MDedge Dermatology

To the Editor:

Drug-induced hyperpigmentation is a common cause of an acquired increase in pigmentation. Belumosudil is an oral selective inhibitor of Rho-associated coiled-coil containing protein kinase (ROCK2) that is approved for the treatment of chronic graft-vs-host disease (GVHD). We describe a patient who developed diffuse skin bronzing 3 weeks after initiation of belumosudil treatment.

A 64-year-old fair-skinned woman presented to the dermatology clinic with bronzing of the skin and dystrophic nails 3 weeks after starting belumosudil for treatment of chronic GVHD. Six months prior to presentation, the patient had received a bone marrow transplant for chronic lymphoid leukemia. She presented to dermatology 6 months after the transplant with a new-onset rash that was suspicious for GVHD. Physical examination revealed pruritic pink papules diffusely scattered on the legs and forearms (Figure 1). The patient declined biopsy at that time and later followed up with oncology. The patient’s oncologist supported a diagnosis of GVHD, and the patient began treatment with belumosudil 200 mg/d which was intended to be taken until treatment failure due to progression of chronic GVHD.

Three weeks after starting belumosudil, the patient developed diffuse bronzing of the skin and brown, evenly colored patches scattered on the trunk, back, and upper and lower extremities on a background of the presumed GVHD rash (Figure 2). The hyperpigmentation was abrupt, starting on the chest and spreading to the abdomen, extremities, and back (Figure 3).

Again, the patient was offered biopsy for the new-onset pigmentation but declined. During this time, she had no notable sun exposure and primarily stayed indoors despite living in a region with a sunny semi-arid climate. Her medication and supplement list were reviewed and included acalabrutinib, a multivitamin, lutein, biotin, and a fish oil supplement. A compete blood cell count as well as ferritin, transferrin, cortisol, and adrenocorticotropic hormone levels were unremarkable.

The patient continued to take belumosudil for treatment of GVHD. The hyperpigmentation faded slightly by a 2-month follow-up visit but persisted and was stable. She has not tried other treatments for GVHD to manage the hyperpigmentation.

Conditions known to cause diffuse bronzing of the skin include Addison disease, hemochromatosis, Cushing disease, and medication adverse events. Our patient presented with an absence of systemic symptoms, normal laboratory results, and no clinical indicators suggesting alternate causes. Given that the onset of the hyperpigmentation was 3 weeks after she started a new medication, we hypothesized that the bronzing was an adverse effect of the belumosudil—though this correlation cannot be definitively proven by this case.

The most common offending agents for drug-induced skin hyperpigmentation are nonsteroidal anti- inflammatory drugs, antimalarials, amiodarone, cytotoxic drugs, and tetracyclines.^1,2 Our patient’s medication list included the cytotoxic agent acalabrutinib, a Bruton tyrosine kinase inhibitor used for the treatment of non-Hodgkin lymphoma. It has been associated with dermatologic findings of ecchymosis, bruising, panniculitis, and cellulitis, but there are no known reports of hyperpigmentation.³ Our patient had been taking acalabrutinib for 6 months when the GVHD rash developed. At the time, she also was taking a multivitamin and lutein, biotin, and fish oil supplements, none of which have been associated with hyperpigmentation.

Polypharmacy adds a layer of difficulty in identifying the inciting cause of pigmentary change. In our case, symptoms began 3 weeks after the initiation of belumosudil. There were no cutaneous reactions observed in the ROCKstar study of belumosudil; the most common adverse events were upper respiratory tract infection, diarrhea, fatigue, nausea, increased liver enzymes, and dyspnea.^4,5 Patients on belumosudil have developed aggressive cutaneous squamous cell carcinoma.⁶ However, a search of PubMed articles indexed for MEDLINE using the search terms acalabrutinib or belumosudil with hyperpigmentation or cutaneous reaction returned no reports of these medications causing hyperpigmentation or cutaneous deposits.

Treatment of drug-induced hyperpigmentation is difficult because discontinuation of the offending agent typically confirms diagnosis, but interruption of treatment is not always possible, as in our patient. The skin changes can fade over time, but effects typically are long lasting.

Dermatologists play a key role in the identification of drug-induced skin hyperpigmentation. After endocrine or metabolic causes of skin hyperpigmentation have been ruled out, a thorough review of the patient’s medication list should be done to assess for a drug-induced cause. Treatment is limited to sun avoidance, as interruption of treatment may not be possible, and lesions typically do fade over time. These chronic skin changes can have a psychosocial effect on patients and regular follow-up is recommended.

To the Editor:

Drug-induced hyperpigmentation is a common cause of an acquired increase in pigmentation. Belumosudil is an oral selective inhibitor of Rho-associated coiled-coil containing protein kinase (ROCK2) that is approved for the treatment of chronic graft-vs-host disease (GVHD). We describe a patient who developed diffuse skin bronzing 3 weeks after initiation of belumosudil treatment.

A 64-year-old fair-skinned woman presented to the dermatology clinic with bronzing of the skin and dystrophic nails 3 weeks after starting belumosudil for treatment of chronic GVHD. Six months prior to presentation, the patient had received a bone marrow transplant for chronic lymphoid leukemia. She presented to dermatology 6 months after the transplant with a new-onset rash that was suspicious for GVHD. Physical examination revealed pruritic pink papules diffusely scattered on the legs and forearms (Figure 1). The patient declined biopsy at that time and later followed up with oncology. The patient’s oncologist supported a diagnosis of GVHD, and the patient began treatment with belumosudil 200 mg/d which was intended to be taken until treatment failure due to progression of chronic GVHD.

Three weeks after starting belumosudil, the patient developed diffuse bronzing of the skin and brown, evenly colored patches scattered on the trunk, back, and upper and lower extremities on a background of the presumed GVHD rash (Figure 2). The hyperpigmentation was abrupt, starting on the chest and spreading to the abdomen, extremities, and back (Figure 3).

Again, the patient was offered biopsy for the new-onset pigmentation but declined. During this time, she had no notable sun exposure and primarily stayed indoors despite living in a region with a sunny semi-arid climate. Her medication and supplement list were reviewed and included acalabrutinib, a multivitamin, lutein, biotin, and a fish oil supplement. A compete blood cell count as well as ferritin, transferrin, cortisol, and adrenocorticotropic hormone levels were unremarkable.

The patient continued to take belumosudil for treatment of GVHD. The hyperpigmentation faded slightly by a 2-month follow-up visit but persisted and was stable. She has not tried other treatments for GVHD to manage the hyperpigmentation.

Conditions known to cause diffuse bronzing of the skin include Addison disease, hemochromatosis, Cushing disease, and medication adverse events. Our patient presented with an absence of systemic symptoms, normal laboratory results, and no clinical indicators suggesting alternate causes. Given that the onset of the hyperpigmentation was 3 weeks after she started a new medication, we hypothesized that the bronzing was an adverse effect of the belumosudil—though this correlation cannot be definitively proven by this case.

The most common offending agents for drug-induced skin hyperpigmentation are nonsteroidal anti- inflammatory drugs, antimalarials, amiodarone, cytotoxic drugs, and tetracyclines.^1,2 Our patient’s medication list included the cytotoxic agent acalabrutinib, a Bruton tyrosine kinase inhibitor used for the treatment of non-Hodgkin lymphoma. It has been associated with dermatologic findings of ecchymosis, bruising, panniculitis, and cellulitis, but there are no known reports of hyperpigmentation.³ Our patient had been taking acalabrutinib for 6 months when the GVHD rash developed. At the time, she also was taking a multivitamin and lutein, biotin, and fish oil supplements, none of which have been associated with hyperpigmentation.

Polypharmacy adds a layer of difficulty in identifying the inciting cause of pigmentary change. In our case, symptoms began 3 weeks after the initiation of belumosudil. There were no cutaneous reactions observed in the ROCKstar study of belumosudil; the most common adverse events were upper respiratory tract infection, diarrhea, fatigue, nausea, increased liver enzymes, and dyspnea.^4,5 Patients on belumosudil have developed aggressive cutaneous squamous cell carcinoma.⁶ However, a search of PubMed articles indexed for MEDLINE using the search terms acalabrutinib or belumosudil with hyperpigmentation or cutaneous reaction returned no reports of these medications causing hyperpigmentation or cutaneous deposits.

Treatment of drug-induced hyperpigmentation is difficult because discontinuation of the offending agent typically confirms diagnosis, but interruption of treatment is not always possible, as in our patient. The skin changes can fade over time, but effects typically are long lasting.

Dermatologists play a key role in the identification of drug-induced skin hyperpigmentation. After endocrine or metabolic causes of skin hyperpigmentation have been ruled out, a thorough review of the patient’s medication list should be done to assess for a drug-induced cause. Treatment is limited to sun avoidance, as interruption of treatment may not be possible, and lesions typically do fade over time. These chronic skin changes can have a psychosocial effect on patients and regular follow-up is recommended.

To the Editor:

Drug-induced hyperpigmentation is a common cause of an acquired increase in pigmentation. Belumosudil is an oral selective inhibitor of Rho-associated coiled-coil containing protein kinase (ROCK2) that is approved for the treatment of chronic graft-vs-host disease (GVHD). We describe a patient who developed diffuse skin bronzing 3 weeks after initiation of belumosudil treatment.

A 64-year-old fair-skinned woman presented to the dermatology clinic with bronzing of the skin and dystrophic nails 3 weeks after starting belumosudil for treatment of chronic GVHD. Six months prior to presentation, the patient had received a bone marrow transplant for chronic lymphoid leukemia. She presented to dermatology 6 months after the transplant with a new-onset rash that was suspicious for GVHD. Physical examination revealed pruritic pink papules diffusely scattered on the legs and forearms (Figure 1). The patient declined biopsy at that time and later followed up with oncology. The patient’s oncologist supported a diagnosis of GVHD, and the patient began treatment with belumosudil 200 mg/d which was intended to be taken until treatment failure due to progression of chronic GVHD.

Three weeks after starting belumosudil, the patient developed diffuse bronzing of the skin and brown, evenly colored patches scattered on the trunk, back, and upper and lower extremities on a background of the presumed GVHD rash (Figure 2). The hyperpigmentation was abrupt, starting on the chest and spreading to the abdomen, extremities, and back (Figure 3).

Again, the patient was offered biopsy for the new-onset pigmentation but declined. During this time, she had no notable sun exposure and primarily stayed indoors despite living in a region with a sunny semi-arid climate. Her medication and supplement list were reviewed and included acalabrutinib, a multivitamin, lutein, biotin, and a fish oil supplement. A compete blood cell count as well as ferritin, transferrin, cortisol, and adrenocorticotropic hormone levels were unremarkable.

The patient continued to take belumosudil for treatment of GVHD. The hyperpigmentation faded slightly by a 2-month follow-up visit but persisted and was stable. She has not tried other treatments for GVHD to manage the hyperpigmentation.

Conditions known to cause diffuse bronzing of the skin include Addison disease, hemochromatosis, Cushing disease, and medication adverse events. Our patient presented with an absence of systemic symptoms, normal laboratory results, and no clinical indicators suggesting alternate causes. Given that the onset of the hyperpigmentation was 3 weeks after she started a new medication, we hypothesized that the bronzing was an adverse effect of the belumosudil—though this correlation cannot be definitively proven by this case.

The most common offending agents for drug-induced skin hyperpigmentation are nonsteroidal anti- inflammatory drugs, antimalarials, amiodarone, cytotoxic drugs, and tetracyclines.^1,2 Our patient’s medication list included the cytotoxic agent acalabrutinib, a Bruton tyrosine kinase inhibitor used for the treatment of non-Hodgkin lymphoma. It has been associated with dermatologic findings of ecchymosis, bruising, panniculitis, and cellulitis, but there are no known reports of hyperpigmentation.³ Our patient had been taking acalabrutinib for 6 months when the GVHD rash developed. At the time, she also was taking a multivitamin and lutein, biotin, and fish oil supplements, none of which have been associated with hyperpigmentation.

Polypharmacy adds a layer of difficulty in identifying the inciting cause of pigmentary change. In our case, symptoms began 3 weeks after the initiation of belumosudil. There were no cutaneous reactions observed in the ROCKstar study of belumosudil; the most common adverse events were upper respiratory tract infection, diarrhea, fatigue, nausea, increased liver enzymes, and dyspnea.^4,5 Patients on belumosudil have developed aggressive cutaneous squamous cell carcinoma.⁶ However, a search of PubMed articles indexed for MEDLINE using the search terms acalabrutinib or belumosudil with hyperpigmentation or cutaneous reaction returned no reports of these medications causing hyperpigmentation or cutaneous deposits.

Treatment of drug-induced hyperpigmentation is difficult because discontinuation of the offending agent typically confirms diagnosis, but interruption of treatment is not always possible, as in our patient. The skin changes can fade over time, but effects typically are long lasting.

Dermatologists play a key role in the identification of drug-induced skin hyperpigmentation. After endocrine or metabolic causes of skin hyperpigmentation have been ruled out, a thorough review of the patient’s medication list should be done to assess for a drug-induced cause. Treatment is limited to sun avoidance, as interruption of treatment may not be possible, and lesions typically do fade over time. These chronic skin changes can have a psychosocial effect on patients and regular follow-up is recommended.

Mohs micrographic surgery (MMS)—developed by Dr. Frederic Mohs in the 1930s—is the gold standard for treating various cutaneous malignancies. It provides maximal conservation of uninvolved tissues while producing higher cure rates compared to wide local excision.^1,2

We sought to assess the various characteristics that impact patient satisfaction to help Mohs surgeons incorporate relatively simple yet clinically significant practices into their patient encounters. We conducted a systematic literature search of peer-reviewed PubMed articles indexed for MEDLINE from database inception through November 2023 using the terms Mohs micrographic surgery and patient satisfaction. Among the inclusion criteria were studies involving participants having undergone MMS, with objective assessments on patient-reported satisfaction or preferences related to patient education, communication, anxiety-alleviating measures, or QOL in MMS. Studies were excluded if they failed to meet these criteria, were outdated and no longer clinically relevant, or measured unalterable factors with no significant impact on how Mohs surgeons could change clinical practice. Of the 157 nonreplicated studies identified, 34 met inclusion criteria.

Perioperative Patient Communication and Education Techniques

Perioperative Patient Communication—Many studies have evaluated the impact of perioperative patient-provider communication and education on patient satisfaction in those undergoing MMS. Studies focusing on preoperative and postoperative telephone calls, patient consultation formats, and patient-perceived impact of such communication modalities have been well documented (Table 1).^3-8 The importance of the patient follow-up after MMS was further supported by a retrospective study concluding that 88.7% (86/97) of patients regarded follow-up visits as important, and 80% (77/97) desired additional follow-up 3 months after MMS.⁹ Additional studies have highlighted the importance of thorough and open perioperative patient-provider communication during MMS (Table 2).^10-12

Patient-Education Techniques—Many studies have assessed the use of visual models to aid in patient education on MMS, specifically the preprocedural consent process (Table 3).^13-16 Additionally, 2 randomized controlled trials assessing the use of at-home and same-day in-office preoperative educational videos concluded that these interventions increased patient knowledge and confidence regarding procedural risks and benefits, with no statistically significant differences in patient anxiety or satisfaction.^17,18

Despite the availability of these educational videos, many patients often turn to online resources for self-education, which is problematic if reader literacy is incongruent with online readability. One study assessing readability of online MMS resources concluded that the most accessed articles exceeded the recommended reading level for adequate patient comprehension.¹⁹ A survey studying a wide range of variables related to patient satisfaction (eg, demographics, socioeconomics, health status) in 339 MMS patients found that those who considered themselves more involved in the decision-making process were more satisfied in the short-term, and married patients had even higher long-term satisfaction. Interestingly, this study also concluded that undergoing 3 or more MMS stages was associated with higher short- and long-term satisfaction, likely secondary to perceived effects of increased overall care, medical attention, and time spent with the provider.²⁰

Synthesis of this information with emphasis on the higher evidence-based studies—including systematic reviews, meta-analyses, and randomized controlled trials—yields the following beneficial interventions regarding patient education and communication^13-20:

• Preoperative and same-day postoperative telephone follow-up (TFU) do not show statistically significant impacts on patient satisfaction; however, TFU allows for identification of postoperative concerns and inadequate pain management, which may have downstream effects on long-term perception of the overall patient experience.
• The use of video-assisted consent yields improved patient satisfaction and knowledge, while video content—traditional or didactic—has no impact on satisfaction in new MMS patients.
• The use of at-home or same-day in-office preoperative educational videos can improve procedural knowledge and risk-benefit understanding of MMS while having no impact on satisfaction.
• Bedside manner and effective in-person communication by the provider often takes precedence in the patient experience; however, implementation of additional educational modalities should be considered.

Patient Anxiety and QOL

Reducing Patient Anxiety—The use of perioperative distractors to reduce patient anxiety may play an integral role when patients undergo MMS, as there often are prolonged waiting periods between stages when patients may feel increasingly vulnerable or anxious. Table 4 reviews studies on perioperative distractors that showed a statistically significant reduction in MMS patient anxiety.^21-24

Although not statistically significant, additional studies evaluating the use of intraoperative anxiety-reduction methods in MMS have demonstrated a downtrend in patient anxiety with the following interventions: engaging in small talk with clinic staff, bringing a guest, eating, watching television, communicating surgical expectations with the provider, handholding, use of a stress ball, and use of 3-dimensional educational MMS models.^25-27 Similarly, a survey of 73 patients undergoing MMS found that patients tended to enjoy complimentary beverages preprocedurally in the waiting room, reading, speaking with their guest, watching television, or using their telephone during wait times.²⁸ Table 5 lists additional perioperative factors encompassing specific patient and surgical characteristics that help reduce patient anxiety.^29-32

Patient QOL—Many methods aimed at decreasing MMS-related patient anxiety often show no direct impact on patient satisfaction, likely due to the multifactorial nature of the patient-perceived experience. A prospective observational study of MMS patients noted a statistically significant improvement in patient QOL scores 3 months postsurgery (P=.0007), demonstrating that MMS generally results in positive patient outcomes despite preprocedural anxiety.³³ An additional prospective study in MMS patients with nonmelanoma skin cancer concluded that sex, age, and closure type—factors often shown to affect anxiety levels—did not significantly impact patient satisfaction.³⁴ Similarly, high satisfaction levels can be expected among MMS patients undergoing treatment of melanoma in situ, with more than 90% of patients rating their treatment experience a 4 (agree) or 5 (strongly agree) out of 5 in short- and long-term satisfaction assessments (38/41 and 40/42, respectively).³⁵ This assessment, conducted 3 months postoperatively, asked patients to score the statement, “I am completely satisfied with the treatment of my skin problem,” on a scale ranging from 1 (strongly disagree) to 5 (strongly agree).

Lastly, patient perception of their surgeon’s skill may contribute to levels of patient satisfaction. Although suture spacing has not been shown to affect surgical outcomes, it has been demonstrated to impact the patient’s perception of surgical skill and is further supported by a study concluding that closures with 2-mm spacing were ranked significantly lower by patients compared with closures with either 4- or 6-mm spacing (P=.005 and P=.012, respectively).³⁶

Synthesis of this information with emphasis on the higher evidence-based studies—including systematic reviews, meta-analyses, and randomized controlled trials—yields the following beneficial interventions regarding anxiety-reducing measures and patient-perceived QOL^21-36:

• Factors shown to decrease patient anxiety include patient personalized music, virtual-reality experience, perioperative informational videos, and 3-dimensional–printed MMS models.
• Many methods aimed at decreasing MMS-related patient anxiety show no direct impact on patient satisfaction, likely due to the multifactorial nature of the patient-perceived experience.
• Higher anxiety can be associated with worse QOL scores in MMS patients, and additional factors that may have a negative impact on anxiety include female sex, younger age, and tumor location on the face.

Conclusion

Many factors affect patient satisfaction in MMS. Increased awareness and acknowledgement of these factors can foster improved clinical practice and patient experience, which can have downstream effects on patient compliance and overall psychosocial and medical well-being. With the movement toward value-based health care, patient satisfaction ratings are likely to play an increasingly important role in physician reimbursement. Adapting one’s practice to include high-quality, time-efficient, patient-centered care goes hand in hand with increasing MMS patient satisfaction. Careful evaluation and scrutiny of one’s current practices while remaining cognizant of patient population, resource availability, and clinical limitations often reveal opportunities for small adjustments that can have a great impact on patient satisfaction. This thorough assessment and review of the published literature aims to assist MMS surgeons in understanding the role that certain factors—(1) perioperative patient communication and education techniques and (2) patient anxiety, QOL, and additional considerations—have on overall satisfaction with MMS. Specific consideration should be placed on the fact that patient satisfaction is multifactorial, and many different interventions can have a positive impact on the overall patient experience.

Mohs micrographic surgery (MMS)—developed by Dr. Frederic Mohs in the 1930s—is the gold standard for treating various cutaneous malignancies. It provides maximal conservation of uninvolved tissues while producing higher cure rates compared to wide local excision.^1,2

We sought to assess the various characteristics that impact patient satisfaction to help Mohs surgeons incorporate relatively simple yet clinically significant practices into their patient encounters. We conducted a systematic literature search of peer-reviewed PubMed articles indexed for MEDLINE from database inception through November 2023 using the terms Mohs micrographic surgery and patient satisfaction. Among the inclusion criteria were studies involving participants having undergone MMS, with objective assessments on patient-reported satisfaction or preferences related to patient education, communication, anxiety-alleviating measures, or QOL in MMS. Studies were excluded if they failed to meet these criteria, were outdated and no longer clinically relevant, or measured unalterable factors with no significant impact on how Mohs surgeons could change clinical practice. Of the 157 nonreplicated studies identified, 34 met inclusion criteria.

Perioperative Patient Communication and Education Techniques

Perioperative Patient Communication—Many studies have evaluated the impact of perioperative patient-provider communication and education on patient satisfaction in those undergoing MMS. Studies focusing on preoperative and postoperative telephone calls, patient consultation formats, and patient-perceived impact of such communication modalities have been well documented (Table 1).^3-8 The importance of the patient follow-up after MMS was further supported by a retrospective study concluding that 88.7% (86/97) of patients regarded follow-up visits as important, and 80% (77/97) desired additional follow-up 3 months after MMS.⁹ Additional studies have highlighted the importance of thorough and open perioperative patient-provider communication during MMS (Table 2).^10-12

Patient-Education Techniques—Many studies have assessed the use of visual models to aid in patient education on MMS, specifically the preprocedural consent process (Table 3).^13-16 Additionally, 2 randomized controlled trials assessing the use of at-home and same-day in-office preoperative educational videos concluded that these interventions increased patient knowledge and confidence regarding procedural risks and benefits, with no statistically significant differences in patient anxiety or satisfaction.^17,18

Despite the availability of these educational videos, many patients often turn to online resources for self-education, which is problematic if reader literacy is incongruent with online readability. One study assessing readability of online MMS resources concluded that the most accessed articles exceeded the recommended reading level for adequate patient comprehension.¹⁹ A survey studying a wide range of variables related to patient satisfaction (eg, demographics, socioeconomics, health status) in 339 MMS patients found that those who considered themselves more involved in the decision-making process were more satisfied in the short-term, and married patients had even higher long-term satisfaction. Interestingly, this study also concluded that undergoing 3 or more MMS stages was associated with higher short- and long-term satisfaction, likely secondary to perceived effects of increased overall care, medical attention, and time spent with the provider.²⁰

Synthesis of this information with emphasis on the higher evidence-based studies—including systematic reviews, meta-analyses, and randomized controlled trials—yields the following beneficial interventions regarding patient education and communication^13-20:

• Preoperative and same-day postoperative telephone follow-up (TFU) do not show statistically significant impacts on patient satisfaction; however, TFU allows for identification of postoperative concerns and inadequate pain management, which may have downstream effects on long-term perception of the overall patient experience.
• The use of video-assisted consent yields improved patient satisfaction and knowledge, while video content—traditional or didactic—has no impact on satisfaction in new MMS patients.
• The use of at-home or same-day in-office preoperative educational videos can improve procedural knowledge and risk-benefit understanding of MMS while having no impact on satisfaction.
• Bedside manner and effective in-person communication by the provider often takes precedence in the patient experience; however, implementation of additional educational modalities should be considered.

Patient Anxiety and QOL

Reducing Patient Anxiety—The use of perioperative distractors to reduce patient anxiety may play an integral role when patients undergo MMS, as there often are prolonged waiting periods between stages when patients may feel increasingly vulnerable or anxious. Table 4 reviews studies on perioperative distractors that showed a statistically significant reduction in MMS patient anxiety.^21-24

Although not statistically significant, additional studies evaluating the use of intraoperative anxiety-reduction methods in MMS have demonstrated a downtrend in patient anxiety with the following interventions: engaging in small talk with clinic staff, bringing a guest, eating, watching television, communicating surgical expectations with the provider, handholding, use of a stress ball, and use of 3-dimensional educational MMS models.^25-27 Similarly, a survey of 73 patients undergoing MMS found that patients tended to enjoy complimentary beverages preprocedurally in the waiting room, reading, speaking with their guest, watching television, or using their telephone during wait times.²⁸ Table 5 lists additional perioperative factors encompassing specific patient and surgical characteristics that help reduce patient anxiety.^29-32

Patient QOL—Many methods aimed at decreasing MMS-related patient anxiety often show no direct impact on patient satisfaction, likely due to the multifactorial nature of the patient-perceived experience. A prospective observational study of MMS patients noted a statistically significant improvement in patient QOL scores 3 months postsurgery (P=.0007), demonstrating that MMS generally results in positive patient outcomes despite preprocedural anxiety.³³ An additional prospective study in MMS patients with nonmelanoma skin cancer concluded that sex, age, and closure type—factors often shown to affect anxiety levels—did not significantly impact patient satisfaction.³⁴ Similarly, high satisfaction levels can be expected among MMS patients undergoing treatment of melanoma in situ, with more than 90% of patients rating their treatment experience a 4 (agree) or 5 (strongly agree) out of 5 in short- and long-term satisfaction assessments (38/41 and 40/42, respectively).³⁵ This assessment, conducted 3 months postoperatively, asked patients to score the statement, “I am completely satisfied with the treatment of my skin problem,” on a scale ranging from 1 (strongly disagree) to 5 (strongly agree).

Lastly, patient perception of their surgeon’s skill may contribute to levels of patient satisfaction. Although suture spacing has not been shown to affect surgical outcomes, it has been demonstrated to impact the patient’s perception of surgical skill and is further supported by a study concluding that closures with 2-mm spacing were ranked significantly lower by patients compared with closures with either 4- or 6-mm spacing (P=.005 and P=.012, respectively).³⁶

Synthesis of this information with emphasis on the higher evidence-based studies—including systematic reviews, meta-analyses, and randomized controlled trials—yields the following beneficial interventions regarding anxiety-reducing measures and patient-perceived QOL^21-36:

• Factors shown to decrease patient anxiety include patient personalized music, virtual-reality experience, perioperative informational videos, and 3-dimensional–printed MMS models.
• Many methods aimed at decreasing MMS-related patient anxiety show no direct impact on patient satisfaction, likely due to the multifactorial nature of the patient-perceived experience.
• Higher anxiety can be associated with worse QOL scores in MMS patients, and additional factors that may have a negative impact on anxiety include female sex, younger age, and tumor location on the face.

Conclusion

Many factors affect patient satisfaction in MMS. Increased awareness and acknowledgement of these factors can foster improved clinical practice and patient experience, which can have downstream effects on patient compliance and overall psychosocial and medical well-being. With the movement toward value-based health care, patient satisfaction ratings are likely to play an increasingly important role in physician reimbursement. Adapting one’s practice to include high-quality, time-efficient, patient-centered care goes hand in hand with increasing MMS patient satisfaction. Careful evaluation and scrutiny of one’s current practices while remaining cognizant of patient population, resource availability, and clinical limitations often reveal opportunities for small adjustments that can have a great impact on patient satisfaction. This thorough assessment and review of the published literature aims to assist MMS surgeons in understanding the role that certain factors—(1) perioperative patient communication and education techniques and (2) patient anxiety, QOL, and additional considerations—have on overall satisfaction with MMS. Specific consideration should be placed on the fact that patient satisfaction is multifactorial, and many different interventions can have a positive impact on the overall patient experience.

Mohs micrographic surgery (MMS)—developed by Dr. Frederic Mohs in the 1930s—is the gold standard for treating various cutaneous malignancies. It provides maximal conservation of uninvolved tissues while producing higher cure rates compared to wide local excision.^1,2

We sought to assess the various characteristics that impact patient satisfaction to help Mohs surgeons incorporate relatively simple yet clinically significant practices into their patient encounters. We conducted a systematic literature search of peer-reviewed PubMed articles indexed for MEDLINE from database inception through November 2023 using the terms Mohs micrographic surgery and patient satisfaction. Among the inclusion criteria were studies involving participants having undergone MMS, with objective assessments on patient-reported satisfaction or preferences related to patient education, communication, anxiety-alleviating measures, or QOL in MMS. Studies were excluded if they failed to meet these criteria, were outdated and no longer clinically relevant, or measured unalterable factors with no significant impact on how Mohs surgeons could change clinical practice. Of the 157 nonreplicated studies identified, 34 met inclusion criteria.

Perioperative Patient Communication and Education Techniques

Perioperative Patient Communication—Many studies have evaluated the impact of perioperative patient-provider communication and education on patient satisfaction in those undergoing MMS. Studies focusing on preoperative and postoperative telephone calls, patient consultation formats, and patient-perceived impact of such communication modalities have been well documented (Table 1).^3-8 The importance of the patient follow-up after MMS was further supported by a retrospective study concluding that 88.7% (86/97) of patients regarded follow-up visits as important, and 80% (77/97) desired additional follow-up 3 months after MMS.⁹ Additional studies have highlighted the importance of thorough and open perioperative patient-provider communication during MMS (Table 2).^10-12

Patient-Education Techniques—Many studies have assessed the use of visual models to aid in patient education on MMS, specifically the preprocedural consent process (Table 3).^13-16 Additionally, 2 randomized controlled trials assessing the use of at-home and same-day in-office preoperative educational videos concluded that these interventions increased patient knowledge and confidence regarding procedural risks and benefits, with no statistically significant differences in patient anxiety or satisfaction.^17,18

Despite the availability of these educational videos, many patients often turn to online resources for self-education, which is problematic if reader literacy is incongruent with online readability. One study assessing readability of online MMS resources concluded that the most accessed articles exceeded the recommended reading level for adequate patient comprehension.¹⁹ A survey studying a wide range of variables related to patient satisfaction (eg, demographics, socioeconomics, health status) in 339 MMS patients found that those who considered themselves more involved in the decision-making process were more satisfied in the short-term, and married patients had even higher long-term satisfaction. Interestingly, this study also concluded that undergoing 3 or more MMS stages was associated with higher short- and long-term satisfaction, likely secondary to perceived effects of increased overall care, medical attention, and time spent with the provider.²⁰

Synthesis of this information with emphasis on the higher evidence-based studies—including systematic reviews, meta-analyses, and randomized controlled trials—yields the following beneficial interventions regarding patient education and communication^13-20:

• Preoperative and same-day postoperative telephone follow-up (TFU) do not show statistically significant impacts on patient satisfaction; however, TFU allows for identification of postoperative concerns and inadequate pain management, which may have downstream effects on long-term perception of the overall patient experience.
• The use of video-assisted consent yields improved patient satisfaction and knowledge, while video content—traditional or didactic—has no impact on satisfaction in new MMS patients.
• The use of at-home or same-day in-office preoperative educational videos can improve procedural knowledge and risk-benefit understanding of MMS while having no impact on satisfaction.
• Bedside manner and effective in-person communication by the provider often takes precedence in the patient experience; however, implementation of additional educational modalities should be considered.

Patient Anxiety and QOL

Reducing Patient Anxiety—The use of perioperative distractors to reduce patient anxiety may play an integral role when patients undergo MMS, as there often are prolonged waiting periods between stages when patients may feel increasingly vulnerable or anxious. Table 4 reviews studies on perioperative distractors that showed a statistically significant reduction in MMS patient anxiety.^21-24

Although not statistically significant, additional studies evaluating the use of intraoperative anxiety-reduction methods in MMS have demonstrated a downtrend in patient anxiety with the following interventions: engaging in small talk with clinic staff, bringing a guest, eating, watching television, communicating surgical expectations with the provider, handholding, use of a stress ball, and use of 3-dimensional educational MMS models.^25-27 Similarly, a survey of 73 patients undergoing MMS found that patients tended to enjoy complimentary beverages preprocedurally in the waiting room, reading, speaking with their guest, watching television, or using their telephone during wait times.²⁸ Table 5 lists additional perioperative factors encompassing specific patient and surgical characteristics that help reduce patient anxiety.^29-32

Patient QOL—Many methods aimed at decreasing MMS-related patient anxiety often show no direct impact on patient satisfaction, likely due to the multifactorial nature of the patient-perceived experience. A prospective observational study of MMS patients noted a statistically significant improvement in patient QOL scores 3 months postsurgery (P=.0007), demonstrating that MMS generally results in positive patient outcomes despite preprocedural anxiety.³³ An additional prospective study in MMS patients with nonmelanoma skin cancer concluded that sex, age, and closure type—factors often shown to affect anxiety levels—did not significantly impact patient satisfaction.³⁴ Similarly, high satisfaction levels can be expected among MMS patients undergoing treatment of melanoma in situ, with more than 90% of patients rating their treatment experience a 4 (agree) or 5 (strongly agree) out of 5 in short- and long-term satisfaction assessments (38/41 and 40/42, respectively).³⁵ This assessment, conducted 3 months postoperatively, asked patients to score the statement, “I am completely satisfied with the treatment of my skin problem,” on a scale ranging from 1 (strongly disagree) to 5 (strongly agree).

Lastly, patient perception of their surgeon’s skill may contribute to levels of patient satisfaction. Although suture spacing has not been shown to affect surgical outcomes, it has been demonstrated to impact the patient’s perception of surgical skill and is further supported by a study concluding that closures with 2-mm spacing were ranked significantly lower by patients compared with closures with either 4- or 6-mm spacing (P=.005 and P=.012, respectively).³⁶

Synthesis of this information with emphasis on the higher evidence-based studies—including systematic reviews, meta-analyses, and randomized controlled trials—yields the following beneficial interventions regarding anxiety-reducing measures and patient-perceived QOL^21-36:

• Factors shown to decrease patient anxiety include patient personalized music, virtual-reality experience, perioperative informational videos, and 3-dimensional–printed MMS models.
• Many methods aimed at decreasing MMS-related patient anxiety show no direct impact on patient satisfaction, likely due to the multifactorial nature of the patient-perceived experience.
• Higher anxiety can be associated with worse QOL scores in MMS patients, and additional factors that may have a negative impact on anxiety include female sex, younger age, and tumor location on the face.

Conclusion

Many factors affect patient satisfaction in MMS. Increased awareness and acknowledgement of these factors can foster improved clinical practice and patient experience, which can have downstream effects on patient compliance and overall psychosocial and medical well-being. With the movement toward value-based health care, patient satisfaction ratings are likely to play an increasingly important role in physician reimbursement. Adapting one’s practice to include high-quality, time-efficient, patient-centered care goes hand in hand with increasing MMS patient satisfaction. Careful evaluation and scrutiny of one’s current practices while remaining cognizant of patient population, resource availability, and clinical limitations often reveal opportunities for small adjustments that can have a great impact on patient satisfaction. This thorough assessment and review of the published literature aims to assist MMS surgeons in understanding the role that certain factors—(1) perioperative patient communication and education techniques and (2) patient anxiety, QOL, and additional considerations—have on overall satisfaction with MMS. Specific consideration should be placed on the fact that patient satisfaction is multifactorial, and many different interventions can have a positive impact on the overall patient experience.

While strong relationships with mentors and advisers are critical to navigating the competitive dermatology match process, the advice medical students receive from different individuals can be contradictory. Unaccredited information online—particularly on social media—as well as data reported by applicants can add to potential confusion.¹ Published research has elicited comments and observations from successfully matched medical students about highly discussed topics such as presentations and publications, letters of recommendation, away rotations, and interviews.^2,3 However, there currently are no published data about advice that dermatology mentors actually offer medical students. In this study, we aimed to investigate this gap in the current literature and examine the advice dermatology faculty, program directors, and other mentors at institutions accredited by the Accreditation Council for Graduate Medical Education across the United States give to medical students applying to dermatology residency.

Methods

A 14-question Johns Hopkins Qualtrics survey was sent via the Association of Professors of Dermatology (APD) listserve in June 2024 soliciting responses from members who consider themselves to be mentors to dermatology applicants across the United States. The survey included multiple-choice questions with the option to select multiple answers and a space for open-ended responses. The questions first gathered information on the respondents, including the capacity in which the mentors advised medical students (eg, program director, department chair, clinical faculty). Mentors were asked for the number of years they had been advising mentees and if they were advising students with a home dermatology program. In addition, mentors were asked what advice they give their mentees about aspects of the application process, including gap years, dual applications, research involvement, couples matching, program signaling, away rotations, internship year, letters of recommendation, geographic signaling, interviewing advice, and volunteering during medical school.

On August 18, 2024, survey results from 115 respondents were aggregated. The responses for each question were quantitatively assessed to determine whether there was consensus on specific advice offered. The open-ended responses also were qualitatively assessed to determine the most common responses.

Results

The respondents included program directors (30% [35/115]), clinical faculty (22% [25/115]), department chairs (18% [21/115]), assistant program directors (15% [17/115]), medical school clerkship directors (8% [9/115]), primary mentors (ie, faculty who did not fall into any of the aforementioned categories but still advised medical students interested in dermatology)(5% [6/115]), division chiefs (1% [1/115]), and deans (1% [1/115]). Respondents had been advising students for a median of 10 years (range, 1-40 years [25th percentile, 5.00 years; 75th percentile, 13.75 years]). The majority (90% [103/115]) of mentors surveyed were advising students with a home dermatology program.

Areas of Consensus

In some areas, there was broad consensus among the advice offered by the mentors that were surveyed (eTable).

Research During Medical School—More than 91% (105/115) of the respondents recommended research to encourage academic growth and indicated that the most important reason for conducting research during medical school is to foster mentor-mentee relationships; however, more than one-third of respondents believed research is overvalued by students and research productivity is not as critical for matching as they perceive it to be. When these responses were categorized by respondent positions, 29% (15/52) of program or assistant directors indicated agreement with the statement that research is overvalued.

Away Rotations—There also was a consensus about the importance of away rotations, with 85% (98/115) of respondents advising students to complete 1 to 2 away rotations at sites of high interest, and 13% (15/115) suggesting that students complete as many away rotations as possible. It is worth noting, however, that the official APD Residency Program Directors Section’s statement on away rotations recommends no more than 2 away rotations (or no more than 3 for students with no home program).⁴

Reapplication Advice—Additionally, in a situation where students do not match into a dermatology residency program, the vast majority (71% [82/115]) of respondents advised students to rank competitive intern years to foster connections and improve the chance of matching on the second attempt.

Volunteering During Medical School—Seventy-seven percent (89/115) of mentors encouraged students to engage in volunteerism and advocacy during medical school to create a well-rounded application, and 69% (79/115) of mentors encouraged students to display leadership in their volunteer efforts.

Areas Without Consensus

Letters of Recommendation—Most respondents recommended submitting letters of recommendation only from dermatology professionals (55% [63/115]), with the remainder recommending students request a letter from anyone who could provide a strong recommendation regardless of specialty mix (42% [48/115]).

Dermatologic Subspecialties—For students interested in dermatologic subspecialties, 73% (84/115) of mentors advised that students be honest during interviews but keep an open mind that interests during residencies may change. Forty-three percent (49/115) of respondents encouraged students to promote a subspecialty interest during their interview only if they can demonstrate effort within that subspecialty on their application.

Couples Matching—Most respondents approach couples matching on a case-by-case basis and assess individual priorities when they do advise on this topic. Respondents often advise applicants to identify a few cities/regions and focus strongly on the programs within those regions to avoid spreading themselves too thin; however, one-third (38/115) of respondents indicated that they do not personally offer advice regarding the couples match.

Areas With Diverse Opinions

Gap Years—Nearly one-quarter (24% [28/115]) of mentors reported that they rarely recommend students take a year off and only support those who are adamant about doing so, or that they never support taking a gap year at all. A slight majority (58% [67/115]) recommend a gap year for students strongly interested in dermatologic research, and 38% (44/115) recommend a gap year for students with weaker applications (Figure 1). We received many open-ended responses to this question, with mentors frequently indicating that they advise students to take a gap year on a case-by-case basis, with 44% (51/115) of commenters recommending that students only take paid gap-year research positions.

Program Signaling—The dermatology residency application process implemented a system of preference signaling tokens (PSTs) starting with the 2021-2022 cycle. Not quite half (46% [53/115]) of respondents recommend students apply only to places that they signaled, while 20% (23/115) advise responding to 10 to 15 additional programs. Very few (8% [9/115]) advise students to signal only in their stated region of interest. Approximately half (49% [56/115]) of mentors recommend students only signal based on the programs they feel would be the best fit for them without regard for perceived competitiveness—which aligns with the APD Residency Program Directors Section’s recommendation⁴—while 37% (43/115) recommend students distribute their signals to a wide range of programs. Sixty-three percent (72/115) of respondents recommend gold signaling to the student’s 3 most desired programs regardless of home and away rotation considerations, while 19% (22/115) recommend students give silver signals to their home and away rotation programs, as a rotation is already a signal of a strong desire to be there (Figure 2).

Dual Application—Fifty-three percent (61/115) of mentors recommended dual applying only for those truly interested in multiple specialties. Eighteen percent (21/115) of respondents advised dual applying for those with less than a 75% chance of matching. Twenty-five percent (29/115) of respondents free-wrote comments about approaching dual applying on a case-by-case basis, with many discussing the downsides of dual application and raising concerns that dual applications can hinder applicants’ success, can seem disingenuous, and seem to be a tool used to improve medical school match rates without benefit for the student.

We also stratified the data to compare overall responses from the total cohort with those from only program and assistant program directors. Across the 14 questions, responses from program and assistant program directors alone were similar to the overall cohort results

Comment

This study evaluated nationwide data on mentorship advising in dermatology, detailing mentors’ advice regarding research, gap years, dual applications, away rotations, intern year, couples matching, program signaling, and volunteering during medical school. Based on our results, most respondents agree on the importance of research during medical school, the utility of away rotations, and the value of volunteering during medical school. Similarly, respondents agreed on the importance of having strong letters of recommendation; while some advised asking only dermatology faculty to write letters, others did not have a specialty preference for the letter writers. Respondents also had varying views about sharing interest in subspecialties during residency interviews. Many of the respondents do not provide recommendations regarding geographic signaling and couples matching, expressing that these are parts of an application that are important to approach on a case-by-case basis. Lastly, respondents had diverse opinions regarding the utility of gap years, whether to encourage or discourage dual applications, and how to advise regarding program signaling.

Our results also showed that one-third of respondents believed that research is not as important as it is perceived to be by dermatology applicants. While engaging in research during medical school was almost unanimously encouraged to foster mentor-mentee relationships, respondents expressed that the number of research experiences and publications was not critical. This is an important topic of discussion, as taking a dedicated year away from medical school to complete a research fellowship is becoming a trend among dermatology applicants.⁵ There has been discussion both on unofficial online platforms as well as in the published literature regarding the pressure for medical students interested in dermatology to publish, which may result in a gap year for research.⁶ The literature on the utility of a gap year in match rates is sparse, with one study showing no difference in match rates among Mayo Clinic dermatology residents who took research years vs those who did not.⁷ However, this contrasts with match rates at top dermatology residency programs where 41% of applicants who took a gap year matched vs 19% who did not.^7,8 These conflicting data are reflected in our study results, with respondents expressing different opinions on the utility of gap years.

There also are important equity concerns regarding the role of research years in the dermatology residency match process. Dermatology is one of the least racially diverse specialties, although there have been efforts to increase representation among residents and attending physicians.^9-11 Research years can be important contributors to this lack of representation, as these often are unpaid and can discourage economically disadvantaged students from applying.^9-11 Additionally, applicants may not have the flexibility to defer future salary for a year to match into dermatology; therefore, mentors should offer multiple options to individual applicants instead of solely encouraging gap years, given the conflicting feelings regarding their productivity.

Another topic of disagreement was dual application. Approximately one-third of respondents said they encourage either all students or those with less than a 75% chance of matching to dual apply, while about half only encourage students who are truly interested in multiple specialties to do so. Additionally, a large subset of respondents said they do not encourage dual applications due to concerns that they make applicants a worse candidate for each specialty and overall have negative effects on matching. Twenty-five percent of respondents opted to leave an open-ended response to this question: some offered the perspective that, if applicants feel a need to dual apply due to a weaker application, they do not advise the applicant to apply to dermatology. Many open ended responses underscored that the respondent does not encourage dual applications because they are inherently more time consuming, could hinder the applicant’s success, can seem disingenuous, and are a tool used to improve medical school match rates without being beneficial for the student. Some respondents also favored reapplying to dermatology the following year instead of dual applying. Finally, a subset of mentors indicated that they approach dual applications on a case-by-case basis, and others reported they do not have much experience advising on this topic. Currently, there are no known data in the literature on the efficacy and utility of dual applications in the dermatology match process; therefore, our study provides valuable insight for applicants interested in the impacts of the dual application. Overall, students should approach this option with mentors on an individual basis but ultimately should be aware of the concerns and mixed perceptions of the dual application process.

With regard to program signaling, previous research has shown that PSTs have a large impact on the chance of being granted an interview.¹² In our study, we provide a comprehensive overview of advising regarding these signals. While mentors often responded that they did not have much experience advising in this domain—and it is too soon to tell the impact of this program signaling—many offered differing opinions. Many said they recommend that students give a gold signal to their 3 most desired programs regardless of home and away rotations and perceived competitiveness, which follows the guidelines issued by the APD; however, 19% recommend only giving silver signals to home and away rotation programs, as participation in those programs is considered a sufficient signal of interest. Additionally, about half of mentors recommended that students only apply where they signal, whereas 20% recommended applying to 10 to 15 programs beyond those signaled. Future studies should investigate the impact of PSTs on interview invitations once sufficient application cycles have occurred.

Study Limitations

This study was conducted via email to the APD listserve. The total number of faculty on this listserve is unknown; therefore, we do not know the total response rate of the survey. Additionally, we surveyed mentors in this listserve, who therefore receive more emails and overall correspondence about the dermatology match and may be more involved in these conversations. The mentors who responded to our survey may have a different approach and response to our various survey questions than a given mentor across the United States who did not respond to this survey. A final limitation of our study is that the survey responses a mentor gives may not fully match the advice that they give their students privately.

Conclusion

Our survey of dermatology mentors across the United States provides valuable insight into how mentors advise for a strong dermatology residency application. Mentors agreed on the importance of research during medical school, away rotations, strong letters of recommendation, and volunteerism and advocacy to promote a strong residency application. Important topics of disagreement include the decision for dermatology applicants to take a dedicated gap year in medical school, how to use tokens/signals effectively, and the dual application process. Our findings also underscore important application components that applicants and mentors should approach on an individual basis. Future studies should investigate the impact of signals/tokens on the match process as well as the utility of gap years and dual applications, working to standardize the advice applicants receive.

While strong relationships with mentors and advisers are critical to navigating the competitive dermatology match process, the advice medical students receive from different individuals can be contradictory. Unaccredited information online—particularly on social media—as well as data reported by applicants can add to potential confusion.¹ Published research has elicited comments and observations from successfully matched medical students about highly discussed topics such as presentations and publications, letters of recommendation, away rotations, and interviews.^2,3 However, there currently are no published data about advice that dermatology mentors actually offer medical students. In this study, we aimed to investigate this gap in the current literature and examine the advice dermatology faculty, program directors, and other mentors at institutions accredited by the Accreditation Council for Graduate Medical Education across the United States give to medical students applying to dermatology residency.

Methods

A 14-question Johns Hopkins Qualtrics survey was sent via the Association of Professors of Dermatology (APD) listserve in June 2024 soliciting responses from members who consider themselves to be mentors to dermatology applicants across the United States. The survey included multiple-choice questions with the option to select multiple answers and a space for open-ended responses. The questions first gathered information on the respondents, including the capacity in which the mentors advised medical students (eg, program director, department chair, clinical faculty). Mentors were asked for the number of years they had been advising mentees and if they were advising students with a home dermatology program. In addition, mentors were asked what advice they give their mentees about aspects of the application process, including gap years, dual applications, research involvement, couples matching, program signaling, away rotations, internship year, letters of recommendation, geographic signaling, interviewing advice, and volunteering during medical school.

On August 18, 2024, survey results from 115 respondents were aggregated. The responses for each question were quantitatively assessed to determine whether there was consensus on specific advice offered. The open-ended responses also were qualitatively assessed to determine the most common responses.

Results

The respondents included program directors (30% [35/115]), clinical faculty (22% [25/115]), department chairs (18% [21/115]), assistant program directors (15% [17/115]), medical school clerkship directors (8% [9/115]), primary mentors (ie, faculty who did not fall into any of the aforementioned categories but still advised medical students interested in dermatology)(5% [6/115]), division chiefs (1% [1/115]), and deans (1% [1/115]). Respondents had been advising students for a median of 10 years (range, 1-40 years [25th percentile, 5.00 years; 75th percentile, 13.75 years]). The majority (90% [103/115]) of mentors surveyed were advising students with a home dermatology program.

Areas of Consensus

In some areas, there was broad consensus among the advice offered by the mentors that were surveyed (eTable).

Research During Medical School—More than 91% (105/115) of the respondents recommended research to encourage academic growth and indicated that the most important reason for conducting research during medical school is to foster mentor-mentee relationships; however, more than one-third of respondents believed research is overvalued by students and research productivity is not as critical for matching as they perceive it to be. When these responses were categorized by respondent positions, 29% (15/52) of program or assistant directors indicated agreement with the statement that research is overvalued.

Away Rotations—There also was a consensus about the importance of away rotations, with 85% (98/115) of respondents advising students to complete 1 to 2 away rotations at sites of high interest, and 13% (15/115) suggesting that students complete as many away rotations as possible. It is worth noting, however, that the official APD Residency Program Directors Section’s statement on away rotations recommends no more than 2 away rotations (or no more than 3 for students with no home program).⁴

Reapplication Advice—Additionally, in a situation where students do not match into a dermatology residency program, the vast majority (71% [82/115]) of respondents advised students to rank competitive intern years to foster connections and improve the chance of matching on the second attempt.

Volunteering During Medical School—Seventy-seven percent (89/115) of mentors encouraged students to engage in volunteerism and advocacy during medical school to create a well-rounded application, and 69% (79/115) of mentors encouraged students to display leadership in their volunteer efforts.

Areas Without Consensus

Letters of Recommendation—Most respondents recommended submitting letters of recommendation only from dermatology professionals (55% [63/115]), with the remainder recommending students request a letter from anyone who could provide a strong recommendation regardless of specialty mix (42% [48/115]).

Dermatologic Subspecialties—For students interested in dermatologic subspecialties, 73% (84/115) of mentors advised that students be honest during interviews but keep an open mind that interests during residencies may change. Forty-three percent (49/115) of respondents encouraged students to promote a subspecialty interest during their interview only if they can demonstrate effort within that subspecialty on their application.

Couples Matching—Most respondents approach couples matching on a case-by-case basis and assess individual priorities when they do advise on this topic. Respondents often advise applicants to identify a few cities/regions and focus strongly on the programs within those regions to avoid spreading themselves too thin; however, one-third (38/115) of respondents indicated that they do not personally offer advice regarding the couples match.

Areas With Diverse Opinions

Gap Years—Nearly one-quarter (24% [28/115]) of mentors reported that they rarely recommend students take a year off and only support those who are adamant about doing so, or that they never support taking a gap year at all. A slight majority (58% [67/115]) recommend a gap year for students strongly interested in dermatologic research, and 38% (44/115) recommend a gap year for students with weaker applications (Figure 1). We received many open-ended responses to this question, with mentors frequently indicating that they advise students to take a gap year on a case-by-case basis, with 44% (51/115) of commenters recommending that students only take paid gap-year research positions.

Program Signaling—The dermatology residency application process implemented a system of preference signaling tokens (PSTs) starting with the 2021-2022 cycle. Not quite half (46% [53/115]) of respondents recommend students apply only to places that they signaled, while 20% (23/115) advise responding to 10 to 15 additional programs. Very few (8% [9/115]) advise students to signal only in their stated region of interest. Approximately half (49% [56/115]) of mentors recommend students only signal based on the programs they feel would be the best fit for them without regard for perceived competitiveness—which aligns with the APD Residency Program Directors Section’s recommendation⁴—while 37% (43/115) recommend students distribute their signals to a wide range of programs. Sixty-three percent (72/115) of respondents recommend gold signaling to the student’s 3 most desired programs regardless of home and away rotation considerations, while 19% (22/115) recommend students give silver signals to their home and away rotation programs, as a rotation is already a signal of a strong desire to be there (Figure 2).

Dual Application—Fifty-three percent (61/115) of mentors recommended dual applying only for those truly interested in multiple specialties. Eighteen percent (21/115) of respondents advised dual applying for those with less than a 75% chance of matching. Twenty-five percent (29/115) of respondents free-wrote comments about approaching dual applying on a case-by-case basis, with many discussing the downsides of dual application and raising concerns that dual applications can hinder applicants’ success, can seem disingenuous, and seem to be a tool used to improve medical school match rates without benefit for the student.

We also stratified the data to compare overall responses from the total cohort with those from only program and assistant program directors. Across the 14 questions, responses from program and assistant program directors alone were similar to the overall cohort results

Comment

This study evaluated nationwide data on mentorship advising in dermatology, detailing mentors’ advice regarding research, gap years, dual applications, away rotations, intern year, couples matching, program signaling, and volunteering during medical school. Based on our results, most respondents agree on the importance of research during medical school, the utility of away rotations, and the value of volunteering during medical school. Similarly, respondents agreed on the importance of having strong letters of recommendation; while some advised asking only dermatology faculty to write letters, others did not have a specialty preference for the letter writers. Respondents also had varying views about sharing interest in subspecialties during residency interviews. Many of the respondents do not provide recommendations regarding geographic signaling and couples matching, expressing that these are parts of an application that are important to approach on a case-by-case basis. Lastly, respondents had diverse opinions regarding the utility of gap years, whether to encourage or discourage dual applications, and how to advise regarding program signaling.

Our results also showed that one-third of respondents believed that research is not as important as it is perceived to be by dermatology applicants. While engaging in research during medical school was almost unanimously encouraged to foster mentor-mentee relationships, respondents expressed that the number of research experiences and publications was not critical. This is an important topic of discussion, as taking a dedicated year away from medical school to complete a research fellowship is becoming a trend among dermatology applicants.⁵ There has been discussion both on unofficial online platforms as well as in the published literature regarding the pressure for medical students interested in dermatology to publish, which may result in a gap year for research.⁶ The literature on the utility of a gap year in match rates is sparse, with one study showing no difference in match rates among Mayo Clinic dermatology residents who took research years vs those who did not.⁷ However, this contrasts with match rates at top dermatology residency programs where 41% of applicants who took a gap year matched vs 19% who did not.^7,8 These conflicting data are reflected in our study results, with respondents expressing different opinions on the utility of gap years.

There also are important equity concerns regarding the role of research years in the dermatology residency match process. Dermatology is one of the least racially diverse specialties, although there have been efforts to increase representation among residents and attending physicians.^9-11 Research years can be important contributors to this lack of representation, as these often are unpaid and can discourage economically disadvantaged students from applying.^9-11 Additionally, applicants may not have the flexibility to defer future salary for a year to match into dermatology; therefore, mentors should offer multiple options to individual applicants instead of solely encouraging gap years, given the conflicting feelings regarding their productivity.

Another topic of disagreement was dual application. Approximately one-third of respondents said they encourage either all students or those with less than a 75% chance of matching to dual apply, while about half only encourage students who are truly interested in multiple specialties to do so. Additionally, a large subset of respondents said they do not encourage dual applications due to concerns that they make applicants a worse candidate for each specialty and overall have negative effects on matching. Twenty-five percent of respondents opted to leave an open-ended response to this question: some offered the perspective that, if applicants feel a need to dual apply due to a weaker application, they do not advise the applicant to apply to dermatology. Many open ended responses underscored that the respondent does not encourage dual applications because they are inherently more time consuming, could hinder the applicant’s success, can seem disingenuous, and are a tool used to improve medical school match rates without being beneficial for the student. Some respondents also favored reapplying to dermatology the following year instead of dual applying. Finally, a subset of mentors indicated that they approach dual applications on a case-by-case basis, and others reported they do not have much experience advising on this topic. Currently, there are no known data in the literature on the efficacy and utility of dual applications in the dermatology match process; therefore, our study provides valuable insight for applicants interested in the impacts of the dual application. Overall, students should approach this option with mentors on an individual basis but ultimately should be aware of the concerns and mixed perceptions of the dual application process.

With regard to program signaling, previous research has shown that PSTs have a large impact on the chance of being granted an interview.¹² In our study, we provide a comprehensive overview of advising regarding these signals. While mentors often responded that they did not have much experience advising in this domain—and it is too soon to tell the impact of this program signaling—many offered differing opinions. Many said they recommend that students give a gold signal to their 3 most desired programs regardless of home and away rotations and perceived competitiveness, which follows the guidelines issued by the APD; however, 19% recommend only giving silver signals to home and away rotation programs, as participation in those programs is considered a sufficient signal of interest. Additionally, about half of mentors recommended that students only apply where they signal, whereas 20% recommended applying to 10 to 15 programs beyond those signaled. Future studies should investigate the impact of PSTs on interview invitations once sufficient application cycles have occurred.

Study Limitations

This study was conducted via email to the APD listserve. The total number of faculty on this listserve is unknown; therefore, we do not know the total response rate of the survey. Additionally, we surveyed mentors in this listserve, who therefore receive more emails and overall correspondence about the dermatology match and may be more involved in these conversations. The mentors who responded to our survey may have a different approach and response to our various survey questions than a given mentor across the United States who did not respond to this survey. A final limitation of our study is that the survey responses a mentor gives may not fully match the advice that they give their students privately.

Conclusion

Our survey of dermatology mentors across the United States provides valuable insight into how mentors advise for a strong dermatology residency application. Mentors agreed on the importance of research during medical school, away rotations, strong letters of recommendation, and volunteerism and advocacy to promote a strong residency application. Important topics of disagreement include the decision for dermatology applicants to take a dedicated gap year in medical school, how to use tokens/signals effectively, and the dual application process. Our findings also underscore important application components that applicants and mentors should approach on an individual basis. Future studies should investigate the impact of signals/tokens on the match process as well as the utility of gap years and dual applications, working to standardize the advice applicants receive.

While strong relationships with mentors and advisers are critical to navigating the competitive dermatology match process, the advice medical students receive from different individuals can be contradictory. Unaccredited information online—particularly on social media—as well as data reported by applicants can add to potential confusion.¹ Published research has elicited comments and observations from successfully matched medical students about highly discussed topics such as presentations and publications, letters of recommendation, away rotations, and interviews.^2,3 However, there currently are no published data about advice that dermatology mentors actually offer medical students. In this study, we aimed to investigate this gap in the current literature and examine the advice dermatology faculty, program directors, and other mentors at institutions accredited by the Accreditation Council for Graduate Medical Education across the United States give to medical students applying to dermatology residency.

Methods

A 14-question Johns Hopkins Qualtrics survey was sent via the Association of Professors of Dermatology (APD) listserve in June 2024 soliciting responses from members who consider themselves to be mentors to dermatology applicants across the United States. The survey included multiple-choice questions with the option to select multiple answers and a space for open-ended responses. The questions first gathered information on the respondents, including the capacity in which the mentors advised medical students (eg, program director, department chair, clinical faculty). Mentors were asked for the number of years they had been advising mentees and if they were advising students with a home dermatology program. In addition, mentors were asked what advice they give their mentees about aspects of the application process, including gap years, dual applications, research involvement, couples matching, program signaling, away rotations, internship year, letters of recommendation, geographic signaling, interviewing advice, and volunteering during medical school.

On August 18, 2024, survey results from 115 respondents were aggregated. The responses for each question were quantitatively assessed to determine whether there was consensus on specific advice offered. The open-ended responses also were qualitatively assessed to determine the most common responses.

Results

The respondents included program directors (30% [35/115]), clinical faculty (22% [25/115]), department chairs (18% [21/115]), assistant program directors (15% [17/115]), medical school clerkship directors (8% [9/115]), primary mentors (ie, faculty who did not fall into any of the aforementioned categories but still advised medical students interested in dermatology)(5% [6/115]), division chiefs (1% [1/115]), and deans (1% [1/115]). Respondents had been advising students for a median of 10 years (range, 1-40 years [25th percentile, 5.00 years; 75th percentile, 13.75 years]). The majority (90% [103/115]) of mentors surveyed were advising students with a home dermatology program.

Areas of Consensus

In some areas, there was broad consensus among the advice offered by the mentors that were surveyed (eTable).

Research During Medical School—More than 91% (105/115) of the respondents recommended research to encourage academic growth and indicated that the most important reason for conducting research during medical school is to foster mentor-mentee relationships; however, more than one-third of respondents believed research is overvalued by students and research productivity is not as critical for matching as they perceive it to be. When these responses were categorized by respondent positions, 29% (15/52) of program or assistant directors indicated agreement with the statement that research is overvalued.

Away Rotations—There also was a consensus about the importance of away rotations, with 85% (98/115) of respondents advising students to complete 1 to 2 away rotations at sites of high interest, and 13% (15/115) suggesting that students complete as many away rotations as possible. It is worth noting, however, that the official APD Residency Program Directors Section’s statement on away rotations recommends no more than 2 away rotations (or no more than 3 for students with no home program).⁴

Reapplication Advice—Additionally, in a situation where students do not match into a dermatology residency program, the vast majority (71% [82/115]) of respondents advised students to rank competitive intern years to foster connections and improve the chance of matching on the second attempt.

Volunteering During Medical School—Seventy-seven percent (89/115) of mentors encouraged students to engage in volunteerism and advocacy during medical school to create a well-rounded application, and 69% (79/115) of mentors encouraged students to display leadership in their volunteer efforts.

Areas Without Consensus

Letters of Recommendation—Most respondents recommended submitting letters of recommendation only from dermatology professionals (55% [63/115]), with the remainder recommending students request a letter from anyone who could provide a strong recommendation regardless of specialty mix (42% [48/115]).

Dermatologic Subspecialties—For students interested in dermatologic subspecialties, 73% (84/115) of mentors advised that students be honest during interviews but keep an open mind that interests during residencies may change. Forty-three percent (49/115) of respondents encouraged students to promote a subspecialty interest during their interview only if they can demonstrate effort within that subspecialty on their application.

Couples Matching—Most respondents approach couples matching on a case-by-case basis and assess individual priorities when they do advise on this topic. Respondents often advise applicants to identify a few cities/regions and focus strongly on the programs within those regions to avoid spreading themselves too thin; however, one-third (38/115) of respondents indicated that they do not personally offer advice regarding the couples match.

Areas With Diverse Opinions

Gap Years—Nearly one-quarter (24% [28/115]) of mentors reported that they rarely recommend students take a year off and only support those who are adamant about doing so, or that they never support taking a gap year at all. A slight majority (58% [67/115]) recommend a gap year for students strongly interested in dermatologic research, and 38% (44/115) recommend a gap year for students with weaker applications (Figure 1). We received many open-ended responses to this question, with mentors frequently indicating that they advise students to take a gap year on a case-by-case basis, with 44% (51/115) of commenters recommending that students only take paid gap-year research positions.

Program Signaling—The dermatology residency application process implemented a system of preference signaling tokens (PSTs) starting with the 2021-2022 cycle. Not quite half (46% [53/115]) of respondents recommend students apply only to places that they signaled, while 20% (23/115) advise responding to 10 to 15 additional programs. Very few (8% [9/115]) advise students to signal only in their stated region of interest. Approximately half (49% [56/115]) of mentors recommend students only signal based on the programs they feel would be the best fit for them without regard for perceived competitiveness—which aligns with the APD Residency Program Directors Section’s recommendation⁴—while 37% (43/115) recommend students distribute their signals to a wide range of programs. Sixty-three percent (72/115) of respondents recommend gold signaling to the student’s 3 most desired programs regardless of home and away rotation considerations, while 19% (22/115) recommend students give silver signals to their home and away rotation programs, as a rotation is already a signal of a strong desire to be there (Figure 2).

Dual Application—Fifty-three percent (61/115) of mentors recommended dual applying only for those truly interested in multiple specialties. Eighteen percent (21/115) of respondents advised dual applying for those with less than a 75% chance of matching. Twenty-five percent (29/115) of respondents free-wrote comments about approaching dual applying on a case-by-case basis, with many discussing the downsides of dual application and raising concerns that dual applications can hinder applicants’ success, can seem disingenuous, and seem to be a tool used to improve medical school match rates without benefit for the student.

We also stratified the data to compare overall responses from the total cohort with those from only program and assistant program directors. Across the 14 questions, responses from program and assistant program directors alone were similar to the overall cohort results

Comment

This study evaluated nationwide data on mentorship advising in dermatology, detailing mentors’ advice regarding research, gap years, dual applications, away rotations, intern year, couples matching, program signaling, and volunteering during medical school. Based on our results, most respondents agree on the importance of research during medical school, the utility of away rotations, and the value of volunteering during medical school. Similarly, respondents agreed on the importance of having strong letters of recommendation; while some advised asking only dermatology faculty to write letters, others did not have a specialty preference for the letter writers. Respondents also had varying views about sharing interest in subspecialties during residency interviews. Many of the respondents do not provide recommendations regarding geographic signaling and couples matching, expressing that these are parts of an application that are important to approach on a case-by-case basis. Lastly, respondents had diverse opinions regarding the utility of gap years, whether to encourage or discourage dual applications, and how to advise regarding program signaling.

Our results also showed that one-third of respondents believed that research is not as important as it is perceived to be by dermatology applicants. While engaging in research during medical school was almost unanimously encouraged to foster mentor-mentee relationships, respondents expressed that the number of research experiences and publications was not critical. This is an important topic of discussion, as taking a dedicated year away from medical school to complete a research fellowship is becoming a trend among dermatology applicants.⁵ There has been discussion both on unofficial online platforms as well as in the published literature regarding the pressure for medical students interested in dermatology to publish, which may result in a gap year for research.⁶ The literature on the utility of a gap year in match rates is sparse, with one study showing no difference in match rates among Mayo Clinic dermatology residents who took research years vs those who did not.⁷ However, this contrasts with match rates at top dermatology residency programs where 41% of applicants who took a gap year matched vs 19% who did not.^7,8 These conflicting data are reflected in our study results, with respondents expressing different opinions on the utility of gap years.

There also are important equity concerns regarding the role of research years in the dermatology residency match process. Dermatology is one of the least racially diverse specialties, although there have been efforts to increase representation among residents and attending physicians.^9-11 Research years can be important contributors to this lack of representation, as these often are unpaid and can discourage economically disadvantaged students from applying.^9-11 Additionally, applicants may not have the flexibility to defer future salary for a year to match into dermatology; therefore, mentors should offer multiple options to individual applicants instead of solely encouraging gap years, given the conflicting feelings regarding their productivity.

Another topic of disagreement was dual application. Approximately one-third of respondents said they encourage either all students or those with less than a 75% chance of matching to dual apply, while about half only encourage students who are truly interested in multiple specialties to do so. Additionally, a large subset of respondents said they do not encourage dual applications due to concerns that they make applicants a worse candidate for each specialty and overall have negative effects on matching. Twenty-five percent of respondents opted to leave an open-ended response to this question: some offered the perspective that, if applicants feel a need to dual apply due to a weaker application, they do not advise the applicant to apply to dermatology. Many open ended responses underscored that the respondent does not encourage dual applications because they are inherently more time consuming, could hinder the applicant’s success, can seem disingenuous, and are a tool used to improve medical school match rates without being beneficial for the student. Some respondents also favored reapplying to dermatology the following year instead of dual applying. Finally, a subset of mentors indicated that they approach dual applications on a case-by-case basis, and others reported they do not have much experience advising on this topic. Currently, there are no known data in the literature on the efficacy and utility of dual applications in the dermatology match process; therefore, our study provides valuable insight for applicants interested in the impacts of the dual application. Overall, students should approach this option with mentors on an individual basis but ultimately should be aware of the concerns and mixed perceptions of the dual application process.

With regard to program signaling, previous research has shown that PSTs have a large impact on the chance of being granted an interview.¹² In our study, we provide a comprehensive overview of advising regarding these signals. While mentors often responded that they did not have much experience advising in this domain—and it is too soon to tell the impact of this program signaling—many offered differing opinions. Many said they recommend that students give a gold signal to their 3 most desired programs regardless of home and away rotations and perceived competitiveness, which follows the guidelines issued by the APD; however, 19% recommend only giving silver signals to home and away rotation programs, as participation in those programs is considered a sufficient signal of interest. Additionally, about half of mentors recommended that students only apply where they signal, whereas 20% recommended applying to 10 to 15 programs beyond those signaled. Future studies should investigate the impact of PSTs on interview invitations once sufficient application cycles have occurred.

Study Limitations

This study was conducted via email to the APD listserve. The total number of faculty on this listserve is unknown; therefore, we do not know the total response rate of the survey. Additionally, we surveyed mentors in this listserve, who therefore receive more emails and overall correspondence about the dermatology match and may be more involved in these conversations. The mentors who responded to our survey may have a different approach and response to our various survey questions than a given mentor across the United States who did not respond to this survey. A final limitation of our study is that the survey responses a mentor gives may not fully match the advice that they give their students privately.

Conclusion

Our survey of dermatology mentors across the United States provides valuable insight into how mentors advise for a strong dermatology residency application. Mentors agreed on the importance of research during medical school, away rotations, strong letters of recommendation, and volunteerism and advocacy to promote a strong residency application. Important topics of disagreement include the decision for dermatology applicants to take a dedicated gap year in medical school, how to use tokens/signals effectively, and the dual application process. Our findings also underscore important application components that applicants and mentors should approach on an individual basis. Future studies should investigate the impact of signals/tokens on the match process as well as the utility of gap years and dual applications, working to standardize the advice applicants receive.

THE DIAGNOSIS: Epithelioid Fibrous Histiocytoma

In our patient, immunohistochemical stains for Factor XIIIa, CD68, and anaplastic lymphoma kinase (ALK) 1 confirmed the diagnosis of epithelioid fibrous histiocytoma (EFH). The location and relatively large size of the lesion led to a joint decision by the patient and physician to perform a complete excision, which was done with no complications.

Once considered a rare variant of dermatofibroma, EFH most commonly manifests as a solitary, vascular-appearing or flesh-colored papule or nodule on the legs. It often develops in the fifth decade of life with greater prevalence in men.^1-5 Our patient is one of the few known cases of EFH in children that have been reported in the literature.^3,6 Although EFH is benign, complete excision typically is performed due to the rarity of the lesion.³

The overexpression of ALK distinguishes EFH from other fibrohistiocytic lesions (Figure 1).⁵ The most common fusion partners are sequestosome 1 and vinculin (VCL), which account for more than 70% of cases.^3,5,7 Interestingly, VCL-ALK fusions have been reported to occur in a subset of pediatric renal cell carcinomas and recently in an ovoid spindle cell neoplasm considered to be a low-grade sarcoma.^3,7-9 Further studies have identified less common fusion partners, including the dynactin subunit 1, ETS variant transcription factor 6, protein-tyrosine phosphatase, receptor-type, F polypeptide-interacting protein-binding protein 1, sperm antigen with calponin homology and coiled-coil domains 1, tropomyosin 3, protein kinase cAMP-dependent type II regulatory subunit alpha, melanophilin, and Echinoderm microtubule-associated protein-like 4 genes.^3,8

In contrast to benign fibrous histiocytomas, EFHs primarily consist of epithelioid cells, have well-defined borders, exhibit prominent vascularity, usually are situated close to the epidermis, and lack multinucleated cells or histiocytes laden with lipids or hemosiderin.² The characteristic histopathologic finding is rounded or angulated epithelioid cells, with eosinophilic cytoplasm accounting for more than 50% of the tumor cell population.^1-3,5 The nuclei of the epithelioid cells are rounded and vesicular with small eosinophilic nucleoli and low mitotic activity. Common clinical features include an exophytic nodule with a classic epidermal collarette and an epidermis that exhibits variable degrees of hyperplasia.^1-3,5 Epithelioid fibrous histiocytomas often are confined to the superficial dermis and rarely extend to the subcutaneous layer. The stroma is collagenous with prominent vascularity, although older lesions can become more hyalinized and sclerotic.³ Histopathologically, these tumors can be a diagnostic challenge, as they often are mistaken for other fibrohistiocytic or melanocytic lesions.

Atypical fibroxanthoma (AFX) manifests as a dome-shaped exophytic nodule that can rapidly grow to 1 to 2 cm. Historically, it was thought to be a pseudomalignancy, but most investigators consider it within the spectrum of pleomorphic dermal sarcoma and undifferentiated pleomorphic sarcoma. Atypical fibroxanthoma usually occurs on the head and neck in elderly patients with sun-damaged skin. Histopathologically, the neoplastic cells of AFX range from atypical spindle cells and pleomorphic round to polygonal epithelioid cells to large, irregularly shaped multinucleated cells, some with foamy cytoplasm (Figure 2). The atypical spindle cells stain diffusely positive for CD10 and vimentin, while small subpopulations stain positively for CD68 or CD163 and procollagen 1. Smooth muscle actin inconsistently stains the tumor, and when it does, the staining typically is faint and patchy. Atypical fibroxanthomas usually do not stain positively for melanocytic, skeletal muscle, or keratinocytic markers.

Cellular dermatofibroma typically manifests as small, dome-shaped papules on the arms and legs that normally range from a few millimeters to 1 cm but occasionally measure up to 2 cm. Histopathologically, there are interweaving fascicles of spindle cells with hyperchromatic nuclei and peripheral splaying of the plump spindle cells that wrap around collagen bundles, known as collagen trapping (Figure 3). Unlike EFH, multinucleated cells and histiocytes with abundant lipids and hemosiderin often accompany the spindle cells in cellular dermatofibromas, which stain strongly positive for CD10 and vimentin, similar to AFX and EFH. The smooth muscle actin–staining pattern usually is faint and patchy, and in some cases, cellular dermatofibroma may not stain at all. Factor XIIIa and CD68 highlight the 2 populations of cells—fibroblasts and histiocytes—that make up the lesion.⁴

Epithelioid sarcoma comprises 2 types: distal (or conventional) type occurring on the distal arms and legs, particularly the hands and fingers of young adults, and proximal type occurring on the trunk and proximal extremities, including the upper arms and thighs.¹⁰ Epithelioid sarcoma is a rare aggressive malignancy that usually manifests as a firm nodule, sometimes with ulceration depending on the size. Histopathologically, diffuse dermal proliferation of ovoid to polygonal epithelioid cells arranged in short fascicles and nodular aggregations is observed (Figure 4). Spindle cells may be observed at the periphery of the lesion. Areas of necrosis are a frequent finding and a helpful diagnostic clue. Nearly all cases stain positively for pancytokeratin, CAM5.2, epithelial membrane antigen, and vimentin, and approximately half stain positively for CD34; there are variable expressions of ERG and smooth muscle actin.¹⁰ In most cases, epithelioid sarcoma does not stain positively for S100 or CD68. The majority (90%) of cases harbor a mutation in the SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 gene, resulting in the loss of INI1 protein expression, which can be demonstrated by immunohistochemistry. ¹⁰ As the cytologic atypia usually is minimal, epithelioid sarcoma may be misdiagnosed as a necrotizing granuloma and benign fibrous lesions, particularly when superficial or small partial biopsies are performed.

Intradermal Spitz nevi can measure from a few millimeters to more than 2 cm and can range from pink to brown to black. The most common locations are the lower extremities as well as the head and neck. Histopathologically, intradermal Spitz nevi have nests of large epithelioid melanocytes with large nuclei and abundant cytoplasm (eFigure). Nuclear pseudo-inclusions, which are cytoplasmic invaginations into the nucleus, are frequent. Unlike the other conditions in the differential, these entities stain positively for melanocytic markers—S100, SOX10, and Melan-A—but not CD68 or CD163.11 A variety of kinase fusions are observed in Spitz nevi, including the ALK gene, neurotrophic tyrosine receptor kinase, ROS proto-oncogene 1, megakaryocyte-erythroid progenitor, and v-raf murine sarcoma viral oncogene homolog B1 genes.¹²

THE DIAGNOSIS: Epithelioid Fibrous Histiocytoma

In our patient, immunohistochemical stains for Factor XIIIa, CD68, and anaplastic lymphoma kinase (ALK) 1 confirmed the diagnosis of epithelioid fibrous histiocytoma (EFH). The location and relatively large size of the lesion led to a joint decision by the patient and physician to perform a complete excision, which was done with no complications.

Once considered a rare variant of dermatofibroma, EFH most commonly manifests as a solitary, vascular-appearing or flesh-colored papule or nodule on the legs. It often develops in the fifth decade of life with greater prevalence in men.^1-5 Our patient is one of the few known cases of EFH in children that have been reported in the literature.^3,6 Although EFH is benign, complete excision typically is performed due to the rarity of the lesion.³

The overexpression of ALK distinguishes EFH from other fibrohistiocytic lesions (Figure 1).⁵ The most common fusion partners are sequestosome 1 and vinculin (VCL), which account for more than 70% of cases.^3,5,7 Interestingly, VCL-ALK fusions have been reported to occur in a subset of pediatric renal cell carcinomas and recently in an ovoid spindle cell neoplasm considered to be a low-grade sarcoma.^3,7-9 Further studies have identified less common fusion partners, including the dynactin subunit 1, ETS variant transcription factor 6, protein-tyrosine phosphatase, receptor-type, F polypeptide-interacting protein-binding protein 1, sperm antigen with calponin homology and coiled-coil domains 1, tropomyosin 3, protein kinase cAMP-dependent type II regulatory subunit alpha, melanophilin, and Echinoderm microtubule-associated protein-like 4 genes.^3,8

In contrast to benign fibrous histiocytomas, EFHs primarily consist of epithelioid cells, have well-defined borders, exhibit prominent vascularity, usually are situated close to the epidermis, and lack multinucleated cells or histiocytes laden with lipids or hemosiderin.² The characteristic histopathologic finding is rounded or angulated epithelioid cells, with eosinophilic cytoplasm accounting for more than 50% of the tumor cell population.^1-3,5 The nuclei of the epithelioid cells are rounded and vesicular with small eosinophilic nucleoli and low mitotic activity. Common clinical features include an exophytic nodule with a classic epidermal collarette and an epidermis that exhibits variable degrees of hyperplasia.^1-3,5 Epithelioid fibrous histiocytomas often are confined to the superficial dermis and rarely extend to the subcutaneous layer. The stroma is collagenous with prominent vascularity, although older lesions can become more hyalinized and sclerotic.³ Histopathologically, these tumors can be a diagnostic challenge, as they often are mistaken for other fibrohistiocytic or melanocytic lesions.

Atypical fibroxanthoma (AFX) manifests as a dome-shaped exophytic nodule that can rapidly grow to 1 to 2 cm. Historically, it was thought to be a pseudomalignancy, but most investigators consider it within the spectrum of pleomorphic dermal sarcoma and undifferentiated pleomorphic sarcoma. Atypical fibroxanthoma usually occurs on the head and neck in elderly patients with sun-damaged skin. Histopathologically, the neoplastic cells of AFX range from atypical spindle cells and pleomorphic round to polygonal epithelioid cells to large, irregularly shaped multinucleated cells, some with foamy cytoplasm (Figure 2). The atypical spindle cells stain diffusely positive for CD10 and vimentin, while small subpopulations stain positively for CD68 or CD163 and procollagen 1. Smooth muscle actin inconsistently stains the tumor, and when it does, the staining typically is faint and patchy. Atypical fibroxanthomas usually do not stain positively for melanocytic, skeletal muscle, or keratinocytic markers.

Cellular dermatofibroma typically manifests as small, dome-shaped papules on the arms and legs that normally range from a few millimeters to 1 cm but occasionally measure up to 2 cm. Histopathologically, there are interweaving fascicles of spindle cells with hyperchromatic nuclei and peripheral splaying of the plump spindle cells that wrap around collagen bundles, known as collagen trapping (Figure 3). Unlike EFH, multinucleated cells and histiocytes with abundant lipids and hemosiderin often accompany the spindle cells in cellular dermatofibromas, which stain strongly positive for CD10 and vimentin, similar to AFX and EFH. The smooth muscle actin–staining pattern usually is faint and patchy, and in some cases, cellular dermatofibroma may not stain at all. Factor XIIIa and CD68 highlight the 2 populations of cells—fibroblasts and histiocytes—that make up the lesion.⁴

Epithelioid sarcoma comprises 2 types: distal (or conventional) type occurring on the distal arms and legs, particularly the hands and fingers of young adults, and proximal type occurring on the trunk and proximal extremities, including the upper arms and thighs.¹⁰ Epithelioid sarcoma is a rare aggressive malignancy that usually manifests as a firm nodule, sometimes with ulceration depending on the size. Histopathologically, diffuse dermal proliferation of ovoid to polygonal epithelioid cells arranged in short fascicles and nodular aggregations is observed (Figure 4). Spindle cells may be observed at the periphery of the lesion. Areas of necrosis are a frequent finding and a helpful diagnostic clue. Nearly all cases stain positively for pancytokeratin, CAM5.2, epithelial membrane antigen, and vimentin, and approximately half stain positively for CD34; there are variable expressions of ERG and smooth muscle actin.¹⁰ In most cases, epithelioid sarcoma does not stain positively for S100 or CD68. The majority (90%) of cases harbor a mutation in the SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 gene, resulting in the loss of INI1 protein expression, which can be demonstrated by immunohistochemistry. ¹⁰ As the cytologic atypia usually is minimal, epithelioid sarcoma may be misdiagnosed as a necrotizing granuloma and benign fibrous lesions, particularly when superficial or small partial biopsies are performed.

Intradermal Spitz nevi can measure from a few millimeters to more than 2 cm and can range from pink to brown to black. The most common locations are the lower extremities as well as the head and neck. Histopathologically, intradermal Spitz nevi have nests of large epithelioid melanocytes with large nuclei and abundant cytoplasm (eFigure). Nuclear pseudo-inclusions, which are cytoplasmic invaginations into the nucleus, are frequent. Unlike the other conditions in the differential, these entities stain positively for melanocytic markers—S100, SOX10, and Melan-A—but not CD68 or CD163.11 A variety of kinase fusions are observed in Spitz nevi, including the ALK gene, neurotrophic tyrosine receptor kinase, ROS proto-oncogene 1, megakaryocyte-erythroid progenitor, and v-raf murine sarcoma viral oncogene homolog B1 genes.¹²

THE DIAGNOSIS: Epithelioid Fibrous Histiocytoma

In our patient, immunohistochemical stains for Factor XIIIa, CD68, and anaplastic lymphoma kinase (ALK) 1 confirmed the diagnosis of epithelioid fibrous histiocytoma (EFH). The location and relatively large size of the lesion led to a joint decision by the patient and physician to perform a complete excision, which was done with no complications.

Once considered a rare variant of dermatofibroma, EFH most commonly manifests as a solitary, vascular-appearing or flesh-colored papule or nodule on the legs. It often develops in the fifth decade of life with greater prevalence in men.^1-5 Our patient is one of the few known cases of EFH in children that have been reported in the literature.^3,6 Although EFH is benign, complete excision typically is performed due to the rarity of the lesion.³

The overexpression of ALK distinguishes EFH from other fibrohistiocytic lesions (Figure 1).⁵ The most common fusion partners are sequestosome 1 and vinculin (VCL), which account for more than 70% of cases.^3,5,7 Interestingly, VCL-ALK fusions have been reported to occur in a subset of pediatric renal cell carcinomas and recently in an ovoid spindle cell neoplasm considered to be a low-grade sarcoma.^3,7-9 Further studies have identified less common fusion partners, including the dynactin subunit 1, ETS variant transcription factor 6, protein-tyrosine phosphatase, receptor-type, F polypeptide-interacting protein-binding protein 1, sperm antigen with calponin homology and coiled-coil domains 1, tropomyosin 3, protein kinase cAMP-dependent type II regulatory subunit alpha, melanophilin, and Echinoderm microtubule-associated protein-like 4 genes.^3,8

In contrast to benign fibrous histiocytomas, EFHs primarily consist of epithelioid cells, have well-defined borders, exhibit prominent vascularity, usually are situated close to the epidermis, and lack multinucleated cells or histiocytes laden with lipids or hemosiderin.² The characteristic histopathologic finding is rounded or angulated epithelioid cells, with eosinophilic cytoplasm accounting for more than 50% of the tumor cell population.^1-3,5 The nuclei of the epithelioid cells are rounded and vesicular with small eosinophilic nucleoli and low mitotic activity. Common clinical features include an exophytic nodule with a classic epidermal collarette and an epidermis that exhibits variable degrees of hyperplasia.^1-3,5 Epithelioid fibrous histiocytomas often are confined to the superficial dermis and rarely extend to the subcutaneous layer. The stroma is collagenous with prominent vascularity, although older lesions can become more hyalinized and sclerotic.³ Histopathologically, these tumors can be a diagnostic challenge, as they often are mistaken for other fibrohistiocytic or melanocytic lesions.

Atypical fibroxanthoma (AFX) manifests as a dome-shaped exophytic nodule that can rapidly grow to 1 to 2 cm. Historically, it was thought to be a pseudomalignancy, but most investigators consider it within the spectrum of pleomorphic dermal sarcoma and undifferentiated pleomorphic sarcoma. Atypical fibroxanthoma usually occurs on the head and neck in elderly patients with sun-damaged skin. Histopathologically, the neoplastic cells of AFX range from atypical spindle cells and pleomorphic round to polygonal epithelioid cells to large, irregularly shaped multinucleated cells, some with foamy cytoplasm (Figure 2). The atypical spindle cells stain diffusely positive for CD10 and vimentin, while small subpopulations stain positively for CD68 or CD163 and procollagen 1. Smooth muscle actin inconsistently stains the tumor, and when it does, the staining typically is faint and patchy. Atypical fibroxanthomas usually do not stain positively for melanocytic, skeletal muscle, or keratinocytic markers.

Cellular dermatofibroma typically manifests as small, dome-shaped papules on the arms and legs that normally range from a few millimeters to 1 cm but occasionally measure up to 2 cm. Histopathologically, there are interweaving fascicles of spindle cells with hyperchromatic nuclei and peripheral splaying of the plump spindle cells that wrap around collagen bundles, known as collagen trapping (Figure 3). Unlike EFH, multinucleated cells and histiocytes with abundant lipids and hemosiderin often accompany the spindle cells in cellular dermatofibromas, which stain strongly positive for CD10 and vimentin, similar to AFX and EFH. The smooth muscle actin–staining pattern usually is faint and patchy, and in some cases, cellular dermatofibroma may not stain at all. Factor XIIIa and CD68 highlight the 2 populations of cells—fibroblasts and histiocytes—that make up the lesion.⁴

Epithelioid sarcoma comprises 2 types: distal (or conventional) type occurring on the distal arms and legs, particularly the hands and fingers of young adults, and proximal type occurring on the trunk and proximal extremities, including the upper arms and thighs.¹⁰ Epithelioid sarcoma is a rare aggressive malignancy that usually manifests as a firm nodule, sometimes with ulceration depending on the size. Histopathologically, diffuse dermal proliferation of ovoid to polygonal epithelioid cells arranged in short fascicles and nodular aggregations is observed (Figure 4). Spindle cells may be observed at the periphery of the lesion. Areas of necrosis are a frequent finding and a helpful diagnostic clue. Nearly all cases stain positively for pancytokeratin, CAM5.2, epithelial membrane antigen, and vimentin, and approximately half stain positively for CD34; there are variable expressions of ERG and smooth muscle actin.¹⁰ In most cases, epithelioid sarcoma does not stain positively for S100 or CD68. The majority (90%) of cases harbor a mutation in the SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 gene, resulting in the loss of INI1 protein expression, which can be demonstrated by immunohistochemistry. ¹⁰ As the cytologic atypia usually is minimal, epithelioid sarcoma may be misdiagnosed as a necrotizing granuloma and benign fibrous lesions, particularly when superficial or small partial biopsies are performed.

Intradermal Spitz nevi can measure from a few millimeters to more than 2 cm and can range from pink to brown to black. The most common locations are the lower extremities as well as the head and neck. Histopathologically, intradermal Spitz nevi have nests of large epithelioid melanocytes with large nuclei and abundant cytoplasm (eFigure). Nuclear pseudo-inclusions, which are cytoplasmic invaginations into the nucleus, are frequent. Unlike the other conditions in the differential, these entities stain positively for melanocytic markers—S100, SOX10, and Melan-A—but not CD68 or CD163.11 A variety of kinase fusions are observed in Spitz nevi, including the ALK gene, neurotrophic tyrosine receptor kinase, ROS proto-oncogene 1, megakaryocyte-erythroid progenitor, and v-raf murine sarcoma viral oncogene homolog B1 genes.¹²

Patients who undergo cutaneous surgery and chronic wound care often are exposed to various topical agents that carry allergenic potential, including antiseptic rinses, bandage adhesives, mineral pastes, and antibiotic ointments.¹ Allergic contact dermatitis (ACD) in postoperative or chronic wounds can lead to considerable morbidity, particularly when the diagnosis is unclear. Differentiating between ACD and wound infection is paramount because the treatments for these conditions often are mutually exclusive.² While patch testing for contact allergy could be considered for postoperative patients or those with chronic wounds who exhibit concerning symptoms such as erythema or pruritus, these scenarios require prompt diagnosis and treatment. Herein, we describe a technique that involves secondary application of potentially allergenic topical components to a small area of normal skin during wound management to facilitate early detection of ACD and differentiation from wound infection.

Practice Gap 

Contact allergies are common in patients with postoperative or chronic wounds. When patch tested, approximately 80% of patients with chronic venous ulcers demonstrated at least 1 positive allergic reaction based on a Canadian study.³ Similarly, postoperative ACD in dermatologic surgery occurs in more than 1.6% of cases in North America and Europe, a rate that is similar to or higher than the rate of postoperative infection, approximately 1% to 2%.⁴ Postoperative patients and those with chronic wounds have multiple risk factors for ACD. Firstly, applying topical therapies to inflamed or compromised skin increases the risk for contact sensitization.⁵ Additionally, multiple topical therapies containing known allergenic components may be recommended for wound care, including impregnated or organic dressings, antibiotic ointments, adhesives, antiseptic washes, and topical therapies containing inactive ingredients such as lanolin derivatives.⁶ Contact with numerous compounds at the same time increases the risk for a contact allergy as well as co-sensitization.⁷ Similarly, the longer topical agents are applied, the greater the risk for a contact allergy, with sensitization liable to occur at any point during treatment.

Preventive topical antibiotics have garnered a negative reputation among dermatologists, often due to varying data on their efficacy and the overuse of highly allergenic over-the-counter topical antibiotics such as neomycin.⁸ However, data also have suggested that topical antibiotics can reduce postoperative infections in higher risk surgical cases, specifically certain head and neck surgeries.⁹ Likewise, topical antibiotics are useful for wound colonization with Pseudomonas, which can remain superficial and slow down healing without progressing to a systemic infection.¹⁰ Such cases can be successfully treated or prevented with topical therapies, thereby bypassing the more concerning adverse effects of systemic antibiotics. In particular, systemic fluoroquinolones often are used to treat Pseudomonas and can have many serious adverse effects, including tendon rupture, drug interactions, and arrhythmias.¹¹ Therefore, it is worth implementing topical treatments for wounds colonized with Pseudomonas to spare patients these potential complications.

When a postoperative patient develops a rash at the surgical site, it is critical to differentiate between wound infection and contact allergy, as the treatments for these two conditions may be mutually exclusive and treating the wrong condition may exacerbate the other, such as mistakenly using topical corticosteroids for a wound infection.⁷ Prompt treatment is necessary for wound infections, as time is limited for patch testing when a rash is already present and the diagnosis is questionable. Allergic contact dermatitis typically erupts 48 to 96 hours following exposure to a contact allergen, often manifesting as intensely pruritic erythematous patches or vesicles.⁶ Wound infections are characterized by pain and warmth, with erythema and edema present in both conditions. Postoperative infections manifest usually 4 to 7 days following surgery.¹² Despite these differences, pruritus and pain are common in the wound healing process; thus, differentiating an infection from ACD on a clinical basis alone is not always possible. Furthermore, presentation of a contact allergy may be delayed beyond the typical 96-hour timeframe if a patient is newly sensitized to an allergen, causing the timeline of rash development to appear similar to that of a wound infection. In such cases, systemic antibiotics often are prescribed empirically; hence, clearer and timelier differentiation between contact allergy and wound infection reduces unnecessary antibiotic prescriptions, thereby avoiding systemic adverse effects and promoting responsible antibiotic stewardship.¹²

The Technique

Since potentially allergenic topical therapies often are indicated in wound management, we propose that patients serve as internal controls to test continuously for contact allergy sensitization. We recommend that patients apply a small amount of the topical agent, product, or dressing to the inner forearm each time they apply it to the wound. If the patient is sensitized to the product initially or becomes sensitized during treatment, evidence of ACD will be visible not only at the site of the wound but also in the area of secondary application. The inner forearm is recommended for convenience and reproducibility, but a patient may choose a different site as long as it remains consistent. Although certain contact allergens rarely may react solely at a site of inflamed skin, our team has quickly identified ACD and avoided misdiagnosis of chronic or postsurgical wound infection using this approach.¹³ Subsequent patch testing is indicated when a contact allergy is detected.

Practice Implications

Topical therapies including ointments, washes, and dressing components have the potential to cause sensitization and contact allergy. Despite the concern for development of ACD, topical antibiotics play a useful role in cutaneous surgery.⁷ Synchronous testing for contact allergy when managing wounds with topical therapies could improve diagnostic accuracy when an allergic reaction occurs. This technique provides a means of harnessing the benefits of topical agents while monitoring the risk for ACD in postoperative and chronic wound care settings.

Patients who undergo cutaneous surgery and chronic wound care often are exposed to various topical agents that carry allergenic potential, including antiseptic rinses, bandage adhesives, mineral pastes, and antibiotic ointments.¹ Allergic contact dermatitis (ACD) in postoperative or chronic wounds can lead to considerable morbidity, particularly when the diagnosis is unclear. Differentiating between ACD and wound infection is paramount because the treatments for these conditions often are mutually exclusive.² While patch testing for contact allergy could be considered for postoperative patients or those with chronic wounds who exhibit concerning symptoms such as erythema or pruritus, these scenarios require prompt diagnosis and treatment. Herein, we describe a technique that involves secondary application of potentially allergenic topical components to a small area of normal skin during wound management to facilitate early detection of ACD and differentiation from wound infection.

Practice Gap 

Contact allergies are common in patients with postoperative or chronic wounds. When patch tested, approximately 80% of patients with chronic venous ulcers demonstrated at least 1 positive allergic reaction based on a Canadian study.³ Similarly, postoperative ACD in dermatologic surgery occurs in more than 1.6% of cases in North America and Europe, a rate that is similar to or higher than the rate of postoperative infection, approximately 1% to 2%.⁴ Postoperative patients and those with chronic wounds have multiple risk factors for ACD. Firstly, applying topical therapies to inflamed or compromised skin increases the risk for contact sensitization.⁵ Additionally, multiple topical therapies containing known allergenic components may be recommended for wound care, including impregnated or organic dressings, antibiotic ointments, adhesives, antiseptic washes, and topical therapies containing inactive ingredients such as lanolin derivatives.⁶ Contact with numerous compounds at the same time increases the risk for a contact allergy as well as co-sensitization.⁷ Similarly, the longer topical agents are applied, the greater the risk for a contact allergy, with sensitization liable to occur at any point during treatment.

Preventive topical antibiotics have garnered a negative reputation among dermatologists, often due to varying data on their efficacy and the overuse of highly allergenic over-the-counter topical antibiotics such as neomycin.⁸ However, data also have suggested that topical antibiotics can reduce postoperative infections in higher risk surgical cases, specifically certain head and neck surgeries.⁹ Likewise, topical antibiotics are useful for wound colonization with Pseudomonas, which can remain superficial and slow down healing without progressing to a systemic infection.¹⁰ Such cases can be successfully treated or prevented with topical therapies, thereby bypassing the more concerning adverse effects of systemic antibiotics. In particular, systemic fluoroquinolones often are used to treat Pseudomonas and can have many serious adverse effects, including tendon rupture, drug interactions, and arrhythmias.¹¹ Therefore, it is worth implementing topical treatments for wounds colonized with Pseudomonas to spare patients these potential complications.

When a postoperative patient develops a rash at the surgical site, it is critical to differentiate between wound infection and contact allergy, as the treatments for these two conditions may be mutually exclusive and treating the wrong condition may exacerbate the other, such as mistakenly using topical corticosteroids for a wound infection.⁷ Prompt treatment is necessary for wound infections, as time is limited for patch testing when a rash is already present and the diagnosis is questionable. Allergic contact dermatitis typically erupts 48 to 96 hours following exposure to a contact allergen, often manifesting as intensely pruritic erythematous patches or vesicles.⁶ Wound infections are characterized by pain and warmth, with erythema and edema present in both conditions. Postoperative infections manifest usually 4 to 7 days following surgery.¹² Despite these differences, pruritus and pain are common in the wound healing process; thus, differentiating an infection from ACD on a clinical basis alone is not always possible. Furthermore, presentation of a contact allergy may be delayed beyond the typical 96-hour timeframe if a patient is newly sensitized to an allergen, causing the timeline of rash development to appear similar to that of a wound infection. In such cases, systemic antibiotics often are prescribed empirically; hence, clearer and timelier differentiation between contact allergy and wound infection reduces unnecessary antibiotic prescriptions, thereby avoiding systemic adverse effects and promoting responsible antibiotic stewardship.¹²

The Technique

Since potentially allergenic topical therapies often are indicated in wound management, we propose that patients serve as internal controls to test continuously for contact allergy sensitization. We recommend that patients apply a small amount of the topical agent, product, or dressing to the inner forearm each time they apply it to the wound. If the patient is sensitized to the product initially or becomes sensitized during treatment, evidence of ACD will be visible not only at the site of the wound but also in the area of secondary application. The inner forearm is recommended for convenience and reproducibility, but a patient may choose a different site as long as it remains consistent. Although certain contact allergens rarely may react solely at a site of inflamed skin, our team has quickly identified ACD and avoided misdiagnosis of chronic or postsurgical wound infection using this approach.¹³ Subsequent patch testing is indicated when a contact allergy is detected.

Practice Implications

Topical therapies including ointments, washes, and dressing components have the potential to cause sensitization and contact allergy. Despite the concern for development of ACD, topical antibiotics play a useful role in cutaneous surgery.⁷ Synchronous testing for contact allergy when managing wounds with topical therapies could improve diagnostic accuracy when an allergic reaction occurs. This technique provides a means of harnessing the benefits of topical agents while monitoring the risk for ACD in postoperative and chronic wound care settings.

Patients who undergo cutaneous surgery and chronic wound care often are exposed to various topical agents that carry allergenic potential, including antiseptic rinses, bandage adhesives, mineral pastes, and antibiotic ointments.¹ Allergic contact dermatitis (ACD) in postoperative or chronic wounds can lead to considerable morbidity, particularly when the diagnosis is unclear. Differentiating between ACD and wound infection is paramount because the treatments for these conditions often are mutually exclusive.² While patch testing for contact allergy could be considered for postoperative patients or those with chronic wounds who exhibit concerning symptoms such as erythema or pruritus, these scenarios require prompt diagnosis and treatment. Herein, we describe a technique that involves secondary application of potentially allergenic topical components to a small area of normal skin during wound management to facilitate early detection of ACD and differentiation from wound infection.

Practice Gap 

Contact allergies are common in patients with postoperative or chronic wounds. When patch tested, approximately 80% of patients with chronic venous ulcers demonstrated at least 1 positive allergic reaction based on a Canadian study.³ Similarly, postoperative ACD in dermatologic surgery occurs in more than 1.6% of cases in North America and Europe, a rate that is similar to or higher than the rate of postoperative infection, approximately 1% to 2%.⁴ Postoperative patients and those with chronic wounds have multiple risk factors for ACD. Firstly, applying topical therapies to inflamed or compromised skin increases the risk for contact sensitization.⁵ Additionally, multiple topical therapies containing known allergenic components may be recommended for wound care, including impregnated or organic dressings, antibiotic ointments, adhesives, antiseptic washes, and topical therapies containing inactive ingredients such as lanolin derivatives.⁶ Contact with numerous compounds at the same time increases the risk for a contact allergy as well as co-sensitization.⁷ Similarly, the longer topical agents are applied, the greater the risk for a contact allergy, with sensitization liable to occur at any point during treatment.

Preventive topical antibiotics have garnered a negative reputation among dermatologists, often due to varying data on their efficacy and the overuse of highly allergenic over-the-counter topical antibiotics such as neomycin.⁸ However, data also have suggested that topical antibiotics can reduce postoperative infections in higher risk surgical cases, specifically certain head and neck surgeries.⁹ Likewise, topical antibiotics are useful for wound colonization with Pseudomonas, which can remain superficial and slow down healing without progressing to a systemic infection.¹⁰ Such cases can be successfully treated or prevented with topical therapies, thereby bypassing the more concerning adverse effects of systemic antibiotics. In particular, systemic fluoroquinolones often are used to treat Pseudomonas and can have many serious adverse effects, including tendon rupture, drug interactions, and arrhythmias.¹¹ Therefore, it is worth implementing topical treatments for wounds colonized with Pseudomonas to spare patients these potential complications.

When a postoperative patient develops a rash at the surgical site, it is critical to differentiate between wound infection and contact allergy, as the treatments for these two conditions may be mutually exclusive and treating the wrong condition may exacerbate the other, such as mistakenly using topical corticosteroids for a wound infection.⁷ Prompt treatment is necessary for wound infections, as time is limited for patch testing when a rash is already present and the diagnosis is questionable. Allergic contact dermatitis typically erupts 48 to 96 hours following exposure to a contact allergen, often manifesting as intensely pruritic erythematous patches or vesicles.⁶ Wound infections are characterized by pain and warmth, with erythema and edema present in both conditions. Postoperative infections manifest usually 4 to 7 days following surgery.¹² Despite these differences, pruritus and pain are common in the wound healing process; thus, differentiating an infection from ACD on a clinical basis alone is not always possible. Furthermore, presentation of a contact allergy may be delayed beyond the typical 96-hour timeframe if a patient is newly sensitized to an allergen, causing the timeline of rash development to appear similar to that of a wound infection. In such cases, systemic antibiotics often are prescribed empirically; hence, clearer and timelier differentiation between contact allergy and wound infection reduces unnecessary antibiotic prescriptions, thereby avoiding systemic adverse effects and promoting responsible antibiotic stewardship.¹²

The Technique

Since potentially allergenic topical therapies often are indicated in wound management, we propose that patients serve as internal controls to test continuously for contact allergy sensitization. We recommend that patients apply a small amount of the topical agent, product, or dressing to the inner forearm each time they apply it to the wound. If the patient is sensitized to the product initially or becomes sensitized during treatment, evidence of ACD will be visible not only at the site of the wound but also in the area of secondary application. The inner forearm is recommended for convenience and reproducibility, but a patient may choose a different site as long as it remains consistent. Although certain contact allergens rarely may react solely at a site of inflamed skin, our team has quickly identified ACD and avoided misdiagnosis of chronic or postsurgical wound infection using this approach.¹³ Subsequent patch testing is indicated when a contact allergy is detected.

Practice Implications

Topical therapies including ointments, washes, and dressing components have the potential to cause sensitization and contact allergy. Despite the concern for development of ACD, topical antibiotics play a useful role in cutaneous surgery.⁷ Synchronous testing for contact allergy when managing wounds with topical therapies could improve diagnostic accuracy when an allergic reaction occurs. This technique provides a means of harnessing the benefits of topical agents while monitoring the risk for ACD in postoperative and chronic wound care settings.

To the Editor:

Acne vulgaris and irritable bowel syndrome (IBS) are both associated with microbial dysbiosis and chronic inflammation.^1-3 While the prevalence of IBS among patients with acne has been examined previously,^4,5 there has been limited focus on the risk for new-onset IBS following acne diagnosis. Current evidence suggests isotretinoin may be associated with a lower risk for IBS compared to oral antibiotics⁶; however, evidence supporting this association is limited outside these cohorts, highlighting the need for further investigation. In this large-scale study, we sought to investigate the incidence of new-onset IBS among patients with acne compared with healthy controls as well as to evaluate whether oral acne treatments (ie, oral antibiotics or isotretinoin) are associated with new-onset IBS in this population.

A retrospective cohort study was conducted using data from the US Collaborative Network in TriNetX from October 2014 to October 2024. Patients were identified using International Classification of Diseases, Tenth Revision, Clinical Modification codes, Current Procedural Terminology codes, Anatomical Therapeutic Chemical Classification System codes, and RxNorm codes (Table 1). These codes were selected based on prior literature review, clinical relevance, and their ability to capture diagnoses of acne and IBS as well as relevant exclusion criteria. Patients were considered eligible if they were between the ages of 18 and 90 years. Individuals with a history of IBS, inflammatory bowel disease, infectious gastroenteritis, or celiac disease were excluded from our analysis. 

To examine potential associations between acne and IBS, 2 primary cohorts were established: patients with acne who were managed without systemic medications and healthy controls (ie, patients with no history of acne) who had no exposure to systemic acne treatments (Figure). Further, to assess the relationship between oral acne treatments (macrolides, tetracyclines, isotretinoin) and IBS, additional cohorts were created for each therapy and were compared to a cohort of patients with acne who were managed without systemic medications. To control for potential concomitant treatments, patients who had received any systemic treatment other than the specific therapy for their treatment cohort were excluded from our analysis.

To account for potential confounders, all cohorts were 1:1 propensity score matched by demographics, tobacco and alcohol use, type 2 diabetes, obesity, anxiety, and depression (eTable). Each cohort was followed for 2 years after their index of event: the date of acne diagnosis for the acne cohort, the date of systemic treatment initiation for the treatment cohorts, and the date of the general adult encounter without abnormal findings for the control cohort. The primary outcome was the incidence of IBS, assessed by odds ratio (OR) and 95% CIs.

We identified 375,944 patients with acne managed without systemic treatment and 3,148,443 healthy controls who met study criteria. After the 1:1 propensity score match, each cohort included 49,690 patients (eTable). In the 2-year period after acne diagnosis, patients were more likely to develop IBS compared with controls (1421 vs 1285 [OR, 1.10; 95% CI, 1.02-1.19])(Table 2). Patients with acne who were treated with tetracyclines (n=208,971) were 30% more likely to develop IBS than those managed without systemic medications (1114 vs 856 [OR, 1.30; 95% CI, 1.19-1.42]). Within the tetracycline cohort, doxycycline-treated patients were 25% more likely to develop IBS compared with those treated with minocycline (213 vs 170 [OR, 1.25; 95% CI, 1.02-1.53]). Similarly, the use of macrolides (n=136,334) for acne treatment was significantly associated with an increased risk for IBS (1023 vs 595 [OR, 1.73; 95% CI, 1.57-1.92; P<.0001]) compared with controls. No statistically significant association was observed between isotretinoin and the incidence of IBS (Table 2).

In this large-scale cohort study, acne was associated with an increased likelihood of developing IBS within 2 years of an acne diagnosis compared with healthy controls. While a prior study also identified this association, it had a broader follow-up window ranging from 8 to 10 years.² In contrast, our analysis specifically quantified the risk within the first 2 years of diagnosis. This distinction suggested potential for earlier IBS onset in patients with acne than has previously been recognized and may serve as an early clinical indicator for IBS risk in this population. 

Our findings further suggested an association between oral tetracyclines and macrolides and an increased risk for IBS. This aligns with existing literature suggesting that oral antibiotic use can disrupt the gut microbiota and lead to potential gastrointestinal complications⁷ and reinforces the importance of careful antibiotic stewardship in dermatologic practice. 

Although isotretinoin initially was surrounded by substantial controversy regarding its potential impact on gut health—particularly in inflammatory bowel ­disease⁸—our results do not support an increased risk for IBS among patients with acne who use isotretinoin. These findings challenge previous concerns and align with research suggesting that isotretinoin could be a safer alternative to antibiotic use for eligible patients who have a history of gastrointestinal disorders.⁶

This study highlights an important but underrecognized link between acne and IBS risk, emphasizing the need for early monitoring of gastrointestinal symptoms and careful antibiotic stewardship in dermatologic practice. Gastroenterology consultation may be advisable for patients with acne who have persistent gastrointestinal symptoms to facilitate a more integrated, patient-centered approach to care.

Limitations of this study include potential misclassification of International Classification of Diseases, Tenth Revision, Clinical Modification codes, selection bias, and residual confounding from unmeasured factors such as diet, lifestyle, disease severity, and treatment adherence due to the reliance on electronic health record data.

Our findings build upon prior evidence linking acne and IBS and offer important insights into the timing of this association following acne diagnosis. Future research should explore biological mechanisms underlying the gut-skin axis and evaluate targeted interventions to mitigate IBS risk in patients with acne.

To the Editor:

Acne vulgaris and irritable bowel syndrome (IBS) are both associated with microbial dysbiosis and chronic inflammation.^1-3 While the prevalence of IBS among patients with acne has been examined previously,^4,5 there has been limited focus on the risk for new-onset IBS following acne diagnosis. Current evidence suggests isotretinoin may be associated with a lower risk for IBS compared to oral antibiotics⁶; however, evidence supporting this association is limited outside these cohorts, highlighting the need for further investigation. In this large-scale study, we sought to investigate the incidence of new-onset IBS among patients with acne compared with healthy controls as well as to evaluate whether oral acne treatments (ie, oral antibiotics or isotretinoin) are associated with new-onset IBS in this population.

A retrospective cohort study was conducted using data from the US Collaborative Network in TriNetX from October 2014 to October 2024. Patients were identified using International Classification of Diseases, Tenth Revision, Clinical Modification codes, Current Procedural Terminology codes, Anatomical Therapeutic Chemical Classification System codes, and RxNorm codes (Table 1). These codes were selected based on prior literature review, clinical relevance, and their ability to capture diagnoses of acne and IBS as well as relevant exclusion criteria. Patients were considered eligible if they were between the ages of 18 and 90 years. Individuals with a history of IBS, inflammatory bowel disease, infectious gastroenteritis, or celiac disease were excluded from our analysis. 

To examine potential associations between acne and IBS, 2 primary cohorts were established: patients with acne who were managed without systemic medications and healthy controls (ie, patients with no history of acne) who had no exposure to systemic acne treatments (Figure). Further, to assess the relationship between oral acne treatments (macrolides, tetracyclines, isotretinoin) and IBS, additional cohorts were created for each therapy and were compared to a cohort of patients with acne who were managed without systemic medications. To control for potential concomitant treatments, patients who had received any systemic treatment other than the specific therapy for their treatment cohort were excluded from our analysis.

To account for potential confounders, all cohorts were 1:1 propensity score matched by demographics, tobacco and alcohol use, type 2 diabetes, obesity, anxiety, and depression (eTable). Each cohort was followed for 2 years after their index of event: the date of acne diagnosis for the acne cohort, the date of systemic treatment initiation for the treatment cohorts, and the date of the general adult encounter without abnormal findings for the control cohort. The primary outcome was the incidence of IBS, assessed by odds ratio (OR) and 95% CIs.

We identified 375,944 patients with acne managed without systemic treatment and 3,148,443 healthy controls who met study criteria. After the 1:1 propensity score match, each cohort included 49,690 patients (eTable). In the 2-year period after acne diagnosis, patients were more likely to develop IBS compared with controls (1421 vs 1285 [OR, 1.10; 95% CI, 1.02-1.19])(Table 2). Patients with acne who were treated with tetracyclines (n=208,971) were 30% more likely to develop IBS than those managed without systemic medications (1114 vs 856 [OR, 1.30; 95% CI, 1.19-1.42]). Within the tetracycline cohort, doxycycline-treated patients were 25% more likely to develop IBS compared with those treated with minocycline (213 vs 170 [OR, 1.25; 95% CI, 1.02-1.53]). Similarly, the use of macrolides (n=136,334) for acne treatment was significantly associated with an increased risk for IBS (1023 vs 595 [OR, 1.73; 95% CI, 1.57-1.92; P<.0001]) compared with controls. No statistically significant association was observed between isotretinoin and the incidence of IBS (Table 2).

In this large-scale cohort study, acne was associated with an increased likelihood of developing IBS within 2 years of an acne diagnosis compared with healthy controls. While a prior study also identified this association, it had a broader follow-up window ranging from 8 to 10 years.² In contrast, our analysis specifically quantified the risk within the first 2 years of diagnosis. This distinction suggested potential for earlier IBS onset in patients with acne than has previously been recognized and may serve as an early clinical indicator for IBS risk in this population. 

Our findings further suggested an association between oral tetracyclines and macrolides and an increased risk for IBS. This aligns with existing literature suggesting that oral antibiotic use can disrupt the gut microbiota and lead to potential gastrointestinal complications⁷ and reinforces the importance of careful antibiotic stewardship in dermatologic practice. 

Although isotretinoin initially was surrounded by substantial controversy regarding its potential impact on gut health—particularly in inflammatory bowel ­disease⁸—our results do not support an increased risk for IBS among patients with acne who use isotretinoin. These findings challenge previous concerns and align with research suggesting that isotretinoin could be a safer alternative to antibiotic use for eligible patients who have a history of gastrointestinal disorders.⁶

This study highlights an important but underrecognized link between acne and IBS risk, emphasizing the need for early monitoring of gastrointestinal symptoms and careful antibiotic stewardship in dermatologic practice. Gastroenterology consultation may be advisable for patients with acne who have persistent gastrointestinal symptoms to facilitate a more integrated, patient-centered approach to care.

Limitations of this study include potential misclassification of International Classification of Diseases, Tenth Revision, Clinical Modification codes, selection bias, and residual confounding from unmeasured factors such as diet, lifestyle, disease severity, and treatment adherence due to the reliance on electronic health record data.

Our findings build upon prior evidence linking acne and IBS and offer important insights into the timing of this association following acne diagnosis. Future research should explore biological mechanisms underlying the gut-skin axis and evaluate targeted interventions to mitigate IBS risk in patients with acne.

To the Editor:

Acne vulgaris and irritable bowel syndrome (IBS) are both associated with microbial dysbiosis and chronic inflammation.^1-3 While the prevalence of IBS among patients with acne has been examined previously,^4,5 there has been limited focus on the risk for new-onset IBS following acne diagnosis. Current evidence suggests isotretinoin may be associated with a lower risk for IBS compared to oral antibiotics⁶; however, evidence supporting this association is limited outside these cohorts, highlighting the need for further investigation. In this large-scale study, we sought to investigate the incidence of new-onset IBS among patients with acne compared with healthy controls as well as to evaluate whether oral acne treatments (ie, oral antibiotics or isotretinoin) are associated with new-onset IBS in this population.

A retrospective cohort study was conducted using data from the US Collaborative Network in TriNetX from October 2014 to October 2024. Patients were identified using International Classification of Diseases, Tenth Revision, Clinical Modification codes, Current Procedural Terminology codes, Anatomical Therapeutic Chemical Classification System codes, and RxNorm codes (Table 1). These codes were selected based on prior literature review, clinical relevance, and their ability to capture diagnoses of acne and IBS as well as relevant exclusion criteria. Patients were considered eligible if they were between the ages of 18 and 90 years. Individuals with a history of IBS, inflammatory bowel disease, infectious gastroenteritis, or celiac disease were excluded from our analysis. 

To examine potential associations between acne and IBS, 2 primary cohorts were established: patients with acne who were managed without systemic medications and healthy controls (ie, patients with no history of acne) who had no exposure to systemic acne treatments (Figure). Further, to assess the relationship between oral acne treatments (macrolides, tetracyclines, isotretinoin) and IBS, additional cohorts were created for each therapy and were compared to a cohort of patients with acne who were managed without systemic medications. To control for potential concomitant treatments, patients who had received any systemic treatment other than the specific therapy for their treatment cohort were excluded from our analysis.

To account for potential confounders, all cohorts were 1:1 propensity score matched by demographics, tobacco and alcohol use, type 2 diabetes, obesity, anxiety, and depression (eTable). Each cohort was followed for 2 years after their index of event: the date of acne diagnosis for the acne cohort, the date of systemic treatment initiation for the treatment cohorts, and the date of the general adult encounter without abnormal findings for the control cohort. The primary outcome was the incidence of IBS, assessed by odds ratio (OR) and 95% CIs.

We identified 375,944 patients with acne managed without systemic treatment and 3,148,443 healthy controls who met study criteria. After the 1:1 propensity score match, each cohort included 49,690 patients (eTable). In the 2-year period after acne diagnosis, patients were more likely to develop IBS compared with controls (1421 vs 1285 [OR, 1.10; 95% CI, 1.02-1.19])(Table 2). Patients with acne who were treated with tetracyclines (n=208,971) were 30% more likely to develop IBS than those managed without systemic medications (1114 vs 856 [OR, 1.30; 95% CI, 1.19-1.42]). Within the tetracycline cohort, doxycycline-treated patients were 25% more likely to develop IBS compared with those treated with minocycline (213 vs 170 [OR, 1.25; 95% CI, 1.02-1.53]). Similarly, the use of macrolides (n=136,334) for acne treatment was significantly associated with an increased risk for IBS (1023 vs 595 [OR, 1.73; 95% CI, 1.57-1.92; P<.0001]) compared with controls. No statistically significant association was observed between isotretinoin and the incidence of IBS (Table 2).

In this large-scale cohort study, acne was associated with an increased likelihood of developing IBS within 2 years of an acne diagnosis compared with healthy controls. While a prior study also identified this association, it had a broader follow-up window ranging from 8 to 10 years.² In contrast, our analysis specifically quantified the risk within the first 2 years of diagnosis. This distinction suggested potential for earlier IBS onset in patients with acne than has previously been recognized and may serve as an early clinical indicator for IBS risk in this population. 

Our findings further suggested an association between oral tetracyclines and macrolides and an increased risk for IBS. This aligns with existing literature suggesting that oral antibiotic use can disrupt the gut microbiota and lead to potential gastrointestinal complications⁷ and reinforces the importance of careful antibiotic stewardship in dermatologic practice. 

Although isotretinoin initially was surrounded by substantial controversy regarding its potential impact on gut health—particularly in inflammatory bowel ­disease⁸—our results do not support an increased risk for IBS among patients with acne who use isotretinoin. These findings challenge previous concerns and align with research suggesting that isotretinoin could be a safer alternative to antibiotic use for eligible patients who have a history of gastrointestinal disorders.⁶

This study highlights an important but underrecognized link between acne and IBS risk, emphasizing the need for early monitoring of gastrointestinal symptoms and careful antibiotic stewardship in dermatologic practice. Gastroenterology consultation may be advisable for patients with acne who have persistent gastrointestinal symptoms to facilitate a more integrated, patient-centered approach to care.

Limitations of this study include potential misclassification of International Classification of Diseases, Tenth Revision, Clinical Modification codes, selection bias, and residual confounding from unmeasured factors such as diet, lifestyle, disease severity, and treatment adherence due to the reliance on electronic health record data.

Our findings build upon prior evidence linking acne and IBS and offer important insights into the timing of this association following acne diagnosis. Future research should explore biological mechanisms underlying the gut-skin axis and evaluate targeted interventions to mitigate IBS risk in patients with acne.

The Comparison

A. Alopecia areata in a young girl with a lighter skin tone. The fine white vellus hairs are signs of regrowth. 

B. Alopecia areata in a 49-year-old man with tightly coiled hair and darker skin tone. Coiled white hairs are noted in the alopecia patches.

Alopecia areata (AA) is a common autoimmune condition characterized by hair loss resulting from a T cell–mediated attack on the hair follicles. It manifests as nonscarring patches of hair loss on the scalp, eyebrows, eyelashes, and beard area as well as more extensive complete loss of scalp and body hair. While AA may affect individuals of any age, most patients develop their first patch(es) of hair loss during childhood.¹ The treatment landscape for AA has evolved considerably in recent years, but barriers to access to newer treatments persist. 

Epidemiology 

Alopecia areata is most prevalent among pediatric and adult individuals of African, Asian, or Hispanic/Latino descent.^2-4 In some studies, Black individuals had higher odds and Asian individuals had lower odds of developing AA, while other studies have reported the highest standardized prevalence among Asian individuals.⁵ In the United States, AA affects about 1.47% of adults and as many as 0.11% of children.^6-8 In Black patients, AA often manifests early with a female predominance.⁵ 

Alopecia areata frequently is associated with autoimmune comorbidities, the most common being thyroid disease.^3,5 In Black patients, AA is associated with more atopic comorbidities, including asthma, atopic dermatitis, and allergic rhinitis.⁵ 

Key Clinical Features 

Alopecia areata clinically manifests similarly across different skin tones; however, in patients with more tightly coiled or curly hair, the extent of scalp hair loss may be underestimated without a full examination. Culturally sensitive approaches to hair and scalp evaluation are essential, especially for Black women, whose hair care practices and scalp conditions may be overlooked or misunderstood during visits to evaluate hair loss. A thoughtful history and gentle examination of the hair and scalp that considers hair texture, cultural practices such as head coverings (eg, headwraps, turbans, hijabs), use of hair adornments (eg, clips, beads, bows), traditional braiding, and use of natural oils or herbal treatments, as well as styling methods including tight hairstyles, use of heat styling tools (eg, flat irons, curling irons), chemical application (eg, straighteners, hair color), and washing or styling frequency can improve diagnostic accuracy and help build trust in the patient-provider relationship. 

Classic signs of AA visualized with dermoscopy include yellow and/or black dots on the scalp and exclamation point hairs. The appearance of fine white vellus hairs within the alopecic patches also may indicate early regrowth. On scalp trichoscopy, black dots are more prominent, and yellow dots are less prominent, in individuals with darker skin tones vs lighter skin tones.⁹ 

Worth Noting 

In addition to a full examination of the scalp, documenting the extent of hair loss using validated severity scales, including the severity of alopecia tool (SALT), alopecia areata severity index (AASI), clinician-reported outcome assessment, and patient-reported outcome measures, can standardize disease severity assessment, facilitate timely insurance or medication approvals, and support objective tracking of treatment response, which may ultimately enhance access to care.¹⁰ 

Prompt treatment of AA is essential. Not surprisingly, patients given a diagnosis of AA may experience considerable emotional and psychological distress—regardless of the extent of the loss.¹¹ Treatment options include mid- to high-potency topical or intralesional corticosteroids and newer and more targeted systemic options, including 3 Janus kinase (JAK) inhibitors—baricitinib, ritlecitinib, and deuruxolitinib—for more extensive disease.¹² Treatment with intralesional corticosteroids may cause transient hypopigmentation, which may be more noticeable in patients with darker skin tones. Delays in treatment with JAK inhibitors can lead to a less-than-optimal response. Of the 3 JAK inhibitors that are approved by the US Food and Drug Administration for AA, only ritlecitinib is approved for children 12 years and older, leaving a therapeutic gap for younger patients that often leads to uncomfortable scalp injections, delayed or no treatment, off-label use of JAK inhibitors as well as the pairing of off-label dupilumab with oral minoxidil.¹² 

Based on adult data, patients with severe disease and a shorter duration of hair loss (ie, <4 years) tend to respond better to JAK inhibitors than those experiencing hair loss for longer periods. Also, those with more severe AA tend to have poorer outcomes than those with less severe disease.¹³ If treatment proves less than optimal, wigs and hair pieces may need to be considered. It is worth noting that some insurance companies will cover the cost of wigs for patients when prescribed as cranial prostheses. 

Health Disparity Highlight 

Health disparities in AA can be influenced by socioeconomic status and access to care. Patients from lower-income backgrounds often face barriers to accessing dermatologic care and treatments such as JAK inhibitors, which may remain inaccessible due to high costs and insurance limitations.¹⁴ These barriers can intersect with other factors such as age, sex, and race, potentially exacerbating disparities. Women with skin of color in underserved communities may experience delayed diagnosis, limited treatment options, and greater psychosocial distress from hair loss.¹⁴ Addressing these inequities requires advocacy, education for both patients and clinicians, and improved access to treatment to ensure comprehensive care for all patients. 

The Comparison

A. Alopecia areata in a young girl with a lighter skin tone. The fine white vellus hairs are signs of regrowth. 

B. Alopecia areata in a 49-year-old man with tightly coiled hair and darker skin tone. Coiled white hairs are noted in the alopecia patches.

Alopecia areata (AA) is a common autoimmune condition characterized by hair loss resulting from a T cell–mediated attack on the hair follicles. It manifests as nonscarring patches of hair loss on the scalp, eyebrows, eyelashes, and beard area as well as more extensive complete loss of scalp and body hair. While AA may affect individuals of any age, most patients develop their first patch(es) of hair loss during childhood.¹ The treatment landscape for AA has evolved considerably in recent years, but barriers to access to newer treatments persist. 

Epidemiology 

Alopecia areata is most prevalent among pediatric and adult individuals of African, Asian, or Hispanic/Latino descent.^2-4 In some studies, Black individuals had higher odds and Asian individuals had lower odds of developing AA, while other studies have reported the highest standardized prevalence among Asian individuals.⁵ In the United States, AA affects about 1.47% of adults and as many as 0.11% of children.^6-8 In Black patients, AA often manifests early with a female predominance.⁵ 

Alopecia areata frequently is associated with autoimmune comorbidities, the most common being thyroid disease.^3,5 In Black patients, AA is associated with more atopic comorbidities, including asthma, atopic dermatitis, and allergic rhinitis.⁵ 

Key Clinical Features 

Alopecia areata clinically manifests similarly across different skin tones; however, in patients with more tightly coiled or curly hair, the extent of scalp hair loss may be underestimated without a full examination. Culturally sensitive approaches to hair and scalp evaluation are essential, especially for Black women, whose hair care practices and scalp conditions may be overlooked or misunderstood during visits to evaluate hair loss. A thoughtful history and gentle examination of the hair and scalp that considers hair texture, cultural practices such as head coverings (eg, headwraps, turbans, hijabs), use of hair adornments (eg, clips, beads, bows), traditional braiding, and use of natural oils or herbal treatments, as well as styling methods including tight hairstyles, use of heat styling tools (eg, flat irons, curling irons), chemical application (eg, straighteners, hair color), and washing or styling frequency can improve diagnostic accuracy and help build trust in the patient-provider relationship. 

Classic signs of AA visualized with dermoscopy include yellow and/or black dots on the scalp and exclamation point hairs. The appearance of fine white vellus hairs within the alopecic patches also may indicate early regrowth. On scalp trichoscopy, black dots are more prominent, and yellow dots are less prominent, in individuals with darker skin tones vs lighter skin tones.⁹ 

Worth Noting 

In addition to a full examination of the scalp, documenting the extent of hair loss using validated severity scales, including the severity of alopecia tool (SALT), alopecia areata severity index (AASI), clinician-reported outcome assessment, and patient-reported outcome measures, can standardize disease severity assessment, facilitate timely insurance or medication approvals, and support objective tracking of treatment response, which may ultimately enhance access to care.¹⁰ 

Prompt treatment of AA is essential. Not surprisingly, patients given a diagnosis of AA may experience considerable emotional and psychological distress—regardless of the extent of the loss.¹¹ Treatment options include mid- to high-potency topical or intralesional corticosteroids and newer and more targeted systemic options, including 3 Janus kinase (JAK) inhibitors—baricitinib, ritlecitinib, and deuruxolitinib—for more extensive disease.¹² Treatment with intralesional corticosteroids may cause transient hypopigmentation, which may be more noticeable in patients with darker skin tones. Delays in treatment with JAK inhibitors can lead to a less-than-optimal response. Of the 3 JAK inhibitors that are approved by the US Food and Drug Administration for AA, only ritlecitinib is approved for children 12 years and older, leaving a therapeutic gap for younger patients that often leads to uncomfortable scalp injections, delayed or no treatment, off-label use of JAK inhibitors as well as the pairing of off-label dupilumab with oral minoxidil.¹² 

Based on adult data, patients with severe disease and a shorter duration of hair loss (ie, <4 years) tend to respond better to JAK inhibitors than those experiencing hair loss for longer periods. Also, those with more severe AA tend to have poorer outcomes than those with less severe disease.¹³ If treatment proves less than optimal, wigs and hair pieces may need to be considered. It is worth noting that some insurance companies will cover the cost of wigs for patients when prescribed as cranial prostheses. 

Health Disparity Highlight 

Health disparities in AA can be influenced by socioeconomic status and access to care. Patients from lower-income backgrounds often face barriers to accessing dermatologic care and treatments such as JAK inhibitors, which may remain inaccessible due to high costs and insurance limitations.¹⁴ These barriers can intersect with other factors such as age, sex, and race, potentially exacerbating disparities. Women with skin of color in underserved communities may experience delayed diagnosis, limited treatment options, and greater psychosocial distress from hair loss.¹⁴ Addressing these inequities requires advocacy, education for both patients and clinicians, and improved access to treatment to ensure comprehensive care for all patients. 

The Comparison

A. Alopecia areata in a young girl with a lighter skin tone. The fine white vellus hairs are signs of regrowth. 

B. Alopecia areata in a 49-year-old man with tightly coiled hair and darker skin tone. Coiled white hairs are noted in the alopecia patches.

Alopecia areata (AA) is a common autoimmune condition characterized by hair loss resulting from a T cell–mediated attack on the hair follicles. It manifests as nonscarring patches of hair loss on the scalp, eyebrows, eyelashes, and beard area as well as more extensive complete loss of scalp and body hair. While AA may affect individuals of any age, most patients develop their first patch(es) of hair loss during childhood.¹ The treatment landscape for AA has evolved considerably in recent years, but barriers to access to newer treatments persist. 

Epidemiology 

Alopecia areata is most prevalent among pediatric and adult individuals of African, Asian, or Hispanic/Latino descent.^2-4 In some studies, Black individuals had higher odds and Asian individuals had lower odds of developing AA, while other studies have reported the highest standardized prevalence among Asian individuals.⁵ In the United States, AA affects about 1.47% of adults and as many as 0.11% of children.^6-8 In Black patients, AA often manifests early with a female predominance.⁵ 

Alopecia areata frequently is associated with autoimmune comorbidities, the most common being thyroid disease.^3,5 In Black patients, AA is associated with more atopic comorbidities, including asthma, atopic dermatitis, and allergic rhinitis.⁵ 

Key Clinical Features 

Alopecia areata clinically manifests similarly across different skin tones; however, in patients with more tightly coiled or curly hair, the extent of scalp hair loss may be underestimated without a full examination. Culturally sensitive approaches to hair and scalp evaluation are essential, especially for Black women, whose hair care practices and scalp conditions may be overlooked or misunderstood during visits to evaluate hair loss. A thoughtful history and gentle examination of the hair and scalp that considers hair texture, cultural practices such as head coverings (eg, headwraps, turbans, hijabs), use of hair adornments (eg, clips, beads, bows), traditional braiding, and use of natural oils or herbal treatments, as well as styling methods including tight hairstyles, use of heat styling tools (eg, flat irons, curling irons), chemical application (eg, straighteners, hair color), and washing or styling frequency can improve diagnostic accuracy and help build trust in the patient-provider relationship. 

Classic signs of AA visualized with dermoscopy include yellow and/or black dots on the scalp and exclamation point hairs. The appearance of fine white vellus hairs within the alopecic patches also may indicate early regrowth. On scalp trichoscopy, black dots are more prominent, and yellow dots are less prominent, in individuals with darker skin tones vs lighter skin tones.⁹ 

Worth Noting 

In addition to a full examination of the scalp, documenting the extent of hair loss using validated severity scales, including the severity of alopecia tool (SALT), alopecia areata severity index (AASI), clinician-reported outcome assessment, and patient-reported outcome measures, can standardize disease severity assessment, facilitate timely insurance or medication approvals, and support objective tracking of treatment response, which may ultimately enhance access to care.¹⁰ 

Prompt treatment of AA is essential. Not surprisingly, patients given a diagnosis of AA may experience considerable emotional and psychological distress—regardless of the extent of the loss.¹¹ Treatment options include mid- to high-potency topical or intralesional corticosteroids and newer and more targeted systemic options, including 3 Janus kinase (JAK) inhibitors—baricitinib, ritlecitinib, and deuruxolitinib—for more extensive disease.¹² Treatment with intralesional corticosteroids may cause transient hypopigmentation, which may be more noticeable in patients with darker skin tones. Delays in treatment with JAK inhibitors can lead to a less-than-optimal response. Of the 3 JAK inhibitors that are approved by the US Food and Drug Administration for AA, only ritlecitinib is approved for children 12 years and older, leaving a therapeutic gap for younger patients that often leads to uncomfortable scalp injections, delayed or no treatment, off-label use of JAK inhibitors as well as the pairing of off-label dupilumab with oral minoxidil.¹² 

Based on adult data, patients with severe disease and a shorter duration of hair loss (ie, <4 years) tend to respond better to JAK inhibitors than those experiencing hair loss for longer periods. Also, those with more severe AA tend to have poorer outcomes than those with less severe disease.¹³ If treatment proves less than optimal, wigs and hair pieces may need to be considered. It is worth noting that some insurance companies will cover the cost of wigs for patients when prescribed as cranial prostheses. 

Health Disparity Highlight 

Health disparities in AA can be influenced by socioeconomic status and access to care. Patients from lower-income backgrounds often face barriers to accessing dermatologic care and treatments such as JAK inhibitors, which may remain inaccessible due to high costs and insurance limitations.¹⁴ These barriers can intersect with other factors such as age, sex, and race, potentially exacerbating disparities. Women with skin of color in underserved communities may experience delayed diagnosis, limited treatment options, and greater psychosocial distress from hair loss.¹⁴ Addressing these inequities requires advocacy, education for both patients and clinicians, and improved access to treatment to ensure comprehensive care for all patients. 

Spironolactone is increasingly used off label for acne treatment and is now being prescribed for women with acne at a frequency similar to oral antibiotics.^1,2 In this article, we provide an overview of spironolactone use for acne treatment and discuss recent clinical trials and practical strategies for patient selection, dosing, adverse effect management, and monitoring (Table).

History and Mechanism of Action

Because sebaceous gland activity is an important component of acne pathogenesis and is regulated by androgens,³ there has long been interest in identifying treatment strategies that can target the role of hormones in activating the sebaceous gland. In the 1980s, it became apparent that spironolactone, originally developed as a potassium-sparing diuretic, also might possess antiandrogenic properties that could be useful in the treatment of acne.⁴ Spironolactone has been found to decrease testosterone production, inhibit testosterone and dihydrotestosterone binding to androgen receptors,^5-8 and block 5α-reductase receptors of the sebaceous glands of skin.⁹

In 1984, Goodfellow et al¹⁰ conducted a trial in which 36 male and female patients with severe acne were randomized to placebo or spironolactone doses ranging from 50 to 200 mg/d. They found that spironolactone resulted in dose-dependent reductions of sebum production as well as improvement in patient- and clinician-reported assessments of acne. In 1986, another placebo-controlled crossover trial by Muhlemann et al¹¹ provided further support for the effectiveness of spironolactone for acne. This trial randomized 21 women to placebo or spironolactone 200 mg/d and found that spironolactone was associated with statistically significant (P<.001) improvements in acne lesion counts.

Recent Observational Studies and Trials

Following these early trials, several large case series have been published describing the successful use of spironolactone for acne, including a 2020 retrospective case series from the Mayo Clinic describing 395 patients.¹² The investigators found that almost 66% of patients had a complete response and almost 85% had a complete response or a partial response greater than 50%. They also found that the median time to initial response and maximal response were 3 and 5 months, respectively, and that efficacy was observed across acne subtypes, including for nodulocystic acne.¹² In addition, a 2021 case series describing 403 patients treated with spironolactone found that approximately 80% had reduction or complete clearance of acne, with improvements observed for both facial and truncal acne. In this cohort, doses of 100 to 150 mg/d typically were the most successful.¹³ A case series of 80 adolescent females also highlighted the efficacy of spironolactone in younger populations.¹⁴

Adding to these observational data, the multicenter, phase 3, double-blind Spironolactone for Adult Female Acne (SAFA) trial included 410 women (mean age, 29.2 years) who were randomized to receive either placebo or intervention (spironolactone 50 mg/d until week 6 and 100 mg/d until week 24).¹⁵ At 24 weeks, greater improvement in quality of life and participant self-assessed improvement were observed in the spironolactone group. In addition, at 12 weeks, rates of success were higher in the spironolactone group using the Investigator Global Assessment score (adjusted odds ratio 5.18 [95% CI, 2.18- 12.28]). Those randomized to receive spironolactone also had lower rates of oral antibiotic use at 52 weeks than the placebo group did (5.8% vs 13.5%, respectively).

In the SAFA trial, spironolactone was well tolerated; the most common adverse effects relative to placebo were lightheadedness (19% for spironolactone vs 12% for placebo) and headache (20% for spironolactone vs 12% for placebo). Notably, more than 95% of patients were able to increase from 50 mg/d to 100 mg/d at week 6, with greater than 90% tolerating 100 mg/d. As observational data suggest that spironolactone takes 3 to 5 months to reach peak efficacy, these findings provide further support that starting at a dose of at least 100 mg/d is likely optimal for most patients.¹⁶

A Potential Alternative to Oral Antibiotics

Oral antibiotics such as tetracyclines have long played a central role in the treatment of acne and remain a first-line treatment option.¹⁷ In addition, many of these antibiotic courses exceed 6 months in duration.¹ In fact, dermatologists prescribe more antibiotics per capita than any other specialty^1,18-20; however, this can be associated with the development of antibiotic resistance,^21,22 as well as other antibiotic-associated complications, including inflammatory bowel disease,²³ pharyngitis,²⁴Clostridium difficile infections, and cancer.^25-29

In addition to these concerns, many patients may prefer nonantibiotic alternatives to oral antibiotics, with more than 75% preferring a nonantibiotic option if available. For female patients with acne, antiandrogens such as spironolactone have been suggested as a potential alternative.³⁰ A 10-year retrospective study of female patients with acne found that those who had ever received hormonal therapy (ie, spironolactone or a combined oral contraceptive) received fewer cumulative days of oral antibiotics than those who did not (226 days vs 302 days, respectively).³¹ In addition, while oral antibiotics were the most common initial therapy prescribed for patients, as they progressed through their treatment course, more patients ended up on hormonal therapy than oral antibiotics. This study suggests that hormonal therapy such as spironolactone could represent an alternative to the use of systemic antibiotics.³¹

Further supporting the role of spironolactone as an alternative to oral antibiotics, a 2018 analysis of claims data found that spironolactone may have similar effectiveness to oral antibiotics for the treatment of acne.32 After adjusting for age and topical retinoid and oral contraceptive use, this study found that there was no significant difference in the odds of being prescribed a different systemic treatment within 1 year (ie, treatment failure) among those starting spironolactone vs those starting oral tetracycline-class antibiotics as their initial therapy for acne.

A multicenter, randomized, double-blind trial (Female Acne Spironolactone vs doxyCycline Efficacy [FASCE]) also evaluated the comparative effectiveness of doxycycline 100 mg/d for 3 months followed by an oral placebo for 3 months vs spironolactone 150 mg/d for 6 months among 133 adult women with acne. This study found that spironolactone had statistically significantly greater rates of Investigator Global Assessment treatment success after 6 months (odds ratio 2.87 [95% CI, 1.38-5.99; P=.007]).³³ Since spironolactone historically has been prescribed less often than oral antibiotics for women with acne, these findings support spironolactone as an underutilized treatment alternative. The ongoing Spironolactone versus Doxycycline for Acne: A Comparative Effectiveness, Noninferiority Evaluation trial—a 16-week, blinded trial comparing 100 mg/d doses of both drugs—should provide additional evidence regarding the relative role of spironolactone and oral antibiotics in the management of acne.³⁴

Ultimately, the decision to use spironolactone or other treatments such as oral antibiotics should be based on shared decision making between clinician and patient. Spironolactone has a relatively slow onset of efficacy, and other options such as oral antibiotics might be preferred by those looking for more immediate results; however, as women with acne often have activity that persists into adulthood, spironolactone might be preferable as a long-term maintenance therapy to avoid complications of prolonged antibiotic use.³⁵ Comorbidities also will influence the optimal choice of therapy (eg, spironolactone might be preferred in someone with inflammatory bowel disease, and oral antibiotics might be preferred in someone with orthostatic hypotension).

Patient Selection

Acne occurring along the lower face or jawline in adult women sometimes is referred to as hormonal acne, but this dogma is not particularly evidence based. An observational study of 374 patients found that almost 90% of adult women had acne involving multiple facial zones with a spectrum of facial acne severity similar to that in adolescents.³⁶ Only a small subset of these patients (11.2%) had acne localized solely to the mandibular area. In addition, acne along the lower face is not predictive of hyperandrogenism (eg, polycystic ovary syndrome).³⁷ Antiandrogen therapies such as spironolactone and clascoterone are effective in both men and women with acne^10,38 and in adolescents and adults, suggesting that hormones play a fundamental role in all acne and that addressing this mechanism can be useful broadly. Therefore, hormonal therapies such as spironolactone should not be restricted to only adult women with acne along the lower face.

While spironolactone can be effective for acne treatment in any age group, it may be most effective for adult women with acne. In the SAFA trial, prespecified subgroup analyses showed a statistically significant (P=.005) interaction term for age (categorized as <25 years and ≥25 years), which suggested that spironolactone might be a more effective treatment for women 25 years and older.¹⁵ In addition, subgroup analyses in the aforementioned 2018 analysis of claims data found that spironolactone was more effective relative to oral antibiotics in adults vs adolescents.³² Despite these limitations, several case series have highlighted that spironolactone is effective among adolescent populations with acne. A case series of spironolactone use in 73 patients aged 19 years or younger found that 68% of patients demonstrated resolution or improvement in their acne after spironolactone treatment.³⁹ Another case series among 80 adolescent females reported 80% of patients experiencing improvement of their acne.¹⁴

For those with more severe acne, spironolactone can be combined with other complementary treatment approaches such as topicals, oral antibiotics, or procedural modalities.⁴⁰

Dosing

We recommend starting spironolactone at a dose of 100 mg/d (the patient can take 50 mg/d for 1 week, then increase to 100 mg/d if there are no adverse effects at the lower dose). In the 1984 trial by Goodfellow et al,¹⁰ participants were randomized to doses of 50 mg/d, 100 mg/d, 150 mg/d, and 200 mg/d. In this trial, efficacy assessed by objective and subjective outcomes did not plateau until doses of 100 mg/d to 150 mg/d. In addition, a case series of 403 patients found that the most successful dosage of spironolactone generally was 100 mg/d or higher.¹³ Most of the patients who were started at this dosage either stayed at this level or escalated, whereas patients who started at lower dosages (25-75 mg/d) frequently increased their dosage over time. The SAFA trial also highlighted that most patients can tolerate a spironolactone dose of 100 mg/d.¹⁵ For specific populations, such as patients with polycystic ovary syndrome, a higher dose (mean dosage of 143 mg/d) may be required for efficacy.⁴¹ Given the slow onset of efficacy, typically taking 3 to 5 months, and the low rate of adverse effects, we believe the optimal starting dose is 100 mg/s to 150 mg/d. If adverse effects occur or lesions clear, then the dosage may be reduced.

Adverse Effects

Spironolactone generally is well tolerated; in the SAFA and FASCE trials, fewer than 1% of participants discontinued due to adverse effects.^15,33 Rates of discontinuation due to adverse effects typically have been less than 5% in case series of patients treated in routine clinical practice.^12-14

Because spironolactone is a diuretic and antihypertensive, the most common adverse effects are related to these characteristics. In the SAFA trial, dizziness, lightheadedness, and vertigo were reported more commonly in the spironolactone group than in the placebo group (19% vs 12%, respectively). Similarly, headaches also were reported more frequently in the spironolactone group than in the placebo group (20% vs 12%, respectively).¹⁵ One case series found that, among the 267 patients on spironolactone whose blood pressure was monitored, the mean reduction in systolic blood pressure was 3.5 mm Hg and the mean reduction in diastolic blood pressure was 0.9 mm Hg.¹³ For those with baseline orthostasis or in those who experience adverse effects related to hypotension, reducing the dose often can be helpful. Of note, while doses of 100 mg/d to 150 mg/d often are the most effective, randomized trials have found that spironolactone still can be effective for acne at doses as low as 25 mg/d to 50 mg/d.^10,38

Menstrual irregularities are another commonly cited adverse effect of spironolactone. While a systematic review found that 15% to 30% of patients treated with spironolactone experience menstrual irregularities, it has been difficult to evaluate whether this is due to the medication or other comorbidities, such as polycystic ovary syndrome.⁴² Notably, in the SAFA trial, rates of menstrual irregularities were equivalent between the spironolactone and placebo groups at a dose of 100 mg/d (32% vs 35%, respectively).¹⁵ In contrast, in the FASCE trial, menstrual irregularities were more commonly reported at a dose of 150 mg/d.³³ These findings are consistent with observational data suggesting that menstrual irregularities are much more common at spironolactone doses greater than 100 mg/d.⁴² Additionally, some evidence supports that for some patients these menstrual irregularities may resolve within 2 to 3 months of continued treatment.⁴³ It has been noted in several studies that menstrual irregularities are less likely to occur in patients who are using combined oral contraceptives; therefore, for patients who are amenable and have no contraindications, combined oral contraceptives can be considered to prevent or address menstrual irregularities.^13,42,44

More generally, combined oral contraceptives can be an excellent combination with spironolactone, as they have complementary characteristics. Spironolactone primarily blocks the effects of androgens, while combined oral contraceptives predominantly block the production of androgens. Whereas spironolactone typically causes hypotension and menstrual irregularities, combined oral contraceptives cause hypertension and help to regulate the menstrual cycle.

Spironolactone carries an official US Food and Drug Administration warning regarding possible tumorigenicity that is based on animal studies that used up to 150 times the normal dose of spironolactone used in humans⁴⁵; however, observational studies in humans have not identified such an association when spironolactone is used in normal clinical settings. A systematic review and metanalysis in 2022 reviewed data from a total population of more than 4 million individuals and found that there was no statistically significant association between spironolactone use and the risk for breast, ovarian, bladder, kidney, gastric, or esophageal cancers.⁴⁶ Additional studies also found no association between spironolactone use and cancers.⁴⁸ A more recent cohort study specifically among patients treated with spironolactone for acne also found no significant increased risk for breast cancer.⁴⁹

Combined oral contraceptives are associated with an increased risk for venous thromboembolisms, and there have been concerns that this risk may be greater in combined oral contraceptives that contain drospirenone.⁵⁰ Drospirenone is molecularly related to spironolactone, which has prompted the consideration of whether spironolactone use also conveys a risk for venous thromboembolism. Reassuringly, a retrospective study of claims data found that individuals on spironolactone were not more likely to develop a pulmonary embolism or a deep venous thrombosis than matched controls treated with tetracycline antibiotics, with a point estimate favoring decreased risk.⁵¹

Monitoring

Given that one of spironolactone’s mechanisms of action is aldosterone antagonism and thus the inhibition of potassium excretion, there have been concerns regarding risk for hyperkalemia. A retrospective study analyzing data from 2000 to 2014 found that, among 974 young women receiving spironolactone therapy, the rate of hyperkalemia was 0.72%, which is equivalent to the 0.76% baseline rate of hyperkalemia in the same population.⁵² Subsequent studies also have found that spironolactone does not appear to be associated with a meaningful risk for hyperkalemia among young healthy patients treated for acne.^38,53 These studies suggest that routine potassium monitoring is of low usefulness for healthy young women taking spironolactone for acne. The 2024 American Academy of Dermatology guidelines on the management of acne also state that potassium monitoring is not needed in healthy patients but that potassium testing should be considered for those with risk factors for hyperkalemia (eg, older age, medical comorbidities, medications).⁴⁰ Clinicians should still engage in shared decision making with patients to determine whether to check potassium. If potassium is to be monitored, it should be checked 1 to 2 weeks after spironolactone is started.^45,54

Since drospirenone also has aldosterone antagonistic properties,⁵⁵ there have been concerns about whether concomitant use of spironolactone and drospirenone-containing combined oral contraceptives might increase the risk for hyperkalemia.⁵⁶ However, a retrospective cohort study analyzing data from more than 1 million women found that drospirenone is not any more likely than levonorgestrel to cause hyperkalemia and that there is no interaction between drospirenone and spironolactone for hyperkalemia.⁵⁷ A subsequent prospective study of 27 women treated with combined oral contraceptives containing ethinyl estradiol/drospirenone and spironolactone also did not find any significant elevations in potassium.⁵⁸ Data from these studies suggest that spironolactone can safely be co-administered with drospirenone-containing combined oral contraceptives.

Reproductive Risks

Despite its utility in treating acne, spironolactone should not be used during pregnancy, and appropriate pregnancy prevention is recommended. Spironolactone crosses the placenta, and some animal studies have shown feminization of male fetuses.⁵⁹ While human data are limited to a few case reports that did not demonstrate an association of major malformations,⁶⁰ it generally is recommended to avoid spironolactone during pregnancy. Small studies have found that spironolactone has minimal transfer to breastmilk and is not associated with adverse effects in breastfed infants.^61-63 Accordingly, the World Health Organization considers spironolactone to be compatible with breastfeeding.⁶⁴ Notably, spironolactone may be associated with lactation suppression^65,66; therefore, it may be best if lactating patients ensure that their milk production is established prior to starting spironolactone and to increase their water intake to offset the diuretic effects.

Spironolactone also can result in gynecomastia in men and therefore typically is not prescribed for the treatment of acne in this population in oral form¹⁰; however, topical antiandrogens such as clascoterone can be used in both women and men with acne.⁶⁷

Conclusion

Spironolactone is a well-tolerated and effective treatment for women with acne, both in adult and adolescent populations. It is a potentially underutilized alternative to oral antibiotics. Spironolactone also is affordable, fully covered without any requirements in almost 90% of states under Medicaid and with a monthly cost of only $4.00 when obtained through major retailers in the United States, making it an optimal long-term treatment option for many patients.^52,68 We recommend a starting dose of 100 mg/d, which can be increased to 150 mg/d to 200 mg/d if needed for better acne control or decreased if adverse effects occur or acne clears. Potassium monitoring is of low usefulness in young healthy women, and studies have not identified an association between spironolactone use and increased risk for cancer.

Spironolactone is increasingly used off label for acne treatment and is now being prescribed for women with acne at a frequency similar to oral antibiotics.^1,2 In this article, we provide an overview of spironolactone use for acne treatment and discuss recent clinical trials and practical strategies for patient selection, dosing, adverse effect management, and monitoring (Table).

History and Mechanism of Action

Because sebaceous gland activity is an important component of acne pathogenesis and is regulated by androgens,³ there has long been interest in identifying treatment strategies that can target the role of hormones in activating the sebaceous gland. In the 1980s, it became apparent that spironolactone, originally developed as a potassium-sparing diuretic, also might possess antiandrogenic properties that could be useful in the treatment of acne.⁴ Spironolactone has been found to decrease testosterone production, inhibit testosterone and dihydrotestosterone binding to androgen receptors,^5-8 and block 5α-reductase receptors of the sebaceous glands of skin.⁹

In 1984, Goodfellow et al¹⁰ conducted a trial in which 36 male and female patients with severe acne were randomized to placebo or spironolactone doses ranging from 50 to 200 mg/d. They found that spironolactone resulted in dose-dependent reductions of sebum production as well as improvement in patient- and clinician-reported assessments of acne. In 1986, another placebo-controlled crossover trial by Muhlemann et al¹¹ provided further support for the effectiveness of spironolactone for acne. This trial randomized 21 women to placebo or spironolactone 200 mg/d and found that spironolactone was associated with statistically significant (P<.001) improvements in acne lesion counts.

Recent Observational Studies and Trials

Following these early trials, several large case series have been published describing the successful use of spironolactone for acne, including a 2020 retrospective case series from the Mayo Clinic describing 395 patients.¹² The investigators found that almost 66% of patients had a complete response and almost 85% had a complete response or a partial response greater than 50%. They also found that the median time to initial response and maximal response were 3 and 5 months, respectively, and that efficacy was observed across acne subtypes, including for nodulocystic acne.¹² In addition, a 2021 case series describing 403 patients treated with spironolactone found that approximately 80% had reduction or complete clearance of acne, with improvements observed for both facial and truncal acne. In this cohort, doses of 100 to 150 mg/d typically were the most successful.¹³ A case series of 80 adolescent females also highlighted the efficacy of spironolactone in younger populations.¹⁴

Adding to these observational data, the multicenter, phase 3, double-blind Spironolactone for Adult Female Acne (SAFA) trial included 410 women (mean age, 29.2 years) who were randomized to receive either placebo or intervention (spironolactone 50 mg/d until week 6 and 100 mg/d until week 24).¹⁵ At 24 weeks, greater improvement in quality of life and participant self-assessed improvement were observed in the spironolactone group. In addition, at 12 weeks, rates of success were higher in the spironolactone group using the Investigator Global Assessment score (adjusted odds ratio 5.18 [95% CI, 2.18- 12.28]). Those randomized to receive spironolactone also had lower rates of oral antibiotic use at 52 weeks than the placebo group did (5.8% vs 13.5%, respectively).

In the SAFA trial, spironolactone was well tolerated; the most common adverse effects relative to placebo were lightheadedness (19% for spironolactone vs 12% for placebo) and headache (20% for spironolactone vs 12% for placebo). Notably, more than 95% of patients were able to increase from 50 mg/d to 100 mg/d at week 6, with greater than 90% tolerating 100 mg/d. As observational data suggest that spironolactone takes 3 to 5 months to reach peak efficacy, these findings provide further support that starting at a dose of at least 100 mg/d is likely optimal for most patients.¹⁶

A Potential Alternative to Oral Antibiotics

Oral antibiotics such as tetracyclines have long played a central role in the treatment of acne and remain a first-line treatment option.¹⁷ In addition, many of these antibiotic courses exceed 6 months in duration.¹ In fact, dermatologists prescribe more antibiotics per capita than any other specialty^1,18-20; however, this can be associated with the development of antibiotic resistance,^21,22 as well as other antibiotic-associated complications, including inflammatory bowel disease,²³ pharyngitis,²⁴Clostridium difficile infections, and cancer.^25-29

In addition to these concerns, many patients may prefer nonantibiotic alternatives to oral antibiotics, with more than 75% preferring a nonantibiotic option if available. For female patients with acne, antiandrogens such as spironolactone have been suggested as a potential alternative.³⁰ A 10-year retrospective study of female patients with acne found that those who had ever received hormonal therapy (ie, spironolactone or a combined oral contraceptive) received fewer cumulative days of oral antibiotics than those who did not (226 days vs 302 days, respectively).³¹ In addition, while oral antibiotics were the most common initial therapy prescribed for patients, as they progressed through their treatment course, more patients ended up on hormonal therapy than oral antibiotics. This study suggests that hormonal therapy such as spironolactone could represent an alternative to the use of systemic antibiotics.³¹

Further supporting the role of spironolactone as an alternative to oral antibiotics, a 2018 analysis of claims data found that spironolactone may have similar effectiveness to oral antibiotics for the treatment of acne.32 After adjusting for age and topical retinoid and oral contraceptive use, this study found that there was no significant difference in the odds of being prescribed a different systemic treatment within 1 year (ie, treatment failure) among those starting spironolactone vs those starting oral tetracycline-class antibiotics as their initial therapy for acne.

A multicenter, randomized, double-blind trial (Female Acne Spironolactone vs doxyCycline Efficacy [FASCE]) also evaluated the comparative effectiveness of doxycycline 100 mg/d for 3 months followed by an oral placebo for 3 months vs spironolactone 150 mg/d for 6 months among 133 adult women with acne. This study found that spironolactone had statistically significantly greater rates of Investigator Global Assessment treatment success after 6 months (odds ratio 2.87 [95% CI, 1.38-5.99; P=.007]).³³ Since spironolactone historically has been prescribed less often than oral antibiotics for women with acne, these findings support spironolactone as an underutilized treatment alternative. The ongoing Spironolactone versus Doxycycline for Acne: A Comparative Effectiveness, Noninferiority Evaluation trial—a 16-week, blinded trial comparing 100 mg/d doses of both drugs—should provide additional evidence regarding the relative role of spironolactone and oral antibiotics in the management of acne.³⁴

Ultimately, the decision to use spironolactone or other treatments such as oral antibiotics should be based on shared decision making between clinician and patient. Spironolactone has a relatively slow onset of efficacy, and other options such as oral antibiotics might be preferred by those looking for more immediate results; however, as women with acne often have activity that persists into adulthood, spironolactone might be preferable as a long-term maintenance therapy to avoid complications of prolonged antibiotic use.³⁵ Comorbidities also will influence the optimal choice of therapy (eg, spironolactone might be preferred in someone with inflammatory bowel disease, and oral antibiotics might be preferred in someone with orthostatic hypotension).

Patient Selection

Acne occurring along the lower face or jawline in adult women sometimes is referred to as hormonal acne, but this dogma is not particularly evidence based. An observational study of 374 patients found that almost 90% of adult women had acne involving multiple facial zones with a spectrum of facial acne severity similar to that in adolescents.³⁶ Only a small subset of these patients (11.2%) had acne localized solely to the mandibular area. In addition, acne along the lower face is not predictive of hyperandrogenism (eg, polycystic ovary syndrome).³⁷ Antiandrogen therapies such as spironolactone and clascoterone are effective in both men and women with acne^10,38 and in adolescents and adults, suggesting that hormones play a fundamental role in all acne and that addressing this mechanism can be useful broadly. Therefore, hormonal therapies such as spironolactone should not be restricted to only adult women with acne along the lower face.

While spironolactone can be effective for acne treatment in any age group, it may be most effective for adult women with acne. In the SAFA trial, prespecified subgroup analyses showed a statistically significant (P=.005) interaction term for age (categorized as <25 years and ≥25 years), which suggested that spironolactone might be a more effective treatment for women 25 years and older.¹⁵ In addition, subgroup analyses in the aforementioned 2018 analysis of claims data found that spironolactone was more effective relative to oral antibiotics in adults vs adolescents.³² Despite these limitations, several case series have highlighted that spironolactone is effective among adolescent populations with acne. A case series of spironolactone use in 73 patients aged 19 years or younger found that 68% of patients demonstrated resolution or improvement in their acne after spironolactone treatment.³⁹ Another case series among 80 adolescent females reported 80% of patients experiencing improvement of their acne.¹⁴

For those with more severe acne, spironolactone can be combined with other complementary treatment approaches such as topicals, oral antibiotics, or procedural modalities.⁴⁰

Dosing

We recommend starting spironolactone at a dose of 100 mg/d (the patient can take 50 mg/d for 1 week, then increase to 100 mg/d if there are no adverse effects at the lower dose). In the 1984 trial by Goodfellow et al,¹⁰ participants were randomized to doses of 50 mg/d, 100 mg/d, 150 mg/d, and 200 mg/d. In this trial, efficacy assessed by objective and subjective outcomes did not plateau until doses of 100 mg/d to 150 mg/d. In addition, a case series of 403 patients found that the most successful dosage of spironolactone generally was 100 mg/d or higher.¹³ Most of the patients who were started at this dosage either stayed at this level or escalated, whereas patients who started at lower dosages (25-75 mg/d) frequently increased their dosage over time. The SAFA trial also highlighted that most patients can tolerate a spironolactone dose of 100 mg/d.¹⁵ For specific populations, such as patients with polycystic ovary syndrome, a higher dose (mean dosage of 143 mg/d) may be required for efficacy.⁴¹ Given the slow onset of efficacy, typically taking 3 to 5 months, and the low rate of adverse effects, we believe the optimal starting dose is 100 mg/s to 150 mg/d. If adverse effects occur or lesions clear, then the dosage may be reduced.

Adverse Effects

Spironolactone generally is well tolerated; in the SAFA and FASCE trials, fewer than 1% of participants discontinued due to adverse effects.^15,33 Rates of discontinuation due to adverse effects typically have been less than 5% in case series of patients treated in routine clinical practice.^12-14

Because spironolactone is a diuretic and antihypertensive, the most common adverse effects are related to these characteristics. In the SAFA trial, dizziness, lightheadedness, and vertigo were reported more commonly in the spironolactone group than in the placebo group (19% vs 12%, respectively). Similarly, headaches also were reported more frequently in the spironolactone group than in the placebo group (20% vs 12%, respectively).¹⁵ One case series found that, among the 267 patients on spironolactone whose blood pressure was monitored, the mean reduction in systolic blood pressure was 3.5 mm Hg and the mean reduction in diastolic blood pressure was 0.9 mm Hg.¹³ For those with baseline orthostasis or in those who experience adverse effects related to hypotension, reducing the dose often can be helpful. Of note, while doses of 100 mg/d to 150 mg/d often are the most effective, randomized trials have found that spironolactone still can be effective for acne at doses as low as 25 mg/d to 50 mg/d.^10,38

Menstrual irregularities are another commonly cited adverse effect of spironolactone. While a systematic review found that 15% to 30% of patients treated with spironolactone experience menstrual irregularities, it has been difficult to evaluate whether this is due to the medication or other comorbidities, such as polycystic ovary syndrome.⁴² Notably, in the SAFA trial, rates of menstrual irregularities were equivalent between the spironolactone and placebo groups at a dose of 100 mg/d (32% vs 35%, respectively).¹⁵ In contrast, in the FASCE trial, menstrual irregularities were more commonly reported at a dose of 150 mg/d.³³ These findings are consistent with observational data suggesting that menstrual irregularities are much more common at spironolactone doses greater than 100 mg/d.⁴² Additionally, some evidence supports that for some patients these menstrual irregularities may resolve within 2 to 3 months of continued treatment.⁴³ It has been noted in several studies that menstrual irregularities are less likely to occur in patients who are using combined oral contraceptives; therefore, for patients who are amenable and have no contraindications, combined oral contraceptives can be considered to prevent or address menstrual irregularities.^13,42,44

More generally, combined oral contraceptives can be an excellent combination with spironolactone, as they have complementary characteristics. Spironolactone primarily blocks the effects of androgens, while combined oral contraceptives predominantly block the production of androgens. Whereas spironolactone typically causes hypotension and menstrual irregularities, combined oral contraceptives cause hypertension and help to regulate the menstrual cycle.

Spironolactone carries an official US Food and Drug Administration warning regarding possible tumorigenicity that is based on animal studies that used up to 150 times the normal dose of spironolactone used in humans⁴⁵; however, observational studies in humans have not identified such an association when spironolactone is used in normal clinical settings. A systematic review and metanalysis in 2022 reviewed data from a total population of more than 4 million individuals and found that there was no statistically significant association between spironolactone use and the risk for breast, ovarian, bladder, kidney, gastric, or esophageal cancers.⁴⁶ Additional studies also found no association between spironolactone use and cancers.⁴⁸ A more recent cohort study specifically among patients treated with spironolactone for acne also found no significant increased risk for breast cancer.⁴⁹

Combined oral contraceptives are associated with an increased risk for venous thromboembolisms, and there have been concerns that this risk may be greater in combined oral contraceptives that contain drospirenone.⁵⁰ Drospirenone is molecularly related to spironolactone, which has prompted the consideration of whether spironolactone use also conveys a risk for venous thromboembolism. Reassuringly, a retrospective study of claims data found that individuals on spironolactone were not more likely to develop a pulmonary embolism or a deep venous thrombosis than matched controls treated with tetracycline antibiotics, with a point estimate favoring decreased risk.⁵¹

Monitoring

Given that one of spironolactone’s mechanisms of action is aldosterone antagonism and thus the inhibition of potassium excretion, there have been concerns regarding risk for hyperkalemia. A retrospective study analyzing data from 2000 to 2014 found that, among 974 young women receiving spironolactone therapy, the rate of hyperkalemia was 0.72%, which is equivalent to the 0.76% baseline rate of hyperkalemia in the same population.⁵² Subsequent studies also have found that spironolactone does not appear to be associated with a meaningful risk for hyperkalemia among young healthy patients treated for acne.^38,53 These studies suggest that routine potassium monitoring is of low usefulness for healthy young women taking spironolactone for acne. The 2024 American Academy of Dermatology guidelines on the management of acne also state that potassium monitoring is not needed in healthy patients but that potassium testing should be considered for those with risk factors for hyperkalemia (eg, older age, medical comorbidities, medications).⁴⁰ Clinicians should still engage in shared decision making with patients to determine whether to check potassium. If potassium is to be monitored, it should be checked 1 to 2 weeks after spironolactone is started.^45,54

Since drospirenone also has aldosterone antagonistic properties,⁵⁵ there have been concerns about whether concomitant use of spironolactone and drospirenone-containing combined oral contraceptives might increase the risk for hyperkalemia.⁵⁶ However, a retrospective cohort study analyzing data from more than 1 million women found that drospirenone is not any more likely than levonorgestrel to cause hyperkalemia and that there is no interaction between drospirenone and spironolactone for hyperkalemia.⁵⁷ A subsequent prospective study of 27 women treated with combined oral contraceptives containing ethinyl estradiol/drospirenone and spironolactone also did not find any significant elevations in potassium.⁵⁸ Data from these studies suggest that spironolactone can safely be co-administered with drospirenone-containing combined oral contraceptives.

Reproductive Risks

Despite its utility in treating acne, spironolactone should not be used during pregnancy, and appropriate pregnancy prevention is recommended. Spironolactone crosses the placenta, and some animal studies have shown feminization of male fetuses.⁵⁹ While human data are limited to a few case reports that did not demonstrate an association of major malformations,⁶⁰ it generally is recommended to avoid spironolactone during pregnancy. Small studies have found that spironolactone has minimal transfer to breastmilk and is not associated with adverse effects in breastfed infants.^61-63 Accordingly, the World Health Organization considers spironolactone to be compatible with breastfeeding.⁶⁴ Notably, spironolactone may be associated with lactation suppression^65,66; therefore, it may be best if lactating patients ensure that their milk production is established prior to starting spironolactone and to increase their water intake to offset the diuretic effects.

Spironolactone also can result in gynecomastia in men and therefore typically is not prescribed for the treatment of acne in this population in oral form¹⁰; however, topical antiandrogens such as clascoterone can be used in both women and men with acne.⁶⁷

Conclusion

Spironolactone is a well-tolerated and effective treatment for women with acne, both in adult and adolescent populations. It is a potentially underutilized alternative to oral antibiotics. Spironolactone also is affordable, fully covered without any requirements in almost 90% of states under Medicaid and with a monthly cost of only $4.00 when obtained through major retailers in the United States, making it an optimal long-term treatment option for many patients.^52,68 We recommend a starting dose of 100 mg/d, which can be increased to 150 mg/d to 200 mg/d if needed for better acne control or decreased if adverse effects occur or acne clears. Potassium monitoring is of low usefulness in young healthy women, and studies have not identified an association between spironolactone use and increased risk for cancer.

Spironolactone is increasingly used off label for acne treatment and is now being prescribed for women with acne at a frequency similar to oral antibiotics.^1,2 In this article, we provide an overview of spironolactone use for acne treatment and discuss recent clinical trials and practical strategies for patient selection, dosing, adverse effect management, and monitoring (Table).

History and Mechanism of Action

Because sebaceous gland activity is an important component of acne pathogenesis and is regulated by androgens,³ there has long been interest in identifying treatment strategies that can target the role of hormones in activating the sebaceous gland. In the 1980s, it became apparent that spironolactone, originally developed as a potassium-sparing diuretic, also might possess antiandrogenic properties that could be useful in the treatment of acne.⁴ Spironolactone has been found to decrease testosterone production, inhibit testosterone and dihydrotestosterone binding to androgen receptors,^5-8 and block 5α-reductase receptors of the sebaceous glands of skin.⁹

In 1984, Goodfellow et al¹⁰ conducted a trial in which 36 male and female patients with severe acne were randomized to placebo or spironolactone doses ranging from 50 to 200 mg/d. They found that spironolactone resulted in dose-dependent reductions of sebum production as well as improvement in patient- and clinician-reported assessments of acne. In 1986, another placebo-controlled crossover trial by Muhlemann et al¹¹ provided further support for the effectiveness of spironolactone for acne. This trial randomized 21 women to placebo or spironolactone 200 mg/d and found that spironolactone was associated with statistically significant (P<.001) improvements in acne lesion counts.

Recent Observational Studies and Trials

Following these early trials, several large case series have been published describing the successful use of spironolactone for acne, including a 2020 retrospective case series from the Mayo Clinic describing 395 patients.¹² The investigators found that almost 66% of patients had a complete response and almost 85% had a complete response or a partial response greater than 50%. They also found that the median time to initial response and maximal response were 3 and 5 months, respectively, and that efficacy was observed across acne subtypes, including for nodulocystic acne.¹² In addition, a 2021 case series describing 403 patients treated with spironolactone found that approximately 80% had reduction or complete clearance of acne, with improvements observed for both facial and truncal acne. In this cohort, doses of 100 to 150 mg/d typically were the most successful.¹³ A case series of 80 adolescent females also highlighted the efficacy of spironolactone in younger populations.¹⁴

Adding to these observational data, the multicenter, phase 3, double-blind Spironolactone for Adult Female Acne (SAFA) trial included 410 women (mean age, 29.2 years) who were randomized to receive either placebo or intervention (spironolactone 50 mg/d until week 6 and 100 mg/d until week 24).¹⁵ At 24 weeks, greater improvement in quality of life and participant self-assessed improvement were observed in the spironolactone group. In addition, at 12 weeks, rates of success were higher in the spironolactone group using the Investigator Global Assessment score (adjusted odds ratio 5.18 [95% CI, 2.18- 12.28]). Those randomized to receive spironolactone also had lower rates of oral antibiotic use at 52 weeks than the placebo group did (5.8% vs 13.5%, respectively).

In the SAFA trial, spironolactone was well tolerated; the most common adverse effects relative to placebo were lightheadedness (19% for spironolactone vs 12% for placebo) and headache (20% for spironolactone vs 12% for placebo). Notably, more than 95% of patients were able to increase from 50 mg/d to 100 mg/d at week 6, with greater than 90% tolerating 100 mg/d. As observational data suggest that spironolactone takes 3 to 5 months to reach peak efficacy, these findings provide further support that starting at a dose of at least 100 mg/d is likely optimal for most patients.¹⁶

A Potential Alternative to Oral Antibiotics

Oral antibiotics such as tetracyclines have long played a central role in the treatment of acne and remain a first-line treatment option.¹⁷ In addition, many of these antibiotic courses exceed 6 months in duration.¹ In fact, dermatologists prescribe more antibiotics per capita than any other specialty^1,18-20; however, this can be associated with the development of antibiotic resistance,^21,22 as well as other antibiotic-associated complications, including inflammatory bowel disease,²³ pharyngitis,²⁴Clostridium difficile infections, and cancer.^25-29

In addition to these concerns, many patients may prefer nonantibiotic alternatives to oral antibiotics, with more than 75% preferring a nonantibiotic option if available. For female patients with acne, antiandrogens such as spironolactone have been suggested as a potential alternative.³⁰ A 10-year retrospective study of female patients with acne found that those who had ever received hormonal therapy (ie, spironolactone or a combined oral contraceptive) received fewer cumulative days of oral antibiotics than those who did not (226 days vs 302 days, respectively).³¹ In addition, while oral antibiotics were the most common initial therapy prescribed for patients, as they progressed through their treatment course, more patients ended up on hormonal therapy than oral antibiotics. This study suggests that hormonal therapy such as spironolactone could represent an alternative to the use of systemic antibiotics.³¹

Further supporting the role of spironolactone as an alternative to oral antibiotics, a 2018 analysis of claims data found that spironolactone may have similar effectiveness to oral antibiotics for the treatment of acne.32 After adjusting for age and topical retinoid and oral contraceptive use, this study found that there was no significant difference in the odds of being prescribed a different systemic treatment within 1 year (ie, treatment failure) among those starting spironolactone vs those starting oral tetracycline-class antibiotics as their initial therapy for acne.

A multicenter, randomized, double-blind trial (Female Acne Spironolactone vs doxyCycline Efficacy [FASCE]) also evaluated the comparative effectiveness of doxycycline 100 mg/d for 3 months followed by an oral placebo for 3 months vs spironolactone 150 mg/d for 6 months among 133 adult women with acne. This study found that spironolactone had statistically significantly greater rates of Investigator Global Assessment treatment success after 6 months (odds ratio 2.87 [95% CI, 1.38-5.99; P=.007]).³³ Since spironolactone historically has been prescribed less often than oral antibiotics for women with acne, these findings support spironolactone as an underutilized treatment alternative. The ongoing Spironolactone versus Doxycycline for Acne: A Comparative Effectiveness, Noninferiority Evaluation trial—a 16-week, blinded trial comparing 100 mg/d doses of both drugs—should provide additional evidence regarding the relative role of spironolactone and oral antibiotics in the management of acne.³⁴

Ultimately, the decision to use spironolactone or other treatments such as oral antibiotics should be based on shared decision making between clinician and patient. Spironolactone has a relatively slow onset of efficacy, and other options such as oral antibiotics might be preferred by those looking for more immediate results; however, as women with acne often have activity that persists into adulthood, spironolactone might be preferable as a long-term maintenance therapy to avoid complications of prolonged antibiotic use.³⁵ Comorbidities also will influence the optimal choice of therapy (eg, spironolactone might be preferred in someone with inflammatory bowel disease, and oral antibiotics might be preferred in someone with orthostatic hypotension).

Patient Selection

Acne occurring along the lower face or jawline in adult women sometimes is referred to as hormonal acne, but this dogma is not particularly evidence based. An observational study of 374 patients found that almost 90% of adult women had acne involving multiple facial zones with a spectrum of facial acne severity similar to that in adolescents.³⁶ Only a small subset of these patients (11.2%) had acne localized solely to the mandibular area. In addition, acne along the lower face is not predictive of hyperandrogenism (eg, polycystic ovary syndrome).³⁷ Antiandrogen therapies such as spironolactone and clascoterone are effective in both men and women with acne^10,38 and in adolescents and adults, suggesting that hormones play a fundamental role in all acne and that addressing this mechanism can be useful broadly. Therefore, hormonal therapies such as spironolactone should not be restricted to only adult women with acne along the lower face.

While spironolactone can be effective for acne treatment in any age group, it may be most effective for adult women with acne. In the SAFA trial, prespecified subgroup analyses showed a statistically significant (P=.005) interaction term for age (categorized as <25 years and ≥25 years), which suggested that spironolactone might be a more effective treatment for women 25 years and older.¹⁵ In addition, subgroup analyses in the aforementioned 2018 analysis of claims data found that spironolactone was more effective relative to oral antibiotics in adults vs adolescents.³² Despite these limitations, several case series have highlighted that spironolactone is effective among adolescent populations with acne. A case series of spironolactone use in 73 patients aged 19 years or younger found that 68% of patients demonstrated resolution or improvement in their acne after spironolactone treatment.³⁹ Another case series among 80 adolescent females reported 80% of patients experiencing improvement of their acne.¹⁴

For those with more severe acne, spironolactone can be combined with other complementary treatment approaches such as topicals, oral antibiotics, or procedural modalities.⁴⁰

Dosing

We recommend starting spironolactone at a dose of 100 mg/d (the patient can take 50 mg/d for 1 week, then increase to 100 mg/d if there are no adverse effects at the lower dose). In the 1984 trial by Goodfellow et al,¹⁰ participants were randomized to doses of 50 mg/d, 100 mg/d, 150 mg/d, and 200 mg/d. In this trial, efficacy assessed by objective and subjective outcomes did not plateau until doses of 100 mg/d to 150 mg/d. In addition, a case series of 403 patients found that the most successful dosage of spironolactone generally was 100 mg/d or higher.¹³ Most of the patients who were started at this dosage either stayed at this level or escalated, whereas patients who started at lower dosages (25-75 mg/d) frequently increased their dosage over time. The SAFA trial also highlighted that most patients can tolerate a spironolactone dose of 100 mg/d.¹⁵ For specific populations, such as patients with polycystic ovary syndrome, a higher dose (mean dosage of 143 mg/d) may be required for efficacy.⁴¹ Given the slow onset of efficacy, typically taking 3 to 5 months, and the low rate of adverse effects, we believe the optimal starting dose is 100 mg/s to 150 mg/d. If adverse effects occur or lesions clear, then the dosage may be reduced.

Adverse Effects

Spironolactone generally is well tolerated; in the SAFA and FASCE trials, fewer than 1% of participants discontinued due to adverse effects.^15,33 Rates of discontinuation due to adverse effects typically have been less than 5% in case series of patients treated in routine clinical practice.^12-14

Because spironolactone is a diuretic and antihypertensive, the most common adverse effects are related to these characteristics. In the SAFA trial, dizziness, lightheadedness, and vertigo were reported more commonly in the spironolactone group than in the placebo group (19% vs 12%, respectively). Similarly, headaches also were reported more frequently in the spironolactone group than in the placebo group (20% vs 12%, respectively).¹⁵ One case series found that, among the 267 patients on spironolactone whose blood pressure was monitored, the mean reduction in systolic blood pressure was 3.5 mm Hg and the mean reduction in diastolic blood pressure was 0.9 mm Hg.¹³ For those with baseline orthostasis or in those who experience adverse effects related to hypotension, reducing the dose often can be helpful. Of note, while doses of 100 mg/d to 150 mg/d often are the most effective, randomized trials have found that spironolactone still can be effective for acne at doses as low as 25 mg/d to 50 mg/d.^10,38

Menstrual irregularities are another commonly cited adverse effect of spironolactone. While a systematic review found that 15% to 30% of patients treated with spironolactone experience menstrual irregularities, it has been difficult to evaluate whether this is due to the medication or other comorbidities, such as polycystic ovary syndrome.⁴² Notably, in the SAFA trial, rates of menstrual irregularities were equivalent between the spironolactone and placebo groups at a dose of 100 mg/d (32% vs 35%, respectively).¹⁵ In contrast, in the FASCE trial, menstrual irregularities were more commonly reported at a dose of 150 mg/d.³³ These findings are consistent with observational data suggesting that menstrual irregularities are much more common at spironolactone doses greater than 100 mg/d.⁴² Additionally, some evidence supports that for some patients these menstrual irregularities may resolve within 2 to 3 months of continued treatment.⁴³ It has been noted in several studies that menstrual irregularities are less likely to occur in patients who are using combined oral contraceptives; therefore, for patients who are amenable and have no contraindications, combined oral contraceptives can be considered to prevent or address menstrual irregularities.^13,42,44

More generally, combined oral contraceptives can be an excellent combination with spironolactone, as they have complementary characteristics. Spironolactone primarily blocks the effects of androgens, while combined oral contraceptives predominantly block the production of androgens. Whereas spironolactone typically causes hypotension and menstrual irregularities, combined oral contraceptives cause hypertension and help to regulate the menstrual cycle.

Spironolactone carries an official US Food and Drug Administration warning regarding possible tumorigenicity that is based on animal studies that used up to 150 times the normal dose of spironolactone used in humans⁴⁵; however, observational studies in humans have not identified such an association when spironolactone is used in normal clinical settings. A systematic review and metanalysis in 2022 reviewed data from a total population of more than 4 million individuals and found that there was no statistically significant association between spironolactone use and the risk for breast, ovarian, bladder, kidney, gastric, or esophageal cancers.⁴⁶ Additional studies also found no association between spironolactone use and cancers.⁴⁸ A more recent cohort study specifically among patients treated with spironolactone for acne also found no significant increased risk for breast cancer.⁴⁹

Combined oral contraceptives are associated with an increased risk for venous thromboembolisms, and there have been concerns that this risk may be greater in combined oral contraceptives that contain drospirenone.⁵⁰ Drospirenone is molecularly related to spironolactone, which has prompted the consideration of whether spironolactone use also conveys a risk for venous thromboembolism. Reassuringly, a retrospective study of claims data found that individuals on spironolactone were not more likely to develop a pulmonary embolism or a deep venous thrombosis than matched controls treated with tetracycline antibiotics, with a point estimate favoring decreased risk.⁵¹

Monitoring

Given that one of spironolactone’s mechanisms of action is aldosterone antagonism and thus the inhibition of potassium excretion, there have been concerns regarding risk for hyperkalemia. A retrospective study analyzing data from 2000 to 2014 found that, among 974 young women receiving spironolactone therapy, the rate of hyperkalemia was 0.72%, which is equivalent to the 0.76% baseline rate of hyperkalemia in the same population.⁵² Subsequent studies also have found that spironolactone does not appear to be associated with a meaningful risk for hyperkalemia among young healthy patients treated for acne.^38,53 These studies suggest that routine potassium monitoring is of low usefulness for healthy young women taking spironolactone for acne. The 2024 American Academy of Dermatology guidelines on the management of acne also state that potassium monitoring is not needed in healthy patients but that potassium testing should be considered for those with risk factors for hyperkalemia (eg, older age, medical comorbidities, medications).⁴⁰ Clinicians should still engage in shared decision making with patients to determine whether to check potassium. If potassium is to be monitored, it should be checked 1 to 2 weeks after spironolactone is started.^45,54

Since drospirenone also has aldosterone antagonistic properties,⁵⁵ there have been concerns about whether concomitant use of spironolactone and drospirenone-containing combined oral contraceptives might increase the risk for hyperkalemia.⁵⁶ However, a retrospective cohort study analyzing data from more than 1 million women found that drospirenone is not any more likely than levonorgestrel to cause hyperkalemia and that there is no interaction between drospirenone and spironolactone for hyperkalemia.⁵⁷ A subsequent prospective study of 27 women treated with combined oral contraceptives containing ethinyl estradiol/drospirenone and spironolactone also did not find any significant elevations in potassium.⁵⁸ Data from these studies suggest that spironolactone can safely be co-administered with drospirenone-containing combined oral contraceptives.

Reproductive Risks

Despite its utility in treating acne, spironolactone should not be used during pregnancy, and appropriate pregnancy prevention is recommended. Spironolactone crosses the placenta, and some animal studies have shown feminization of male fetuses.⁵⁹ While human data are limited to a few case reports that did not demonstrate an association of major malformations,⁶⁰ it generally is recommended to avoid spironolactone during pregnancy. Small studies have found that spironolactone has minimal transfer to breastmilk and is not associated with adverse effects in breastfed infants.^61-63 Accordingly, the World Health Organization considers spironolactone to be compatible with breastfeeding.⁶⁴ Notably, spironolactone may be associated with lactation suppression^65,66; therefore, it may be best if lactating patients ensure that their milk production is established prior to starting spironolactone and to increase their water intake to offset the diuretic effects.

Spironolactone also can result in gynecomastia in men and therefore typically is not prescribed for the treatment of acne in this population in oral form¹⁰; however, topical antiandrogens such as clascoterone can be used in both women and men with acne.⁶⁷

Conclusion

Spironolactone is a well-tolerated and effective treatment for women with acne, both in adult and adolescent populations. It is a potentially underutilized alternative to oral antibiotics. Spironolactone also is affordable, fully covered without any requirements in almost 90% of states under Medicaid and with a monthly cost of only $4.00 when obtained through major retailers in the United States, making it an optimal long-term treatment option for many patients.^52,68 We recommend a starting dose of 100 mg/d, which can be increased to 150 mg/d to 200 mg/d if needed for better acne control or decreased if adverse effects occur or acne clears. Potassium monitoring is of low usefulness in young healthy women, and studies have not identified an association between spironolactone use and increased risk for cancer.

Rosacea is a chronic inflammatory skin condition affecting the central face—including the cheeks, nose, chin, and forehead—that causes considerable discomfort.¹ Its pathogenesis involves immune dysregulation, genetic predisposition, and microbial dysbiosis.² While immune and environmental factors are known triggers of rosacea, recent research highlights the roles of the gut and skin microbiomes in disease progression. While the skin microbiome interacts directly with the immune system to regulate inflammation and skin homeostasis, the gut microbiome also influences cutaneous inflammation, emphasizing the need to address both topical and internal microbiome imbalances.³ In this article, we review gut and skin microbial alterations in rosacea, focusing on the skin microbiome and including the gut-skin axis implications as well as therapeutic strategies aimed at microbiome balance to enhance patient outcomes.

Skin Microbiome Alterations in Rosacea

The human skin microbiome interacts with the immune system, and microbial imbalances have been shown to contribute to immune dysregulation. Several key microbial species have been identified as playing a large role in rosacea, including Demodex folliculorum, Staphylococcus epidermidis, Bacillus oleronius, and Cutibacterium acnes (Figure).

Demodex folliculorum is a microscopic mite is found in hair follicles and sebaceous glands. Patients with rosacea have higher densities of D folliculorum, which trigger follicular occlusion and immune activation.¹Bacillus oleronius be isolated from D folliculorum and can further activate toll-like receptor 2, leading to cytokine production and immune cell infiltration.^3,4 Increased propagation of this mite correlates with shifts in skin microbiome composition, demonstrating increased inflammatory microbial populations.³

Staphylococcus epidermidis normally is commensal but can become pathogenic (pathobiont) in rosacea due to disruptions in the skin microenvironment, where it can form biofilms and produce virulence factors, particularly in papulopustular rosacea.⁵

Bacillus oleronius has been isolated from D folliculorum mites and provokes inflammatory responses in patients with rosacea by triggering toll-like receptor 2 activation and cytokine secretion.⁶

Cutibacterium acnes commonly is associated with acne vulgaris. Its role in rosacea is unclear, but recent research suggests it may have a protective effect. A single-arm trial investigated the effects of minocycline on rosacea and found that treatment significantly reduced C acnes but increased microbial species diversity, improving inflammation.⁷ One longitudinal cohort study of 12 patients with rosacea found that C acnes levels were lower in those older than 60 years. Rosacea severity increased with age and correlated with a decline in C acnes, suggesting that it may confer some protective effect in rosacea.⁸ This finding is supported by studies that have shown a reduction in C acnes levels in patients with rosacea compared to controls.^4,8

Important mechanisms in rosacea include epidermal barrier dysfunction, transepidermal water loss, and decreased stratum corneum hydration, particularly in erythematotelangiectatic and papulopustular subtypes. The resulting alkaline skin pH contributes to barrier instability and heightened inflammation, permitting pathogenic bacteria to proliferate and disrupt skin microbial homeostasis.⁹ A recent study identified metabolic changes in the skin microbiome of patients with rosacea, showing that increased heme and hydrogen sulfide in rosacea skin microbiomes likely drive inflammation, while healthy skin microbiomes produce more anti-inflammatory adenosylcobalamin, thiazole, and L-isoleucine.¹ These findings highlight the link between microbial imbalances and inflammation in rosacea.

The Gut-Skin Axis in Rosacea

Gut microbiota play a critical role in managing systemic inflammation, and microbial dysbiosis in the intestine can influence the skin microbiome in rosacea. Patients with rosacea who have gastrointestinal conditions such as small intestinal bacterial overgrowth and Helicobacter pylori infection experience more severe rosacea symptoms.^3,10

Patients with rosacea have distinctive gut microbiota compositions, with an increased prevalence of proinflammatory bacterial species, potentially affecting the skin microbiome.^8,11 Systemic antibiotics have been shown to modulate the gut microbiome, indirectly influencing the skin microbiome.¹¹ A recent study demonstrated that doxycycline treatment in patients with rosacea altered skin microbial diversity, reducing C acnes while increasing Weissella confusa—highlighting the complicated relationship between systemic antibiotics and the gut-skin axis.⁸

Specific probiotics, such as Escherichia coli Nissle, when given orally shifted gut microbial balance to protective microbiota with increased Lactobacillus and Bifidobacteria species and decreased pathogenic bacteria. This improved rosacea symptoms, normalized immunoglobulin A levels, and suppressed cytokine interleukin 8 levels.¹⁰ Recent studies also suggest oral sarecycline, a narrow-spectrum antibiotic, may improve papulopustular rosacea symptoms through its anti-inflammatory effects while having minimal impact on gut microbiota diversity.^11,12

Gut-derived short-chain fatty acids, which are known to regulate immune function, also have been shown to influence the composition of skin microbiota, suggesting a direct link between gut dysbiosis and skin microbial imbalances. Notably, antibiotic and probiotic treatments targeting the gut microbiome (eg, rifaximin for small intestinal bacterial overgrowth) have been associated with improvements in rosacea symptoms, further underscoring the interconnectedness of the gut-skin axis.¹³ Understanding how gut-derived inflammation alters the skin microbiome may provide new therapeutic avenues for restoring microbial balance and reducing rosacea severity.

Immune Dysregulation and Inflammatory Pathways

Mechanisms of microbiome-driven inflammation via the innate immune system contribute to rosacea pathogenesis. Toll-like receptor 2 is upregulated in rosacea, producing increased peptides including cathelicidins.¹³ When abnormally processed, cathelicidins produce proinflammatory peptides and worsen rosacea symptoms such as erythema, telangiectasias, and neutrophilic infiltration by dysregulating the immune system and the skin barrier.⁶

Heightened levels of cytokines interleukin 8 and interferon α have been identified in patients with rosacea. These cytokines are involved in rosacea pathogenesis, including leukocyte recruitment, angiogenesis, and tissue remodeling and further activate the inflammatory cascade.^8,14

Mendelian randomization studies have provided confirmation of a causal link between skin microbiota alterations and inflammatory skin diseases including rosacea.² Specific alterations in bacteria such as Cutibacterium and Staphylococcus microbial species have been associated with shifts in host immune gene expression, potentially predisposing individuals to abnormal immune activation and inflammation.^2,8 These studies show the potential of leveraging precision medicine to design therapies that target pathways that improve microbial imbalances seen in rosacea.

Environmental and Lifestyle Factors Affecting the Skin Microbiome

Individuals with rosacea often have increased sensitivity to environmental and lifestyle stressors such as high temperatures, UV exposure, and sugar and alcohol consumption. These factors influence the composition of the skin microbiome and potentially contribute to rosacea development and disease exacerbation; therefore, trigger avoidance is an important way to manage rosacea.

High temperatures and UV exposure—Demodex activity increases in response to heat exposure and subsequently worsens rosacea symptoms, while exposure to UV radiation can change the composition of the skin microbiome by encouraging inflammatory responses such as oxidative stress reactions.⁴ This effect on the skin microbiome is driven partly by the increased presence of certain skin microbial species, such as S epidermidis, which secrete virulence factors at higher temperatures and further contribute to inflammation.^1,4

High-glycemic diet and alcohol consumption—High-glycemic diets and alcohol intake have been associated with gut dysbiosis and increased disease severity in rosacea. Processed foods and high sugar consumption can promote proinflammatory reactions that cause skin dysbiosis and exacerbate symptoms.¹⁵ Increased consumption of anti-inflammatory foods or consumption of probiotics and prebiotics can improve microbial balance.

Therapeutic Implications

The influence of the skin and gut microbiome on rosacea have been well described in the medical literature; therefore, many therapeutic strategies aim to address microbiome dysbiosis, including the use of antibiotics, anthelmintics, and a range of topical agents as well as probiotics, microbiome-friendly skin care products, and dietary modifications.

Antibiotics and Anthelmintics—Topical and oral antibiotics such as metronidazole and doxycycline reduce microbial load and inflammation.^5,7,8 Ivermectin, an anthelmintic, has demonstrated efficacy in decreasing Demodex colonization and associated inflammation by interfering with mite survival and reducing bacterial interactions on the skin.⁵ Recent literature also has explored next-generation antibiotics that disrupt biofilm production by bacteria, which could positively affect outcomes while safeguarding antibiotic stewardship.¹⁵ Given its targeted antimicrobial activity and low propensity for microbial resistance, sarecycline represents a promising therapeutic option for managing rosacea symptoms with reduced risk for microbiome-related adverse events.^12,16

Probiotics and Skin Care Interventions—Probiotics, prebiotics, and postbiotics have emerged as promising approaches to improve rosacea outcomes. Topical probiotics have been shown to maintain skin microbiome homeostasis, reduce inflammation, and enhance epidermal barrier function, making them a promising adjunctive therapy for rosacea.^17,18 Physiological pH cleansers and moisturizers formulated with microbiome-friendly ingredients may reduce transepidermal water loss and improve skin hydration, which are critical in microbial equilibrium.⁹ Oral administration of E coli Nissle, Lactobacillus, and Bifidobacterium have shown potential in improving microbial balance and reducing disease severity.¹⁰

Other Topical Therapies—Azelaic acid and benzoyl peroxide can improve rosacea symptoms by decreasing inflammation and also may shift the skin microbiome.^19,20 Formulations of topical therapies, including microencapsulated benzoyl peroxide, show improved efficacy in targeting pathogenic bacteria while maintaining tolerability.¹⁹

Dietary Modifications—Avoiding triggers such as alcohol and high-glycemic foods can help reduce gut and skin dysbiosis.¹³ Polyphenol-rich foods and prebiotic fiber may promote beneficial gut and skin microbial composition and currently are being studied.¹³

Emerging Therapies—Long-pulsed alexandrite laser therapy has been shown to reduce facial erythema and modulate skin microbiota.²¹ Patients with treatment-resistant rosacea may benefit from advanced precision targeted antimicrobials.

The future of rosacea treatment may involve integrating established and emerging microbiome-targeted treatment strategies to improve short- and long-term patient outcomes in rosacea.

Conclusion

As our understanding of rosacea, its pathogenesis, and the role of the skin microbiome continues to grow, so does our ability to develop increasingly effective and well-tolerated treatments. Future research should focus on how changes to the skin microbiome can influence disease progression and treatment responses as well as potential therapies targeting the skin microbiome. Integrating precision treatments that restore microbial balance alongside more traditional therapies may improve outcomes by addressing both inflammation and epidermal barrier dysfunction. Additionally, strategies that support a healthy skin microbiome, such as microbiome-friendly skin care and topical probiotics, should be further explored to enhance long-term disease management. There remains a dearth of literature addressing how the skin microbiome of patients with rosacea can be optimized to maximize treatment, highlighting the need for more research into these interventions.

Rosacea is a chronic inflammatory skin condition affecting the central face—including the cheeks, nose, chin, and forehead—that causes considerable discomfort.¹ Its pathogenesis involves immune dysregulation, genetic predisposition, and microbial dysbiosis.² While immune and environmental factors are known triggers of rosacea, recent research highlights the roles of the gut and skin microbiomes in disease progression. While the skin microbiome interacts directly with the immune system to regulate inflammation and skin homeostasis, the gut microbiome also influences cutaneous inflammation, emphasizing the need to address both topical and internal microbiome imbalances.³ In this article, we review gut and skin microbial alterations in rosacea, focusing on the skin microbiome and including the gut-skin axis implications as well as therapeutic strategies aimed at microbiome balance to enhance patient outcomes.

Skin Microbiome Alterations in Rosacea

The human skin microbiome interacts with the immune system, and microbial imbalances have been shown to contribute to immune dysregulation. Several key microbial species have been identified as playing a large role in rosacea, including Demodex folliculorum, Staphylococcus epidermidis, Bacillus oleronius, and Cutibacterium acnes (Figure).

Demodex folliculorum is a microscopic mite is found in hair follicles and sebaceous glands. Patients with rosacea have higher densities of D folliculorum, which trigger follicular occlusion and immune activation.¹Bacillus oleronius be isolated from D folliculorum and can further activate toll-like receptor 2, leading to cytokine production and immune cell infiltration.^3,4 Increased propagation of this mite correlates with shifts in skin microbiome composition, demonstrating increased inflammatory microbial populations.³

Staphylococcus epidermidis normally is commensal but can become pathogenic (pathobiont) in rosacea due to disruptions in the skin microenvironment, where it can form biofilms and produce virulence factors, particularly in papulopustular rosacea.⁵

Bacillus oleronius has been isolated from D folliculorum mites and provokes inflammatory responses in patients with rosacea by triggering toll-like receptor 2 activation and cytokine secretion.⁶

Cutibacterium acnes commonly is associated with acne vulgaris. Its role in rosacea is unclear, but recent research suggests it may have a protective effect. A single-arm trial investigated the effects of minocycline on rosacea and found that treatment significantly reduced C acnes but increased microbial species diversity, improving inflammation.⁷ One longitudinal cohort study of 12 patients with rosacea found that C acnes levels were lower in those older than 60 years. Rosacea severity increased with age and correlated with a decline in C acnes, suggesting that it may confer some protective effect in rosacea.⁸ This finding is supported by studies that have shown a reduction in C acnes levels in patients with rosacea compared to controls.^4,8

Important mechanisms in rosacea include epidermal barrier dysfunction, transepidermal water loss, and decreased stratum corneum hydration, particularly in erythematotelangiectatic and papulopustular subtypes. The resulting alkaline skin pH contributes to barrier instability and heightened inflammation, permitting pathogenic bacteria to proliferate and disrupt skin microbial homeostasis.⁹ A recent study identified metabolic changes in the skin microbiome of patients with rosacea, showing that increased heme and hydrogen sulfide in rosacea skin microbiomes likely drive inflammation, while healthy skin microbiomes produce more anti-inflammatory adenosylcobalamin, thiazole, and L-isoleucine.¹ These findings highlight the link between microbial imbalances and inflammation in rosacea.

The Gut-Skin Axis in Rosacea

Gut microbiota play a critical role in managing systemic inflammation, and microbial dysbiosis in the intestine can influence the skin microbiome in rosacea. Patients with rosacea who have gastrointestinal conditions such as small intestinal bacterial overgrowth and Helicobacter pylori infection experience more severe rosacea symptoms.^3,10

Patients with rosacea have distinctive gut microbiota compositions, with an increased prevalence of proinflammatory bacterial species, potentially affecting the skin microbiome.^8,11 Systemic antibiotics have been shown to modulate the gut microbiome, indirectly influencing the skin microbiome.¹¹ A recent study demonstrated that doxycycline treatment in patients with rosacea altered skin microbial diversity, reducing C acnes while increasing Weissella confusa—highlighting the complicated relationship between systemic antibiotics and the gut-skin axis.⁸

Specific probiotics, such as Escherichia coli Nissle, when given orally shifted gut microbial balance to protective microbiota with increased Lactobacillus and Bifidobacteria species and decreased pathogenic bacteria. This improved rosacea symptoms, normalized immunoglobulin A levels, and suppressed cytokine interleukin 8 levels.¹⁰ Recent studies also suggest oral sarecycline, a narrow-spectrum antibiotic, may improve papulopustular rosacea symptoms through its anti-inflammatory effects while having minimal impact on gut microbiota diversity.^11,12

Gut-derived short-chain fatty acids, which are known to regulate immune function, also have been shown to influence the composition of skin microbiota, suggesting a direct link between gut dysbiosis and skin microbial imbalances. Notably, antibiotic and probiotic treatments targeting the gut microbiome (eg, rifaximin for small intestinal bacterial overgrowth) have been associated with improvements in rosacea symptoms, further underscoring the interconnectedness of the gut-skin axis.¹³ Understanding how gut-derived inflammation alters the skin microbiome may provide new therapeutic avenues for restoring microbial balance and reducing rosacea severity.

Immune Dysregulation and Inflammatory Pathways

Mechanisms of microbiome-driven inflammation via the innate immune system contribute to rosacea pathogenesis. Toll-like receptor 2 is upregulated in rosacea, producing increased peptides including cathelicidins.¹³ When abnormally processed, cathelicidins produce proinflammatory peptides and worsen rosacea symptoms such as erythema, telangiectasias, and neutrophilic infiltration by dysregulating the immune system and the skin barrier.⁶

Heightened levels of cytokines interleukin 8 and interferon α have been identified in patients with rosacea. These cytokines are involved in rosacea pathogenesis, including leukocyte recruitment, angiogenesis, and tissue remodeling and further activate the inflammatory cascade.^8,14

Mendelian randomization studies have provided confirmation of a causal link between skin microbiota alterations and inflammatory skin diseases including rosacea.² Specific alterations in bacteria such as Cutibacterium and Staphylococcus microbial species have been associated with shifts in host immune gene expression, potentially predisposing individuals to abnormal immune activation and inflammation.^2,8 These studies show the potential of leveraging precision medicine to design therapies that target pathways that improve microbial imbalances seen in rosacea.

Environmental and Lifestyle Factors Affecting the Skin Microbiome

Individuals with rosacea often have increased sensitivity to environmental and lifestyle stressors such as high temperatures, UV exposure, and sugar and alcohol consumption. These factors influence the composition of the skin microbiome and potentially contribute to rosacea development and disease exacerbation; therefore, trigger avoidance is an important way to manage rosacea.

High temperatures and UV exposure—Demodex activity increases in response to heat exposure and subsequently worsens rosacea symptoms, while exposure to UV radiation can change the composition of the skin microbiome by encouraging inflammatory responses such as oxidative stress reactions.⁴ This effect on the skin microbiome is driven partly by the increased presence of certain skin microbial species, such as S epidermidis, which secrete virulence factors at higher temperatures and further contribute to inflammation.^1,4

High-glycemic diet and alcohol consumption—High-glycemic diets and alcohol intake have been associated with gut dysbiosis and increased disease severity in rosacea. Processed foods and high sugar consumption can promote proinflammatory reactions that cause skin dysbiosis and exacerbate symptoms.¹⁵ Increased consumption of anti-inflammatory foods or consumption of probiotics and prebiotics can improve microbial balance.

Therapeutic Implications

The influence of the skin and gut microbiome on rosacea have been well described in the medical literature; therefore, many therapeutic strategies aim to address microbiome dysbiosis, including the use of antibiotics, anthelmintics, and a range of topical agents as well as probiotics, microbiome-friendly skin care products, and dietary modifications.

Antibiotics and Anthelmintics—Topical and oral antibiotics such as metronidazole and doxycycline reduce microbial load and inflammation.^5,7,8 Ivermectin, an anthelmintic, has demonstrated efficacy in decreasing Demodex colonization and associated inflammation by interfering with mite survival and reducing bacterial interactions on the skin.⁵ Recent literature also has explored next-generation antibiotics that disrupt biofilm production by bacteria, which could positively affect outcomes while safeguarding antibiotic stewardship.¹⁵ Given its targeted antimicrobial activity and low propensity for microbial resistance, sarecycline represents a promising therapeutic option for managing rosacea symptoms with reduced risk for microbiome-related adverse events.^12,16

Probiotics and Skin Care Interventions—Probiotics, prebiotics, and postbiotics have emerged as promising approaches to improve rosacea outcomes. Topical probiotics have been shown to maintain skin microbiome homeostasis, reduce inflammation, and enhance epidermal barrier function, making them a promising adjunctive therapy for rosacea.^17,18 Physiological pH cleansers and moisturizers formulated with microbiome-friendly ingredients may reduce transepidermal water loss and improve skin hydration, which are critical in microbial equilibrium.⁹ Oral administration of E coli Nissle, Lactobacillus, and Bifidobacterium have shown potential in improving microbial balance and reducing disease severity.¹⁰

Other Topical Therapies—Azelaic acid and benzoyl peroxide can improve rosacea symptoms by decreasing inflammation and also may shift the skin microbiome.^19,20 Formulations of topical therapies, including microencapsulated benzoyl peroxide, show improved efficacy in targeting pathogenic bacteria while maintaining tolerability.¹⁹

Dietary Modifications—Avoiding triggers such as alcohol and high-glycemic foods can help reduce gut and skin dysbiosis.¹³ Polyphenol-rich foods and prebiotic fiber may promote beneficial gut and skin microbial composition and currently are being studied.¹³

Emerging Therapies—Long-pulsed alexandrite laser therapy has been shown to reduce facial erythema and modulate skin microbiota.²¹ Patients with treatment-resistant rosacea may benefit from advanced precision targeted antimicrobials.

The future of rosacea treatment may involve integrating established and emerging microbiome-targeted treatment strategies to improve short- and long-term patient outcomes in rosacea.

Conclusion

As our understanding of rosacea, its pathogenesis, and the role of the skin microbiome continues to grow, so does our ability to develop increasingly effective and well-tolerated treatments. Future research should focus on how changes to the skin microbiome can influence disease progression and treatment responses as well as potential therapies targeting the skin microbiome. Integrating precision treatments that restore microbial balance alongside more traditional therapies may improve outcomes by addressing both inflammation and epidermal barrier dysfunction. Additionally, strategies that support a healthy skin microbiome, such as microbiome-friendly skin care and topical probiotics, should be further explored to enhance long-term disease management. There remains a dearth of literature addressing how the skin microbiome of patients with rosacea can be optimized to maximize treatment, highlighting the need for more research into these interventions.

Rosacea is a chronic inflammatory skin condition affecting the central face—including the cheeks, nose, chin, and forehead—that causes considerable discomfort.¹ Its pathogenesis involves immune dysregulation, genetic predisposition, and microbial dysbiosis.² While immune and environmental factors are known triggers of rosacea, recent research highlights the roles of the gut and skin microbiomes in disease progression. While the skin microbiome interacts directly with the immune system to regulate inflammation and skin homeostasis, the gut microbiome also influences cutaneous inflammation, emphasizing the need to address both topical and internal microbiome imbalances.³ In this article, we review gut and skin microbial alterations in rosacea, focusing on the skin microbiome and including the gut-skin axis implications as well as therapeutic strategies aimed at microbiome balance to enhance patient outcomes.

Skin Microbiome Alterations in Rosacea

The human skin microbiome interacts with the immune system, and microbial imbalances have been shown to contribute to immune dysregulation. Several key microbial species have been identified as playing a large role in rosacea, including Demodex folliculorum, Staphylococcus epidermidis, Bacillus oleronius, and Cutibacterium acnes (Figure).

Demodex folliculorum is a microscopic mite is found in hair follicles and sebaceous glands. Patients with rosacea have higher densities of D folliculorum, which trigger follicular occlusion and immune activation.¹Bacillus oleronius be isolated from D folliculorum and can further activate toll-like receptor 2, leading to cytokine production and immune cell infiltration.^3,4 Increased propagation of this mite correlates with shifts in skin microbiome composition, demonstrating increased inflammatory microbial populations.³

Staphylococcus epidermidis normally is commensal but can become pathogenic (pathobiont) in rosacea due to disruptions in the skin microenvironment, where it can form biofilms and produce virulence factors, particularly in papulopustular rosacea.⁵

Bacillus oleronius has been isolated from D folliculorum mites and provokes inflammatory responses in patients with rosacea by triggering toll-like receptor 2 activation and cytokine secretion.⁶

Cutibacterium acnes commonly is associated with acne vulgaris. Its role in rosacea is unclear, but recent research suggests it may have a protective effect. A single-arm trial investigated the effects of minocycline on rosacea and found that treatment significantly reduced C acnes but increased microbial species diversity, improving inflammation.⁷ One longitudinal cohort study of 12 patients with rosacea found that C acnes levels were lower in those older than 60 years. Rosacea severity increased with age and correlated with a decline in C acnes, suggesting that it may confer some protective effect in rosacea.⁸ This finding is supported by studies that have shown a reduction in C acnes levels in patients with rosacea compared to controls.^4,8

Important mechanisms in rosacea include epidermal barrier dysfunction, transepidermal water loss, and decreased stratum corneum hydration, particularly in erythematotelangiectatic and papulopustular subtypes. The resulting alkaline skin pH contributes to barrier instability and heightened inflammation, permitting pathogenic bacteria to proliferate and disrupt skin microbial homeostasis.⁹ A recent study identified metabolic changes in the skin microbiome of patients with rosacea, showing that increased heme and hydrogen sulfide in rosacea skin microbiomes likely drive inflammation, while healthy skin microbiomes produce more anti-inflammatory adenosylcobalamin, thiazole, and L-isoleucine.¹ These findings highlight the link between microbial imbalances and inflammation in rosacea.

The Gut-Skin Axis in Rosacea

Gut microbiota play a critical role in managing systemic inflammation, and microbial dysbiosis in the intestine can influence the skin microbiome in rosacea. Patients with rosacea who have gastrointestinal conditions such as small intestinal bacterial overgrowth and Helicobacter pylori infection experience more severe rosacea symptoms.^3,10

Patients with rosacea have distinctive gut microbiota compositions, with an increased prevalence of proinflammatory bacterial species, potentially affecting the skin microbiome.^8,11 Systemic antibiotics have been shown to modulate the gut microbiome, indirectly influencing the skin microbiome.¹¹ A recent study demonstrated that doxycycline treatment in patients with rosacea altered skin microbial diversity, reducing C acnes while increasing Weissella confusa—highlighting the complicated relationship between systemic antibiotics and the gut-skin axis.⁸

Specific probiotics, such as Escherichia coli Nissle, when given orally shifted gut microbial balance to protective microbiota with increased Lactobacillus and Bifidobacteria species and decreased pathogenic bacteria. This improved rosacea symptoms, normalized immunoglobulin A levels, and suppressed cytokine interleukin 8 levels.¹⁰ Recent studies also suggest oral sarecycline, a narrow-spectrum antibiotic, may improve papulopustular rosacea symptoms through its anti-inflammatory effects while having minimal impact on gut microbiota diversity.^11,12

Gut-derived short-chain fatty acids, which are known to regulate immune function, also have been shown to influence the composition of skin microbiota, suggesting a direct link between gut dysbiosis and skin microbial imbalances. Notably, antibiotic and probiotic treatments targeting the gut microbiome (eg, rifaximin for small intestinal bacterial overgrowth) have been associated with improvements in rosacea symptoms, further underscoring the interconnectedness of the gut-skin axis.¹³ Understanding how gut-derived inflammation alters the skin microbiome may provide new therapeutic avenues for restoring microbial balance and reducing rosacea severity.

Immune Dysregulation and Inflammatory Pathways

Mechanisms of microbiome-driven inflammation via the innate immune system contribute to rosacea pathogenesis. Toll-like receptor 2 is upregulated in rosacea, producing increased peptides including cathelicidins.¹³ When abnormally processed, cathelicidins produce proinflammatory peptides and worsen rosacea symptoms such as erythema, telangiectasias, and neutrophilic infiltration by dysregulating the immune system and the skin barrier.⁶

Heightened levels of cytokines interleukin 8 and interferon α have been identified in patients with rosacea. These cytokines are involved in rosacea pathogenesis, including leukocyte recruitment, angiogenesis, and tissue remodeling and further activate the inflammatory cascade.^8,14

Mendelian randomization studies have provided confirmation of a causal link between skin microbiota alterations and inflammatory skin diseases including rosacea.² Specific alterations in bacteria such as Cutibacterium and Staphylococcus microbial species have been associated with shifts in host immune gene expression, potentially predisposing individuals to abnormal immune activation and inflammation.^2,8 These studies show the potential of leveraging precision medicine to design therapies that target pathways that improve microbial imbalances seen in rosacea.

Environmental and Lifestyle Factors Affecting the Skin Microbiome

Individuals with rosacea often have increased sensitivity to environmental and lifestyle stressors such as high temperatures, UV exposure, and sugar and alcohol consumption. These factors influence the composition of the skin microbiome and potentially contribute to rosacea development and disease exacerbation; therefore, trigger avoidance is an important way to manage rosacea.

High temperatures and UV exposure—Demodex activity increases in response to heat exposure and subsequently worsens rosacea symptoms, while exposure to UV radiation can change the composition of the skin microbiome by encouraging inflammatory responses such as oxidative stress reactions.⁴ This effect on the skin microbiome is driven partly by the increased presence of certain skin microbial species, such as S epidermidis, which secrete virulence factors at higher temperatures and further contribute to inflammation.^1,4

High-glycemic diet and alcohol consumption—High-glycemic diets and alcohol intake have been associated with gut dysbiosis and increased disease severity in rosacea. Processed foods and high sugar consumption can promote proinflammatory reactions that cause skin dysbiosis and exacerbate symptoms.¹⁵ Increased consumption of anti-inflammatory foods or consumption of probiotics and prebiotics can improve microbial balance.

Therapeutic Implications

The influence of the skin and gut microbiome on rosacea have been well described in the medical literature; therefore, many therapeutic strategies aim to address microbiome dysbiosis, including the use of antibiotics, anthelmintics, and a range of topical agents as well as probiotics, microbiome-friendly skin care products, and dietary modifications.

Antibiotics and Anthelmintics—Topical and oral antibiotics such as metronidazole and doxycycline reduce microbial load and inflammation.^5,7,8 Ivermectin, an anthelmintic, has demonstrated efficacy in decreasing Demodex colonization and associated inflammation by interfering with mite survival and reducing bacterial interactions on the skin.⁵ Recent literature also has explored next-generation antibiotics that disrupt biofilm production by bacteria, which could positively affect outcomes while safeguarding antibiotic stewardship.¹⁵ Given its targeted antimicrobial activity and low propensity for microbial resistance, sarecycline represents a promising therapeutic option for managing rosacea symptoms with reduced risk for microbiome-related adverse events.^12,16

Probiotics and Skin Care Interventions—Probiotics, prebiotics, and postbiotics have emerged as promising approaches to improve rosacea outcomes. Topical probiotics have been shown to maintain skin microbiome homeostasis, reduce inflammation, and enhance epidermal barrier function, making them a promising adjunctive therapy for rosacea.^17,18 Physiological pH cleansers and moisturizers formulated with microbiome-friendly ingredients may reduce transepidermal water loss and improve skin hydration, which are critical in microbial equilibrium.⁹ Oral administration of E coli Nissle, Lactobacillus, and Bifidobacterium have shown potential in improving microbial balance and reducing disease severity.¹⁰

Other Topical Therapies—Azelaic acid and benzoyl peroxide can improve rosacea symptoms by decreasing inflammation and also may shift the skin microbiome.^19,20 Formulations of topical therapies, including microencapsulated benzoyl peroxide, show improved efficacy in targeting pathogenic bacteria while maintaining tolerability.¹⁹

Dietary Modifications—Avoiding triggers such as alcohol and high-glycemic foods can help reduce gut and skin dysbiosis.¹³ Polyphenol-rich foods and prebiotic fiber may promote beneficial gut and skin microbial composition and currently are being studied.¹³

Emerging Therapies—Long-pulsed alexandrite laser therapy has been shown to reduce facial erythema and modulate skin microbiota.²¹ Patients with treatment-resistant rosacea may benefit from advanced precision targeted antimicrobials.

The future of rosacea treatment may involve integrating established and emerging microbiome-targeted treatment strategies to improve short- and long-term patient outcomes in rosacea.

Conclusion

As our understanding of rosacea, its pathogenesis, and the role of the skin microbiome continues to grow, so does our ability to develop increasingly effective and well-tolerated treatments. Future research should focus on how changes to the skin microbiome can influence disease progression and treatment responses as well as potential therapies targeting the skin microbiome. Integrating precision treatments that restore microbial balance alongside more traditional therapies may improve outcomes by addressing both inflammation and epidermal barrier dysfunction. Additionally, strategies that support a healthy skin microbiome, such as microbiome-friendly skin care and topical probiotics, should be further explored to enhance long-term disease management. There remains a dearth of literature addressing how the skin microbiome of patients with rosacea can be optimized to maximize treatment, highlighting the need for more research into these interventions.

How did I develop a strong interest in acne and rosacea? Interest on a personal level was with me throughout my adolescence and post-teen years as I suffered with very severe facial acne from ages 13 through 23 (1967-1977). I was sometimes called “pizza face” in high school, and biweekly trips to a dermatology office that always had a packed waiting room were of little help that I could appreciate visibly. Six straight years of extractions, intralesional injections, draining of fluctuant cysts, UVC light treatments, oral tetracycline, irritating topical formulations of benzoyl peroxide and tretinoin, and topical sulfacetamide-sulfur products resulted in minimal improvement. However, maybe all of this did something to what was happening underneath the skin surface, as I have no residual acne scars. I do recall vividly that I walked the halls in high school and college consistently affected by a very red face from the topical agents and smelling like rotten eggs from the topical sulfur application. I fortunately handled it well emotionally and socially, for which I am very thankful. Many people affected with acne do not.

In dermatology, I have always had a strong interest in pathophysiology and therapeutics, rooted I am sure in my background as a pharmacist. Although I was always interested in acne therapy, I was fully captivated by a presentation given by Dr. Jim Leyden many years ago at a small meeting in Myrtle Beach, South Carolina. He brought the subject of acne to life in a way that more than grabbed my complete attention and ignited an interest in learning everything I could about it. Over time, I was fortunate enough to work alongside Dr. Leyden and many other household names in acne at meetings and publications to further education on one of the most common disease states seen in ambulatory dermatology practices worldwide. The rest is history, leading to almost 4 decades of work in acne on many levels in dermatology, all being efforts that I am grateful for.

What I have observed to date is that we have had few revolutionary advances in acne therapy, the major one being oral isotretinoin, which was first brought to market in 1982. We are still utilizing many of the same therapeutic agents that I used back when I was treated for acne. A few new topical compounds have emerged, such as dapsone and clascoterone, and a narrow-spectrum tetracycline agent, sarecycline, also was developed. These agents do represent important advances with some specific benefits. There have been many major improvements in drug delivery formulations, including several vehicle technologies that allow augmented skin tolerability, increased efficacy, and improved stability, allowing for combination therapy products containing 2 or 3 active ingredients. A recent example is the first triple-combination topical acne therapy with excellent supporting data on speed of onset, efficacy, and safety.¹

Technological advances also have aided in the development of modified- or extended-release formulations of oral antibiotics, such as doxycycline and minocycline, which allow for reduced adverse effects and lower daily dosages. Lidose formulations of isotretinoin have circumvented the need for concurrent ingestion of a high-fat meal to facilitate its absorption in the gastrointestinal tract (as required with conventional formulations). Many hours also have been spent on delivery devices and vehicles such as pumps, foams, and aqueous-based gels. Let us not forget the efforts and myriad products directed at skin care, cosmeceuticals, and physical devices (lasers and lights) for acne. Regardless of the above, we have not seen the monumental therapeutic and research revolution for acne that we have experienced more recently with biologic agents, Janus kinase inhibitors, and other modes of action for many common disease states such as atopic dermatitis, psoriasis, alopecia areata, vitiligo, hidradenitis suppurativa, prurigo nodularis, and chronic spontaneous urticaria.

Unfortunately, the slow development of advances in treatments for acne has been compounded further by the widespread availability of generic equivalents of most topical and oral therapies along with several over-the- counter topical medications. The expanded skin care and cosmeceutical product world has further diluted the perceived value of topical prescription therapies for acne. The marked difficulty in achieving and sustaining total clearance of acne, with the exception of many individuals treated with oral isotretinoin, results in many patients searching for other options, often through sources beyond dermatology practices (eg, the internet). While some of these sources may provide valid suggestions, they often are not truly substantiated by valid clinical research and are not formally regulated by the US Food and Drug Administration.

All of the above, in addition to the barriers to medication coverage put in place by third-party organizations such as pharmacy benefit managers, have contributed to the extreme slowdown in the development of new prescription therapies for acne. What this leads me to believe is that until there is a true meeting of the minds of all stakeholders on policies that facilitate access to both established and newly available acne therapies, there will be an enduring diminished incentive to support the development of newer acne treatments that will continue to spiral progressively downward. Some research on acne will always continue, such as the search for an acne vaccine and cutaneous microbiome alterations that are in progress.^2,3 However, I do not see much happening in the foreseeable future. I am not inherently a pessimist or a “prophet of doom,” so I sincerely hope I am wrong.

How did I develop a strong interest in acne and rosacea? Interest on a personal level was with me throughout my adolescence and post-teen years as I suffered with very severe facial acne from ages 13 through 23 (1967-1977). I was sometimes called “pizza face” in high school, and biweekly trips to a dermatology office that always had a packed waiting room were of little help that I could appreciate visibly. Six straight years of extractions, intralesional injections, draining of fluctuant cysts, UVC light treatments, oral tetracycline, irritating topical formulations of benzoyl peroxide and tretinoin, and topical sulfacetamide-sulfur products resulted in minimal improvement. However, maybe all of this did something to what was happening underneath the skin surface, as I have no residual acne scars. I do recall vividly that I walked the halls in high school and college consistently affected by a very red face from the topical agents and smelling like rotten eggs from the topical sulfur application. I fortunately handled it well emotionally and socially, for which I am very thankful. Many people affected with acne do not.

In dermatology, I have always had a strong interest in pathophysiology and therapeutics, rooted I am sure in my background as a pharmacist. Although I was always interested in acne therapy, I was fully captivated by a presentation given by Dr. Jim Leyden many years ago at a small meeting in Myrtle Beach, South Carolina. He brought the subject of acne to life in a way that more than grabbed my complete attention and ignited an interest in learning everything I could about it. Over time, I was fortunate enough to work alongside Dr. Leyden and many other household names in acne at meetings and publications to further education on one of the most common disease states seen in ambulatory dermatology practices worldwide. The rest is history, leading to almost 4 decades of work in acne on many levels in dermatology, all being efforts that I am grateful for.

What I have observed to date is that we have had few revolutionary advances in acne therapy, the major one being oral isotretinoin, which was first brought to market in 1982. We are still utilizing many of the same therapeutic agents that I used back when I was treated for acne. A few new topical compounds have emerged, such as dapsone and clascoterone, and a narrow-spectrum tetracycline agent, sarecycline, also was developed. These agents do represent important advances with some specific benefits. There have been many major improvements in drug delivery formulations, including several vehicle technologies that allow augmented skin tolerability, increased efficacy, and improved stability, allowing for combination therapy products containing 2 or 3 active ingredients. A recent example is the first triple-combination topical acne therapy with excellent supporting data on speed of onset, efficacy, and safety.¹

Technological advances also have aided in the development of modified- or extended-release formulations of oral antibiotics, such as doxycycline and minocycline, which allow for reduced adverse effects and lower daily dosages. Lidose formulations of isotretinoin have circumvented the need for concurrent ingestion of a high-fat meal to facilitate its absorption in the gastrointestinal tract (as required with conventional formulations). Many hours also have been spent on delivery devices and vehicles such as pumps, foams, and aqueous-based gels. Let us not forget the efforts and myriad products directed at skin care, cosmeceuticals, and physical devices (lasers and lights) for acne. Regardless of the above, we have not seen the monumental therapeutic and research revolution for acne that we have experienced more recently with biologic agents, Janus kinase inhibitors, and other modes of action for many common disease states such as atopic dermatitis, psoriasis, alopecia areata, vitiligo, hidradenitis suppurativa, prurigo nodularis, and chronic spontaneous urticaria.

Unfortunately, the slow development of advances in treatments for acne has been compounded further by the widespread availability of generic equivalents of most topical and oral therapies along with several over-the- counter topical medications. The expanded skin care and cosmeceutical product world has further diluted the perceived value of topical prescription therapies for acne. The marked difficulty in achieving and sustaining total clearance of acne, with the exception of many individuals treated with oral isotretinoin, results in many patients searching for other options, often through sources beyond dermatology practices (eg, the internet). While some of these sources may provide valid suggestions, they often are not truly substantiated by valid clinical research and are not formally regulated by the US Food and Drug Administration.

All of the above, in addition to the barriers to medication coverage put in place by third-party organizations such as pharmacy benefit managers, have contributed to the extreme slowdown in the development of new prescription therapies for acne. What this leads me to believe is that until there is a true meeting of the minds of all stakeholders on policies that facilitate access to both established and newly available acne therapies, there will be an enduring diminished incentive to support the development of newer acne treatments that will continue to spiral progressively downward. Some research on acne will always continue, such as the search for an acne vaccine and cutaneous microbiome alterations that are in progress.^2,3 However, I do not see much happening in the foreseeable future. I am not inherently a pessimist or a “prophet of doom,” so I sincerely hope I am wrong.

How did I develop a strong interest in acne and rosacea? Interest on a personal level was with me throughout my adolescence and post-teen years as I suffered with very severe facial acne from ages 13 through 23 (1967-1977). I was sometimes called “pizza face” in high school, and biweekly trips to a dermatology office that always had a packed waiting room were of little help that I could appreciate visibly. Six straight years of extractions, intralesional injections, draining of fluctuant cysts, UVC light treatments, oral tetracycline, irritating topical formulations of benzoyl peroxide and tretinoin, and topical sulfacetamide-sulfur products resulted in minimal improvement. However, maybe all of this did something to what was happening underneath the skin surface, as I have no residual acne scars. I do recall vividly that I walked the halls in high school and college consistently affected by a very red face from the topical agents and smelling like rotten eggs from the topical sulfur application. I fortunately handled it well emotionally and socially, for which I am very thankful. Many people affected with acne do not.

In dermatology, I have always had a strong interest in pathophysiology and therapeutics, rooted I am sure in my background as a pharmacist. Although I was always interested in acne therapy, I was fully captivated by a presentation given by Dr. Jim Leyden many years ago at a small meeting in Myrtle Beach, South Carolina. He brought the subject of acne to life in a way that more than grabbed my complete attention and ignited an interest in learning everything I could about it. Over time, I was fortunate enough to work alongside Dr. Leyden and many other household names in acne at meetings and publications to further education on one of the most common disease states seen in ambulatory dermatology practices worldwide. The rest is history, leading to almost 4 decades of work in acne on many levels in dermatology, all being efforts that I am grateful for.

What I have observed to date is that we have had few revolutionary advances in acne therapy, the major one being oral isotretinoin, which was first brought to market in 1982. We are still utilizing many of the same therapeutic agents that I used back when I was treated for acne. A few new topical compounds have emerged, such as dapsone and clascoterone, and a narrow-spectrum tetracycline agent, sarecycline, also was developed. These agents do represent important advances with some specific benefits. There have been many major improvements in drug delivery formulations, including several vehicle technologies that allow augmented skin tolerability, increased efficacy, and improved stability, allowing for combination therapy products containing 2 or 3 active ingredients. A recent example is the first triple-combination topical acne therapy with excellent supporting data on speed of onset, efficacy, and safety.¹

Technological advances also have aided in the development of modified- or extended-release formulations of oral antibiotics, such as doxycycline and minocycline, which allow for reduced adverse effects and lower daily dosages. Lidose formulations of isotretinoin have circumvented the need for concurrent ingestion of a high-fat meal to facilitate its absorption in the gastrointestinal tract (as required with conventional formulations). Many hours also have been spent on delivery devices and vehicles such as pumps, foams, and aqueous-based gels. Let us not forget the efforts and myriad products directed at skin care, cosmeceuticals, and physical devices (lasers and lights) for acne. Regardless of the above, we have not seen the monumental therapeutic and research revolution for acne that we have experienced more recently with biologic agents, Janus kinase inhibitors, and other modes of action for many common disease states such as atopic dermatitis, psoriasis, alopecia areata, vitiligo, hidradenitis suppurativa, prurigo nodularis, and chronic spontaneous urticaria.

Unfortunately, the slow development of advances in treatments for acne has been compounded further by the widespread availability of generic equivalents of most topical and oral therapies along with several over-the- counter topical medications. The expanded skin care and cosmeceutical product world has further diluted the perceived value of topical prescription therapies for acne. The marked difficulty in achieving and sustaining total clearance of acne, with the exception of many individuals treated with oral isotretinoin, results in many patients searching for other options, often through sources beyond dermatology practices (eg, the internet). While some of these sources may provide valid suggestions, they often are not truly substantiated by valid clinical research and are not formally regulated by the US Food and Drug Administration.

All of the above, in addition to the barriers to medication coverage put in place by third-party organizations such as pharmacy benefit managers, have contributed to the extreme slowdown in the development of new prescription therapies for acne. What this leads me to believe is that until there is a true meeting of the minds of all stakeholders on policies that facilitate access to both established and newly available acne therapies, there will be an enduring diminished incentive to support the development of newer acne treatments that will continue to spiral progressively downward. Some research on acne will always continue, such as the search for an acne vaccine and cutaneous microbiome alterations that are in progress.^2,3 However, I do not see much happening in the foreseeable future. I am not inherently a pessimist or a “prophet of doom,” so I sincerely hope I am wrong.