azelaic acid or clindamycin phosphate for mild to moderate acne. More severe cases warrant the consideration of systemic medications as second line, as more severe acne is better treated with oral antibiotics such as the macrolides erythromycin or clindamycin or systemic corticosteroids when concern exists for severe scarring. The additional use of physical sunscreen also is recommended.

An important topic to address during the clinical encounter is cautious intake of oral supplements for acne during pregnancy, as they may contain harmful and teratogenic ingredients. A recent search focusing on acne supplements available online between March and May 2020 uncovered 49 different supplements, 26 (53%) of which contained vitamin A.⁹³ Importantly, 3 (6%) of these 49 supplements were likely teratogenic, 4 (8%) contained vitamin A doses exceeding the recommended daily nutritional intake level, and 15 (31%) harbored an unknown teratogenic risk. Furthermore, among the 6 (12%) supplements with vitamin A levels exceeding 10,000 IU, 2 lacked any mention of pregnancy warning, including the supplement with the highest vitamin A dose found in this study.⁹³ Because dietary supplements are not subject to the same stringent regulations by the FDA as drugs, inadvertent use by unaware patients ought to be prevented by careful counseling and education.

Finally, patients should be counseled to seek care following delivery for potentially updated medication management of acne, especially if they are breastfeeding. Co-management with a pediatrician may be indicated during lactation, particularly when newborns are born preterm or with other health conditions that may warrant additional caution with the use of certain agents.

Acne vulgaris, or acne, is a highly common inflammatory skin disorder affecting up to 85% of the population, and it constitutes the most commonly presenting chief concern in routine dermatology practice.¹ Older teenagers and young adults are most often affected by acne.² Although acne generally is more common in males, adult-onset acne occurs more frequently in women.^2,3 Black and Hispanic women are at higher risk for acne compared to those of Asian, White, or Continental Indian descent.⁴ As such, acne is a common concern in all women of childbearing age.

Concerns for maternal and fetal safety are important therapeutic considerations, especially because hormonal and physiologic changes in pregnancy can lead to onset of inflammatory acne lesions, particularly during the second and third trimesters.⁵ Female patients younger than 25 years; with a higher body mass index, prior irregular menstruation, or polycystic ovary syndrome; or those experiencing their first pregnancy are thought to be more commonly affected.^5-7 In fact, acne affects up to 43% of pregnant women, and lesions typically extend beyond the face to involve the trunk.^6,8-10 Importantly, one-third of women with a history of acne experience symptom relapse after disease-free periods, while two-thirds of those with ongoing disease experience symptom deterioration during pregnancy.¹⁰ Although acne is not a life-threatening condition, it has a well-documented, detrimental impact on social, emotional, and psychological well-being, namely self-perception, social interactions, quality-of-life scores, depression, and anxiety.¹¹

Therefore, safe and effective treatment of pregnant women is of paramount importance. Because pregnant women are not included in clinical trials, there is a paucity of medication safety data, further augmented by inefficient access to available information. The US Food and Drug Administration (FDA) pregnancy safety categories were updated in 2015, letting go of the traditional A, B, C, D, and X categories.¹² The Table reviews the current pregnancy classification system. In this narrative review, we summarize the most recent available data and recommendations on the safety and efficacy of acne treatment during pregnancy.

CT113001026_e_Table.jpg

Topical Treatments for Acne

Benzoyl Peroxide—Benzoyl peroxide commonly is used as first-line therapy alone or in combination with other agents for the treatment of mild to moderate acne.¹³ It is safe for use during pregnancy.¹⁴ Although the medication is systemically absorbed, it undergoes complete metabolism to benzoic acid, a commonly used food additive.^15,16 Benzoic acid has low bioavailability, as it gets rapidly metabolized by the kidneys; therefore, benzoyl peroxide is unlikely to reach clinically significant levels in the maternal circulation and consequently the fetal circulation. Additionally, it has a low risk for causing congenital malformations.¹⁷

Salicylic Acid—For mild to moderate acne, salicylic acid is a second-line agent that likely is safe for use by pregnant women at low concentrations and over limited body surface areas.^14,18,19 There is minimal systemic absorption of the drug.²⁰ Additionally, aspirin, which is broken down in the body into salicylic acid, is used in low doses for the treatment of pre-eclampsia during pregnancy.²¹

Dapsone—The use of dapsone gel 5% as a second-line agent has shown efficacy for mild to moderate acne.²² The oral formulation, commonly used for malaria and leprosy prophylaxis, has failed to show associated fetal toxicity or congenital anomalies.^23,24 It also has been used as a first-line treatment for dermatitis herpetiformis in pregnancy.²⁵ Although the medication likely is safe, it is better to minimize its use during the third trimester to reduce the theoretical risk for hyperbilirubinemia in the neonate.^17,26-29

Azelaic Acid—Azelaic acid effectively targets noninflammatory and inflammatory acne and generally is well tolerated, harboring a good safety profile.³⁰ Topical 20% azelaic acid has localized antibacterial and comedolytic effects and is safe for use during pregnancy.^31,32

Glycolic Acid—Limited data exist on the safety of glycolic acid during pregnancy. In vitro studies have shown up to 27% systemic absorption depending on pH, concentration, and duration of application.³³ Animal reproductive studies involving rats have shown fetal multisystem malformations and developmental abnormalities with oral administration of glycolic acid at doses far exceeding those used in humans.³⁴ Although no human reproductive studies exist, topical glycolic acid is unlikely to reach the developing fetus in notable amounts, and the medication is likely safe for use.^17,35

Clindamycin—Topical clindamycin phosphate is an effective and well-tolerated agent for the treatment of mild to moderate acne.³⁶ Its systemic absorption is minimal, and it is considered safe for use during all trimesters of pregnancy.^{14,17,26,27,35,37}

Erythromycin—Topical erythromycin is another commonly prescribed topical antibiotic used to target mild to moderate acne. However, its use recently has been associated with a decrease in efficacy secondary to the rise of antibacterial resistance in the community.^38-40 Nevertheless, it remains a safe treatment for use during all trimesters of pregnancy.^{14,17,26,27,35,37}

Topical Retinoids—Vitamin A derivatives (also known as retinoids) are the mainstay for the treatment of mild to moderate acne. Limited data exist regarding pregnancy outcomes after in utero exposure.⁴¹ A rare case report suggested topical tretinoin has been associated with fetal otocerebral anomalies.⁴² For tazarotene, teratogenic effects were seen in animal reproductive studies at doses exceeding maximum recommended human doses.^41,43 However, a large meta-analysis failed to find a clear risk for increased congenital malformations, spontaneous abortions, stillbirth, elective termination of pregnancy, low birthweight, or prematurity following first-trimester exposure to topical retinoids.⁴⁴ As the level of exposure that could lead to teratogenicity in humans is unknown, avoidance of both tretinoin and tazarotene is recommended in pregnant women.^41,45 Nevertheless, women inadvertently exposed should be reassured.⁴⁴

Conversely, adapalene has been associated with 1 case of anophthalmia and agenesis of the optic chiasma in a fetus following exposure until 13 weeks’ gestation.⁴⁶ However, a large, open-label trial prior to the patient transitioning from adapalene to over-the-counter treatment showed that the drug harbors a large and reassuring margin of safety and no risk for teratogenicity in a maximal usage trial and Pregnancy Safety Review.⁴⁷ Therefore, adapalene gel 0.1% is a safe and effective medication for the treatment of acne in a nonprescription environment and does not pose harm to the fetus.

Clascoterone—Clascoterone is a novel topical antiandrogenic drug approved for the treatment of hormonal and inflammatory moderate to severe acne.^48-51 Human reproductive data are limited to 1 case of pregnancy that occurred during phase 3 trial investigations, and no adverse outcomes were reported.⁵¹ Minimal systemic absorption follows topical use.⁵² Nonetheless, dose-independent malformations were reported in animal reproductive studies.⁵³ As such, it remains better to avoid the use of clascoterone during pregnancy pending further safety data.

Minocycline Foam—Minocycline foam 4% is approved to treat inflammatory lesions of nonnodular moderate to severe acne in patients 9 years and older.⁵⁴ Systemic absorption is minimal, and the drug has limited bioavailability with minimal systemic accumulation in the patient’s serum.⁵⁵ Given this information, it is unlikely that topical minocycline will reach notable levels in the fetal serum or harbor teratogenic effects, as seen with the oral formulation.⁵⁶ However, it may be best to avoid its use during the second and third trimesters given the potential risk for tooth discoloration in the fetus.^57,58

Systemic Treatments for Acne

Isotretinoin—Isotretinoin is the most effective treatment for moderate to severe acne with a well-documented potential for long-term clearance.⁵⁹ Its use during pregnancy is absolutely contraindicated, as the medication is a well-known teratogen. Associated congenital malformations include numerous craniofacial defects, cardiovascular and neurologic malformations, or thymic disorders that are estimated to affect 20% to 35% of infants exposed in utero.⁶⁰ Furthermore, strict contraception use during treatment is mandated for patients who can become pregnant. It is recommended to wait at least 1 month and 1 menstrual cycle after medication discontinuation before attempting to conceive.¹⁷ Pregnancy termination is recommended if conception occurs during treatment with isotretinoin.

Spironolactone—Spironolactone is an androgen-receptor antagonist commonly prescribed off label for mild to severe acne in females.^61,62 Spironolactone promotes the feminization of male fetuses and should be avoided in pregnancy.⁶³

Doxycycline/Minocycline—Tetracyclines are the most commonly prescribed oral antibiotics for moderate to severe acne.⁶⁴ Although highly effective at treating acne, tetracyclines generally should be avoided in pregnancy. First-trimester use of doxycycline is not absolutely contraindicated but should be reserved for severe illness and not employed for the treatment of acne. However, accidental exposure to doxycycline has not been associated with congenital malformations.⁶⁵ Nevertheless, after the 15th week of gestation, permanent tooth discoloration and bone growth inhibition in the fetus are serious and well-documented risks.^14,17 Additional adverse events following in utero exposure include infantile inguinal hernia, hypospadias, and limb hypoplasia.⁶³

Sarecycline—Sarecycline is a novel tetracycline-class antibiotic for the treatment of moderate to severe inflammatory acne. It has a narrower spectrum of activity compared to its counterparts within its class, which translates to an improved safety profile, namely when it comes to gastrointestinal tract microbiome disruption and potentially decreased likelihood of developing bacterial resistance.⁶⁶ Data on human reproductive studies are limited, but it is advisable to avoid sarecycline in pregnancy, as it may cause adverse developmental effects in the fetus, such as reduced bone growth, in addition to the well-known tetracycline-associated risk for permanent discoloration of the teeth if used during the second and third trimesters.^67,68

Erythromycin—Oral erythromycin targets moderate to severe inflammatory acne and is considered safe for use during pregnancy.^69,70 There has been 1 study reporting an increased risk for atrial and ventricular septal defects (1.8%) and pyloric stenosis (0.2%), but these risks are still uncertain, and erythromycin is considered compatible with pregnancy.⁷¹ However, erythromycin estolate formulations should be avoided given the associated 10% to 15% risk for reversible cholestatic liver injury.⁷² Erythromycin base or erythromycin ethylsuccinate formulations should be favored.

Systemic Steroids—Prednisone is indicated for severe acne with scarring and should only be used during pregnancy after clearance from the patient’s obstetrician. Doses of 0.5 mg/kg or less should be prescribed in combination with systemic antibiotics as well as agents for bone and gastrointestinal tract prophylaxis.²⁹

Zinc—The exact mechanism by which zinc exerts its effects to improve acne remains largely obscure. It has been found effective against inflammatory lesions of mild to moderate acne.⁷³ Generally recommended dosages range from 30 to 200 mg/d but may be associated with gastrointestinal tract disturbances. Dosages of 75 mg/d have shown no harm to the fetus.⁷⁴ When taking this supplement, patients should not exceed the recommended doses given the risk for hypocupremia associated with high-dose zinc supplementation.

Light-Based Therapies

Phototherapy—Narrowband UVB phototherapy is effective for the treatment of mild to moderate acne.⁷⁵ It has been proven to be a safe treatment option during pregnancy, but its use has been associated with decreased folic acid levels.^76-79 Therefore, in addition to attaining baseline folic acid serum levels, supplementation with folic acid prior to treatment, as per routine prenatal guidelines, should be sought.⁸⁰

AviClear—The AviClear (Cutera) laser is the first device cleared by the FDA for mild to severe acne in March 2022.⁸¹ The FDA clearance for the Accure (Accure Acne Inc) laser, also targeting mild to severe acne, followed soon after (November 2022). Both lasers harbor a wavelength of 1726 nm and target sebaceous glands with electrothermolysis.^82,83 Further research and long-term safety data are required before using them in pregnancy.

Other Therapies

Cosmetic Peels—Glycolic acid peels induce epidermolysis and desquamation.⁸⁴ Although data on use during pregnancy are limited, these peels have limited dermal penetration and are considered safe for use in pregnancy.^33,85,86 Similarly, keratolytic lactic acid peels harbor limited dermal penetration and can be safely used in pregnant women.^87-89 Salicylic acid peels also work through epidermolysis and desquamation⁸⁴; however, they tend to penetrate deeper into the skin, reaching down to the basal layer, if large areas are treated or when applied under occlusion.^86,90 Although their use is not contraindicated in pregnancy, they should be limited to small areas of coverage.⁹¹

Intralesional Triamcinolone—Acne cysts and inflammatory papules can be treated with intralesional triamcinolone injections to relieve acute symptoms such as pain.⁹² Low doses at concentrations of 2.5 mg/mL are considered compatible with pregnancy when indicated.²⁹

Approaching the Patient Clinical Encounter

In patients seeking treatment prior to conception, a few recommendations can be made to minimize the risk for acne recurrence or flares during pregnancy. For instance, because data show an association between increased acne severity in those with a higher body mass index and in pregnancy, weight loss may be recommended prior to pregnancy to help mitigate symptoms after conception.⁷ The Figure summarizes our recommendations for approaching and treating acne in pregnancy.

ret_Yaghi_figure.jpg

In all patients, grading the severity of the patient’s acne as mild, moderate, or severe is the first step. The presence of scarring is an additional consideration during the physical examination and should be documented. A careful discussion of treatment expectations and prognosis should be the focus before treatment initiation. Meticulous documentation of the physical examination and discussion with the patient should be prioritized.

To minimize toxicity and risks to the developing fetus, monotherapy is favored. Topical therapy should be considered first line. Safe regimens include mild nonabrasive washes, such as those containing benzoyl peroxide or glycolic acid, or topical azelaic acid or clindamycin phosphate for mild to moderate acne. More severe cases warrant the consideration of systemic medications as second line, as more severe acne is better treated with oral antibiotics such as the macrolides erythromycin or clindamycin or systemic corticosteroids when concern exists for severe scarring. The additional use of physical sunscreen also is recommended.

An important topic to address during the clinical encounter is cautious intake of oral supplements for acne during pregnancy, as they may contain harmful and teratogenic ingredients. A recent search focusing on acne supplements available online between March and May 2020 uncovered 49 different supplements, 26 (53%) of which contained vitamin A.⁹³ Importantly, 3 (6%) of these 49 supplements were likely teratogenic, 4 (8%) contained vitamin A doses exceeding the recommended daily nutritional intake level, and 15 (31%) harbored an unknown teratogenic risk. Furthermore, among the 6 (12%) supplements with vitamin A levels exceeding 10,000 IU, 2 lacked any mention of pregnancy warning, including the supplement with the highest vitamin A dose found in this study.⁹³ Because dietary supplements are not subject to the same stringent regulations by the FDA as drugs, inadvertent use by unaware patients ought to be prevented by careful counseling and education.

Finally, patients should be counseled to seek care following delivery for potentially updated medication management of acne, especially if they are breastfeeding. Co-management with a pediatrician may be indicated during lactation, particularly when newborns are born preterm or with other health conditions that may warrant additional caution with the use of certain agents.