Article

To the Editor:

Indeterminate cell histiocytosis (ICH) is a rare neoplastic dendritic cell disorder with a poorly understood histogenesis and pathogenesis.¹ The clinical manifestation of ICH is broad and can include isolated or multiple papules or nodules on the face, neck, trunk, arms, or legs. Our case demonstrates a rare occurrence of ICH that initially was misdiagnosed and highlights the use of cobimetinib, a MEK inhibitor, as a potential new therapeutic option for ICH.

A 74-year-old man with a history of type 2 diabetes mellitus presented for evaluation of a progressive pruritic rash of approximately 5 years’ duration. The eruption previously had been diagnosed as Langerhans cell histiocytosis. It started on the chest and spread to the face, neck, trunk, and arms. The patient denied systemic symptoms and had no known history of malignancy.

Physical examination revealed pink to orange smooth papules, nodules, and small plaques on the ears, cheeks, trunk, neck, and arms (Figure 1). Baseline laboratory results showed a normal complete blood count and comprehensive metabolic panel, elevated lactate dehydrogenase and erythrocyte sedimentation rate, and hyperlipidemia. Serology for hepatitis B and C was negative. Bone marrow biopsy was normal, and positron emission tomography/ computed tomography demonstrated no evidence of extracutaneous disease. A punch biopsy of a lesion on the left forearm revealed epithelioid histiocytic proliferation in the dermis extending into the subcutis with a background infiltrate of small lymphocytes. Immunohistochemistry was positive for CD1a and CD56 and was variably positive for CD4 but negative for CD163, CD68, S100, Langerin, cyclin D1, myeloperoxidase, CD21, and CD23. No mutation was detected in BRAF codon 600. Given the negative Langerin stain, these findings were compatible with a diagnosis of ICH. After considering the lack of standard treatment options as well as the recent approval of cobimetinib for histiocytic disorders, we initiated treatment with cobimetinib at the standard dose of 60 mg daily for 21 days followed by a 7-day break.

One month into treatment, the patient’s lesions were less erythematous, and he reported improvement in pruritus. Two months into treatment, there was continued improvement in cutaneous symptoms with flattening of the lesions on the chest and back. At this time, the patient developed edema of the face and ears (Figure 2) and reported weakness, blurred vision, and decreased appetite. He was advised to take an additional 7-day treatment break before resuming cobimetinib at a decreased dose of 40 mg daily. The patient returned to the clinic 1 month later with improved systemic symptoms and continued flattening of the lesions. Five months into treatment, the lesions had continued to improve with complete resolution of the facial plaques (Figure 3).

Indeterminate cell histiocytosis is a rarely diagnosed condition characterized by the proliferation of indeterminate histiocytes that morphologically and immunophenotypically resemble Langerhans cells but lack their characteristic Birbeck granules.² There is no standard treatment for ICH, but previous reports have described improvement with a variety of treatment options including methotrexate,^3,4 UVB phototherapy,⁵ and topical delgocitinib 0.5%.⁶

Because histiocytic disorders are characterized by mutations in the mitogen-activated protein kinase pathway, it is possible that they would be responsive to MEK inhibition. Cobimetinib, a MEK inhibitor initially approved to treat metastatic melanoma, was approved by the US Food and Drug Administration to treat histiocytic disorders in October 2022.⁷ The approval followed the release of data from a phase 2 trial of cobimetinib in 18 adults with various histiocytic disorders, which demonstrated an 89% (16/18) overall response rate with 94% (17/18) of patients remaining progression free at 1 year.⁸ While cobimetinib has not specifically been studied in ICH, given the high response rate in histiocytic disorders and the lack of standard treatment options for ICH, the decision was made to initiate treatment with cobimetinib in our patient. Based on the observed improvement in our patient, we propose cobimetinib as a treatment option for patients with cutaneous ICH and recommend additional studies to confirm its safety and efficacy in patients with this disorder.

To the Editor:

Indeterminate cell histiocytosis (ICH) is a rare neoplastic dendritic cell disorder with a poorly understood histogenesis and pathogenesis.¹ The clinical manifestation of ICH is broad and can include isolated or multiple papules or nodules on the face, neck, trunk, arms, or legs. Our case demonstrates a rare occurrence of ICH that initially was misdiagnosed and highlights the use of cobimetinib, a MEK inhibitor, as a potential new therapeutic option for ICH.

A 74-year-old man with a history of type 2 diabetes mellitus presented for evaluation of a progressive pruritic rash of approximately 5 years’ duration. The eruption previously had been diagnosed as Langerhans cell histiocytosis. It started on the chest and spread to the face, neck, trunk, and arms. The patient denied systemic symptoms and had no known history of malignancy.

Physical examination revealed pink to orange smooth papules, nodules, and small plaques on the ears, cheeks, trunk, neck, and arms (Figure 1). Baseline laboratory results showed a normal complete blood count and comprehensive metabolic panel, elevated lactate dehydrogenase and erythrocyte sedimentation rate, and hyperlipidemia. Serology for hepatitis B and C was negative. Bone marrow biopsy was normal, and positron emission tomography/ computed tomography demonstrated no evidence of extracutaneous disease. A punch biopsy of a lesion on the left forearm revealed epithelioid histiocytic proliferation in the dermis extending into the subcutis with a background infiltrate of small lymphocytes. Immunohistochemistry was positive for CD1a and CD56 and was variably positive for CD4 but negative for CD163, CD68, S100, Langerin, cyclin D1, myeloperoxidase, CD21, and CD23. No mutation was detected in BRAF codon 600. Given the negative Langerin stain, these findings were compatible with a diagnosis of ICH. After considering the lack of standard treatment options as well as the recent approval of cobimetinib for histiocytic disorders, we initiated treatment with cobimetinib at the standard dose of 60 mg daily for 21 days followed by a 7-day break.

One month into treatment, the patient’s lesions were less erythematous, and he reported improvement in pruritus. Two months into treatment, there was continued improvement in cutaneous symptoms with flattening of the lesions on the chest and back. At this time, the patient developed edema of the face and ears (Figure 2) and reported weakness, blurred vision, and decreased appetite. He was advised to take an additional 7-day treatment break before resuming cobimetinib at a decreased dose of 40 mg daily. The patient returned to the clinic 1 month later with improved systemic symptoms and continued flattening of the lesions. Five months into treatment, the lesions had continued to improve with complete resolution of the facial plaques (Figure 3).

Indeterminate cell histiocytosis is a rarely diagnosed condition characterized by the proliferation of indeterminate histiocytes that morphologically and immunophenotypically resemble Langerhans cells but lack their characteristic Birbeck granules.² There is no standard treatment for ICH, but previous reports have described improvement with a variety of treatment options including methotrexate,^3,4 UVB phototherapy,⁵ and topical delgocitinib 0.5%.⁶

Because histiocytic disorders are characterized by mutations in the mitogen-activated protein kinase pathway, it is possible that they would be responsive to MEK inhibition. Cobimetinib, a MEK inhibitor initially approved to treat metastatic melanoma, was approved by the US Food and Drug Administration to treat histiocytic disorders in October 2022.⁷ The approval followed the release of data from a phase 2 trial of cobimetinib in 18 adults with various histiocytic disorders, which demonstrated an 89% (16/18) overall response rate with 94% (17/18) of patients remaining progression free at 1 year.⁸ While cobimetinib has not specifically been studied in ICH, given the high response rate in histiocytic disorders and the lack of standard treatment options for ICH, the decision was made to initiate treatment with cobimetinib in our patient. Based on the observed improvement in our patient, we propose cobimetinib as a treatment option for patients with cutaneous ICH and recommend additional studies to confirm its safety and efficacy in patients with this disorder.

To the Editor:

Indeterminate cell histiocytosis (ICH) is a rare neoplastic dendritic cell disorder with a poorly understood histogenesis and pathogenesis.¹ The clinical manifestation of ICH is broad and can include isolated or multiple papules or nodules on the face, neck, trunk, arms, or legs. Our case demonstrates a rare occurrence of ICH that initially was misdiagnosed and highlights the use of cobimetinib, a MEK inhibitor, as a potential new therapeutic option for ICH.

A 74-year-old man with a history of type 2 diabetes mellitus presented for evaluation of a progressive pruritic rash of approximately 5 years’ duration. The eruption previously had been diagnosed as Langerhans cell histiocytosis. It started on the chest and spread to the face, neck, trunk, and arms. The patient denied systemic symptoms and had no known history of malignancy.

Physical examination revealed pink to orange smooth papules, nodules, and small plaques on the ears, cheeks, trunk, neck, and arms (Figure 1). Baseline laboratory results showed a normal complete blood count and comprehensive metabolic panel, elevated lactate dehydrogenase and erythrocyte sedimentation rate, and hyperlipidemia. Serology for hepatitis B and C was negative. Bone marrow biopsy was normal, and positron emission tomography/ computed tomography demonstrated no evidence of extracutaneous disease. A punch biopsy of a lesion on the left forearm revealed epithelioid histiocytic proliferation in the dermis extending into the subcutis with a background infiltrate of small lymphocytes. Immunohistochemistry was positive for CD1a and CD56 and was variably positive for CD4 but negative for CD163, CD68, S100, Langerin, cyclin D1, myeloperoxidase, CD21, and CD23. No mutation was detected in BRAF codon 600. Given the negative Langerin stain, these findings were compatible with a diagnosis of ICH. After considering the lack of standard treatment options as well as the recent approval of cobimetinib for histiocytic disorders, we initiated treatment with cobimetinib at the standard dose of 60 mg daily for 21 days followed by a 7-day break.

One month into treatment, the patient’s lesions were less erythematous, and he reported improvement in pruritus. Two months into treatment, there was continued improvement in cutaneous symptoms with flattening of the lesions on the chest and back. At this time, the patient developed edema of the face and ears (Figure 2) and reported weakness, blurred vision, and decreased appetite. He was advised to take an additional 7-day treatment break before resuming cobimetinib at a decreased dose of 40 mg daily. The patient returned to the clinic 1 month later with improved systemic symptoms and continued flattening of the lesions. Five months into treatment, the lesions had continued to improve with complete resolution of the facial plaques (Figure 3).

Indeterminate cell histiocytosis is a rarely diagnosed condition characterized by the proliferation of indeterminate histiocytes that morphologically and immunophenotypically resemble Langerhans cells but lack their characteristic Birbeck granules.² There is no standard treatment for ICH, but previous reports have described improvement with a variety of treatment options including methotrexate,^3,4 UVB phototherapy,⁵ and topical delgocitinib 0.5%.⁶

Because histiocytic disorders are characterized by mutations in the mitogen-activated protein kinase pathway, it is possible that they would be responsive to MEK inhibition. Cobimetinib, a MEK inhibitor initially approved to treat metastatic melanoma, was approved by the US Food and Drug Administration to treat histiocytic disorders in October 2022.⁷ The approval followed the release of data from a phase 2 trial of cobimetinib in 18 adults with various histiocytic disorders, which demonstrated an 89% (16/18) overall response rate with 94% (17/18) of patients remaining progression free at 1 year.⁸ While cobimetinib has not specifically been studied in ICH, given the high response rate in histiocytic disorders and the lack of standard treatment options for ICH, the decision was made to initiate treatment with cobimetinib in our patient. Based on the observed improvement in our patient, we propose cobimetinib as a treatment option for patients with cutaneous ICH and recommend additional studies to confirm its safety and efficacy in patients with this disorder.

Hidradenitis suppurativa (HS) is a debilitating dermatologic condition characterized by recurrent episodes of neutrophilic inflammation affecting the apocrine and pilosebaceous units that most commonly affects individuals aged 20 to 40 years. Originating from the hair follicles, inflammation initiates the formation of painful nodules and abscesses that can progress to sinus tracts or fistulas accompanied by the development of extensive scarring, exquisite pain, and malodorous drainage.¹ The lesions most commonly occur in intertriginous zones as well as areas rich in apocrine glands. The distinctive and sometimes irreversible clinical features of HS profoundly influence patients’ well-being and have lasting social, personal, and emotional impacts on their lives.²

Bimekizumab is a monoclonal antibody that specifically targets IL-17A and IL-17F, aiming to inhibit the downstream effects responsible for the chronic inflammation and tissue damage characteristic of HS.³ In HS lesions, IL-17 cytokines produced by T helper 17 (Th17) cells stimulate the production of chemokines (such as CC motif chemokine ligand 20) and neutrophil-attracting chemokines (including C-X-C motif chemokine ligands 1 and 8), cytokines (such as granulocyte colony-stimulating factor and IL-19), and epidermal antimicrobial proteins.^1,2 This cascade results in the chemotaxis of monocytes and neutrophils in the skin, recruiting additional Th17 and myeloid cells and further amplifying IL-17 production.¹

Bimekizumab’s mechanism of action strategically disrupts this feed-forward inflammatory loop, decreasing the transcription of neutrophil-attracting chemokines, IL-19, and epidermal antimicrobial proteins (Figure).^1,2 This leads to diminished recruitment of Th17 cells and inhibits the chemotaxis of monocytes and neutrophils in the skin, effectively addressing the chronic inflammation and tissue damage characteristic of HS.

We present a comprehensive review of the current standards of care, the underlying molecular pathophysiology of HS, and evaluation of the efficacy and safety of bimekizumab.

Evaluating HS Severity

The Hurley staging system provides a valuable framework for evaluating the severity of HS based on lesion characteristics. Stage I is characterized by abscess formation without tracts or scars. Stage II is characterized by recurrent abscesses with sinus tracts and scarring. Stage III is characterized by diffuse involvement, multiple interconnected sinus tracts, and abscesses across an entire area, leaving little to no uninvolved skin.⁴

Treatment strategies for HS vary based on Hurley staging (eTable).^5-11 For mild cases (stage I), topical and intralesional therapies are common, while moderate to severe cases (stages II and III) may require extensive surgical approaches or systemic drugs such as antibiotics, hormonal therapies, retinoids, or immunosuppressive/biologic agents.²

Adalimumab, an anti–tumor necrosis factor (TNF) α monoclonal antibody, was the first US Food and Drug Administration (FDA)–approved biologic for HS. Secukinumab, a monoclonal antibody against IL-17A, subsequently was approved by the FDA for moderate to severe HS.¹² Off-label use of biologics including infliximab and ustekinumab expands the available treatment options for HS. In one Phase II randomized clinical trial (RCT), infliximab showed efficacy in reducing Hidradenitis Suppurativa Severity Index scores, with 26.7% (4/15) of patients achieving a 50% or greater reduction compared to placebo, although this was not statistically significant. Similarly, ustekinumab demonstrated promising results, with 47.1% (8/17) of patients achieving Hidradenitis Suppurativa Clinical Response (HiSCR) at week 40.² This multifaceted approach aims to address the varying degrees of severity and optimize outcomes for individuals with HS.

Molecular Pathophysiology of HS

The pathogenesis of HS is multifactorial, involving a complex interplay of genetic, environmental, and behavioral factors.² Approximately 33% to 40% of patients with HS worldwide report a first-degree relative with the condition, indicating a hereditary element with an autosomal-dominant transmission pattern and highlighting the global relevance of genetic factors in HS.⁴ Hidradenitis suppurativa is highly prevalent in individuals with obesity, likely due to increased intertriginous surface area, skin friction, sweat production, and hormonal changes in these patients. Smoking also commonly is associated with HS, with nicotine potentially contributing to increased follicular plugging.¹ Hormonal influences also play a role, as evidenced by a greater prevalence of HS in females, disease onset typically occurring between puberty and menopause, and symptomatic fluctuations correlating with menstrual cycles and exogenous hormones.⁴

Altered infundibular keratinization with subsequent hyperkeratosis/occlusion and innate immune pathway activation are key events leading to development of HS.¹ These events are mediated by release of pathogen- and danger-associated molecular patterns, leading to inflammasome-mediated IL-1α release, followed by downstream cytokine release.² Elevated levels of TNF-α, IL-1Β, IL-10, IL-17, and particularly IL-17A have been detected in HS lesional skin. The IL-17 family comprises multiple members, namely IL-17A, IL-17C, IL-17E, and IL17F. IL-17A and IL-17F often are co-expressed and secreted predominantly by a subset of CD4+ T helper cells, namely Th17 cells.² IL-17 cytokines exert pro-inflammatory effects, influencing immune cell activity and contributing to skin inflammation, particularly in HS.

Given the pivotal role of IL-17 in the pathogenesis of HS, the exploration of IL-17–targeted agents has become a focal point in clinical research. Bimekizumab, a novel IL-17 inhibitor, has emerged as a promising candidate, offering a potential breakthrough in the treatment landscape for individuals affected by HS.

Bimekizumab for HS Management

A phase II, double-blind, placebo-controlled RCT included 90 patients with moderate to severe HS (age range, 18-70 years) who were randomly assigned in a 2:1:1 ratio to receive either bimekizumab 320 mg every 2 weeks (with a 640-mg loading dose at baseline)(n=46), placebo (n=21), or adalimumab 40 mg once weekly from week 4 onward (following an initial 160-mg loading dose at baseline and 80-mg dose at week 2)(n=21). The study included a 12-week treatment period followed by a 20-week safety follow-up period. The primary endpoint was the achievement of HiSCR₅₀—defined as a reduction of at least 50% nodules, coupled with no increase in the number of abscesses or draining fistulas relative to baseline—at week 12. Additionally, the study assessed the number of patients who achieved a modified HiSCR with 75% reduction (HiSCR₇₅) of combined abscess and inflammatory nodule count or a modified HiSCR with 90% reduction (HiSCR₉₀). At week 12, the modeled response rates were estimated using a Bayesian logistic regression model. For HiSCR₅₀, the modeled rate for bimekizumab was 57.3%, with an observed rate of 62.5% (25/40), compared to a modeled rate of 26.1% for placebo (observed rate, 27.8% [5/18]). The posterior probability of superiority for bimekizumab over placebo was 0.998. By week 12, bimekizumab-treated patients achieved modeled HiSCR₇₅ and HiSCR₉₀ rates of 46.0% and 32.0%, respectively, with observed rates of 50.0% (20/40) for HiSCR₇₅ and 35.0% (14/40) for HiSCR₉₀. In comparison, placebo-treated patients achieved modeled HiSCR75 and HiSCR₉₀ rates of 10.0% and 0%, respectively, with observed rates of 11.1% (2/18) for HiSCR₇₅ and 0% (0/18) for HiSCR₉₀. Adalimumab-treated participants demonstrated intermediate results, achieving modeled HiSCR₇₅ and HiSCR₉₀ rates of 35.0% and 15.0%, respectively, with observed rates of 38.88% (7/18) for HiSCR₇₅ and 16.66% (3/18) for HiSCR₉₀.⁷

Bimekizumab was effective in the treatment of moderate to severe HS with comparable results to adalimumab.⁷ The incidence of treatment-emergent adverse events was similar across treatment arms (bimekizumab, 69.6% [32/46]; placebo, 61.9% [13/21]; adalimumab, 71.4% [15/21]). The most common treatment-emergent adverse events in the biologic treatment arms were infections (43.5% [20/46] in the bimekizumab group and 42.9% [9/21] in the adalimumab group), skin and subcutaneous tissue disorders (28.3% [13/46] in the bimekizumab group and 42.9% [9/21] in the adalimumab group), and general disorders/administration site conditions (21.7% [10/46] in the bimekizumab group and 23.8% [5/21] in the adalimumab group). Serious adverse events occurred in 4.3% (2/46) of patients in the bimekizumab group, 9.5% (2/21) of patients in the placebo group, and 4.8% (1/21) of patients in the adalimumab group. Serious adverse events that required hospitalization were due to anemia and empyema in the bimekizumab group; worsening HS in the adalimumab group; and myocardial infarction, hypoesthesia, headache, and dizziness in the placebo group. No deaths occurred in this study. Overall, bimekizumab was well tolerated, and discontinuation rates were low across all arms. The primary reason for discontinuation was withdrawal of consent (not due to an adverse event) or loss to follow-up.⁷

Two completed 48-week phase III RCTs, BE HEARD I and BE HEARD II, evaluated the efficacy and safety of bimekizumab in patients with moderate to severe HS.¹³ In both trials, 2 bimekizumab dosing regimens (320 mg every 2 weeks and 320 mg every 4 weeks) were compared with placebo during the 16-week initial and 32-week maintenance treatment periods. The primary endpoint of week 16 was achieved by 47.8% (138/289) and 51.9% (151/291) of patients receiving bimekizumab every 2 weeks in BE HEARD I (n=505) and BE HEARD II (n=509), respectively, compared with 29.2% (21/72) and 32.4% (24/74) of the placebo group. The bimekizumab 320 mg every 4 weeks dosing regimen met the primary endpoint only in BE HEARD II, with 53.5% (77/144) of patients achieving HiSCR₅₀ compared to 32.4% (24/74) with placebo (P=0.0038).¹³ Both trials met the key secondary endpoint of HiSCR₇₅ at week 16 for bimekizumab 320 mg every 2 weeks vs placebo. In BE HEARD I, 33.6% (97/289) of patients receiving bimekizumab achieved HiSCR₇₅ versus 18.1% (13/72) taking placebo. In BE HEARD II, 35.7% (104/291) of patients receiving bimekizumab achieved HiSCR₇₅ vs 16.2% (12/74) taking placebo. Responses were maintained or increased through week 48 in both trials. The most common treatment-emergent adverse events through week 48 were worsening HS, COVID-19 infection, diarrhea, oral candidiasis, and headache.¹³

A smaller scale case series investigated the use of bimekizumab in 4 female patients aged 20 to 62 years with moderate to severe HS and concomitant plaque or inverse psoriasis.⁸ A monthly loading dose of 320 mg was given during weeks 0 to 12 followed by a maintenance dose of 320 mg administered every 8 weeks. The International Hidradenitis Suppurativa Score System, visual analogue scale, and Dermatology Life Quality Index were used to assess the effectiveness of therapy by comparing scores before and after 4 and 16 weeks of treatment. A reduction of pain and improvement of HS lesions was observed in 3 (75.0%) patients after the first dosage of bimekizumab, with completed remission of HS by week 16. The fourth patient (25.0%) experienced substantial improvement in all measures, although not complete remission. All 4 patients remained on bimekizumab, and no adverse effects were reported.⁸

A meta-analysis evaluated 16 RCTs of 9 biologics and 3 small-molecule inhibitors in 2076 patients with HS.¹⁰ Secukinumab was not included in this meta-analysis. Only adalimumab (risk ratio, 1.77; 95% CI, 1.44-2.17) and bimekizumab (risk ratio, 2.25; 95% CI, 1.03-4.92) were superior to placebo in achieving HiSCR response at weeks 12 to 16 in 5 RCTs and 1 RCT, respectively; however, no statistically significant differences were noted between adalimumab and bimekizumab (P=.56). This analysis concluded that adalimumab and bimekizumab are the only 2 biologics efficacious in reaching HiSCR and consistently improved both disease severity and quality of life in patients with HS with an acceptable safety profile.¹⁰ Furthermore, these biologics had no increase in serious adverse events when compared to placebo.¹⁰

A network meta-analysis of 10 clinical trials involving more than 900 total participants evaluated nonsurgical therapies for HS. The analysis used Surface Under the Cumulative Ranking curve (SUCRA) values to estimate the efficacy of treatments in achieving clinical response according to HiSCR criteria. These values range from 0% to 100%, with 100% representing the best possible ranking for efficacy. Bimekizumab showed the highest estimated efficacy with a SUCRA value of 67%, followed by adalimumab (64%), anakinra (49%), and placebo (19%). These SUCRA values indicate the relative ranking of treatments, with higher values suggesting greater likelihood of achieving clinical response, rather than representing the actual percentage of patients achieving HiSCR. Bimekizumab was found to be more efficacious than placebo (P<.05).¹⁴

Building on the initial evidence of bimekizumab’s efficacy, BE HEARD I and BE HEARD II addressed some limitations of prior studies, including small sample sizes and insufficient stratification.¹³ Notably, stratification by baseline Hurley stage severity (ie, the most severe stage of disease assigned at baseline) and baseline systemic antibiotic use helped mitigate bias and ensured a more robust assessment of treatment efficacy; however, certain limitations persist. While the trials demonstrated rapid and clinically meaningful responses maintained up to 48 weeks, longer-term data beyond this period are limited, leaving gaps in understanding the durability of treatment effects over years. Additionally, despite appropriate stratification, the generalizability of the findings to broader patient populations remains unclear, as trial participants may not fully represent the diversity of patients seen in clinical practice.¹³

Future research is needed to address these limitations. The use of validated HS biomarkers as endpoints could enhance the ability to evaluate biologic efficacy and identify predictors of response. Comparative studies with other biologics also are warranted to establish the relative efficacy of bimekizumab within the growing therapeutic landscape for HS. Finally, real-world evidence from larger and more diverse populations will be critical to confirm the trial findings and assess long-term safety and effectiveness in routine clinical practice.¹³

Conclusion

The existing literature and recent phase III RCTs, BE HEARD I and BE HEARD II, demonstrate that bimekizumab is an effective treatment for moderate to severe HS, with robust efficacy according to HiSCR scores and sustained responses through 48 weeks. These trials addressed some prior limitations, including small sample sizes and insufficient stratification, providing a more comprehensive evaluation of bimekizumab’s clinical impact. The safety profile of bimekizumab remains favorable, with low discontinuation rates and manageable adverse events, such as infection, gastrointestinal upset, headache, and injection-site reactions. Long-term efficacy and safety data beyond 48 weeks still are needed to fully establish its durability and impact in diverse populations. The recent FDA approval of bimekizumab for moderate to severe HS provides patients with a new treatment option, offering a more positive clinical outlook.

Hidradenitis suppurativa (HS) is a debilitating dermatologic condition characterized by recurrent episodes of neutrophilic inflammation affecting the apocrine and pilosebaceous units that most commonly affects individuals aged 20 to 40 years. Originating from the hair follicles, inflammation initiates the formation of painful nodules and abscesses that can progress to sinus tracts or fistulas accompanied by the development of extensive scarring, exquisite pain, and malodorous drainage.¹ The lesions most commonly occur in intertriginous zones as well as areas rich in apocrine glands. The distinctive and sometimes irreversible clinical features of HS profoundly influence patients’ well-being and have lasting social, personal, and emotional impacts on their lives.²

Bimekizumab is a monoclonal antibody that specifically targets IL-17A and IL-17F, aiming to inhibit the downstream effects responsible for the chronic inflammation and tissue damage characteristic of HS.³ In HS lesions, IL-17 cytokines produced by T helper 17 (Th17) cells stimulate the production of chemokines (such as CC motif chemokine ligand 20) and neutrophil-attracting chemokines (including C-X-C motif chemokine ligands 1 and 8), cytokines (such as granulocyte colony-stimulating factor and IL-19), and epidermal antimicrobial proteins.^1,2 This cascade results in the chemotaxis of monocytes and neutrophils in the skin, recruiting additional Th17 and myeloid cells and further amplifying IL-17 production.¹

Bimekizumab’s mechanism of action strategically disrupts this feed-forward inflammatory loop, decreasing the transcription of neutrophil-attracting chemokines, IL-19, and epidermal antimicrobial proteins (Figure).^1,2 This leads to diminished recruitment of Th17 cells and inhibits the chemotaxis of monocytes and neutrophils in the skin, effectively addressing the chronic inflammation and tissue damage characteristic of HS.

We present a comprehensive review of the current standards of care, the underlying molecular pathophysiology of HS, and evaluation of the efficacy and safety of bimekizumab.

Evaluating HS Severity

The Hurley staging system provides a valuable framework for evaluating the severity of HS based on lesion characteristics. Stage I is characterized by abscess formation without tracts or scars. Stage II is characterized by recurrent abscesses with sinus tracts and scarring. Stage III is characterized by diffuse involvement, multiple interconnected sinus tracts, and abscesses across an entire area, leaving little to no uninvolved skin.⁴

Treatment strategies for HS vary based on Hurley staging (eTable).^5-11 For mild cases (stage I), topical and intralesional therapies are common, while moderate to severe cases (stages II and III) may require extensive surgical approaches or systemic drugs such as antibiotics, hormonal therapies, retinoids, or immunosuppressive/biologic agents.²

Adalimumab, an anti–tumor necrosis factor (TNF) α monoclonal antibody, was the first US Food and Drug Administration (FDA)–approved biologic for HS. Secukinumab, a monoclonal antibody against IL-17A, subsequently was approved by the FDA for moderate to severe HS.¹² Off-label use of biologics including infliximab and ustekinumab expands the available treatment options for HS. In one Phase II randomized clinical trial (RCT), infliximab showed efficacy in reducing Hidradenitis Suppurativa Severity Index scores, with 26.7% (4/15) of patients achieving a 50% or greater reduction compared to placebo, although this was not statistically significant. Similarly, ustekinumab demonstrated promising results, with 47.1% (8/17) of patients achieving Hidradenitis Suppurativa Clinical Response (HiSCR) at week 40.² This multifaceted approach aims to address the varying degrees of severity and optimize outcomes for individuals with HS.

Molecular Pathophysiology of HS

The pathogenesis of HS is multifactorial, involving a complex interplay of genetic, environmental, and behavioral factors.² Approximately 33% to 40% of patients with HS worldwide report a first-degree relative with the condition, indicating a hereditary element with an autosomal-dominant transmission pattern and highlighting the global relevance of genetic factors in HS.⁴ Hidradenitis suppurativa is highly prevalent in individuals with obesity, likely due to increased intertriginous surface area, skin friction, sweat production, and hormonal changes in these patients. Smoking also commonly is associated with HS, with nicotine potentially contributing to increased follicular plugging.¹ Hormonal influences also play a role, as evidenced by a greater prevalence of HS in females, disease onset typically occurring between puberty and menopause, and symptomatic fluctuations correlating with menstrual cycles and exogenous hormones.⁴

Altered infundibular keratinization with subsequent hyperkeratosis/occlusion and innate immune pathway activation are key events leading to development of HS.¹ These events are mediated by release of pathogen- and danger-associated molecular patterns, leading to inflammasome-mediated IL-1α release, followed by downstream cytokine release.² Elevated levels of TNF-α, IL-1Β, IL-10, IL-17, and particularly IL-17A have been detected in HS lesional skin. The IL-17 family comprises multiple members, namely IL-17A, IL-17C, IL-17E, and IL17F. IL-17A and IL-17F often are co-expressed and secreted predominantly by a subset of CD4+ T helper cells, namely Th17 cells.² IL-17 cytokines exert pro-inflammatory effects, influencing immune cell activity and contributing to skin inflammation, particularly in HS.

Given the pivotal role of IL-17 in the pathogenesis of HS, the exploration of IL-17–targeted agents has become a focal point in clinical research. Bimekizumab, a novel IL-17 inhibitor, has emerged as a promising candidate, offering a potential breakthrough in the treatment landscape for individuals affected by HS.

Bimekizumab for HS Management

A phase II, double-blind, placebo-controlled RCT included 90 patients with moderate to severe HS (age range, 18-70 years) who were randomly assigned in a 2:1:1 ratio to receive either bimekizumab 320 mg every 2 weeks (with a 640-mg loading dose at baseline)(n=46), placebo (n=21), or adalimumab 40 mg once weekly from week 4 onward (following an initial 160-mg loading dose at baseline and 80-mg dose at week 2)(n=21). The study included a 12-week treatment period followed by a 20-week safety follow-up period. The primary endpoint was the achievement of HiSCR₅₀—defined as a reduction of at least 50% nodules, coupled with no increase in the number of abscesses or draining fistulas relative to baseline—at week 12. Additionally, the study assessed the number of patients who achieved a modified HiSCR with 75% reduction (HiSCR₇₅) of combined abscess and inflammatory nodule count or a modified HiSCR with 90% reduction (HiSCR₉₀). At week 12, the modeled response rates were estimated using a Bayesian logistic regression model. For HiSCR₅₀, the modeled rate for bimekizumab was 57.3%, with an observed rate of 62.5% (25/40), compared to a modeled rate of 26.1% for placebo (observed rate, 27.8% [5/18]). The posterior probability of superiority for bimekizumab over placebo was 0.998. By week 12, bimekizumab-treated patients achieved modeled HiSCR₇₅ and HiSCR₉₀ rates of 46.0% and 32.0%, respectively, with observed rates of 50.0% (20/40) for HiSCR₇₅ and 35.0% (14/40) for HiSCR₉₀. In comparison, placebo-treated patients achieved modeled HiSCR75 and HiSCR₉₀ rates of 10.0% and 0%, respectively, with observed rates of 11.1% (2/18) for HiSCR₇₅ and 0% (0/18) for HiSCR₉₀. Adalimumab-treated participants demonstrated intermediate results, achieving modeled HiSCR₇₅ and HiSCR₉₀ rates of 35.0% and 15.0%, respectively, with observed rates of 38.88% (7/18) for HiSCR₇₅ and 16.66% (3/18) for HiSCR₉₀.⁷

Bimekizumab was effective in the treatment of moderate to severe HS with comparable results to adalimumab.⁷ The incidence of treatment-emergent adverse events was similar across treatment arms (bimekizumab, 69.6% [32/46]; placebo, 61.9% [13/21]; adalimumab, 71.4% [15/21]). The most common treatment-emergent adverse events in the biologic treatment arms were infections (43.5% [20/46] in the bimekizumab group and 42.9% [9/21] in the adalimumab group), skin and subcutaneous tissue disorders (28.3% [13/46] in the bimekizumab group and 42.9% [9/21] in the adalimumab group), and general disorders/administration site conditions (21.7% [10/46] in the bimekizumab group and 23.8% [5/21] in the adalimumab group). Serious adverse events occurred in 4.3% (2/46) of patients in the bimekizumab group, 9.5% (2/21) of patients in the placebo group, and 4.8% (1/21) of patients in the adalimumab group. Serious adverse events that required hospitalization were due to anemia and empyema in the bimekizumab group; worsening HS in the adalimumab group; and myocardial infarction, hypoesthesia, headache, and dizziness in the placebo group. No deaths occurred in this study. Overall, bimekizumab was well tolerated, and discontinuation rates were low across all arms. The primary reason for discontinuation was withdrawal of consent (not due to an adverse event) or loss to follow-up.⁷

Two completed 48-week phase III RCTs, BE HEARD I and BE HEARD II, evaluated the efficacy and safety of bimekizumab in patients with moderate to severe HS.¹³ In both trials, 2 bimekizumab dosing regimens (320 mg every 2 weeks and 320 mg every 4 weeks) were compared with placebo during the 16-week initial and 32-week maintenance treatment periods. The primary endpoint of week 16 was achieved by 47.8% (138/289) and 51.9% (151/291) of patients receiving bimekizumab every 2 weeks in BE HEARD I (n=505) and BE HEARD II (n=509), respectively, compared with 29.2% (21/72) and 32.4% (24/74) of the placebo group. The bimekizumab 320 mg every 4 weeks dosing regimen met the primary endpoint only in BE HEARD II, with 53.5% (77/144) of patients achieving HiSCR₅₀ compared to 32.4% (24/74) with placebo (P=0.0038).¹³ Both trials met the key secondary endpoint of HiSCR₇₅ at week 16 for bimekizumab 320 mg every 2 weeks vs placebo. In BE HEARD I, 33.6% (97/289) of patients receiving bimekizumab achieved HiSCR₇₅ versus 18.1% (13/72) taking placebo. In BE HEARD II, 35.7% (104/291) of patients receiving bimekizumab achieved HiSCR₇₅ vs 16.2% (12/74) taking placebo. Responses were maintained or increased through week 48 in both trials. The most common treatment-emergent adverse events through week 48 were worsening HS, COVID-19 infection, diarrhea, oral candidiasis, and headache.¹³

A smaller scale case series investigated the use of bimekizumab in 4 female patients aged 20 to 62 years with moderate to severe HS and concomitant plaque or inverse psoriasis.⁸ A monthly loading dose of 320 mg was given during weeks 0 to 12 followed by a maintenance dose of 320 mg administered every 8 weeks. The International Hidradenitis Suppurativa Score System, visual analogue scale, and Dermatology Life Quality Index were used to assess the effectiveness of therapy by comparing scores before and after 4 and 16 weeks of treatment. A reduction of pain and improvement of HS lesions was observed in 3 (75.0%) patients after the first dosage of bimekizumab, with completed remission of HS by week 16. The fourth patient (25.0%) experienced substantial improvement in all measures, although not complete remission. All 4 patients remained on bimekizumab, and no adverse effects were reported.⁸

A meta-analysis evaluated 16 RCTs of 9 biologics and 3 small-molecule inhibitors in 2076 patients with HS.¹⁰ Secukinumab was not included in this meta-analysis. Only adalimumab (risk ratio, 1.77; 95% CI, 1.44-2.17) and bimekizumab (risk ratio, 2.25; 95% CI, 1.03-4.92) were superior to placebo in achieving HiSCR response at weeks 12 to 16 in 5 RCTs and 1 RCT, respectively; however, no statistically significant differences were noted between adalimumab and bimekizumab (P=.56). This analysis concluded that adalimumab and bimekizumab are the only 2 biologics efficacious in reaching HiSCR and consistently improved both disease severity and quality of life in patients with HS with an acceptable safety profile.¹⁰ Furthermore, these biologics had no increase in serious adverse events when compared to placebo.¹⁰

A network meta-analysis of 10 clinical trials involving more than 900 total participants evaluated nonsurgical therapies for HS. The analysis used Surface Under the Cumulative Ranking curve (SUCRA) values to estimate the efficacy of treatments in achieving clinical response according to HiSCR criteria. These values range from 0% to 100%, with 100% representing the best possible ranking for efficacy. Bimekizumab showed the highest estimated efficacy with a SUCRA value of 67%, followed by adalimumab (64%), anakinra (49%), and placebo (19%). These SUCRA values indicate the relative ranking of treatments, with higher values suggesting greater likelihood of achieving clinical response, rather than representing the actual percentage of patients achieving HiSCR. Bimekizumab was found to be more efficacious than placebo (P<.05).¹⁴

Building on the initial evidence of bimekizumab’s efficacy, BE HEARD I and BE HEARD II addressed some limitations of prior studies, including small sample sizes and insufficient stratification.¹³ Notably, stratification by baseline Hurley stage severity (ie, the most severe stage of disease assigned at baseline) and baseline systemic antibiotic use helped mitigate bias and ensured a more robust assessment of treatment efficacy; however, certain limitations persist. While the trials demonstrated rapid and clinically meaningful responses maintained up to 48 weeks, longer-term data beyond this period are limited, leaving gaps in understanding the durability of treatment effects over years. Additionally, despite appropriate stratification, the generalizability of the findings to broader patient populations remains unclear, as trial participants may not fully represent the diversity of patients seen in clinical practice.¹³

Future research is needed to address these limitations. The use of validated HS biomarkers as endpoints could enhance the ability to evaluate biologic efficacy and identify predictors of response. Comparative studies with other biologics also are warranted to establish the relative efficacy of bimekizumab within the growing therapeutic landscape for HS. Finally, real-world evidence from larger and more diverse populations will be critical to confirm the trial findings and assess long-term safety and effectiveness in routine clinical practice.¹³

Conclusion

The existing literature and recent phase III RCTs, BE HEARD I and BE HEARD II, demonstrate that bimekizumab is an effective treatment for moderate to severe HS, with robust efficacy according to HiSCR scores and sustained responses through 48 weeks. These trials addressed some prior limitations, including small sample sizes and insufficient stratification, providing a more comprehensive evaluation of bimekizumab’s clinical impact. The safety profile of bimekizumab remains favorable, with low discontinuation rates and manageable adverse events, such as infection, gastrointestinal upset, headache, and injection-site reactions. Long-term efficacy and safety data beyond 48 weeks still are needed to fully establish its durability and impact in diverse populations. The recent FDA approval of bimekizumab for moderate to severe HS provides patients with a new treatment option, offering a more positive clinical outlook.

Hidradenitis suppurativa (HS) is a debilitating dermatologic condition characterized by recurrent episodes of neutrophilic inflammation affecting the apocrine and pilosebaceous units that most commonly affects individuals aged 20 to 40 years. Originating from the hair follicles, inflammation initiates the formation of painful nodules and abscesses that can progress to sinus tracts or fistulas accompanied by the development of extensive scarring, exquisite pain, and malodorous drainage.¹ The lesions most commonly occur in intertriginous zones as well as areas rich in apocrine glands. The distinctive and sometimes irreversible clinical features of HS profoundly influence patients’ well-being and have lasting social, personal, and emotional impacts on their lives.²

Bimekizumab is a monoclonal antibody that specifically targets IL-17A and IL-17F, aiming to inhibit the downstream effects responsible for the chronic inflammation and tissue damage characteristic of HS.³ In HS lesions, IL-17 cytokines produced by T helper 17 (Th17) cells stimulate the production of chemokines (such as CC motif chemokine ligand 20) and neutrophil-attracting chemokines (including C-X-C motif chemokine ligands 1 and 8), cytokines (such as granulocyte colony-stimulating factor and IL-19), and epidermal antimicrobial proteins.^1,2 This cascade results in the chemotaxis of monocytes and neutrophils in the skin, recruiting additional Th17 and myeloid cells and further amplifying IL-17 production.¹

Bimekizumab’s mechanism of action strategically disrupts this feed-forward inflammatory loop, decreasing the transcription of neutrophil-attracting chemokines, IL-19, and epidermal antimicrobial proteins (Figure).^1,2 This leads to diminished recruitment of Th17 cells and inhibits the chemotaxis of monocytes and neutrophils in the skin, effectively addressing the chronic inflammation and tissue damage characteristic of HS.

We present a comprehensive review of the current standards of care, the underlying molecular pathophysiology of HS, and evaluation of the efficacy and safety of bimekizumab.

Evaluating HS Severity

The Hurley staging system provides a valuable framework for evaluating the severity of HS based on lesion characteristics. Stage I is characterized by abscess formation without tracts or scars. Stage II is characterized by recurrent abscesses with sinus tracts and scarring. Stage III is characterized by diffuse involvement, multiple interconnected sinus tracts, and abscesses across an entire area, leaving little to no uninvolved skin.⁴

Treatment strategies for HS vary based on Hurley staging (eTable).^5-11 For mild cases (stage I), topical and intralesional therapies are common, while moderate to severe cases (stages II and III) may require extensive surgical approaches or systemic drugs such as antibiotics, hormonal therapies, retinoids, or immunosuppressive/biologic agents.²

Adalimumab, an anti–tumor necrosis factor (TNF) α monoclonal antibody, was the first US Food and Drug Administration (FDA)–approved biologic for HS. Secukinumab, a monoclonal antibody against IL-17A, subsequently was approved by the FDA for moderate to severe HS.¹² Off-label use of biologics including infliximab and ustekinumab expands the available treatment options for HS. In one Phase II randomized clinical trial (RCT), infliximab showed efficacy in reducing Hidradenitis Suppurativa Severity Index scores, with 26.7% (4/15) of patients achieving a 50% or greater reduction compared to placebo, although this was not statistically significant. Similarly, ustekinumab demonstrated promising results, with 47.1% (8/17) of patients achieving Hidradenitis Suppurativa Clinical Response (HiSCR) at week 40.² This multifaceted approach aims to address the varying degrees of severity and optimize outcomes for individuals with HS.

Molecular Pathophysiology of HS

The pathogenesis of HS is multifactorial, involving a complex interplay of genetic, environmental, and behavioral factors.² Approximately 33% to 40% of patients with HS worldwide report a first-degree relative with the condition, indicating a hereditary element with an autosomal-dominant transmission pattern and highlighting the global relevance of genetic factors in HS.⁴ Hidradenitis suppurativa is highly prevalent in individuals with obesity, likely due to increased intertriginous surface area, skin friction, sweat production, and hormonal changes in these patients. Smoking also commonly is associated with HS, with nicotine potentially contributing to increased follicular plugging.¹ Hormonal influences also play a role, as evidenced by a greater prevalence of HS in females, disease onset typically occurring between puberty and menopause, and symptomatic fluctuations correlating with menstrual cycles and exogenous hormones.⁴

Altered infundibular keratinization with subsequent hyperkeratosis/occlusion and innate immune pathway activation are key events leading to development of HS.¹ These events are mediated by release of pathogen- and danger-associated molecular patterns, leading to inflammasome-mediated IL-1α release, followed by downstream cytokine release.² Elevated levels of TNF-α, IL-1Β, IL-10, IL-17, and particularly IL-17A have been detected in HS lesional skin. The IL-17 family comprises multiple members, namely IL-17A, IL-17C, IL-17E, and IL17F. IL-17A and IL-17F often are co-expressed and secreted predominantly by a subset of CD4+ T helper cells, namely Th17 cells.² IL-17 cytokines exert pro-inflammatory effects, influencing immune cell activity and contributing to skin inflammation, particularly in HS.

Given the pivotal role of IL-17 in the pathogenesis of HS, the exploration of IL-17–targeted agents has become a focal point in clinical research. Bimekizumab, a novel IL-17 inhibitor, has emerged as a promising candidate, offering a potential breakthrough in the treatment landscape for individuals affected by HS.

Bimekizumab for HS Management

A phase II, double-blind, placebo-controlled RCT included 90 patients with moderate to severe HS (age range, 18-70 years) who were randomly assigned in a 2:1:1 ratio to receive either bimekizumab 320 mg every 2 weeks (with a 640-mg loading dose at baseline)(n=46), placebo (n=21), or adalimumab 40 mg once weekly from week 4 onward (following an initial 160-mg loading dose at baseline and 80-mg dose at week 2)(n=21). The study included a 12-week treatment period followed by a 20-week safety follow-up period. The primary endpoint was the achievement of HiSCR₅₀—defined as a reduction of at least 50% nodules, coupled with no increase in the number of abscesses or draining fistulas relative to baseline—at week 12. Additionally, the study assessed the number of patients who achieved a modified HiSCR with 75% reduction (HiSCR₇₅) of combined abscess and inflammatory nodule count or a modified HiSCR with 90% reduction (HiSCR₉₀). At week 12, the modeled response rates were estimated using a Bayesian logistic regression model. For HiSCR₅₀, the modeled rate for bimekizumab was 57.3%, with an observed rate of 62.5% (25/40), compared to a modeled rate of 26.1% for placebo (observed rate, 27.8% [5/18]). The posterior probability of superiority for bimekizumab over placebo was 0.998. By week 12, bimekizumab-treated patients achieved modeled HiSCR₇₅ and HiSCR₉₀ rates of 46.0% and 32.0%, respectively, with observed rates of 50.0% (20/40) for HiSCR₇₅ and 35.0% (14/40) for HiSCR₉₀. In comparison, placebo-treated patients achieved modeled HiSCR75 and HiSCR₉₀ rates of 10.0% and 0%, respectively, with observed rates of 11.1% (2/18) for HiSCR₇₅ and 0% (0/18) for HiSCR₉₀. Adalimumab-treated participants demonstrated intermediate results, achieving modeled HiSCR₇₅ and HiSCR₉₀ rates of 35.0% and 15.0%, respectively, with observed rates of 38.88% (7/18) for HiSCR₇₅ and 16.66% (3/18) for HiSCR₉₀.⁷

Bimekizumab was effective in the treatment of moderate to severe HS with comparable results to adalimumab.⁷ The incidence of treatment-emergent adverse events was similar across treatment arms (bimekizumab, 69.6% [32/46]; placebo, 61.9% [13/21]; adalimumab, 71.4% [15/21]). The most common treatment-emergent adverse events in the biologic treatment arms were infections (43.5% [20/46] in the bimekizumab group and 42.9% [9/21] in the adalimumab group), skin and subcutaneous tissue disorders (28.3% [13/46] in the bimekizumab group and 42.9% [9/21] in the adalimumab group), and general disorders/administration site conditions (21.7% [10/46] in the bimekizumab group and 23.8% [5/21] in the adalimumab group). Serious adverse events occurred in 4.3% (2/46) of patients in the bimekizumab group, 9.5% (2/21) of patients in the placebo group, and 4.8% (1/21) of patients in the adalimumab group. Serious adverse events that required hospitalization were due to anemia and empyema in the bimekizumab group; worsening HS in the adalimumab group; and myocardial infarction, hypoesthesia, headache, and dizziness in the placebo group. No deaths occurred in this study. Overall, bimekizumab was well tolerated, and discontinuation rates were low across all arms. The primary reason for discontinuation was withdrawal of consent (not due to an adverse event) or loss to follow-up.⁷

Two completed 48-week phase III RCTs, BE HEARD I and BE HEARD II, evaluated the efficacy and safety of bimekizumab in patients with moderate to severe HS.¹³ In both trials, 2 bimekizumab dosing regimens (320 mg every 2 weeks and 320 mg every 4 weeks) were compared with placebo during the 16-week initial and 32-week maintenance treatment periods. The primary endpoint of week 16 was achieved by 47.8% (138/289) and 51.9% (151/291) of patients receiving bimekizumab every 2 weeks in BE HEARD I (n=505) and BE HEARD II (n=509), respectively, compared with 29.2% (21/72) and 32.4% (24/74) of the placebo group. The bimekizumab 320 mg every 4 weeks dosing regimen met the primary endpoint only in BE HEARD II, with 53.5% (77/144) of patients achieving HiSCR₅₀ compared to 32.4% (24/74) with placebo (P=0.0038).¹³ Both trials met the key secondary endpoint of HiSCR₇₅ at week 16 for bimekizumab 320 mg every 2 weeks vs placebo. In BE HEARD I, 33.6% (97/289) of patients receiving bimekizumab achieved HiSCR₇₅ versus 18.1% (13/72) taking placebo. In BE HEARD II, 35.7% (104/291) of patients receiving bimekizumab achieved HiSCR₇₅ vs 16.2% (12/74) taking placebo. Responses were maintained or increased through week 48 in both trials. The most common treatment-emergent adverse events through week 48 were worsening HS, COVID-19 infection, diarrhea, oral candidiasis, and headache.¹³

A smaller scale case series investigated the use of bimekizumab in 4 female patients aged 20 to 62 years with moderate to severe HS and concomitant plaque or inverse psoriasis.⁸ A monthly loading dose of 320 mg was given during weeks 0 to 12 followed by a maintenance dose of 320 mg administered every 8 weeks. The International Hidradenitis Suppurativa Score System, visual analogue scale, and Dermatology Life Quality Index were used to assess the effectiveness of therapy by comparing scores before and after 4 and 16 weeks of treatment. A reduction of pain and improvement of HS lesions was observed in 3 (75.0%) patients after the first dosage of bimekizumab, with completed remission of HS by week 16. The fourth patient (25.0%) experienced substantial improvement in all measures, although not complete remission. All 4 patients remained on bimekizumab, and no adverse effects were reported.⁸

A meta-analysis evaluated 16 RCTs of 9 biologics and 3 small-molecule inhibitors in 2076 patients with HS.¹⁰ Secukinumab was not included in this meta-analysis. Only adalimumab (risk ratio, 1.77; 95% CI, 1.44-2.17) and bimekizumab (risk ratio, 2.25; 95% CI, 1.03-4.92) were superior to placebo in achieving HiSCR response at weeks 12 to 16 in 5 RCTs and 1 RCT, respectively; however, no statistically significant differences were noted between adalimumab and bimekizumab (P=.56). This analysis concluded that adalimumab and bimekizumab are the only 2 biologics efficacious in reaching HiSCR and consistently improved both disease severity and quality of life in patients with HS with an acceptable safety profile.¹⁰ Furthermore, these biologics had no increase in serious adverse events when compared to placebo.¹⁰

A network meta-analysis of 10 clinical trials involving more than 900 total participants evaluated nonsurgical therapies for HS. The analysis used Surface Under the Cumulative Ranking curve (SUCRA) values to estimate the efficacy of treatments in achieving clinical response according to HiSCR criteria. These values range from 0% to 100%, with 100% representing the best possible ranking for efficacy. Bimekizumab showed the highest estimated efficacy with a SUCRA value of 67%, followed by adalimumab (64%), anakinra (49%), and placebo (19%). These SUCRA values indicate the relative ranking of treatments, with higher values suggesting greater likelihood of achieving clinical response, rather than representing the actual percentage of patients achieving HiSCR. Bimekizumab was found to be more efficacious than placebo (P<.05).¹⁴

Building on the initial evidence of bimekizumab’s efficacy, BE HEARD I and BE HEARD II addressed some limitations of prior studies, including small sample sizes and insufficient stratification.¹³ Notably, stratification by baseline Hurley stage severity (ie, the most severe stage of disease assigned at baseline) and baseline systemic antibiotic use helped mitigate bias and ensured a more robust assessment of treatment efficacy; however, certain limitations persist. While the trials demonstrated rapid and clinically meaningful responses maintained up to 48 weeks, longer-term data beyond this period are limited, leaving gaps in understanding the durability of treatment effects over years. Additionally, despite appropriate stratification, the generalizability of the findings to broader patient populations remains unclear, as trial participants may not fully represent the diversity of patients seen in clinical practice.¹³

Future research is needed to address these limitations. The use of validated HS biomarkers as endpoints could enhance the ability to evaluate biologic efficacy and identify predictors of response. Comparative studies with other biologics also are warranted to establish the relative efficacy of bimekizumab within the growing therapeutic landscape for HS. Finally, real-world evidence from larger and more diverse populations will be critical to confirm the trial findings and assess long-term safety and effectiveness in routine clinical practice.¹³

Conclusion

The existing literature and recent phase III RCTs, BE HEARD I and BE HEARD II, demonstrate that bimekizumab is an effective treatment for moderate to severe HS, with robust efficacy according to HiSCR scores and sustained responses through 48 weeks. These trials addressed some prior limitations, including small sample sizes and insufficient stratification, providing a more comprehensive evaluation of bimekizumab’s clinical impact. The safety profile of bimekizumab remains favorable, with low discontinuation rates and manageable adverse events, such as infection, gastrointestinal upset, headache, and injection-site reactions. Long-term efficacy and safety data beyond 48 weeks still are needed to fully establish its durability and impact in diverse populations. The recent FDA approval of bimekizumab for moderate to severe HS provides patients with a new treatment option, offering a more positive clinical outlook.

THE DIAGNOSIS: Cutaneous Endometriosis

Endometriosis is the ectopic presence of endometrial tissue and occurs in approximately 13% of women of childbearing age.¹ This non-neoplastic lesion can manifest on the skin in less than 5.5% of endometriosis cases worldwide. Historically, secondary cutaneous endometriosis (CE) most frequently has been associated with prior gynecologic surgery (often cesarean section)²; however, an increased incidence of primary CE in patients without prior surgical history recently has been documented in the literature.³ While secondary CE usually manifests at the site of a surgical scar, primary CE has a predilection for the umbilicus (Villar nodule). In both primary and secondary CE, patients present clinically with a solitary nodule and abdominal pain that may be exacerbated during menstruation. Bleeding without associated pain may be more common in primary CE, while bleeding with pain may be more common in secondary CE. Cutaneous endometriosis often is overlooked given its low incidence, leading to delayed diagnosis. Primary CE often is misdiagnosed clinically as a pyogenic granuloma, Sister Mary Joseph nodule, or keloid, while secondary CE may be mistaken for a fibroma, incisional hernia, or granuloma.²

Primary and secondary CE have identical histopathologic features. Glands of variable size consisting of a single epithelial layer of columnar cells are present in the reticular dermis or subcutis (quiz image).⁴ The accompanying periglandular stroma often is uniform, consisting of spindle-shaped basophilic cells with abundant vascular structures. The stroma may contain moderate numbers of mitotic figures, a chronic inflammatory infiltrate, and extravasated red blood cells. The ectopic tissue may be inactive or display morphologic changes resembling those of the endometrium in the normal menstrual cycle.⁴ As the ectopic tissue progresses through the stages of menstruation, the glandular morphology also transforms. The proliferative stage demonstrates increased epithelial mitotic figures, the secretory stage exhibits intraluminal secretion, and during menstruation there are degenerative epithelial cells and evidence of vascular congestion. A mixture of glandular stages may be seen in biopsy results. Robust immunohistochemical expression of CD10 in the endometrial stroma can aid in diagnosis (Figure 1). Estrogen and progesterone receptor immunostaining also shows strong nuclear positivity, except in decidualized tissue.⁴ Unlike intestinal glands, endometrial glands do not express CDX2 or CK20.⁵ Complete surgical excision of CE usually is curative; however, recurrence has been documented in 10% (3/30) of cases.²

Breast carcinoma is the most common internal malignancy associated with cutaneous metastasis and may develop prior to visceral diagnosis. It is possible that tumor cells travel through the communicating networks of the cutaneous lymphatic ducts and the mammary lymphatic plexus; however, cutaneous manifestation often is located on the ipsilateral breast, and therefore tumor expansion rather than true metastasis cannot always be ruled out. On histopathology, findings of breast adenocarcinoma include tumor cells that tend to show either interstitial, nodular, mixed, or intravascular growth patterns (Figure 2). Tumor cells may invade the stroma in clusters or as individual cells. Sites of distant metastasis may show an increased likelihood of vascular and lymphatic invasion.⁶

Nodular hidradenoma often manifests as a solitary nodule in the head or neck region, predominantly in women.⁷ Pathology shows well-demarcated intradermal aggregates of tumor cells within a hyalinized stroma; connection to the epidermis is not a feature of nodular hidradenoma. The epithelial component consists of polygonal cells with eosinophilic to amphophilic cytoplasm as well as large glycogenated cells with pale to clear cytoplasm (leading to the alternative term clear cell hidradenoma)(Figure 3). The cystic portion represents deterioration of tumor cells. Surgical excision usually is curative, although lesions may recur. Malignant transformation is rare.⁷

Sister Mary Joseph nodule is a cutaneous involvement of the umbilicus by a metastatic malignancy, often from an intra-abdominal primary malignancy (most commonly ovarian carcinoma in women and colonic carcinoma in men). Clinically, patients present with a solitary firm nodule or plaque within the umbilicus.^8,9 Histopathology recapitulates the primary tumor (Figure 4).⁹ Sister Mary Joseph nodule portends a poor prognosis, with a survival rate of less than 8 months from the time of diagnosis.¹⁰

Urachal duct cyst develops from a remnant of the urachus that closed appropriately at the umbilicus and bladder but did not completely regress. It may manifest as an extraperitoneal mass at the umbilicus. Clinically, urachal duct cysts may be asymptomatic until an inciting event (eg, inflammation, deposition of calculus, or malignancy) occurs.¹¹ Histopathology shows cystically dilated structures lined with a transitional epithelium (Figure 5).¹² Urachal duct cysts usually are diagnosed in children or young adults and subsequently are excised.¹¹

THE DIAGNOSIS: Cutaneous Endometriosis

Endometriosis is the ectopic presence of endometrial tissue and occurs in approximately 13% of women of childbearing age.¹ This non-neoplastic lesion can manifest on the skin in less than 5.5% of endometriosis cases worldwide. Historically, secondary cutaneous endometriosis (CE) most frequently has been associated with prior gynecologic surgery (often cesarean section)²; however, an increased incidence of primary CE in patients without prior surgical history recently has been documented in the literature.³ While secondary CE usually manifests at the site of a surgical scar, primary CE has a predilection for the umbilicus (Villar nodule). In both primary and secondary CE, patients present clinically with a solitary nodule and abdominal pain that may be exacerbated during menstruation. Bleeding without associated pain may be more common in primary CE, while bleeding with pain may be more common in secondary CE. Cutaneous endometriosis often is overlooked given its low incidence, leading to delayed diagnosis. Primary CE often is misdiagnosed clinically as a pyogenic granuloma, Sister Mary Joseph nodule, or keloid, while secondary CE may be mistaken for a fibroma, incisional hernia, or granuloma.²

Primary and secondary CE have identical histopathologic features. Glands of variable size consisting of a single epithelial layer of columnar cells are present in the reticular dermis or subcutis (quiz image).⁴ The accompanying periglandular stroma often is uniform, consisting of spindle-shaped basophilic cells with abundant vascular structures. The stroma may contain moderate numbers of mitotic figures, a chronic inflammatory infiltrate, and extravasated red blood cells. The ectopic tissue may be inactive or display morphologic changes resembling those of the endometrium in the normal menstrual cycle.⁴ As the ectopic tissue progresses through the stages of menstruation, the glandular morphology also transforms. The proliferative stage demonstrates increased epithelial mitotic figures, the secretory stage exhibits intraluminal secretion, and during menstruation there are degenerative epithelial cells and evidence of vascular congestion. A mixture of glandular stages may be seen in biopsy results. Robust immunohistochemical expression of CD10 in the endometrial stroma can aid in diagnosis (Figure 1). Estrogen and progesterone receptor immunostaining also shows strong nuclear positivity, except in decidualized tissue.⁴ Unlike intestinal glands, endometrial glands do not express CDX2 or CK20.⁵ Complete surgical excision of CE usually is curative; however, recurrence has been documented in 10% (3/30) of cases.²

Breast carcinoma is the most common internal malignancy associated with cutaneous metastasis and may develop prior to visceral diagnosis. It is possible that tumor cells travel through the communicating networks of the cutaneous lymphatic ducts and the mammary lymphatic plexus; however, cutaneous manifestation often is located on the ipsilateral breast, and therefore tumor expansion rather than true metastasis cannot always be ruled out. On histopathology, findings of breast adenocarcinoma include tumor cells that tend to show either interstitial, nodular, mixed, or intravascular growth patterns (Figure 2). Tumor cells may invade the stroma in clusters or as individual cells. Sites of distant metastasis may show an increased likelihood of vascular and lymphatic invasion.⁶

Nodular hidradenoma often manifests as a solitary nodule in the head or neck region, predominantly in women.⁷ Pathology shows well-demarcated intradermal aggregates of tumor cells within a hyalinized stroma; connection to the epidermis is not a feature of nodular hidradenoma. The epithelial component consists of polygonal cells with eosinophilic to amphophilic cytoplasm as well as large glycogenated cells with pale to clear cytoplasm (leading to the alternative term clear cell hidradenoma)(Figure 3). The cystic portion represents deterioration of tumor cells. Surgical excision usually is curative, although lesions may recur. Malignant transformation is rare.⁷

Sister Mary Joseph nodule is a cutaneous involvement of the umbilicus by a metastatic malignancy, often from an intra-abdominal primary malignancy (most commonly ovarian carcinoma in women and colonic carcinoma in men). Clinically, patients present with a solitary firm nodule or plaque within the umbilicus.^8,9 Histopathology recapitulates the primary tumor (Figure 4).⁹ Sister Mary Joseph nodule portends a poor prognosis, with a survival rate of less than 8 months from the time of diagnosis.¹⁰

Urachal duct cyst develops from a remnant of the urachus that closed appropriately at the umbilicus and bladder but did not completely regress. It may manifest as an extraperitoneal mass at the umbilicus. Clinically, urachal duct cysts may be asymptomatic until an inciting event (eg, inflammation, deposition of calculus, or malignancy) occurs.¹¹ Histopathology shows cystically dilated structures lined with a transitional epithelium (Figure 5).¹² Urachal duct cysts usually are diagnosed in children or young adults and subsequently are excised.¹¹

THE DIAGNOSIS: Cutaneous Endometriosis

Endometriosis is the ectopic presence of endometrial tissue and occurs in approximately 13% of women of childbearing age.¹ This non-neoplastic lesion can manifest on the skin in less than 5.5% of endometriosis cases worldwide. Historically, secondary cutaneous endometriosis (CE) most frequently has been associated with prior gynecologic surgery (often cesarean section)²; however, an increased incidence of primary CE in patients without prior surgical history recently has been documented in the literature.³ While secondary CE usually manifests at the site of a surgical scar, primary CE has a predilection for the umbilicus (Villar nodule). In both primary and secondary CE, patients present clinically with a solitary nodule and abdominal pain that may be exacerbated during menstruation. Bleeding without associated pain may be more common in primary CE, while bleeding with pain may be more common in secondary CE. Cutaneous endometriosis often is overlooked given its low incidence, leading to delayed diagnosis. Primary CE often is misdiagnosed clinically as a pyogenic granuloma, Sister Mary Joseph nodule, or keloid, while secondary CE may be mistaken for a fibroma, incisional hernia, or granuloma.²

Primary and secondary CE have identical histopathologic features. Glands of variable size consisting of a single epithelial layer of columnar cells are present in the reticular dermis or subcutis (quiz image).⁴ The accompanying periglandular stroma often is uniform, consisting of spindle-shaped basophilic cells with abundant vascular structures. The stroma may contain moderate numbers of mitotic figures, a chronic inflammatory infiltrate, and extravasated red blood cells. The ectopic tissue may be inactive or display morphologic changes resembling those of the endometrium in the normal menstrual cycle.⁴ As the ectopic tissue progresses through the stages of menstruation, the glandular morphology also transforms. The proliferative stage demonstrates increased epithelial mitotic figures, the secretory stage exhibits intraluminal secretion, and during menstruation there are degenerative epithelial cells and evidence of vascular congestion. A mixture of glandular stages may be seen in biopsy results. Robust immunohistochemical expression of CD10 in the endometrial stroma can aid in diagnosis (Figure 1). Estrogen and progesterone receptor immunostaining also shows strong nuclear positivity, except in decidualized tissue.⁴ Unlike intestinal glands, endometrial glands do not express CDX2 or CK20.⁵ Complete surgical excision of CE usually is curative; however, recurrence has been documented in 10% (3/30) of cases.²

Breast carcinoma is the most common internal malignancy associated with cutaneous metastasis and may develop prior to visceral diagnosis. It is possible that tumor cells travel through the communicating networks of the cutaneous lymphatic ducts and the mammary lymphatic plexus; however, cutaneous manifestation often is located on the ipsilateral breast, and therefore tumor expansion rather than true metastasis cannot always be ruled out. On histopathology, findings of breast adenocarcinoma include tumor cells that tend to show either interstitial, nodular, mixed, or intravascular growth patterns (Figure 2). Tumor cells may invade the stroma in clusters or as individual cells. Sites of distant metastasis may show an increased likelihood of vascular and lymphatic invasion.⁶

Nodular hidradenoma often manifests as a solitary nodule in the head or neck region, predominantly in women.⁷ Pathology shows well-demarcated intradermal aggregates of tumor cells within a hyalinized stroma; connection to the epidermis is not a feature of nodular hidradenoma. The epithelial component consists of polygonal cells with eosinophilic to amphophilic cytoplasm as well as large glycogenated cells with pale to clear cytoplasm (leading to the alternative term clear cell hidradenoma)(Figure 3). The cystic portion represents deterioration of tumor cells. Surgical excision usually is curative, although lesions may recur. Malignant transformation is rare.⁷

Sister Mary Joseph nodule is a cutaneous involvement of the umbilicus by a metastatic malignancy, often from an intra-abdominal primary malignancy (most commonly ovarian carcinoma in women and colonic carcinoma in men). Clinically, patients present with a solitary firm nodule or plaque within the umbilicus.^8,9 Histopathology recapitulates the primary tumor (Figure 4).⁹ Sister Mary Joseph nodule portends a poor prognosis, with a survival rate of less than 8 months from the time of diagnosis.¹⁰

Urachal duct cyst develops from a remnant of the urachus that closed appropriately at the umbilicus and bladder but did not completely regress. It may manifest as an extraperitoneal mass at the umbilicus. Clinically, urachal duct cysts may be asymptomatic until an inciting event (eg, inflammation, deposition of calculus, or malignancy) occurs.¹¹ Histopathology shows cystically dilated structures lined with a transitional epithelium (Figure 5).¹² Urachal duct cysts usually are diagnosed in children or young adults and subsequently are excised.¹¹

Seborrheic dermatitis (SD) is a common chronic inflammatory skin condition that predominantly affects areas with high concentrations of sebaceous glands such as the scalp and face. Up to 5% of the worldwide population is affected by SD each year, causing a major burden of disease for patients and the health care system.¹ In 2023, the cost of medical treatment for SD in the United States was $300 million, with outpatient office visits alone costing $58 million and prescription drugs costing $109 million. Indirect costs of disease (eg, lost workdays) account for another $51 million.¹ Since SD frequently manifests on the face, it tends to have negative effects on the patient’s quality of life, resulting in psychological distress and low self-esteem.²

Patients with SD may describe symptoms of excessive dandruff and itching along with hyperpigmentation or hypopigmentation of the skin; Black patients tend to present with the classic manifestations: a combination of scaling, flaking, and erythematous patches on the scalp, ears, and face, particularly around the eyebrows, eyelids, and nose. With SD being the second most common diagnosis in Black patients who seek care from a dermatologist, it is important to have effective treatment approaches for SD in this patient population.³

In this study, we aimed to evaluate medical and nonmedical treatment options for SD in Black patients by identifying common practices and products mentioned on consumer websites and in the medical literature.

Methods

A Google search was conducted during 2 time periods (September 2022—October 2022 and March 2023—April 2023) using the terms products for itchy scalp in Black patients, products for dandruff in Black patients, itchy scalp in Black women, itchy scalp in Black men, treatment for scalp itch in Black patients, and dry scalp in Black hair. Products that were recommended by at least 1 website on the first page of search results were included in our list of products, and the ingredients were reviewed by the authors. We excluded individual retailer websites as well as those that did not provide specific recommendations on products or ingredients to use when treating SD. To ensure reliability and standardization, we did not review products that were suggested by ads in the shopping section on the first page of search results.

We also evaluated medical treatments used for SD in dermatology literature. A PubMed search of articles indexed for MEDLINE using the terms seborrheic dermatitis treatment for Black patients, treatment for dandruff for Black patients, and seborrheic dermatitis and skin of color was conducted. We excluded articles that did not address treatment options for SD, were specific to treating SD in patient populations with specific comorbidities being studied, discussed SD in animals, or were published prior to 1990.

Results

We identified 16 unique consumer websites with product or ingredient recommendations for SD in Black patients, none of which were provided by authors with a medical or scientific background; however, 4 (25%) websites included insights from board-certified dermatologists. A total of 16 ingredients were recommended, 15 (94%) of which were mentioned at least twice in our search results (eTable 1).

Overall, we noticed that ingredients labeled as natural or organic were common in over-the-counter (OTC) products, and ingredients such as sulfates and parabens were avoided. Common OTC ingredients for antidandruff and anti-itch shampoos and conditioners include zinc pyrithione, selenium sulfide, coal tar, salicylic acid, and citric acid. Additionally, coconut oil, tea tree oil, apple cider vinegar, and charcoal are common natural alternatives used to address SD symptoms.

Our review of the literature yielded limited recommendations tailored specifically to Black patients with SD. Of 108 abstracts, articles, or textbook chapters providing treatment recommendations for SD, 6 (6%) specifically discussed treatments for Black patients. All articles were written by authors with medical or scientific backgrounds. Of the treatment options discussed, topical antifungals generally were considered first-line for SD in all patients, with ketoconazole shampoo being a common first choice.^4,5

Comment

Our study indicated that many consumer websites recommend unstudied nonmedical treatments for SD. Zinc pyrithione was one of the most commonly mentioned ingredients in OTC products to treat SD targeted toward Black patients, as its properties have contributed to ease of hair combing and less frizz.⁶ Zinc pyrithione has antifungal properties that reduce the proliferation of Malassezia furfur as well as anti-inflammatory properties that reduce irritation, pruritus, and erythema in areas affected by SD.⁷ Tea tree and peppermint oils also were commonly mentioned; the theory is that these oils mitigate SD by reducing yeast growth and soothing inflammation through antioxidant activity.^8,9 Coal tar also is used due to its keratoplastic properties, which slow the growth of skin cells and ultimately reduce scaling and dryness.¹⁰ Yeast thrives in basic pH conditions; apple cider vinegar is used as an ingredient in OTC products for SD because its acidic pH creates a less favorable environment for yeast to grow.¹¹ Although many of the ingredients found in OTC products we identified have not yet been studied, they have properties that theoretically would be helpful in treating SD.

Our review of the medical literature revealed that while there are treatments that are effective for SD, the recommended use may not consider the cultural differences that exist for Black patients. For instance, reports in the literature regarding ketoconazole shampoo revealed that ketoconazole increases the risk for hair shaft dryness, damage, and subsequent breakage, especially in Black women who also may be using heat styling or chemical relaxers.⁵ As a result, ketoconazole should be used with caution in Black women, with an emphasis on direct application to the scalp rather than the hair shafts.¹² Additional options reported for Black patients include ciclopirox olamine and zinc pyrithione, which may have fewer risks.¹³

When prescribing medicated shampoos, traditional instructions regarding frequency of use to control symptoms of SD range from 2 to 3 times weekly to daily for a specified period of time determined by the dermatologist.¹⁴ However, frequency of hair washing varies greatly among Black patients, sometimes occurring only once monthly. The frequency also may change based on styling techniques (eg, braids, weaves, and wigs).¹⁵ Based on previous research underscoring the tendency for Black patients to use medicated shampoos less frequently than White patients, it is important for clinicians to understand that these cultural practices can undermine the effectiveness when medicated shampoos are prescribed for SD.¹⁶

Additionally, topical corticosteroids often are used in conjunction with antifungals to help decrease inflammation of the scalp.¹⁷ An option reported for Black patients is topical fluocinolone 0.01%; however, package instructions state to apply topically to the scalp nightly and wash the hair thoroughly each morning, which may not be feasible for Black patients based on previously mentioned differences in hair-washing techniques. An alternative option may be to apply the medication 3 to 4 times per week, washing the hair weekly rather than daily.¹⁸ Fluocinolone can be used as an ointment, solution, oil, or cream.^19,20 When comparing treatment vehicles for SD, a study conducted by Chappell et al²¹ found that Black patients preferred using ointment or oil vehicles; White patients preferred foams and sprays, which may not be suitable for Afro hair patterns. As such, using less-drying modalities may increase compliance and treatment success in Black patients. For patients who may have involvement on the hairline, face, or ears along with hypopigmentation (which is a common skin concern associated with SD), calcineurin inhibitors can be used until resolution occurs.^5,22 High et al¹⁵ found that twice-daily use of pimecrolimus rapidly normalized skin pigmentation during the first 2 weeks of use. Overall, personalization of treatment may not only avoid adverse effects but also ensure patient compliance, with the overall goal of treating to reduce yeast activity, pruritus, and dyschromia.²²

Interestingly, after the website searches were completed for this study, the US Food and Drug Administration approved topical roflumilast foam for SD. In a phase III trial of 457 total patients, 36 Black patients were included.²³ It was determined that 79.5% of patients overall throughout the trial achieved Investigator Global Assessment success (score of 0 [clear] or 1 [almost clear]) plus ≥2-point improvement from baseline (on a scale of 0 [clear] to 4 [severe]) at weeks 2, 4, and 8. Although there currently are no long-term studies, roflumilast may be a promising option for Black patients with SD.²³

Aside from developing an individualized treatment approach for Black patients with SD, it is important to ask targeted questions during the clinical encounter to identify factors that may be exacerbating symptoms, especially due to the wide range of hair care practices used by the Black community (eTable 2). Asking targeted questions is especially important, as prior studies have shown that extensions, hair relaxers, and particular hair products can irritate the scalp and increase the likelihood of developing SD.^21,24 Rucker Wright et al²⁵ evaluated different hair care practices among young Black females and their association with the development of SD. The authors found that using hair extensions (either braided, cornrowed, or ponytails), chemical relaxers, and hair oils every 2 weeks was associated with SD. The study also found that SD rates were roughly 20% higher among Black girls with extensions compared to Black girls without extensions, regardless of how frequently hair was washed.²⁵

Many Black patients grease the scalp with oils that are beneficial for lubrication and reduction of abrasive damage caused by grooming; however, they also may increase incidence of SD.²⁶ Tight curls worn by Black patients also can impede sebum from traveling down the hair shaft, leading to oil buildup on the scalp. This is the ideal environment for increased Malassezia density and higher risk for SD development.²⁷ To balance the beneficial effects of hair oils with the increased susceptibility for SD, providers should emphasize applying these oils only to distal hair shafts, which are more likely to be damaged, and avoiding application to the scalp.¹⁹

Conclusion

Given its long-term relapsing and remitting nature, SD can be distressing for Black patients, many of whom may seek additional treatment options aside from those recommended by health care professionals. In order to better educate patients, it is important for dermatologists to know not only the common ingredients that may be present in OTC products but also the thought process behind why patients use them. Additionally, prescription treatments for Black patients with SD may require nuanced alterations to the product instructions that may prevent health disparities and provide culturally sensitive care. Overall, the literature regarding treatment for Black patients with SD is limited, and more high-quality studies are needed.

Seborrheic dermatitis (SD) is a common chronic inflammatory skin condition that predominantly affects areas with high concentrations of sebaceous glands such as the scalp and face. Up to 5% of the worldwide population is affected by SD each year, causing a major burden of disease for patients and the health care system.¹ In 2023, the cost of medical treatment for SD in the United States was $300 million, with outpatient office visits alone costing $58 million and prescription drugs costing $109 million. Indirect costs of disease (eg, lost workdays) account for another $51 million.¹ Since SD frequently manifests on the face, it tends to have negative effects on the patient’s quality of life, resulting in psychological distress and low self-esteem.²

Patients with SD may describe symptoms of excessive dandruff and itching along with hyperpigmentation or hypopigmentation of the skin; Black patients tend to present with the classic manifestations: a combination of scaling, flaking, and erythematous patches on the scalp, ears, and face, particularly around the eyebrows, eyelids, and nose. With SD being the second most common diagnosis in Black patients who seek care from a dermatologist, it is important to have effective treatment approaches for SD in this patient population.³

In this study, we aimed to evaluate medical and nonmedical treatment options for SD in Black patients by identifying common practices and products mentioned on consumer websites and in the medical literature.

Methods

A Google search was conducted during 2 time periods (September 2022—October 2022 and March 2023—April 2023) using the terms products for itchy scalp in Black patients, products for dandruff in Black patients, itchy scalp in Black women, itchy scalp in Black men, treatment for scalp itch in Black patients, and dry scalp in Black hair. Products that were recommended by at least 1 website on the first page of search results were included in our list of products, and the ingredients were reviewed by the authors. We excluded individual retailer websites as well as those that did not provide specific recommendations on products or ingredients to use when treating SD. To ensure reliability and standardization, we did not review products that were suggested by ads in the shopping section on the first page of search results.

We also evaluated medical treatments used for SD in dermatology literature. A PubMed search of articles indexed for MEDLINE using the terms seborrheic dermatitis treatment for Black patients, treatment for dandruff for Black patients, and seborrheic dermatitis and skin of color was conducted. We excluded articles that did not address treatment options for SD, were specific to treating SD in patient populations with specific comorbidities being studied, discussed SD in animals, or were published prior to 1990.

Results

We identified 16 unique consumer websites with product or ingredient recommendations for SD in Black patients, none of which were provided by authors with a medical or scientific background; however, 4 (25%) websites included insights from board-certified dermatologists. A total of 16 ingredients were recommended, 15 (94%) of which were mentioned at least twice in our search results (eTable 1).

Overall, we noticed that ingredients labeled as natural or organic were common in over-the-counter (OTC) products, and ingredients such as sulfates and parabens were avoided. Common OTC ingredients for antidandruff and anti-itch shampoos and conditioners include zinc pyrithione, selenium sulfide, coal tar, salicylic acid, and citric acid. Additionally, coconut oil, tea tree oil, apple cider vinegar, and charcoal are common natural alternatives used to address SD symptoms.

Our review of the literature yielded limited recommendations tailored specifically to Black patients with SD. Of 108 abstracts, articles, or textbook chapters providing treatment recommendations for SD, 6 (6%) specifically discussed treatments for Black patients. All articles were written by authors with medical or scientific backgrounds. Of the treatment options discussed, topical antifungals generally were considered first-line for SD in all patients, with ketoconazole shampoo being a common first choice.^4,5

Comment

Our study indicated that many consumer websites recommend unstudied nonmedical treatments for SD. Zinc pyrithione was one of the most commonly mentioned ingredients in OTC products to treat SD targeted toward Black patients, as its properties have contributed to ease of hair combing and less frizz.⁶ Zinc pyrithione has antifungal properties that reduce the proliferation of Malassezia furfur as well as anti-inflammatory properties that reduce irritation, pruritus, and erythema in areas affected by SD.⁷ Tea tree and peppermint oils also were commonly mentioned; the theory is that these oils mitigate SD by reducing yeast growth and soothing inflammation through antioxidant activity.^8,9 Coal tar also is used due to its keratoplastic properties, which slow the growth of skin cells and ultimately reduce scaling and dryness.¹⁰ Yeast thrives in basic pH conditions; apple cider vinegar is used as an ingredient in OTC products for SD because its acidic pH creates a less favorable environment for yeast to grow.¹¹ Although many of the ingredients found in OTC products we identified have not yet been studied, they have properties that theoretically would be helpful in treating SD.

Our review of the medical literature revealed that while there are treatments that are effective for SD, the recommended use may not consider the cultural differences that exist for Black patients. For instance, reports in the literature regarding ketoconazole shampoo revealed that ketoconazole increases the risk for hair shaft dryness, damage, and subsequent breakage, especially in Black women who also may be using heat styling or chemical relaxers.⁵ As a result, ketoconazole should be used with caution in Black women, with an emphasis on direct application to the scalp rather than the hair shafts.¹² Additional options reported for Black patients include ciclopirox olamine and zinc pyrithione, which may have fewer risks.¹³

When prescribing medicated shampoos, traditional instructions regarding frequency of use to control symptoms of SD range from 2 to 3 times weekly to daily for a specified period of time determined by the dermatologist.¹⁴ However, frequency of hair washing varies greatly among Black patients, sometimes occurring only once monthly. The frequency also may change based on styling techniques (eg, braids, weaves, and wigs).¹⁵ Based on previous research underscoring the tendency for Black patients to use medicated shampoos less frequently than White patients, it is important for clinicians to understand that these cultural practices can undermine the effectiveness when medicated shampoos are prescribed for SD.¹⁶

Additionally, topical corticosteroids often are used in conjunction with antifungals to help decrease inflammation of the scalp.¹⁷ An option reported for Black patients is topical fluocinolone 0.01%; however, package instructions state to apply topically to the scalp nightly and wash the hair thoroughly each morning, which may not be feasible for Black patients based on previously mentioned differences in hair-washing techniques. An alternative option may be to apply the medication 3 to 4 times per week, washing the hair weekly rather than daily.¹⁸ Fluocinolone can be used as an ointment, solution, oil, or cream.^19,20 When comparing treatment vehicles for SD, a study conducted by Chappell et al²¹ found that Black patients preferred using ointment or oil vehicles; White patients preferred foams and sprays, which may not be suitable for Afro hair patterns. As such, using less-drying modalities may increase compliance and treatment success in Black patients. For patients who may have involvement on the hairline, face, or ears along with hypopigmentation (which is a common skin concern associated with SD), calcineurin inhibitors can be used until resolution occurs.^5,22 High et al¹⁵ found that twice-daily use of pimecrolimus rapidly normalized skin pigmentation during the first 2 weeks of use. Overall, personalization of treatment may not only avoid adverse effects but also ensure patient compliance, with the overall goal of treating to reduce yeast activity, pruritus, and dyschromia.²²

Interestingly, after the website searches were completed for this study, the US Food and Drug Administration approved topical roflumilast foam for SD. In a phase III trial of 457 total patients, 36 Black patients were included.²³ It was determined that 79.5% of patients overall throughout the trial achieved Investigator Global Assessment success (score of 0 [clear] or 1 [almost clear]) plus ≥2-point improvement from baseline (on a scale of 0 [clear] to 4 [severe]) at weeks 2, 4, and 8. Although there currently are no long-term studies, roflumilast may be a promising option for Black patients with SD.²³

Aside from developing an individualized treatment approach for Black patients with SD, it is important to ask targeted questions during the clinical encounter to identify factors that may be exacerbating symptoms, especially due to the wide range of hair care practices used by the Black community (eTable 2). Asking targeted questions is especially important, as prior studies have shown that extensions, hair relaxers, and particular hair products can irritate the scalp and increase the likelihood of developing SD.^21,24 Rucker Wright et al²⁵ evaluated different hair care practices among young Black females and their association with the development of SD. The authors found that using hair extensions (either braided, cornrowed, or ponytails), chemical relaxers, and hair oils every 2 weeks was associated with SD. The study also found that SD rates were roughly 20% higher among Black girls with extensions compared to Black girls without extensions, regardless of how frequently hair was washed.²⁵

Many Black patients grease the scalp with oils that are beneficial for lubrication and reduction of abrasive damage caused by grooming; however, they also may increase incidence of SD.²⁶ Tight curls worn by Black patients also can impede sebum from traveling down the hair shaft, leading to oil buildup on the scalp. This is the ideal environment for increased Malassezia density and higher risk for SD development.²⁷ To balance the beneficial effects of hair oils with the increased susceptibility for SD, providers should emphasize applying these oils only to distal hair shafts, which are more likely to be damaged, and avoiding application to the scalp.¹⁹

Conclusion

Given its long-term relapsing and remitting nature, SD can be distressing for Black patients, many of whom may seek additional treatment options aside from those recommended by health care professionals. In order to better educate patients, it is important for dermatologists to know not only the common ingredients that may be present in OTC products but also the thought process behind why patients use them. Additionally, prescription treatments for Black patients with SD may require nuanced alterations to the product instructions that may prevent health disparities and provide culturally sensitive care. Overall, the literature regarding treatment for Black patients with SD is limited, and more high-quality studies are needed.

Seborrheic dermatitis (SD) is a common chronic inflammatory skin condition that predominantly affects areas with high concentrations of sebaceous glands such as the scalp and face. Up to 5% of the worldwide population is affected by SD each year, causing a major burden of disease for patients and the health care system.¹ In 2023, the cost of medical treatment for SD in the United States was $300 million, with outpatient office visits alone costing $58 million and prescription drugs costing $109 million. Indirect costs of disease (eg, lost workdays) account for another $51 million.¹ Since SD frequently manifests on the face, it tends to have negative effects on the patient’s quality of life, resulting in psychological distress and low self-esteem.²

Patients with SD may describe symptoms of excessive dandruff and itching along with hyperpigmentation or hypopigmentation of the skin; Black patients tend to present with the classic manifestations: a combination of scaling, flaking, and erythematous patches on the scalp, ears, and face, particularly around the eyebrows, eyelids, and nose. With SD being the second most common diagnosis in Black patients who seek care from a dermatologist, it is important to have effective treatment approaches for SD in this patient population.³

In this study, we aimed to evaluate medical and nonmedical treatment options for SD in Black patients by identifying common practices and products mentioned on consumer websites and in the medical literature.

Methods

A Google search was conducted during 2 time periods (September 2022—October 2022 and March 2023—April 2023) using the terms products for itchy scalp in Black patients, products for dandruff in Black patients, itchy scalp in Black women, itchy scalp in Black men, treatment for scalp itch in Black patients, and dry scalp in Black hair. Products that were recommended by at least 1 website on the first page of search results were included in our list of products, and the ingredients were reviewed by the authors. We excluded individual retailer websites as well as those that did not provide specific recommendations on products or ingredients to use when treating SD. To ensure reliability and standardization, we did not review products that were suggested by ads in the shopping section on the first page of search results.

We also evaluated medical treatments used for SD in dermatology literature. A PubMed search of articles indexed for MEDLINE using the terms seborrheic dermatitis treatment for Black patients, treatment for dandruff for Black patients, and seborrheic dermatitis and skin of color was conducted. We excluded articles that did not address treatment options for SD, were specific to treating SD in patient populations with specific comorbidities being studied, discussed SD in animals, or were published prior to 1990.

Results

We identified 16 unique consumer websites with product or ingredient recommendations for SD in Black patients, none of which were provided by authors with a medical or scientific background; however, 4 (25%) websites included insights from board-certified dermatologists. A total of 16 ingredients were recommended, 15 (94%) of which were mentioned at least twice in our search results (eTable 1).

Overall, we noticed that ingredients labeled as natural or organic were common in over-the-counter (OTC) products, and ingredients such as sulfates and parabens were avoided. Common OTC ingredients for antidandruff and anti-itch shampoos and conditioners include zinc pyrithione, selenium sulfide, coal tar, salicylic acid, and citric acid. Additionally, coconut oil, tea tree oil, apple cider vinegar, and charcoal are common natural alternatives used to address SD symptoms.

Our review of the literature yielded limited recommendations tailored specifically to Black patients with SD. Of 108 abstracts, articles, or textbook chapters providing treatment recommendations for SD, 6 (6%) specifically discussed treatments for Black patients. All articles were written by authors with medical or scientific backgrounds. Of the treatment options discussed, topical antifungals generally were considered first-line for SD in all patients, with ketoconazole shampoo being a common first choice.^4,5

Comment

Our study indicated that many consumer websites recommend unstudied nonmedical treatments for SD. Zinc pyrithione was one of the most commonly mentioned ingredients in OTC products to treat SD targeted toward Black patients, as its properties have contributed to ease of hair combing and less frizz.⁶ Zinc pyrithione has antifungal properties that reduce the proliferation of Malassezia furfur as well as anti-inflammatory properties that reduce irritation, pruritus, and erythema in areas affected by SD.⁷ Tea tree and peppermint oils also were commonly mentioned; the theory is that these oils mitigate SD by reducing yeast growth and soothing inflammation through antioxidant activity.^8,9 Coal tar also is used due to its keratoplastic properties, which slow the growth of skin cells and ultimately reduce scaling and dryness.¹⁰ Yeast thrives in basic pH conditions; apple cider vinegar is used as an ingredient in OTC products for SD because its acidic pH creates a less favorable environment for yeast to grow.¹¹ Although many of the ingredients found in OTC products we identified have not yet been studied, they have properties that theoretically would be helpful in treating SD.

Our review of the medical literature revealed that while there are treatments that are effective for SD, the recommended use may not consider the cultural differences that exist for Black patients. For instance, reports in the literature regarding ketoconazole shampoo revealed that ketoconazole increases the risk for hair shaft dryness, damage, and subsequent breakage, especially in Black women who also may be using heat styling or chemical relaxers.⁵ As a result, ketoconazole should be used with caution in Black women, with an emphasis on direct application to the scalp rather than the hair shafts.¹² Additional options reported for Black patients include ciclopirox olamine and zinc pyrithione, which may have fewer risks.¹³

When prescribing medicated shampoos, traditional instructions regarding frequency of use to control symptoms of SD range from 2 to 3 times weekly to daily for a specified period of time determined by the dermatologist.¹⁴ However, frequency of hair washing varies greatly among Black patients, sometimes occurring only once monthly. The frequency also may change based on styling techniques (eg, braids, weaves, and wigs).¹⁵ Based on previous research underscoring the tendency for Black patients to use medicated shampoos less frequently than White patients, it is important for clinicians to understand that these cultural practices can undermine the effectiveness when medicated shampoos are prescribed for SD.¹⁶

Additionally, topical corticosteroids often are used in conjunction with antifungals to help decrease inflammation of the scalp.¹⁷ An option reported for Black patients is topical fluocinolone 0.01%; however, package instructions state to apply topically to the scalp nightly and wash the hair thoroughly each morning, which may not be feasible for Black patients based on previously mentioned differences in hair-washing techniques. An alternative option may be to apply the medication 3 to 4 times per week, washing the hair weekly rather than daily.¹⁸ Fluocinolone can be used as an ointment, solution, oil, or cream.^19,20 When comparing treatment vehicles for SD, a study conducted by Chappell et al²¹ found that Black patients preferred using ointment or oil vehicles; White patients preferred foams and sprays, which may not be suitable for Afro hair patterns. As such, using less-drying modalities may increase compliance and treatment success in Black patients. For patients who may have involvement on the hairline, face, or ears along with hypopigmentation (which is a common skin concern associated with SD), calcineurin inhibitors can be used until resolution occurs.^5,22 High et al¹⁵ found that twice-daily use of pimecrolimus rapidly normalized skin pigmentation during the first 2 weeks of use. Overall, personalization of treatment may not only avoid adverse effects but also ensure patient compliance, with the overall goal of treating to reduce yeast activity, pruritus, and dyschromia.²²

Interestingly, after the website searches were completed for this study, the US Food and Drug Administration approved topical roflumilast foam for SD. In a phase III trial of 457 total patients, 36 Black patients were included.²³ It was determined that 79.5% of patients overall throughout the trial achieved Investigator Global Assessment success (score of 0 [clear] or 1 [almost clear]) plus ≥2-point improvement from baseline (on a scale of 0 [clear] to 4 [severe]) at weeks 2, 4, and 8. Although there currently are no long-term studies, roflumilast may be a promising option for Black patients with SD.²³

Aside from developing an individualized treatment approach for Black patients with SD, it is important to ask targeted questions during the clinical encounter to identify factors that may be exacerbating symptoms, especially due to the wide range of hair care practices used by the Black community (eTable 2). Asking targeted questions is especially important, as prior studies have shown that extensions, hair relaxers, and particular hair products can irritate the scalp and increase the likelihood of developing SD.^21,24 Rucker Wright et al²⁵ evaluated different hair care practices among young Black females and their association with the development of SD. The authors found that using hair extensions (either braided, cornrowed, or ponytails), chemical relaxers, and hair oils every 2 weeks was associated with SD. The study also found that SD rates were roughly 20% higher among Black girls with extensions compared to Black girls without extensions, regardless of how frequently hair was washed.²⁵

Many Black patients grease the scalp with oils that are beneficial for lubrication and reduction of abrasive damage caused by grooming; however, they also may increase incidence of SD.²⁶ Tight curls worn by Black patients also can impede sebum from traveling down the hair shaft, leading to oil buildup on the scalp. This is the ideal environment for increased Malassezia density and higher risk for SD development.²⁷ To balance the beneficial effects of hair oils with the increased susceptibility for SD, providers should emphasize applying these oils only to distal hair shafts, which are more likely to be damaged, and avoiding application to the scalp.¹⁹

Conclusion

Given its long-term relapsing and remitting nature, SD can be distressing for Black patients, many of whom may seek additional treatment options aside from those recommended by health care professionals. In order to better educate patients, it is important for dermatologists to know not only the common ingredients that may be present in OTC products but also the thought process behind why patients use them. Additionally, prescription treatments for Black patients with SD may require nuanced alterations to the product instructions that may prevent health disparities and provide culturally sensitive care. Overall, the literature regarding treatment for Black patients with SD is limited, and more high-quality studies are needed.

PRACTICE GAP

Photography is an essential tool in modern dermatologic practice, aiding in the evaluation, documentation, and monitoring of nevi, skin cancers, and other cutaneous pathologies.¹ With the rapid technologic advancement of smartphone cameras, high-quality clinical and dermoscopic images have become increasingly easy to attain; however, best practices for optimizing smartphone photography are limited in the medical literature. We have collated a series of recommendations to help fill this knowledge gap.

A search of PubMed articles indexed for MEDLINE was conducted using the terms clinical imaging AND smartphone, clinical photography AND smartphone, dermatology AND photography, dermatology AND imaging, dermoscopy AND photography, and dermoscopy AND imaging. We also consulted with Elizabeth Seiverling, MD (Annville, Pennsylvania) and Jennifer Stein, MD (New York, New York)—both renowned experts in the fields of dermatology, dermoscopy, and medical photography—via email and video meetings conducted during the period from June 1, 2022, through August 20, 2022. Our goal in creating this guide is to facilitate standardized yet simple ways to integrate smartphone photography into current dermatologic practice.

THE TECHNIQUE

Clinical Photography

Clinical images should be captured in a space with ample indirect natural light, such as a patient examination room with frosted or draped windows, ensuring patient privacy is maintained.^1,2 The smartphone’s flash can be used if natural lighting is insufficient, but caution should be exercised when photographing patients with darker skin types, as the flash may create an undesired glare. To combat this, consider using a small clip-on light-emitting diode ring light positioned at a 45° angle for more uniform lighting and reduced glare (eFigures 1 and 2).² This additional light source helps to distribute light evenly across the patient’s skin, enhancing detail visibility, minimizing harsh shadows, and ensuring a more accurate representation of skin pigmentation.²

When a magnified image is required (eg, to capture suspicious lesions with unique and detailed findings such as irregular borders or atypical pigmentation), use the smartphone’s digital zoom function rather than physically moving the camera lens closer to the subject. Moving the camera too close can cause proximity distortion, artificially enlarging objects close to the lens and degrading the quality of the image.^1,2 Unnecessary camera features such as portrait mode, live focus, and filters should be turned off to maintain image accuracy. It also is important to avoid excessive manual adjustments to exposure and brightness settings.^1,2 The tap-to-focus feature that is integrated into many smartphone cameras can be utilized to ensure the capture of sharp, focused images. After verifying the image preview on the smartphone display, take the photograph. Immediately review the captured image to ensure it is clear and well lit and accurately depicts the area of interest, including its color, texture, and any relevant details, without glare or distortion. If the image does not meet these criteria, promptly reattempt to achieve the desired quality.

Dermoscopic Photography

Dermoscopy, which enables magnified examination of skin lesions, is increasingly being utilized in dermatology. While traditional dermoscopic photography requires specialized equipment, such as large single-lens reflex cameras with dedicated dermoscopic lens attachments, smartphone cameras now can be used to obtain dermoscopic images of reasonable quality.^3,4 Adhering to specific practices can help to optimize the quality of dermoscopic images obtained via this technique.

Before capturing an image, it is essential to prepare both the lesion and the surrounding skin. Ensure the area is cleaned thoroughly and trim any hairs that may obscure the image. Apply an interface fluid such as rubbing alcohol or ultrasonography gel to improve image clarity by reducing surface tension and reflections, minimizing glare, and ensuring even light transmission throughout the lesion.⁵ As recommended for clinical photography, images should be captured in a space with ample indirect light. For best results, we recommend utilizing the primary photo capture option instead of portrait or panoramic mode or additional settings. It is crucial to disable features such as live focus, filters, night mode, and flash, as they may alter image accuracy; however, use of the tap-to-focus feature or manual settings adjustment is encouraged to ensure a high-resolution photograph.

Once these smartphone settings have been verified, position the dermatoscope directly over the lesion of interest. Next, place the smartphone camera lens directly against the eyepiece of the dermatoscope (Figure). Center the lesion in the field of view on the screen. Most smartphones enable adjustment to the image magnification on the photo capture screen. A single tap on the screen should populate the zoom options (eg, ×0.5, ×1, ×3) and allow for adjustment. For the majority of dermoscopic photographs, we recommend standard ×1 magnification, as it typically provides a clear and accurate representation of the lesion without introducing the possibility of image distortion. To obtain a close-up image, use the smartphone’s digital zoom function prior to taking the photograph rather than zooming in on the image after it has been captured; however, to minimize proximity distortion and maintain optimal image quality, avoid exceeding the halfway point on the camera’s zoom dial. After verifying the image preview on the smartphone display, capture the photograph. Immediate review is recommended to allow for prompt reattempt at capturing the image if needed.

PRACTICE IMPLICATIONS

The inherent convenience and accessibility offered by smartphone photography further solidifies its status as a valuable tool in modern dermatologic practice. By adhering to the best practices outlined in this guide, dermatologists can utilize smartphones to capture high-quality clinical and dermoscopic images that support accurate diagnosis and enhance patient care. This approach helps streamline workflows, enhance consistency in image quality, and standardize image capture across different settings and providers.

Additionally, smartphone photography can enhance both education and telemedicine by enabling physicians to easily share high-quality images with colleagues for virtual consultations, second opinions, and collaborative diagnoses. This sharing of images fosters learning opportunities, supports knowledge exchange, and allows for real-time feedback—all of which can improve clinical decision-making. Moreover, it broadens access to dermatologic expertise, strengthens communication between health care providers, and facilitates timely decision-making. As a result, patients benefit from more efficient, accurate, and collaborative care.

PRACTICE GAP

Photography is an essential tool in modern dermatologic practice, aiding in the evaluation, documentation, and monitoring of nevi, skin cancers, and other cutaneous pathologies.¹ With the rapid technologic advancement of smartphone cameras, high-quality clinical and dermoscopic images have become increasingly easy to attain; however, best practices for optimizing smartphone photography are limited in the medical literature. We have collated a series of recommendations to help fill this knowledge gap.

A search of PubMed articles indexed for MEDLINE was conducted using the terms clinical imaging AND smartphone, clinical photography AND smartphone, dermatology AND photography, dermatology AND imaging, dermoscopy AND photography, and dermoscopy AND imaging. We also consulted with Elizabeth Seiverling, MD (Annville, Pennsylvania) and Jennifer Stein, MD (New York, New York)—both renowned experts in the fields of dermatology, dermoscopy, and medical photography—via email and video meetings conducted during the period from June 1, 2022, through August 20, 2022. Our goal in creating this guide is to facilitate standardized yet simple ways to integrate smartphone photography into current dermatologic practice.

THE TECHNIQUE

Clinical Photography

Clinical images should be captured in a space with ample indirect natural light, such as a patient examination room with frosted or draped windows, ensuring patient privacy is maintained.^1,2 The smartphone’s flash can be used if natural lighting is insufficient, but caution should be exercised when photographing patients with darker skin types, as the flash may create an undesired glare. To combat this, consider using a small clip-on light-emitting diode ring light positioned at a 45° angle for more uniform lighting and reduced glare (eFigures 1 and 2).² This additional light source helps to distribute light evenly across the patient’s skin, enhancing detail visibility, minimizing harsh shadows, and ensuring a more accurate representation of skin pigmentation.²

When a magnified image is required (eg, to capture suspicious lesions with unique and detailed findings such as irregular borders or atypical pigmentation), use the smartphone’s digital zoom function rather than physically moving the camera lens closer to the subject. Moving the camera too close can cause proximity distortion, artificially enlarging objects close to the lens and degrading the quality of the image.^1,2 Unnecessary camera features such as portrait mode, live focus, and filters should be turned off to maintain image accuracy. It also is important to avoid excessive manual adjustments to exposure and brightness settings.^1,2 The tap-to-focus feature that is integrated into many smartphone cameras can be utilized to ensure the capture of sharp, focused images. After verifying the image preview on the smartphone display, take the photograph. Immediately review the captured image to ensure it is clear and well lit and accurately depicts the area of interest, including its color, texture, and any relevant details, without glare or distortion. If the image does not meet these criteria, promptly reattempt to achieve the desired quality.

Dermoscopic Photography

Dermoscopy, which enables magnified examination of skin lesions, is increasingly being utilized in dermatology. While traditional dermoscopic photography requires specialized equipment, such as large single-lens reflex cameras with dedicated dermoscopic lens attachments, smartphone cameras now can be used to obtain dermoscopic images of reasonable quality.^3,4 Adhering to specific practices can help to optimize the quality of dermoscopic images obtained via this technique.

Before capturing an image, it is essential to prepare both the lesion and the surrounding skin. Ensure the area is cleaned thoroughly and trim any hairs that may obscure the image. Apply an interface fluid such as rubbing alcohol or ultrasonography gel to improve image clarity by reducing surface tension and reflections, minimizing glare, and ensuring even light transmission throughout the lesion.⁵ As recommended for clinical photography, images should be captured in a space with ample indirect light. For best results, we recommend utilizing the primary photo capture option instead of portrait or panoramic mode or additional settings. It is crucial to disable features such as live focus, filters, night mode, and flash, as they may alter image accuracy; however, use of the tap-to-focus feature or manual settings adjustment is encouraged to ensure a high-resolution photograph.

Once these smartphone settings have been verified, position the dermatoscope directly over the lesion of interest. Next, place the smartphone camera lens directly against the eyepiece of the dermatoscope (Figure). Center the lesion in the field of view on the screen. Most smartphones enable adjustment to the image magnification on the photo capture screen. A single tap on the screen should populate the zoom options (eg, ×0.5, ×1, ×3) and allow for adjustment. For the majority of dermoscopic photographs, we recommend standard ×1 magnification, as it typically provides a clear and accurate representation of the lesion without introducing the possibility of image distortion. To obtain a close-up image, use the smartphone’s digital zoom function prior to taking the photograph rather than zooming in on the image after it has been captured; however, to minimize proximity distortion and maintain optimal image quality, avoid exceeding the halfway point on the camera’s zoom dial. After verifying the image preview on the smartphone display, capture the photograph. Immediate review is recommended to allow for prompt reattempt at capturing the image if needed.

PRACTICE IMPLICATIONS

The inherent convenience and accessibility offered by smartphone photography further solidifies its status as a valuable tool in modern dermatologic practice. By adhering to the best practices outlined in this guide, dermatologists can utilize smartphones to capture high-quality clinical and dermoscopic images that support accurate diagnosis and enhance patient care. This approach helps streamline workflows, enhance consistency in image quality, and standardize image capture across different settings and providers.

Additionally, smartphone photography can enhance both education and telemedicine by enabling physicians to easily share high-quality images with colleagues for virtual consultations, second opinions, and collaborative diagnoses. This sharing of images fosters learning opportunities, supports knowledge exchange, and allows for real-time feedback—all of which can improve clinical decision-making. Moreover, it broadens access to dermatologic expertise, strengthens communication between health care providers, and facilitates timely decision-making. As a result, patients benefit from more efficient, accurate, and collaborative care.

PRACTICE GAP

Photography is an essential tool in modern dermatologic practice, aiding in the evaluation, documentation, and monitoring of nevi, skin cancers, and other cutaneous pathologies.¹ With the rapid technologic advancement of smartphone cameras, high-quality clinical and dermoscopic images have become increasingly easy to attain; however, best practices for optimizing smartphone photography are limited in the medical literature. We have collated a series of recommendations to help fill this knowledge gap.

A search of PubMed articles indexed for MEDLINE was conducted using the terms clinical imaging AND smartphone, clinical photography AND smartphone, dermatology AND photography, dermatology AND imaging, dermoscopy AND photography, and dermoscopy AND imaging. We also consulted with Elizabeth Seiverling, MD (Annville, Pennsylvania) and Jennifer Stein, MD (New York, New York)—both renowned experts in the fields of dermatology, dermoscopy, and medical photography—via email and video meetings conducted during the period from June 1, 2022, through August 20, 2022. Our goal in creating this guide is to facilitate standardized yet simple ways to integrate smartphone photography into current dermatologic practice.

THE TECHNIQUE

Clinical Photography

Clinical images should be captured in a space with ample indirect natural light, such as a patient examination room with frosted or draped windows, ensuring patient privacy is maintained.^1,2 The smartphone’s flash can be used if natural lighting is insufficient, but caution should be exercised when photographing patients with darker skin types, as the flash may create an undesired glare. To combat this, consider using a small clip-on light-emitting diode ring light positioned at a 45° angle for more uniform lighting and reduced glare (eFigures 1 and 2).² This additional light source helps to distribute light evenly across the patient’s skin, enhancing detail visibility, minimizing harsh shadows, and ensuring a more accurate representation of skin pigmentation.²

When a magnified image is required (eg, to capture suspicious lesions with unique and detailed findings such as irregular borders or atypical pigmentation), use the smartphone’s digital zoom function rather than physically moving the camera lens closer to the subject. Moving the camera too close can cause proximity distortion, artificially enlarging objects close to the lens and degrading the quality of the image.^1,2 Unnecessary camera features such as portrait mode, live focus, and filters should be turned off to maintain image accuracy. It also is important to avoid excessive manual adjustments to exposure and brightness settings.^1,2 The tap-to-focus feature that is integrated into many smartphone cameras can be utilized to ensure the capture of sharp, focused images. After verifying the image preview on the smartphone display, take the photograph. Immediately review the captured image to ensure it is clear and well lit and accurately depicts the area of interest, including its color, texture, and any relevant details, without glare or distortion. If the image does not meet these criteria, promptly reattempt to achieve the desired quality.

Dermoscopic Photography

Dermoscopy, which enables magnified examination of skin lesions, is increasingly being utilized in dermatology. While traditional dermoscopic photography requires specialized equipment, such as large single-lens reflex cameras with dedicated dermoscopic lens attachments, smartphone cameras now can be used to obtain dermoscopic images of reasonable quality.^3,4 Adhering to specific practices can help to optimize the quality of dermoscopic images obtained via this technique.

Before capturing an image, it is essential to prepare both the lesion and the surrounding skin. Ensure the area is cleaned thoroughly and trim any hairs that may obscure the image. Apply an interface fluid such as rubbing alcohol or ultrasonography gel to improve image clarity by reducing surface tension and reflections, minimizing glare, and ensuring even light transmission throughout the lesion.⁵ As recommended for clinical photography, images should be captured in a space with ample indirect light. For best results, we recommend utilizing the primary photo capture option instead of portrait or panoramic mode or additional settings. It is crucial to disable features such as live focus, filters, night mode, and flash, as they may alter image accuracy; however, use of the tap-to-focus feature or manual settings adjustment is encouraged to ensure a high-resolution photograph.

Once these smartphone settings have been verified, position the dermatoscope directly over the lesion of interest. Next, place the smartphone camera lens directly against the eyepiece of the dermatoscope (Figure). Center the lesion in the field of view on the screen. Most smartphones enable adjustment to the image magnification on the photo capture screen. A single tap on the screen should populate the zoom options (eg, ×0.5, ×1, ×3) and allow for adjustment. For the majority of dermoscopic photographs, we recommend standard ×1 magnification, as it typically provides a clear and accurate representation of the lesion without introducing the possibility of image distortion. To obtain a close-up image, use the smartphone’s digital zoom function prior to taking the photograph rather than zooming in on the image after it has been captured; however, to minimize proximity distortion and maintain optimal image quality, avoid exceeding the halfway point on the camera’s zoom dial. After verifying the image preview on the smartphone display, capture the photograph. Immediate review is recommended to allow for prompt reattempt at capturing the image if needed.

PRACTICE IMPLICATIONS

The inherent convenience and accessibility offered by smartphone photography further solidifies its status as a valuable tool in modern dermatologic practice. By adhering to the best practices outlined in this guide, dermatologists can utilize smartphones to capture high-quality clinical and dermoscopic images that support accurate diagnosis and enhance patient care. This approach helps streamline workflows, enhance consistency in image quality, and standardize image capture across different settings and providers.

Additionally, smartphone photography can enhance both education and telemedicine by enabling physicians to easily share high-quality images with colleagues for virtual consultations, second opinions, and collaborative diagnoses. This sharing of images fosters learning opportunities, supports knowledge exchange, and allows for real-time feedback—all of which can improve clinical decision-making. Moreover, it broadens access to dermatologic expertise, strengthens communication between health care providers, and facilitates timely decision-making. As a result, patients benefit from more efficient, accurate, and collaborative care.

To the Editor:
Patients with nonmelanoma skin cancers exhibit high quality-of-life satisfaction after treatment with Mohs micrographic surgery (MMS) or excision.^1,2 However, perioperative anxiety in patients undergoing MMS is common, especially during the immediate preoperative period.³ Anxiety activates the sympathetic nervous system, resulting in physiologic changes such as tachycardia and hypertension.^4,5 These sequelae may not only increase patient distress but also increase intraoperative bleeding, complication rates, and recovery times.^4,5 Thus, the preoperative period represents a critical window for interventions aimed at reducing anxiety. Anxiety peaks during the perioperative period for a myriad of reasons, including anticipation of pain or potential complications. Enhancing patient comfort and well-being during the procedure may help reduce negative emotional sequelae, alleviate fear during procedures, and increase patient satisfaction.³

Weighted blankets (WBs) frequently are utilized in occupational and physical therapy as a deep pressure stimulation tool to alleviate anxiety by mimicking the experience of being massaged or swaddled.⁶ Deep pressure tools increase parasympathetic tone, help reduce anxiety, and provide a calming effect.^7,8 Nonhospitalized individuals were more relaxed during mental health evaluations when using a WB, and deep pressure tools have frequently been used to calm individuals with autism spectrum disorders or attention-deficit/hyperactivity disorders.⁶ Furthermore, WBs have successfully been used to reduce anxiety in mental health care settings, as well as during chemotherapy infusions.^6,9 The literature is sparse regarding the use of WB in the perioperative setting. Potential benefit has been demonstrated in the setting of dental cleanings and wisdom teeth extractions.^7,8 In the current study, we investigated whether use of a WB could reduce preoperative anxiety in the setting of MMS.

Institutional review board approval was obtained from the University of Virginia (Charlottesville, Virginia), and adult patients undergoing MMS to the head or neck were recruited to participate in a single-blind randomized controlled trial in the spring of 2023. Patients undergoing MMS on other areas of the body were excluded because the placement of the WB could interfere with the procedure. Other exclusion criteria included pregnancy, dementia, or current treatment with an anxiolytic medication.

Twenty-seven patients were included in the study, and informed consent was obtained. Patients were randomized to use a WB or standard hospital towel (control). The medical-grade WBs weighed 8.5 pounds, while the cotton hospital towels weighed less than 1 pound. The WBs were cleaned in between patients with standard germicidal disposable wipes.

Patient data were collected from electronic medical records including age, sex, weight, history of prior MMS, and current use of antihypertensives and/or beta-blockers. Data also were collected on the presence of anxiety disorders, major depression, fibromyalgia, tobacco and alcohol use, hyperthyroidism, hyperhidrosis, cardiac arrhythmias (including atrial fibrillation), chronic obstructive pulmonary disease, asthma, coronary artery disease, diabetes mellitus, peripheral neuropathy, and menopausal symptoms.

During the procedure, anxiety was monitored using the State-Trait Anxiety Inventory (STAI) Form Y-1, the visual analogue scale for anxiety (VAS-A), and vital signs including heart rate, blood pressure, and respiratory rate. Vital signs were evaluated by nursing staff with the patient sitting up and the WB or hospital towel removed. Using these assessments, anxiety was measured at 3 different timepoints: upon arrival to the clinic (timepoint A), after the patient rested in a reclined beach-chair position with the WB or hospital towel placed over them for 10 minutes before administration of local anesthetic and starting the procedure (timepoint B), and after the first MMS stage was taken (timepoint C).

A power analysis was not completed due to a lack of previous studies on the use of WBs during MMS. Group means were analyzed using two-tailed t-tests and one-way analysis of variance. A P value of .05 indicated statistical significance.

Fourteen patients were randomized to the WB group and 13 were randomized to the control group. Patient demographics are outlined in the eTable. In the WB group, mean STAI scores progressively decreased at each timepoint (A: 15.3, B: 13.6, C: 12.7) and mean VAS-A scores followed a similar trend (A: 24.2, B: 19.3, C: 10.5). In the control group, the mean STAI scores remained stable at timepoints A and B (17.7) and then decreased at timepoint C (14.8). The mean VAS-A scores in the control group followed a similar pattern, remaining stable at timepoints A (22.9) and B (22.8) and then decreasing at timepoint C (14.4). These changes were not statistically significant.

Mean vital signs for both the WB and control groups were relatively stable across all timepoints, although they tended to decrease by timepoint C. In the WB group, mean heart rates were 69, 69, and 67 beats per minute at timepoints A, B, and C, respectively. Mean systolic blood pressures were 137 mm Hg, 138 mm Hg, and 136 mm Hg and mean diastolic pressures were 71 mm Hg, 68 mm Hg, and 66 mm Hg at timepoints A, B, and C, respectively. Mean respiratory rates were 20, 19, and 18 breaths per minute at timepoints A, B, and C, respectively. In the control group, mean heart rates were 70, 69, and 68 beats per minute across timepoints A, B, and C, respectively. Mean systolic blood pressures were 137 mm Hg, 138 mm Hg, and 133 mm Hg and mean diastolic pressures were 71 mm Hg, 74 mm Hg, and 68 mm Hg at timepoints A, B, and C, respectively. Mean respiratory rates were 19, 18, and 18 breaths per minute at timepoints A, B, and C, respectively. These changes were not statistically significant.

Our pilot study examined the effects of using a WB to alleviate preoperative anxiety during MMS. Our results suggest that WBs may modestly improve subjective anxiety immediately prior to undergoing MMS. Mean STAI and VAS-A scores decreased from timepoint A to timepoint B in the WB group vs the control group in which these scores remained stable. Although our study was not powered to determine statistical differences and significance was not reached, our results suggest a favorable trend in decreased anxiety scores. Our analysis was limited by a small sample size; therefore, additional larger-scale studies will be needed to confirm this trend.

Our results are broadly consistent with earlier studies that found improvement in physiologic proxies of anxiety with the use of WBs during chemotherapy infusions, dental procedures, and acute inpatient mental health hospitalizations.^7-10 During periods of high anxiety, use of WBs shifts the autonomic nervous system from a sympathetic to a parasympathetic state, as demonstrated by increased high-frequency heart rate variability, a marker of parasympathetic activity.^6,11 While the exact mechanism of how WBs and other deep pressure stimulation tools affect high-frequency heart rate variability is unclear, one study showed that patients undergoing dental extractions were better equipped when using deep pressure stimulation tools to utilize calming techniques and regulate stress.¹² The use of WBs and other deep pressure stimulation tools may extend beyond the perioperative setting and also may be an effective tool for clinicians in other settings (eg, clinic visits, physical examinations).

In our study, all participants demonstrated the greatest reduction in anxiety at timepoint C after the first MMS stage, likely related to patients relaxing more after knowing what to expect from the surgery; this also may have been reflected somewhat in the slight downward trend noted in vital signs across both study groups. One concern regarding WB use in surgical settings is whether the added pressure could trigger unfavorable circulatory effects, such as elevated blood pressure. In our study, with the exception of diastolic blood pressure, vital signs appeared unaffected by the type of blanket used and remained relatively stable from timepoint A to timepoint B and decreased at timepoint C. Diastolic blood pressure in the WB group decreased from timepoint A to timepoint B, then decreased further from timepoint B to timepoint C. This mirrored the decreasing STAI score trend, compared to the control group who increased from timepoint A to timepoint B and reached a nadir at timepoint C. Consistent with prior WB studies, there were no adverse effects from WBs, including adverse impacts on vital signs.^6,9

The original recruitment goal was not met due to staffing issues related to the COVID-19 pandemic, and subgroup analyses were deferred as a result of sample size limitations. It is possible that the WB intervention may have a larger impact on subpopulations more prone to perioperative anxiety (eg, patients undergoing MMS for the first time). However, the results of our pilot study suggest a beneficial effect from the use of WBs. While these preliminary data are promising, additional studies in the perioperative setting are needed to more accurately determine the clinical utility of WBs during MMS and other procedures.

To the Editor:
Patients with nonmelanoma skin cancers exhibit high quality-of-life satisfaction after treatment with Mohs micrographic surgery (MMS) or excision.^1,2 However, perioperative anxiety in patients undergoing MMS is common, especially during the immediate preoperative period.³ Anxiety activates the sympathetic nervous system, resulting in physiologic changes such as tachycardia and hypertension.^4,5 These sequelae may not only increase patient distress but also increase intraoperative bleeding, complication rates, and recovery times.^4,5 Thus, the preoperative period represents a critical window for interventions aimed at reducing anxiety. Anxiety peaks during the perioperative period for a myriad of reasons, including anticipation of pain or potential complications. Enhancing patient comfort and well-being during the procedure may help reduce negative emotional sequelae, alleviate fear during procedures, and increase patient satisfaction.³

Weighted blankets (WBs) frequently are utilized in occupational and physical therapy as a deep pressure stimulation tool to alleviate anxiety by mimicking the experience of being massaged or swaddled.⁶ Deep pressure tools increase parasympathetic tone, help reduce anxiety, and provide a calming effect.^7,8 Nonhospitalized individuals were more relaxed during mental health evaluations when using a WB, and deep pressure tools have frequently been used to calm individuals with autism spectrum disorders or attention-deficit/hyperactivity disorders.⁶ Furthermore, WBs have successfully been used to reduce anxiety in mental health care settings, as well as during chemotherapy infusions.^6,9 The literature is sparse regarding the use of WB in the perioperative setting. Potential benefit has been demonstrated in the setting of dental cleanings and wisdom teeth extractions.^7,8 In the current study, we investigated whether use of a WB could reduce preoperative anxiety in the setting of MMS.

Institutional review board approval was obtained from the University of Virginia (Charlottesville, Virginia), and adult patients undergoing MMS to the head or neck were recruited to participate in a single-blind randomized controlled trial in the spring of 2023. Patients undergoing MMS on other areas of the body were excluded because the placement of the WB could interfere with the procedure. Other exclusion criteria included pregnancy, dementia, or current treatment with an anxiolytic medication.

Twenty-seven patients were included in the study, and informed consent was obtained. Patients were randomized to use a WB or standard hospital towel (control). The medical-grade WBs weighed 8.5 pounds, while the cotton hospital towels weighed less than 1 pound. The WBs were cleaned in between patients with standard germicidal disposable wipes.

Patient data were collected from electronic medical records including age, sex, weight, history of prior MMS, and current use of antihypertensives and/or beta-blockers. Data also were collected on the presence of anxiety disorders, major depression, fibromyalgia, tobacco and alcohol use, hyperthyroidism, hyperhidrosis, cardiac arrhythmias (including atrial fibrillation), chronic obstructive pulmonary disease, asthma, coronary artery disease, diabetes mellitus, peripheral neuropathy, and menopausal symptoms.

During the procedure, anxiety was monitored using the State-Trait Anxiety Inventory (STAI) Form Y-1, the visual analogue scale for anxiety (VAS-A), and vital signs including heart rate, blood pressure, and respiratory rate. Vital signs were evaluated by nursing staff with the patient sitting up and the WB or hospital towel removed. Using these assessments, anxiety was measured at 3 different timepoints: upon arrival to the clinic (timepoint A), after the patient rested in a reclined beach-chair position with the WB or hospital towel placed over them for 10 minutes before administration of local anesthetic and starting the procedure (timepoint B), and after the first MMS stage was taken (timepoint C).

A power analysis was not completed due to a lack of previous studies on the use of WBs during MMS. Group means were analyzed using two-tailed t-tests and one-way analysis of variance. A P value of .05 indicated statistical significance.

Fourteen patients were randomized to the WB group and 13 were randomized to the control group. Patient demographics are outlined in the eTable. In the WB group, mean STAI scores progressively decreased at each timepoint (A: 15.3, B: 13.6, C: 12.7) and mean VAS-A scores followed a similar trend (A: 24.2, B: 19.3, C: 10.5). In the control group, the mean STAI scores remained stable at timepoints A and B (17.7) and then decreased at timepoint C (14.8). The mean VAS-A scores in the control group followed a similar pattern, remaining stable at timepoints A (22.9) and B (22.8) and then decreasing at timepoint C (14.4). These changes were not statistically significant.

Mean vital signs for both the WB and control groups were relatively stable across all timepoints, although they tended to decrease by timepoint C. In the WB group, mean heart rates were 69, 69, and 67 beats per minute at timepoints A, B, and C, respectively. Mean systolic blood pressures were 137 mm Hg, 138 mm Hg, and 136 mm Hg and mean diastolic pressures were 71 mm Hg, 68 mm Hg, and 66 mm Hg at timepoints A, B, and C, respectively. Mean respiratory rates were 20, 19, and 18 breaths per minute at timepoints A, B, and C, respectively. In the control group, mean heart rates were 70, 69, and 68 beats per minute across timepoints A, B, and C, respectively. Mean systolic blood pressures were 137 mm Hg, 138 mm Hg, and 133 mm Hg and mean diastolic pressures were 71 mm Hg, 74 mm Hg, and 68 mm Hg at timepoints A, B, and C, respectively. Mean respiratory rates were 19, 18, and 18 breaths per minute at timepoints A, B, and C, respectively. These changes were not statistically significant.

Our pilot study examined the effects of using a WB to alleviate preoperative anxiety during MMS. Our results suggest that WBs may modestly improve subjective anxiety immediately prior to undergoing MMS. Mean STAI and VAS-A scores decreased from timepoint A to timepoint B in the WB group vs the control group in which these scores remained stable. Although our study was not powered to determine statistical differences and significance was not reached, our results suggest a favorable trend in decreased anxiety scores. Our analysis was limited by a small sample size; therefore, additional larger-scale studies will be needed to confirm this trend.

Our results are broadly consistent with earlier studies that found improvement in physiologic proxies of anxiety with the use of WBs during chemotherapy infusions, dental procedures, and acute inpatient mental health hospitalizations.^7-10 During periods of high anxiety, use of WBs shifts the autonomic nervous system from a sympathetic to a parasympathetic state, as demonstrated by increased high-frequency heart rate variability, a marker of parasympathetic activity.^6,11 While the exact mechanism of how WBs and other deep pressure stimulation tools affect high-frequency heart rate variability is unclear, one study showed that patients undergoing dental extractions were better equipped when using deep pressure stimulation tools to utilize calming techniques and regulate stress.¹² The use of WBs and other deep pressure stimulation tools may extend beyond the perioperative setting and also may be an effective tool for clinicians in other settings (eg, clinic visits, physical examinations).

In our study, all participants demonstrated the greatest reduction in anxiety at timepoint C after the first MMS stage, likely related to patients relaxing more after knowing what to expect from the surgery; this also may have been reflected somewhat in the slight downward trend noted in vital signs across both study groups. One concern regarding WB use in surgical settings is whether the added pressure could trigger unfavorable circulatory effects, such as elevated blood pressure. In our study, with the exception of diastolic blood pressure, vital signs appeared unaffected by the type of blanket used and remained relatively stable from timepoint A to timepoint B and decreased at timepoint C. Diastolic blood pressure in the WB group decreased from timepoint A to timepoint B, then decreased further from timepoint B to timepoint C. This mirrored the decreasing STAI score trend, compared to the control group who increased from timepoint A to timepoint B and reached a nadir at timepoint C. Consistent with prior WB studies, there were no adverse effects from WBs, including adverse impacts on vital signs.^6,9

The original recruitment goal was not met due to staffing issues related to the COVID-19 pandemic, and subgroup analyses were deferred as a result of sample size limitations. It is possible that the WB intervention may have a larger impact on subpopulations more prone to perioperative anxiety (eg, patients undergoing MMS for the first time). However, the results of our pilot study suggest a beneficial effect from the use of WBs. While these preliminary data are promising, additional studies in the perioperative setting are needed to more accurately determine the clinical utility of WBs during MMS and other procedures.

To the Editor:
Patients with nonmelanoma skin cancers exhibit high quality-of-life satisfaction after treatment with Mohs micrographic surgery (MMS) or excision.^1,2 However, perioperative anxiety in patients undergoing MMS is common, especially during the immediate preoperative period.³ Anxiety activates the sympathetic nervous system, resulting in physiologic changes such as tachycardia and hypertension.^4,5 These sequelae may not only increase patient distress but also increase intraoperative bleeding, complication rates, and recovery times.^4,5 Thus, the preoperative period represents a critical window for interventions aimed at reducing anxiety. Anxiety peaks during the perioperative period for a myriad of reasons, including anticipation of pain or potential complications. Enhancing patient comfort and well-being during the procedure may help reduce negative emotional sequelae, alleviate fear during procedures, and increase patient satisfaction.³

Weighted blankets (WBs) frequently are utilized in occupational and physical therapy as a deep pressure stimulation tool to alleviate anxiety by mimicking the experience of being massaged or swaddled.⁶ Deep pressure tools increase parasympathetic tone, help reduce anxiety, and provide a calming effect.^7,8 Nonhospitalized individuals were more relaxed during mental health evaluations when using a WB, and deep pressure tools have frequently been used to calm individuals with autism spectrum disorders or attention-deficit/hyperactivity disorders.⁶ Furthermore, WBs have successfully been used to reduce anxiety in mental health care settings, as well as during chemotherapy infusions.^6,9 The literature is sparse regarding the use of WB in the perioperative setting. Potential benefit has been demonstrated in the setting of dental cleanings and wisdom teeth extractions.^7,8 In the current study, we investigated whether use of a WB could reduce preoperative anxiety in the setting of MMS.

Institutional review board approval was obtained from the University of Virginia (Charlottesville, Virginia), and adult patients undergoing MMS to the head or neck were recruited to participate in a single-blind randomized controlled trial in the spring of 2023. Patients undergoing MMS on other areas of the body were excluded because the placement of the WB could interfere with the procedure. Other exclusion criteria included pregnancy, dementia, or current treatment with an anxiolytic medication.

Twenty-seven patients were included in the study, and informed consent was obtained. Patients were randomized to use a WB or standard hospital towel (control). The medical-grade WBs weighed 8.5 pounds, while the cotton hospital towels weighed less than 1 pound. The WBs were cleaned in between patients with standard germicidal disposable wipes.

Patient data were collected from electronic medical records including age, sex, weight, history of prior MMS, and current use of antihypertensives and/or beta-blockers. Data also were collected on the presence of anxiety disorders, major depression, fibromyalgia, tobacco and alcohol use, hyperthyroidism, hyperhidrosis, cardiac arrhythmias (including atrial fibrillation), chronic obstructive pulmonary disease, asthma, coronary artery disease, diabetes mellitus, peripheral neuropathy, and menopausal symptoms.

During the procedure, anxiety was monitored using the State-Trait Anxiety Inventory (STAI) Form Y-1, the visual analogue scale for anxiety (VAS-A), and vital signs including heart rate, blood pressure, and respiratory rate. Vital signs were evaluated by nursing staff with the patient sitting up and the WB or hospital towel removed. Using these assessments, anxiety was measured at 3 different timepoints: upon arrival to the clinic (timepoint A), after the patient rested in a reclined beach-chair position with the WB or hospital towel placed over them for 10 minutes before administration of local anesthetic and starting the procedure (timepoint B), and after the first MMS stage was taken (timepoint C).

A power analysis was not completed due to a lack of previous studies on the use of WBs during MMS. Group means were analyzed using two-tailed t-tests and one-way analysis of variance. A P value of .05 indicated statistical significance.

Fourteen patients were randomized to the WB group and 13 were randomized to the control group. Patient demographics are outlined in the eTable. In the WB group, mean STAI scores progressively decreased at each timepoint (A: 15.3, B: 13.6, C: 12.7) and mean VAS-A scores followed a similar trend (A: 24.2, B: 19.3, C: 10.5). In the control group, the mean STAI scores remained stable at timepoints A and B (17.7) and then decreased at timepoint C (14.8). The mean VAS-A scores in the control group followed a similar pattern, remaining stable at timepoints A (22.9) and B (22.8) and then decreasing at timepoint C (14.4). These changes were not statistically significant.

Mean vital signs for both the WB and control groups were relatively stable across all timepoints, although they tended to decrease by timepoint C. In the WB group, mean heart rates were 69, 69, and 67 beats per minute at timepoints A, B, and C, respectively. Mean systolic blood pressures were 137 mm Hg, 138 mm Hg, and 136 mm Hg and mean diastolic pressures were 71 mm Hg, 68 mm Hg, and 66 mm Hg at timepoints A, B, and C, respectively. Mean respiratory rates were 20, 19, and 18 breaths per minute at timepoints A, B, and C, respectively. In the control group, mean heart rates were 70, 69, and 68 beats per minute across timepoints A, B, and C, respectively. Mean systolic blood pressures were 137 mm Hg, 138 mm Hg, and 133 mm Hg and mean diastolic pressures were 71 mm Hg, 74 mm Hg, and 68 mm Hg at timepoints A, B, and C, respectively. Mean respiratory rates were 19, 18, and 18 breaths per minute at timepoints A, B, and C, respectively. These changes were not statistically significant.

Our pilot study examined the effects of using a WB to alleviate preoperative anxiety during MMS. Our results suggest that WBs may modestly improve subjective anxiety immediately prior to undergoing MMS. Mean STAI and VAS-A scores decreased from timepoint A to timepoint B in the WB group vs the control group in which these scores remained stable. Although our study was not powered to determine statistical differences and significance was not reached, our results suggest a favorable trend in decreased anxiety scores. Our analysis was limited by a small sample size; therefore, additional larger-scale studies will be needed to confirm this trend.

Our results are broadly consistent with earlier studies that found improvement in physiologic proxies of anxiety with the use of WBs during chemotherapy infusions, dental procedures, and acute inpatient mental health hospitalizations.^7-10 During periods of high anxiety, use of WBs shifts the autonomic nervous system from a sympathetic to a parasympathetic state, as demonstrated by increased high-frequency heart rate variability, a marker of parasympathetic activity.^6,11 While the exact mechanism of how WBs and other deep pressure stimulation tools affect high-frequency heart rate variability is unclear, one study showed that patients undergoing dental extractions were better equipped when using deep pressure stimulation tools to utilize calming techniques and regulate stress.¹² The use of WBs and other deep pressure stimulation tools may extend beyond the perioperative setting and also may be an effective tool for clinicians in other settings (eg, clinic visits, physical examinations).

In our study, all participants demonstrated the greatest reduction in anxiety at timepoint C after the first MMS stage, likely related to patients relaxing more after knowing what to expect from the surgery; this also may have been reflected somewhat in the slight downward trend noted in vital signs across both study groups. One concern regarding WB use in surgical settings is whether the added pressure could trigger unfavorable circulatory effects, such as elevated blood pressure. In our study, with the exception of diastolic blood pressure, vital signs appeared unaffected by the type of blanket used and remained relatively stable from timepoint A to timepoint B and decreased at timepoint C. Diastolic blood pressure in the WB group decreased from timepoint A to timepoint B, then decreased further from timepoint B to timepoint C. This mirrored the decreasing STAI score trend, compared to the control group who increased from timepoint A to timepoint B and reached a nadir at timepoint C. Consistent with prior WB studies, there were no adverse effects from WBs, including adverse impacts on vital signs.^6,9

The original recruitment goal was not met due to staffing issues related to the COVID-19 pandemic, and subgroup analyses were deferred as a result of sample size limitations. It is possible that the WB intervention may have a larger impact on subpopulations more prone to perioperative anxiety (eg, patients undergoing MMS for the first time). However, the results of our pilot study suggest a beneficial effect from the use of WBs. While these preliminary data are promising, additional studies in the perioperative setting are needed to more accurately determine the clinical utility of WBs during MMS and other procedures.

Type 2 diabetes mellitus (T2DM) is a chronic disease characterized by uncontrolled hyperglycemia. Over the past few decades, its prevalence has steadily increased, now affecting approximately 10% of adults worldwide and ranking among the top 10 leading causes of death globally.¹ The pathophysiology of T2DM involves persistent hyperglycemia that drives insulin resistance and a progressive decline in insulin production from the pancreas.² Medical management of this condition aims to reduce blood glucose levels or enhance insulin production and sensitivity. Aside from lifestyle modifications, metformin is considered the first-line treatment for glycemic control according to the 2023 American Association of Clinical Endocrinology’s T2DM management algorithm.³ These updated guidelines stratify adjunct treatments by individualized glycemic targets and patient needs. For patients who are overweight or obese, glucagonlike peptide 1 (GLP-1) and dual GLP-1/ gastric inhibitory polypeptide (GIP) agonists are the preferred adjunct or second-line treatments.³

In this review, we highlight the dermatologic adverse effects and potential therapeutic benefits of metformin as well as GLP-1 and GLP-1/GIP agonists.

METFORMIN

Metformin is a biguanide agent used as a first-line treatment for T2DM because of its ability to reduce hepatic glucose production and increase peripheral tissue glucose uptake.⁴ In addition to its effects on glucose, metformin has been shown to have anti-inflammatory properties via inhibition of the nuclear factor κB and mammalian target of rapamycin (mTOR) pathways, leading to decreased production of cytokines associated with T helper (Th) 1 and Th17 cell responses, such as IL-17, interferon gamma (IFN-γ), and tumor necrosis factor α (TNF-α).^5-7 These findings have spurred interest among clinicians in the potential use of metformin for inflammatory conditions, including dermatologic diseases such as psoriasis and hidradenitis suppurativa (HS).⁸

Adverse Effects

Metformin is administered orally and generally is well tolerated. The most common adverse effects include gastrointestinal symptoms such as diarrhea, nausea, vomiting, and abdominal pain.⁹ While cutaneous adverse effects are rare, multiple dermatologic adverse reactions to metformin have been reported,^10,11 including leukocytoclastic vasculitis,^11-13 fixed drug eruptions,^14-17 drug rash with eosinophilia and systemic symptoms (DRESS) syndrome,¹⁸ and photosensitivity reactions.¹⁹ Leukocytoclastic vasculitis and DRESS syndrome typically develop within the first month following metformin initiation, while fixed drug eruption and photosensitivity reactions have more variable timing, occurring weeks to years after treatment initiation.^12-19

Dermatologic Implications

Acanthosis Nigricans—Acanthosis nigricans (AN) is characterized by hyperpigmentation and velvety skin thickening, typically in intertriginous areas such as the back of the neck, axillae, and groin.²⁰ It commonly is associated with insulin resistance and obesity.^21-23 Treatments for AN primarily center around insulin sensitivity and weight loss,^24,25 with some benefit observed from the use of keratolytic agents.^26,27 Metformin may have utility in treating AN through its effects on insulin sensitivity and glycemic control. Multiple case reports have noted marked improvements in AN in patients with and without obesity with the addition of metformin to their existing treatment regimens in doses ranging from 500 mg to 1700 mg daily.^28-30 However, an unblinded randomized controlled trial (RCT) comparing the efficacy of metformin (500 mg 3 times daily) with rosiglitazone (4 mg/d), another T2DM medication, on AN neck lesions in patients who were overweight and obese found no significant effects in lesion severity and only modest improvements in skin texture in both groups at 12 weeks following treatment initiation.³¹ Another RCT comparing metformin (500 mg twice daily) with a twice-daily capsule containing α-lipoic acid, biotin, chromium polynicotinate, and zinc sulfate, showed significant (P<.001) improvements in AN neck lesions in both groups after 12 weeks.³² According to Sung et al,⁸ longer duration of therapy (>6 months), higher doses (1700–2000 mg), and lower baseline weight were associated with higher efficacy of metformin for treatment of AN. Overall, the use of metformin as an adjunct treatment for AN, particularly in patients with underlying hyperglycemia, is supported in the literature, but further studies are needed to clarify dosing, duration of therapy, and patient populations that will benefit most from adding metformin to their treatment regimens.

Hirsutism—Hirsutism, which is characterized by excessive hair growth in androgen-dependent areas, can be challenging to treat. Metformin has been shown to reduce circulating insulin, luteinizing hormone, androstenedione, and testosterone, thus improving underlying hyperandrogenism, particularly in patients with polycystic ovary syndrome (PCOS).^33-35 Although single studies evaluating the efficacy of metformin for treatment of hirsutism in patients with PCOS have shown potential benefits,^36-38 meta-analyses showed no significant effects of metformin compared to placebo or oral contraceptives and decreased benefits compared to spironolactone and flutamide.³⁹ Given these findings showing that metformin was no more effective than placebo or other treatments, the current Endocrine Society guidelines recommend against the use of metformin for hirsutism.^39,40 There may be a role for metformin as an adjuvant therapy in certain populations (eg, patients with comorbid T2DM), although further studies stratifying risk factors such as body mass index and age are needed.⁴¹

Hidradenitis Suppurativa—Hidradenitis suppurativa is a follicular occlusive disease characterized by recurrent inflamed nodules leading to chronic dermal abscesses, fibrosis, and sinus tract formation primarily in intertriginous areas such as the axillae and groin.⁴² Medical management depends on disease severity but usually involves antibiotic treatment with adjunct therapies such as oral contraceptives, antiandrogenic medications (eg, spironolactone), biologic medications, and metformin.⁴² Preclinical and clinical data suggest that metformin can impact HS through metabolic and immunomodulatory mechanisms.^5,42 Like many chronic inflammatory disorders, HS is associated with metabolic syndrome.^43,44 A study evaluating insulin secretion after oral glucose tolerance testing showed increased insulin levels in patients with HS compared to controls (P=.02), with 60% (6/10) of patients with HS meeting criteria for insulin resistance. In addition, serum insulin levels in insulin-resistant patients with HS correlated with increased lesional skin mTOR gene expression at 30 (r=.80) and 60 (r=1.00) minutes, and mTOR was found to be upregulated in lesional and extralesional skin in patients with HS compared to healthy controls (P<.01).45 Insulin activates mTOR signaling, which mediates cell growth and survival, among other processes.⁴⁶ Thus, metformin’s ability to increase insulin sensitivity and inhibit mTOR signaling could be beneficial in the setting of HS. Additionally, insulin and insulinlike growth factor 1 (IGF-1) increase androgen signaling, a process that has been implicated in HS.⁴⁷

Metformin also may impact HS through its effects on testosterone and other hormones.⁴⁸ A study evaluating peripheral blood mononuclear cells in patients with HS showed reduced IL-17, IFN-γ, TNF-α, and IL-6 levels in patients who were taking metformin (dose not reported) for longer than 6 months compared to patients who were not on metformin. Further analysis of ex vivo HS lesions cultured with metformin showed decreased IL-17, IFN-γ, TNF-α, and IL-8 expression in tissue, suggesting an antiinflammatory role of metformin in HS.⁵

Although there are no known RCTs assessing the efficacy of metformin in HS, existing clinical data are supportive of the use of metformin for refractory HS.⁴⁹ Following a case report describing a patient with T2DM and stable HS while on metformin,⁵⁰ several cohort studies have assessed the efficacy of metformin for the treatment of HS. A prospective study evaluating the efficacy of metformin monotherapy (starting dose of 500 mg/d, titrated to 500 mg 3 times daily) in patients with and without T2DM with HS refractory to other therapies found clinical improvement in 72% (18/25) of patients using the Sartorius Hidradenitis Suppurativa Score, improving from a mean (SD) score of 34.40 (12.46) to 26.76 (11.22) at 12 weeks (P=.0055,) and 22.39 (11.30) at 24 weeks (P=.0001). Additionally, 64% (16/25) of patients showed improved quality of life as evaluated by the Dermatology Life Quality Index (DLQI), which decreased from a mean (SD) score of 15.00 (4.96) to 10.08 (5.96)(P=.0017) at 12 weeks and 7.65 (7.12)(P=.000009) at 24 weeks on treatment.⁴⁸ In a retrospective study of 53 patients with HS taking metformin started at 500 mg daily and increased to 500 mg twice daily after 2 weeks (when tolerated), 68% (36/53) showed some clinical response, with 19% (7/36) of those patients having achieved complete response to metformin monotherapy (defined as no active HS).⁵¹ Similarly, a retrospective study of pediatric patients with HS evaluating metformin (doses ranging from 500-2000 mg daily) as an adjunct therapy described a subset of patients with decreased frequency of HS flares with metformin.⁵² These studies emphasize the safety profile of metformin and support its current use as an adjunctive therapy for HS.

Acne Vulgaris—Acne vulgaris (AV) is a chronic inflammatory disorder affecting the pilosebaceous follicles.¹¹ Similar to HS, AV has metabolic and hormonal influences that can be targeted by metformin.⁵³ In AV, androgens lead to increased sebum production by binding to androgen receptors on sebocytes, which in turn attracts Cutibacterium acnes and promotes hyperkeratinization, inducing inflammation.⁵⁴ Thus, the antiandrogenic effects of metformin may be beneficial for treatment of AV. Additionally, sebocytes express receptors for insulin and IGF-1, which can increase the size and number of sebocytes, as well as promote lipogenesis and inflammatory response, influencing sebum production.⁵⁴ Serum levels for IGF-1 have been observed to be increased in patients with AV⁵⁵ and reduced by metformin.⁵⁶ A recent meta-analysis assessing the efficacy of metformin on AV indicated that 87% (13/15) of studies noted disease improvement on metformin, with 47% (7/15) of studies showing statistically significant (P<0.05) decreases in acne severity.57 Although most studies showed improvement, 47% (7/15) did not find significant differences between metformin and other interventions, indicating the availability of comparable treatment options. Overall, there has been a positive association between metformin use and acne improvement.⁵⁷ However, it is important to note that most studies have focused on females with PCOS,⁵⁷ and the main benefits of metformin in acne might be seen when managing comorbid conditions, particularly those associated with metabolic dysregulation and insulin resistance. Further studies are needed to determine the generalizability of prior results.

Psoriasis—Psoriasis is a chronic autoinflammatory disease characterized by epidermal hyperplasia with multiple cutaneous manifestations and potential for multiorgan involvement. Comorbid conditions include psoriatic arthritis, metabolic syndrome, and cardiovascular disease.⁵⁸ Current treatment options depend on several factors (eg, disease severity, location of cutaneous lesions, comorbidities) and include topical, systemic, and phototherapy options, many of which target the immune system.^58,59 A meta-analysis of 3 RCTs showed that metformin (500 mg/d or 1000 mg/d) was associated with significantly improved Psoriasis Area and Severity Index (PASI) 75% reductions (odds ratio [OR], 22.02; 95% CI, 2.12-228.49; P=.01) and 75% reductions in erythema, scaling, and induration (OR, 9.12; 95% CI, 2.13-39.02; P=.003) compared to placebo.⁶⁰ In addition, an RCT evaluating the efficacy of metformin (1000 mg/d) or pioglitazone (30 mg/d) for 12 weeks in patients with psoriasis with metabolic syndrome found significant improvements in PASI75 (P=.001) and erythema, scaling, and induration (P=.016) scores as well as in Physician Global Assessment scores (P=.012) compared to placebo and no differences compared to pioglitazone.⁶¹ While current psoriasis management guidelines do not include metformin, its use may be worth consideration as an adjunct therapy in patients with psoriasis and comorbidities such as T2DM and metabolic syndrome.⁵⁹ Metformin’s potential benefits in psoriasis may lie outside its metabolic influences and occur secondary to its immunomodulatory effects, including targeting of the Th17 axis or cytokine-specific pathways such as TNF-α, which are known to be involved in psoriasis pathogenesis.⁵⁸

Central Centrifugal Cicatricial Alopecia—Central centrifugal cicatricial alopecia (CCCA) is a form of scarring alopecia characterized by chronic inflammation leading to permanent loss of hair follicles on the crown of the scalp.⁶² Current treatments include topical and intralesional corticosteroids, as well as oral antibiotics. In addition, therapies including the antimalarial hydroxychloroquine and immunosuppressants mycophenolate and cyclosporine are used in refractory disease.^63,64 A case report described 2 patients with hair regrowth after 4 and 6 months of treatment with topical metformin 10% compounded in a proprietary transdermal vehicle.⁶⁵ The authors speculated that metformin’s effects on CCCA could be attributed to its known agonistic effects on the adenosine monophosphate-activated protein kinase (AMPK) pathway with subsequent reduction in inflammation-induced fibrosis.^65,66 Microarray⁶⁷ and proteomic⁶⁸ analysis have shown that AMPK is known to be downregulated in CCCA , making it an interesting therapeutic target in this disease. A recent retrospective case series demonstrated that 67% (8/12) of patients with refractory CCCA had symptomatic improvement, and 50% (6/12) showed hair regrowth after 6 months of low-dose (500 mg/d) oral metformin treatment.⁶² In addition, metformin therapy showed antifibrotic and anti-inflammatory effects when comparing scalp biopsies before and after treatment. Results showed decreased expression of fibrosisrelated genes (matrix metalloproteinase 7, collagen type IV á 1 chain), and gene set variation analysis showing reduced Th17 (P=.04) and increased AMPK signaling (P=.02) gene set expression.⁶² These findings are consistent with previous studies describing the upregulation of AMPK66 and downregulation of Th176 following metformin treatment. The immunomodulatory effects of metformin could be attributed to AMPK-mediated mTOR and NF-κB downregulation,⁶² although more studies are needed to understand these mechanisms and further explore the use of metformin in CCCA.

Skin Cancer—Metformin also has been evaluated in the setting of skin malignancies, including melanoma, squamous cell carcinoma, and basal cell carcinoma. Preclinical data suggest that metformin decreases cell viability in tumors through interactions with pathways involved in proinflammatory and prosurvival mechanisms such as NF-κB and mTOR.^69,70 Additionally, given metformin’s inhibitory effects on oxidative phosphorylation, it has been postulated that it could be used to overcome treatment resistance driven by metabolic reprogramming.^71,72 Most studies related to metformin and skin malignancies are still in preclinical stages; however, a meta-analysis of RCTs and cohort studies did not find significant associations between metformin use and skin cancer risk, although data trended toward a modest reduction in skin cancer among metformin users.⁷³ A retrospective cohort study of melanoma in patients with T2DM taking metformin (250-2000 mg/d) found that the 5-year incidence of recurrence was lower in the metformin cohort compared to nonusers (43.8% vs 58.2%, respectively)(P=.002), and overall survival rates trended upward in the higher body mass index (>30) and melanoma stages 1 and 2 groups but did not reach statistical significance.⁷⁴ In addition, a whole population casecontrol study in Iceland reported that metformin use at least 2 years before first-time basal cell carcinoma diagnosis was associated with a lower risk for disease (adjusted OR, 0.71; 95% CI, 0.61-0.83) with no significant dose-dependent differences; there were no notable effects on squamous cell carcinoma risk.⁷⁵ Further preclinical and clinical data are needed to elucidate metformin’s effects on skin malignancies.

GLP-1 AND DUAL GLP-1/GIP AGONISTS

Glucagonlike peptide 1 and dual GLP-1/GIP agonists are emerging classes of medications currently approved as adjunct and second-line therapies for T2DM, particularly in patients who are overweight or obese as well as in those who are at risk for hypoglycemia.³ Currently approved GLP-1 agonists for T2DM include semaglutide, dulaglutide, exenatide, liraglutide, and lixisenatide, while tirzepatide is the only approved dual GLP-1/GIP agonist. Activating GLP-1 and GIP receptors stimulates insulin secretion and decreases glucagon production by the pancreas, thereby reducing blood glucose levels. Additionally, some of these medications are approved for obesity given their effects in delayed gastric emptying and increased satiety, among other factors.

Over the past few years, multiple case reports have described the associations between GLP-1 agonist use and improvement of dermatologic conditions, particularly those associated with T2DM and obesity, including HS and psoriasis.^76,77 The mechanisms through which this occurs are not fully elucidated, although basic science and clinical studies have shown that GLP-1 agonists have immunomodulatory effects by reducing proinflammatory cytokines and altering immune cell populations.^77-80 The numerous ongoing clinical trials and research studies will help further elucidate their benefits in other disease settings.⁸¹

Adverse Reactions

Most GLP-1 and GLP-1/GIP agonists are administered subcutaneously, and the most commonly reported cutaneous adverse effects are injection site reactions.⁸² Anaphylactic reactions to these medications also have been reported, although it is unclear if these were specific to the active ingredients or to injection excipients.^83,84 A review of 33 cases of cutaneous reactions to GLP-1 agonists reported 11 (33%) dermal hypersensitivity reactions occurring as early as 4 weeks and as late as 3 years after treatment initiation. It also described 10 (30%) cases of eosinophilic panniculitis that developed within 3 weeks to 5 months of GLP-1 treatment, 3 (9%) cases of bullous pemphigoid that occurred within the first 2 months, 2 (6%) morbilliform drug eruptions that occurred within 5 weeks, 2 (6%) cases of angioedema that occurred 15 minutes to 2 weeks after treatment initiation, and 7 (21%) other isolated cutaneous reactions. Extended-release exenatide had the most reported reactions followed by liraglutide and subcutaneous semaglutide.⁸⁵

In a different study, semaglutide use was most commonly associated with injection site reactions followed by alopecia, especially with oral administration. Unique cases of angioedema (2 days after injection), cutaneous hypersensitivity (within 10 months on treatment), bullous pemphigoid (within 2 months on treatment), eosinophilic fasciitis (within 2 weeks on treatment), and leukocytoclastic vasculitis (unclear timing), most of which resolved after discontinuation, also were reported.⁸⁶ A recent case report linked semaglutide (0.5 mg/wk) to a case of drug-induced systemic lupus erythematosus that developed within 3 months of treatment initiation and described systemic lupus erythematosus–like symptoms in a subset of patients using this medication, namely females older than 60 years, within the first month of treatment.⁸⁷ Hyperhidrosis was listed as a common adverse event in exenatide clinical trials, and various cases of panniculitis with exenatide use have been reported.^82,88 Alopecia, mainly attributed to accelerated telogen effluvium secondary to rapid weight loss, also has been reported, although hair loss is not officially listed as an adverse effect of GLP-1 agonists, and reports are highly variable.⁸⁹ Also secondary to weight loss, facial changes including sunken eyes, development of wrinkles, sagging jowls around the neck and jaw, and a hollowed appearance, among others, are recognized as undesirable adverse effects.⁹⁰ Mansour et al⁹⁰ described the potential challenges and considerations to these rising concerns associated with GLP1-agonist use.

Dermatologic Implications

Hidradenitis Suppurativa—Weight loss commonly is recommended as a lifestyle modification in the management of HS. Multiple reports have described clinical improvement of HS following weight loss with other medical interventions, such as dietary measures and bariatric surgery.^91-94 Thus, it has been postulated that medically supported weight loss with GLP-1 agonists can help improve HS⁹⁵; however, the data on the effectiveness of GLP-1 agonists on HS are still scarce and mostly have been reported in individual patients. One case report described a patient with improvements in their recalcitrant HS and DLQI score following weight loss on liraglutide (initial dose of 0.6 mg/d, titrated to 1.8 mg/d).⁷⁶ In addition, a recent case report described improvements in HS and DLQI score following concomitant tirzepatide (initial dose of 2.5 mg/0.5 mL weekly, titrated to 7.5 mg/0.5 mL weekly) and infliximab treatment.⁹⁶ The off-label use of these medications for HS is debated, and further studies regarding the benefits of GLP-1 agonists on HS still are needed.

Psoriasis—Similarly, several case reports have commented on the effects of GLP-1 agonists on psoriasis.^97,98 An early study found GLP-1 receptors were expressed in psoriasis plaques but not in healthy skin and discussed that this could be due to immune infiltration in the plaques, providing a potential rationale for using anti-inflammatory GLP-1 agonists for psoriasis.⁹⁹ Two prospective cohort studies observed improvements in PASI and DLQI scores in patients with psoriasis and T2DM after liraglutide treatment and noted important changes in immune cell populations.^80,100 A recent RCT also found improvements in DLQI and PASI scores (P<.05) in patients with T2DM following liraglutide (1.8 mg/d) treatment, along with overall decreases in inflammatory cytokines, such as IL-23, IL-17, and TNF-α.⁷⁷ However, another RCT in patients with obesity did not observe significant improvements in PASI and DLQI scores compared to placebo after 8 weeks of liraglutide (initial dose of 0.6 mg/d, titrated to 1.8 mg/d) treatment. ⁹⁹ Although these results could have been influenced by the short length of treatment compared to other studies, which observed participants for more than 10 weeks, they highlight the need for tailored studies considering the different comorbidities to identify patients who could benefit the most from these therapies.

Alopecia—Although some studies have reported increased rates of alopecia following GLP-1 agonist treatment, others have speculated about the potential role of these medications in treating hair loss through improved insulin sensitivity and scalp blood flow.^86,89 For example, a case report described a patient with improvement in androgenetic alopecia within 6 months of tirzepatide monotherapy at 2.5 mg weekly for the first 3 months followed by an increased dose of 5 mg weekly.¹⁰¹ The authors described the role of insulin in increasing dihydrotestosterone levels, which leads to miniaturization of the dermal papilla of hair follicles and argued that improvement of insulin resistance could benefit hair loss. Further studies can help elucidate the role of these medications on alopecia.

FINAL THOUGHTS

Standard T2DM treatments including metformin and GLP-1 and GLP-1/GIP agonists exhibit metabolic, immunologic, and hormonal effects that should be explored in other disease contexts. We reviewed the current data on T2DM medications in dermatologic conditions to highlight the need for additional studies to better understand the role that these medications play across diverse patient populations. Type 2 diabetes mellitus is a common comorbidity in dermatology patients, and understanding the multifactorial effects of these medications can help optimize treatment strategies, especially in patients with coexisting dermatologic and metabolic diseases.

Type 2 diabetes mellitus (T2DM) is a chronic disease characterized by uncontrolled hyperglycemia. Over the past few decades, its prevalence has steadily increased, now affecting approximately 10% of adults worldwide and ranking among the top 10 leading causes of death globally.¹ The pathophysiology of T2DM involves persistent hyperglycemia that drives insulin resistance and a progressive decline in insulin production from the pancreas.² Medical management of this condition aims to reduce blood glucose levels or enhance insulin production and sensitivity. Aside from lifestyle modifications, metformin is considered the first-line treatment for glycemic control according to the 2023 American Association of Clinical Endocrinology’s T2DM management algorithm.³ These updated guidelines stratify adjunct treatments by individualized glycemic targets and patient needs. For patients who are overweight or obese, glucagonlike peptide 1 (GLP-1) and dual GLP-1/ gastric inhibitory polypeptide (GIP) agonists are the preferred adjunct or second-line treatments.³

In this review, we highlight the dermatologic adverse effects and potential therapeutic benefits of metformin as well as GLP-1 and GLP-1/GIP agonists.

METFORMIN

Metformin is a biguanide agent used as a first-line treatment for T2DM because of its ability to reduce hepatic glucose production and increase peripheral tissue glucose uptake.⁴ In addition to its effects on glucose, metformin has been shown to have anti-inflammatory properties via inhibition of the nuclear factor κB and mammalian target of rapamycin (mTOR) pathways, leading to decreased production of cytokines associated with T helper (Th) 1 and Th17 cell responses, such as IL-17, interferon gamma (IFN-γ), and tumor necrosis factor α (TNF-α).^5-7 These findings have spurred interest among clinicians in the potential use of metformin for inflammatory conditions, including dermatologic diseases such as psoriasis and hidradenitis suppurativa (HS).⁸

Adverse Effects

Metformin is administered orally and generally is well tolerated. The most common adverse effects include gastrointestinal symptoms such as diarrhea, nausea, vomiting, and abdominal pain.⁹ While cutaneous adverse effects are rare, multiple dermatologic adverse reactions to metformin have been reported,^10,11 including leukocytoclastic vasculitis,^11-13 fixed drug eruptions,^14-17 drug rash with eosinophilia and systemic symptoms (DRESS) syndrome,¹⁸ and photosensitivity reactions.¹⁹ Leukocytoclastic vasculitis and DRESS syndrome typically develop within the first month following metformin initiation, while fixed drug eruption and photosensitivity reactions have more variable timing, occurring weeks to years after treatment initiation.^12-19

Dermatologic Implications

Acanthosis Nigricans—Acanthosis nigricans (AN) is characterized by hyperpigmentation and velvety skin thickening, typically in intertriginous areas such as the back of the neck, axillae, and groin.²⁰ It commonly is associated with insulin resistance and obesity.^21-23 Treatments for AN primarily center around insulin sensitivity and weight loss,^24,25 with some benefit observed from the use of keratolytic agents.^26,27 Metformin may have utility in treating AN through its effects on insulin sensitivity and glycemic control. Multiple case reports have noted marked improvements in AN in patients with and without obesity with the addition of metformin to their existing treatment regimens in doses ranging from 500 mg to 1700 mg daily.^28-30 However, an unblinded randomized controlled trial (RCT) comparing the efficacy of metformin (500 mg 3 times daily) with rosiglitazone (4 mg/d), another T2DM medication, on AN neck lesions in patients who were overweight and obese found no significant effects in lesion severity and only modest improvements in skin texture in both groups at 12 weeks following treatment initiation.³¹ Another RCT comparing metformin (500 mg twice daily) with a twice-daily capsule containing α-lipoic acid, biotin, chromium polynicotinate, and zinc sulfate, showed significant (P<.001) improvements in AN neck lesions in both groups after 12 weeks.³² According to Sung et al,⁸ longer duration of therapy (>6 months), higher doses (1700–2000 mg), and lower baseline weight were associated with higher efficacy of metformin for treatment of AN. Overall, the use of metformin as an adjunct treatment for AN, particularly in patients with underlying hyperglycemia, is supported in the literature, but further studies are needed to clarify dosing, duration of therapy, and patient populations that will benefit most from adding metformin to their treatment regimens.

Hirsutism—Hirsutism, which is characterized by excessive hair growth in androgen-dependent areas, can be challenging to treat. Metformin has been shown to reduce circulating insulin, luteinizing hormone, androstenedione, and testosterone, thus improving underlying hyperandrogenism, particularly in patients with polycystic ovary syndrome (PCOS).^33-35 Although single studies evaluating the efficacy of metformin for treatment of hirsutism in patients with PCOS have shown potential benefits,^36-38 meta-analyses showed no significant effects of metformin compared to placebo or oral contraceptives and decreased benefits compared to spironolactone and flutamide.³⁹ Given these findings showing that metformin was no more effective than placebo or other treatments, the current Endocrine Society guidelines recommend against the use of metformin for hirsutism.^39,40 There may be a role for metformin as an adjuvant therapy in certain populations (eg, patients with comorbid T2DM), although further studies stratifying risk factors such as body mass index and age are needed.⁴¹

Hidradenitis Suppurativa—Hidradenitis suppurativa is a follicular occlusive disease characterized by recurrent inflamed nodules leading to chronic dermal abscesses, fibrosis, and sinus tract formation primarily in intertriginous areas such as the axillae and groin.⁴² Medical management depends on disease severity but usually involves antibiotic treatment with adjunct therapies such as oral contraceptives, antiandrogenic medications (eg, spironolactone), biologic medications, and metformin.⁴² Preclinical and clinical data suggest that metformin can impact HS through metabolic and immunomodulatory mechanisms.^5,42 Like many chronic inflammatory disorders, HS is associated with metabolic syndrome.^43,44 A study evaluating insulin secretion after oral glucose tolerance testing showed increased insulin levels in patients with HS compared to controls (P=.02), with 60% (6/10) of patients with HS meeting criteria for insulin resistance. In addition, serum insulin levels in insulin-resistant patients with HS correlated with increased lesional skin mTOR gene expression at 30 (r=.80) and 60 (r=1.00) minutes, and mTOR was found to be upregulated in lesional and extralesional skin in patients with HS compared to healthy controls (P<.01).45 Insulin activates mTOR signaling, which mediates cell growth and survival, among other processes.⁴⁶ Thus, metformin’s ability to increase insulin sensitivity and inhibit mTOR signaling could be beneficial in the setting of HS. Additionally, insulin and insulinlike growth factor 1 (IGF-1) increase androgen signaling, a process that has been implicated in HS.⁴⁷

Metformin also may impact HS through its effects on testosterone and other hormones.⁴⁸ A study evaluating peripheral blood mononuclear cells in patients with HS showed reduced IL-17, IFN-γ, TNF-α, and IL-6 levels in patients who were taking metformin (dose not reported) for longer than 6 months compared to patients who were not on metformin. Further analysis of ex vivo HS lesions cultured with metformin showed decreased IL-17, IFN-γ, TNF-α, and IL-8 expression in tissue, suggesting an antiinflammatory role of metformin in HS.⁵

Although there are no known RCTs assessing the efficacy of metformin in HS, existing clinical data are supportive of the use of metformin for refractory HS.⁴⁹ Following a case report describing a patient with T2DM and stable HS while on metformin,⁵⁰ several cohort studies have assessed the efficacy of metformin for the treatment of HS. A prospective study evaluating the efficacy of metformin monotherapy (starting dose of 500 mg/d, titrated to 500 mg 3 times daily) in patients with and without T2DM with HS refractory to other therapies found clinical improvement in 72% (18/25) of patients using the Sartorius Hidradenitis Suppurativa Score, improving from a mean (SD) score of 34.40 (12.46) to 26.76 (11.22) at 12 weeks (P=.0055,) and 22.39 (11.30) at 24 weeks (P=.0001). Additionally, 64% (16/25) of patients showed improved quality of life as evaluated by the Dermatology Life Quality Index (DLQI), which decreased from a mean (SD) score of 15.00 (4.96) to 10.08 (5.96)(P=.0017) at 12 weeks and 7.65 (7.12)(P=.000009) at 24 weeks on treatment.⁴⁸ In a retrospective study of 53 patients with HS taking metformin started at 500 mg daily and increased to 500 mg twice daily after 2 weeks (when tolerated), 68% (36/53) showed some clinical response, with 19% (7/36) of those patients having achieved complete response to metformin monotherapy (defined as no active HS).⁵¹ Similarly, a retrospective study of pediatric patients with HS evaluating metformin (doses ranging from 500-2000 mg daily) as an adjunct therapy described a subset of patients with decreased frequency of HS flares with metformin.⁵² These studies emphasize the safety profile of metformin and support its current use as an adjunctive therapy for HS.

Acne Vulgaris—Acne vulgaris (AV) is a chronic inflammatory disorder affecting the pilosebaceous follicles.¹¹ Similar to HS, AV has metabolic and hormonal influences that can be targeted by metformin.⁵³ In AV, androgens lead to increased sebum production by binding to androgen receptors on sebocytes, which in turn attracts Cutibacterium acnes and promotes hyperkeratinization, inducing inflammation.⁵⁴ Thus, the antiandrogenic effects of metformin may be beneficial for treatment of AV. Additionally, sebocytes express receptors for insulin and IGF-1, which can increase the size and number of sebocytes, as well as promote lipogenesis and inflammatory response, influencing sebum production.⁵⁴ Serum levels for IGF-1 have been observed to be increased in patients with AV⁵⁵ and reduced by metformin.⁵⁶ A recent meta-analysis assessing the efficacy of metformin on AV indicated that 87% (13/15) of studies noted disease improvement on metformin, with 47% (7/15) of studies showing statistically significant (P<0.05) decreases in acne severity.57 Although most studies showed improvement, 47% (7/15) did not find significant differences between metformin and other interventions, indicating the availability of comparable treatment options. Overall, there has been a positive association between metformin use and acne improvement.⁵⁷ However, it is important to note that most studies have focused on females with PCOS,⁵⁷ and the main benefits of metformin in acne might be seen when managing comorbid conditions, particularly those associated with metabolic dysregulation and insulin resistance. Further studies are needed to determine the generalizability of prior results.

Psoriasis—Psoriasis is a chronic autoinflammatory disease characterized by epidermal hyperplasia with multiple cutaneous manifestations and potential for multiorgan involvement. Comorbid conditions include psoriatic arthritis, metabolic syndrome, and cardiovascular disease.⁵⁸ Current treatment options depend on several factors (eg, disease severity, location of cutaneous lesions, comorbidities) and include topical, systemic, and phototherapy options, many of which target the immune system.^58,59 A meta-analysis of 3 RCTs showed that metformin (500 mg/d or 1000 mg/d) was associated with significantly improved Psoriasis Area and Severity Index (PASI) 75% reductions (odds ratio [OR], 22.02; 95% CI, 2.12-228.49; P=.01) and 75% reductions in erythema, scaling, and induration (OR, 9.12; 95% CI, 2.13-39.02; P=.003) compared to placebo.⁶⁰ In addition, an RCT evaluating the efficacy of metformin (1000 mg/d) or pioglitazone (30 mg/d) for 12 weeks in patients with psoriasis with metabolic syndrome found significant improvements in PASI75 (P=.001) and erythema, scaling, and induration (P=.016) scores as well as in Physician Global Assessment scores (P=.012) compared to placebo and no differences compared to pioglitazone.⁶¹ While current psoriasis management guidelines do not include metformin, its use may be worth consideration as an adjunct therapy in patients with psoriasis and comorbidities such as T2DM and metabolic syndrome.⁵⁹ Metformin’s potential benefits in psoriasis may lie outside its metabolic influences and occur secondary to its immunomodulatory effects, including targeting of the Th17 axis or cytokine-specific pathways such as TNF-α, which are known to be involved in psoriasis pathogenesis.⁵⁸

Central Centrifugal Cicatricial Alopecia—Central centrifugal cicatricial alopecia (CCCA) is a form of scarring alopecia characterized by chronic inflammation leading to permanent loss of hair follicles on the crown of the scalp.⁶² Current treatments include topical and intralesional corticosteroids, as well as oral antibiotics. In addition, therapies including the antimalarial hydroxychloroquine and immunosuppressants mycophenolate and cyclosporine are used in refractory disease.^63,64 A case report described 2 patients with hair regrowth after 4 and 6 months of treatment with topical metformin 10% compounded in a proprietary transdermal vehicle.⁶⁵ The authors speculated that metformin’s effects on CCCA could be attributed to its known agonistic effects on the adenosine monophosphate-activated protein kinase (AMPK) pathway with subsequent reduction in inflammation-induced fibrosis.^65,66 Microarray⁶⁷ and proteomic⁶⁸ analysis have shown that AMPK is known to be downregulated in CCCA , making it an interesting therapeutic target in this disease. A recent retrospective case series demonstrated that 67% (8/12) of patients with refractory CCCA had symptomatic improvement, and 50% (6/12) showed hair regrowth after 6 months of low-dose (500 mg/d) oral metformin treatment.⁶² In addition, metformin therapy showed antifibrotic and anti-inflammatory effects when comparing scalp biopsies before and after treatment. Results showed decreased expression of fibrosisrelated genes (matrix metalloproteinase 7, collagen type IV á 1 chain), and gene set variation analysis showing reduced Th17 (P=.04) and increased AMPK signaling (P=.02) gene set expression.⁶² These findings are consistent with previous studies describing the upregulation of AMPK66 and downregulation of Th176 following metformin treatment. The immunomodulatory effects of metformin could be attributed to AMPK-mediated mTOR and NF-κB downregulation,⁶² although more studies are needed to understand these mechanisms and further explore the use of metformin in CCCA.

Skin Cancer—Metformin also has been evaluated in the setting of skin malignancies, including melanoma, squamous cell carcinoma, and basal cell carcinoma. Preclinical data suggest that metformin decreases cell viability in tumors through interactions with pathways involved in proinflammatory and prosurvival mechanisms such as NF-κB and mTOR.^69,70 Additionally, given metformin’s inhibitory effects on oxidative phosphorylation, it has been postulated that it could be used to overcome treatment resistance driven by metabolic reprogramming.^71,72 Most studies related to metformin and skin malignancies are still in preclinical stages; however, a meta-analysis of RCTs and cohort studies did not find significant associations between metformin use and skin cancer risk, although data trended toward a modest reduction in skin cancer among metformin users.⁷³ A retrospective cohort study of melanoma in patients with T2DM taking metformin (250-2000 mg/d) found that the 5-year incidence of recurrence was lower in the metformin cohort compared to nonusers (43.8% vs 58.2%, respectively)(P=.002), and overall survival rates trended upward in the higher body mass index (>30) and melanoma stages 1 and 2 groups but did not reach statistical significance.⁷⁴ In addition, a whole population casecontrol study in Iceland reported that metformin use at least 2 years before first-time basal cell carcinoma diagnosis was associated with a lower risk for disease (adjusted OR, 0.71; 95% CI, 0.61-0.83) with no significant dose-dependent differences; there were no notable effects on squamous cell carcinoma risk.⁷⁵ Further preclinical and clinical data are needed to elucidate metformin’s effects on skin malignancies.

GLP-1 AND DUAL GLP-1/GIP AGONISTS

Glucagonlike peptide 1 and dual GLP-1/GIP agonists are emerging classes of medications currently approved as adjunct and second-line therapies for T2DM, particularly in patients who are overweight or obese as well as in those who are at risk for hypoglycemia.³ Currently approved GLP-1 agonists for T2DM include semaglutide, dulaglutide, exenatide, liraglutide, and lixisenatide, while tirzepatide is the only approved dual GLP-1/GIP agonist. Activating GLP-1 and GIP receptors stimulates insulin secretion and decreases glucagon production by the pancreas, thereby reducing blood glucose levels. Additionally, some of these medications are approved for obesity given their effects in delayed gastric emptying and increased satiety, among other factors.

Over the past few years, multiple case reports have described the associations between GLP-1 agonist use and improvement of dermatologic conditions, particularly those associated with T2DM and obesity, including HS and psoriasis.^76,77 The mechanisms through which this occurs are not fully elucidated, although basic science and clinical studies have shown that GLP-1 agonists have immunomodulatory effects by reducing proinflammatory cytokines and altering immune cell populations.^77-80 The numerous ongoing clinical trials and research studies will help further elucidate their benefits in other disease settings.⁸¹

Adverse Reactions

Most GLP-1 and GLP-1/GIP agonists are administered subcutaneously, and the most commonly reported cutaneous adverse effects are injection site reactions.⁸² Anaphylactic reactions to these medications also have been reported, although it is unclear if these were specific to the active ingredients or to injection excipients.^83,84 A review of 33 cases of cutaneous reactions to GLP-1 agonists reported 11 (33%) dermal hypersensitivity reactions occurring as early as 4 weeks and as late as 3 years after treatment initiation. It also described 10 (30%) cases of eosinophilic panniculitis that developed within 3 weeks to 5 months of GLP-1 treatment, 3 (9%) cases of bullous pemphigoid that occurred within the first 2 months, 2 (6%) morbilliform drug eruptions that occurred within 5 weeks, 2 (6%) cases of angioedema that occurred 15 minutes to 2 weeks after treatment initiation, and 7 (21%) other isolated cutaneous reactions. Extended-release exenatide had the most reported reactions followed by liraglutide and subcutaneous semaglutide.⁸⁵

In a different study, semaglutide use was most commonly associated with injection site reactions followed by alopecia, especially with oral administration. Unique cases of angioedema (2 days after injection), cutaneous hypersensitivity (within 10 months on treatment), bullous pemphigoid (within 2 months on treatment), eosinophilic fasciitis (within 2 weeks on treatment), and leukocytoclastic vasculitis (unclear timing), most of which resolved after discontinuation, also were reported.⁸⁶ A recent case report linked semaglutide (0.5 mg/wk) to a case of drug-induced systemic lupus erythematosus that developed within 3 months of treatment initiation and described systemic lupus erythematosus–like symptoms in a subset of patients using this medication, namely females older than 60 years, within the first month of treatment.⁸⁷ Hyperhidrosis was listed as a common adverse event in exenatide clinical trials, and various cases of panniculitis with exenatide use have been reported.^82,88 Alopecia, mainly attributed to accelerated telogen effluvium secondary to rapid weight loss, also has been reported, although hair loss is not officially listed as an adverse effect of GLP-1 agonists, and reports are highly variable.⁸⁹ Also secondary to weight loss, facial changes including sunken eyes, development of wrinkles, sagging jowls around the neck and jaw, and a hollowed appearance, among others, are recognized as undesirable adverse effects.⁹⁰ Mansour et al⁹⁰ described the potential challenges and considerations to these rising concerns associated with GLP1-agonist use.

Dermatologic Implications

Hidradenitis Suppurativa—Weight loss commonly is recommended as a lifestyle modification in the management of HS. Multiple reports have described clinical improvement of HS following weight loss with other medical interventions, such as dietary measures and bariatric surgery.^91-94 Thus, it has been postulated that medically supported weight loss with GLP-1 agonists can help improve HS⁹⁵; however, the data on the effectiveness of GLP-1 agonists on HS are still scarce and mostly have been reported in individual patients. One case report described a patient with improvements in their recalcitrant HS and DLQI score following weight loss on liraglutide (initial dose of 0.6 mg/d, titrated to 1.8 mg/d).⁷⁶ In addition, a recent case report described improvements in HS and DLQI score following concomitant tirzepatide (initial dose of 2.5 mg/0.5 mL weekly, titrated to 7.5 mg/0.5 mL weekly) and infliximab treatment.⁹⁶ The off-label use of these medications for HS is debated, and further studies regarding the benefits of GLP-1 agonists on HS still are needed.

Psoriasis—Similarly, several case reports have commented on the effects of GLP-1 agonists on psoriasis.^97,98 An early study found GLP-1 receptors were expressed in psoriasis plaques but not in healthy skin and discussed that this could be due to immune infiltration in the plaques, providing a potential rationale for using anti-inflammatory GLP-1 agonists for psoriasis.⁹⁹ Two prospective cohort studies observed improvements in PASI and DLQI scores in patients with psoriasis and T2DM after liraglutide treatment and noted important changes in immune cell populations.^80,100 A recent RCT also found improvements in DLQI and PASI scores (P<.05) in patients with T2DM following liraglutide (1.8 mg/d) treatment, along with overall decreases in inflammatory cytokines, such as IL-23, IL-17, and TNF-α.⁷⁷ However, another RCT in patients with obesity did not observe significant improvements in PASI and DLQI scores compared to placebo after 8 weeks of liraglutide (initial dose of 0.6 mg/d, titrated to 1.8 mg/d) treatment. ⁹⁹ Although these results could have been influenced by the short length of treatment compared to other studies, which observed participants for more than 10 weeks, they highlight the need for tailored studies considering the different comorbidities to identify patients who could benefit the most from these therapies.

Alopecia—Although some studies have reported increased rates of alopecia following GLP-1 agonist treatment, others have speculated about the potential role of these medications in treating hair loss through improved insulin sensitivity and scalp blood flow.^86,89 For example, a case report described a patient with improvement in androgenetic alopecia within 6 months of tirzepatide monotherapy at 2.5 mg weekly for the first 3 months followed by an increased dose of 5 mg weekly.¹⁰¹ The authors described the role of insulin in increasing dihydrotestosterone levels, which leads to miniaturization of the dermal papilla of hair follicles and argued that improvement of insulin resistance could benefit hair loss. Further studies can help elucidate the role of these medications on alopecia.

FINAL THOUGHTS

Standard T2DM treatments including metformin and GLP-1 and GLP-1/GIP agonists exhibit metabolic, immunologic, and hormonal effects that should be explored in other disease contexts. We reviewed the current data on T2DM medications in dermatologic conditions to highlight the need for additional studies to better understand the role that these medications play across diverse patient populations. Type 2 diabetes mellitus is a common comorbidity in dermatology patients, and understanding the multifactorial effects of these medications can help optimize treatment strategies, especially in patients with coexisting dermatologic and metabolic diseases.

Type 2 diabetes mellitus (T2DM) is a chronic disease characterized by uncontrolled hyperglycemia. Over the past few decades, its prevalence has steadily increased, now affecting approximately 10% of adults worldwide and ranking among the top 10 leading causes of death globally.¹ The pathophysiology of T2DM involves persistent hyperglycemia that drives insulin resistance and a progressive decline in insulin production from the pancreas.² Medical management of this condition aims to reduce blood glucose levels or enhance insulin production and sensitivity. Aside from lifestyle modifications, metformin is considered the first-line treatment for glycemic control according to the 2023 American Association of Clinical Endocrinology’s T2DM management algorithm.³ These updated guidelines stratify adjunct treatments by individualized glycemic targets and patient needs. For patients who are overweight or obese, glucagonlike peptide 1 (GLP-1) and dual GLP-1/ gastric inhibitory polypeptide (GIP) agonists are the preferred adjunct or second-line treatments.³

In this review, we highlight the dermatologic adverse effects and potential therapeutic benefits of metformin as well as GLP-1 and GLP-1/GIP agonists.

METFORMIN

Metformin is a biguanide agent used as a first-line treatment for T2DM because of its ability to reduce hepatic glucose production and increase peripheral tissue glucose uptake.⁴ In addition to its effects on glucose, metformin has been shown to have anti-inflammatory properties via inhibition of the nuclear factor κB and mammalian target of rapamycin (mTOR) pathways, leading to decreased production of cytokines associated with T helper (Th) 1 and Th17 cell responses, such as IL-17, interferon gamma (IFN-γ), and tumor necrosis factor α (TNF-α).^5-7 These findings have spurred interest among clinicians in the potential use of metformin for inflammatory conditions, including dermatologic diseases such as psoriasis and hidradenitis suppurativa (HS).⁸

Adverse Effects

Metformin is administered orally and generally is well tolerated. The most common adverse effects include gastrointestinal symptoms such as diarrhea, nausea, vomiting, and abdominal pain.⁹ While cutaneous adverse effects are rare, multiple dermatologic adverse reactions to metformin have been reported,^10,11 including leukocytoclastic vasculitis,^11-13 fixed drug eruptions,^14-17 drug rash with eosinophilia and systemic symptoms (DRESS) syndrome,¹⁸ and photosensitivity reactions.¹⁹ Leukocytoclastic vasculitis and DRESS syndrome typically develop within the first month following metformin initiation, while fixed drug eruption and photosensitivity reactions have more variable timing, occurring weeks to years after treatment initiation.^12-19

Dermatologic Implications

Acanthosis Nigricans—Acanthosis nigricans (AN) is characterized by hyperpigmentation and velvety skin thickening, typically in intertriginous areas such as the back of the neck, axillae, and groin.²⁰ It commonly is associated with insulin resistance and obesity.^21-23 Treatments for AN primarily center around insulin sensitivity and weight loss,^24,25 with some benefit observed from the use of keratolytic agents.^26,27 Metformin may have utility in treating AN through its effects on insulin sensitivity and glycemic control. Multiple case reports have noted marked improvements in AN in patients with and without obesity with the addition of metformin to their existing treatment regimens in doses ranging from 500 mg to 1700 mg daily.^28-30 However, an unblinded randomized controlled trial (RCT) comparing the efficacy of metformin (500 mg 3 times daily) with rosiglitazone (4 mg/d), another T2DM medication, on AN neck lesions in patients who were overweight and obese found no significant effects in lesion severity and only modest improvements in skin texture in both groups at 12 weeks following treatment initiation.³¹ Another RCT comparing metformin (500 mg twice daily) with a twice-daily capsule containing α-lipoic acid, biotin, chromium polynicotinate, and zinc sulfate, showed significant (P<.001) improvements in AN neck lesions in both groups after 12 weeks.³² According to Sung et al,⁸ longer duration of therapy (>6 months), higher doses (1700–2000 mg), and lower baseline weight were associated with higher efficacy of metformin for treatment of AN. Overall, the use of metformin as an adjunct treatment for AN, particularly in patients with underlying hyperglycemia, is supported in the literature, but further studies are needed to clarify dosing, duration of therapy, and patient populations that will benefit most from adding metformin to their treatment regimens.

Hirsutism—Hirsutism, which is characterized by excessive hair growth in androgen-dependent areas, can be challenging to treat. Metformin has been shown to reduce circulating insulin, luteinizing hormone, androstenedione, and testosterone, thus improving underlying hyperandrogenism, particularly in patients with polycystic ovary syndrome (PCOS).^33-35 Although single studies evaluating the efficacy of metformin for treatment of hirsutism in patients with PCOS have shown potential benefits,^36-38 meta-analyses showed no significant effects of metformin compared to placebo or oral contraceptives and decreased benefits compared to spironolactone and flutamide.³⁹ Given these findings showing that metformin was no more effective than placebo or other treatments, the current Endocrine Society guidelines recommend against the use of metformin for hirsutism.^39,40 There may be a role for metformin as an adjuvant therapy in certain populations (eg, patients with comorbid T2DM), although further studies stratifying risk factors such as body mass index and age are needed.⁴¹

Hidradenitis Suppurativa—Hidradenitis suppurativa is a follicular occlusive disease characterized by recurrent inflamed nodules leading to chronic dermal abscesses, fibrosis, and sinus tract formation primarily in intertriginous areas such as the axillae and groin.⁴² Medical management depends on disease severity but usually involves antibiotic treatment with adjunct therapies such as oral contraceptives, antiandrogenic medications (eg, spironolactone), biologic medications, and metformin.⁴² Preclinical and clinical data suggest that metformin can impact HS through metabolic and immunomodulatory mechanisms.^5,42 Like many chronic inflammatory disorders, HS is associated with metabolic syndrome.^43,44 A study evaluating insulin secretion after oral glucose tolerance testing showed increased insulin levels in patients with HS compared to controls (P=.02), with 60% (6/10) of patients with HS meeting criteria for insulin resistance. In addition, serum insulin levels in insulin-resistant patients with HS correlated with increased lesional skin mTOR gene expression at 30 (r=.80) and 60 (r=1.00) minutes, and mTOR was found to be upregulated in lesional and extralesional skin in patients with HS compared to healthy controls (P<.01).45 Insulin activates mTOR signaling, which mediates cell growth and survival, among other processes.⁴⁶ Thus, metformin’s ability to increase insulin sensitivity and inhibit mTOR signaling could be beneficial in the setting of HS. Additionally, insulin and insulinlike growth factor 1 (IGF-1) increase androgen signaling, a process that has been implicated in HS.⁴⁷

Metformin also may impact HS through its effects on testosterone and other hormones.⁴⁸ A study evaluating peripheral blood mononuclear cells in patients with HS showed reduced IL-17, IFN-γ, TNF-α, and IL-6 levels in patients who were taking metformin (dose not reported) for longer than 6 months compared to patients who were not on metformin. Further analysis of ex vivo HS lesions cultured with metformin showed decreased IL-17, IFN-γ, TNF-α, and IL-8 expression in tissue, suggesting an antiinflammatory role of metformin in HS.⁵

Although there are no known RCTs assessing the efficacy of metformin in HS, existing clinical data are supportive of the use of metformin for refractory HS.⁴⁹ Following a case report describing a patient with T2DM and stable HS while on metformin,⁵⁰ several cohort studies have assessed the efficacy of metformin for the treatment of HS. A prospective study evaluating the efficacy of metformin monotherapy (starting dose of 500 mg/d, titrated to 500 mg 3 times daily) in patients with and without T2DM with HS refractory to other therapies found clinical improvement in 72% (18/25) of patients using the Sartorius Hidradenitis Suppurativa Score, improving from a mean (SD) score of 34.40 (12.46) to 26.76 (11.22) at 12 weeks (P=.0055,) and 22.39 (11.30) at 24 weeks (P=.0001). Additionally, 64% (16/25) of patients showed improved quality of life as evaluated by the Dermatology Life Quality Index (DLQI), which decreased from a mean (SD) score of 15.00 (4.96) to 10.08 (5.96)(P=.0017) at 12 weeks and 7.65 (7.12)(P=.000009) at 24 weeks on treatment.⁴⁸ In a retrospective study of 53 patients with HS taking metformin started at 500 mg daily and increased to 500 mg twice daily after 2 weeks (when tolerated), 68% (36/53) showed some clinical response, with 19% (7/36) of those patients having achieved complete response to metformin monotherapy (defined as no active HS).⁵¹ Similarly, a retrospective study of pediatric patients with HS evaluating metformin (doses ranging from 500-2000 mg daily) as an adjunct therapy described a subset of patients with decreased frequency of HS flares with metformin.⁵² These studies emphasize the safety profile of metformin and support its current use as an adjunctive therapy for HS.

Acne Vulgaris—Acne vulgaris (AV) is a chronic inflammatory disorder affecting the pilosebaceous follicles.¹¹ Similar to HS, AV has metabolic and hormonal influences that can be targeted by metformin.⁵³ In AV, androgens lead to increased sebum production by binding to androgen receptors on sebocytes, which in turn attracts Cutibacterium acnes and promotes hyperkeratinization, inducing inflammation.⁵⁴ Thus, the antiandrogenic effects of metformin may be beneficial for treatment of AV. Additionally, sebocytes express receptors for insulin and IGF-1, which can increase the size and number of sebocytes, as well as promote lipogenesis and inflammatory response, influencing sebum production.⁵⁴ Serum levels for IGF-1 have been observed to be increased in patients with AV⁵⁵ and reduced by metformin.⁵⁶ A recent meta-analysis assessing the efficacy of metformin on AV indicated that 87% (13/15) of studies noted disease improvement on metformin, with 47% (7/15) of studies showing statistically significant (P<0.05) decreases in acne severity.57 Although most studies showed improvement, 47% (7/15) did not find significant differences between metformin and other interventions, indicating the availability of comparable treatment options. Overall, there has been a positive association between metformin use and acne improvement.⁵⁷ However, it is important to note that most studies have focused on females with PCOS,⁵⁷ and the main benefits of metformin in acne might be seen when managing comorbid conditions, particularly those associated with metabolic dysregulation and insulin resistance. Further studies are needed to determine the generalizability of prior results.

Psoriasis—Psoriasis is a chronic autoinflammatory disease characterized by epidermal hyperplasia with multiple cutaneous manifestations and potential for multiorgan involvement. Comorbid conditions include psoriatic arthritis, metabolic syndrome, and cardiovascular disease.⁵⁸ Current treatment options depend on several factors (eg, disease severity, location of cutaneous lesions, comorbidities) and include topical, systemic, and phototherapy options, many of which target the immune system.^58,59 A meta-analysis of 3 RCTs showed that metformin (500 mg/d or 1000 mg/d) was associated with significantly improved Psoriasis Area and Severity Index (PASI) 75% reductions (odds ratio [OR], 22.02; 95% CI, 2.12-228.49; P=.01) and 75% reductions in erythema, scaling, and induration (OR, 9.12; 95% CI, 2.13-39.02; P=.003) compared to placebo.⁶⁰ In addition, an RCT evaluating the efficacy of metformin (1000 mg/d) or pioglitazone (30 mg/d) for 12 weeks in patients with psoriasis with metabolic syndrome found significant improvements in PASI75 (P=.001) and erythema, scaling, and induration (P=.016) scores as well as in Physician Global Assessment scores (P=.012) compared to placebo and no differences compared to pioglitazone.⁶¹ While current psoriasis management guidelines do not include metformin, its use may be worth consideration as an adjunct therapy in patients with psoriasis and comorbidities such as T2DM and metabolic syndrome.⁵⁹ Metformin’s potential benefits in psoriasis may lie outside its metabolic influences and occur secondary to its immunomodulatory effects, including targeting of the Th17 axis or cytokine-specific pathways such as TNF-α, which are known to be involved in psoriasis pathogenesis.⁵⁸

Central Centrifugal Cicatricial Alopecia—Central centrifugal cicatricial alopecia (CCCA) is a form of scarring alopecia characterized by chronic inflammation leading to permanent loss of hair follicles on the crown of the scalp.⁶² Current treatments include topical and intralesional corticosteroids, as well as oral antibiotics. In addition, therapies including the antimalarial hydroxychloroquine and immunosuppressants mycophenolate and cyclosporine are used in refractory disease.^63,64 A case report described 2 patients with hair regrowth after 4 and 6 months of treatment with topical metformin 10% compounded in a proprietary transdermal vehicle.⁶⁵ The authors speculated that metformin’s effects on CCCA could be attributed to its known agonistic effects on the adenosine monophosphate-activated protein kinase (AMPK) pathway with subsequent reduction in inflammation-induced fibrosis.^65,66 Microarray⁶⁷ and proteomic⁶⁸ analysis have shown that AMPK is known to be downregulated in CCCA , making it an interesting therapeutic target in this disease. A recent retrospective case series demonstrated that 67% (8/12) of patients with refractory CCCA had symptomatic improvement, and 50% (6/12) showed hair regrowth after 6 months of low-dose (500 mg/d) oral metformin treatment.⁶² In addition, metformin therapy showed antifibrotic and anti-inflammatory effects when comparing scalp biopsies before and after treatment. Results showed decreased expression of fibrosisrelated genes (matrix metalloproteinase 7, collagen type IV á 1 chain), and gene set variation analysis showing reduced Th17 (P=.04) and increased AMPK signaling (P=.02) gene set expression.⁶² These findings are consistent with previous studies describing the upregulation of AMPK66 and downregulation of Th176 following metformin treatment. The immunomodulatory effects of metformin could be attributed to AMPK-mediated mTOR and NF-κB downregulation,⁶² although more studies are needed to understand these mechanisms and further explore the use of metformin in CCCA.

Skin Cancer—Metformin also has been evaluated in the setting of skin malignancies, including melanoma, squamous cell carcinoma, and basal cell carcinoma. Preclinical data suggest that metformin decreases cell viability in tumors through interactions with pathways involved in proinflammatory and prosurvival mechanisms such as NF-κB and mTOR.^69,70 Additionally, given metformin’s inhibitory effects on oxidative phosphorylation, it has been postulated that it could be used to overcome treatment resistance driven by metabolic reprogramming.^71,72 Most studies related to metformin and skin malignancies are still in preclinical stages; however, a meta-analysis of RCTs and cohort studies did not find significant associations between metformin use and skin cancer risk, although data trended toward a modest reduction in skin cancer among metformin users.⁷³ A retrospective cohort study of melanoma in patients with T2DM taking metformin (250-2000 mg/d) found that the 5-year incidence of recurrence was lower in the metformin cohort compared to nonusers (43.8% vs 58.2%, respectively)(P=.002), and overall survival rates trended upward in the higher body mass index (>30) and melanoma stages 1 and 2 groups but did not reach statistical significance.⁷⁴ In addition, a whole population casecontrol study in Iceland reported that metformin use at least 2 years before first-time basal cell carcinoma diagnosis was associated with a lower risk for disease (adjusted OR, 0.71; 95% CI, 0.61-0.83) with no significant dose-dependent differences; there were no notable effects on squamous cell carcinoma risk.⁷⁵ Further preclinical and clinical data are needed to elucidate metformin’s effects on skin malignancies.

GLP-1 AND DUAL GLP-1/GIP AGONISTS

Glucagonlike peptide 1 and dual GLP-1/GIP agonists are emerging classes of medications currently approved as adjunct and second-line therapies for T2DM, particularly in patients who are overweight or obese as well as in those who are at risk for hypoglycemia.³ Currently approved GLP-1 agonists for T2DM include semaglutide, dulaglutide, exenatide, liraglutide, and lixisenatide, while tirzepatide is the only approved dual GLP-1/GIP agonist. Activating GLP-1 and GIP receptors stimulates insulin secretion and decreases glucagon production by the pancreas, thereby reducing blood glucose levels. Additionally, some of these medications are approved for obesity given their effects in delayed gastric emptying and increased satiety, among other factors.

Over the past few years, multiple case reports have described the associations between GLP-1 agonist use and improvement of dermatologic conditions, particularly those associated with T2DM and obesity, including HS and psoriasis.^76,77 The mechanisms through which this occurs are not fully elucidated, although basic science and clinical studies have shown that GLP-1 agonists have immunomodulatory effects by reducing proinflammatory cytokines and altering immune cell populations.^77-80 The numerous ongoing clinical trials and research studies will help further elucidate their benefits in other disease settings.⁸¹

Adverse Reactions

Most GLP-1 and GLP-1/GIP agonists are administered subcutaneously, and the most commonly reported cutaneous adverse effects are injection site reactions.⁸² Anaphylactic reactions to these medications also have been reported, although it is unclear if these were specific to the active ingredients or to injection excipients.^83,84 A review of 33 cases of cutaneous reactions to GLP-1 agonists reported 11 (33%) dermal hypersensitivity reactions occurring as early as 4 weeks and as late as 3 years after treatment initiation. It also described 10 (30%) cases of eosinophilic panniculitis that developed within 3 weeks to 5 months of GLP-1 treatment, 3 (9%) cases of bullous pemphigoid that occurred within the first 2 months, 2 (6%) morbilliform drug eruptions that occurred within 5 weeks, 2 (6%) cases of angioedema that occurred 15 minutes to 2 weeks after treatment initiation, and 7 (21%) other isolated cutaneous reactions. Extended-release exenatide had the most reported reactions followed by liraglutide and subcutaneous semaglutide.⁸⁵

In a different study, semaglutide use was most commonly associated with injection site reactions followed by alopecia, especially with oral administration. Unique cases of angioedema (2 days after injection), cutaneous hypersensitivity (within 10 months on treatment), bullous pemphigoid (within 2 months on treatment), eosinophilic fasciitis (within 2 weeks on treatment), and leukocytoclastic vasculitis (unclear timing), most of which resolved after discontinuation, also were reported.⁸⁶ A recent case report linked semaglutide (0.5 mg/wk) to a case of drug-induced systemic lupus erythematosus that developed within 3 months of treatment initiation and described systemic lupus erythematosus–like symptoms in a subset of patients using this medication, namely females older than 60 years, within the first month of treatment.⁸⁷ Hyperhidrosis was listed as a common adverse event in exenatide clinical trials, and various cases of panniculitis with exenatide use have been reported.^82,88 Alopecia, mainly attributed to accelerated telogen effluvium secondary to rapid weight loss, also has been reported, although hair loss is not officially listed as an adverse effect of GLP-1 agonists, and reports are highly variable.⁸⁹ Also secondary to weight loss, facial changes including sunken eyes, development of wrinkles, sagging jowls around the neck and jaw, and a hollowed appearance, among others, are recognized as undesirable adverse effects.⁹⁰ Mansour et al⁹⁰ described the potential challenges and considerations to these rising concerns associated with GLP1-agonist use.

Dermatologic Implications

Hidradenitis Suppurativa—Weight loss commonly is recommended as a lifestyle modification in the management of HS. Multiple reports have described clinical improvement of HS following weight loss with other medical interventions, such as dietary measures and bariatric surgery.^91-94 Thus, it has been postulated that medically supported weight loss with GLP-1 agonists can help improve HS⁹⁵; however, the data on the effectiveness of GLP-1 agonists on HS are still scarce and mostly have been reported in individual patients. One case report described a patient with improvements in their recalcitrant HS and DLQI score following weight loss on liraglutide (initial dose of 0.6 mg/d, titrated to 1.8 mg/d).⁷⁶ In addition, a recent case report described improvements in HS and DLQI score following concomitant tirzepatide (initial dose of 2.5 mg/0.5 mL weekly, titrated to 7.5 mg/0.5 mL weekly) and infliximab treatment.⁹⁶ The off-label use of these medications for HS is debated, and further studies regarding the benefits of GLP-1 agonists on HS still are needed.

Psoriasis—Similarly, several case reports have commented on the effects of GLP-1 agonists on psoriasis.^97,98 An early study found GLP-1 receptors were expressed in psoriasis plaques but not in healthy skin and discussed that this could be due to immune infiltration in the plaques, providing a potential rationale for using anti-inflammatory GLP-1 agonists for psoriasis.⁹⁹ Two prospective cohort studies observed improvements in PASI and DLQI scores in patients with psoriasis and T2DM after liraglutide treatment and noted important changes in immune cell populations.^80,100 A recent RCT also found improvements in DLQI and PASI scores (P<.05) in patients with T2DM following liraglutide (1.8 mg/d) treatment, along with overall decreases in inflammatory cytokines, such as IL-23, IL-17, and TNF-α.⁷⁷ However, another RCT in patients with obesity did not observe significant improvements in PASI and DLQI scores compared to placebo after 8 weeks of liraglutide (initial dose of 0.6 mg/d, titrated to 1.8 mg/d) treatment. ⁹⁹ Although these results could have been influenced by the short length of treatment compared to other studies, which observed participants for more than 10 weeks, they highlight the need for tailored studies considering the different comorbidities to identify patients who could benefit the most from these therapies.

Alopecia—Although some studies have reported increased rates of alopecia following GLP-1 agonist treatment, others have speculated about the potential role of these medications in treating hair loss through improved insulin sensitivity and scalp blood flow.^86,89 For example, a case report described a patient with improvement in androgenetic alopecia within 6 months of tirzepatide monotherapy at 2.5 mg weekly for the first 3 months followed by an increased dose of 5 mg weekly.¹⁰¹ The authors described the role of insulin in increasing dihydrotestosterone levels, which leads to miniaturization of the dermal papilla of hair follicles and argued that improvement of insulin resistance could benefit hair loss. Further studies can help elucidate the role of these medications on alopecia.

FINAL THOUGHTS

Standard T2DM treatments including metformin and GLP-1 and GLP-1/GIP agonists exhibit metabolic, immunologic, and hormonal effects that should be explored in other disease contexts. We reviewed the current data on T2DM medications in dermatologic conditions to highlight the need for additional studies to better understand the role that these medications play across diverse patient populations. Type 2 diabetes mellitus is a common comorbidity in dermatology patients, and understanding the multifactorial effects of these medications can help optimize treatment strategies, especially in patients with coexisting dermatologic and metabolic diseases.

THE DIAGNOSIS: Trichodiscoma

Histologic evaluation revealed an unremarkable epidermal surface and a subjacent well-demarcated superficial dermal nodule showing a proliferation, sometimes fascicular, of wavy and spindled fibroblasts with some stellate forms within a variably loose fibrous stroma. Some angioplasia and vascular ectasia also were seen (Figure). A diagnosis of trichodiscoma was made based on these histologic findings.

While the patient’s personal and family history of pneumothorax originally had been attributed to other causes, the diagnosis of trichodiscoma raised suspicion for Birt-Hogg-Dubé syndrome due to the classic association of skin lesions (often trichodiscomas), renal cell carcinoma, and spontaneous pneumothorax in this condition. The patient was sent for genetic testing for the associated folliculin (FLCN) gene, which was positive and thereby confirmed the diagnosis of Birt-Hogg-Dubé syndrome. At the most recent follow-up almost 2 years after initial presentation, the lesions on the earlobe were stable. The patient has since undergone screening for abdominal and renal neoplasia with negative results, and he has had no other occurrences of pneumothorax.

Our case highlights the association between trichodiscomas and Birt-Hogg-Dubé syndrome, which necessitates screening for renal cell carcinoma, pneumothorax, and lung cysts.¹ Birt-Hogg-Dubé syndrome is an autosomal- dominant disorder of the skin and lungs that is characterized by a predisposition for renal carcinoma, pneumothorax, and colon polyps as well as cutaneous markers that include fibrofolliculomas, acrochordons, and trichodiscomas; the trichodiscomas tend to manifest as numerous smooth, flesh-colored or grayish-white papules on the face, ears, neck, and/or upper trunk.¹

Trichodiscomas are benign lesions and do not require treatment²; however, if they are cosmetically bothersome to the patient, surgical excision is an option for single lesions. For more widespread cutaneous disease, combination therapy with a CO₂ laser and erbium-doped yttrium aluminum garnet laser may be utilized.³ The differential diagnosis for trichodiscoma includes basal cell carcinoma, fibrous papule, dermal nevus, and trichofolliculoma.

Basal cell carcinoma is the most common type of skin cancer.⁴ Clinically, it typically manifests as pink or flesh-colored papules on the head or neck, often with overlying ulceration or telangiectasia. Due to its association with chronic sun exposure, the median age of diagnosis for basal cell carcinoma is 68 years. Histopathologically, basal cell carcinoma is characterized by islands or nests of atypical basaloid cells with palisading cells at the periphery.⁴ Treatment depends on the location and size of the lesion, but Mohs micrographic surgery is the most common intervention on the face and ears.⁵

In contrast, fibrous papules are benign lesions that manifest clinically as small, firm, flesh-colored papules that most commonly are found on the nose.^6,7 On dermatopathology, classic findings include fibrovascular proliferation and scattered multinucleated triangular or stellate cells in the upper dermis.⁷ Due to the benign nature of the lesion, treatment is not required⁶; however, shave excision, electrodessication, and laser therapies can be attempted if the patient chooses to pursue treatment.⁸

Dermal nevus is a type of benign acquired melanocytic nevus that manifests clinically as a light-brown to flesh-colored, dome-shaped or papillomatous papule.⁹ It typically develops in areas that are exposed to the sun, including the face.¹⁰ There also have been cases of dermal nevi on the ear.¹¹ Histopathology shows melanocytic nevus cells that have completely detached from the epidermis and are located entirely in the dermis.¹² While dermal nevi are benign and treatment is not necessary, surgical excision is an option for patients who request removal.¹³

Trichofolliculoma is a benign tumor of the adnexa that shows follicular differentiation on histopathology.¹⁴ On physical examination, it manifests as an isolated flesh-colored papule or nodule with a central pore from which tufted hairs protrude. These lesions usually appear on the face or scalp and occur more commonly in women than in men. While these may be clinically indistinguishable from trichodiscomas, the absence of protruding hair in our patient’s case makes trichofolliculoma less likely. When biopsied, histopathology classically shows a cystically dilated hair follicle with keratinous material and several mature and immature branched follicular structures. Preferred treatment for trichofolliculomas is surgical excision, and recurrence is rare.¹⁴

THE DIAGNOSIS: Trichodiscoma

Histologic evaluation revealed an unremarkable epidermal surface and a subjacent well-demarcated superficial dermal nodule showing a proliferation, sometimes fascicular, of wavy and spindled fibroblasts with some stellate forms within a variably loose fibrous stroma. Some angioplasia and vascular ectasia also were seen (Figure). A diagnosis of trichodiscoma was made based on these histologic findings.

While the patient’s personal and family history of pneumothorax originally had been attributed to other causes, the diagnosis of trichodiscoma raised suspicion for Birt-Hogg-Dubé syndrome due to the classic association of skin lesions (often trichodiscomas), renal cell carcinoma, and spontaneous pneumothorax in this condition. The patient was sent for genetic testing for the associated folliculin (FLCN) gene, which was positive and thereby confirmed the diagnosis of Birt-Hogg-Dubé syndrome. At the most recent follow-up almost 2 years after initial presentation, the lesions on the earlobe were stable. The patient has since undergone screening for abdominal and renal neoplasia with negative results, and he has had no other occurrences of pneumothorax.

Our case highlights the association between trichodiscomas and Birt-Hogg-Dubé syndrome, which necessitates screening for renal cell carcinoma, pneumothorax, and lung cysts.¹ Birt-Hogg-Dubé syndrome is an autosomal- dominant disorder of the skin and lungs that is characterized by a predisposition for renal carcinoma, pneumothorax, and colon polyps as well as cutaneous markers that include fibrofolliculomas, acrochordons, and trichodiscomas; the trichodiscomas tend to manifest as numerous smooth, flesh-colored or grayish-white papules on the face, ears, neck, and/or upper trunk.¹

Trichodiscomas are benign lesions and do not require treatment²; however, if they are cosmetically bothersome to the patient, surgical excision is an option for single lesions. For more widespread cutaneous disease, combination therapy with a CO₂ laser and erbium-doped yttrium aluminum garnet laser may be utilized.³ The differential diagnosis for trichodiscoma includes basal cell carcinoma, fibrous papule, dermal nevus, and trichofolliculoma.

Basal cell carcinoma is the most common type of skin cancer.⁴ Clinically, it typically manifests as pink or flesh-colored papules on the head or neck, often with overlying ulceration or telangiectasia. Due to its association with chronic sun exposure, the median age of diagnosis for basal cell carcinoma is 68 years. Histopathologically, basal cell carcinoma is characterized by islands or nests of atypical basaloid cells with palisading cells at the periphery.⁴ Treatment depends on the location and size of the lesion, but Mohs micrographic surgery is the most common intervention on the face and ears.⁵

In contrast, fibrous papules are benign lesions that manifest clinically as small, firm, flesh-colored papules that most commonly are found on the nose.^6,7 On dermatopathology, classic findings include fibrovascular proliferation and scattered multinucleated triangular or stellate cells in the upper dermis.⁷ Due to the benign nature of the lesion, treatment is not required⁶; however, shave excision, electrodessication, and laser therapies can be attempted if the patient chooses to pursue treatment.⁸

Dermal nevus is a type of benign acquired melanocytic nevus that manifests clinically as a light-brown to flesh-colored, dome-shaped or papillomatous papule.⁹ It typically develops in areas that are exposed to the sun, including the face.¹⁰ There also have been cases of dermal nevi on the ear.¹¹ Histopathology shows melanocytic nevus cells that have completely detached from the epidermis and are located entirely in the dermis.¹² While dermal nevi are benign and treatment is not necessary, surgical excision is an option for patients who request removal.¹³

Trichofolliculoma is a benign tumor of the adnexa that shows follicular differentiation on histopathology.¹⁴ On physical examination, it manifests as an isolated flesh-colored papule or nodule with a central pore from which tufted hairs protrude. These lesions usually appear on the face or scalp and occur more commonly in women than in men. While these may be clinically indistinguishable from trichodiscomas, the absence of protruding hair in our patient’s case makes trichofolliculoma less likely. When biopsied, histopathology classically shows a cystically dilated hair follicle with keratinous material and several mature and immature branched follicular structures. Preferred treatment for trichofolliculomas is surgical excision, and recurrence is rare.¹⁴

THE DIAGNOSIS: Trichodiscoma

Histologic evaluation revealed an unremarkable epidermal surface and a subjacent well-demarcated superficial dermal nodule showing a proliferation, sometimes fascicular, of wavy and spindled fibroblasts with some stellate forms within a variably loose fibrous stroma. Some angioplasia and vascular ectasia also were seen (Figure). A diagnosis of trichodiscoma was made based on these histologic findings.

While the patient’s personal and family history of pneumothorax originally had been attributed to other causes, the diagnosis of trichodiscoma raised suspicion for Birt-Hogg-Dubé syndrome due to the classic association of skin lesions (often trichodiscomas), renal cell carcinoma, and spontaneous pneumothorax in this condition. The patient was sent for genetic testing for the associated folliculin (FLCN) gene, which was positive and thereby confirmed the diagnosis of Birt-Hogg-Dubé syndrome. At the most recent follow-up almost 2 years after initial presentation, the lesions on the earlobe were stable. The patient has since undergone screening for abdominal and renal neoplasia with negative results, and he has had no other occurrences of pneumothorax.

Our case highlights the association between trichodiscomas and Birt-Hogg-Dubé syndrome, which necessitates screening for renal cell carcinoma, pneumothorax, and lung cysts.¹ Birt-Hogg-Dubé syndrome is an autosomal- dominant disorder of the skin and lungs that is characterized by a predisposition for renal carcinoma, pneumothorax, and colon polyps as well as cutaneous markers that include fibrofolliculomas, acrochordons, and trichodiscomas; the trichodiscomas tend to manifest as numerous smooth, flesh-colored or grayish-white papules on the face, ears, neck, and/or upper trunk.¹

Trichodiscomas are benign lesions and do not require treatment²; however, if they are cosmetically bothersome to the patient, surgical excision is an option for single lesions. For more widespread cutaneous disease, combination therapy with a CO₂ laser and erbium-doped yttrium aluminum garnet laser may be utilized.³ The differential diagnosis for trichodiscoma includes basal cell carcinoma, fibrous papule, dermal nevus, and trichofolliculoma.

Basal cell carcinoma is the most common type of skin cancer.⁴ Clinically, it typically manifests as pink or flesh-colored papules on the head or neck, often with overlying ulceration or telangiectasia. Due to its association with chronic sun exposure, the median age of diagnosis for basal cell carcinoma is 68 years. Histopathologically, basal cell carcinoma is characterized by islands or nests of atypical basaloid cells with palisading cells at the periphery.⁴ Treatment depends on the location and size of the lesion, but Mohs micrographic surgery is the most common intervention on the face and ears.⁵

In contrast, fibrous papules are benign lesions that manifest clinically as small, firm, flesh-colored papules that most commonly are found on the nose.^6,7 On dermatopathology, classic findings include fibrovascular proliferation and scattered multinucleated triangular or stellate cells in the upper dermis.⁷ Due to the benign nature of the lesion, treatment is not required⁶; however, shave excision, electrodessication, and laser therapies can be attempted if the patient chooses to pursue treatment.⁸

Dermal nevus is a type of benign acquired melanocytic nevus that manifests clinically as a light-brown to flesh-colored, dome-shaped or papillomatous papule.⁹ It typically develops in areas that are exposed to the sun, including the face.¹⁰ There also have been cases of dermal nevi on the ear.¹¹ Histopathology shows melanocytic nevus cells that have completely detached from the epidermis and are located entirely in the dermis.¹² While dermal nevi are benign and treatment is not necessary, surgical excision is an option for patients who request removal.¹³

Trichofolliculoma is a benign tumor of the adnexa that shows follicular differentiation on histopathology.¹⁴ On physical examination, it manifests as an isolated flesh-colored papule or nodule with a central pore from which tufted hairs protrude. These lesions usually appear on the face or scalp and occur more commonly in women than in men. While these may be clinically indistinguishable from trichodiscomas, the absence of protruding hair in our patient’s case makes trichofolliculoma less likely. When biopsied, histopathology classically shows a cystically dilated hair follicle with keratinous material and several mature and immature branched follicular structures. Preferred treatment for trichofolliculomas is surgical excision, and recurrence is rare.¹⁴