Cutis

A 72-year-old man with a history of multiple cancers, including melanoma, squamous cell carcinoma (SCC), and basal cell carcinoma (BCC), presented to the dermatology clinic for a regularly scheduled full-body skin examination. His family history was negative for malignancy, but due to his personal history of both primary internal cancers and skin cancers, the patient previously had been referred by dermatology to a medical geneticist for evaluation. He tested positive for a pathogenic POT1 (protection of telomeres 1) variant associated with tumor predisposition, which most often is associated with cutaneous melanoma, chronic lymphocytic leukemia (CLL), angiosarcoma, and gliomas.¹

At the current presentation, physical examination revealed a small, asymmetric, pink papule on the superior thoracic spine. A biopsy of the lesion was performed (Figure 1). Pathology demonstrated cornifying cystic structures with a granulomatous response at the surface of the tumor, ductal differentiation with depth, and infiltrative strands and cords of hyperchromatic cells within a collagenous stroma at the base of the specimen (Figures 2A and 2B). One unusual finding was the presence of prominent clear-cell change within the superficial portion of the neoplasm (Figure 2C). Immunohistochemical stains revealed strong p63 and p40 positivity. Epithelial membrane antigen staining was positive in the hyperchromatic strands and cords with depth but not in the clear-cell superficial portion. Similarly, periodic acid–Schiff–positive material increased within tumor cells in proportion to depth of infiltration. Additional immunohistochemical staining showed carcinoembryonic antigen was largely negative (with rare positivity in a few ductal lumina), with negative results for S100, SOX10, CD117, BerEP4, factor XIIIa, CD34, and cytokeratin 7 (Figures 2D and 2E).

The differential diagnoses included trichilemmal carcinoma (which may manifest with CD34 expression),² clear cell BCC, adenoid cystic carcinoma (tubular variant), sebaceous carcinoma, and eccrine carcinoma. Importantly, the patient was under continuous oncologic surveillance, with no evidence of a primary internal tumor to suggest metastasis. Despite negative carcinoembryonic antigen staining, the immunohistochemical and histopathologic findings fit best with a primary cutaneous malignant eccrine tumor, specifically microcystic adnexal carcinoma (MAC), in which p63 typically stains peripheral cells but solid variants have been described.³

Eccrine carcinoma is exceedingly rare, reported in 0.01% of diagnosed cutaneous malignancies, and demonstrates overlapping features to other malignant eccrine tumors. It possesses an inconsistent immunohistochemical staining profile, making the distinction from other malignant sweat gland tumors challenging.⁴ Given that the morphologic features were otherwise classic for MAC in our patient, we favored a clear-cell variant.

Sixteen years prior to the current presentation, our patient presented to urology with a history of prostatitis and increasing prostate-specific antigen levels. Biopsies were negative until prostate-specific antigen reached 13 ng/mL, confirming stage 1A prostate cancer. The patient subsequently underwent a robot-assisted radical prostatectomy. At age 63 years, dysphagia that was unresponsive to antibiotics led to a tonsillar biopsy revealing T2N2bM0 stage IVA SCC of the right tonsil with confirmed HPV type 16 with extracapsular extension. The patient underwent transoral robotic radical tonsillectomy and right neck dissection, followed by adjuvant chemoradiation consisting of intensity-modulated radiation therapy (IMRT) to a total dose of 63 Gy in 33 fractions, with concurrent weekly cisplatin. At age 67 years, dyspepsia, dysphagia, pyrosis, and gastroesophageal reflux prompted endoscopy, revealing T1aNxMx esophageal adenocarcinoma. Three months later, the patient underwent laparoscopic-assisted esophagectomy, with no recurrence. At age 68 years, an atypical intramelanocytic proliferation was found on the left cheek and was treated with Mohs micrographic surgery.

At age 71 years, acral lentiginous malignant melanoma (Breslow thickness 0.8 mm; Clark level IV; American Joint Committee on Cancer T1b) was diagnosed on the left plantar foot and treated with Mohs micrographic surgery. Sentinel lymph node biopsy was negative. Squamous cell carcinoma in situ on the frontal scalp and nodular BCC on the right upper back also were diagnosed.

While there are no guidelines for surveillance of individuals with POT1, recommendations were given in consensus from a medical genetics team,¹ including comprehensive monitoring—specifically baseline imaging utilizing brain and full-body magnetic resonance imaging. Furthermore, considering the crucial role of POT1 in maintaining telomeres, it was advised to measure telomere length as part of the surveillance process. Given the patient’s susceptibility to CLL, routine complete blood count assessments were recommended. Additionally, we advised close monitoring for seizures and consideration of genetic testing in first-degree relatives.

Literature Review

Given our patient’s history of multiple skin cancers, including the most recent MAC, we sought to conduct a review of the literature to evaluate existing skin cancer associations and reports for patients with known POT1 mutations to guide recommendations for dermatologic surveillance (Table). A search of PubMed articles indexed for MEDLINE through April 2023 using the terms microcystic adnexal carcinoma, POT1, melanoma, basal cell carcinoma, squamous cell carcinoma, and skin cancer yielded no reported cases of MAC associated with POT1 mutations. POT1 is one of 6 proteins (TERF1, TERF2, RAP1, TIN2, TPP1, and POT1) belonging to the shelterin complex, which plays a crucial role in telomeric DNA remodeling and regulation of telomere length.⁵ Mutation in the POT1 gene disrupts the shelterin complex, causing telomeres to become elongated and unstable, resulting in chromosomal abnormalities and promoting cancer development.⁵

While our literature review did not reveal any associations between the shelterin complex genes and MAC, mutations in the POT1 gene have been studied in other types of skin cancer, particularly melanoma.¹ One of the earliest studies was conducted in 2014 by Shi et al,⁶ in which whole-exome sequencing was performed on families with a history of melanoma. Multiple POT1 gene pathogenic variants associated with increased telomere length and fragility were identified in unrelated families. Subsequent studies have confirmed POT1 variants in melanoma-prone families,⁷ supporting an association between increased telomere length and melanoma risk^8-11; however, other studies have yielded nonsignificant findings.^12,13 Further investigation also has identified morphologic characteristics consistent with POT1 mutation, including spitzoid morphology.¹⁴

The association between POT1 mutations and nonmelanoma skin cancers has been relatively understudied. While a few studies have explored this link, results have shown mixed findings. Some studies have suggested a potential role for POT1 mutations in cutaneous SCC risk,¹⁵ while other studies have shown no significant associations for both BCC and SCC risk and telomere gene mutations.¹⁶ Additionally, mRNA levels of POT1 were upregulated in BCC cases compared to normal tissue in a gene expression.¹⁷

Comment

In the literature, POT1 mutations are well established as high-penetrance alterations associated with melanoma.^9,18,19 However, the correlation between POT1 and other forms of skin cancer is not yet delineated. Recent insights suggest that POT1 mutations play a major role in promoting melanoma progression through telomere elongation, an established driver of melanoma progression, thereby extending the proliferative capacity of incipient cancer cells.²⁰ This notion is supported by observations of increased telomere length in melanomaprone families with POT1 mutations. Given this association, research has focused on examining the relationship between telomere length and skin cancer.

Several studies have examined the relationship between telomere length and the risk for various types of skin cancer, including melanoma, BCC, and SCC. Prior investigations have suggested that shorter telomere length is associated with a decreased risk for melanoma and an increased risk for BCC, while no significant association has been observed for SCC.¹⁶ However, subsequent reports analyzing POT1 variants have failed to reveal any conclusive associations between BCC and SCC and telomere length.^16,21

In contrast, other genetic variants associated with melanoma susceptibility have demonstrated notable associations with BCC and SCC; for instance, the CDKN2A (cyclin-dependent kinase inhibitor 2A) gene, which is the first gene linked to high-risk familial melanoma, exhibits an increased presence of mutations in individuals with BCC and SCC.²² Similarly, the MC1R (melanocortin 1 receptor) variant, a gene involved in human pigmentation and known to increase the risk for melanoma, carries a statistically significantly higher risk for BCC (summary odds ratio, 1.39; 95% CI, 1.15-1.69) and SCC (summary odds ratio, 1.61; 95% CI, 1.35-1.91) when at least one variant is present and an even greater risk with 2 or more variants.²³

Considering the potential importance of POT1 mutations and their association with melanoma, as well as the inconsistencies surrounding POT1 mutations and their associations with BCC and SCC, further research may clarify the impact of POT1 mutations on the development and progression of different types of skin cancers and improve understanding of the complex interplay among telomere length, genetic variants, and skin cancer susceptibility. Given the established risk for melanoma with POT1 mutations, regular dermatology surveillance seems prudent. Dermatologists should consider referring patients with multiple skin cancers (especially melanoma) and any strong family history of internal malignancies to genetic testing for POT1. Though melanoma, CLL, angiosarcoma, and gliomas are the most commonly associated malignancies with POT1 mutations, as our case demonstrates, presentations can be heterogeneous, and the spectrum of malignancies associated with POT1 may be more expansive than previously thought.

For our patient, the current surveillance plan is fullbody skin examinations every 3 months. Given no prior family history of malignancies, presumably our patient’s case was a spontaneous mutation. Interestingly, despite his many primary cancer diagnoses and metastases, our patient has responded well to all treatments without recurrence. It is unclear if these characteristics and treatment successes are features of POT1associated cancers. Further research is needed to refine recommendations for screening and management of patients with identified POT1 mutations.

Conclusion

This case report highlights a rare occurrence of MAC in a patient with a POT1 mutation. Given the limited research conducted on investigating POT1 mutations and skin cancer, it is important to consider various forms of skin cancer, in addition to melanoma, when treating patients with a POT1 mutation.

A 72-year-old man with a history of multiple cancers, including melanoma, squamous cell carcinoma (SCC), and basal cell carcinoma (BCC), presented to the dermatology clinic for a regularly scheduled full-body skin examination. His family history was negative for malignancy, but due to his personal history of both primary internal cancers and skin cancers, the patient previously had been referred by dermatology to a medical geneticist for evaluation. He tested positive for a pathogenic POT1 (protection of telomeres 1) variant associated with tumor predisposition, which most often is associated with cutaneous melanoma, chronic lymphocytic leukemia (CLL), angiosarcoma, and gliomas.¹

At the current presentation, physical examination revealed a small, asymmetric, pink papule on the superior thoracic spine. A biopsy of the lesion was performed (Figure 1). Pathology demonstrated cornifying cystic structures with a granulomatous response at the surface of the tumor, ductal differentiation with depth, and infiltrative strands and cords of hyperchromatic cells within a collagenous stroma at the base of the specimen (Figures 2A and 2B). One unusual finding was the presence of prominent clear-cell change within the superficial portion of the neoplasm (Figure 2C). Immunohistochemical stains revealed strong p63 and p40 positivity. Epithelial membrane antigen staining was positive in the hyperchromatic strands and cords with depth but not in the clear-cell superficial portion. Similarly, periodic acid–Schiff–positive material increased within tumor cells in proportion to depth of infiltration. Additional immunohistochemical staining showed carcinoembryonic antigen was largely negative (with rare positivity in a few ductal lumina), with negative results for S100, SOX10, CD117, BerEP4, factor XIIIa, CD34, and cytokeratin 7 (Figures 2D and 2E).

The differential diagnoses included trichilemmal carcinoma (which may manifest with CD34 expression),² clear cell BCC, adenoid cystic carcinoma (tubular variant), sebaceous carcinoma, and eccrine carcinoma. Importantly, the patient was under continuous oncologic surveillance, with no evidence of a primary internal tumor to suggest metastasis. Despite negative carcinoembryonic antigen staining, the immunohistochemical and histopathologic findings fit best with a primary cutaneous malignant eccrine tumor, specifically microcystic adnexal carcinoma (MAC), in which p63 typically stains peripheral cells but solid variants have been described.³

Eccrine carcinoma is exceedingly rare, reported in 0.01% of diagnosed cutaneous malignancies, and demonstrates overlapping features to other malignant eccrine tumors. It possesses an inconsistent immunohistochemical staining profile, making the distinction from other malignant sweat gland tumors challenging.⁴ Given that the morphologic features were otherwise classic for MAC in our patient, we favored a clear-cell variant.

Sixteen years prior to the current presentation, our patient presented to urology with a history of prostatitis and increasing prostate-specific antigen levels. Biopsies were negative until prostate-specific antigen reached 13 ng/mL, confirming stage 1A prostate cancer. The patient subsequently underwent a robot-assisted radical prostatectomy. At age 63 years, dysphagia that was unresponsive to antibiotics led to a tonsillar biopsy revealing T2N2bM0 stage IVA SCC of the right tonsil with confirmed HPV type 16 with extracapsular extension. The patient underwent transoral robotic radical tonsillectomy and right neck dissection, followed by adjuvant chemoradiation consisting of intensity-modulated radiation therapy (IMRT) to a total dose of 63 Gy in 33 fractions, with concurrent weekly cisplatin. At age 67 years, dyspepsia, dysphagia, pyrosis, and gastroesophageal reflux prompted endoscopy, revealing T1aNxMx esophageal adenocarcinoma. Three months later, the patient underwent laparoscopic-assisted esophagectomy, with no recurrence. At age 68 years, an atypical intramelanocytic proliferation was found on the left cheek and was treated with Mohs micrographic surgery.

At age 71 years, acral lentiginous malignant melanoma (Breslow thickness 0.8 mm; Clark level IV; American Joint Committee on Cancer T1b) was diagnosed on the left plantar foot and treated with Mohs micrographic surgery. Sentinel lymph node biopsy was negative. Squamous cell carcinoma in situ on the frontal scalp and nodular BCC on the right upper back also were diagnosed.

While there are no guidelines for surveillance of individuals with POT1, recommendations were given in consensus from a medical genetics team,¹ including comprehensive monitoring—specifically baseline imaging utilizing brain and full-body magnetic resonance imaging. Furthermore, considering the crucial role of POT1 in maintaining telomeres, it was advised to measure telomere length as part of the surveillance process. Given the patient’s susceptibility to CLL, routine complete blood count assessments were recommended. Additionally, we advised close monitoring for seizures and consideration of genetic testing in first-degree relatives.

Literature Review

Given our patient’s history of multiple skin cancers, including the most recent MAC, we sought to conduct a review of the literature to evaluate existing skin cancer associations and reports for patients with known POT1 mutations to guide recommendations for dermatologic surveillance (Table). A search of PubMed articles indexed for MEDLINE through April 2023 using the terms microcystic adnexal carcinoma, POT1, melanoma, basal cell carcinoma, squamous cell carcinoma, and skin cancer yielded no reported cases of MAC associated with POT1 mutations. POT1 is one of 6 proteins (TERF1, TERF2, RAP1, TIN2, TPP1, and POT1) belonging to the shelterin complex, which plays a crucial role in telomeric DNA remodeling and regulation of telomere length.⁵ Mutation in the POT1 gene disrupts the shelterin complex, causing telomeres to become elongated and unstable, resulting in chromosomal abnormalities and promoting cancer development.⁵

While our literature review did not reveal any associations between the shelterin complex genes and MAC, mutations in the POT1 gene have been studied in other types of skin cancer, particularly melanoma.¹ One of the earliest studies was conducted in 2014 by Shi et al,⁶ in which whole-exome sequencing was performed on families with a history of melanoma. Multiple POT1 gene pathogenic variants associated with increased telomere length and fragility were identified in unrelated families. Subsequent studies have confirmed POT1 variants in melanoma-prone families,⁷ supporting an association between increased telomere length and melanoma risk^8-11; however, other studies have yielded nonsignificant findings.^12,13 Further investigation also has identified morphologic characteristics consistent with POT1 mutation, including spitzoid morphology.¹⁴

The association between POT1 mutations and nonmelanoma skin cancers has been relatively understudied. While a few studies have explored this link, results have shown mixed findings. Some studies have suggested a potential role for POT1 mutations in cutaneous SCC risk,¹⁵ while other studies have shown no significant associations for both BCC and SCC risk and telomere gene mutations.¹⁶ Additionally, mRNA levels of POT1 were upregulated in BCC cases compared to normal tissue in a gene expression.¹⁷

Comment

In the literature, POT1 mutations are well established as high-penetrance alterations associated with melanoma.^9,18,19 However, the correlation between POT1 and other forms of skin cancer is not yet delineated. Recent insights suggest that POT1 mutations play a major role in promoting melanoma progression through telomere elongation, an established driver of melanoma progression, thereby extending the proliferative capacity of incipient cancer cells.²⁰ This notion is supported by observations of increased telomere length in melanomaprone families with POT1 mutations. Given this association, research has focused on examining the relationship between telomere length and skin cancer.

Several studies have examined the relationship between telomere length and the risk for various types of skin cancer, including melanoma, BCC, and SCC. Prior investigations have suggested that shorter telomere length is associated with a decreased risk for melanoma and an increased risk for BCC, while no significant association has been observed for SCC.¹⁶ However, subsequent reports analyzing POT1 variants have failed to reveal any conclusive associations between BCC and SCC and telomere length.^16,21

In contrast, other genetic variants associated with melanoma susceptibility have demonstrated notable associations with BCC and SCC; for instance, the CDKN2A (cyclin-dependent kinase inhibitor 2A) gene, which is the first gene linked to high-risk familial melanoma, exhibits an increased presence of mutations in individuals with BCC and SCC.²² Similarly, the MC1R (melanocortin 1 receptor) variant, a gene involved in human pigmentation and known to increase the risk for melanoma, carries a statistically significantly higher risk for BCC (summary odds ratio, 1.39; 95% CI, 1.15-1.69) and SCC (summary odds ratio, 1.61; 95% CI, 1.35-1.91) when at least one variant is present and an even greater risk with 2 or more variants.²³

Considering the potential importance of POT1 mutations and their association with melanoma, as well as the inconsistencies surrounding POT1 mutations and their associations with BCC and SCC, further research may clarify the impact of POT1 mutations on the development and progression of different types of skin cancers and improve understanding of the complex interplay among telomere length, genetic variants, and skin cancer susceptibility. Given the established risk for melanoma with POT1 mutations, regular dermatology surveillance seems prudent. Dermatologists should consider referring patients with multiple skin cancers (especially melanoma) and any strong family history of internal malignancies to genetic testing for POT1. Though melanoma, CLL, angiosarcoma, and gliomas are the most commonly associated malignancies with POT1 mutations, as our case demonstrates, presentations can be heterogeneous, and the spectrum of malignancies associated with POT1 may be more expansive than previously thought.

For our patient, the current surveillance plan is fullbody skin examinations every 3 months. Given no prior family history of malignancies, presumably our patient’s case was a spontaneous mutation. Interestingly, despite his many primary cancer diagnoses and metastases, our patient has responded well to all treatments without recurrence. It is unclear if these characteristics and treatment successes are features of POT1associated cancers. Further research is needed to refine recommendations for screening and management of patients with identified POT1 mutations.

Conclusion

This case report highlights a rare occurrence of MAC in a patient with a POT1 mutation. Given the limited research conducted on investigating POT1 mutations and skin cancer, it is important to consider various forms of skin cancer, in addition to melanoma, when treating patients with a POT1 mutation.

A 72-year-old man with a history of multiple cancers, including melanoma, squamous cell carcinoma (SCC), and basal cell carcinoma (BCC), presented to the dermatology clinic for a regularly scheduled full-body skin examination. His family history was negative for malignancy, but due to his personal history of both primary internal cancers and skin cancers, the patient previously had been referred by dermatology to a medical geneticist for evaluation. He tested positive for a pathogenic POT1 (protection of telomeres 1) variant associated with tumor predisposition, which most often is associated with cutaneous melanoma, chronic lymphocytic leukemia (CLL), angiosarcoma, and gliomas.¹

At the current presentation, physical examination revealed a small, asymmetric, pink papule on the superior thoracic spine. A biopsy of the lesion was performed (Figure 1). Pathology demonstrated cornifying cystic structures with a granulomatous response at the surface of the tumor, ductal differentiation with depth, and infiltrative strands and cords of hyperchromatic cells within a collagenous stroma at the base of the specimen (Figures 2A and 2B). One unusual finding was the presence of prominent clear-cell change within the superficial portion of the neoplasm (Figure 2C). Immunohistochemical stains revealed strong p63 and p40 positivity. Epithelial membrane antigen staining was positive in the hyperchromatic strands and cords with depth but not in the clear-cell superficial portion. Similarly, periodic acid–Schiff–positive material increased within tumor cells in proportion to depth of infiltration. Additional immunohistochemical staining showed carcinoembryonic antigen was largely negative (with rare positivity in a few ductal lumina), with negative results for S100, SOX10, CD117, BerEP4, factor XIIIa, CD34, and cytokeratin 7 (Figures 2D and 2E).

The differential diagnoses included trichilemmal carcinoma (which may manifest with CD34 expression),² clear cell BCC, adenoid cystic carcinoma (tubular variant), sebaceous carcinoma, and eccrine carcinoma. Importantly, the patient was under continuous oncologic surveillance, with no evidence of a primary internal tumor to suggest metastasis. Despite negative carcinoembryonic antigen staining, the immunohistochemical and histopathologic findings fit best with a primary cutaneous malignant eccrine tumor, specifically microcystic adnexal carcinoma (MAC), in which p63 typically stains peripheral cells but solid variants have been described.³

Eccrine carcinoma is exceedingly rare, reported in 0.01% of diagnosed cutaneous malignancies, and demonstrates overlapping features to other malignant eccrine tumors. It possesses an inconsistent immunohistochemical staining profile, making the distinction from other malignant sweat gland tumors challenging.⁴ Given that the morphologic features were otherwise classic for MAC in our patient, we favored a clear-cell variant.

Sixteen years prior to the current presentation, our patient presented to urology with a history of prostatitis and increasing prostate-specific antigen levels. Biopsies were negative until prostate-specific antigen reached 13 ng/mL, confirming stage 1A prostate cancer. The patient subsequently underwent a robot-assisted radical prostatectomy. At age 63 years, dysphagia that was unresponsive to antibiotics led to a tonsillar biopsy revealing T2N2bM0 stage IVA SCC of the right tonsil with confirmed HPV type 16 with extracapsular extension. The patient underwent transoral robotic radical tonsillectomy and right neck dissection, followed by adjuvant chemoradiation consisting of intensity-modulated radiation therapy (IMRT) to a total dose of 63 Gy in 33 fractions, with concurrent weekly cisplatin. At age 67 years, dyspepsia, dysphagia, pyrosis, and gastroesophageal reflux prompted endoscopy, revealing T1aNxMx esophageal adenocarcinoma. Three months later, the patient underwent laparoscopic-assisted esophagectomy, with no recurrence. At age 68 years, an atypical intramelanocytic proliferation was found on the left cheek and was treated with Mohs micrographic surgery.

At age 71 years, acral lentiginous malignant melanoma (Breslow thickness 0.8 mm; Clark level IV; American Joint Committee on Cancer T1b) was diagnosed on the left plantar foot and treated with Mohs micrographic surgery. Sentinel lymph node biopsy was negative. Squamous cell carcinoma in situ on the frontal scalp and nodular BCC on the right upper back also were diagnosed.

While there are no guidelines for surveillance of individuals with POT1, recommendations were given in consensus from a medical genetics team,¹ including comprehensive monitoring—specifically baseline imaging utilizing brain and full-body magnetic resonance imaging. Furthermore, considering the crucial role of POT1 in maintaining telomeres, it was advised to measure telomere length as part of the surveillance process. Given the patient’s susceptibility to CLL, routine complete blood count assessments were recommended. Additionally, we advised close monitoring for seizures and consideration of genetic testing in first-degree relatives.

Literature Review

Given our patient’s history of multiple skin cancers, including the most recent MAC, we sought to conduct a review of the literature to evaluate existing skin cancer associations and reports for patients with known POT1 mutations to guide recommendations for dermatologic surveillance (Table). A search of PubMed articles indexed for MEDLINE through April 2023 using the terms microcystic adnexal carcinoma, POT1, melanoma, basal cell carcinoma, squamous cell carcinoma, and skin cancer yielded no reported cases of MAC associated with POT1 mutations. POT1 is one of 6 proteins (TERF1, TERF2, RAP1, TIN2, TPP1, and POT1) belonging to the shelterin complex, which plays a crucial role in telomeric DNA remodeling and regulation of telomere length.⁵ Mutation in the POT1 gene disrupts the shelterin complex, causing telomeres to become elongated and unstable, resulting in chromosomal abnormalities and promoting cancer development.⁵

While our literature review did not reveal any associations between the shelterin complex genes and MAC, mutations in the POT1 gene have been studied in other types of skin cancer, particularly melanoma.¹ One of the earliest studies was conducted in 2014 by Shi et al,⁶ in which whole-exome sequencing was performed on families with a history of melanoma. Multiple POT1 gene pathogenic variants associated with increased telomere length and fragility were identified in unrelated families. Subsequent studies have confirmed POT1 variants in melanoma-prone families,⁷ supporting an association between increased telomere length and melanoma risk^8-11; however, other studies have yielded nonsignificant findings.^12,13 Further investigation also has identified morphologic characteristics consistent with POT1 mutation, including spitzoid morphology.¹⁴

The association between POT1 mutations and nonmelanoma skin cancers has been relatively understudied. While a few studies have explored this link, results have shown mixed findings. Some studies have suggested a potential role for POT1 mutations in cutaneous SCC risk,¹⁵ while other studies have shown no significant associations for both BCC and SCC risk and telomere gene mutations.¹⁶ Additionally, mRNA levels of POT1 were upregulated in BCC cases compared to normal tissue in a gene expression.¹⁷

Comment

In the literature, POT1 mutations are well established as high-penetrance alterations associated with melanoma.^9,18,19 However, the correlation between POT1 and other forms of skin cancer is not yet delineated. Recent insights suggest that POT1 mutations play a major role in promoting melanoma progression through telomere elongation, an established driver of melanoma progression, thereby extending the proliferative capacity of incipient cancer cells.²⁰ This notion is supported by observations of increased telomere length in melanomaprone families with POT1 mutations. Given this association, research has focused on examining the relationship between telomere length and skin cancer.

Several studies have examined the relationship between telomere length and the risk for various types of skin cancer, including melanoma, BCC, and SCC. Prior investigations have suggested that shorter telomere length is associated with a decreased risk for melanoma and an increased risk for BCC, while no significant association has been observed for SCC.¹⁶ However, subsequent reports analyzing POT1 variants have failed to reveal any conclusive associations between BCC and SCC and telomere length.^16,21

In contrast, other genetic variants associated with melanoma susceptibility have demonstrated notable associations with BCC and SCC; for instance, the CDKN2A (cyclin-dependent kinase inhibitor 2A) gene, which is the first gene linked to high-risk familial melanoma, exhibits an increased presence of mutations in individuals with BCC and SCC.²² Similarly, the MC1R (melanocortin 1 receptor) variant, a gene involved in human pigmentation and known to increase the risk for melanoma, carries a statistically significantly higher risk for BCC (summary odds ratio, 1.39; 95% CI, 1.15-1.69) and SCC (summary odds ratio, 1.61; 95% CI, 1.35-1.91) when at least one variant is present and an even greater risk with 2 or more variants.²³

Considering the potential importance of POT1 mutations and their association with melanoma, as well as the inconsistencies surrounding POT1 mutations and their associations with BCC and SCC, further research may clarify the impact of POT1 mutations on the development and progression of different types of skin cancers and improve understanding of the complex interplay among telomere length, genetic variants, and skin cancer susceptibility. Given the established risk for melanoma with POT1 mutations, regular dermatology surveillance seems prudent. Dermatologists should consider referring patients with multiple skin cancers (especially melanoma) and any strong family history of internal malignancies to genetic testing for POT1. Though melanoma, CLL, angiosarcoma, and gliomas are the most commonly associated malignancies with POT1 mutations, as our case demonstrates, presentations can be heterogeneous, and the spectrum of malignancies associated with POT1 may be more expansive than previously thought.

For our patient, the current surveillance plan is fullbody skin examinations every 3 months. Given no prior family history of malignancies, presumably our patient’s case was a spontaneous mutation. Interestingly, despite his many primary cancer diagnoses and metastases, our patient has responded well to all treatments without recurrence. It is unclear if these characteristics and treatment successes are features of POT1associated cancers. Further research is needed to refine recommendations for screening and management of patients with identified POT1 mutations.

Conclusion

This case report highlights a rare occurrence of MAC in a patient with a POT1 mutation. Given the limited research conducted on investigating POT1 mutations and skin cancer, it is important to consider various forms of skin cancer, in addition to melanoma, when treating patients with a POT1 mutation.

THE DIAGNOSIS: Mycobacteria infection

Despite the initial biopsy for tissue culture showing no growth, a subsequent biopsy performed 1 month later yielded a positive result. Mycobacterium marinum was identified through organism genome sequencing. The patient was further treated by infectious disease with clarithromycin and ethambutol, with complete resolution of the lesions.

Although initial staining with acid-fast bacilli and tissue culture were negative, we suspected a diagnosis of mycobacterial infection with sporotrichoid spread of multiple nodular and ulcerated lesions that was unresponsive to antibiotics. Performing a tissue culture is crucial for diagnosing mycobacterial skin and soft-tissue infections, as an acid-fast bacilli stain alone cannot distinguish between different mycobacterial species. Lowenstein-Jensen agar is a selective medium specifically used for the culture and isolation of Mycobacterium species. The strict temperature requirement of 30 °C to 32 °C (86-89.6 °F) for the growth of this organism suggests that the infection predominantly affects the limbs, which tend to have a slightly lower temperature compared to the core of the body.¹ In our case, the histologic findings and clinical history suggested granulomatous involvement due to fungi or mycobacteria.

Cutaneous leishmaniasis is characterized by ulcers with possible accompanying nodular lymphangitis; however, the patient did not have relevant travel history. Leishmaniasis results from a parasite transmitted by a sandfly, with most cases occurring in Afghanistan, Algeria, Brazil, Iran, Pakistan, Peru, Saudi Arabia, and Syria.²

Ecthyma gangrenosum is characterized by tender necrotic plaques seen predominantly in immunocompromised patients and is associated with Pseudomonas aeruginosa bacteremia.³ Our patient had lesions present for a duration of 5 months, which is inconsistent with the more rapidly progressing course of ecthyma gangrenosum.

Leukocytoclastic vasculitis may manifest with palpable purpura of the lower extremities. An infectious trigger, such as Mycobacterium, may lead to a leukocytoclastic vasculitis. The histopathologic findings classically demonstrate neutrophil deposition in vessel walls, deposition of fibrin in the vessel lumen, and nuclear debris.⁴

Despite the presence of granulomatous changes in our patient, the presentation of ulcerated nodules in a sporotrichoid pattern on one extremity suggests a diagnosis of infectious etiology rather than sarcoidosis.

THE DIAGNOSIS: Mycobacteria infection

Despite the initial biopsy for tissue culture showing no growth, a subsequent biopsy performed 1 month later yielded a positive result. Mycobacterium marinum was identified through organism genome sequencing. The patient was further treated by infectious disease with clarithromycin and ethambutol, with complete resolution of the lesions.

Although initial staining with acid-fast bacilli and tissue culture were negative, we suspected a diagnosis of mycobacterial infection with sporotrichoid spread of multiple nodular and ulcerated lesions that was unresponsive to antibiotics. Performing a tissue culture is crucial for diagnosing mycobacterial skin and soft-tissue infections, as an acid-fast bacilli stain alone cannot distinguish between different mycobacterial species. Lowenstein-Jensen agar is a selective medium specifically used for the culture and isolation of Mycobacterium species. The strict temperature requirement of 30 °C to 32 °C (86-89.6 °F) for the growth of this organism suggests that the infection predominantly affects the limbs, which tend to have a slightly lower temperature compared to the core of the body.¹ In our case, the histologic findings and clinical history suggested granulomatous involvement due to fungi or mycobacteria.

Cutaneous leishmaniasis is characterized by ulcers with possible accompanying nodular lymphangitis; however, the patient did not have relevant travel history. Leishmaniasis results from a parasite transmitted by a sandfly, with most cases occurring in Afghanistan, Algeria, Brazil, Iran, Pakistan, Peru, Saudi Arabia, and Syria.²

Ecthyma gangrenosum is characterized by tender necrotic plaques seen predominantly in immunocompromised patients and is associated with Pseudomonas aeruginosa bacteremia.³ Our patient had lesions present for a duration of 5 months, which is inconsistent with the more rapidly progressing course of ecthyma gangrenosum.

Leukocytoclastic vasculitis may manifest with palpable purpura of the lower extremities. An infectious trigger, such as Mycobacterium, may lead to a leukocytoclastic vasculitis. The histopathologic findings classically demonstrate neutrophil deposition in vessel walls, deposition of fibrin in the vessel lumen, and nuclear debris.⁴

Despite the presence of granulomatous changes in our patient, the presentation of ulcerated nodules in a sporotrichoid pattern on one extremity suggests a diagnosis of infectious etiology rather than sarcoidosis.

THE DIAGNOSIS: Mycobacteria infection

Despite the initial biopsy for tissue culture showing no growth, a subsequent biopsy performed 1 month later yielded a positive result. Mycobacterium marinum was identified through organism genome sequencing. The patient was further treated by infectious disease with clarithromycin and ethambutol, with complete resolution of the lesions.

Although initial staining with acid-fast bacilli and tissue culture were negative, we suspected a diagnosis of mycobacterial infection with sporotrichoid spread of multiple nodular and ulcerated lesions that was unresponsive to antibiotics. Performing a tissue culture is crucial for diagnosing mycobacterial skin and soft-tissue infections, as an acid-fast bacilli stain alone cannot distinguish between different mycobacterial species. Lowenstein-Jensen agar is a selective medium specifically used for the culture and isolation of Mycobacterium species. The strict temperature requirement of 30 °C to 32 °C (86-89.6 °F) for the growth of this organism suggests that the infection predominantly affects the limbs, which tend to have a slightly lower temperature compared to the core of the body.¹ In our case, the histologic findings and clinical history suggested granulomatous involvement due to fungi or mycobacteria.

Cutaneous leishmaniasis is characterized by ulcers with possible accompanying nodular lymphangitis; however, the patient did not have relevant travel history. Leishmaniasis results from a parasite transmitted by a sandfly, with most cases occurring in Afghanistan, Algeria, Brazil, Iran, Pakistan, Peru, Saudi Arabia, and Syria.²

Ecthyma gangrenosum is characterized by tender necrotic plaques seen predominantly in immunocompromised patients and is associated with Pseudomonas aeruginosa bacteremia.³ Our patient had lesions present for a duration of 5 months, which is inconsistent with the more rapidly progressing course of ecthyma gangrenosum.

Leukocytoclastic vasculitis may manifest with palpable purpura of the lower extremities. An infectious trigger, such as Mycobacterium, may lead to a leukocytoclastic vasculitis. The histopathologic findings classically demonstrate neutrophil deposition in vessel walls, deposition of fibrin in the vessel lumen, and nuclear debris.⁴

Despite the presence of granulomatous changes in our patient, the presentation of ulcerated nodules in a sporotrichoid pattern on one extremity suggests a diagnosis of infectious etiology rather than sarcoidosis.

THE DIAGNOSIS: Angiolymphoid Hyperplasia With Eosinophilia

Angiolymphoid hyperplasia with eosinophilia (ALHE) is a rare, benign, inflammatory vascular proliferation with lymphocytic and eosinophilic infiltration. Bleeding and pruritus associated with ALHE can substantially affect a patient’s quality of life, necessitating correct diagnosis and effective treatment.¹ The etiopathogenesis of ALHE is poorly understood, and it often is attributed to an underlying vascular malformation or local trauma. Vascular proliferation due to hyperestrogenemia could explain why pregnancy is considered a predisposing factor for ALHE.^1,2

Angiolymphoid hyperplasia with eosinophilia typically manifests with solitary or multiple pink to red-brown, dome-shaped papules or nodules occurring most frequently on the head and neck. Lesions may be either asymptomatic or associated with pruritus, pain, and spontaneous bleeding.¹ Dermoscopy is crucial to diagnosis. The most frequent dermoscopic findings include a polymorphic vascular pattern such as dotted and linear irregular vessels over a pink background, white lines, white dots, white structureless areas, and red-purple lacunae.^2,3 Histopathology will demonstrate a vascular proliferation with plump epithelioid endothelial cells showing abundant eosinophilic cytoplasm, accompanied by a variable lymphocytic and eosinophilic inflammatory infiltrate (Figure 1).¹

In our case, dermoscopic-histopathologic correlation suggested that the polymorphic vascular pattern and clods on a pink background corresponded to thin- and thick-walled vessels containing plump endothelial cells and intraluminal erythrocytes within the superficial and deep dermis. White structures could represent underlying fibrosis and altered dermal collagen due to vascular proliferation. The brown pigment network and peripheral brownish pigmentation were most likely secondary to increased melanin and accentuation of the pigment network in the setting of Fitzpatrick skin types IV to V, although pruritic trauma with postinflammatory hyperpigmentation may also have contributed, making dermoscopic-histopathologic correlation challenging.

Surgical excision is considered the primary treatment modality for ALHE, with the lowest recurrence rates.¹ Alternative therapeutic options include intralesional steroids, cryotherapy, sclerotherapy, radiofrequency, pulsed dye laser, and carbon dioxide laser, with varying efficacy reported.¹ Our patient was treated with a combination of a long-pulse Nd:YAG laser (pulse width of 30 ms) to target the vascular component, followed by a single session with an ablative Er:YAG laser. After 4 weeks, healing with good cosmetic results was observed (Figure 2). At 6-month follow-up, there was no recurrence of the lesions.

Kimura disease, often considered the closest differential diagnosis for ALHE, is a rare lymphoproliferative fibroinflammatory condition. Patients present with subcutaneous nodules on the head and neck, often associated with lymphadenopathy. Elevated serum IgE levels and peripheral blood eosinophilia are common.¹ Another consideration in the differential diagnosis is cutaneous bacillary angiomatosis caused by Bartonella species, a vascular proliferative condition that mostly affects individuals with HIV, transplant recipients, and those taking immunosuppressive medications.⁴ Pyogenic granuloma, also known as lobular capillary haemangioma, is another benign vascular proliferation that resembles ALHE. Clinically, it manifests as a solitary, painless, flesh-colored to erythematous papulonodule; however, multiple grouped lesions also can occur. The lesions often are associated with bleeding and erosions.⁵ Epithelioid hemangioendothelioma is a rare vascular tumor most frequently manifesting in the liver, lungs, or bones, and very rarely is limited to skin. Cutaneous epithelioid hemangioendothelioma mimics ALHE and may manifest as a solitary erythematous mass, multiple dome-shaped masses, or dermal nodules.⁶

THE DIAGNOSIS: Angiolymphoid Hyperplasia With Eosinophilia

Angiolymphoid hyperplasia with eosinophilia (ALHE) is a rare, benign, inflammatory vascular proliferation with lymphocytic and eosinophilic infiltration. Bleeding and pruritus associated with ALHE can substantially affect a patient’s quality of life, necessitating correct diagnosis and effective treatment.¹ The etiopathogenesis of ALHE is poorly understood, and it often is attributed to an underlying vascular malformation or local trauma. Vascular proliferation due to hyperestrogenemia could explain why pregnancy is considered a predisposing factor for ALHE.^1,2

Angiolymphoid hyperplasia with eosinophilia typically manifests with solitary or multiple pink to red-brown, dome-shaped papules or nodules occurring most frequently on the head and neck. Lesions may be either asymptomatic or associated with pruritus, pain, and spontaneous bleeding.¹ Dermoscopy is crucial to diagnosis. The most frequent dermoscopic findings include a polymorphic vascular pattern such as dotted and linear irregular vessels over a pink background, white lines, white dots, white structureless areas, and red-purple lacunae.^2,3 Histopathology will demonstrate a vascular proliferation with plump epithelioid endothelial cells showing abundant eosinophilic cytoplasm, accompanied by a variable lymphocytic and eosinophilic inflammatory infiltrate (Figure 1).¹

In our case, dermoscopic-histopathologic correlation suggested that the polymorphic vascular pattern and clods on a pink background corresponded to thin- and thick-walled vessels containing plump endothelial cells and intraluminal erythrocytes within the superficial and deep dermis. White structures could represent underlying fibrosis and altered dermal collagen due to vascular proliferation. The brown pigment network and peripheral brownish pigmentation were most likely secondary to increased melanin and accentuation of the pigment network in the setting of Fitzpatrick skin types IV to V, although pruritic trauma with postinflammatory hyperpigmentation may also have contributed, making dermoscopic-histopathologic correlation challenging.

Surgical excision is considered the primary treatment modality for ALHE, with the lowest recurrence rates.¹ Alternative therapeutic options include intralesional steroids, cryotherapy, sclerotherapy, radiofrequency, pulsed dye laser, and carbon dioxide laser, with varying efficacy reported.¹ Our patient was treated with a combination of a long-pulse Nd:YAG laser (pulse width of 30 ms) to target the vascular component, followed by a single session with an ablative Er:YAG laser. After 4 weeks, healing with good cosmetic results was observed (Figure 2). At 6-month follow-up, there was no recurrence of the lesions.

Kimura disease, often considered the closest differential diagnosis for ALHE, is a rare lymphoproliferative fibroinflammatory condition. Patients present with subcutaneous nodules on the head and neck, often associated with lymphadenopathy. Elevated serum IgE levels and peripheral blood eosinophilia are common.¹ Another consideration in the differential diagnosis is cutaneous bacillary angiomatosis caused by Bartonella species, a vascular proliferative condition that mostly affects individuals with HIV, transplant recipients, and those taking immunosuppressive medications.⁴ Pyogenic granuloma, also known as lobular capillary haemangioma, is another benign vascular proliferation that resembles ALHE. Clinically, it manifests as a solitary, painless, flesh-colored to erythematous papulonodule; however, multiple grouped lesions also can occur. The lesions often are associated with bleeding and erosions.⁵ Epithelioid hemangioendothelioma is a rare vascular tumor most frequently manifesting in the liver, lungs, or bones, and very rarely is limited to skin. Cutaneous epithelioid hemangioendothelioma mimics ALHE and may manifest as a solitary erythematous mass, multiple dome-shaped masses, or dermal nodules.⁶

THE DIAGNOSIS: Angiolymphoid Hyperplasia With Eosinophilia

Angiolymphoid hyperplasia with eosinophilia (ALHE) is a rare, benign, inflammatory vascular proliferation with lymphocytic and eosinophilic infiltration. Bleeding and pruritus associated with ALHE can substantially affect a patient’s quality of life, necessitating correct diagnosis and effective treatment.¹ The etiopathogenesis of ALHE is poorly understood, and it often is attributed to an underlying vascular malformation or local trauma. Vascular proliferation due to hyperestrogenemia could explain why pregnancy is considered a predisposing factor for ALHE.^1,2

Angiolymphoid hyperplasia with eosinophilia typically manifests with solitary or multiple pink to red-brown, dome-shaped papules or nodules occurring most frequently on the head and neck. Lesions may be either asymptomatic or associated with pruritus, pain, and spontaneous bleeding.¹ Dermoscopy is crucial to diagnosis. The most frequent dermoscopic findings include a polymorphic vascular pattern such as dotted and linear irregular vessels over a pink background, white lines, white dots, white structureless areas, and red-purple lacunae.^2,3 Histopathology will demonstrate a vascular proliferation with plump epithelioid endothelial cells showing abundant eosinophilic cytoplasm, accompanied by a variable lymphocytic and eosinophilic inflammatory infiltrate (Figure 1).¹

In our case, dermoscopic-histopathologic correlation suggested that the polymorphic vascular pattern and clods on a pink background corresponded to thin- and thick-walled vessels containing plump endothelial cells and intraluminal erythrocytes within the superficial and deep dermis. White structures could represent underlying fibrosis and altered dermal collagen due to vascular proliferation. The brown pigment network and peripheral brownish pigmentation were most likely secondary to increased melanin and accentuation of the pigment network in the setting of Fitzpatrick skin types IV to V, although pruritic trauma with postinflammatory hyperpigmentation may also have contributed, making dermoscopic-histopathologic correlation challenging.

Surgical excision is considered the primary treatment modality for ALHE, with the lowest recurrence rates.¹ Alternative therapeutic options include intralesional steroids, cryotherapy, sclerotherapy, radiofrequency, pulsed dye laser, and carbon dioxide laser, with varying efficacy reported.¹ Our patient was treated with a combination of a long-pulse Nd:YAG laser (pulse width of 30 ms) to target the vascular component, followed by a single session with an ablative Er:YAG laser. After 4 weeks, healing with good cosmetic results was observed (Figure 2). At 6-month follow-up, there was no recurrence of the lesions.

Kimura disease, often considered the closest differential diagnosis for ALHE, is a rare lymphoproliferative fibroinflammatory condition. Patients present with subcutaneous nodules on the head and neck, often associated with lymphadenopathy. Elevated serum IgE levels and peripheral blood eosinophilia are common.¹ Another consideration in the differential diagnosis is cutaneous bacillary angiomatosis caused by Bartonella species, a vascular proliferative condition that mostly affects individuals with HIV, transplant recipients, and those taking immunosuppressive medications.⁴ Pyogenic granuloma, also known as lobular capillary haemangioma, is another benign vascular proliferation that resembles ALHE. Clinically, it manifests as a solitary, painless, flesh-colored to erythematous papulonodule; however, multiple grouped lesions also can occur. The lesions often are associated with bleeding and erosions.⁵ Epithelioid hemangioendothelioma is a rare vascular tumor most frequently manifesting in the liver, lungs, or bones, and very rarely is limited to skin. Cutaneous epithelioid hemangioendothelioma mimics ALHE and may manifest as a solitary erythematous mass, multiple dome-shaped masses, or dermal nodules.⁶

Horse flies (Tabanidae) are hematophagous dipteran insects that feed on the blood of their hosts, including humans.¹ Their bites can cause minor cutaneous reactions (eg, urticaria) or, rarely, severe reactions such as anaphylaxis. They also are vectors of tularemia, which may manifest with cutaneous ulcers and systemic illness. In this article, we discuss identifying features of horse flies as well as clinical manifestations from bite reactions, symptomatic and emergency management, and strategies for prevention and control.

Morphology and Geographic Distribution

Horse flies, which can grow as large as 30 mm, can be identified by their brown or black bodies and characteristic large heads and proboscises, wing venation, large calypters, pulvilliform empodium between large pulvilli, and lack of bristles on the body.² Occasionally, their bodies may be gray, yellow, green, or blue, but this is less likely than in the other species of the Tabanidae family. Short hairs are present on the head and thorax. The eyes are large and often patterned, multicolored, and bright, though they also can exhibit shades of dark brown, gray, or black. There is variation in the appearance of male vs female horse flies: females have eyes that are widely spaced apart, while males have eyes that are closer together.² It is important to note the difference between male and female horseflies, as hematophagy is exhibited only by females.¹

Horse flies are found worldwide, with the exception of Hawaii, Greenland, and Iceland.^3,4 They are especially prevalent in warm and moist regions, as these conditions are optimal for breeding.^3-5 They tend to be active during the day and inactive at night due to a preference for sunlight and warmth.⁶ Due to this preference, horse flies’ seasonal activity depends on the climate; for many regions, activity persists from summer to early autumn.⁷

Clinical Manifestations and Treatment

Female horse flies use their mouthparts to pierce the host’s skin, inject saliva, and suck blood. The saliva contains anticoagulant properties. The bites are painful for the host, and various reactions can occur, including large urticarial wheals or papules at the site of the bite. Treatment for these minor cutaneous reactions is largely symptomatic. The bite site should be washed with soap and water; ice can be applied to help reduce inflammation.⁸ Oral antihistamines may be administered to reduce pruritus and treat urticaria. Topical steroids also can be prescribed for symptomatic relief. Acetaminophen and nonsteroidal anti-inflammatory drugs can be administered for pain control.⁸

While most cases of horse fly bites are minor, there have been reports of anaphylaxis.⁹ Horse fly bite–induced anaphylaxis can manifest as generalized itching, urticaria, and angioedema within minutes of being bitten. This may be followed by pharyngeal constriction, shortness of breath, nausea, vomiting, shivers, perspiration, and loss of consciousness.⁹ Anaphylaxis symptoms should be treated with immediate administration of intramuscular epinephrine.¹⁰

Pathogen Transmission, Prevention, and Control

Although horse flies have been found to carry numerous viruses, bacteria, and protozoa that affect other mammals, there is not enough evidence to suggest that they are vectors of transmission for humans for most diseases.^11,12 In particular, West Nile virus and Borrelia burgdorferi both have been found in horse flies, but there are no reports of transmission of these diseases to humans through their bites.¹²

Horse flies, their close cousins deer flies (specifically Chrysops discalis), and ticks are known vectors of Francisella tularensis.¹³ These bacteria cause tularemia, which can manifest with symptoms such as fever, headache, and malaise. Ulceroglandular tularemia is the most common manifestation, in which the patient develops a cutaneous ulceration at the site of the horse fly bite and exhibits associated tender regional lymphadenopathy.¹⁴ Exudative conjunctivitis, exudative pharyngitis, abdominal pain, diarrhea, vomiting, and severe bilateral pneumonia also are common symptoms. The most severe form of tularemia is systemic or typhoidal tularemia, which can manifest with fever, septic shock, and hepatosplenomegaly.¹⁴ The current treatment of choice for all forms of tularemia is intravenous gentamicin, with a recommended dosage of 5 mg/kg/d for 7 to 14 days; streptomycin is an acceptable alternative.^14-16 Ciprofloxacin is used less commonly and is reserved for milder disease. Incision and drainage of the affected lymph nodes also may be necessary.¹⁴ It is important to promptly identify and treat tularemia, as the mortality rate can be as high as 50% for untreated disease, especially in patients with systemic symptoms. Even after treatment, many patients exhibit residual scarring at the site of the ulcer, as well as lung, kidney, and muscle damage.¹⁴

It is advised to avoid contact with horse flies due to the range of symptom severity caused by their bites, but avoidance and control can be difficult. Malaise traps, consisting of a tent and polyester netting, can be used to capture the insects.¹⁷ Octenol has been shown to be effective for attracting horse flies and can be applied to the trap in order to increase its effectiveness.¹⁸ A Manitoba horse fly trap is a modified version of the Malaise trap that contains a suspended dark sphere to further attract horse flies.¹⁹ Patients also should be instructed to wear long-sleeved shirts and pants when outdoors in areas with horse flies to avoid contact, and application of DEET (N,N-diethylmeta-toluamide), picaridin, citronella, or geraniol-based repellents also can be effective in reducing exposure.²⁰

Final Thoughts

Horse flies are large, blood‑feeding dipteran insects whose bites usually produce painful local reactions. Although most bites are benign, they rarely can cause anaphylaxis, and certain Tabanidae insects can transmit Francisella tularensis; therefore, clinicians should consider the risk for tularemia infection in patients presenting with horse fly bites and start appropriate antibiotic therapy when indicated. Due to the risks, prevention of bites and reduction of contact with horse flies via protective clothing, repellents, and trapping methods is recommended. Patients should be advised on bite care and to seek urgent care for systemic symptoms or rapidly progressive local signs.

Horse flies (Tabanidae) are hematophagous dipteran insects that feed on the blood of their hosts, including humans.¹ Their bites can cause minor cutaneous reactions (eg, urticaria) or, rarely, severe reactions such as anaphylaxis. They also are vectors of tularemia, which may manifest with cutaneous ulcers and systemic illness. In this article, we discuss identifying features of horse flies as well as clinical manifestations from bite reactions, symptomatic and emergency management, and strategies for prevention and control.

Morphology and Geographic Distribution

Horse flies, which can grow as large as 30 mm, can be identified by their brown or black bodies and characteristic large heads and proboscises, wing venation, large calypters, pulvilliform empodium between large pulvilli, and lack of bristles on the body.² Occasionally, their bodies may be gray, yellow, green, or blue, but this is less likely than in the other species of the Tabanidae family. Short hairs are present on the head and thorax. The eyes are large and often patterned, multicolored, and bright, though they also can exhibit shades of dark brown, gray, or black. There is variation in the appearance of male vs female horse flies: females have eyes that are widely spaced apart, while males have eyes that are closer together.² It is important to note the difference between male and female horseflies, as hematophagy is exhibited only by females.¹

Horse flies are found worldwide, with the exception of Hawaii, Greenland, and Iceland.^3,4 They are especially prevalent in warm and moist regions, as these conditions are optimal for breeding.^3-5 They tend to be active during the day and inactive at night due to a preference for sunlight and warmth.⁶ Due to this preference, horse flies’ seasonal activity depends on the climate; for many regions, activity persists from summer to early autumn.⁷

Clinical Manifestations and Treatment

Female horse flies use their mouthparts to pierce the host’s skin, inject saliva, and suck blood. The saliva contains anticoagulant properties. The bites are painful for the host, and various reactions can occur, including large urticarial wheals or papules at the site of the bite. Treatment for these minor cutaneous reactions is largely symptomatic. The bite site should be washed with soap and water; ice can be applied to help reduce inflammation.⁸ Oral antihistamines may be administered to reduce pruritus and treat urticaria. Topical steroids also can be prescribed for symptomatic relief. Acetaminophen and nonsteroidal anti-inflammatory drugs can be administered for pain control.⁸

While most cases of horse fly bites are minor, there have been reports of anaphylaxis.⁹ Horse fly bite–induced anaphylaxis can manifest as generalized itching, urticaria, and angioedema within minutes of being bitten. This may be followed by pharyngeal constriction, shortness of breath, nausea, vomiting, shivers, perspiration, and loss of consciousness.⁹ Anaphylaxis symptoms should be treated with immediate administration of intramuscular epinephrine.¹⁰

Pathogen Transmission, Prevention, and Control

Although horse flies have been found to carry numerous viruses, bacteria, and protozoa that affect other mammals, there is not enough evidence to suggest that they are vectors of transmission for humans for most diseases.^11,12 In particular, West Nile virus and Borrelia burgdorferi both have been found in horse flies, but there are no reports of transmission of these diseases to humans through their bites.¹²

Horse flies, their close cousins deer flies (specifically Chrysops discalis), and ticks are known vectors of Francisella tularensis.¹³ These bacteria cause tularemia, which can manifest with symptoms such as fever, headache, and malaise. Ulceroglandular tularemia is the most common manifestation, in which the patient develops a cutaneous ulceration at the site of the horse fly bite and exhibits associated tender regional lymphadenopathy.¹⁴ Exudative conjunctivitis, exudative pharyngitis, abdominal pain, diarrhea, vomiting, and severe bilateral pneumonia also are common symptoms. The most severe form of tularemia is systemic or typhoidal tularemia, which can manifest with fever, septic shock, and hepatosplenomegaly.¹⁴ The current treatment of choice for all forms of tularemia is intravenous gentamicin, with a recommended dosage of 5 mg/kg/d for 7 to 14 days; streptomycin is an acceptable alternative.^14-16 Ciprofloxacin is used less commonly and is reserved for milder disease. Incision and drainage of the affected lymph nodes also may be necessary.¹⁴ It is important to promptly identify and treat tularemia, as the mortality rate can be as high as 50% for untreated disease, especially in patients with systemic symptoms. Even after treatment, many patients exhibit residual scarring at the site of the ulcer, as well as lung, kidney, and muscle damage.¹⁴

It is advised to avoid contact with horse flies due to the range of symptom severity caused by their bites, but avoidance and control can be difficult. Malaise traps, consisting of a tent and polyester netting, can be used to capture the insects.¹⁷ Octenol has been shown to be effective for attracting horse flies and can be applied to the trap in order to increase its effectiveness.¹⁸ A Manitoba horse fly trap is a modified version of the Malaise trap that contains a suspended dark sphere to further attract horse flies.¹⁹ Patients also should be instructed to wear long-sleeved shirts and pants when outdoors in areas with horse flies to avoid contact, and application of DEET (N,N-diethylmeta-toluamide), picaridin, citronella, or geraniol-based repellents also can be effective in reducing exposure.²⁰

Final Thoughts

Horse flies are large, blood‑feeding dipteran insects whose bites usually produce painful local reactions. Although most bites are benign, they rarely can cause anaphylaxis, and certain Tabanidae insects can transmit Francisella tularensis; therefore, clinicians should consider the risk for tularemia infection in patients presenting with horse fly bites and start appropriate antibiotic therapy when indicated. Due to the risks, prevention of bites and reduction of contact with horse flies via protective clothing, repellents, and trapping methods is recommended. Patients should be advised on bite care and to seek urgent care for systemic symptoms or rapidly progressive local signs.

Horse flies (Tabanidae) are hematophagous dipteran insects that feed on the blood of their hosts, including humans.¹ Their bites can cause minor cutaneous reactions (eg, urticaria) or, rarely, severe reactions such as anaphylaxis. They also are vectors of tularemia, which may manifest with cutaneous ulcers and systemic illness. In this article, we discuss identifying features of horse flies as well as clinical manifestations from bite reactions, symptomatic and emergency management, and strategies for prevention and control.

Morphology and Geographic Distribution

Horse flies, which can grow as large as 30 mm, can be identified by their brown or black bodies and characteristic large heads and proboscises, wing venation, large calypters, pulvilliform empodium between large pulvilli, and lack of bristles on the body.² Occasionally, their bodies may be gray, yellow, green, or blue, but this is less likely than in the other species of the Tabanidae family. Short hairs are present on the head and thorax. The eyes are large and often patterned, multicolored, and bright, though they also can exhibit shades of dark brown, gray, or black. There is variation in the appearance of male vs female horse flies: females have eyes that are widely spaced apart, while males have eyes that are closer together.² It is important to note the difference between male and female horseflies, as hematophagy is exhibited only by females.¹

Horse flies are found worldwide, with the exception of Hawaii, Greenland, and Iceland.^3,4 They are especially prevalent in warm and moist regions, as these conditions are optimal for breeding.^3-5 They tend to be active during the day and inactive at night due to a preference for sunlight and warmth.⁶ Due to this preference, horse flies’ seasonal activity depends on the climate; for many regions, activity persists from summer to early autumn.⁷

Clinical Manifestations and Treatment

Female horse flies use their mouthparts to pierce the host’s skin, inject saliva, and suck blood. The saliva contains anticoagulant properties. The bites are painful for the host, and various reactions can occur, including large urticarial wheals or papules at the site of the bite. Treatment for these minor cutaneous reactions is largely symptomatic. The bite site should be washed with soap and water; ice can be applied to help reduce inflammation.⁸ Oral antihistamines may be administered to reduce pruritus and treat urticaria. Topical steroids also can be prescribed for symptomatic relief. Acetaminophen and nonsteroidal anti-inflammatory drugs can be administered for pain control.⁸

While most cases of horse fly bites are minor, there have been reports of anaphylaxis.⁹ Horse fly bite–induced anaphylaxis can manifest as generalized itching, urticaria, and angioedema within minutes of being bitten. This may be followed by pharyngeal constriction, shortness of breath, nausea, vomiting, shivers, perspiration, and loss of consciousness.⁹ Anaphylaxis symptoms should be treated with immediate administration of intramuscular epinephrine.¹⁰

Pathogen Transmission, Prevention, and Control

Although horse flies have been found to carry numerous viruses, bacteria, and protozoa that affect other mammals, there is not enough evidence to suggest that they are vectors of transmission for humans for most diseases.^11,12 In particular, West Nile virus and Borrelia burgdorferi both have been found in horse flies, but there are no reports of transmission of these diseases to humans through their bites.¹²

Horse flies, their close cousins deer flies (specifically Chrysops discalis), and ticks are known vectors of Francisella tularensis.¹³ These bacteria cause tularemia, which can manifest with symptoms such as fever, headache, and malaise. Ulceroglandular tularemia is the most common manifestation, in which the patient develops a cutaneous ulceration at the site of the horse fly bite and exhibits associated tender regional lymphadenopathy.¹⁴ Exudative conjunctivitis, exudative pharyngitis, abdominal pain, diarrhea, vomiting, and severe bilateral pneumonia also are common symptoms. The most severe form of tularemia is systemic or typhoidal tularemia, which can manifest with fever, septic shock, and hepatosplenomegaly.¹⁴ The current treatment of choice for all forms of tularemia is intravenous gentamicin, with a recommended dosage of 5 mg/kg/d for 7 to 14 days; streptomycin is an acceptable alternative.^14-16 Ciprofloxacin is used less commonly and is reserved for milder disease. Incision and drainage of the affected lymph nodes also may be necessary.¹⁴ It is important to promptly identify and treat tularemia, as the mortality rate can be as high as 50% for untreated disease, especially in patients with systemic symptoms. Even after treatment, many patients exhibit residual scarring at the site of the ulcer, as well as lung, kidney, and muscle damage.¹⁴

It is advised to avoid contact with horse flies due to the range of symptom severity caused by their bites, but avoidance and control can be difficult. Malaise traps, consisting of a tent and polyester netting, can be used to capture the insects.¹⁷ Octenol has been shown to be effective for attracting horse flies and can be applied to the trap in order to increase its effectiveness.¹⁸ A Manitoba horse fly trap is a modified version of the Malaise trap that contains a suspended dark sphere to further attract horse flies.¹⁹ Patients also should be instructed to wear long-sleeved shirts and pants when outdoors in areas with horse flies to avoid contact, and application of DEET (N,N-diethylmeta-toluamide), picaridin, citronella, or geraniol-based repellents also can be effective in reducing exposure.²⁰

Final Thoughts

Horse flies are large, blood‑feeding dipteran insects whose bites usually produce painful local reactions. Although most bites are benign, they rarely can cause anaphylaxis, and certain Tabanidae insects can transmit Francisella tularensis; therefore, clinicians should consider the risk for tularemia infection in patients presenting with horse fly bites and start appropriate antibiotic therapy when indicated. Due to the risks, prevention of bites and reduction of contact with horse flies via protective clothing, repellents, and trapping methods is recommended. Patients should be advised on bite care and to seek urgent care for systemic symptoms or rapidly progressive local signs.

Hand dermatitis (HD) is a common dermatologic concern that can impair quality of life, work productivity, and daily functioning.¹ Occupational HD is defined as hand eczema caused or worsened by workplace exposures. When caused by work, HD may lead to reduced productivity and even job loss. Subtypes of HD include irritant contact dermatitis (ICD), allergic contact dermatitis (ACD), protein contact dermatitis (PCD), atopic dermatitis (AD), hyperkeratotic HD, and dyshidrotic eczema.^2,3

Often caused by wet work, ICD is the most common subtype, whereas PCD—which is caused by immediate hypersensitivity to protein—is less common and usually seen in food service workers.^3,4 When HD does not improve with standard treatment, particularly in occupational cases, patch testing is prudent to evaluate for contact allergens. In this article, we review practical considerations for evaluation and management of occupational irritant and allergic HD, highlighting relevant exposures and pearls on workup and management.

Epidemiology of Hand Dermatitis

A 2021 systematic review and meta-analysis of European studies reported a 1-year HD prevalence of 9.1% and a lifetime prevalence of 14.5%.⁵ Hand dermatitis is most common in women; individuals aged 30 to 39 years; and those who are employed, underscoring the role of workplace exposure.⁶ High-risk occupations are those involving substantial wet work, such as hairdressers, beauticians, cleaners, and health care and construction workers.⁷ Individuals with a history of AD also are at high risk for HD.⁸

Hand Dermatitis Subtypes

Irritant Contact Dermatitis—Irritant contact dermatitis, the most common form of occupational HD, is caused by repeated exposure to irritants (eg, water, detergents, cleansers, and soaps) that disrupt the skin barrier.⁹ Occupations that involve wet work are a major risk factor, associated with a 56% higher likelihood of ICD.⁸ Wet work involves frequent handwashing, prolonged contact with liquids, or occlusive glove use.⁹ As a ubiquitous skin irritant, water can penetrate the stratum corneum, impair the skin barrier, and increase sensitization risk. The dorsal hands usually are affected by ICD due to the thinner stratum corneum in this area.⁹

Allergic Contact Dermatitis—Allergic contact dermatitis should be considered in cases of chronic, recurrent, or treatment-resistant disease. Clinical clues include dermatitis beyond irritant contact sites, recurrent pruritic and vesicular HD, and flares with occupational exposures or materials; however, it can be difficult to distinguish ACD from ICD on clinical presentation alone, as they have many overlapping features. When ACD is suspected, patch testing remains the gold standard for identifying allergens and guiding avoidance strategies, product alternatives, and workplace modifications.

Unique Occupational Considerations

Hairdressers—Hairdressers have an increased risk for HD due to wet work and exposure to sensitizers, with a pooled lifetime prevalence of 38.2% (including ICD, ACD, and occupational cases).¹⁰ Notably, frequent shampooing, rinsing, cutting wet hair, handwashing, and glove use increase the risk for ICD. Hairdressers also are exposed to allergens in hair products, including p-phenylenediamine, toluene-2,5-diamine, persulfate salts, glyceryl thioglycolate, preservatives, and fragrances. Occupational exposure to the preservative methylisothiazolinone is high among hairdressers, with a sensitization rate of 10.5% in HD cases.¹¹

It has been reported that hyperkeratotic fissured eczema of the dorsal hands caused by wet work often indicates ICD, whereas pruritic dyshidrotic eczema involving the lateral fingers or palms suggests ACD; however, these conditions can share overlapping features.⁷ If ACD is suspected, broad patch testing with baseline and hairdresser series, along with specific chemicals that may be encountered in the workplace, is necessary. Management includes allergen avoidance, reduced wet work tasks, use of nitrile gloves with glove changes to mitigate occlusive effects, and skin barrier protection with emollients.

Health Care Workers—Health care workers are vulnerable to HD due to intensive hand hygiene, prolonged glove use, and allergen exposures, with a lifetime prevalence of self-reported HD of 33.4%.¹² Common allergens among health care workers include rubber accelerators, most often from rubber gloves.¹³ Frequent handwashing and glove use can further impair the skin barrier, increasing irritant and sensitization risks.¹⁴ In contrast, alcohol-based hand sanitizers containing emollients are less irritating, with prior analyses showing no significant association with HD risk.^15,16 Conversely, handwashing 8 to 10 times daily increased HD risk, with a relative risk of 1.51.¹⁵

Surgeons and proceduralists face unique risks for HD from preoperative scrubbing with products that can contain potential allergens such as chlorhexidine gluconate, chloroxylenol, povidone-iodine, fragrance, cocamide diethanolamine, lanolin, alkyl glucosides, sodium benzoate, sorbic acid, tocopherol, and propylene glycol.^17,18 Subsequent occlusion under glove layers drives ICD and ACD risks, highlighting the importance of patch testing in affected individuals. While patch testing, exposure avoidance, and limited glove use can mitigate HD risk, frequent handwashing can contribute to refractory HD.

Food Service Workers—Food service workers have an increased risk for HD from allergens and irritants. In a retrospective study of patients with occupational food-related HD (N=372), 57% were diagnosed with ICD, 22% with PCD, and 1.8% with ACD.¹⁹ Skin barrier disruption from wet work, occlusion from glove use, and contact with food proteins increase HD risk, especially in bakers exposed to flours and grains, which can cause IgE–mediated PCD manifesting with contact urticaria. Protein contact dermatitis is confirmed by prick testing with suspected foods.²⁰ Additionally, exposure to garlic can cause ICD and ACD due to sulfur-containing compounds, particularly allicin and diallyl disulfide.^21,22 Pineapple also can trigger ICD associated with bromelain, a proteolytic enzyme that can break down the skin.²³ Nickel exposure is another concern, as steel utensils and cookware can release nickel onto the skin of sensitized individuals.²⁴ Rubber accelerator exposure from gloves also contributes to contact allergy and HD among food service workers; vinyl gloves usually are a good alternative in this setting.²⁵ Management of food-related HD involves exposure avoidance, which may affect occupational viability

Construction Workers—Construction workers are at risk for occupational HD due to contact with irritants and sensitizers such as paints, adhesives, asphalt, cement, solvents, and gloves.²⁶ A retrospective analysis of North American Contact Dermatitis Group data identified HD in 37.2% (253/681) of patch-tested construction workers. The most common occupational allergens include potassium dichromate, which can be present in cement and leather items; bisphenol A epoxy resin; cobalt chloride hexahydrate; and the rubber accelerators carba mix and thiuram mix.²⁶ A thorough occupational history should assess materials handled, and patch testing should include common construction-related allergens to inform avoidance strategies. Workplace task modification can reduce exposure, as certain managerial roles in construction work may involve less contact with irritants and sensitizers.²⁶

Nail Technicians—Nail technicians are at risk for HD, especially ACD from acrylate monomers used in nail gels, dips, and acrylics. In a 10-year analysis, around 87.5% (14/16) of nail technicians with contact allergy to methacrylate demonstrated hand involvement.²⁷ Common acrylate monomers include 2-hydroxyethyl methacrylate, 2-hydroxypropyl methacrylate, and ethyl cyanoacrylate. ²⁸ Evaluation requires a detailed occupational history, assessing HD onset relative to exposure, services performed, glove-use practices, and whether symptoms improve away from work. While gloves may appear to reduce exposure, a glove-penetration study showed that acrylate-containing nail products can penetrate commonly used disposable gloves from within seconds to approximately 20 minutes, depending on glove and product type.²⁹ Among available options, nitrile gloves may provide dexterity and allergen avoidance when acrylate exposure is brief, with glove changes required every 15 to 30 minutes.³⁰ Patch testing with 2-hydroxyethyl methacrylate and ethyl cyanoacrylate can identify nail acrylate allergy; however, avoidance can be challenging for nail technicians, as these products often are ubiquitous in their work.

Florists—Florists can develop HD from plant allergens and irritants, particularly tulipalin A and calcium oxalate, with a lifetime prevalence of 19.6%.³¹ Tulipalin A is a well-documented sensitizer causing ACD among florists exposed to tulip bulbs and other Alstroemeria flowers.³² The term tulip fingers actually was coined to describe ACD caused by tulip bulbs in the European tulip industry.³³ Patch testing involves testing for tulipalin A, which may be commercially limited, or tulip plant materials; however, fresh tulips require open testing with small amounts due to higher allergen concentration.³² Additionally, the term daffodil itch describes a type of ICD caused by calcium oxalate crystals in daffodil bulbs and tulip sap.^32,34 Diagnosis of plant-related HD requires an occupational history and targeted patch testing, while glove protection and exposure avoidance are essential for improvement.

Evaluation and Management

The workup for HD involves physical examination and medical history, including disease onset, course, and history of AD, along with occupational and exposure history to identify allergens and irritants. Understanding the patient’s tasks and responsibilities and workplace practices along with the materials they handle allows the dermatologist to anticipate relevant allergens for patch testing.

Patch testing should be comprehensive, as baseline screening series alone may miss between 26.3% and 50% of occupationally relevant allergens.^35,36 Comprehensive patch testing also should include specialty series and supplemental allergens based on the patient’s clinical history and exposures. Specialty series may include hairdressing, bakery, cosmetics, dental, machinists, and adhesives.³⁷ Gloves also warrant attention, as they may be overlooked as a sensitizer following repeated contact and occlusion. In persistent HD associated with glove use, patch testing should include a rubber accelerator series with relevant allergens, such as thiurams, carbamates, mercaptobenzothiazole, diphenylguanidine, and the patient’s own gloves.³⁸ Latex allergy also should be considered, particularly in immediate-type reactions, and can be evaluated with latex-specific IgE testing.³⁹

Management of HD relies on accurate diagnosis and allergen avoidance, which can be challenging in occupational settings. Structured tools, such as the American Contact Dermatitis Society’s Contact Allergen Management Program (https://www.contactderm.org/ resources/acds-camp), can help identify safe alternatives.

In occupational HD, risk assessment should identify occupational exposures and determine appropriate personal protective equipment while minimizing the risk for HD associated with such equipment. Protective gloves are advised to prevent contact with allergens and irritants. When glove use lasts more than 10 minutes, cotton glove liners may be worn to avoid occlusion and moisture retention.⁴⁰ For wet work, vinyl gloves are recommended, with regular emollient use to support skin-barrier repair. Overall, gloves should be used when possible, changed regularly, and worn for limited periods of time to prevent ICD.

Work modification may be required to reduce exposure and flares, including task reassignment or substitution of materials containing allergens and irritants. Occupational HD may necessitate workplace accommodations, disability evaluation, medical leave, or even permanent job change. Dermatologists play a crucial role in the medical determination of work relatedness and functional impairment, guiding patients through occupational health, disability, and workers’ compensation when warranted.

Treatments for Occupational HD

Treatment of occupational HD depends on disease severity, chronicity, and avoidance of allergens and irritants in ACD, ICD, and PCD. Foundational management includes regular emollient use, which can even serve as monotherapy in mild occupational HD.⁴⁰ Corticosteroids are the cornerstone of topical therapy, while calcineurin inhibitors can be used as a steroid-sparing option in milder disease.⁴¹ Off-label topical calcipotriol and AD-approved therapies crisaborole and ruxolitinib may be effective. For refractory disease after topical treatments, phototherapy can be considered.⁴⁰ Biologic and targeted therapies also have emerged as potential treatments. Dupilumab is effective for atopic chronic HD and has demonstrated promise for nonatopic chronic HD.⁴² Recently, delgocitinib, a topical pan–Janus kinase inhibitor cream, showed clinical efficacy for chronic hand eczema and was approved by the US Food and Drug Administration.⁴³ Off-label use of alternative systemic therapies, including acitretin, cyclosporine, methotrexate, and azathioprine, and other biologics and systemic Janus kinase inhibitors also may treat HD, but larger studies are lacking.⁴⁰

Our Final Interpretation

Occupational HD is a common skin condition with multiple etiologies. It is important for clinicians to gather a thorough occupational and exposure history to narrow the differential diagnosis, inform patch testing, and guide effective management. In practice, successful treatment depends on screening for and diagnosis of workplace exposures driving disease.

Hand dermatitis (HD) is a common dermatologic concern that can impair quality of life, work productivity, and daily functioning.¹ Occupational HD is defined as hand eczema caused or worsened by workplace exposures. When caused by work, HD may lead to reduced productivity and even job loss. Subtypes of HD include irritant contact dermatitis (ICD), allergic contact dermatitis (ACD), protein contact dermatitis (PCD), atopic dermatitis (AD), hyperkeratotic HD, and dyshidrotic eczema.^2,3

Often caused by wet work, ICD is the most common subtype, whereas PCD—which is caused by immediate hypersensitivity to protein—is less common and usually seen in food service workers.^3,4 When HD does not improve with standard treatment, particularly in occupational cases, patch testing is prudent to evaluate for contact allergens. In this article, we review practical considerations for evaluation and management of occupational irritant and allergic HD, highlighting relevant exposures and pearls on workup and management.

Epidemiology of Hand Dermatitis

A 2021 systematic review and meta-analysis of European studies reported a 1-year HD prevalence of 9.1% and a lifetime prevalence of 14.5%.⁵ Hand dermatitis is most common in women; individuals aged 30 to 39 years; and those who are employed, underscoring the role of workplace exposure.⁶ High-risk occupations are those involving substantial wet work, such as hairdressers, beauticians, cleaners, and health care and construction workers.⁷ Individuals with a history of AD also are at high risk for HD.⁸

Hand Dermatitis Subtypes

Irritant Contact Dermatitis—Irritant contact dermatitis, the most common form of occupational HD, is caused by repeated exposure to irritants (eg, water, detergents, cleansers, and soaps) that disrupt the skin barrier.⁹ Occupations that involve wet work are a major risk factor, associated with a 56% higher likelihood of ICD.⁸ Wet work involves frequent handwashing, prolonged contact with liquids, or occlusive glove use.⁹ As a ubiquitous skin irritant, water can penetrate the stratum corneum, impair the skin barrier, and increase sensitization risk. The dorsal hands usually are affected by ICD due to the thinner stratum corneum in this area.⁹

Allergic Contact Dermatitis—Allergic contact dermatitis should be considered in cases of chronic, recurrent, or treatment-resistant disease. Clinical clues include dermatitis beyond irritant contact sites, recurrent pruritic and vesicular HD, and flares with occupational exposures or materials; however, it can be difficult to distinguish ACD from ICD on clinical presentation alone, as they have many overlapping features. When ACD is suspected, patch testing remains the gold standard for identifying allergens and guiding avoidance strategies, product alternatives, and workplace modifications.

Unique Occupational Considerations

Hairdressers—Hairdressers have an increased risk for HD due to wet work and exposure to sensitizers, with a pooled lifetime prevalence of 38.2% (including ICD, ACD, and occupational cases).¹⁰ Notably, frequent shampooing, rinsing, cutting wet hair, handwashing, and glove use increase the risk for ICD. Hairdressers also are exposed to allergens in hair products, including p-phenylenediamine, toluene-2,5-diamine, persulfate salts, glyceryl thioglycolate, preservatives, and fragrances. Occupational exposure to the preservative methylisothiazolinone is high among hairdressers, with a sensitization rate of 10.5% in HD cases.¹¹

It has been reported that hyperkeratotic fissured eczema of the dorsal hands caused by wet work often indicates ICD, whereas pruritic dyshidrotic eczema involving the lateral fingers or palms suggests ACD; however, these conditions can share overlapping features.⁷ If ACD is suspected, broad patch testing with baseline and hairdresser series, along with specific chemicals that may be encountered in the workplace, is necessary. Management includes allergen avoidance, reduced wet work tasks, use of nitrile gloves with glove changes to mitigate occlusive effects, and skin barrier protection with emollients.

Health Care Workers—Health care workers are vulnerable to HD due to intensive hand hygiene, prolonged glove use, and allergen exposures, with a lifetime prevalence of self-reported HD of 33.4%.¹² Common allergens among health care workers include rubber accelerators, most often from rubber gloves.¹³ Frequent handwashing and glove use can further impair the skin barrier, increasing irritant and sensitization risks.¹⁴ In contrast, alcohol-based hand sanitizers containing emollients are less irritating, with prior analyses showing no significant association with HD risk.^15,16 Conversely, handwashing 8 to 10 times daily increased HD risk, with a relative risk of 1.51.¹⁵

Surgeons and proceduralists face unique risks for HD from preoperative scrubbing with products that can contain potential allergens such as chlorhexidine gluconate, chloroxylenol, povidone-iodine, fragrance, cocamide diethanolamine, lanolin, alkyl glucosides, sodium benzoate, sorbic acid, tocopherol, and propylene glycol.^17,18 Subsequent occlusion under glove layers drives ICD and ACD risks, highlighting the importance of patch testing in affected individuals. While patch testing, exposure avoidance, and limited glove use can mitigate HD risk, frequent handwashing can contribute to refractory HD.

Food Service Workers—Food service workers have an increased risk for HD from allergens and irritants. In a retrospective study of patients with occupational food-related HD (N=372), 57% were diagnosed with ICD, 22% with PCD, and 1.8% with ACD.¹⁹ Skin barrier disruption from wet work, occlusion from glove use, and contact with food proteins increase HD risk, especially in bakers exposed to flours and grains, which can cause IgE–mediated PCD manifesting with contact urticaria. Protein contact dermatitis is confirmed by prick testing with suspected foods.²⁰ Additionally, exposure to garlic can cause ICD and ACD due to sulfur-containing compounds, particularly allicin and diallyl disulfide.^21,22 Pineapple also can trigger ICD associated with bromelain, a proteolytic enzyme that can break down the skin.²³ Nickel exposure is another concern, as steel utensils and cookware can release nickel onto the skin of sensitized individuals.²⁴ Rubber accelerator exposure from gloves also contributes to contact allergy and HD among food service workers; vinyl gloves usually are a good alternative in this setting.²⁵ Management of food-related HD involves exposure avoidance, which may affect occupational viability

Construction Workers—Construction workers are at risk for occupational HD due to contact with irritants and sensitizers such as paints, adhesives, asphalt, cement, solvents, and gloves.²⁶ A retrospective analysis of North American Contact Dermatitis Group data identified HD in 37.2% (253/681) of patch-tested construction workers. The most common occupational allergens include potassium dichromate, which can be present in cement and leather items; bisphenol A epoxy resin; cobalt chloride hexahydrate; and the rubber accelerators carba mix and thiuram mix.²⁶ A thorough occupational history should assess materials handled, and patch testing should include common construction-related allergens to inform avoidance strategies. Workplace task modification can reduce exposure, as certain managerial roles in construction work may involve less contact with irritants and sensitizers.²⁶

Nail Technicians—Nail technicians are at risk for HD, especially ACD from acrylate monomers used in nail gels, dips, and acrylics. In a 10-year analysis, around 87.5% (14/16) of nail technicians with contact allergy to methacrylate demonstrated hand involvement.²⁷ Common acrylate monomers include 2-hydroxyethyl methacrylate, 2-hydroxypropyl methacrylate, and ethyl cyanoacrylate. ²⁸ Evaluation requires a detailed occupational history, assessing HD onset relative to exposure, services performed, glove-use practices, and whether symptoms improve away from work. While gloves may appear to reduce exposure, a glove-penetration study showed that acrylate-containing nail products can penetrate commonly used disposable gloves from within seconds to approximately 20 minutes, depending on glove and product type.²⁹ Among available options, nitrile gloves may provide dexterity and allergen avoidance when acrylate exposure is brief, with glove changes required every 15 to 30 minutes.³⁰ Patch testing with 2-hydroxyethyl methacrylate and ethyl cyanoacrylate can identify nail acrylate allergy; however, avoidance can be challenging for nail technicians, as these products often are ubiquitous in their work.

Florists—Florists can develop HD from plant allergens and irritants, particularly tulipalin A and calcium oxalate, with a lifetime prevalence of 19.6%.³¹ Tulipalin A is a well-documented sensitizer causing ACD among florists exposed to tulip bulbs and other Alstroemeria flowers.³² The term tulip fingers actually was coined to describe ACD caused by tulip bulbs in the European tulip industry.³³ Patch testing involves testing for tulipalin A, which may be commercially limited, or tulip plant materials; however, fresh tulips require open testing with small amounts due to higher allergen concentration.³² Additionally, the term daffodil itch describes a type of ICD caused by calcium oxalate crystals in daffodil bulbs and tulip sap.^32,34 Diagnosis of plant-related HD requires an occupational history and targeted patch testing, while glove protection and exposure avoidance are essential for improvement.

Evaluation and Management

The workup for HD involves physical examination and medical history, including disease onset, course, and history of AD, along with occupational and exposure history to identify allergens and irritants. Understanding the patient’s tasks and responsibilities and workplace practices along with the materials they handle allows the dermatologist to anticipate relevant allergens for patch testing.

Patch testing should be comprehensive, as baseline screening series alone may miss between 26.3% and 50% of occupationally relevant allergens.^35,36 Comprehensive patch testing also should include specialty series and supplemental allergens based on the patient’s clinical history and exposures. Specialty series may include hairdressing, bakery, cosmetics, dental, machinists, and adhesives.³⁷ Gloves also warrant attention, as they may be overlooked as a sensitizer following repeated contact and occlusion. In persistent HD associated with glove use, patch testing should include a rubber accelerator series with relevant allergens, such as thiurams, carbamates, mercaptobenzothiazole, diphenylguanidine, and the patient’s own gloves.³⁸ Latex allergy also should be considered, particularly in immediate-type reactions, and can be evaluated with latex-specific IgE testing.³⁹

Management of HD relies on accurate diagnosis and allergen avoidance, which can be challenging in occupational settings. Structured tools, such as the American Contact Dermatitis Society’s Contact Allergen Management Program (https://www.contactderm.org/ resources/acds-camp), can help identify safe alternatives.

In occupational HD, risk assessment should identify occupational exposures and determine appropriate personal protective equipment while minimizing the risk for HD associated with such equipment. Protective gloves are advised to prevent contact with allergens and irritants. When glove use lasts more than 10 minutes, cotton glove liners may be worn to avoid occlusion and moisture retention.⁴⁰ For wet work, vinyl gloves are recommended, with regular emollient use to support skin-barrier repair. Overall, gloves should be used when possible, changed regularly, and worn for limited periods of time to prevent ICD.

Work modification may be required to reduce exposure and flares, including task reassignment or substitution of materials containing allergens and irritants. Occupational HD may necessitate workplace accommodations, disability evaluation, medical leave, or even permanent job change. Dermatologists play a crucial role in the medical determination of work relatedness and functional impairment, guiding patients through occupational health, disability, and workers’ compensation when warranted.

Treatments for Occupational HD

Treatment of occupational HD depends on disease severity, chronicity, and avoidance of allergens and irritants in ACD, ICD, and PCD. Foundational management includes regular emollient use, which can even serve as monotherapy in mild occupational HD.⁴⁰ Corticosteroids are the cornerstone of topical therapy, while calcineurin inhibitors can be used as a steroid-sparing option in milder disease.⁴¹ Off-label topical calcipotriol and AD-approved therapies crisaborole and ruxolitinib may be effective. For refractory disease after topical treatments, phototherapy can be considered.⁴⁰ Biologic and targeted therapies also have emerged as potential treatments. Dupilumab is effective for atopic chronic HD and has demonstrated promise for nonatopic chronic HD.⁴² Recently, delgocitinib, a topical pan–Janus kinase inhibitor cream, showed clinical efficacy for chronic hand eczema and was approved by the US Food and Drug Administration.⁴³ Off-label use of alternative systemic therapies, including acitretin, cyclosporine, methotrexate, and azathioprine, and other biologics and systemic Janus kinase inhibitors also may treat HD, but larger studies are lacking.⁴⁰

Our Final Interpretation

Occupational HD is a common skin condition with multiple etiologies. It is important for clinicians to gather a thorough occupational and exposure history to narrow the differential diagnosis, inform patch testing, and guide effective management. In practice, successful treatment depends on screening for and diagnosis of workplace exposures driving disease.

Hand dermatitis (HD) is a common dermatologic concern that can impair quality of life, work productivity, and daily functioning.¹ Occupational HD is defined as hand eczema caused or worsened by workplace exposures. When caused by work, HD may lead to reduced productivity and even job loss. Subtypes of HD include irritant contact dermatitis (ICD), allergic contact dermatitis (ACD), protein contact dermatitis (PCD), atopic dermatitis (AD), hyperkeratotic HD, and dyshidrotic eczema.^2,3

Often caused by wet work, ICD is the most common subtype, whereas PCD—which is caused by immediate hypersensitivity to protein—is less common and usually seen in food service workers.^3,4 When HD does not improve with standard treatment, particularly in occupational cases, patch testing is prudent to evaluate for contact allergens. In this article, we review practical considerations for evaluation and management of occupational irritant and allergic HD, highlighting relevant exposures and pearls on workup and management.

Epidemiology of Hand Dermatitis

A 2021 systematic review and meta-analysis of European studies reported a 1-year HD prevalence of 9.1% and a lifetime prevalence of 14.5%.⁵ Hand dermatitis is most common in women; individuals aged 30 to 39 years; and those who are employed, underscoring the role of workplace exposure.⁶ High-risk occupations are those involving substantial wet work, such as hairdressers, beauticians, cleaners, and health care and construction workers.⁷ Individuals with a history of AD also are at high risk for HD.⁸

Hand Dermatitis Subtypes

Irritant Contact Dermatitis—Irritant contact dermatitis, the most common form of occupational HD, is caused by repeated exposure to irritants (eg, water, detergents, cleansers, and soaps) that disrupt the skin barrier.⁹ Occupations that involve wet work are a major risk factor, associated with a 56% higher likelihood of ICD.⁸ Wet work involves frequent handwashing, prolonged contact with liquids, or occlusive glove use.⁹ As a ubiquitous skin irritant, water can penetrate the stratum corneum, impair the skin barrier, and increase sensitization risk. The dorsal hands usually are affected by ICD due to the thinner stratum corneum in this area.⁹

Allergic Contact Dermatitis—Allergic contact dermatitis should be considered in cases of chronic, recurrent, or treatment-resistant disease. Clinical clues include dermatitis beyond irritant contact sites, recurrent pruritic and vesicular HD, and flares with occupational exposures or materials; however, it can be difficult to distinguish ACD from ICD on clinical presentation alone, as they have many overlapping features. When ACD is suspected, patch testing remains the gold standard for identifying allergens and guiding avoidance strategies, product alternatives, and workplace modifications.

Unique Occupational Considerations

Hairdressers—Hairdressers have an increased risk for HD due to wet work and exposure to sensitizers, with a pooled lifetime prevalence of 38.2% (including ICD, ACD, and occupational cases).¹⁰ Notably, frequent shampooing, rinsing, cutting wet hair, handwashing, and glove use increase the risk for ICD. Hairdressers also are exposed to allergens in hair products, including p-phenylenediamine, toluene-2,5-diamine, persulfate salts, glyceryl thioglycolate, preservatives, and fragrances. Occupational exposure to the preservative methylisothiazolinone is high among hairdressers, with a sensitization rate of 10.5% in HD cases.¹¹

It has been reported that hyperkeratotic fissured eczema of the dorsal hands caused by wet work often indicates ICD, whereas pruritic dyshidrotic eczema involving the lateral fingers or palms suggests ACD; however, these conditions can share overlapping features.⁷ If ACD is suspected, broad patch testing with baseline and hairdresser series, along with specific chemicals that may be encountered in the workplace, is necessary. Management includes allergen avoidance, reduced wet work tasks, use of nitrile gloves with glove changes to mitigate occlusive effects, and skin barrier protection with emollients.

Health Care Workers—Health care workers are vulnerable to HD due to intensive hand hygiene, prolonged glove use, and allergen exposures, with a lifetime prevalence of self-reported HD of 33.4%.¹² Common allergens among health care workers include rubber accelerators, most often from rubber gloves.¹³ Frequent handwashing and glove use can further impair the skin barrier, increasing irritant and sensitization risks.¹⁴ In contrast, alcohol-based hand sanitizers containing emollients are less irritating, with prior analyses showing no significant association with HD risk.^15,16 Conversely, handwashing 8 to 10 times daily increased HD risk, with a relative risk of 1.51.¹⁵

Surgeons and proceduralists face unique risks for HD from preoperative scrubbing with products that can contain potential allergens such as chlorhexidine gluconate, chloroxylenol, povidone-iodine, fragrance, cocamide diethanolamine, lanolin, alkyl glucosides, sodium benzoate, sorbic acid, tocopherol, and propylene glycol.^17,18 Subsequent occlusion under glove layers drives ICD and ACD risks, highlighting the importance of patch testing in affected individuals. While patch testing, exposure avoidance, and limited glove use can mitigate HD risk, frequent handwashing can contribute to refractory HD.

Food Service Workers—Food service workers have an increased risk for HD from allergens and irritants. In a retrospective study of patients with occupational food-related HD (N=372), 57% were diagnosed with ICD, 22% with PCD, and 1.8% with ACD.¹⁹ Skin barrier disruption from wet work, occlusion from glove use, and contact with food proteins increase HD risk, especially in bakers exposed to flours and grains, which can cause IgE–mediated PCD manifesting with contact urticaria. Protein contact dermatitis is confirmed by prick testing with suspected foods.²⁰ Additionally, exposure to garlic can cause ICD and ACD due to sulfur-containing compounds, particularly allicin and diallyl disulfide.^21,22 Pineapple also can trigger ICD associated with bromelain, a proteolytic enzyme that can break down the skin.²³ Nickel exposure is another concern, as steel utensils and cookware can release nickel onto the skin of sensitized individuals.²⁴ Rubber accelerator exposure from gloves also contributes to contact allergy and HD among food service workers; vinyl gloves usually are a good alternative in this setting.²⁵ Management of food-related HD involves exposure avoidance, which may affect occupational viability

Construction Workers—Construction workers are at risk for occupational HD due to contact with irritants and sensitizers such as paints, adhesives, asphalt, cement, solvents, and gloves.²⁶ A retrospective analysis of North American Contact Dermatitis Group data identified HD in 37.2% (253/681) of patch-tested construction workers. The most common occupational allergens include potassium dichromate, which can be present in cement and leather items; bisphenol A epoxy resin; cobalt chloride hexahydrate; and the rubber accelerators carba mix and thiuram mix.²⁶ A thorough occupational history should assess materials handled, and patch testing should include common construction-related allergens to inform avoidance strategies. Workplace task modification can reduce exposure, as certain managerial roles in construction work may involve less contact with irritants and sensitizers.²⁶

Nail Technicians—Nail technicians are at risk for HD, especially ACD from acrylate monomers used in nail gels, dips, and acrylics. In a 10-year analysis, around 87.5% (14/16) of nail technicians with contact allergy to methacrylate demonstrated hand involvement.²⁷ Common acrylate monomers include 2-hydroxyethyl methacrylate, 2-hydroxypropyl methacrylate, and ethyl cyanoacrylate. ²⁸ Evaluation requires a detailed occupational history, assessing HD onset relative to exposure, services performed, glove-use practices, and whether symptoms improve away from work. While gloves may appear to reduce exposure, a glove-penetration study showed that acrylate-containing nail products can penetrate commonly used disposable gloves from within seconds to approximately 20 minutes, depending on glove and product type.²⁹ Among available options, nitrile gloves may provide dexterity and allergen avoidance when acrylate exposure is brief, with glove changes required every 15 to 30 minutes.³⁰ Patch testing with 2-hydroxyethyl methacrylate and ethyl cyanoacrylate can identify nail acrylate allergy; however, avoidance can be challenging for nail technicians, as these products often are ubiquitous in their work.

Florists—Florists can develop HD from plant allergens and irritants, particularly tulipalin A and calcium oxalate, with a lifetime prevalence of 19.6%.³¹ Tulipalin A is a well-documented sensitizer causing ACD among florists exposed to tulip bulbs and other Alstroemeria flowers.³² The term tulip fingers actually was coined to describe ACD caused by tulip bulbs in the European tulip industry.³³ Patch testing involves testing for tulipalin A, which may be commercially limited, or tulip plant materials; however, fresh tulips require open testing with small amounts due to higher allergen concentration.³² Additionally, the term daffodil itch describes a type of ICD caused by calcium oxalate crystals in daffodil bulbs and tulip sap.^32,34 Diagnosis of plant-related HD requires an occupational history and targeted patch testing, while glove protection and exposure avoidance are essential for improvement.

Evaluation and Management

The workup for HD involves physical examination and medical history, including disease onset, course, and history of AD, along with occupational and exposure history to identify allergens and irritants. Understanding the patient’s tasks and responsibilities and workplace practices along with the materials they handle allows the dermatologist to anticipate relevant allergens for patch testing.

Patch testing should be comprehensive, as baseline screening series alone may miss between 26.3% and 50% of occupationally relevant allergens.^35,36 Comprehensive patch testing also should include specialty series and supplemental allergens based on the patient’s clinical history and exposures. Specialty series may include hairdressing, bakery, cosmetics, dental, machinists, and adhesives.³⁷ Gloves also warrant attention, as they may be overlooked as a sensitizer following repeated contact and occlusion. In persistent HD associated with glove use, patch testing should include a rubber accelerator series with relevant allergens, such as thiurams, carbamates, mercaptobenzothiazole, diphenylguanidine, and the patient’s own gloves.³⁸ Latex allergy also should be considered, particularly in immediate-type reactions, and can be evaluated with latex-specific IgE testing.³⁹

Management of HD relies on accurate diagnosis and allergen avoidance, which can be challenging in occupational settings. Structured tools, such as the American Contact Dermatitis Society’s Contact Allergen Management Program (https://www.contactderm.org/ resources/acds-camp), can help identify safe alternatives.

In occupational HD, risk assessment should identify occupational exposures and determine appropriate personal protective equipment while minimizing the risk for HD associated with such equipment. Protective gloves are advised to prevent contact with allergens and irritants. When glove use lasts more than 10 minutes, cotton glove liners may be worn to avoid occlusion and moisture retention.⁴⁰ For wet work, vinyl gloves are recommended, with regular emollient use to support skin-barrier repair. Overall, gloves should be used when possible, changed regularly, and worn for limited periods of time to prevent ICD.

Work modification may be required to reduce exposure and flares, including task reassignment or substitution of materials containing allergens and irritants. Occupational HD may necessitate workplace accommodations, disability evaluation, medical leave, or even permanent job change. Dermatologists play a crucial role in the medical determination of work relatedness and functional impairment, guiding patients through occupational health, disability, and workers’ compensation when warranted.

Treatments for Occupational HD

Treatment of occupational HD depends on disease severity, chronicity, and avoidance of allergens and irritants in ACD, ICD, and PCD. Foundational management includes regular emollient use, which can even serve as monotherapy in mild occupational HD.⁴⁰ Corticosteroids are the cornerstone of topical therapy, while calcineurin inhibitors can be used as a steroid-sparing option in milder disease.⁴¹ Off-label topical calcipotriol and AD-approved therapies crisaborole and ruxolitinib may be effective. For refractory disease after topical treatments, phototherapy can be considered.⁴⁰ Biologic and targeted therapies also have emerged as potential treatments. Dupilumab is effective for atopic chronic HD and has demonstrated promise for nonatopic chronic HD.⁴² Recently, delgocitinib, a topical pan–Janus kinase inhibitor cream, showed clinical efficacy for chronic hand eczema and was approved by the US Food and Drug Administration.⁴³ Off-label use of alternative systemic therapies, including acitretin, cyclosporine, methotrexate, and azathioprine, and other biologics and systemic Janus kinase inhibitors also may treat HD, but larger studies are lacking.⁴⁰

Our Final Interpretation

Occupational HD is a common skin condition with multiple etiologies. It is important for clinicians to gather a thorough occupational and exposure history to narrow the differential diagnosis, inform patch testing, and guide effective management. In practice, successful treatment depends on screening for and diagnosis of workplace exposures driving disease.

How do social media trends and influencer driven product fads affect the patterns of contact dermatitis you are seeing?

DR. YU: Social media and influencers are huge marketing opportunities for cosmetic and personal care companies and drive consumer demand. One example from a few years ago is slime as a toy for kids. For a period of time, every kid was making slime at home, resulting in high numbers of hand allergic contact dermatitis. Making slime requires a combination of borax (irritant), glue (irritant and allergen), laundry detergent or dish soap (irritant and allergen), and fragrances (irritant and allergen). This fad has been slowing since I cowrote an article on it (doi:10.1111 /pde.13792). More recently, the rise of “Sephora kids” (preteens and adolescents influenced by social media trends promoting multistep skin care and anti-aging products) has raised concerns about contact dermatitis, as many of these products contain ingredients that can disrupt the skin barrier or trigger sensitization in younger patients.

How can products labeled free of fragrances or preservatives still trigger allergic contact dermatitis?

DR. YU: Fragrances are frequently in the top 10 ingredients that cause allergic contact dermatitis in adults and children. For people with sensitive skin, we almost unequivocally recommend fragrance-free products. Now, not all fragrance-free products are truly free of fragrance allergens. Some fragrance chemicals may be used for another purpose (benzyl alcohol as a preservative, for example), so the product can still be fragrance free even though benzyl alcohol has a fragrance. Most products cannot truly be preservative free if they are expected to have a shelf life. One-time-use products do exist and can be preservative free, but they are very rare and very expensive to manufacture and maintain.

Have you seen spikes in reactions from trendy products like CBD-infused creams, botanical serums, or exfoliating acids?

DR. YU: Not yet, but I would not be surprised that this is rising in prevalence. The issue might not be CBD itself; it’s really the other additives in these CBD products that will cause problems. Looking at some CBD products for sale from major retailers, many contain fragrances such as lemongrass oil and botanical extracts such as calendula that have been noted to cause allergic contact dermatitis.

Do certain patient behaviors (eg, layering multiple natural products, frequent product switching, prolonged leave-on use) increase the risk for ACD?

DR. YU: Absolutely possible. The more products you use, the more likely you will develop allergic contact dermatitis due to increased exposure to potential allergens. We know that leave-on products are higher risk than rinse-offs in general. Furthermore, more products used also increase the risk for irritant dermatitis that might break the skin barrier, increasing the odds that someone will develop allergic contact dermatitis. We see this often with facial skin care products where some people might layer on glycolic acid with retinoid acid with vitamin C oil with kojic acid, etc, all leading to irritation on the face.

How do emerging consumer product trends influence your patch-testing approach?

DR. YU: We try to customize our patch-tested allergens to the patient’s rash and symptoms. If it’s a patient with facial dermatitis, for example, we would patch test the patient to a core allergen series (eg, American Contact Dermatitis Society 90, North American Comprehensive 80, North American Contact Dermatitis Group 80) and add on other supplemental panels including cosmetic series if applicable. It is also preferable to patch test for products that are used and/or suspected of causing the rash. For example, if a blush is a suspected cause of dermatitis, we would certainly patch test to that as well. We generally try to encourage the patient to bring in all their products so we can evaluate them for appropriateness for patch testing.

Which consumer-driven ingredients do you now consider high-yield targets for testing?

DR. YU: Fragrances, preservatives, and botanical extracts are all likely causes of allergic contact dermatitis. We are uncovering new allergens all the time, so testing directly to patient products is also important. Just because something has not been reported to be a contact allergen doesn’t mean it can’t become one.

Have you observed any demographic or cultural trends in patients with allergic contact dermatitis related to consumer products?

DR. YU: There are various papers that outline different allergens in adults vs children vs older adults. However, in general, the prevalence of contact dermatitis is very similar across all age groups and distributions. I do think there are definitely gender and cultural variations. Women are more likely to be allergic to nickel, for example, which is more often found in jewelry. However, there really aren’t studies that demonstrate one population is more likely to develop allergic contact dermatitis than others. It really comes down to exposure. For example, neomycin, which is contained in triple antibiotics in the United States and is sold over the counter, is a common allergen here. However, it’s not readily available in other countries, and therefore, neomycin is a rare allergen in those countries.

Looking forward, which emerging consumer trends do you anticipate will create the next wave of contact dermatitis cases?

DR. YU: We have seen an increase in allergic contact dermatitis in the wearables industry, especially in continuous glucose monitors. They are now being sold over the counter so people without diabetes and without a prescription will be able to purchase them from retailers like Amazon or CVS. The adhesives in these glucose monitors have been shown to cause allergic contact dermatitis in a sizeable number of kids and adults. I suspect this problem will continue to increase with increased exposure to the allergens in these adhesives.

How do social media trends and influencer driven product fads affect the patterns of contact dermatitis you are seeing?

DR. YU: Social media and influencers are huge marketing opportunities for cosmetic and personal care companies and drive consumer demand. One example from a few years ago is slime as a toy for kids. For a period of time, every kid was making slime at home, resulting in high numbers of hand allergic contact dermatitis. Making slime requires a combination of borax (irritant), glue (irritant and allergen), laundry detergent or dish soap (irritant and allergen), and fragrances (irritant and allergen). This fad has been slowing since I cowrote an article on it (doi:10.1111 /pde.13792). More recently, the rise of “Sephora kids” (preteens and adolescents influenced by social media trends promoting multistep skin care and anti-aging products) has raised concerns about contact dermatitis, as many of these products contain ingredients that can disrupt the skin barrier or trigger sensitization in younger patients.

How can products labeled free of fragrances or preservatives still trigger allergic contact dermatitis?

DR. YU: Fragrances are frequently in the top 10 ingredients that cause allergic contact dermatitis in adults and children. For people with sensitive skin, we almost unequivocally recommend fragrance-free products. Now, not all fragrance-free products are truly free of fragrance allergens. Some fragrance chemicals may be used for another purpose (benzyl alcohol as a preservative, for example), so the product can still be fragrance free even though benzyl alcohol has a fragrance. Most products cannot truly be preservative free if they are expected to have a shelf life. One-time-use products do exist and can be preservative free, but they are very rare and very expensive to manufacture and maintain.

Have you seen spikes in reactions from trendy products like CBD-infused creams, botanical serums, or exfoliating acids?

DR. YU: Not yet, but I would not be surprised that this is rising in prevalence. The issue might not be CBD itself; it’s really the other additives in these CBD products that will cause problems. Looking at some CBD products for sale from major retailers, many contain fragrances such as lemongrass oil and botanical extracts such as calendula that have been noted to cause allergic contact dermatitis.

Do certain patient behaviors (eg, layering multiple natural products, frequent product switching, prolonged leave-on use) increase the risk for ACD?

DR. YU: Absolutely possible. The more products you use, the more likely you will develop allergic contact dermatitis due to increased exposure to potential allergens. We know that leave-on products are higher risk than rinse-offs in general. Furthermore, more products used also increase the risk for irritant dermatitis that might break the skin barrier, increasing the odds that someone will develop allergic contact dermatitis. We see this often with facial skin care products where some people might layer on glycolic acid with retinoid acid with vitamin C oil with kojic acid, etc, all leading to irritation on the face.

How do emerging consumer product trends influence your patch-testing approach?

DR. YU: We try to customize our patch-tested allergens to the patient’s rash and symptoms. If it’s a patient with facial dermatitis, for example, we would patch test the patient to a core allergen series (eg, American Contact Dermatitis Society 90, North American Comprehensive 80, North American Contact Dermatitis Group 80) and add on other supplemental panels including cosmetic series if applicable. It is also preferable to patch test for products that are used and/or suspected of causing the rash. For example, if a blush is a suspected cause of dermatitis, we would certainly patch test to that as well. We generally try to encourage the patient to bring in all their products so we can evaluate them for appropriateness for patch testing.

Which consumer-driven ingredients do you now consider high-yield targets for testing?

DR. YU: Fragrances, preservatives, and botanical extracts are all likely causes of allergic contact dermatitis. We are uncovering new allergens all the time, so testing directly to patient products is also important. Just because something has not been reported to be a contact allergen doesn’t mean it can’t become one.

Have you observed any demographic or cultural trends in patients with allergic contact dermatitis related to consumer products?

DR. YU: There are various papers that outline different allergens in adults vs children vs older adults. However, in general, the prevalence of contact dermatitis is very similar across all age groups and distributions. I do think there are definitely gender and cultural variations. Women are more likely to be allergic to nickel, for example, which is more often found in jewelry. However, there really aren’t studies that demonstrate one population is more likely to develop allergic contact dermatitis than others. It really comes down to exposure. For example, neomycin, which is contained in triple antibiotics in the United States and is sold over the counter, is a common allergen here. However, it’s not readily available in other countries, and therefore, neomycin is a rare allergen in those countries.

Looking forward, which emerging consumer trends do you anticipate will create the next wave of contact dermatitis cases?

DR. YU: We have seen an increase in allergic contact dermatitis in the wearables industry, especially in continuous glucose monitors. They are now being sold over the counter so people without diabetes and without a prescription will be able to purchase them from retailers like Amazon or CVS. The adhesives in these glucose monitors have been shown to cause allergic contact dermatitis in a sizeable number of kids and adults. I suspect this problem will continue to increase with increased exposure to the allergens in these adhesives.

How do social media trends and influencer driven product fads affect the patterns of contact dermatitis you are seeing?

DR. YU: Social media and influencers are huge marketing opportunities for cosmetic and personal care companies and drive consumer demand. One example from a few years ago is slime as a toy for kids. For a period of time, every kid was making slime at home, resulting in high numbers of hand allergic contact dermatitis. Making slime requires a combination of borax (irritant), glue (irritant and allergen), laundry detergent or dish soap (irritant and allergen), and fragrances (irritant and allergen). This fad has been slowing since I cowrote an article on it (doi:10.1111 /pde.13792). More recently, the rise of “Sephora kids” (preteens and adolescents influenced by social media trends promoting multistep skin care and anti-aging products) has raised concerns about contact dermatitis, as many of these products contain ingredients that can disrupt the skin barrier or trigger sensitization in younger patients.

How can products labeled free of fragrances or preservatives still trigger allergic contact dermatitis?

DR. YU: Fragrances are frequently in the top 10 ingredients that cause allergic contact dermatitis in adults and children. For people with sensitive skin, we almost unequivocally recommend fragrance-free products. Now, not all fragrance-free products are truly free of fragrance allergens. Some fragrance chemicals may be used for another purpose (benzyl alcohol as a preservative, for example), so the product can still be fragrance free even though benzyl alcohol has a fragrance. Most products cannot truly be preservative free if they are expected to have a shelf life. One-time-use products do exist and can be preservative free, but they are very rare and very expensive to manufacture and maintain.

Have you seen spikes in reactions from trendy products like CBD-infused creams, botanical serums, or exfoliating acids?

DR. YU: Not yet, but I would not be surprised that this is rising in prevalence. The issue might not be CBD itself; it’s really the other additives in these CBD products that will cause problems. Looking at some CBD products for sale from major retailers, many contain fragrances such as lemongrass oil and botanical extracts such as calendula that have been noted to cause allergic contact dermatitis.

Do certain patient behaviors (eg, layering multiple natural products, frequent product switching, prolonged leave-on use) increase the risk for ACD?

DR. YU: Absolutely possible. The more products you use, the more likely you will develop allergic contact dermatitis due to increased exposure to potential allergens. We know that leave-on products are higher risk than rinse-offs in general. Furthermore, more products used also increase the risk for irritant dermatitis that might break the skin barrier, increasing the odds that someone will develop allergic contact dermatitis. We see this often with facial skin care products where some people might layer on glycolic acid with retinoid acid with vitamin C oil with kojic acid, etc, all leading to irritation on the face.

How do emerging consumer product trends influence your patch-testing approach?

DR. YU: We try to customize our patch-tested allergens to the patient’s rash and symptoms. If it’s a patient with facial dermatitis, for example, we would patch test the patient to a core allergen series (eg, American Contact Dermatitis Society 90, North American Comprehensive 80, North American Contact Dermatitis Group 80) and add on other supplemental panels including cosmetic series if applicable. It is also preferable to patch test for products that are used and/or suspected of causing the rash. For example, if a blush is a suspected cause of dermatitis, we would certainly patch test to that as well. We generally try to encourage the patient to bring in all their products so we can evaluate them for appropriateness for patch testing.

Which consumer-driven ingredients do you now consider high-yield targets for testing?

DR. YU: Fragrances, preservatives, and botanical extracts are all likely causes of allergic contact dermatitis. We are uncovering new allergens all the time, so testing directly to patient products is also important. Just because something has not been reported to be a contact allergen doesn’t mean it can’t become one.

Have you observed any demographic or cultural trends in patients with allergic contact dermatitis related to consumer products?

DR. YU: There are various papers that outline different allergens in adults vs children vs older adults. However, in general, the prevalence of contact dermatitis is very similar across all age groups and distributions. I do think there are definitely gender and cultural variations. Women are more likely to be allergic to nickel, for example, which is more often found in jewelry. However, there really aren’t studies that demonstrate one population is more likely to develop allergic contact dermatitis than others. It really comes down to exposure. For example, neomycin, which is contained in triple antibiotics in the United States and is sold over the counter, is a common allergen here. However, it’s not readily available in other countries, and therefore, neomycin is a rare allergen in those countries.

Looking forward, which emerging consumer trends do you anticipate will create the next wave of contact dermatitis cases?

DR. YU: We have seen an increase in allergic contact dermatitis in the wearables industry, especially in continuous glucose monitors. They are now being sold over the counter so people without diabetes and without a prescription will be able to purchase them from retailers like Amazon or CVS. The adhesives in these glucose monitors have been shown to cause allergic contact dermatitis in a sizeable number of kids and adults. I suspect this problem will continue to increase with increased exposure to the allergens in these adhesives.

Practice Gap

Chronic localized granulomatous inflammation can be difficult to manage, particularly when manifesting on the face. Intralesional corticosteroids may lead to atrophy and dyspigmentation and therefore must be used cautiously in cosmetically sensitive areas.¹ Surgical removal can lead to recurrence, and systemic agents may carry risks disproportionate to disease burden. Although tumor necrosis factor (TNF) α inhibitors are effective systemically, their localized use in cutaneous granulomatous dermatoses remains underreported.^1-3 We describe a technique using intralesional injection of adalimumab to treat chronic refractory cutaneous granulomatous inflammation.

The Technique

A 69-year-old woman presented with a crusted erythematous papule with surrounding inflammation on the left nasal ala of 5 years’ duration (Figure 1). Histopathology demonstrated a localized cutaneous granulomatous process. There was no clinical, radiographic, or laboratory evidence of systemic sarcoidosis. Infectious causes were excluded through negative tissue cultures and special stains, including auramine-rhodamine. Over a 3-month period following initial presentation, the lesion proved refractory to intralesional 5-fluorouracil, intralesional triamcinolone acetonide, pentoxifylline, N-acetylcysteine, and shave excision (Figure 2).

At 3-month follow-up, given the lesion’s persistence despite local and systemic anti-inflammatory approaches and our intent to avoid repeated corticosteroid exposure or more aggressive surgery in a cosmetically sensitive facial site, we attempted treatment with intralesional adalimumab. A 40-mg/0.4-mL dose of adalimumab was withdrawn directly from a prefilled autoinjector and placed into a sterile container, then transferred to a syringe fitted with a 30-gauge needle. Finally, the full 0.4 mL was injected intralesionally (Figure 3) until complete blanching of the lesion was achieved.

At 1-month follow-up, the lesion demonstrated decreased erythema and crusting (Figure 4A). The patient subsequently underwent 12 adalimumab injections over an 18-month period with marked reduction in size and erythema of the lesion without complications (Figure 4B). In addition, doxycycline 100 mg/d was started 11 months after the first adalimumab injection to address mild residual inflammation (Figure 4C); after 4 months, the dose was reduced to 50 mg/d due to gastrointestinal adverse effects. Doxycycline was maintained for 3 additional months with persistent improvement of the lesion.

Practice Implication

Intralesional administration of adalimumab may represent a useful therapeutic option for localized refractory granulomatous inflammation, particularly in sensitive areas such as the face, where conventional therapies may be limited by adverse effects or suboptimal response. Localized delivery of TNF-α inhibition directly to the site of inflammation may allow for clinical improvement while minimizing systemic exposure associated with biologic therapy.² This approach may be particularly advantageous in cases in which repeated intralesional corticosteroid injections raise concern for atrophy or dyspigmentation, or when surgical intervention carries a risk for recurrence or cosmetic morbidity.^1,2 Given the established role of TNF-α in granuloma formation and maintenance, intralesional adalimumab provides a biologically plausible targeted therapeutic strategy. Further studies are needed to evaluate the potential applications in other cutaneous granulomatous dermatoses.^2,3

Practice Gap

Chronic localized granulomatous inflammation can be difficult to manage, particularly when manifesting on the face. Intralesional corticosteroids may lead to atrophy and dyspigmentation and therefore must be used cautiously in cosmetically sensitive areas.¹ Surgical removal can lead to recurrence, and systemic agents may carry risks disproportionate to disease burden. Although tumor necrosis factor (TNF) α inhibitors are effective systemically, their localized use in cutaneous granulomatous dermatoses remains underreported.^1-3 We describe a technique using intralesional injection of adalimumab to treat chronic refractory cutaneous granulomatous inflammation.

The Technique

A 69-year-old woman presented with a crusted erythematous papule with surrounding inflammation on the left nasal ala of 5 years’ duration (Figure 1). Histopathology demonstrated a localized cutaneous granulomatous process. There was no clinical, radiographic, or laboratory evidence of systemic sarcoidosis. Infectious causes were excluded through negative tissue cultures and special stains, including auramine-rhodamine. Over a 3-month period following initial presentation, the lesion proved refractory to intralesional 5-fluorouracil, intralesional triamcinolone acetonide, pentoxifylline, N-acetylcysteine, and shave excision (Figure 2).

At 3-month follow-up, given the lesion’s persistence despite local and systemic anti-inflammatory approaches and our intent to avoid repeated corticosteroid exposure or more aggressive surgery in a cosmetically sensitive facial site, we attempted treatment with intralesional adalimumab. A 40-mg/0.4-mL dose of adalimumab was withdrawn directly from a prefilled autoinjector and placed into a sterile container, then transferred to a syringe fitted with a 30-gauge needle. Finally, the full 0.4 mL was injected intralesionally (Figure 3) until complete blanching of the lesion was achieved.

At 1-month follow-up, the lesion demonstrated decreased erythema and crusting (Figure 4A). The patient subsequently underwent 12 adalimumab injections over an 18-month period with marked reduction in size and erythema of the lesion without complications (Figure 4B). In addition, doxycycline 100 mg/d was started 11 months after the first adalimumab injection to address mild residual inflammation (Figure 4C); after 4 months, the dose was reduced to 50 mg/d due to gastrointestinal adverse effects. Doxycycline was maintained for 3 additional months with persistent improvement of the lesion.

Practice Implication

Intralesional administration of adalimumab may represent a useful therapeutic option for localized refractory granulomatous inflammation, particularly in sensitive areas such as the face, where conventional therapies may be limited by adverse effects or suboptimal response. Localized delivery of TNF-α inhibition directly to the site of inflammation may allow for clinical improvement while minimizing systemic exposure associated with biologic therapy.² This approach may be particularly advantageous in cases in which repeated intralesional corticosteroid injections raise concern for atrophy or dyspigmentation, or when surgical intervention carries a risk for recurrence or cosmetic morbidity.^1,2 Given the established role of TNF-α in granuloma formation and maintenance, intralesional adalimumab provides a biologically plausible targeted therapeutic strategy. Further studies are needed to evaluate the potential applications in other cutaneous granulomatous dermatoses.^2,3

Practice Gap

Chronic localized granulomatous inflammation can be difficult to manage, particularly when manifesting on the face. Intralesional corticosteroids may lead to atrophy and dyspigmentation and therefore must be used cautiously in cosmetically sensitive areas.¹ Surgical removal can lead to recurrence, and systemic agents may carry risks disproportionate to disease burden. Although tumor necrosis factor (TNF) α inhibitors are effective systemically, their localized use in cutaneous granulomatous dermatoses remains underreported.^1-3 We describe a technique using intralesional injection of adalimumab to treat chronic refractory cutaneous granulomatous inflammation.

The Technique

A 69-year-old woman presented with a crusted erythematous papule with surrounding inflammation on the left nasal ala of 5 years’ duration (Figure 1). Histopathology demonstrated a localized cutaneous granulomatous process. There was no clinical, radiographic, or laboratory evidence of systemic sarcoidosis. Infectious causes were excluded through negative tissue cultures and special stains, including auramine-rhodamine. Over a 3-month period following initial presentation, the lesion proved refractory to intralesional 5-fluorouracil, intralesional triamcinolone acetonide, pentoxifylline, N-acetylcysteine, and shave excision (Figure 2).

At 3-month follow-up, given the lesion’s persistence despite local and systemic anti-inflammatory approaches and our intent to avoid repeated corticosteroid exposure or more aggressive surgery in a cosmetically sensitive facial site, we attempted treatment with intralesional adalimumab. A 40-mg/0.4-mL dose of adalimumab was withdrawn directly from a prefilled autoinjector and placed into a sterile container, then transferred to a syringe fitted with a 30-gauge needle. Finally, the full 0.4 mL was injected intralesionally (Figure 3) until complete blanching of the lesion was achieved.

At 1-month follow-up, the lesion demonstrated decreased erythema and crusting (Figure 4A). The patient subsequently underwent 12 adalimumab injections over an 18-month period with marked reduction in size and erythema of the lesion without complications (Figure 4B). In addition, doxycycline 100 mg/d was started 11 months after the first adalimumab injection to address mild residual inflammation (Figure 4C); after 4 months, the dose was reduced to 50 mg/d due to gastrointestinal adverse effects. Doxycycline was maintained for 3 additional months with persistent improvement of the lesion.

Practice Implication

Intralesional administration of adalimumab may represent a useful therapeutic option for localized refractory granulomatous inflammation, particularly in sensitive areas such as the face, where conventional therapies may be limited by adverse effects or suboptimal response. Localized delivery of TNF-α inhibition directly to the site of inflammation may allow for clinical improvement while minimizing systemic exposure associated with biologic therapy.² This approach may be particularly advantageous in cases in which repeated intralesional corticosteroid injections raise concern for atrophy or dyspigmentation, or when surgical intervention carries a risk for recurrence or cosmetic morbidity.^1,2 Given the established role of TNF-α in granuloma formation and maintenance, intralesional adalimumab provides a biologically plausible targeted therapeutic strategy. Further studies are needed to evaluate the potential applications in other cutaneous granulomatous dermatoses.^2,3

THE DIAGNOSIS: Sarcoidlike Reaction

Sarcoidlike reaction (SLR) is a rare cutaneous immune-related adverse event characterized by a multisystem granulomatous reaction indistinguishable from sarcoidosis but temporally associated with a trigger.¹ Drug-induced SLR typically involves the mediastinal or hilar lymph nodes, with frequent involvement of the lungs and skin; cutaneous manifestations typically encompass erythematous papulonodular eruptions on the trunk and extremities.^1-3 Sarcoidosis predominantly affects middle-aged women of African American or Scandinavian descent; genetic predisposition likely is a contributing factor.⁴ Unlike sarcoidosis, SLR is linked to various triggers such as medication or malignancy.

Immune checkpoint inhibitors (ICIs), particularly anti–PD-1 agents, have been linked to SLR through overexpression of proinflammatory cytokines, resulting in excessive T-helper 1 cell and macrophage activation and granulomatous eruption; notably, cutaneous immune-related adverse events often are correlated with greater treatment efficacy.^5,6 Overall, anticancer therapy–induced SLR is most commonly reported in patients receiving ICIs for melanoma but it also has been described with ICI therapy for other cancers and with chemotherapy for melanoma. ^1,3 Although most cases demonstrate both cutaneous and extracutaneous involvement, approximately 13 reported cases have been exclusively cutaneous.¹ Recognition of SLR is important because misdiagnosis as true sarcoidosis may prompt unnecessary testing or therapy; furthermore, distinction from tumor progression is critical.³ The lesions can mimic other granulomatous or inflammatory dermatoses, posing a diagnostic challenge.

On histopathology, SLR typically demonstrates well-formed, noncaseating dermal granulomas composed of epithelioid histiocytes and Langhans or foreign-body giant cells, a sparse lymphocytic rim, and few plasma cells.^2,4 Immunohistochemistry shows CD68-positive histiocytes predominating within the granulomas. Asteroid and Schaumann bodies occasionally are present.⁷ Special stains will be negative for microorganisms. Sarcoidosis manifests essentially identically from both a clinical and histopathologic perspective (Figure 1). Temporal association with an offending agent and symptomatic resolution following drug cessation remain the most reliable features for distinguishing SLR from sarcoidosis.⁷

Tuberculoid leprosy is a chronic infectious disease caused by Mycobacterium leprae (found most commonly in tropical regions) and manifesting as localized hypopigmented macules or papules with raised erythematous margins.⁸ Histopathologically, lesions show well-formed granulomas composed of epithelioid histiocytes and Langhans giant cells without necrosis, surrounded by a prominent lymphocytic rim (Figure 2).⁹ Rarely, focal caseous necrosis occurs, particularly in involved nerves.¹⁰ Hallmark features include enlarged cutaneous nerves surrounded by dermal granulomas and absence of bacilli on special stains; eccrine glands are infrequently involved.⁹ Standard treatment is 6 months of combination therapy with dapsone and rifampin.

Generalized granuloma annulare is an inflammatory dermatosis manifesting as diffuse erythematous annular papules, classically on the trunk and extremities.¹¹ It predominantly affects individuals in their fifth and sixth decades of life and may be drug induced.² Histopathology may reveal palisaded granulomas with central necrobiotic collagen, intercalating histiocytes, and interstitial mucin (Figure 3).² Pathology also may show interstitial histiocytes and lymphocytes intercalating between collagen bundles with increased mucin but absent palisading or necrobiosis or a mixed pattern.^2,12 Alcian blue or colloidal iron stains highlight mucin to help distinguish from other granulomatous processes. Multinucleated giant cells are rare. The nonnecrobiotic histologic pattern can mimic sarcoidosis, necessitating clinical correlation for correct diagnosis.¹³ Certain cases show genetic predisposition, such as HLA-B35, with a relapsing course often requiring combined systemic immunosuppression and phototherapy.¹⁴

Granulomatosis with polyangiitis is a systemic vasculitis that classically manifests as palpable purpura on the lower extremities, often with ulceration. Localized erythematous papules on the extensor surfaces may occur less commonly.¹⁵ Pathogenesis involves antineutrophil cytoplasmic antibodies inducing neutrophil degranulation, release of reactive oxygen species and proinflammatory cytokines, and subsequent endothelial damage.¹⁵ Histopathology shows necrotizing granulomatous inflammation and necrotizing vasculitis of small and medium vessels with nuclear debris.¹⁵ Poorly formed granulomas containing abundant neutrophils and mixed perivascular inflammatory infiltrates may be seen with or without vasculitis (Figure 4). Systemic features commonly include chronic rhinosinusitis, pauci-immune glomerulonephritis, and pulmonary nodules.¹⁵ Pharmacotherapy includes glucocorticoids combined with a glucocorticoid-sparing agent.

THE DIAGNOSIS: Sarcoidlike Reaction

Sarcoidlike reaction (SLR) is a rare cutaneous immune-related adverse event characterized by a multisystem granulomatous reaction indistinguishable from sarcoidosis but temporally associated with a trigger.¹ Drug-induced SLR typically involves the mediastinal or hilar lymph nodes, with frequent involvement of the lungs and skin; cutaneous manifestations typically encompass erythematous papulonodular eruptions on the trunk and extremities.^1-3 Sarcoidosis predominantly affects middle-aged women of African American or Scandinavian descent; genetic predisposition likely is a contributing factor.⁴ Unlike sarcoidosis, SLR is linked to various triggers such as medication or malignancy.

Immune checkpoint inhibitors (ICIs), particularly anti–PD-1 agents, have been linked to SLR through overexpression of proinflammatory cytokines, resulting in excessive T-helper 1 cell and macrophage activation and granulomatous eruption; notably, cutaneous immune-related adverse events often are correlated with greater treatment efficacy.^5,6 Overall, anticancer therapy–induced SLR is most commonly reported in patients receiving ICIs for melanoma but it also has been described with ICI therapy for other cancers and with chemotherapy for melanoma. ^1,3 Although most cases demonstrate both cutaneous and extracutaneous involvement, approximately 13 reported cases have been exclusively cutaneous.¹ Recognition of SLR is important because misdiagnosis as true sarcoidosis may prompt unnecessary testing or therapy; furthermore, distinction from tumor progression is critical.³ The lesions can mimic other granulomatous or inflammatory dermatoses, posing a diagnostic challenge.

On histopathology, SLR typically demonstrates well-formed, noncaseating dermal granulomas composed of epithelioid histiocytes and Langhans or foreign-body giant cells, a sparse lymphocytic rim, and few plasma cells.^2,4 Immunohistochemistry shows CD68-positive histiocytes predominating within the granulomas. Asteroid and Schaumann bodies occasionally are present.⁷ Special stains will be negative for microorganisms. Sarcoidosis manifests essentially identically from both a clinical and histopathologic perspective (Figure 1). Temporal association with an offending agent and symptomatic resolution following drug cessation remain the most reliable features for distinguishing SLR from sarcoidosis.⁷

Tuberculoid leprosy is a chronic infectious disease caused by Mycobacterium leprae (found most commonly in tropical regions) and manifesting as localized hypopigmented macules or papules with raised erythematous margins.⁸ Histopathologically, lesions show well-formed granulomas composed of epithelioid histiocytes and Langhans giant cells without necrosis, surrounded by a prominent lymphocytic rim (Figure 2).⁹ Rarely, focal caseous necrosis occurs, particularly in involved nerves.¹⁰ Hallmark features include enlarged cutaneous nerves surrounded by dermal granulomas and absence of bacilli on special stains; eccrine glands are infrequently involved.⁹ Standard treatment is 6 months of combination therapy with dapsone and rifampin.

Generalized granuloma annulare is an inflammatory dermatosis manifesting as diffuse erythematous annular papules, classically on the trunk and extremities.¹¹ It predominantly affects individuals in their fifth and sixth decades of life and may be drug induced.² Histopathology may reveal palisaded granulomas with central necrobiotic collagen, intercalating histiocytes, and interstitial mucin (Figure 3).² Pathology also may show interstitial histiocytes and lymphocytes intercalating between collagen bundles with increased mucin but absent palisading or necrobiosis or a mixed pattern.^2,12 Alcian blue or colloidal iron stains highlight mucin to help distinguish from other granulomatous processes. Multinucleated giant cells are rare. The nonnecrobiotic histologic pattern can mimic sarcoidosis, necessitating clinical correlation for correct diagnosis.¹³ Certain cases show genetic predisposition, such as HLA-B35, with a relapsing course often requiring combined systemic immunosuppression and phototherapy.¹⁴

Granulomatosis with polyangiitis is a systemic vasculitis that classically manifests as palpable purpura on the lower extremities, often with ulceration. Localized erythematous papules on the extensor surfaces may occur less commonly.¹⁵ Pathogenesis involves antineutrophil cytoplasmic antibodies inducing neutrophil degranulation, release of reactive oxygen species and proinflammatory cytokines, and subsequent endothelial damage.¹⁵ Histopathology shows necrotizing granulomatous inflammation and necrotizing vasculitis of small and medium vessels with nuclear debris.¹⁵ Poorly formed granulomas containing abundant neutrophils and mixed perivascular inflammatory infiltrates may be seen with or without vasculitis (Figure 4). Systemic features commonly include chronic rhinosinusitis, pauci-immune glomerulonephritis, and pulmonary nodules.¹⁵ Pharmacotherapy includes glucocorticoids combined with a glucocorticoid-sparing agent.

THE DIAGNOSIS: Sarcoidlike Reaction

Sarcoidlike reaction (SLR) is a rare cutaneous immune-related adverse event characterized by a multisystem granulomatous reaction indistinguishable from sarcoidosis but temporally associated with a trigger.¹ Drug-induced SLR typically involves the mediastinal or hilar lymph nodes, with frequent involvement of the lungs and skin; cutaneous manifestations typically encompass erythematous papulonodular eruptions on the trunk and extremities.^1-3 Sarcoidosis predominantly affects middle-aged women of African American or Scandinavian descent; genetic predisposition likely is a contributing factor.⁴ Unlike sarcoidosis, SLR is linked to various triggers such as medication or malignancy.

Immune checkpoint inhibitors (ICIs), particularly anti–PD-1 agents, have been linked to SLR through overexpression of proinflammatory cytokines, resulting in excessive T-helper 1 cell and macrophage activation and granulomatous eruption; notably, cutaneous immune-related adverse events often are correlated with greater treatment efficacy.^5,6 Overall, anticancer therapy–induced SLR is most commonly reported in patients receiving ICIs for melanoma but it also has been described with ICI therapy for other cancers and with chemotherapy for melanoma. ^1,3 Although most cases demonstrate both cutaneous and extracutaneous involvement, approximately 13 reported cases have been exclusively cutaneous.¹ Recognition of SLR is important because misdiagnosis as true sarcoidosis may prompt unnecessary testing or therapy; furthermore, distinction from tumor progression is critical.³ The lesions can mimic other granulomatous or inflammatory dermatoses, posing a diagnostic challenge.

On histopathology, SLR typically demonstrates well-formed, noncaseating dermal granulomas composed of epithelioid histiocytes and Langhans or foreign-body giant cells, a sparse lymphocytic rim, and few plasma cells.^2,4 Immunohistochemistry shows CD68-positive histiocytes predominating within the granulomas. Asteroid and Schaumann bodies occasionally are present.⁷ Special stains will be negative for microorganisms. Sarcoidosis manifests essentially identically from both a clinical and histopathologic perspective (Figure 1). Temporal association with an offending agent and symptomatic resolution following drug cessation remain the most reliable features for distinguishing SLR from sarcoidosis.⁷

Tuberculoid leprosy is a chronic infectious disease caused by Mycobacterium leprae (found most commonly in tropical regions) and manifesting as localized hypopigmented macules or papules with raised erythematous margins.⁸ Histopathologically, lesions show well-formed granulomas composed of epithelioid histiocytes and Langhans giant cells without necrosis, surrounded by a prominent lymphocytic rim (Figure 2).⁹ Rarely, focal caseous necrosis occurs, particularly in involved nerves.¹⁰ Hallmark features include enlarged cutaneous nerves surrounded by dermal granulomas and absence of bacilli on special stains; eccrine glands are infrequently involved.⁹ Standard treatment is 6 months of combination therapy with dapsone and rifampin.

Generalized granuloma annulare is an inflammatory dermatosis manifesting as diffuse erythematous annular papules, classically on the trunk and extremities.¹¹ It predominantly affects individuals in their fifth and sixth decades of life and may be drug induced.² Histopathology may reveal palisaded granulomas with central necrobiotic collagen, intercalating histiocytes, and interstitial mucin (Figure 3).² Pathology also may show interstitial histiocytes and lymphocytes intercalating between collagen bundles with increased mucin but absent palisading or necrobiosis or a mixed pattern.^2,12 Alcian blue or colloidal iron stains highlight mucin to help distinguish from other granulomatous processes. Multinucleated giant cells are rare. The nonnecrobiotic histologic pattern can mimic sarcoidosis, necessitating clinical correlation for correct diagnosis.¹³ Certain cases show genetic predisposition, such as HLA-B35, with a relapsing course often requiring combined systemic immunosuppression and phototherapy.¹⁴

Granulomatosis with polyangiitis is a systemic vasculitis that classically manifests as palpable purpura on the lower extremities, often with ulceration. Localized erythematous papules on the extensor surfaces may occur less commonly.¹⁵ Pathogenesis involves antineutrophil cytoplasmic antibodies inducing neutrophil degranulation, release of reactive oxygen species and proinflammatory cytokines, and subsequent endothelial damage.¹⁵ Histopathology shows necrotizing granulomatous inflammation and necrotizing vasculitis of small and medium vessels with nuclear debris.¹⁵ Poorly formed granulomas containing abundant neutrophils and mixed perivascular inflammatory infiltrates may be seen with or without vasculitis (Figure 4). Systemic features commonly include chronic rhinosinusitis, pauci-immune glomerulonephritis, and pulmonary nodules.¹⁵ Pharmacotherapy includes glucocorticoids combined with a glucocorticoid-sparing agent.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition characterized by painful nodules, abscesses, scarring, and sinus tracts that commonly manifest in the axillary, inguinal, perianal, and inframammary regions.¹ Hidradenitis suppurativa has been associated with several metabolic and cardiovascular comorbidities as well as polycystic ovary syndrome (PCOS)(recently renamed polyendocrine metabolic ovarian syndrome),^2,3 a condition characterized by hyperandrogenism, chronic anovulation, and polycystic ovaries.² Multiple comorbidities of PCOS overlap with those of HS, including type 2 diabetes, cardiovascular disease, and metabolic syndrome.^1,3-5 While HS may be associated with PCOS, there is limited literature analyzing the association between these conditions. This study aimed to analyze the association between HS and PCOS using data from the National Institute of Health’s All of Us Research Program database (https://allofus.nih.gov/). While other studies have looked at the association between HS and PCOS, ours is among the first to analyze the relationship between multiple race/ ethnicity groups, which is especially important given racial disparities in HS and comorbid diseases.

Methods

A cross-sectional, population-based study of females included in the All of Us Research Program database was conducted. Patients with HS were identified using the Systematized Nomenclature of Medicine–Clinical Terms (SNOMED CT) code 59393003, while PCOS was identified with the code 237055002. Type 2 diabetes was identified with the following SNOMED CT codes: 44054006, 313436004, 237599002, 199230006, 359642000, and 81531005. Obesity was identified with the following codes: 414916001, 238136002, 190966007, 296526005, 294493008, 238134004, 83911000119104, and 415530009. Male patients and those who did not answer questions regarding sociodemographic variables were excluded from the final analysis. P values were calculated using Pearson χ² tests. Multivariate logistic regression was used to calculate adjusted odds ratios and unadjusted odds ratios to analyze the association between HS and PCOS while controlling for age, race/ethnicity, smoking status, type 2 diabetes, and obesity. Statistical analyses were conducted using a 95% CI.

Results

The final analysis included 78,742 patients. The prevalence of PCOS was 5.64% in the HS group vs 0.93% in the non-HS group (eTable 1). Individuals with HS had higher rates of smoking cigarettes (57.71% vs 37.67%), obesity (51.08% vs 17.22%), and type 2 diabetes (20.73% vs 9.11%) than individuals without HS, respectively.

Multivariate logistic regression analyses revealed that individuals with HS were 2.06 times more likely to have PCOS after adjusting for sociodemographic variables and comorbidities (95% CI, 1.41-3.02; P<.001). Adjusted subgroup analyses by race/ethnicity did not yield statistically significant results; however, unadjusted analyses revealed that individuals with HS had significantly increased odds of PCOS across all race/ethnicity groups (eTable 2). Interaction terms analysis to determine if the relationship between HS and PCOS differs by race/ ethnicity did not yield statistically significant results. However, independent of HS status, non-Hispanic Black and Hispanic patients were less likely to have PCOS compared to White individuals (adjusted odds ratio, 0.37 and 0.56, respectively; P<.001). Disparities in access to care could have led to underdiagnosis of PCOS among non-Hispanic Black and Hispanic patients. Lastly, individuals with type 2 diabetes were 10.43 times more likely to have PCOS than those without, while patients with obesity were 11.14 times more likely to have PCOS than those without.

Comment

This study demonstrated that females with HS are 2.06 times more likely to have PCOS than those without HS, even after controlling for important sociodemographic variables and comorbidities. While adjusted subgroup analyses did not yield statistically significant results, unadjusted analyses demonstrated increased odds of PCOS in patients with HS across all race/ethnicity groups, suggesting that sociodemographic variables and comorbidities substantially influence the relationship between HS and PCOS; for instance, patients with type 2 diabetes and obesity are approximately 10- to 11-fold more likely to have PCOS than patients without these conditions. Non-Hispanic Black and Hispanic patients were less likely to have PCOS compared with White patients, indicating possible underdiagnosis of PCOS in these populations and highlighting the need for increased PCOS screening. Limitations of this study include the reliance on SNOMED CT codes, which may have led to underdiagnosis of HS or PCOS, as well as the inability to differentiate between mild and severe HS in the database.

Hyperandrogenism is believed to contribute to the pathogenesis of both HS and PCOS, supporting the potential use of antiandrogen therapies, such as spironolactone, in managing both conditions.^2,3 Furthermore, oral contraceptives may have a role in managing both conditions. In HS, oral contraceptives help to mitigate flares associated with hormonal changes during menstruation, while in PCOS, they are used to regulate the hormonal cycle and reduce hirsutism.^2-4 However, not all women experience menstrual flares of HS, suggesting that variations in HS phenotypes may influence individual responses to hormonal changes.¹ Additionally, the considerable overlap in metabolic and cardiovascular comorbidities between HS and PCOS indicates that shared pathomechanisms may contribute to the association between these conditions.^1,2 For example, proinflammatory adipokines released in both HS and PCOS may contribute to inflammation, cardiovascular disease, and insulin resistance.^3,5

Conclusion

Further research is needed to better understand the shared pathophysiology that links these 2 diseases and to identify targeted approaches for optimizing management and improving patient outcomes. The association between HS and PCOS highlights the importance of screening for metabolic and reproductive comorbidities in patients with HS. Early recognition and management of both HS and PCOS can improve long-term outcomes.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition characterized by painful nodules, abscesses, scarring, and sinus tracts that commonly manifest in the axillary, inguinal, perianal, and inframammary regions.¹ Hidradenitis suppurativa has been associated with several metabolic and cardiovascular comorbidities as well as polycystic ovary syndrome (PCOS)(recently renamed polyendocrine metabolic ovarian syndrome),^2,3 a condition characterized by hyperandrogenism, chronic anovulation, and polycystic ovaries.² Multiple comorbidities of PCOS overlap with those of HS, including type 2 diabetes, cardiovascular disease, and metabolic syndrome.^1,3-5 While HS may be associated with PCOS, there is limited literature analyzing the association between these conditions. This study aimed to analyze the association between HS and PCOS using data from the National Institute of Health’s All of Us Research Program database (https://allofus.nih.gov/). While other studies have looked at the association between HS and PCOS, ours is among the first to analyze the relationship between multiple race/ ethnicity groups, which is especially important given racial disparities in HS and comorbid diseases.

Methods

A cross-sectional, population-based study of females included in the All of Us Research Program database was conducted. Patients with HS were identified using the Systematized Nomenclature of Medicine–Clinical Terms (SNOMED CT) code 59393003, while PCOS was identified with the code 237055002. Type 2 diabetes was identified with the following SNOMED CT codes: 44054006, 313436004, 237599002, 199230006, 359642000, and 81531005. Obesity was identified with the following codes: 414916001, 238136002, 190966007, 296526005, 294493008, 238134004, 83911000119104, and 415530009. Male patients and those who did not answer questions regarding sociodemographic variables were excluded from the final analysis. P values were calculated using Pearson χ² tests. Multivariate logistic regression was used to calculate adjusted odds ratios and unadjusted odds ratios to analyze the association between HS and PCOS while controlling for age, race/ethnicity, smoking status, type 2 diabetes, and obesity. Statistical analyses were conducted using a 95% CI.

Results

The final analysis included 78,742 patients. The prevalence of PCOS was 5.64% in the HS group vs 0.93% in the non-HS group (eTable 1). Individuals with HS had higher rates of smoking cigarettes (57.71% vs 37.67%), obesity (51.08% vs 17.22%), and type 2 diabetes (20.73% vs 9.11%) than individuals without HS, respectively.

Multivariate logistic regression analyses revealed that individuals with HS were 2.06 times more likely to have PCOS after adjusting for sociodemographic variables and comorbidities (95% CI, 1.41-3.02; P<.001). Adjusted subgroup analyses by race/ethnicity did not yield statistically significant results; however, unadjusted analyses revealed that individuals with HS had significantly increased odds of PCOS across all race/ethnicity groups (eTable 2). Interaction terms analysis to determine if the relationship between HS and PCOS differs by race/ ethnicity did not yield statistically significant results. However, independent of HS status, non-Hispanic Black and Hispanic patients were less likely to have PCOS compared to White individuals (adjusted odds ratio, 0.37 and 0.56, respectively; P<.001). Disparities in access to care could have led to underdiagnosis of PCOS among non-Hispanic Black and Hispanic patients. Lastly, individuals with type 2 diabetes were 10.43 times more likely to have PCOS than those without, while patients with obesity were 11.14 times more likely to have PCOS than those without.

Comment

This study demonstrated that females with HS are 2.06 times more likely to have PCOS than those without HS, even after controlling for important sociodemographic variables and comorbidities. While adjusted subgroup analyses did not yield statistically significant results, unadjusted analyses demonstrated increased odds of PCOS in patients with HS across all race/ethnicity groups, suggesting that sociodemographic variables and comorbidities substantially influence the relationship between HS and PCOS; for instance, patients with type 2 diabetes and obesity are approximately 10- to 11-fold more likely to have PCOS than patients without these conditions. Non-Hispanic Black and Hispanic patients were less likely to have PCOS compared with White patients, indicating possible underdiagnosis of PCOS in these populations and highlighting the need for increased PCOS screening. Limitations of this study include the reliance on SNOMED CT codes, which may have led to underdiagnosis of HS or PCOS, as well as the inability to differentiate between mild and severe HS in the database.

Hyperandrogenism is believed to contribute to the pathogenesis of both HS and PCOS, supporting the potential use of antiandrogen therapies, such as spironolactone, in managing both conditions.^2,3 Furthermore, oral contraceptives may have a role in managing both conditions. In HS, oral contraceptives help to mitigate flares associated with hormonal changes during menstruation, while in PCOS, they are used to regulate the hormonal cycle and reduce hirsutism.^2-4 However, not all women experience menstrual flares of HS, suggesting that variations in HS phenotypes may influence individual responses to hormonal changes.¹ Additionally, the considerable overlap in metabolic and cardiovascular comorbidities between HS and PCOS indicates that shared pathomechanisms may contribute to the association between these conditions.^1,2 For example, proinflammatory adipokines released in both HS and PCOS may contribute to inflammation, cardiovascular disease, and insulin resistance.^3,5

Conclusion

Further research is needed to better understand the shared pathophysiology that links these 2 diseases and to identify targeted approaches for optimizing management and improving patient outcomes. The association between HS and PCOS highlights the importance of screening for metabolic and reproductive comorbidities in patients with HS. Early recognition and management of both HS and PCOS can improve long-term outcomes.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition characterized by painful nodules, abscesses, scarring, and sinus tracts that commonly manifest in the axillary, inguinal, perianal, and inframammary regions.¹ Hidradenitis suppurativa has been associated with several metabolic and cardiovascular comorbidities as well as polycystic ovary syndrome (PCOS)(recently renamed polyendocrine metabolic ovarian syndrome),^2,3 a condition characterized by hyperandrogenism, chronic anovulation, and polycystic ovaries.² Multiple comorbidities of PCOS overlap with those of HS, including type 2 diabetes, cardiovascular disease, and metabolic syndrome.^1,3-5 While HS may be associated with PCOS, there is limited literature analyzing the association between these conditions. This study aimed to analyze the association between HS and PCOS using data from the National Institute of Health’s All of Us Research Program database (https://allofus.nih.gov/). While other studies have looked at the association between HS and PCOS, ours is among the first to analyze the relationship between multiple race/ ethnicity groups, which is especially important given racial disparities in HS and comorbid diseases.

Methods

A cross-sectional, population-based study of females included in the All of Us Research Program database was conducted. Patients with HS were identified using the Systematized Nomenclature of Medicine–Clinical Terms (SNOMED CT) code 59393003, while PCOS was identified with the code 237055002. Type 2 diabetes was identified with the following SNOMED CT codes: 44054006, 313436004, 237599002, 199230006, 359642000, and 81531005. Obesity was identified with the following codes: 414916001, 238136002, 190966007, 296526005, 294493008, 238134004, 83911000119104, and 415530009. Male patients and those who did not answer questions regarding sociodemographic variables were excluded from the final analysis. P values were calculated using Pearson χ² tests. Multivariate logistic regression was used to calculate adjusted odds ratios and unadjusted odds ratios to analyze the association between HS and PCOS while controlling for age, race/ethnicity, smoking status, type 2 diabetes, and obesity. Statistical analyses were conducted using a 95% CI.

Results

The final analysis included 78,742 patients. The prevalence of PCOS was 5.64% in the HS group vs 0.93% in the non-HS group (eTable 1). Individuals with HS had higher rates of smoking cigarettes (57.71% vs 37.67%), obesity (51.08% vs 17.22%), and type 2 diabetes (20.73% vs 9.11%) than individuals without HS, respectively.

Multivariate logistic regression analyses revealed that individuals with HS were 2.06 times more likely to have PCOS after adjusting for sociodemographic variables and comorbidities (95% CI, 1.41-3.02; P<.001). Adjusted subgroup analyses by race/ethnicity did not yield statistically significant results; however, unadjusted analyses revealed that individuals with HS had significantly increased odds of PCOS across all race/ethnicity groups (eTable 2). Interaction terms analysis to determine if the relationship between HS and PCOS differs by race/ ethnicity did not yield statistically significant results. However, independent of HS status, non-Hispanic Black and Hispanic patients were less likely to have PCOS compared to White individuals (adjusted odds ratio, 0.37 and 0.56, respectively; P<.001). Disparities in access to care could have led to underdiagnosis of PCOS among non-Hispanic Black and Hispanic patients. Lastly, individuals with type 2 diabetes were 10.43 times more likely to have PCOS than those without, while patients with obesity were 11.14 times more likely to have PCOS than those without.

Comment

This study demonstrated that females with HS are 2.06 times more likely to have PCOS than those without HS, even after controlling for important sociodemographic variables and comorbidities. While adjusted subgroup analyses did not yield statistically significant results, unadjusted analyses demonstrated increased odds of PCOS in patients with HS across all race/ethnicity groups, suggesting that sociodemographic variables and comorbidities substantially influence the relationship between HS and PCOS; for instance, patients with type 2 diabetes and obesity are approximately 10- to 11-fold more likely to have PCOS than patients without these conditions. Non-Hispanic Black and Hispanic patients were less likely to have PCOS compared with White patients, indicating possible underdiagnosis of PCOS in these populations and highlighting the need for increased PCOS screening. Limitations of this study include the reliance on SNOMED CT codes, which may have led to underdiagnosis of HS or PCOS, as well as the inability to differentiate between mild and severe HS in the database.

Hyperandrogenism is believed to contribute to the pathogenesis of both HS and PCOS, supporting the potential use of antiandrogen therapies, such as spironolactone, in managing both conditions.^2,3 Furthermore, oral contraceptives may have a role in managing both conditions. In HS, oral contraceptives help to mitigate flares associated with hormonal changes during menstruation, while in PCOS, they are used to regulate the hormonal cycle and reduce hirsutism.^2-4 However, not all women experience menstrual flares of HS, suggesting that variations in HS phenotypes may influence individual responses to hormonal changes.¹ Additionally, the considerable overlap in metabolic and cardiovascular comorbidities between HS and PCOS indicates that shared pathomechanisms may contribute to the association between these conditions.^1,2 For example, proinflammatory adipokines released in both HS and PCOS may contribute to inflammation, cardiovascular disease, and insulin resistance.^3,5

Conclusion

Further research is needed to better understand the shared pathophysiology that links these 2 diseases and to identify targeted approaches for optimizing management and improving patient outcomes. The association between HS and PCOS highlights the importance of screening for metabolic and reproductive comorbidities in patients with HS. Early recognition and management of both HS and PCOS can improve long-term outcomes.

Atopic dermatitis (AD) is a chronic skin condition generally characterized by pruritic and erythematous papules and plaques.¹ While AD commonly manifests in childhood, 1 in 4 patients living with AD report adult onset of the disease.² The clinical presentation and prevalence of AD vary across age groups, skin tones, and racial and ethnic groups. Globally, AD is estimated to have a prevalence of 2.6%; however, rates vary widely by region.¹ Morphology and distribution of AD lesions also vary by population; therefore, defining one classic presentation of AD is not sufficient in diverse patient populations.³

Epidemiology

The prevalence of AD ranges from 0.2% to 24.6% worldwide, with higher rates in Africa and Oceania and lower rates in India and Northern and Eastern Europe.¹ In the United States, AD affects all racial and ethnic groups; however, prevalence and severity are increased in Black children compared with White children.⁴ In one prospective cohort study, Hispanic children and non-Hispanic Black children aged 3 years and younger had greater odds of AD persisting into mid childhood (approximately age 7 years) compared with non-Hispanic White children.^5,6

Key Clinical Features

Clinical features of AD are heterogeneous and may include differences in color, morphology, and distribution. Brown, hyperpigmented, gray, and/or violaceous plaques may predominate in patients with skin of color (SOC) compared with the erythematous plaques commonly described in lighter skin tones.^1,3 Established scoring systems for AD rely on erythema as a key diagnostic feature, but because erythema can be difficult to detect in darker skin tones, disease severity may be underestimated and diagnosis may be delayed in this population.⁴

Atopic dermatitis in SOC may manifest as lichenoid plaques,⁷ prurigo nodules,^7,8 lichenification,¹ and follicular accentuation.⁹ Lichen planus–like AD is a distinct variant characterized by lichenoid plaques with a predilection for the extensor surfaces and face in patients with darker skin tones^1,8 occurring in approximately 9% of patients in one study.¹⁰

Other key clinical features of AD in patients with SOC include pityriasis alba,¹⁰ increased risk for postinflammatory pigment alteration (including hyperpigmentation and/or hypopigmentation),¹ and greater trunk and extensor involvement.^1,11

Worth Noting

The scientific landscape for AD has grown rapidly, increasing our understanding of its pathophysiology, treatment, and social impact. Nonsteroidal treatments available for pediatric and adult patients with AD have increased in recent years, including crisaborole (approved for use in those ages ≥3 months), tacrolimus (≥2 years), and pimecrolimus (≥2 years). Injectable options include dupilumab (≥6 months), lebrikizumab (≥12 years), nemolizumab (≥12 years), and tralokinumab (≥12 years). Oral options include abrocitinib (≥12 years) and upadacitinib (≥12 years).¹² Topical options include roflumilast 0.15% cream (≥6 years)¹² and 0.05% cream (≥2-5 years),¹³ ruxolitinib 1.5% cream (≥2 years),¹⁴ and tapinarof 1% cream (≥2 years).¹²

For some patients, postinflammatory pigment alteration associated with AD has a higher impact on quality of life than the AD itself.⁷ In a study of 260 US adults with AD, the emotional impact of pigmentary changes was greatest in Black patients, with 53.3% reporting that pigment changes bothered them “a lot” or “very much.”¹⁵

Genome-wide association studies have not identified a single determinant that explains racial and ethnic differences in susceptibility to AD.⁴ Instead, social determinants of health are thought to play a role in the difference in AD prevalence and severity across groups in the United States.¹⁶

Health Disparity Highlight

In an analysis of 20 US metropolitan cities, urban and inner-city residence was associated with approximately 1.7-fold increased odds of AD.⁴ Among pediatric patients with moderate to severe AD, Black children were more likely to be exposed to tobacco smoke¹⁷ and traffic-related air pollution.¹⁸ Low socioeconomic status and low income also have been associated with moderate¹⁶ and severe¹⁹ AD. At the same education level, Black individuals in the United States receive less income than their White counterparts and have markedly less wealth at equivalent incomes.²⁰

In utero exposure to maternal stress is associated with AD.⁴ Increased IgE levels have been recorded in children who develop AD, with Black children having the highest IgE levels overall compared to other children.¹⁸

An analysis of medical records from an urban medical center in Baltimore, Maryland, from 2013 through 2018 showed that Black patients with AD were less likely to receive topical corticosteroids, topical calcineurin inhibitors, a topical phosphodiesterase 4 inhibitor, and a biologic compared to White patients with AD.²¹

Since the disproportionate burden experienced by patients with AD is not physiologic, it is imperative to address these systemic complexities and address the barriers impacting treatment availability to improve health outcomes for all patients living with AD.

Atopic dermatitis (AD) is a chronic skin condition generally characterized by pruritic and erythematous papules and plaques.¹ While AD commonly manifests in childhood, 1 in 4 patients living with AD report adult onset of the disease.² The clinical presentation and prevalence of AD vary across age groups, skin tones, and racial and ethnic groups. Globally, AD is estimated to have a prevalence of 2.6%; however, rates vary widely by region.¹ Morphology and distribution of AD lesions also vary by population; therefore, defining one classic presentation of AD is not sufficient in diverse patient populations.³

Epidemiology

The prevalence of AD ranges from 0.2% to 24.6% worldwide, with higher rates in Africa and Oceania and lower rates in India and Northern and Eastern Europe.¹ In the United States, AD affects all racial and ethnic groups; however, prevalence and severity are increased in Black children compared with White children.⁴ In one prospective cohort study, Hispanic children and non-Hispanic Black children aged 3 years and younger had greater odds of AD persisting into mid childhood (approximately age 7 years) compared with non-Hispanic White children.^5,6

Key Clinical Features

Clinical features of AD are heterogeneous and may include differences in color, morphology, and distribution. Brown, hyperpigmented, gray, and/or violaceous plaques may predominate in patients with skin of color (SOC) compared with the erythematous plaques commonly described in lighter skin tones.^1,3 Established scoring systems for AD rely on erythema as a key diagnostic feature, but because erythema can be difficult to detect in darker skin tones, disease severity may be underestimated and diagnosis may be delayed in this population.⁴

Atopic dermatitis in SOC may manifest as lichenoid plaques,⁷ prurigo nodules,^7,8 lichenification,¹ and follicular accentuation.⁹ Lichen planus–like AD is a distinct variant characterized by lichenoid plaques with a predilection for the extensor surfaces and face in patients with darker skin tones^1,8 occurring in approximately 9% of patients in one study.¹⁰

Other key clinical features of AD in patients with SOC include pityriasis alba,¹⁰ increased risk for postinflammatory pigment alteration (including hyperpigmentation and/or hypopigmentation),¹ and greater trunk and extensor involvement.^1,11

Worth Noting

The scientific landscape for AD has grown rapidly, increasing our understanding of its pathophysiology, treatment, and social impact. Nonsteroidal treatments available for pediatric and adult patients with AD have increased in recent years, including crisaborole (approved for use in those ages ≥3 months), tacrolimus (≥2 years), and pimecrolimus (≥2 years). Injectable options include dupilumab (≥6 months), lebrikizumab (≥12 years), nemolizumab (≥12 years), and tralokinumab (≥12 years). Oral options include abrocitinib (≥12 years) and upadacitinib (≥12 years).¹² Topical options include roflumilast 0.15% cream (≥6 years)¹² and 0.05% cream (≥2-5 years),¹³ ruxolitinib 1.5% cream (≥2 years),¹⁴ and tapinarof 1% cream (≥2 years).¹²

For some patients, postinflammatory pigment alteration associated with AD has a higher impact on quality of life than the AD itself.⁷ In a study of 260 US adults with AD, the emotional impact of pigmentary changes was greatest in Black patients, with 53.3% reporting that pigment changes bothered them “a lot” or “very much.”¹⁵

Genome-wide association studies have not identified a single determinant that explains racial and ethnic differences in susceptibility to AD.⁴ Instead, social determinants of health are thought to play a role in the difference in AD prevalence and severity across groups in the United States.¹⁶

Health Disparity Highlight

In an analysis of 20 US metropolitan cities, urban and inner-city residence was associated with approximately 1.7-fold increased odds of AD.⁴ Among pediatric patients with moderate to severe AD, Black children were more likely to be exposed to tobacco smoke¹⁷ and traffic-related air pollution.¹⁸ Low socioeconomic status and low income also have been associated with moderate¹⁶ and severe¹⁹ AD. At the same education level, Black individuals in the United States receive less income than their White counterparts and have markedly less wealth at equivalent incomes.²⁰

In utero exposure to maternal stress is associated with AD.⁴ Increased IgE levels have been recorded in children who develop AD, with Black children having the highest IgE levels overall compared to other children.¹⁸

An analysis of medical records from an urban medical center in Baltimore, Maryland, from 2013 through 2018 showed that Black patients with AD were less likely to receive topical corticosteroids, topical calcineurin inhibitors, a topical phosphodiesterase 4 inhibitor, and a biologic compared to White patients with AD.²¹

Since the disproportionate burden experienced by patients with AD is not physiologic, it is imperative to address these systemic complexities and address the barriers impacting treatment availability to improve health outcomes for all patients living with AD.

Atopic dermatitis (AD) is a chronic skin condition generally characterized by pruritic and erythematous papules and plaques.¹ While AD commonly manifests in childhood, 1 in 4 patients living with AD report adult onset of the disease.² The clinical presentation and prevalence of AD vary across age groups, skin tones, and racial and ethnic groups. Globally, AD is estimated to have a prevalence of 2.6%; however, rates vary widely by region.¹ Morphology and distribution of AD lesions also vary by population; therefore, defining one classic presentation of AD is not sufficient in diverse patient populations.³

Epidemiology

The prevalence of AD ranges from 0.2% to 24.6% worldwide, with higher rates in Africa and Oceania and lower rates in India and Northern and Eastern Europe.¹ In the United States, AD affects all racial and ethnic groups; however, prevalence and severity are increased in Black children compared with White children.⁴ In one prospective cohort study, Hispanic children and non-Hispanic Black children aged 3 years and younger had greater odds of AD persisting into mid childhood (approximately age 7 years) compared with non-Hispanic White children.^5,6

Key Clinical Features

Clinical features of AD are heterogeneous and may include differences in color, morphology, and distribution. Brown, hyperpigmented, gray, and/or violaceous plaques may predominate in patients with skin of color (SOC) compared with the erythematous plaques commonly described in lighter skin tones.^1,3 Established scoring systems for AD rely on erythema as a key diagnostic feature, but because erythema can be difficult to detect in darker skin tones, disease severity may be underestimated and diagnosis may be delayed in this population.⁴

Atopic dermatitis in SOC may manifest as lichenoid plaques,⁷ prurigo nodules,^7,8 lichenification,¹ and follicular accentuation.⁹ Lichen planus–like AD is a distinct variant characterized by lichenoid plaques with a predilection for the extensor surfaces and face in patients with darker skin tones^1,8 occurring in approximately 9% of patients in one study.¹⁰

Other key clinical features of AD in patients with SOC include pityriasis alba,¹⁰ increased risk for postinflammatory pigment alteration (including hyperpigmentation and/or hypopigmentation),¹ and greater trunk and extensor involvement.^1,11

Worth Noting

The scientific landscape for AD has grown rapidly, increasing our understanding of its pathophysiology, treatment, and social impact. Nonsteroidal treatments available for pediatric and adult patients with AD have increased in recent years, including crisaborole (approved for use in those ages ≥3 months), tacrolimus (≥2 years), and pimecrolimus (≥2 years). Injectable options include dupilumab (≥6 months), lebrikizumab (≥12 years), nemolizumab (≥12 years), and tralokinumab (≥12 years). Oral options include abrocitinib (≥12 years) and upadacitinib (≥12 years).¹² Topical options include roflumilast 0.15% cream (≥6 years)¹² and 0.05% cream (≥2-5 years),¹³ ruxolitinib 1.5% cream (≥2 years),¹⁴ and tapinarof 1% cream (≥2 years).¹²

For some patients, postinflammatory pigment alteration associated with AD has a higher impact on quality of life than the AD itself.⁷ In a study of 260 US adults with AD, the emotional impact of pigmentary changes was greatest in Black patients, with 53.3% reporting that pigment changes bothered them “a lot” or “very much.”¹⁵

Genome-wide association studies have not identified a single determinant that explains racial and ethnic differences in susceptibility to AD.⁴ Instead, social determinants of health are thought to play a role in the difference in AD prevalence and severity across groups in the United States.¹⁶

Health Disparity Highlight

In an analysis of 20 US metropolitan cities, urban and inner-city residence was associated with approximately 1.7-fold increased odds of AD.⁴ Among pediatric patients with moderate to severe AD, Black children were more likely to be exposed to tobacco smoke¹⁷ and traffic-related air pollution.¹⁸ Low socioeconomic status and low income also have been associated with moderate¹⁶ and severe¹⁹ AD. At the same education level, Black individuals in the United States receive less income than their White counterparts and have markedly less wealth at equivalent incomes.²⁰

In utero exposure to maternal stress is associated with AD.⁴ Increased IgE levels have been recorded in children who develop AD, with Black children having the highest IgE levels overall compared to other children.¹⁸

An analysis of medical records from an urban medical center in Baltimore, Maryland, from 2013 through 2018 showed that Black patients with AD were less likely to receive topical corticosteroids, topical calcineurin inhibitors, a topical phosphodiesterase 4 inhibitor, and a biologic compared to White patients with AD.²¹

Since the disproportionate burden experienced by patients with AD is not physiologic, it is imperative to address these systemic complexities and address the barriers impacting treatment availability to improve health outcomes for all patients living with AD.