Clinical Review

Folliculitis decalvans (FD) is classified as a rare primary neutrophilic cicatricial alopecia occurring predominantly in middle-aged adults. Although the true etiology is still unknown, the pathogenesis behind the inflammatory follicular lesions stems from possible Staphylococcus aureus infection and an impaired host immune system in response to released superantigens. ¹ The clinical severity of this inflammatory scalp disorder can range from mild to severe and debilitating. Multiple treatment regimens have been developed with the goal of maintaining full remission. We provide a summary of tumor necrosis factor (TNF) inhibitors, Janus kinase (JAK) inhibitors, phosphodiesterase 4 (PDE4) inhibitors, and monoclonal antibodies being utilized for patients with therapy-recalcitrant FD.

Methods

We conducted a PubMed, Medline, and Google Scholar search for the terms refractory FD, recalcitrant FD, or therapy-resistant FD to identify articles published in English from 1998 to 2022. Articles that reported recalcitrant cases and subsequent therapy with TNF inhibitors, JAK inhibitors, PDE4 inhibitors, and monoclonal antibodies were included. Articles were excluded if recalcitrant cases were not clearly defined. Remission was defined as no recurrence in lesions or pustules or as a reduction in the inflammatory process with stabilization upon continuation or discontinuation of the therapy regimen. Two reviewers (T.F. and K.U.) independently searched for and screened each report.

Results 

Treatment of recalcitrant FD with biologics or small molecule inhibitors was discussed in 9 studies with a combined total of 35 patients.^2-10 The treatment regimens included TNF inhibitors, JAK inhibitors, PDE4 inhibitors, and monoclonal antibodies (Table).

The TNF inhibitors were utilized in 6 reports with a combined total of 29 patients. Treatments included adalimumab or biosimilar adalimumab (27/29 patients), infliximab (1/29 patients), and certolizumab pegol (1/29 patients). Remission was reported in 26 of 29 cases. There were 2 nonresponders to adalimumab and marked improvement with certolizumab pegol without complete resolution. The use of the JAK inhibitor baricitinib in 4 patients resulted in remission. In all 4 patients, baricitinib was used with concurrent treatments, and remission was achieved in an average of 2.25 months. The use of a PDE4 inhibitor, apremilast, was reported in 1 case; remission was achieved in 3 weeks. Secukinumab, a monoclonal antibody that targets IL-17, was utilized in 1 patient. Marked improvement was seen after 2 months, with complete remission in 7 months. 

Comment

Traditional treatment regimens for FD most often include a combination of topical and oral antibiotics; isotretinoin; and oral, topical, or intralesional corticosteroids. In the past, interventions typically were suppressive as opposed to curative; however, recent treatment advancements have shown promise in achieving lasting remission.

Most reports targeting treatment-resistant FD involved the use of TNF inhibitors, including adalimumab, biosimilar adalimumab, infliximab, and certolizumab pegol.  Adalimumab was the most frequently used TNF inhibitor, with 24 of 26 treated patients achieving remission. Adalimumab may have been used the most in the treatment of FD because TNF is pronounced in other neutrophilic dermatoses that have been successfully treated with TNF inhibitors. It has been reported that adalimumab needs to be continued, as stoppage or interruption led to relapse.³

Although there are few reports of the use of JAK inhibitors, PDE4 inhibitors, and monoclonal antibodies for FD, these treatment modalities show promise, as their use led to marked improvement or lasting remission with ongoing treatment. The use of the PDE4 inhibitor apremilast displayed the most rapid improvement of any of the reviewed treatments, with remission achieved in just 3 weeks.⁹ The rapid success of apremilast may be attributed to the inhibitory effect on neutrophils.

Miguel-Gómez et al¹¹ provided a therapeutic protocol for FD based on the severity of disease (N=60). The protocol included rifampicin plus clindamycin for the treatment of severe disease, as 90.5% (19/21) of resistant cases showed clinical response, with remission of 5 months’ duration. Although this may be acceptable for some patients, others may require an alternative approach. Tietze et al¹² showed that rifampicin and clindamycin had the lowest success rate for long-term remission, with 8 of 10 patients relapsing within 2 to 4 months. In addition, the emergence of antimicrobial resistance remains a major concern in the treatment of FD. Upon the review of the most recent reports of successful treatment of ­therapy-resistant FD, biologics and small molecule inhibitors have shown remission extending through a 12-month follow-up period. We suggest considering the addition of biologics and small molecule inhibitors to the treatment protocol for severe or resistant disease.

Limitations—In the articles reviewed, the definition of remission was inconsistent among authors—some characterized it as no recurrence in lesions or pustules and some as a reduction in the inflammatory process. True duration of remission was difficult to assess from case reports, as follow-up periods varied prior to publication. The studies included in this review consisted mainly of small sample sizes owing to the rarity of FD, and consequently, strength of evidence is lacking. Inherent to the nature of systematic reviews, publication bias may have occurred. Lastly, several studies were impacted by difficulty in obtaining optimal treatment due to financial hardship, and regimens were adjusted accordingly.

Conclusion

The relapsing nature of FD leads to frustration and poor quality of life for patients. There is a paucity of data to guide treatment when FD remains recalcitrant to traditional therapy. Therapies such as TNF inhibitors, JAK inhibitors, PDE4 inhibitors, and monoclonal antibodies have shown success in the treatment of this often ­difficult-to-treat disease. Small sample sizes in reports discussing treatment for resistant cases as well as conflicting results make it challenging to draw conclusions about treatment efficacy. Larger studies are needed to understand the long-term outcomes of treatment options. Regardless, disease severity, patient history, patient preferences, and treatment goals can guide the selection of therapeutic options.

Folliculitis decalvans (FD) is classified as a rare primary neutrophilic cicatricial alopecia occurring predominantly in middle-aged adults. Although the true etiology is still unknown, the pathogenesis behind the inflammatory follicular lesions stems from possible Staphylococcus aureus infection and an impaired host immune system in response to released superantigens. ¹ The clinical severity of this inflammatory scalp disorder can range from mild to severe and debilitating. Multiple treatment regimens have been developed with the goal of maintaining full remission. We provide a summary of tumor necrosis factor (TNF) inhibitors, Janus kinase (JAK) inhibitors, phosphodiesterase 4 (PDE4) inhibitors, and monoclonal antibodies being utilized for patients with therapy-recalcitrant FD.

Methods

We conducted a PubMed, Medline, and Google Scholar search for the terms refractory FD, recalcitrant FD, or therapy-resistant FD to identify articles published in English from 1998 to 2022. Articles that reported recalcitrant cases and subsequent therapy with TNF inhibitors, JAK inhibitors, PDE4 inhibitors, and monoclonal antibodies were included. Articles were excluded if recalcitrant cases were not clearly defined. Remission was defined as no recurrence in lesions or pustules or as a reduction in the inflammatory process with stabilization upon continuation or discontinuation of the therapy regimen. Two reviewers (T.F. and K.U.) independently searched for and screened each report.

Results 

Treatment of recalcitrant FD with biologics or small molecule inhibitors was discussed in 9 studies with a combined total of 35 patients.^2-10 The treatment regimens included TNF inhibitors, JAK inhibitors, PDE4 inhibitors, and monoclonal antibodies (Table).

The TNF inhibitors were utilized in 6 reports with a combined total of 29 patients. Treatments included adalimumab or biosimilar adalimumab (27/29 patients), infliximab (1/29 patients), and certolizumab pegol (1/29 patients). Remission was reported in 26 of 29 cases. There were 2 nonresponders to adalimumab and marked improvement with certolizumab pegol without complete resolution. The use of the JAK inhibitor baricitinib in 4 patients resulted in remission. In all 4 patients, baricitinib was used with concurrent treatments, and remission was achieved in an average of 2.25 months. The use of a PDE4 inhibitor, apremilast, was reported in 1 case; remission was achieved in 3 weeks. Secukinumab, a monoclonal antibody that targets IL-17, was utilized in 1 patient. Marked improvement was seen after 2 months, with complete remission in 7 months. 

Comment

Traditional treatment regimens for FD most often include a combination of topical and oral antibiotics; isotretinoin; and oral, topical, or intralesional corticosteroids. In the past, interventions typically were suppressive as opposed to curative; however, recent treatment advancements have shown promise in achieving lasting remission.

Most reports targeting treatment-resistant FD involved the use of TNF inhibitors, including adalimumab, biosimilar adalimumab, infliximab, and certolizumab pegol.  Adalimumab was the most frequently used TNF inhibitor, with 24 of 26 treated patients achieving remission. Adalimumab may have been used the most in the treatment of FD because TNF is pronounced in other neutrophilic dermatoses that have been successfully treated with TNF inhibitors. It has been reported that adalimumab needs to be continued, as stoppage or interruption led to relapse.³

Although there are few reports of the use of JAK inhibitors, PDE4 inhibitors, and monoclonal antibodies for FD, these treatment modalities show promise, as their use led to marked improvement or lasting remission with ongoing treatment. The use of the PDE4 inhibitor apremilast displayed the most rapid improvement of any of the reviewed treatments, with remission achieved in just 3 weeks.⁹ The rapid success of apremilast may be attributed to the inhibitory effect on neutrophils.

Miguel-Gómez et al¹¹ provided a therapeutic protocol for FD based on the severity of disease (N=60). The protocol included rifampicin plus clindamycin for the treatment of severe disease, as 90.5% (19/21) of resistant cases showed clinical response, with remission of 5 months’ duration. Although this may be acceptable for some patients, others may require an alternative approach. Tietze et al¹² showed that rifampicin and clindamycin had the lowest success rate for long-term remission, with 8 of 10 patients relapsing within 2 to 4 months. In addition, the emergence of antimicrobial resistance remains a major concern in the treatment of FD. Upon the review of the most recent reports of successful treatment of ­therapy-resistant FD, biologics and small molecule inhibitors have shown remission extending through a 12-month follow-up period. We suggest considering the addition of biologics and small molecule inhibitors to the treatment protocol for severe or resistant disease.

Limitations—In the articles reviewed, the definition of remission was inconsistent among authors—some characterized it as no recurrence in lesions or pustules and some as a reduction in the inflammatory process. True duration of remission was difficult to assess from case reports, as follow-up periods varied prior to publication. The studies included in this review consisted mainly of small sample sizes owing to the rarity of FD, and consequently, strength of evidence is lacking. Inherent to the nature of systematic reviews, publication bias may have occurred. Lastly, several studies were impacted by difficulty in obtaining optimal treatment due to financial hardship, and regimens were adjusted accordingly.

Conclusion

The relapsing nature of FD leads to frustration and poor quality of life for patients. There is a paucity of data to guide treatment when FD remains recalcitrant to traditional therapy. Therapies such as TNF inhibitors, JAK inhibitors, PDE4 inhibitors, and monoclonal antibodies have shown success in the treatment of this often ­difficult-to-treat disease. Small sample sizes in reports discussing treatment for resistant cases as well as conflicting results make it challenging to draw conclusions about treatment efficacy. Larger studies are needed to understand the long-term outcomes of treatment options. Regardless, disease severity, patient history, patient preferences, and treatment goals can guide the selection of therapeutic options.

Folliculitis decalvans (FD) is classified as a rare primary neutrophilic cicatricial alopecia occurring predominantly in middle-aged adults. Although the true etiology is still unknown, the pathogenesis behind the inflammatory follicular lesions stems from possible Staphylococcus aureus infection and an impaired host immune system in response to released superantigens. ¹ The clinical severity of this inflammatory scalp disorder can range from mild to severe and debilitating. Multiple treatment regimens have been developed with the goal of maintaining full remission. We provide a summary of tumor necrosis factor (TNF) inhibitors, Janus kinase (JAK) inhibitors, phosphodiesterase 4 (PDE4) inhibitors, and monoclonal antibodies being utilized for patients with therapy-recalcitrant FD.

Methods

We conducted a PubMed, Medline, and Google Scholar search for the terms refractory FD, recalcitrant FD, or therapy-resistant FD to identify articles published in English from 1998 to 2022. Articles that reported recalcitrant cases and subsequent therapy with TNF inhibitors, JAK inhibitors, PDE4 inhibitors, and monoclonal antibodies were included. Articles were excluded if recalcitrant cases were not clearly defined. Remission was defined as no recurrence in lesions or pustules or as a reduction in the inflammatory process with stabilization upon continuation or discontinuation of the therapy regimen. Two reviewers (T.F. and K.U.) independently searched for and screened each report.

Results 

Treatment of recalcitrant FD with biologics or small molecule inhibitors was discussed in 9 studies with a combined total of 35 patients.^2-10 The treatment regimens included TNF inhibitors, JAK inhibitors, PDE4 inhibitors, and monoclonal antibodies (Table).

The TNF inhibitors were utilized in 6 reports with a combined total of 29 patients. Treatments included adalimumab or biosimilar adalimumab (27/29 patients), infliximab (1/29 patients), and certolizumab pegol (1/29 patients). Remission was reported in 26 of 29 cases. There were 2 nonresponders to adalimumab and marked improvement with certolizumab pegol without complete resolution. The use of the JAK inhibitor baricitinib in 4 patients resulted in remission. In all 4 patients, baricitinib was used with concurrent treatments, and remission was achieved in an average of 2.25 months. The use of a PDE4 inhibitor, apremilast, was reported in 1 case; remission was achieved in 3 weeks. Secukinumab, a monoclonal antibody that targets IL-17, was utilized in 1 patient. Marked improvement was seen after 2 months, with complete remission in 7 months. 

Comment

Traditional treatment regimens for FD most often include a combination of topical and oral antibiotics; isotretinoin; and oral, topical, or intralesional corticosteroids. In the past, interventions typically were suppressive as opposed to curative; however, recent treatment advancements have shown promise in achieving lasting remission.

Most reports targeting treatment-resistant FD involved the use of TNF inhibitors, including adalimumab, biosimilar adalimumab, infliximab, and certolizumab pegol.  Adalimumab was the most frequently used TNF inhibitor, with 24 of 26 treated patients achieving remission. Adalimumab may have been used the most in the treatment of FD because TNF is pronounced in other neutrophilic dermatoses that have been successfully treated with TNF inhibitors. It has been reported that adalimumab needs to be continued, as stoppage or interruption led to relapse.³

Although there are few reports of the use of JAK inhibitors, PDE4 inhibitors, and monoclonal antibodies for FD, these treatment modalities show promise, as their use led to marked improvement or lasting remission with ongoing treatment. The use of the PDE4 inhibitor apremilast displayed the most rapid improvement of any of the reviewed treatments, with remission achieved in just 3 weeks.⁹ The rapid success of apremilast may be attributed to the inhibitory effect on neutrophils.

Miguel-Gómez et al¹¹ provided a therapeutic protocol for FD based on the severity of disease (N=60). The protocol included rifampicin plus clindamycin for the treatment of severe disease, as 90.5% (19/21) of resistant cases showed clinical response, with remission of 5 months’ duration. Although this may be acceptable for some patients, others may require an alternative approach. Tietze et al¹² showed that rifampicin and clindamycin had the lowest success rate for long-term remission, with 8 of 10 patients relapsing within 2 to 4 months. In addition, the emergence of antimicrobial resistance remains a major concern in the treatment of FD. Upon the review of the most recent reports of successful treatment of ­therapy-resistant FD, biologics and small molecule inhibitors have shown remission extending through a 12-month follow-up period. We suggest considering the addition of biologics and small molecule inhibitors to the treatment protocol for severe or resistant disease.

Limitations—In the articles reviewed, the definition of remission was inconsistent among authors—some characterized it as no recurrence in lesions or pustules and some as a reduction in the inflammatory process. True duration of remission was difficult to assess from case reports, as follow-up periods varied prior to publication. The studies included in this review consisted mainly of small sample sizes owing to the rarity of FD, and consequently, strength of evidence is lacking. Inherent to the nature of systematic reviews, publication bias may have occurred. Lastly, several studies were impacted by difficulty in obtaining optimal treatment due to financial hardship, and regimens were adjusted accordingly.

Conclusion

The relapsing nature of FD leads to frustration and poor quality of life for patients. There is a paucity of data to guide treatment when FD remains recalcitrant to traditional therapy. Therapies such as TNF inhibitors, JAK inhibitors, PDE4 inhibitors, and monoclonal antibodies have shown success in the treatment of this often ­difficult-to-treat disease. Small sample sizes in reports discussing treatment for resistant cases as well as conflicting results make it challenging to draw conclusions about treatment efficacy. Larger studies are needed to understand the long-term outcomes of treatment options. Regardless, disease severity, patient history, patient preferences, and treatment goals can guide the selection of therapeutic options.

The risk for developing skin cancer can be somewhat attributed to variations in skin pigmentation. Historically, lighter skin pigmentation has been observed in populations living in higher latitudes and darker pigmentation in populations near the equator. Although skin pigmentation is a conglomeration of genetic and environmental factors, anthropologic studies have demonstrated an association of human skin lightening with historic human migratory patterns.¹ It is postulated that migration to latitudes with less UVB light penetration has resulted in a compensatory natural selection of lighter skin types. Furthermore, the driving force behind this migration-associated skin lightening has remained unclear.¹

The need for folate metabolism, vitamin D synthesis, and barrier protection, as well as cultural practices, has been postulated as driving factors for skin pigmentation variation. Synthesis of vitamin D is a UV radiation (UVR)–dependent process and has remained a prominent theoretical driver for the basis of evolutionary skin lightening. Vitamin D can be acquired both exogenously or endogenously via dietary supplementation or sunlight; however, historically it has been obtained through UVB exposure primarily. Once UVB is absorbed by the skin, it catalyzes conversion of 7-dehydrocholesterol to previtamin D₃, which is converted to vitamin D in the kidneys.^2,3 It is suggested that lighter skin tones have an advantage over darker skin tones in synthesizing vitamin D at higher latitudes where there is less UVB, thus leading to the adaptation process.1 In this systematic review, we analyzed the evolutionary vitamin D adaptation hypothesis and assessed the validity of evidence supporting this theory in the literature.

Methods

A search of PubMed, Embase, and the Cochrane Reviews database was conducted using the terms evolution, vitamin D, and skin to generate articles published from 2010 to 2022 that evaluated the influence of UVR-dependent production of vitamin D on skin pigmentation through historical migration patterns (Figure). Studies were excluded during an initial screening of abstracts followed by full-text assessment if they only had abstracts and if articles were inaccessible for review or in the form of case reports and commentaries.

The following data were extracted from each included study: reference citation, affiliated institutions of authors, author specialties, journal name, year of publication, study period, type of article, type of study, mechanism of adaptation, data concluding or supporting vitamin D as the driver, and data concluding or suggesting against vitamin D as the driver. Data concluding or supporting vitamin D as the driver were recorded from statistically significant results, study conclusions, and direct quotations. Data concluding or suggesting against vitamin D as the driver also were recorded from significant results, study conclusions, and direct quotes. The mechanism of adaptation was based on vitamin D synthesis modulation, melanin upregulation, genetic selections, genetic drift, mating patterns, increased vitamin D sensitivity, interbreeding, and diet.

Studies included in the analysis were placed into 1 of 3 categories: supporting, neutral, and against. Strength of Recommendation Taxonomy (SORT) criteria were used to classify the level of evidence of each article.⁴ Each article’s level of evidence was then graded (Table 1). The SORT grading levels were based on quality and evidence type: level 1 signified good-quality, patient-oriented evidence; level 2 signified limited-quality, patient-oriented evidence; and level 3 signified other evidence.⁴

Results

Article Selection—A total of 229 articles were identified for screening, and 39 studies met inclusion criteria.^1-3,5-40 Systematic and retrospective reviews were the most common types of studies. Genomic analysis/sequencing/genome-wide association studies (GWAS) were the most common methods of analysis. Of these 39 articles, 26 were classified as supporting the evolutionary vitamin D adaptation hypothesis, 10 were classified as neutral, and 3 were classified as against (Table 1). 

Of the articles classified as supporting the vitamin D hypothesis, 13 articles were level 1 evidence, 9 were level 2, and 4 were level 3. Key findings supporting the vitamin D hypothesis included genetic natural selection favoring vitamin D synthesis genes at higher latitudes with lower UVR and the skin lightening that occurred to protect against vitamin D deficiency (Table 1). Specific genes supporting these findings included 7-dehydrocholesterol reductase (DHCR7), vitamin D receptor (VDR), tyrosinase (TYR), tyrosinase-related protein 1 (TYRP1), oculocutaneous albinism type 2 melanosomal transmembrane protein (OCA2), solute carrier family 45 member 2 (SLC45A2), solute carrier family 4 member 5 (SLC24A5), Kit ligand (KITLG), melanocortin 1 receptor (MC1R), and HECT and RLD domain containing E3 ubiquitin protein ligase 2 (HERC2)(Table 2).

Comment

The importance of appropriate vitamin D levels is hypothesized as a potent driver in skin lightening because the vitamin is essential for many biochemical processes within the human body. Proper calcification of bones requires activated vitamin D to prevent rickets in childhood. Pelvic deformation in women with rickets can obstruct childbirth in primitive medical environments.¹⁵ This direct reproductive impairment suggests a strong selective pressure for skin lightening in populations that migrated northward to enhance vitamin D synthesis. 

Of the 39 articles that we reviewed, the majority (n=26 [66.7%]) supported the hypothesis that vitamin D synthesis was the main driver behind skin lightening, whereas 3 (7.7%) did not support the hypothesis and 10 (25.6%) were neutral. Other leading theories explaining skin lightening included the idea that enhanced melanogenesis protected against folate degradation; genetic selection for light-skin alleles due to genetic drift; skin lightening being the result of sexual selection; and a combination of factors, including dietary choices, clothing preferences, and skin permeability barriers. 

Articles With Supporting Evidence for the Vitamin D Theory—As Homo sapiens migrated out of Africa, migration patterns demonstrated the correlation between distance from the equator and skin pigmentation from natural selection. Individuals with darker skin pigment required higher levels of UVR to synthesize vitamin D. According to Beleza et al,1 as humans migrated to areas of higher latitudes with lower levels of UVR, natural selection favored the development of lighter skin to maximize vitamin D production. Vitamin D is linked to calcium metabolism, and its deficiency can lead to bone malformations and poor immune function.³⁵ Several genes affecting melanogenesis and skin pigment have been found to have geospatial patterns that map to different geographic locations of various populations, indicating how human migration patterns out of Africa created this natural selection for skin lightening. The gene KITLG—associated with lighter skin pigmentation—has been found in high frequencies in both European and East Asian populations and is proposed to have increased in frequency after the migration out of Africa. However, the genes TYRP1, SLC24A5, and SLC45A2 were found at high frequencies only in European populations, and this selection occurred 11,000 to 19,000 years ago during the Last Glacial Maximum (15,000–20,000 years ago), demonstrating the selection for European over East Asian characteristics. During this period, seasonal changes increased the risk for vitamin D deficiency and provided an urgency for selection to a lighter skin pigment.¹

The migration of H sapiens to northern latitudes prompted the selection of alleles that would increasevitamin D synthesis to counteract the reduced UV exposure. Genetic analysis studies have found key associations between genes encoding for the metabolism of vitamin D and pigmentation. Among this complex network are the essential downstream enzymes in the melanocortin receptor 1 pathway, including TYR and TYRP1. Forty-six of 960 single-nucleotide polymorphisms located in 29 different genes involved in skin pigmentation that were analyzed in a cohort of 2970 individuals were significantly associated with serum vitamin D levels (P<.05). The exocyst complex component 2 (EXOC2), TYR, and TYRP1 gene variants were shown to have the greatest influence on vitamin D status.⁹ These data reveal how pigment genotypes are predictive of vitamin D levels and the epistatic potential among many genes in this complex network. 

Gene variation plays an important role in vitamin D status when comparing genetic polymorphisms in populations in northern latitudes to African populations. Vitamin D₃ precursor availability is decreased by 7-DHCR catalyzing the precursors substrate to cholesterol. In a study using GWAS, it was found that “variations in DHCR7 may aid vitamin D production by conserving cutaneous 7-DHC levels. A high prevalence of DHCR7 variants were found in European and Northeast Asian populations but not in African populations, suggesting that selection occurred for these DHCR7 mutations in populations who migrated to more northern latitudes.⁵ Multilocus networks have been established between the VDR promotor and skin color genes (Table 2) that exhibit a strong in-Africa vs out-of-Africa frequency pattern. It also has been shown that genetic variation (suggesting a long-term evolutionary inclination) and epigenetic modification (indicative of short-term exposure) of VDR lends support to the vitamin D hypothesis. As latitude decreases, prevalence of VDR FokI (F allele), BsmI (B allele), ApaI (A allele), and TaqI (T allele) also decreases in a linear manner, linking latitude to VDR polymorphisms. Plasma vitamin D levels and photoperiod of conception—UV exposure during the periconceptional period—also were extrapolative of VDR methylation in a study involving 80 participants, where these 2 factors accounted for 17% of variance in methylation.⁶

Other noteworthy genes included HERC2, which has implications in the expression of OCA2 (melanocyte-specific transporter protein), and IRF4, which encodes for an important enzyme in folate-dependent melanin production. In an Australian cross-sectional study that analyzed vitamin D and pigmentation gene polymorphisms in conjunction with plasma vitamin D levels, the most notable rate of vitamin D loss occurred in individuals with the darkest pigmentation HERC2 (AA) genotype.³¹ In contrast, the lightest pigmentation HERC2 (GG) genotypes had increased vitamin D₃ photosynthesis. Interestingly, the lightest interferon regulatory factor 4 (IRF4) TT genotype and the darkest HERC2 AA genotype, rendering the greatest folate loss and largest synthesis of vitamin D₃, were not seen in combination in any of the participants.³⁰ In addition to HERC2, derived alleles from pigment-associated genes SLC24A5*A and SLC45A2*G demonstrated greater frequencies in Europeans (>90%) compared to Africans and East Asians, where the allelic frequencies were either rare or absent.1 This evidence delineates not only the complexity but also the strong relationship between skin pigmentation, latitude, and vitamin D status. The GWAS also have supported this concept. In comparing European populations to African populations, there was a 4-fold increase in the frequencies of “derived alleles of the vitamin D transport protein (GC, rs3755967), the 25(OH)D₃ synthesizing enzyme (CYP2R1, rs10741657), VDR (rs2228570 (commonly known as FokI polymorphism), rs1544410 (Bsm1), and rs731236 (Taq1) and the VDR target genes CYP24A1 (rs17216707), CD14 (rs2569190), and CARD9 (rs4077515).”³²

Articles With Evidence Against the Vitamin D Theory—This review analyzed the level of support for the theory that vitamin D was the main driver for skin lightening. Although most articles supported this theory, there were articles that listed other plausible counterarguments. Jablonski and Chaplin3 suggested that humans living in higher latitudes compensated for increased demand of vitamin D by placing cultural importance on a diet of vitamin D–rich foods and thus would not have experienced decreased vitamin D levels, which we hypothesize were the driver for skin lightening. Elias et al³⁹ argued that initial pigment dilution may have instead served to improve metabolic conservation, as the authors found no evidence of rickets—the sequelae of vitamin D deficiency—in pre–industrial age human fossils. Elias and Williams3⁸ proposed that differences in skin pigment are due to a more intact skin permeability barrier as “a requirement for life in a desiccating terrestrial environment,” which is seen in darker skin tones compared to lighter skin tones and thus can survive better in warmer climates with less risk of infections or dehydration.

Articles With Neutral Evidence for the Vitamin D Theory—Greaves⁴¹ argued against the idea that skin evolved to become lighter to protect against vitamin D deficiency. They proposed that the chimpanzee, which is the human’s most closely related species, had light skin covered by hair, and the loss of this hair led to exposed pale skin that created a need for increased melanin production for protection from UVR. Greaves⁴¹ stated that the MC1R gene (associated with darker pigmentation) was selected for in African populations, and those with pale skin retained their original pigment as they migrated to higher latitudes. Further research has demonstrated that the genetic natural selection for skin pigment is a complex process that involves multiple gene variants found throughout cultures across the globe.

Conclusion

Skin pigmentation has continuously evolved alongside humans. Genetic selection for lighter skin coincides with a favorable selection for genes involved in vitamin D synthesis as humans migrated to northern latitudes, which enabled humans to produce adequate levels of exogenous vitamin D in low-UVR areas and in turn promoted survival. Early humans without access to supplementation or foods rich in vitamin D acquired vitamin D primarily through sunlight. In comparison to modern society, where vitamin D supplementation is accessible and human lifespans are prolonged, lighter skin tone is now a risk factor for malignant cancers of the skin rather than being a protective adaptation. Current sun behavior recommendations conclude that the body’s need for vitamin D is satisfied by UV exposure to the arms, legs, hands, and/or face for only 5 to 30 minutes between 10 am and 4 pm daily without sunscreen.^42-44 Approximately 600 IU of vitamin D supplementation daily is recommended in a typical adult younger than 70 years to avoid deficiency. In adults 70 years and older who are not receiving adequate sunlight exposure, 800 IU of daily vitamin D supplementation is recommended.⁴⁵

The hypothesis that skin lightening primarily was driven by the need for vitamin D can only be partially supported by our review. Studies have shown that there is a corresponding complex network of genes that determines skin pigmentation as well as vitamin D synthesis and conservation. However, there is sufficient evidence that skin lightening is multifactorial in nature, and vitamin D alone may not be the sole driver. The information in this review can be used by health care providers to educate patients on sun protection, given the lesser threat of severe vitamin D deficiency in developed communities today that have access to adequate nutrition and supplementation.

Skin lightening and its coinciding evolutionary drivers are a rather neglected area of research. Due to heterogeneous cohorts and conservative data analysis, GWAS studies run the risk of type II error, yielding a limitation in our data analysis.⁹ Furthermore, the data regarding specific time frames in evolutionary skin lightening as well as the intensity of gene polymorphisms are limited.1 Further studies are needed to determine the interconnectedness of the current skin-lightening theories to identify other important factors that may play a role in the process. Determining the key event can help us better understand skin-adaptation mechanisms and create a framework for understanding the vital process involved in adaptation, survival, and disease manifestation in different patient populations.

The risk for developing skin cancer can be somewhat attributed to variations in skin pigmentation. Historically, lighter skin pigmentation has been observed in populations living in higher latitudes and darker pigmentation in populations near the equator. Although skin pigmentation is a conglomeration of genetic and environmental factors, anthropologic studies have demonstrated an association of human skin lightening with historic human migratory patterns.¹ It is postulated that migration to latitudes with less UVB light penetration has resulted in a compensatory natural selection of lighter skin types. Furthermore, the driving force behind this migration-associated skin lightening has remained unclear.¹

The need for folate metabolism, vitamin D synthesis, and barrier protection, as well as cultural practices, has been postulated as driving factors for skin pigmentation variation. Synthesis of vitamin D is a UV radiation (UVR)–dependent process and has remained a prominent theoretical driver for the basis of evolutionary skin lightening. Vitamin D can be acquired both exogenously or endogenously via dietary supplementation or sunlight; however, historically it has been obtained through UVB exposure primarily. Once UVB is absorbed by the skin, it catalyzes conversion of 7-dehydrocholesterol to previtamin D₃, which is converted to vitamin D in the kidneys.^2,3 It is suggested that lighter skin tones have an advantage over darker skin tones in synthesizing vitamin D at higher latitudes where there is less UVB, thus leading to the adaptation process.1 In this systematic review, we analyzed the evolutionary vitamin D adaptation hypothesis and assessed the validity of evidence supporting this theory in the literature.

Methods

A search of PubMed, Embase, and the Cochrane Reviews database was conducted using the terms evolution, vitamin D, and skin to generate articles published from 2010 to 2022 that evaluated the influence of UVR-dependent production of vitamin D on skin pigmentation through historical migration patterns (Figure). Studies were excluded during an initial screening of abstracts followed by full-text assessment if they only had abstracts and if articles were inaccessible for review or in the form of case reports and commentaries.

The following data were extracted from each included study: reference citation, affiliated institutions of authors, author specialties, journal name, year of publication, study period, type of article, type of study, mechanism of adaptation, data concluding or supporting vitamin D as the driver, and data concluding or suggesting against vitamin D as the driver. Data concluding or supporting vitamin D as the driver were recorded from statistically significant results, study conclusions, and direct quotations. Data concluding or suggesting against vitamin D as the driver also were recorded from significant results, study conclusions, and direct quotes. The mechanism of adaptation was based on vitamin D synthesis modulation, melanin upregulation, genetic selections, genetic drift, mating patterns, increased vitamin D sensitivity, interbreeding, and diet.

Studies included in the analysis were placed into 1 of 3 categories: supporting, neutral, and against. Strength of Recommendation Taxonomy (SORT) criteria were used to classify the level of evidence of each article.⁴ Each article’s level of evidence was then graded (Table 1). The SORT grading levels were based on quality and evidence type: level 1 signified good-quality, patient-oriented evidence; level 2 signified limited-quality, patient-oriented evidence; and level 3 signified other evidence.⁴

Results

Article Selection—A total of 229 articles were identified for screening, and 39 studies met inclusion criteria.^1-3,5-40 Systematic and retrospective reviews were the most common types of studies. Genomic analysis/sequencing/genome-wide association studies (GWAS) were the most common methods of analysis. Of these 39 articles, 26 were classified as supporting the evolutionary vitamin D adaptation hypothesis, 10 were classified as neutral, and 3 were classified as against (Table 1). 

Of the articles classified as supporting the vitamin D hypothesis, 13 articles were level 1 evidence, 9 were level 2, and 4 were level 3. Key findings supporting the vitamin D hypothesis included genetic natural selection favoring vitamin D synthesis genes at higher latitudes with lower UVR and the skin lightening that occurred to protect against vitamin D deficiency (Table 1). Specific genes supporting these findings included 7-dehydrocholesterol reductase (DHCR7), vitamin D receptor (VDR), tyrosinase (TYR), tyrosinase-related protein 1 (TYRP1), oculocutaneous albinism type 2 melanosomal transmembrane protein (OCA2), solute carrier family 45 member 2 (SLC45A2), solute carrier family 4 member 5 (SLC24A5), Kit ligand (KITLG), melanocortin 1 receptor (MC1R), and HECT and RLD domain containing E3 ubiquitin protein ligase 2 (HERC2)(Table 2).

Comment

The importance of appropriate vitamin D levels is hypothesized as a potent driver in skin lightening because the vitamin is essential for many biochemical processes within the human body. Proper calcification of bones requires activated vitamin D to prevent rickets in childhood. Pelvic deformation in women with rickets can obstruct childbirth in primitive medical environments.¹⁵ This direct reproductive impairment suggests a strong selective pressure for skin lightening in populations that migrated northward to enhance vitamin D synthesis. 

Of the 39 articles that we reviewed, the majority (n=26 [66.7%]) supported the hypothesis that vitamin D synthesis was the main driver behind skin lightening, whereas 3 (7.7%) did not support the hypothesis and 10 (25.6%) were neutral. Other leading theories explaining skin lightening included the idea that enhanced melanogenesis protected against folate degradation; genetic selection for light-skin alleles due to genetic drift; skin lightening being the result of sexual selection; and a combination of factors, including dietary choices, clothing preferences, and skin permeability barriers. 

Articles With Supporting Evidence for the Vitamin D Theory—As Homo sapiens migrated out of Africa, migration patterns demonstrated the correlation between distance from the equator and skin pigmentation from natural selection. Individuals with darker skin pigment required higher levels of UVR to synthesize vitamin D. According to Beleza et al,1 as humans migrated to areas of higher latitudes with lower levels of UVR, natural selection favored the development of lighter skin to maximize vitamin D production. Vitamin D is linked to calcium metabolism, and its deficiency can lead to bone malformations and poor immune function.³⁵ Several genes affecting melanogenesis and skin pigment have been found to have geospatial patterns that map to different geographic locations of various populations, indicating how human migration patterns out of Africa created this natural selection for skin lightening. The gene KITLG—associated with lighter skin pigmentation—has been found in high frequencies in both European and East Asian populations and is proposed to have increased in frequency after the migration out of Africa. However, the genes TYRP1, SLC24A5, and SLC45A2 were found at high frequencies only in European populations, and this selection occurred 11,000 to 19,000 years ago during the Last Glacial Maximum (15,000–20,000 years ago), demonstrating the selection for European over East Asian characteristics. During this period, seasonal changes increased the risk for vitamin D deficiency and provided an urgency for selection to a lighter skin pigment.¹

The migration of H sapiens to northern latitudes prompted the selection of alleles that would increasevitamin D synthesis to counteract the reduced UV exposure. Genetic analysis studies have found key associations between genes encoding for the metabolism of vitamin D and pigmentation. Among this complex network are the essential downstream enzymes in the melanocortin receptor 1 pathway, including TYR and TYRP1. Forty-six of 960 single-nucleotide polymorphisms located in 29 different genes involved in skin pigmentation that were analyzed in a cohort of 2970 individuals were significantly associated with serum vitamin D levels (P<.05). The exocyst complex component 2 (EXOC2), TYR, and TYRP1 gene variants were shown to have the greatest influence on vitamin D status.⁹ These data reveal how pigment genotypes are predictive of vitamin D levels and the epistatic potential among many genes in this complex network. 

Gene variation plays an important role in vitamin D status when comparing genetic polymorphisms in populations in northern latitudes to African populations. Vitamin D₃ precursor availability is decreased by 7-DHCR catalyzing the precursors substrate to cholesterol. In a study using GWAS, it was found that “variations in DHCR7 may aid vitamin D production by conserving cutaneous 7-DHC levels. A high prevalence of DHCR7 variants were found in European and Northeast Asian populations but not in African populations, suggesting that selection occurred for these DHCR7 mutations in populations who migrated to more northern latitudes.⁵ Multilocus networks have been established between the VDR promotor and skin color genes (Table 2) that exhibit a strong in-Africa vs out-of-Africa frequency pattern. It also has been shown that genetic variation (suggesting a long-term evolutionary inclination) and epigenetic modification (indicative of short-term exposure) of VDR lends support to the vitamin D hypothesis. As latitude decreases, prevalence of VDR FokI (F allele), BsmI (B allele), ApaI (A allele), and TaqI (T allele) also decreases in a linear manner, linking latitude to VDR polymorphisms. Plasma vitamin D levels and photoperiod of conception—UV exposure during the periconceptional period—also were extrapolative of VDR methylation in a study involving 80 participants, where these 2 factors accounted for 17% of variance in methylation.⁶

Other noteworthy genes included HERC2, which has implications in the expression of OCA2 (melanocyte-specific transporter protein), and IRF4, which encodes for an important enzyme in folate-dependent melanin production. In an Australian cross-sectional study that analyzed vitamin D and pigmentation gene polymorphisms in conjunction with plasma vitamin D levels, the most notable rate of vitamin D loss occurred in individuals with the darkest pigmentation HERC2 (AA) genotype.³¹ In contrast, the lightest pigmentation HERC2 (GG) genotypes had increased vitamin D₃ photosynthesis. Interestingly, the lightest interferon regulatory factor 4 (IRF4) TT genotype and the darkest HERC2 AA genotype, rendering the greatest folate loss and largest synthesis of vitamin D₃, were not seen in combination in any of the participants.³⁰ In addition to HERC2, derived alleles from pigment-associated genes SLC24A5*A and SLC45A2*G demonstrated greater frequencies in Europeans (>90%) compared to Africans and East Asians, where the allelic frequencies were either rare or absent.1 This evidence delineates not only the complexity but also the strong relationship between skin pigmentation, latitude, and vitamin D status. The GWAS also have supported this concept. In comparing European populations to African populations, there was a 4-fold increase in the frequencies of “derived alleles of the vitamin D transport protein (GC, rs3755967), the 25(OH)D₃ synthesizing enzyme (CYP2R1, rs10741657), VDR (rs2228570 (commonly known as FokI polymorphism), rs1544410 (Bsm1), and rs731236 (Taq1) and the VDR target genes CYP24A1 (rs17216707), CD14 (rs2569190), and CARD9 (rs4077515).”³²

Articles With Evidence Against the Vitamin D Theory—This review analyzed the level of support for the theory that vitamin D was the main driver for skin lightening. Although most articles supported this theory, there were articles that listed other plausible counterarguments. Jablonski and Chaplin3 suggested that humans living in higher latitudes compensated for increased demand of vitamin D by placing cultural importance on a diet of vitamin D–rich foods and thus would not have experienced decreased vitamin D levels, which we hypothesize were the driver for skin lightening. Elias et al³⁹ argued that initial pigment dilution may have instead served to improve metabolic conservation, as the authors found no evidence of rickets—the sequelae of vitamin D deficiency—in pre–industrial age human fossils. Elias and Williams3⁸ proposed that differences in skin pigment are due to a more intact skin permeability barrier as “a requirement for life in a desiccating terrestrial environment,” which is seen in darker skin tones compared to lighter skin tones and thus can survive better in warmer climates with less risk of infections or dehydration.

Articles With Neutral Evidence for the Vitamin D Theory—Greaves⁴¹ argued against the idea that skin evolved to become lighter to protect against vitamin D deficiency. They proposed that the chimpanzee, which is the human’s most closely related species, had light skin covered by hair, and the loss of this hair led to exposed pale skin that created a need for increased melanin production for protection from UVR. Greaves⁴¹ stated that the MC1R gene (associated with darker pigmentation) was selected for in African populations, and those with pale skin retained their original pigment as they migrated to higher latitudes. Further research has demonstrated that the genetic natural selection for skin pigment is a complex process that involves multiple gene variants found throughout cultures across the globe.

Conclusion

Skin pigmentation has continuously evolved alongside humans. Genetic selection for lighter skin coincides with a favorable selection for genes involved in vitamin D synthesis as humans migrated to northern latitudes, which enabled humans to produce adequate levels of exogenous vitamin D in low-UVR areas and in turn promoted survival. Early humans without access to supplementation or foods rich in vitamin D acquired vitamin D primarily through sunlight. In comparison to modern society, where vitamin D supplementation is accessible and human lifespans are prolonged, lighter skin tone is now a risk factor for malignant cancers of the skin rather than being a protective adaptation. Current sun behavior recommendations conclude that the body’s need for vitamin D is satisfied by UV exposure to the arms, legs, hands, and/or face for only 5 to 30 minutes between 10 am and 4 pm daily without sunscreen.^42-44 Approximately 600 IU of vitamin D supplementation daily is recommended in a typical adult younger than 70 years to avoid deficiency. In adults 70 years and older who are not receiving adequate sunlight exposure, 800 IU of daily vitamin D supplementation is recommended.⁴⁵

The hypothesis that skin lightening primarily was driven by the need for vitamin D can only be partially supported by our review. Studies have shown that there is a corresponding complex network of genes that determines skin pigmentation as well as vitamin D synthesis and conservation. However, there is sufficient evidence that skin lightening is multifactorial in nature, and vitamin D alone may not be the sole driver. The information in this review can be used by health care providers to educate patients on sun protection, given the lesser threat of severe vitamin D deficiency in developed communities today that have access to adequate nutrition and supplementation.

Skin lightening and its coinciding evolutionary drivers are a rather neglected area of research. Due to heterogeneous cohorts and conservative data analysis, GWAS studies run the risk of type II error, yielding a limitation in our data analysis.⁹ Furthermore, the data regarding specific time frames in evolutionary skin lightening as well as the intensity of gene polymorphisms are limited.1 Further studies are needed to determine the interconnectedness of the current skin-lightening theories to identify other important factors that may play a role in the process. Determining the key event can help us better understand skin-adaptation mechanisms and create a framework for understanding the vital process involved in adaptation, survival, and disease manifestation in different patient populations.

The risk for developing skin cancer can be somewhat attributed to variations in skin pigmentation. Historically, lighter skin pigmentation has been observed in populations living in higher latitudes and darker pigmentation in populations near the equator. Although skin pigmentation is a conglomeration of genetic and environmental factors, anthropologic studies have demonstrated an association of human skin lightening with historic human migratory patterns.¹ It is postulated that migration to latitudes with less UVB light penetration has resulted in a compensatory natural selection of lighter skin types. Furthermore, the driving force behind this migration-associated skin lightening has remained unclear.¹

The need for folate metabolism, vitamin D synthesis, and barrier protection, as well as cultural practices, has been postulated as driving factors for skin pigmentation variation. Synthesis of vitamin D is a UV radiation (UVR)–dependent process and has remained a prominent theoretical driver for the basis of evolutionary skin lightening. Vitamin D can be acquired both exogenously or endogenously via dietary supplementation or sunlight; however, historically it has been obtained through UVB exposure primarily. Once UVB is absorbed by the skin, it catalyzes conversion of 7-dehydrocholesterol to previtamin D₃, which is converted to vitamin D in the kidneys.^2,3 It is suggested that lighter skin tones have an advantage over darker skin tones in synthesizing vitamin D at higher latitudes where there is less UVB, thus leading to the adaptation process.1 In this systematic review, we analyzed the evolutionary vitamin D adaptation hypothesis and assessed the validity of evidence supporting this theory in the literature.

Methods

A search of PubMed, Embase, and the Cochrane Reviews database was conducted using the terms evolution, vitamin D, and skin to generate articles published from 2010 to 2022 that evaluated the influence of UVR-dependent production of vitamin D on skin pigmentation through historical migration patterns (Figure). Studies were excluded during an initial screening of abstracts followed by full-text assessment if they only had abstracts and if articles were inaccessible for review or in the form of case reports and commentaries.

The following data were extracted from each included study: reference citation, affiliated institutions of authors, author specialties, journal name, year of publication, study period, type of article, type of study, mechanism of adaptation, data concluding or supporting vitamin D as the driver, and data concluding or suggesting against vitamin D as the driver. Data concluding or supporting vitamin D as the driver were recorded from statistically significant results, study conclusions, and direct quotations. Data concluding or suggesting against vitamin D as the driver also were recorded from significant results, study conclusions, and direct quotes. The mechanism of adaptation was based on vitamin D synthesis modulation, melanin upregulation, genetic selections, genetic drift, mating patterns, increased vitamin D sensitivity, interbreeding, and diet.

Studies included in the analysis were placed into 1 of 3 categories: supporting, neutral, and against. Strength of Recommendation Taxonomy (SORT) criteria were used to classify the level of evidence of each article.⁴ Each article’s level of evidence was then graded (Table 1). The SORT grading levels were based on quality and evidence type: level 1 signified good-quality, patient-oriented evidence; level 2 signified limited-quality, patient-oriented evidence; and level 3 signified other evidence.⁴

Results

Article Selection—A total of 229 articles were identified for screening, and 39 studies met inclusion criteria.^1-3,5-40 Systematic and retrospective reviews were the most common types of studies. Genomic analysis/sequencing/genome-wide association studies (GWAS) were the most common methods of analysis. Of these 39 articles, 26 were classified as supporting the evolutionary vitamin D adaptation hypothesis, 10 were classified as neutral, and 3 were classified as against (Table 1). 

Of the articles classified as supporting the vitamin D hypothesis, 13 articles were level 1 evidence, 9 were level 2, and 4 were level 3. Key findings supporting the vitamin D hypothesis included genetic natural selection favoring vitamin D synthesis genes at higher latitudes with lower UVR and the skin lightening that occurred to protect against vitamin D deficiency (Table 1). Specific genes supporting these findings included 7-dehydrocholesterol reductase (DHCR7), vitamin D receptor (VDR), tyrosinase (TYR), tyrosinase-related protein 1 (TYRP1), oculocutaneous albinism type 2 melanosomal transmembrane protein (OCA2), solute carrier family 45 member 2 (SLC45A2), solute carrier family 4 member 5 (SLC24A5), Kit ligand (KITLG), melanocortin 1 receptor (MC1R), and HECT and RLD domain containing E3 ubiquitin protein ligase 2 (HERC2)(Table 2).

Comment

The importance of appropriate vitamin D levels is hypothesized as a potent driver in skin lightening because the vitamin is essential for many biochemical processes within the human body. Proper calcification of bones requires activated vitamin D to prevent rickets in childhood. Pelvic deformation in women with rickets can obstruct childbirth in primitive medical environments.¹⁵ This direct reproductive impairment suggests a strong selective pressure for skin lightening in populations that migrated northward to enhance vitamin D synthesis. 

Of the 39 articles that we reviewed, the majority (n=26 [66.7%]) supported the hypothesis that vitamin D synthesis was the main driver behind skin lightening, whereas 3 (7.7%) did not support the hypothesis and 10 (25.6%) were neutral. Other leading theories explaining skin lightening included the idea that enhanced melanogenesis protected against folate degradation; genetic selection for light-skin alleles due to genetic drift; skin lightening being the result of sexual selection; and a combination of factors, including dietary choices, clothing preferences, and skin permeability barriers. 

Articles With Supporting Evidence for the Vitamin D Theory—As Homo sapiens migrated out of Africa, migration patterns demonstrated the correlation between distance from the equator and skin pigmentation from natural selection. Individuals with darker skin pigment required higher levels of UVR to synthesize vitamin D. According to Beleza et al,1 as humans migrated to areas of higher latitudes with lower levels of UVR, natural selection favored the development of lighter skin to maximize vitamin D production. Vitamin D is linked to calcium metabolism, and its deficiency can lead to bone malformations and poor immune function.³⁵ Several genes affecting melanogenesis and skin pigment have been found to have geospatial patterns that map to different geographic locations of various populations, indicating how human migration patterns out of Africa created this natural selection for skin lightening. The gene KITLG—associated with lighter skin pigmentation—has been found in high frequencies in both European and East Asian populations and is proposed to have increased in frequency after the migration out of Africa. However, the genes TYRP1, SLC24A5, and SLC45A2 were found at high frequencies only in European populations, and this selection occurred 11,000 to 19,000 years ago during the Last Glacial Maximum (15,000–20,000 years ago), demonstrating the selection for European over East Asian characteristics. During this period, seasonal changes increased the risk for vitamin D deficiency and provided an urgency for selection to a lighter skin pigment.¹

The migration of H sapiens to northern latitudes prompted the selection of alleles that would increasevitamin D synthesis to counteract the reduced UV exposure. Genetic analysis studies have found key associations between genes encoding for the metabolism of vitamin D and pigmentation. Among this complex network are the essential downstream enzymes in the melanocortin receptor 1 pathway, including TYR and TYRP1. Forty-six of 960 single-nucleotide polymorphisms located in 29 different genes involved in skin pigmentation that were analyzed in a cohort of 2970 individuals were significantly associated with serum vitamin D levels (P<.05). The exocyst complex component 2 (EXOC2), TYR, and TYRP1 gene variants were shown to have the greatest influence on vitamin D status.⁹ These data reveal how pigment genotypes are predictive of vitamin D levels and the epistatic potential among many genes in this complex network. 

Gene variation plays an important role in vitamin D status when comparing genetic polymorphisms in populations in northern latitudes to African populations. Vitamin D₃ precursor availability is decreased by 7-DHCR catalyzing the precursors substrate to cholesterol. In a study using GWAS, it was found that “variations in DHCR7 may aid vitamin D production by conserving cutaneous 7-DHC levels. A high prevalence of DHCR7 variants were found in European and Northeast Asian populations but not in African populations, suggesting that selection occurred for these DHCR7 mutations in populations who migrated to more northern latitudes.⁵ Multilocus networks have been established between the VDR promotor and skin color genes (Table 2) that exhibit a strong in-Africa vs out-of-Africa frequency pattern. It also has been shown that genetic variation (suggesting a long-term evolutionary inclination) and epigenetic modification (indicative of short-term exposure) of VDR lends support to the vitamin D hypothesis. As latitude decreases, prevalence of VDR FokI (F allele), BsmI (B allele), ApaI (A allele), and TaqI (T allele) also decreases in a linear manner, linking latitude to VDR polymorphisms. Plasma vitamin D levels and photoperiod of conception—UV exposure during the periconceptional period—also were extrapolative of VDR methylation in a study involving 80 participants, where these 2 factors accounted for 17% of variance in methylation.⁶

Other noteworthy genes included HERC2, which has implications in the expression of OCA2 (melanocyte-specific transporter protein), and IRF4, which encodes for an important enzyme in folate-dependent melanin production. In an Australian cross-sectional study that analyzed vitamin D and pigmentation gene polymorphisms in conjunction with plasma vitamin D levels, the most notable rate of vitamin D loss occurred in individuals with the darkest pigmentation HERC2 (AA) genotype.³¹ In contrast, the lightest pigmentation HERC2 (GG) genotypes had increased vitamin D₃ photosynthesis. Interestingly, the lightest interferon regulatory factor 4 (IRF4) TT genotype and the darkest HERC2 AA genotype, rendering the greatest folate loss and largest synthesis of vitamin D₃, were not seen in combination in any of the participants.³⁰ In addition to HERC2, derived alleles from pigment-associated genes SLC24A5*A and SLC45A2*G demonstrated greater frequencies in Europeans (>90%) compared to Africans and East Asians, where the allelic frequencies were either rare or absent.1 This evidence delineates not only the complexity but also the strong relationship between skin pigmentation, latitude, and vitamin D status. The GWAS also have supported this concept. In comparing European populations to African populations, there was a 4-fold increase in the frequencies of “derived alleles of the vitamin D transport protein (GC, rs3755967), the 25(OH)D₃ synthesizing enzyme (CYP2R1, rs10741657), VDR (rs2228570 (commonly known as FokI polymorphism), rs1544410 (Bsm1), and rs731236 (Taq1) and the VDR target genes CYP24A1 (rs17216707), CD14 (rs2569190), and CARD9 (rs4077515).”³²

Articles With Evidence Against the Vitamin D Theory—This review analyzed the level of support for the theory that vitamin D was the main driver for skin lightening. Although most articles supported this theory, there were articles that listed other plausible counterarguments. Jablonski and Chaplin3 suggested that humans living in higher latitudes compensated for increased demand of vitamin D by placing cultural importance on a diet of vitamin D–rich foods and thus would not have experienced decreased vitamin D levels, which we hypothesize were the driver for skin lightening. Elias et al³⁹ argued that initial pigment dilution may have instead served to improve metabolic conservation, as the authors found no evidence of rickets—the sequelae of vitamin D deficiency—in pre–industrial age human fossils. Elias and Williams3⁸ proposed that differences in skin pigment are due to a more intact skin permeability barrier as “a requirement for life in a desiccating terrestrial environment,” which is seen in darker skin tones compared to lighter skin tones and thus can survive better in warmer climates with less risk of infections or dehydration.

Articles With Neutral Evidence for the Vitamin D Theory—Greaves⁴¹ argued against the idea that skin evolved to become lighter to protect against vitamin D deficiency. They proposed that the chimpanzee, which is the human’s most closely related species, had light skin covered by hair, and the loss of this hair led to exposed pale skin that created a need for increased melanin production for protection from UVR. Greaves⁴¹ stated that the MC1R gene (associated with darker pigmentation) was selected for in African populations, and those with pale skin retained their original pigment as they migrated to higher latitudes. Further research has demonstrated that the genetic natural selection for skin pigment is a complex process that involves multiple gene variants found throughout cultures across the globe.

Conclusion

Skin pigmentation has continuously evolved alongside humans. Genetic selection for lighter skin coincides with a favorable selection for genes involved in vitamin D synthesis as humans migrated to northern latitudes, which enabled humans to produce adequate levels of exogenous vitamin D in low-UVR areas and in turn promoted survival. Early humans without access to supplementation or foods rich in vitamin D acquired vitamin D primarily through sunlight. In comparison to modern society, where vitamin D supplementation is accessible and human lifespans are prolonged, lighter skin tone is now a risk factor for malignant cancers of the skin rather than being a protective adaptation. Current sun behavior recommendations conclude that the body’s need for vitamin D is satisfied by UV exposure to the arms, legs, hands, and/or face for only 5 to 30 minutes between 10 am and 4 pm daily without sunscreen.^42-44 Approximately 600 IU of vitamin D supplementation daily is recommended in a typical adult younger than 70 years to avoid deficiency. In adults 70 years and older who are not receiving adequate sunlight exposure, 800 IU of daily vitamin D supplementation is recommended.⁴⁵

The hypothesis that skin lightening primarily was driven by the need for vitamin D can only be partially supported by our review. Studies have shown that there is a corresponding complex network of genes that determines skin pigmentation as well as vitamin D synthesis and conservation. However, there is sufficient evidence that skin lightening is multifactorial in nature, and vitamin D alone may not be the sole driver. The information in this review can be used by health care providers to educate patients on sun protection, given the lesser threat of severe vitamin D deficiency in developed communities today that have access to adequate nutrition and supplementation.

Skin lightening and its coinciding evolutionary drivers are a rather neglected area of research. Due to heterogeneous cohorts and conservative data analysis, GWAS studies run the risk of type II error, yielding a limitation in our data analysis.⁹ Furthermore, the data regarding specific time frames in evolutionary skin lightening as well as the intensity of gene polymorphisms are limited.1 Further studies are needed to determine the interconnectedness of the current skin-lightening theories to identify other important factors that may play a role in the process. Determining the key event can help us better understand skin-adaptation mechanisms and create a framework for understanding the vital process involved in adaptation, survival, and disease manifestation in different patient populations.

Angiosarcomas are aggressive endothelial cell tumors of vascular origin that account for 1% to 2% of all soft tissue sarcomas in the United States.^1,2 They can affect any organ in the body but most commonly affect the skin and soft tissue. Cutaneous angiosarcoma (CAS) is a rare type of skin cancer that can present in 2 forms: primary and secondary. The primary form lacks a known underlying cause, but secondary CAS commonly is linked to prior radiation therapy of the breast as well as lymphedema of the breast and arm. Secondary CAS may require different treatment than primary CAS, as radiation therapy poses risks to patients with radiation-induced CAS.³ The prognosis of CAS is poor due to delayed diagnosis. Current treatment modalities have a high rate of local recurrence and/or distant metastasis, but recent advances in surgery and other therapies such as radiation and immunotherapy provide hope for more successful disease control.

Dermatologists may be responsible for the initial diagnosis and management of CAS. They must be familiar with its presentation, as this condition can be difficult to diagnose and mimics other diseases. Additionally, dermatologists must understand the role of varying treatment modalities including Mohs micrographic surgery (MMS) in the management of CAS. This review will provide an overview of the epidemiology, presentation, and pathologic features of CAS and will discuss both emerging and existing treatments.

Epidemiology

Cutaneous angiosarcoma may present in various locations in the body, predominantly on the head and neck.^4,5 Approximately 85% of cases arise in patients older than 60 years, and most of these patients are White men.^1,4,5 The risk factors for the development of CAS include prior radiation exposure; chronic lymphedema (ie, Stewart-Treves syndrome); and familial syndromes including neurofibromatosis 1, BRCA1 or BRCA2 mutations, Maffucci syndrome, and Klippel-Trenaunay syndrome. Exogenous exposure to toxins such as vinyl chloride, thorium dioxide, or anabolic steroids also is associated with angiosarcoma, primarily in the form of visceral disease such as hepatic angiosarcoma.⁶

The average tumor size is approximately 4 to 5 cm; however, some tumors may grow larger than 10 cm.^7,8 Metastasis through hematogenous or lymphatic spread is fairly common, occurring in approximately 16% to 35% of patients. The lungs and liver are the most common sites of metastasis.^9,10 The age-adjusted incidence rate of CAS is decreasing for patients younger than 50 years, from 1.30 in 1995 to 2004 to 1.10 in 2005 to 2014, but increasing for individuals older than 70 years, from 2.53 in 1995 to 2004 to 2.87 in 2005 to 2014.⁴ The incidence of angiosarcoma also has grown in the female population, likely due to the increasing use of radiotherapy for the treatment of breast cancer.¹¹

The high rates of CAS on the head and neck may be explained by the increased vascularity and UV exposure in these locations.¹² In a Surveillance, Epidemiology, and End Results population-based study (N=811), 43% of patients with CAS had a history of other malignancies such as breast, prostate, genitourinary, gastrointestinal tract, and respiratory tract cancers.⁴ Cutaneous angiosarcoma can develop secondary to the primary cancer treatment, as seen in patients who develop CAS following radiation therapy.¹¹

The underlying mechanism of CAS is believed to involve dysregulation of angiogenesis due to the vascular origin of these tumors. Studies have identified overexpression of vascular endothelial growth factor (VEGF), TP53 mutations, and RAS pathway mutations as potential contributing factors to the pathogenesis of angiosarcoma.⁶ Molecular differences between primary and secondary angiosarcomas are not well documented; however, radiation-associated CAS has been found to have higher expression of LYN and PRKCΘ, while non–radiation-induced lesions express FTL1 and AKT3.² Chromosomal abnormalities have been identified in a small set of primary CAS patients, but the specific role of these abnormalities in the pathogenesis of CAS remains unclear.⁷

Prognosis

Cutaneous angiosarcoma has a poor prognosis, with 3-year disease-specific survival rates as low as 40% and 5-year rates as low as 17%.^4,5,13,14 Survival rates increased from 1985 to 2014, likely due to earlier diagnoses and more effective treatments.⁴ Several factors are associated with worse prognosis, including metastatic disease, increasing age, scalp and neck tumor location, tumor size greater than 5 cm, necrosis, multiple skin lesions, and nodular and epithelioid morphology.^4,5,10,13-16 Factors including sex, race, and presence of another malignancy do not affect survival.^4,5 Prognosis in CAS may be evaluated by TNM tumor staging. The American Joint Committee on Cancer Staging Manual (8th edition) for soft tissue sarcoma (STS) commonly is used; however, CAS is not included in this staging system because it does not share the same behavior and natural history as other types of STS. This staging system provides separate guidelines for STS of the head and neck and STS of the extremities and trunk because of the smaller size but paradoxically higher risk for head and neck tumors.¹⁷ Given that there is no agreed-upon staging system for CAS, prognosis and communication among providers may be complicated.

Early CAS typically presents as single or multifocal ill-defined, enlarging, violaceous or dusky red macules or patches (Figure 1). Lesions often rapidly develop into raised nodules and plaques that may bleed and ulcerate. Other common symptoms include pain, edema, neuropathy, anemia, and weight loss; however, it is not uncommon for lesions to be asymptomatic.^8,18-20 Nodular lesions are more common on the scalp, and patches are more common on the face and neck.¹⁶ Tumors typically extend into the dermis, and aggressive cancers may invade the subcutaneous tissue and fascia.²

Cutaneous angiosarcoma may mimic ecchymosis, hemangioma, lymphangioma, edema, cellulitis, or scarring alopecia. Its nonspecific features make it difficult to recognize without dermoscopy or ultrasonography, which often results in delayed diagnosis and treatment. The median delay typically is 5 to 7 months and up to 1 year for some patients.^7,16 Cutaneous angiosarcoma of the scalp tends to have a longer diagnostic delay than other areas of the body, which may be attributable to challenges in tumor identification and visualization by patients.¹⁶

Dermoscopy and ultrasonography can aid in the diagnosis of CAS. Dermoscopy may demonstrate a range of colors with yellow, brown, or red areas in a violaceous background. Other reported features include white veils and lines, purple ovals, pink-purple “steamlike” areas, and atypical vessels (Figure 2).^21-23 Dermoscopic findings may appear similar to other vascular tumors, such as hemangioma and Kaposi sarcoma, or nonvascular tumors, including amelanotic melanoma, Merkel cell carcinoma, and primary cutaneous B-cell lymphoma. Ultrasonography may show ill-defined, hypoechoic areas with anechoic reticular channels and a hypoechoic subepidermal layer.²¹ Other radiologic modalities, such as computed tomography, magnetic resonance imaging, or positron emission tomography, are nonspecific and are more useful in evaluating the extent of tumor spread in visceral angiosarcoma. Magnetic resonance imaging in CAS may indicate malignancy with the presence of high T2 and T1 signal intensity and high-flow serpentine vessels.²⁴

Histopathology

Histologically, angiosarcoma is characterized by anastomosing irregular vascular channels lined by a single layer of endothelial cells displaying slight to moderate atypia.²⁵ These vascular channels dissect between collagen bundles and adipocytes. Monocyte infiltration may be observed.⁶ The neoplastic endothelial cells may present as spindle-shaped, round, polygonal, or epithelioid with eosinophilic cytoplasm. Histologic features differ based on the type of clinical lesion (Figure 3). In a study of CAS in Asian populations, nodular tumors showed solid sheets of pleomorphic spindle cells, many mitotic figures, and widely hemorrhagic spaces, whereas nonnodular tumors showed irregular vascular spaces dissecting collagen.¹⁶ Poorly differentiated tumors may present with hyperchromatic nuclei and prominent nucleoli, papillary endothelial formations, mitoses, and possible hemorrhage or necrosis.^2,6,8 Histologic specimens also may reveal calcified bodies and hemosiderin particles.¹⁹ Angiosarcomas typically are invasive without a clear capsule or border.⁶

Photograph courtesy of Kim HooKim, MD (Camden, New Jersey).

Secondary CAS in the setting of lymphedema and radiation therapy has MYC amplification and is positive for MYC via immunohistochemistry, which is uncommon in primary angiosarcoma.²⁶ Immunohistochemical staining of tumor specimens is helpful to confirm the diagnosis of CAS. These markers include CD31, CD34, CD117, cytokeratin, vimentin, epithelial membrane antigen, factor VIII–related antigen, Ulex europaeus agglutinin-1, von Willebrand factor, and VEGF.^6,19,27,28 Notably, advanced angiosarcomas with progressive dedifferentiation often lose these markers.

Treatment

Surgery—The majority of patients treated for CAS undergo surgical resection, as surgery has been shown to have the best prognosis for patients.^5,9,10,13,15 Achieving R0 resection (microscopically negative margins) is the most important factor in determining the success of treatment, with incomplete surgical resection resulting in higher rates of systemic and local spread.²⁹ Abraham et al⁸ found that the median disease-specific survival of patients with microscopically negative margins was 83.7 months; patients with microscopically positive and grossly positive margins had median disease-specific survival of 63.4 and 18.1 months, respectively. In a case series of patients undergoing resection with negative surgical margins, 4 patients demonstrated no evidence of local recurrence or systemic disease at an average of 4.3 years after therapy, and the other 4 patients each had 1 local recurrence but were disease free an average of 4.8 years after removal of the recurrent lesion. In a series of 27 patients with positive surgical margins, there was local recurrence within 2 years for most patients.¹²

Large tumors invading nearby structures may not be amenable to surgical resection because of extensive local growth, propensity for skip lesions, and localization near vital organs of the head and neck.^5,7 The extended delay in diagnosis often seen in CAS allows for advanced local progression, resulting in large areas of resection. In a case series (N=8), the average surgical defect measured 14.3×11.8 cm, necessitating reconstruction with either a tissue flap or split-thickness skin graft in every case because primary closure was not possible. More than 80% of patients in this study still had positive margins after surgery, necessitating the use of additional chemotherapy or radiation to eradicate remaining disease.⁷ In several studies, multimodality therapy was associated with improved overall survival.^7,14,30

Mohs Micrographic Surgery—Mohs micrographic surgery is the standard of care for many aggressive cutaneous malignancies on the head, but its utility for the treatment of CAS is uncertain. Only a few studies have compared the efficacy of MMS vs wide local excision (WLE). There have been reports of recurrence-free follow-up at 12, 16, 18, 20, and 72 months after MMS.^31-36 The latter case showed a patient who underwent MMS with a 72-month relapse-free survival, whereas other patients who underwent WLE only survived 5 to 7 months without recurrence.³⁶ In another study, there was a local recurrence rate of 42.9% after a median follow-up of 4 years in 7 patients with CAS treated with complete circumferential peripheral and deep margin assessment, which is less than the reported recurrence rates of 72% to 84% after standard excisional procedures.^28,37

Houpe et al³⁸ conducted a systematic review of the use of WLE vs MMS; the median overall survival was longest for WLE in conjunction with chemotherapy, radiotherapy, and immunotherapy at 39.3 months, followed by MMS alone at 37 months. Mohs micrographic surgery in conjunction with chemotherapy and radiotherapy was used in 1 patient, with a median overall survival of 82 months. Wide local excision alone resulted in a median overall survival of 19.8 months. Although these data are promising and suggest that the combination of surgery with adjuvant therapy may be more beneficial than surgery alone, it is important to note that there were only 9 cases treated with MMS compared with 825 cases treated with WLE.³⁸

Several studies have documented that paraffin-embedded sections may be more useful than frozen sections in the determination of margin positivity from a surgical specimen, as frozen sections showed a poor negative predictive value of 33.3%.^7,35 Mohs micrographic surgery has been proposed for tumors measuring less than 5 cm; however, the most recent appropriate use criteria for MMS of the American Academy of Dermatology, American College of Mohs Surgery, American Society for Dermatologic Surgery Association, and American Society for Mohs Surgery deemed the use of MMS for angiosarcoma uncertain.^32,33,37 Further research is necessary to elucidate the role of MMS in the management of CAS.

Radiotherapy—Radiotherapy is a common adjuvant to surgical resection but has been used palliatively in patients with tumors that are unresectable. Improved local control and disease-free survival have been observed with the combination of radiation and surgery. A dose response to radiotherapy has been demonstrated,^18,30 with 1 study showing that patients who received more than 5000 cGy of radiotherapy achieved better local control than patients who received 4500 cGy or less.¹⁸ Pawlik et al⁷ showed a decreased chance of death with the addition of adjunctive radiotherapy, and patients who underwent postoperative radiotherapy demonstrated a median survival almost 4-times longer than patients who did not receive radiation. Morrison et al³⁹ reported that radiation therapy administered to patients with no clinically evident disease after surgical resection resulted in improved local control and overall survival vs patients who were irradiated with clinically evident disease.

Complications of radiotherapy for angiosarcoma have been reported, including xerostomia, nonfunctionally significant fibrosis, chronic ulceration/cellulitis of the scalp, necrosis requiring debridement, severe ocular complications, and fibrosis of the eyelids requiring surgical intervention.¹⁴ Radiation therapy also poses unique risks to patients with radiation-induced angiosarcoma of the breast, as many of these patients have already received the maximum recommended dose of radiation in the affected areas and additional radiation could exacerbate their CAS.

Chemotherapy—Chemotherapy occasionally is used as an adjunct to surgical resection with positive margins or as palliative care when surgical resection is not possible. Unfortunately, STSs have a response rate of less than 40% to standard chemotherapy.⁴⁰ Studies in which the use of chemotherapy is evaluated for CAS have mixed results. Mark et al¹⁸ reported no significant overall survival benefit when comparing CAS treated with surgery plus radiotherapy with or without chemotherapy. Torres et al⁴¹ evaluated radiation-induced angiosarcoma of the breast and found a reduced risk for local recurrence in patients receiving chemotherapy in addition to surgery, indicating that chemotherapy may be useful in this subset of patients when radiation is not recommended.

Cytotoxic chemotherapy agents such as paclitaxel, doxorubicin, or doxorubicin in combination with mesna and ifosfamide (MAI) are common.³⁹ Median progression-free survival is 5.4 months, 4 to 5.6 months, and 3.9 months for MAI, paclitaxel, and doxorubicin, respectively.^8,9,42-46 Improved prognosis with MAI may indicate that combination chemotherapy regimens are more effective than single-agent regimens. Cutaneous angiosarcomas may respond better to paclitaxel than doxorubicin, and angiosarcomas of the scalp and face have shown a better response to paclitaxel.^47,48

Other Therapies—Although there have not been large-scale studies performed on alternative treatments, there are several case reports on the use of immune modulators, biologics, β-blockers, and various other therapies in the treatment of CAS. The following studies include small sample sizes of patients with metastatic or locally aggressive disease not amenable to surgical resection, which may affect reported outcomes and survival times.^49-57 In addition, several studies include patients with visceral angiosarcoma, which may not be generalizable to the CAS population. Even so, these treatment alternatives should not be overlooked because there are few agents that are truly efficacious in the treatment of CAS.

Results on the use of VEGF and tyrosine kinase inhibitors have been disappointing. There have been reports of median progression-free survival of only 3.8 months with sorafenib treatment, 3 months with pazopanib, and 6 months with bevacizumab.^49-51 However, one study of patients who were treated with bevacizumab combined with radiation and surgery resulted in a complete response in 2 patients, with no evidence of residual disease at the last follow-up of 8.5 months and 2.1 years.⁵²

Studies on the utility of β-blockers in the treatment of CAS have shown mixed results. Pasquier et al⁵³ evaluated the use of adjunctive therapy with propranolol and vinblastine-based chemotherapy, with a promising median progression-free survival of 11 months compared with an average of 3 to 6 months with conventional chemotherapy regimens. However, in vitro studies reported by Pasquier et al⁵³ indicated that the addition of propranolol to doxorubicin or paclitaxel did not result in increased efficacy. Chow et al⁵⁴ demonstrated that propranolol monotherapy resulted in a reduction of the proliferative index of scalp angiosarcoma by 34% after only 1 week of treatment. This was followed by combination therapy of propranolol, paclitaxel, and radiation, which resulted in substantial tumor regression and no evidence of metastasis after 8 months of therapy.⁵⁴

Immune checkpoint inhibitors have been a recent subject of interest in the treatment of angiosarcoma. Two case reports showed improvement in CAS of the face and primary pleural angiosarcoma with a course of pembrolizumab.^55,56 In another case series, investigators used immune checkpoint inhibitors in 7 patients with cutaneous, breast, or radiation-associated angiosarcoma and found partial response in several patients treated with pembrolizumab and ipilimumab-nivolumab and complete response in 1 patient treated with anti–cytotoxic T-lymphocyte–associated protein 4 antibodies. The authors of this study hypothesized that treatment response was associated with the mutational profile of tumors, including mutational signatures of UV radiation with a large number of C-to-T substitutions similar to melanomas.⁵⁷

Conclusion

Cutaneous angiosarcoma is a rare and aggressive tumor with a poor prognosis due to delayed detection. A thorough skin examination and heightened awareness of CAS by dermatologists may result in early biopsy and shortened time to a definitive diagnosis. Until quality evidence allows for the creation of consensus guidelines, care at a cancer center that specializes in rare and difficult-to-treat tumors and employs a multidisciplinary approach is essential to optimizing patient outcomes. Current knowledge supports surgery with negative margins as the mainstay of treatment, with adjuvant radiation, chemotherapy, and targeted therapies as possible additions for extensive disease. The role of MMS is uncertain, and because of the lack of contiguity in CAS, it may not be an optimal treatment.

Angiosarcomas are aggressive endothelial cell tumors of vascular origin that account for 1% to 2% of all soft tissue sarcomas in the United States.^1,2 They can affect any organ in the body but most commonly affect the skin and soft tissue. Cutaneous angiosarcoma (CAS) is a rare type of skin cancer that can present in 2 forms: primary and secondary. The primary form lacks a known underlying cause, but secondary CAS commonly is linked to prior radiation therapy of the breast as well as lymphedema of the breast and arm. Secondary CAS may require different treatment than primary CAS, as radiation therapy poses risks to patients with radiation-induced CAS.³ The prognosis of CAS is poor due to delayed diagnosis. Current treatment modalities have a high rate of local recurrence and/or distant metastasis, but recent advances in surgery and other therapies such as radiation and immunotherapy provide hope for more successful disease control.

Dermatologists may be responsible for the initial diagnosis and management of CAS. They must be familiar with its presentation, as this condition can be difficult to diagnose and mimics other diseases. Additionally, dermatologists must understand the role of varying treatment modalities including Mohs micrographic surgery (MMS) in the management of CAS. This review will provide an overview of the epidemiology, presentation, and pathologic features of CAS and will discuss both emerging and existing treatments.

Epidemiology

Cutaneous angiosarcoma may present in various locations in the body, predominantly on the head and neck.^4,5 Approximately 85% of cases arise in patients older than 60 years, and most of these patients are White men.^1,4,5 The risk factors for the development of CAS include prior radiation exposure; chronic lymphedema (ie, Stewart-Treves syndrome); and familial syndromes including neurofibromatosis 1, BRCA1 or BRCA2 mutations, Maffucci syndrome, and Klippel-Trenaunay syndrome. Exogenous exposure to toxins such as vinyl chloride, thorium dioxide, or anabolic steroids also is associated with angiosarcoma, primarily in the form of visceral disease such as hepatic angiosarcoma.⁶

The average tumor size is approximately 4 to 5 cm; however, some tumors may grow larger than 10 cm.^7,8 Metastasis through hematogenous or lymphatic spread is fairly common, occurring in approximately 16% to 35% of patients. The lungs and liver are the most common sites of metastasis.^9,10 The age-adjusted incidence rate of CAS is decreasing for patients younger than 50 years, from 1.30 in 1995 to 2004 to 1.10 in 2005 to 2014, but increasing for individuals older than 70 years, from 2.53 in 1995 to 2004 to 2.87 in 2005 to 2014.⁴ The incidence of angiosarcoma also has grown in the female population, likely due to the increasing use of radiotherapy for the treatment of breast cancer.¹¹

The high rates of CAS on the head and neck may be explained by the increased vascularity and UV exposure in these locations.¹² In a Surveillance, Epidemiology, and End Results population-based study (N=811), 43% of patients with CAS had a history of other malignancies such as breast, prostate, genitourinary, gastrointestinal tract, and respiratory tract cancers.⁴ Cutaneous angiosarcoma can develop secondary to the primary cancer treatment, as seen in patients who develop CAS following radiation therapy.¹¹

The underlying mechanism of CAS is believed to involve dysregulation of angiogenesis due to the vascular origin of these tumors. Studies have identified overexpression of vascular endothelial growth factor (VEGF), TP53 mutations, and RAS pathway mutations as potential contributing factors to the pathogenesis of angiosarcoma.⁶ Molecular differences between primary and secondary angiosarcomas are not well documented; however, radiation-associated CAS has been found to have higher expression of LYN and PRKCΘ, while non–radiation-induced lesions express FTL1 and AKT3.² Chromosomal abnormalities have been identified in a small set of primary CAS patients, but the specific role of these abnormalities in the pathogenesis of CAS remains unclear.⁷

Prognosis

Cutaneous angiosarcoma has a poor prognosis, with 3-year disease-specific survival rates as low as 40% and 5-year rates as low as 17%.^4,5,13,14 Survival rates increased from 1985 to 2014, likely due to earlier diagnoses and more effective treatments.⁴ Several factors are associated with worse prognosis, including metastatic disease, increasing age, scalp and neck tumor location, tumor size greater than 5 cm, necrosis, multiple skin lesions, and nodular and epithelioid morphology.^4,5,10,13-16 Factors including sex, race, and presence of another malignancy do not affect survival.^4,5 Prognosis in CAS may be evaluated by TNM tumor staging. The American Joint Committee on Cancer Staging Manual (8th edition) for soft tissue sarcoma (STS) commonly is used; however, CAS is not included in this staging system because it does not share the same behavior and natural history as other types of STS. This staging system provides separate guidelines for STS of the head and neck and STS of the extremities and trunk because of the smaller size but paradoxically higher risk for head and neck tumors.¹⁷ Given that there is no agreed-upon staging system for CAS, prognosis and communication among providers may be complicated.

Early CAS typically presents as single or multifocal ill-defined, enlarging, violaceous or dusky red macules or patches (Figure 1). Lesions often rapidly develop into raised nodules and plaques that may bleed and ulcerate. Other common symptoms include pain, edema, neuropathy, anemia, and weight loss; however, it is not uncommon for lesions to be asymptomatic.^8,18-20 Nodular lesions are more common on the scalp, and patches are more common on the face and neck.¹⁶ Tumors typically extend into the dermis, and aggressive cancers may invade the subcutaneous tissue and fascia.²

Cutaneous angiosarcoma may mimic ecchymosis, hemangioma, lymphangioma, edema, cellulitis, or scarring alopecia. Its nonspecific features make it difficult to recognize without dermoscopy or ultrasonography, which often results in delayed diagnosis and treatment. The median delay typically is 5 to 7 months and up to 1 year for some patients.^7,16 Cutaneous angiosarcoma of the scalp tends to have a longer diagnostic delay than other areas of the body, which may be attributable to challenges in tumor identification and visualization by patients.¹⁶

Dermoscopy and ultrasonography can aid in the diagnosis of CAS. Dermoscopy may demonstrate a range of colors with yellow, brown, or red areas in a violaceous background. Other reported features include white veils and lines, purple ovals, pink-purple “steamlike” areas, and atypical vessels (Figure 2).^21-23 Dermoscopic findings may appear similar to other vascular tumors, such as hemangioma and Kaposi sarcoma, or nonvascular tumors, including amelanotic melanoma, Merkel cell carcinoma, and primary cutaneous B-cell lymphoma. Ultrasonography may show ill-defined, hypoechoic areas with anechoic reticular channels and a hypoechoic subepidermal layer.²¹ Other radiologic modalities, such as computed tomography, magnetic resonance imaging, or positron emission tomography, are nonspecific and are more useful in evaluating the extent of tumor spread in visceral angiosarcoma. Magnetic resonance imaging in CAS may indicate malignancy with the presence of high T2 and T1 signal intensity and high-flow serpentine vessels.²⁴

Histopathology

Histologically, angiosarcoma is characterized by anastomosing irregular vascular channels lined by a single layer of endothelial cells displaying slight to moderate atypia.²⁵ These vascular channels dissect between collagen bundles and adipocytes. Monocyte infiltration may be observed.⁶ The neoplastic endothelial cells may present as spindle-shaped, round, polygonal, or epithelioid with eosinophilic cytoplasm. Histologic features differ based on the type of clinical lesion (Figure 3). In a study of CAS in Asian populations, nodular tumors showed solid sheets of pleomorphic spindle cells, many mitotic figures, and widely hemorrhagic spaces, whereas nonnodular tumors showed irregular vascular spaces dissecting collagen.¹⁶ Poorly differentiated tumors may present with hyperchromatic nuclei and prominent nucleoli, papillary endothelial formations, mitoses, and possible hemorrhage or necrosis.^2,6,8 Histologic specimens also may reveal calcified bodies and hemosiderin particles.¹⁹ Angiosarcomas typically are invasive without a clear capsule or border.⁶

Photograph courtesy of Kim HooKim, MD (Camden, New Jersey).

Secondary CAS in the setting of lymphedema and radiation therapy has MYC amplification and is positive for MYC via immunohistochemistry, which is uncommon in primary angiosarcoma.²⁶ Immunohistochemical staining of tumor specimens is helpful to confirm the diagnosis of CAS. These markers include CD31, CD34, CD117, cytokeratin, vimentin, epithelial membrane antigen, factor VIII–related antigen, Ulex europaeus agglutinin-1, von Willebrand factor, and VEGF.^6,19,27,28 Notably, advanced angiosarcomas with progressive dedifferentiation often lose these markers.

Treatment

Surgery—The majority of patients treated for CAS undergo surgical resection, as surgery has been shown to have the best prognosis for patients.^5,9,10,13,15 Achieving R0 resection (microscopically negative margins) is the most important factor in determining the success of treatment, with incomplete surgical resection resulting in higher rates of systemic and local spread.²⁹ Abraham et al⁸ found that the median disease-specific survival of patients with microscopically negative margins was 83.7 months; patients with microscopically positive and grossly positive margins had median disease-specific survival of 63.4 and 18.1 months, respectively. In a case series of patients undergoing resection with negative surgical margins, 4 patients demonstrated no evidence of local recurrence or systemic disease at an average of 4.3 years after therapy, and the other 4 patients each had 1 local recurrence but were disease free an average of 4.8 years after removal of the recurrent lesion. In a series of 27 patients with positive surgical margins, there was local recurrence within 2 years for most patients.¹²

Large tumors invading nearby structures may not be amenable to surgical resection because of extensive local growth, propensity for skip lesions, and localization near vital organs of the head and neck.^5,7 The extended delay in diagnosis often seen in CAS allows for advanced local progression, resulting in large areas of resection. In a case series (N=8), the average surgical defect measured 14.3×11.8 cm, necessitating reconstruction with either a tissue flap or split-thickness skin graft in every case because primary closure was not possible. More than 80% of patients in this study still had positive margins after surgery, necessitating the use of additional chemotherapy or radiation to eradicate remaining disease.⁷ In several studies, multimodality therapy was associated with improved overall survival.^7,14,30

Mohs Micrographic Surgery—Mohs micrographic surgery is the standard of care for many aggressive cutaneous malignancies on the head, but its utility for the treatment of CAS is uncertain. Only a few studies have compared the efficacy of MMS vs wide local excision (WLE). There have been reports of recurrence-free follow-up at 12, 16, 18, 20, and 72 months after MMS.^31-36 The latter case showed a patient who underwent MMS with a 72-month relapse-free survival, whereas other patients who underwent WLE only survived 5 to 7 months without recurrence.³⁶ In another study, there was a local recurrence rate of 42.9% after a median follow-up of 4 years in 7 patients with CAS treated with complete circumferential peripheral and deep margin assessment, which is less than the reported recurrence rates of 72% to 84% after standard excisional procedures.^28,37

Houpe et al³⁸ conducted a systematic review of the use of WLE vs MMS; the median overall survival was longest for WLE in conjunction with chemotherapy, radiotherapy, and immunotherapy at 39.3 months, followed by MMS alone at 37 months. Mohs micrographic surgery in conjunction with chemotherapy and radiotherapy was used in 1 patient, with a median overall survival of 82 months. Wide local excision alone resulted in a median overall survival of 19.8 months. Although these data are promising and suggest that the combination of surgery with adjuvant therapy may be more beneficial than surgery alone, it is important to note that there were only 9 cases treated with MMS compared with 825 cases treated with WLE.³⁸

Several studies have documented that paraffin-embedded sections may be more useful than frozen sections in the determination of margin positivity from a surgical specimen, as frozen sections showed a poor negative predictive value of 33.3%.^7,35 Mohs micrographic surgery has been proposed for tumors measuring less than 5 cm; however, the most recent appropriate use criteria for MMS of the American Academy of Dermatology, American College of Mohs Surgery, American Society for Dermatologic Surgery Association, and American Society for Mohs Surgery deemed the use of MMS for angiosarcoma uncertain.^32,33,37 Further research is necessary to elucidate the role of MMS in the management of CAS.

Radiotherapy—Radiotherapy is a common adjuvant to surgical resection but has been used palliatively in patients with tumors that are unresectable. Improved local control and disease-free survival have been observed with the combination of radiation and surgery. A dose response to radiotherapy has been demonstrated,^18,30 with 1 study showing that patients who received more than 5000 cGy of radiotherapy achieved better local control than patients who received 4500 cGy or less.¹⁸ Pawlik et al⁷ showed a decreased chance of death with the addition of adjunctive radiotherapy, and patients who underwent postoperative radiotherapy demonstrated a median survival almost 4-times longer than patients who did not receive radiation. Morrison et al³⁹ reported that radiation therapy administered to patients with no clinically evident disease after surgical resection resulted in improved local control and overall survival vs patients who were irradiated with clinically evident disease.

Complications of radiotherapy for angiosarcoma have been reported, including xerostomia, nonfunctionally significant fibrosis, chronic ulceration/cellulitis of the scalp, necrosis requiring debridement, severe ocular complications, and fibrosis of the eyelids requiring surgical intervention.¹⁴ Radiation therapy also poses unique risks to patients with radiation-induced angiosarcoma of the breast, as many of these patients have already received the maximum recommended dose of radiation in the affected areas and additional radiation could exacerbate their CAS.

Chemotherapy—Chemotherapy occasionally is used as an adjunct to surgical resection with positive margins or as palliative care when surgical resection is not possible. Unfortunately, STSs have a response rate of less than 40% to standard chemotherapy.⁴⁰ Studies in which the use of chemotherapy is evaluated for CAS have mixed results. Mark et al¹⁸ reported no significant overall survival benefit when comparing CAS treated with surgery plus radiotherapy with or without chemotherapy. Torres et al⁴¹ evaluated radiation-induced angiosarcoma of the breast and found a reduced risk for local recurrence in patients receiving chemotherapy in addition to surgery, indicating that chemotherapy may be useful in this subset of patients when radiation is not recommended.

Cytotoxic chemotherapy agents such as paclitaxel, doxorubicin, or doxorubicin in combination with mesna and ifosfamide (MAI) are common.³⁹ Median progression-free survival is 5.4 months, 4 to 5.6 months, and 3.9 months for MAI, paclitaxel, and doxorubicin, respectively.^8,9,42-46 Improved prognosis with MAI may indicate that combination chemotherapy regimens are more effective than single-agent regimens. Cutaneous angiosarcomas may respond better to paclitaxel than doxorubicin, and angiosarcomas of the scalp and face have shown a better response to paclitaxel.^47,48

Other Therapies—Although there have not been large-scale studies performed on alternative treatments, there are several case reports on the use of immune modulators, biologics, β-blockers, and various other therapies in the treatment of CAS. The following studies include small sample sizes of patients with metastatic or locally aggressive disease not amenable to surgical resection, which may affect reported outcomes and survival times.^49-57 In addition, several studies include patients with visceral angiosarcoma, which may not be generalizable to the CAS population. Even so, these treatment alternatives should not be overlooked because there are few agents that are truly efficacious in the treatment of CAS.

Results on the use of VEGF and tyrosine kinase inhibitors have been disappointing. There have been reports of median progression-free survival of only 3.8 months with sorafenib treatment, 3 months with pazopanib, and 6 months with bevacizumab.^49-51 However, one study of patients who were treated with bevacizumab combined with radiation and surgery resulted in a complete response in 2 patients, with no evidence of residual disease at the last follow-up of 8.5 months and 2.1 years.⁵²

Studies on the utility of β-blockers in the treatment of CAS have shown mixed results. Pasquier et al⁵³ evaluated the use of adjunctive therapy with propranolol and vinblastine-based chemotherapy, with a promising median progression-free survival of 11 months compared with an average of 3 to 6 months with conventional chemotherapy regimens. However, in vitro studies reported by Pasquier et al⁵³ indicated that the addition of propranolol to doxorubicin or paclitaxel did not result in increased efficacy. Chow et al⁵⁴ demonstrated that propranolol monotherapy resulted in a reduction of the proliferative index of scalp angiosarcoma by 34% after only 1 week of treatment. This was followed by combination therapy of propranolol, paclitaxel, and radiation, which resulted in substantial tumor regression and no evidence of metastasis after 8 months of therapy.⁵⁴

Immune checkpoint inhibitors have been a recent subject of interest in the treatment of angiosarcoma. Two case reports showed improvement in CAS of the face and primary pleural angiosarcoma with a course of pembrolizumab.^55,56 In another case series, investigators used immune checkpoint inhibitors in 7 patients with cutaneous, breast, or radiation-associated angiosarcoma and found partial response in several patients treated with pembrolizumab and ipilimumab-nivolumab and complete response in 1 patient treated with anti–cytotoxic T-lymphocyte–associated protein 4 antibodies. The authors of this study hypothesized that treatment response was associated with the mutational profile of tumors, including mutational signatures of UV radiation with a large number of C-to-T substitutions similar to melanomas.⁵⁷

Conclusion

Cutaneous angiosarcoma is a rare and aggressive tumor with a poor prognosis due to delayed detection. A thorough skin examination and heightened awareness of CAS by dermatologists may result in early biopsy and shortened time to a definitive diagnosis. Until quality evidence allows for the creation of consensus guidelines, care at a cancer center that specializes in rare and difficult-to-treat tumors and employs a multidisciplinary approach is essential to optimizing patient outcomes. Current knowledge supports surgery with negative margins as the mainstay of treatment, with adjuvant radiation, chemotherapy, and targeted therapies as possible additions for extensive disease. The role of MMS is uncertain, and because of the lack of contiguity in CAS, it may not be an optimal treatment.

Angiosarcomas are aggressive endothelial cell tumors of vascular origin that account for 1% to 2% of all soft tissue sarcomas in the United States.^1,2 They can affect any organ in the body but most commonly affect the skin and soft tissue. Cutaneous angiosarcoma (CAS) is a rare type of skin cancer that can present in 2 forms: primary and secondary. The primary form lacks a known underlying cause, but secondary CAS commonly is linked to prior radiation therapy of the breast as well as lymphedema of the breast and arm. Secondary CAS may require different treatment than primary CAS, as radiation therapy poses risks to patients with radiation-induced CAS.³ The prognosis of CAS is poor due to delayed diagnosis. Current treatment modalities have a high rate of local recurrence and/or distant metastasis, but recent advances in surgery and other therapies such as radiation and immunotherapy provide hope for more successful disease control.

Dermatologists may be responsible for the initial diagnosis and management of CAS. They must be familiar with its presentation, as this condition can be difficult to diagnose and mimics other diseases. Additionally, dermatologists must understand the role of varying treatment modalities including Mohs micrographic surgery (MMS) in the management of CAS. This review will provide an overview of the epidemiology, presentation, and pathologic features of CAS and will discuss both emerging and existing treatments.

Epidemiology

Cutaneous angiosarcoma may present in various locations in the body, predominantly on the head and neck.^4,5 Approximately 85% of cases arise in patients older than 60 years, and most of these patients are White men.^1,4,5 The risk factors for the development of CAS include prior radiation exposure; chronic lymphedema (ie, Stewart-Treves syndrome); and familial syndromes including neurofibromatosis 1, BRCA1 or BRCA2 mutations, Maffucci syndrome, and Klippel-Trenaunay syndrome. Exogenous exposure to toxins such as vinyl chloride, thorium dioxide, or anabolic steroids also is associated with angiosarcoma, primarily in the form of visceral disease such as hepatic angiosarcoma.⁶

The average tumor size is approximately 4 to 5 cm; however, some tumors may grow larger than 10 cm.^7,8 Metastasis through hematogenous or lymphatic spread is fairly common, occurring in approximately 16% to 35% of patients. The lungs and liver are the most common sites of metastasis.^9,10 The age-adjusted incidence rate of CAS is decreasing for patients younger than 50 years, from 1.30 in 1995 to 2004 to 1.10 in 2005 to 2014, but increasing for individuals older than 70 years, from 2.53 in 1995 to 2004 to 2.87 in 2005 to 2014.⁴ The incidence of angiosarcoma also has grown in the female population, likely due to the increasing use of radiotherapy for the treatment of breast cancer.¹¹

The high rates of CAS on the head and neck may be explained by the increased vascularity and UV exposure in these locations.¹² In a Surveillance, Epidemiology, and End Results population-based study (N=811), 43% of patients with CAS had a history of other malignancies such as breast, prostate, genitourinary, gastrointestinal tract, and respiratory tract cancers.⁴ Cutaneous angiosarcoma can develop secondary to the primary cancer treatment, as seen in patients who develop CAS following radiation therapy.¹¹

The underlying mechanism of CAS is believed to involve dysregulation of angiogenesis due to the vascular origin of these tumors. Studies have identified overexpression of vascular endothelial growth factor (VEGF), TP53 mutations, and RAS pathway mutations as potential contributing factors to the pathogenesis of angiosarcoma.⁶ Molecular differences between primary and secondary angiosarcomas are not well documented; however, radiation-associated CAS has been found to have higher expression of LYN and PRKCΘ, while non–radiation-induced lesions express FTL1 and AKT3.² Chromosomal abnormalities have been identified in a small set of primary CAS patients, but the specific role of these abnormalities in the pathogenesis of CAS remains unclear.⁷

Prognosis

Cutaneous angiosarcoma has a poor prognosis, with 3-year disease-specific survival rates as low as 40% and 5-year rates as low as 17%.^4,5,13,14 Survival rates increased from 1985 to 2014, likely due to earlier diagnoses and more effective treatments.⁴ Several factors are associated with worse prognosis, including metastatic disease, increasing age, scalp and neck tumor location, tumor size greater than 5 cm, necrosis, multiple skin lesions, and nodular and epithelioid morphology.^4,5,10,13-16 Factors including sex, race, and presence of another malignancy do not affect survival.^4,5 Prognosis in CAS may be evaluated by TNM tumor staging. The American Joint Committee on Cancer Staging Manual (8th edition) for soft tissue sarcoma (STS) commonly is used; however, CAS is not included in this staging system because it does not share the same behavior and natural history as other types of STS. This staging system provides separate guidelines for STS of the head and neck and STS of the extremities and trunk because of the smaller size but paradoxically higher risk for head and neck tumors.¹⁷ Given that there is no agreed-upon staging system for CAS, prognosis and communication among providers may be complicated.

Early CAS typically presents as single or multifocal ill-defined, enlarging, violaceous or dusky red macules or patches (Figure 1). Lesions often rapidly develop into raised nodules and plaques that may bleed and ulcerate. Other common symptoms include pain, edema, neuropathy, anemia, and weight loss; however, it is not uncommon for lesions to be asymptomatic.^8,18-20 Nodular lesions are more common on the scalp, and patches are more common on the face and neck.¹⁶ Tumors typically extend into the dermis, and aggressive cancers may invade the subcutaneous tissue and fascia.²

Cutaneous angiosarcoma may mimic ecchymosis, hemangioma, lymphangioma, edema, cellulitis, or scarring alopecia. Its nonspecific features make it difficult to recognize without dermoscopy or ultrasonography, which often results in delayed diagnosis and treatment. The median delay typically is 5 to 7 months and up to 1 year for some patients.^7,16 Cutaneous angiosarcoma of the scalp tends to have a longer diagnostic delay than other areas of the body, which may be attributable to challenges in tumor identification and visualization by patients.¹⁶

Dermoscopy and ultrasonography can aid in the diagnosis of CAS. Dermoscopy may demonstrate a range of colors with yellow, brown, or red areas in a violaceous background. Other reported features include white veils and lines, purple ovals, pink-purple “steamlike” areas, and atypical vessels (Figure 2).^21-23 Dermoscopic findings may appear similar to other vascular tumors, such as hemangioma and Kaposi sarcoma, or nonvascular tumors, including amelanotic melanoma, Merkel cell carcinoma, and primary cutaneous B-cell lymphoma. Ultrasonography may show ill-defined, hypoechoic areas with anechoic reticular channels and a hypoechoic subepidermal layer.²¹ Other radiologic modalities, such as computed tomography, magnetic resonance imaging, or positron emission tomography, are nonspecific and are more useful in evaluating the extent of tumor spread in visceral angiosarcoma. Magnetic resonance imaging in CAS may indicate malignancy with the presence of high T2 and T1 signal intensity and high-flow serpentine vessels.²⁴

Histopathology

Histologically, angiosarcoma is characterized by anastomosing irregular vascular channels lined by a single layer of endothelial cells displaying slight to moderate atypia.²⁵ These vascular channels dissect between collagen bundles and adipocytes. Monocyte infiltration may be observed.⁶ The neoplastic endothelial cells may present as spindle-shaped, round, polygonal, or epithelioid with eosinophilic cytoplasm. Histologic features differ based on the type of clinical lesion (Figure 3). In a study of CAS in Asian populations, nodular tumors showed solid sheets of pleomorphic spindle cells, many mitotic figures, and widely hemorrhagic spaces, whereas nonnodular tumors showed irregular vascular spaces dissecting collagen.¹⁶ Poorly differentiated tumors may present with hyperchromatic nuclei and prominent nucleoli, papillary endothelial formations, mitoses, and possible hemorrhage or necrosis.^2,6,8 Histologic specimens also may reveal calcified bodies and hemosiderin particles.¹⁹ Angiosarcomas typically are invasive without a clear capsule or border.⁶

Photograph courtesy of Kim HooKim, MD (Camden, New Jersey).

Secondary CAS in the setting of lymphedema and radiation therapy has MYC amplification and is positive for MYC via immunohistochemistry, which is uncommon in primary angiosarcoma.²⁶ Immunohistochemical staining of tumor specimens is helpful to confirm the diagnosis of CAS. These markers include CD31, CD34, CD117, cytokeratin, vimentin, epithelial membrane antigen, factor VIII–related antigen, Ulex europaeus agglutinin-1, von Willebrand factor, and VEGF.^6,19,27,28 Notably, advanced angiosarcomas with progressive dedifferentiation often lose these markers.

Treatment

Surgery—The majority of patients treated for CAS undergo surgical resection, as surgery has been shown to have the best prognosis for patients.^5,9,10,13,15 Achieving R0 resection (microscopically negative margins) is the most important factor in determining the success of treatment, with incomplete surgical resection resulting in higher rates of systemic and local spread.²⁹ Abraham et al⁸ found that the median disease-specific survival of patients with microscopically negative margins was 83.7 months; patients with microscopically positive and grossly positive margins had median disease-specific survival of 63.4 and 18.1 months, respectively. In a case series of patients undergoing resection with negative surgical margins, 4 patients demonstrated no evidence of local recurrence or systemic disease at an average of 4.3 years after therapy, and the other 4 patients each had 1 local recurrence but were disease free an average of 4.8 years after removal of the recurrent lesion. In a series of 27 patients with positive surgical margins, there was local recurrence within 2 years for most patients.¹²

Large tumors invading nearby structures may not be amenable to surgical resection because of extensive local growth, propensity for skip lesions, and localization near vital organs of the head and neck.^5,7 The extended delay in diagnosis often seen in CAS allows for advanced local progression, resulting in large areas of resection. In a case series (N=8), the average surgical defect measured 14.3×11.8 cm, necessitating reconstruction with either a tissue flap or split-thickness skin graft in every case because primary closure was not possible. More than 80% of patients in this study still had positive margins after surgery, necessitating the use of additional chemotherapy or radiation to eradicate remaining disease.⁷ In several studies, multimodality therapy was associated with improved overall survival.^7,14,30

Mohs Micrographic Surgery—Mohs micrographic surgery is the standard of care for many aggressive cutaneous malignancies on the head, but its utility for the treatment of CAS is uncertain. Only a few studies have compared the efficacy of MMS vs wide local excision (WLE). There have been reports of recurrence-free follow-up at 12, 16, 18, 20, and 72 months after MMS.^31-36 The latter case showed a patient who underwent MMS with a 72-month relapse-free survival, whereas other patients who underwent WLE only survived 5 to 7 months without recurrence.³⁶ In another study, there was a local recurrence rate of 42.9% after a median follow-up of 4 years in 7 patients with CAS treated with complete circumferential peripheral and deep margin assessment, which is less than the reported recurrence rates of 72% to 84% after standard excisional procedures.^28,37

Houpe et al³⁸ conducted a systematic review of the use of WLE vs MMS; the median overall survival was longest for WLE in conjunction with chemotherapy, radiotherapy, and immunotherapy at 39.3 months, followed by MMS alone at 37 months. Mohs micrographic surgery in conjunction with chemotherapy and radiotherapy was used in 1 patient, with a median overall survival of 82 months. Wide local excision alone resulted in a median overall survival of 19.8 months. Although these data are promising and suggest that the combination of surgery with adjuvant therapy may be more beneficial than surgery alone, it is important to note that there were only 9 cases treated with MMS compared with 825 cases treated with WLE.³⁸

Several studies have documented that paraffin-embedded sections may be more useful than frozen sections in the determination of margin positivity from a surgical specimen, as frozen sections showed a poor negative predictive value of 33.3%.^7,35 Mohs micrographic surgery has been proposed for tumors measuring less than 5 cm; however, the most recent appropriate use criteria for MMS of the American Academy of Dermatology, American College of Mohs Surgery, American Society for Dermatologic Surgery Association, and American Society for Mohs Surgery deemed the use of MMS for angiosarcoma uncertain.^32,33,37 Further research is necessary to elucidate the role of MMS in the management of CAS.

Radiotherapy—Radiotherapy is a common adjuvant to surgical resection but has been used palliatively in patients with tumors that are unresectable. Improved local control and disease-free survival have been observed with the combination of radiation and surgery. A dose response to radiotherapy has been demonstrated,^18,30 with 1 study showing that patients who received more than 5000 cGy of radiotherapy achieved better local control than patients who received 4500 cGy or less.¹⁸ Pawlik et al⁷ showed a decreased chance of death with the addition of adjunctive radiotherapy, and patients who underwent postoperative radiotherapy demonstrated a median survival almost 4-times longer than patients who did not receive radiation. Morrison et al³⁹ reported that radiation therapy administered to patients with no clinically evident disease after surgical resection resulted in improved local control and overall survival vs patients who were irradiated with clinically evident disease.

Complications of radiotherapy for angiosarcoma have been reported, including xerostomia, nonfunctionally significant fibrosis, chronic ulceration/cellulitis of the scalp, necrosis requiring debridement, severe ocular complications, and fibrosis of the eyelids requiring surgical intervention.¹⁴ Radiation therapy also poses unique risks to patients with radiation-induced angiosarcoma of the breast, as many of these patients have already received the maximum recommended dose of radiation in the affected areas and additional radiation could exacerbate their CAS.

Chemotherapy—Chemotherapy occasionally is used as an adjunct to surgical resection with positive margins or as palliative care when surgical resection is not possible. Unfortunately, STSs have a response rate of less than 40% to standard chemotherapy.⁴⁰ Studies in which the use of chemotherapy is evaluated for CAS have mixed results. Mark et al¹⁸ reported no significant overall survival benefit when comparing CAS treated with surgery plus radiotherapy with or without chemotherapy. Torres et al⁴¹ evaluated radiation-induced angiosarcoma of the breast and found a reduced risk for local recurrence in patients receiving chemotherapy in addition to surgery, indicating that chemotherapy may be useful in this subset of patients when radiation is not recommended.

Cytotoxic chemotherapy agents such as paclitaxel, doxorubicin, or doxorubicin in combination with mesna and ifosfamide (MAI) are common.³⁹ Median progression-free survival is 5.4 months, 4 to 5.6 months, and 3.9 months for MAI, paclitaxel, and doxorubicin, respectively.^8,9,42-46 Improved prognosis with MAI may indicate that combination chemotherapy regimens are more effective than single-agent regimens. Cutaneous angiosarcomas may respond better to paclitaxel than doxorubicin, and angiosarcomas of the scalp and face have shown a better response to paclitaxel.^47,48

Other Therapies—Although there have not been large-scale studies performed on alternative treatments, there are several case reports on the use of immune modulators, biologics, β-blockers, and various other therapies in the treatment of CAS. The following studies include small sample sizes of patients with metastatic or locally aggressive disease not amenable to surgical resection, which may affect reported outcomes and survival times.^49-57 In addition, several studies include patients with visceral angiosarcoma, which may not be generalizable to the CAS population. Even so, these treatment alternatives should not be overlooked because there are few agents that are truly efficacious in the treatment of CAS.

Results on the use of VEGF and tyrosine kinase inhibitors have been disappointing. There have been reports of median progression-free survival of only 3.8 months with sorafenib treatment, 3 months with pazopanib, and 6 months with bevacizumab.^49-51 However, one study of patients who were treated with bevacizumab combined with radiation and surgery resulted in a complete response in 2 patients, with no evidence of residual disease at the last follow-up of 8.5 months and 2.1 years.⁵²

Studies on the utility of β-blockers in the treatment of CAS have shown mixed results. Pasquier et al⁵³ evaluated the use of adjunctive therapy with propranolol and vinblastine-based chemotherapy, with a promising median progression-free survival of 11 months compared with an average of 3 to 6 months with conventional chemotherapy regimens. However, in vitro studies reported by Pasquier et al⁵³ indicated that the addition of propranolol to doxorubicin or paclitaxel did not result in increased efficacy. Chow et al⁵⁴ demonstrated that propranolol monotherapy resulted in a reduction of the proliferative index of scalp angiosarcoma by 34% after only 1 week of treatment. This was followed by combination therapy of propranolol, paclitaxel, and radiation, which resulted in substantial tumor regression and no evidence of metastasis after 8 months of therapy.⁵⁴

Immune checkpoint inhibitors have been a recent subject of interest in the treatment of angiosarcoma. Two case reports showed improvement in CAS of the face and primary pleural angiosarcoma with a course of pembrolizumab.^55,56 In another case series, investigators used immune checkpoint inhibitors in 7 patients with cutaneous, breast, or radiation-associated angiosarcoma and found partial response in several patients treated with pembrolizumab and ipilimumab-nivolumab and complete response in 1 patient treated with anti–cytotoxic T-lymphocyte–associated protein 4 antibodies. The authors of this study hypothesized that treatment response was associated with the mutational profile of tumors, including mutational signatures of UV radiation with a large number of C-to-T substitutions similar to melanomas.⁵⁷

Conclusion

Cutaneous angiosarcoma is a rare and aggressive tumor with a poor prognosis due to delayed detection. A thorough skin examination and heightened awareness of CAS by dermatologists may result in early biopsy and shortened time to a definitive diagnosis. Until quality evidence allows for the creation of consensus guidelines, care at a cancer center that specializes in rare and difficult-to-treat tumors and employs a multidisciplinary approach is essential to optimizing patient outcomes. Current knowledge supports surgery with negative margins as the mainstay of treatment, with adjuvant radiation, chemotherapy, and targeted therapies as possible additions for extensive disease. The role of MMS is uncertain, and because of the lack of contiguity in CAS, it may not be an optimal treatment.

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.

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

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

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

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.

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.

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

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

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

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.

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.

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

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

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

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.

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.

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

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.

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

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.

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

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

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

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

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.

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

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