Acne

Purpose of Medical Standards in the US Military

Young adults in the United States traditionally have viewed military service as a viable career given its stable salary, career training, opportunities for progression, comprehensive health care coverage, tuition assistance, and other benefits; however, not all who desire to serve in the US Military are eligible to join. The Department of Defense (DoD) maintains fitness and health requirements (ie, accession standards), which are codified in DoD Instruction 6130.03, Volume 1,¹ that help ensure potential recruits can safely and fully perform their military duties. These accession standards change over time with the evolving understanding of diseases, medical advances, and accrued experience conducting operations in various environments. Accession standards serve to both preserve the health of the applicant and to ensure military mission success.

Dermatologic diseases have been prevalent in conflicts throughout US military history, representing a considerable source of morbidity to service members, inability of service members to remain on active duty, and costly use of resources. Hospitalizations of US Army soldiers for skin conditions led to the loss of more than 2 million days of service in World War I.² In World War II, skin diseases made up 25% and 75% of all temperate and tropical climate visits, respectively. Cutaneous diseases were the most frequently addressed category for US service members in Vietnam, representing more than 1.5 million visits and nearly 10% of disease-related evacuations.² Skin disease remains vital in 21st-century conflict. At a military hospital in Afghanistan, a review of 2421 outpatient medical records from June through July 2007 identified that dermatologic conditions resulted in 20% of military patient evaluations, 7% of nontraumatic hospital admissions, and 2% of total patient evacuations, at an estimated cost of $80,000 per evacuee.³ Between 2003 and 2006, 918 service members were evacuated for dermatologic reasons from combat zones in Afghanistan and Iraq.⁴

Unpredictable military environments may result in flares of a previously controlled condition, new skin diseases, or infection with endemic diseases. Mild cases of common conditions such as psoriasis or atopic dermatitis can present an unacceptable risk for severe flare in the setting of deployed military operations.⁵ Personnel may face extremes in temperature and humidity and work long hours under stress with limited or nonexistent opportunities for hygiene or self-care. Shared equipment and close living quarters permit the spread of infectious diseases and complicate the treatment of infestations. Military equipment and supplies such as gas masks and insect repellents can contain compounds that act as irritants or sensitizing agents, leading to contact dermatitis or urticaria. When dermatologic conditions develop or flare, further challenges are associated with evaluation and management. Health care resources vary considerably by location, with potential limitations in the availability of medications; supplies; refrigeration capabilities; and laboratory, microbiology, and histology services. Furthermore, dermatology referrals and services typically are not feasible in most deployed settings,³ though teledermatology has been available in the armed forces since 2002.

Deployed environments compound the consequences of dermatologic conditions and can impact the military mission. Military units deploy with the number of personnel needed to complete a mission and cannot replace members who become ill or injured or are medically evacuated. Something seemingly trivial, such as poor sleep due to pruritic dermatitis, may impair daytime alertness with potentially grave consequences in critical tasks such as guard or flying duties. The evacuation of a service member can compromise those left behind, and losing a service member with a unique required skill set may jeopardize a unit’s chance of success. Additionally, the impact of an evacuation itself extends beyond its direct cost and effects on the service member’s unit. The military does not maintain dedicated medical evacuation aircraft, instead repurposing aircraft in the deployed setting as needed.⁶ Evacuations can delay flights initially scheduled to move troops, ammunition, food, or other supplies and equipment elsewhere.

Disqualifying Skin and Soft Tissue Conditions

Current accession standards, which are listed in a publicly released document (DoD Instruction 6130.03, Volume 1), are updated based on medical, societal, and technical advances.¹ These standards differ from retention standards, which apply to members actively serving in the military. Although the DoD creates a minimum standard for the entire military, the US Army, Navy, and Air Force adopt these standards and adjust as required for each branch’s needs. An updated copy can be found on the DoD Directives Division website (https://www.esd.whs.mil/dd/) or Med Standards, a third-party mobile application (app) available as a free download for Apple iOS and Android devices (https://www.doc-apps.com/). The app also includes each military branch’s interpretation of the requirements.

The accession standards outline medical conditions that, if present or verified in an applicant’s medical history, preclude joining the military (eTable). These standards are organized into general systems, with a section dedicated to dermatologic (skin and soft tissue) conditions.¹ When a candidate has a potentially disqualifying medical condition identified by a screening questionnaire, medical record review, or military entrance physical examination, a referral for a determination of fitness for duty may be required. Medical accession standards are not solely driven by the diagnosis but also by the extent, nature, and timing of medical management. Procedures or prescriptions requiring frequent clinical monitoring, special handling, or severe dietary restrictions may deem the applicant’s condition potentially unsuitable. The need for immunosuppressive, anticoagulant, or refrigerated medications can impact a patient’s eligibility due to future deployment requirements and suitability for prolonged service, especially if treated for any substantial length of time. Chronic dermatologic conditions that are unresponsive to treatment, are susceptible to exacerbation despite treatment, require regular follow-up care, or interfere with the wear of military gear may be inconsistent with future deployment standards. Although the dermatologist should primarily focus on the skin and soft tissue conditions section of the accession standards, some dermatologic conditions can overlap with other medical systems and be located in a different section; for example, the section on lower extremity conditions includes a disqualifying condition of “[c]urrent ingrown toenails, if infected or symptomatic.”¹

Waiver Process

Medical conditions listed in the accession standards are deemed ineligible for military service; however, applicants can apply for a waiver.¹ The goal is for service members to be well controlled without treatment or with treatment widely available at military clinics and hospitals. Waivers ensure that service members are “[m]edically capable of performing duties without aggravating physical defects or medical conditions,” are “[m]edically adaptable to the military environment without geographical area limitations,” and are “free of medical conditions or physical defects that may reasonably be expected to require excessive time lost from duty for necessary treatment or hospitalization, or may result in separation from the Military Service for unfitness.”¹ The waiver process requires an evaluation from specialists with verification and documentation but does not guarantee approval. Although each military branch follows the same guidelines for disqualifying medical conditions, the evaluation and waiver process varies.

Considerations for Civilian Dermatologists

For several reasons, accurate and detailed medical documentation is essential for patients who pursue military service. Applicants must complete detailed health questionnaires and may need to provide copies of health records. The military electronic health record connects to large civilian health information exchanges and pulls primary documentation from records at many hospitals and clinics. Although applicants may request supportive clarification from their dermatologists, the military relies on primary medical documentation throughout the recruitment process. Accurate diagnostic codes reduce ambiguity, as accession standards are organized by diagnosis; for example, an unspecified history of psoriasis disqualifies applicants unless documentation supports nonrecurrent childhood guttate psoriasis.¹ Clear documentation of symptom severity, response to treatment, or resolution of a condition may elucidate suitability for service when matching a potentially disqualifying condition to a standard is not straightforward. Correct documentation will ensure that potential service members achieve a waiver when it is appropriate. If they are found to be unfit, it may save a patient from a bad outcome or a military unit from mission failure.

Dermatologists in the United States can reference current military medical accession standards to guide patients when needed. For example, a prospective recruit may be hesitant to start isotretinoin for severe nodulocystic acne, concerned that this medication may preclude them from joining the military. The current standards state that “[a]pplicants under treatment with systemic retinoids . . . do not meet the standard until 4 weeks after completing therapy,” while active severe nodulocystic acne is a disqualifying condition.¹ Therefore, the patient could proceed with isotretinoin therapy and, pending clinical response, meet accession standards as soon as 4 weeks after treatment. A clear understanding of the purpose of these standards, including protecting the applicant’s health and maximizing the chance of combat mission accomplishment, helps to reinforce responsibilities when caring for patients who wish to serve.

Purpose of Medical Standards in the US Military

Young adults in the United States traditionally have viewed military service as a viable career given its stable salary, career training, opportunities for progression, comprehensive health care coverage, tuition assistance, and other benefits; however, not all who desire to serve in the US Military are eligible to join. The Department of Defense (DoD) maintains fitness and health requirements (ie, accession standards), which are codified in DoD Instruction 6130.03, Volume 1,¹ that help ensure potential recruits can safely and fully perform their military duties. These accession standards change over time with the evolving understanding of diseases, medical advances, and accrued experience conducting operations in various environments. Accession standards serve to both preserve the health of the applicant and to ensure military mission success.

Dermatologic diseases have been prevalent in conflicts throughout US military history, representing a considerable source of morbidity to service members, inability of service members to remain on active duty, and costly use of resources. Hospitalizations of US Army soldiers for skin conditions led to the loss of more than 2 million days of service in World War I.² In World War II, skin diseases made up 25% and 75% of all temperate and tropical climate visits, respectively. Cutaneous diseases were the most frequently addressed category for US service members in Vietnam, representing more than 1.5 million visits and nearly 10% of disease-related evacuations.² Skin disease remains vital in 21st-century conflict. At a military hospital in Afghanistan, a review of 2421 outpatient medical records from June through July 2007 identified that dermatologic conditions resulted in 20% of military patient evaluations, 7% of nontraumatic hospital admissions, and 2% of total patient evacuations, at an estimated cost of $80,000 per evacuee.³ Between 2003 and 2006, 918 service members were evacuated for dermatologic reasons from combat zones in Afghanistan and Iraq.⁴

Unpredictable military environments may result in flares of a previously controlled condition, new skin diseases, or infection with endemic diseases. Mild cases of common conditions such as psoriasis or atopic dermatitis can present an unacceptable risk for severe flare in the setting of deployed military operations.⁵ Personnel may face extremes in temperature and humidity and work long hours under stress with limited or nonexistent opportunities for hygiene or self-care. Shared equipment and close living quarters permit the spread of infectious diseases and complicate the treatment of infestations. Military equipment and supplies such as gas masks and insect repellents can contain compounds that act as irritants or sensitizing agents, leading to contact dermatitis or urticaria. When dermatologic conditions develop or flare, further challenges are associated with evaluation and management. Health care resources vary considerably by location, with potential limitations in the availability of medications; supplies; refrigeration capabilities; and laboratory, microbiology, and histology services. Furthermore, dermatology referrals and services typically are not feasible in most deployed settings,³ though teledermatology has been available in the armed forces since 2002.

Deployed environments compound the consequences of dermatologic conditions and can impact the military mission. Military units deploy with the number of personnel needed to complete a mission and cannot replace members who become ill or injured or are medically evacuated. Something seemingly trivial, such as poor sleep due to pruritic dermatitis, may impair daytime alertness with potentially grave consequences in critical tasks such as guard or flying duties. The evacuation of a service member can compromise those left behind, and losing a service member with a unique required skill set may jeopardize a unit’s chance of success. Additionally, the impact of an evacuation itself extends beyond its direct cost and effects on the service member’s unit. The military does not maintain dedicated medical evacuation aircraft, instead repurposing aircraft in the deployed setting as needed.⁶ Evacuations can delay flights initially scheduled to move troops, ammunition, food, or other supplies and equipment elsewhere.

Disqualifying Skin and Soft Tissue Conditions

Current accession standards, which are listed in a publicly released document (DoD Instruction 6130.03, Volume 1), are updated based on medical, societal, and technical advances.¹ These standards differ from retention standards, which apply to members actively serving in the military. Although the DoD creates a minimum standard for the entire military, the US Army, Navy, and Air Force adopt these standards and adjust as required for each branch’s needs. An updated copy can be found on the DoD Directives Division website (https://www.esd.whs.mil/dd/) or Med Standards, a third-party mobile application (app) available as a free download for Apple iOS and Android devices (https://www.doc-apps.com/). The app also includes each military branch’s interpretation of the requirements.

The accession standards outline medical conditions that, if present or verified in an applicant’s medical history, preclude joining the military (eTable). These standards are organized into general systems, with a section dedicated to dermatologic (skin and soft tissue) conditions.¹ When a candidate has a potentially disqualifying medical condition identified by a screening questionnaire, medical record review, or military entrance physical examination, a referral for a determination of fitness for duty may be required. Medical accession standards are not solely driven by the diagnosis but also by the extent, nature, and timing of medical management. Procedures or prescriptions requiring frequent clinical monitoring, special handling, or severe dietary restrictions may deem the applicant’s condition potentially unsuitable. The need for immunosuppressive, anticoagulant, or refrigerated medications can impact a patient’s eligibility due to future deployment requirements and suitability for prolonged service, especially if treated for any substantial length of time. Chronic dermatologic conditions that are unresponsive to treatment, are susceptible to exacerbation despite treatment, require regular follow-up care, or interfere with the wear of military gear may be inconsistent with future deployment standards. Although the dermatologist should primarily focus on the skin and soft tissue conditions section of the accession standards, some dermatologic conditions can overlap with other medical systems and be located in a different section; for example, the section on lower extremity conditions includes a disqualifying condition of “[c]urrent ingrown toenails, if infected or symptomatic.”¹

Waiver Process

Medical conditions listed in the accession standards are deemed ineligible for military service; however, applicants can apply for a waiver.¹ The goal is for service members to be well controlled without treatment or with treatment widely available at military clinics and hospitals. Waivers ensure that service members are “[m]edically capable of performing duties without aggravating physical defects or medical conditions,” are “[m]edically adaptable to the military environment without geographical area limitations,” and are “free of medical conditions or physical defects that may reasonably be expected to require excessive time lost from duty for necessary treatment or hospitalization, or may result in separation from the Military Service for unfitness.”¹ The waiver process requires an evaluation from specialists with verification and documentation but does not guarantee approval. Although each military branch follows the same guidelines for disqualifying medical conditions, the evaluation and waiver process varies.

Considerations for Civilian Dermatologists

For several reasons, accurate and detailed medical documentation is essential for patients who pursue military service. Applicants must complete detailed health questionnaires and may need to provide copies of health records. The military electronic health record connects to large civilian health information exchanges and pulls primary documentation from records at many hospitals and clinics. Although applicants may request supportive clarification from their dermatologists, the military relies on primary medical documentation throughout the recruitment process. Accurate diagnostic codes reduce ambiguity, as accession standards are organized by diagnosis; for example, an unspecified history of psoriasis disqualifies applicants unless documentation supports nonrecurrent childhood guttate psoriasis.¹ Clear documentation of symptom severity, response to treatment, or resolution of a condition may elucidate suitability for service when matching a potentially disqualifying condition to a standard is not straightforward. Correct documentation will ensure that potential service members achieve a waiver when it is appropriate. If they are found to be unfit, it may save a patient from a bad outcome or a military unit from mission failure.

Dermatologists in the United States can reference current military medical accession standards to guide patients when needed. For example, a prospective recruit may be hesitant to start isotretinoin for severe nodulocystic acne, concerned that this medication may preclude them from joining the military. The current standards state that “[a]pplicants under treatment with systemic retinoids . . . do not meet the standard until 4 weeks after completing therapy,” while active severe nodulocystic acne is a disqualifying condition.¹ Therefore, the patient could proceed with isotretinoin therapy and, pending clinical response, meet accession standards as soon as 4 weeks after treatment. A clear understanding of the purpose of these standards, including protecting the applicant’s health and maximizing the chance of combat mission accomplishment, helps to reinforce responsibilities when caring for patients who wish to serve.

Purpose of Medical Standards in the US Military

Young adults in the United States traditionally have viewed military service as a viable career given its stable salary, career training, opportunities for progression, comprehensive health care coverage, tuition assistance, and other benefits; however, not all who desire to serve in the US Military are eligible to join. The Department of Defense (DoD) maintains fitness and health requirements (ie, accession standards), which are codified in DoD Instruction 6130.03, Volume 1,¹ that help ensure potential recruits can safely and fully perform their military duties. These accession standards change over time with the evolving understanding of diseases, medical advances, and accrued experience conducting operations in various environments. Accession standards serve to both preserve the health of the applicant and to ensure military mission success.

Dermatologic diseases have been prevalent in conflicts throughout US military history, representing a considerable source of morbidity to service members, inability of service members to remain on active duty, and costly use of resources. Hospitalizations of US Army soldiers for skin conditions led to the loss of more than 2 million days of service in World War I.² In World War II, skin diseases made up 25% and 75% of all temperate and tropical climate visits, respectively. Cutaneous diseases were the most frequently addressed category for US service members in Vietnam, representing more than 1.5 million visits and nearly 10% of disease-related evacuations.² Skin disease remains vital in 21st-century conflict. At a military hospital in Afghanistan, a review of 2421 outpatient medical records from June through July 2007 identified that dermatologic conditions resulted in 20% of military patient evaluations, 7% of nontraumatic hospital admissions, and 2% of total patient evacuations, at an estimated cost of $80,000 per evacuee.³ Between 2003 and 2006, 918 service members were evacuated for dermatologic reasons from combat zones in Afghanistan and Iraq.⁴

Unpredictable military environments may result in flares of a previously controlled condition, new skin diseases, or infection with endemic diseases. Mild cases of common conditions such as psoriasis or atopic dermatitis can present an unacceptable risk for severe flare in the setting of deployed military operations.⁵ Personnel may face extremes in temperature and humidity and work long hours under stress with limited or nonexistent opportunities for hygiene or self-care. Shared equipment and close living quarters permit the spread of infectious diseases and complicate the treatment of infestations. Military equipment and supplies such as gas masks and insect repellents can contain compounds that act as irritants or sensitizing agents, leading to contact dermatitis or urticaria. When dermatologic conditions develop or flare, further challenges are associated with evaluation and management. Health care resources vary considerably by location, with potential limitations in the availability of medications; supplies; refrigeration capabilities; and laboratory, microbiology, and histology services. Furthermore, dermatology referrals and services typically are not feasible in most deployed settings,³ though teledermatology has been available in the armed forces since 2002.

Deployed environments compound the consequences of dermatologic conditions and can impact the military mission. Military units deploy with the number of personnel needed to complete a mission and cannot replace members who become ill or injured or are medically evacuated. Something seemingly trivial, such as poor sleep due to pruritic dermatitis, may impair daytime alertness with potentially grave consequences in critical tasks such as guard or flying duties. The evacuation of a service member can compromise those left behind, and losing a service member with a unique required skill set may jeopardize a unit’s chance of success. Additionally, the impact of an evacuation itself extends beyond its direct cost and effects on the service member’s unit. The military does not maintain dedicated medical evacuation aircraft, instead repurposing aircraft in the deployed setting as needed.⁶ Evacuations can delay flights initially scheduled to move troops, ammunition, food, or other supplies and equipment elsewhere.

Disqualifying Skin and Soft Tissue Conditions

Current accession standards, which are listed in a publicly released document (DoD Instruction 6130.03, Volume 1), are updated based on medical, societal, and technical advances.¹ These standards differ from retention standards, which apply to members actively serving in the military. Although the DoD creates a minimum standard for the entire military, the US Army, Navy, and Air Force adopt these standards and adjust as required for each branch’s needs. An updated copy can be found on the DoD Directives Division website (https://www.esd.whs.mil/dd/) or Med Standards, a third-party mobile application (app) available as a free download for Apple iOS and Android devices (https://www.doc-apps.com/). The app also includes each military branch’s interpretation of the requirements.

The accession standards outline medical conditions that, if present or verified in an applicant’s medical history, preclude joining the military (eTable). These standards are organized into general systems, with a section dedicated to dermatologic (skin and soft tissue) conditions.¹ When a candidate has a potentially disqualifying medical condition identified by a screening questionnaire, medical record review, or military entrance physical examination, a referral for a determination of fitness for duty may be required. Medical accession standards are not solely driven by the diagnosis but also by the extent, nature, and timing of medical management. Procedures or prescriptions requiring frequent clinical monitoring, special handling, or severe dietary restrictions may deem the applicant’s condition potentially unsuitable. The need for immunosuppressive, anticoagulant, or refrigerated medications can impact a patient’s eligibility due to future deployment requirements and suitability for prolonged service, especially if treated for any substantial length of time. Chronic dermatologic conditions that are unresponsive to treatment, are susceptible to exacerbation despite treatment, require regular follow-up care, or interfere with the wear of military gear may be inconsistent with future deployment standards. Although the dermatologist should primarily focus on the skin and soft tissue conditions section of the accession standards, some dermatologic conditions can overlap with other medical systems and be located in a different section; for example, the section on lower extremity conditions includes a disqualifying condition of “[c]urrent ingrown toenails, if infected or symptomatic.”¹

Waiver Process

Medical conditions listed in the accession standards are deemed ineligible for military service; however, applicants can apply for a waiver.¹ The goal is for service members to be well controlled without treatment or with treatment widely available at military clinics and hospitals. Waivers ensure that service members are “[m]edically capable of performing duties without aggravating physical defects or medical conditions,” are “[m]edically adaptable to the military environment without geographical area limitations,” and are “free of medical conditions or physical defects that may reasonably be expected to require excessive time lost from duty for necessary treatment or hospitalization, or may result in separation from the Military Service for unfitness.”¹ The waiver process requires an evaluation from specialists with verification and documentation but does not guarantee approval. Although each military branch follows the same guidelines for disqualifying medical conditions, the evaluation and waiver process varies.

Considerations for Civilian Dermatologists

For several reasons, accurate and detailed medical documentation is essential for patients who pursue military service. Applicants must complete detailed health questionnaires and may need to provide copies of health records. The military electronic health record connects to large civilian health information exchanges and pulls primary documentation from records at many hospitals and clinics. Although applicants may request supportive clarification from their dermatologists, the military relies on primary medical documentation throughout the recruitment process. Accurate diagnostic codes reduce ambiguity, as accession standards are organized by diagnosis; for example, an unspecified history of psoriasis disqualifies applicants unless documentation supports nonrecurrent childhood guttate psoriasis.¹ Clear documentation of symptom severity, response to treatment, or resolution of a condition may elucidate suitability for service when matching a potentially disqualifying condition to a standard is not straightforward. Correct documentation will ensure that potential service members achieve a waiver when it is appropriate. If they are found to be unfit, it may save a patient from a bad outcome or a military unit from mission failure.

Dermatologists in the United States can reference current military medical accession standards to guide patients when needed. For example, a prospective recruit may be hesitant to start isotretinoin for severe nodulocystic acne, concerned that this medication may preclude them from joining the military. The current standards state that “[a]pplicants under treatment with systemic retinoids . . . do not meet the standard until 4 weeks after completing therapy,” while active severe nodulocystic acne is a disqualifying condition.¹ Therefore, the patient could proceed with isotretinoin therapy and, pending clinical response, meet accession standards as soon as 4 weeks after treatment. A clear understanding of the purpose of these standards, including protecting the applicant’s health and maximizing the chance of combat mission accomplishment, helps to reinforce responsibilities when caring for patients who wish to serve.

Isotretinoin is used in the treatment of nodulocystic and severe papulopustular acne. During the treatment period, laboratory monitoring is recommended to identify the risk for complications such as hepatotoxicity, teratogenicity, rhabdomyolysis, hyperlipidemia, and pancreatitis.¹ There is a lack of consensus of the frequency of follow-up of laboratory parameters during isotretinoin treatment. This study evaluated the changes in laboratory parameters used in daily practice for patients with acne who were treated with isotretinoin to determine the optimum test repetition frequency.

Materials and Methods

We conducted a retrospective study of data from patients who received oral isotretinoin therapy for acne between January 2021 and July 2022 via the electronic medical records at Konya Numune Hospital and Konya Private Medova Hospital (both in Konya, Turkey). Patients who received an oral isotretinoin total cumulative dose greater than 120 mg/kg were included in the study. Patient demographic data; cumulative isotretinoin doses; and alanine transaminase (ALT), aspartate transaminase (AST), γ-glutamyltransferase (GGT), creatinine kinase (CK), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) levels during treatment were recorded. Baseline laboratory levels of those parameters were compared with levels of the same parameters from the second and fourth months of treatment. Comparisons for all parameters were made between the second- and fourth-month levels. Reference ranges are shown in Table 1. Abnormalities were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events v3.0 grading system.² This study was approved by the Karatay University (Konya, Turkey) ethical committee.

Statistical Analysis—The descriptive statistics of the measurements were presented as means, standard deviations, or medians (first and third quartiles). With respect to the normal distribution, the consistency of the measurements was evaluated with the Kolmogorov-Smirnov test, and small deviations from the normal distribution were observed. Changes in laboratory measurements were evaluated with simple repeated-measures analysis of variance, and changes that differed significantly were determined by a Holm-Sidak post hoc test. Relationships between total cumulative doses and laboratory measurements at second visits were evaluated by the Pearson correlation analysis. The statistical significance level was P<.05. SPSS Statistics 23 (IBM) was used in the calculations.

Results

Consecutive Data at Baseline and Follow-up—A total of 415 patients with a mean age (SD) of 21.49 (7.25) years (range, 12–53 years) were included in our study. The mean total cumulative dose (SD) of the patients was 7267.27 (1878.4) mg. The consecutive data of the means of the laboratory parameters are shown in Table 1 and Figure 1. There was no significant change in the ALT levels between baseline and the fourth month as well as between the second- and fourth-month assessments (both P=.311). When comparing the differences among AST, GGT, and LDL-C measurements, the levels increased significantly between baseline and the second month and between baseline and the fourth month (all P<.001). There was no significant difference in CK levels at all assessments (all P=.304). When the differences between TG measurements were compared, the changes between baseline and the second month (P<.001), baseline and the fourth month (P<.001), and the second and fourth months (P=.013) were significant (Figure 1).

Abnormal Laboratory Measurements—The distribution of abnormal laboratory measurements during treatment is shown in Table 2 and Figure 2. Grade 3 or higher elevations of liver transaminases (ALT, AST) and GGT were observed in fewer than 2% of patients during treatment compared with baseline (grade 3 elevations of ALT and AST together in 2 patients; grade 4 AST elevation in 1 patient; grade 3 elevations of ALT, AST, and GGT combined in 1 patient; isolated grade 3 GGT elevation in 1 patient). All of the patients who developed grade 3 liver transaminases and isolated grade 3 GGT elevation had improved values when these were rechecked within 2 weeks.

In the patient who developed hepatotoxicity in the second month, the ALT level rose from a baseline of 19 U/L to 169 U/L, the AST level from a baseline of 19 U/L to 61 U/L, and the GGT level from a baseline of 24 U/L to 124 U/L. The patient was asymptomatic. Liver function test levels returned to reference range 4 weeks after discontinuation of therapy. Hepatotoxicity did not recur after treatment was re-administered.

The patient who developed grade 4 AST elevation (364 U/L) experienced fatigue and myalgia. He had done vigorous exercise up to 2 days before the test and also had a grade 4 CK elevation (12,310 U/L). He was thought to have isotretinoin-related rhabdomyolysis. His treatment was discontinued, and he was advised to hydrate and rest. Treatment was re-started after 2 weeks. With frequent laboratory monitoring and avoidance of vigorous physical activity, the patient completed the remaining course of isotretinoin without any laboratory abnormalities or symptoms.

Creatinine kinase abnormalities in the second and fourth months compared with baseline were not statistically significant. The patients with grade 3 or higher CK elevations, except for the case with rhabdomyolysis, had no clinical signs or other characteristic laboratory findings of rhabdomyolysis.

Hypercholesterolemia (LDL-C ≥130 mg/dL) occurred most frequently, with a maximum of 280 mg/dL in 1 patient (in the fourth month) and less than 250 mg/dL in all other patients. Hypercholesterolemia occurred in 183 (44.1%) patients in the second month and in 166 (40.0%) patients in the fourth month. However, baseline abnormalities also were frequent (86 [20.7%]), and hypercholesterolemia persisted in the second and fourth months in all of these patients.

It was observed that the patients with TG abnormalities increased continuously in the second (99 [23.9%]) and fourth (113 [27.2%]) months compared with baseline (49 [11.8%]). Grade 3 TG elevations were observed in 2.2% of patients (n=9; 5 patients in the second month, 4 patients in the fourth month) during treatment compared with baseline, and all patients had grade 1 or 2 hypertriglyceridemia at baseline. Of the patients with grade 3 TG elevation, 3 patients in the second month and 2 patients in the fourth month were obese at baseline. No grade 4 TG elevations were observed. Complications related to hyperlipidemia, such as pancreatitis, were observed in 1 patient. No patient terminated treatment because of lipid abnormalities. The treatment of our patients with major hypercholesterolemia and/or grade 3 hypertriglyceridemia was interrupted. The hyperlipidemia of these patients was controlled by a low-fat diet and a short-term dose reduction.

Relationship Between Total Cumulative Dose and Laboratory Parameters—The relationships between the total cumulative dose and changes up to the fourth month are presented in Table 3. As the total dose increased, the changes in TG and LDL-C levels significantly increased in the fourth month (both P=.001). However, the degree of these relationships was weak. No significant correlation was found between the periodic changes of other laboratory parameters and the total dose.

Comment

The parameters followed in our study show that TG levels tend to increase continuously from baseline during isotretinoin treatment, while ALT, AST, GGT, and LDL-C levels increase in the second month and decrease at 4 months. Although this same trend occurs with CK levels, the change was not statistically significant. The most common laboratory abnormality in our study was hyperlipidemia. Levels of LDL-C and TG were both found to be statistically elevated in the second and fourth months of treatment compared with baseline. Parthasarathy et al³ reported that obesity had an important role in the increase of lipid levels in patients using isotretinoin at baseline. In our study, 5 of 9 patients (55.6%) with grade 3 TG elevation were obese, which supports the theory that obesity plays an important role in the increase in lipid levels. Up-to-date laboratory follow-up of lipids suggests that there is no need to follow up serum lipids after the second month of treatment. Patients with risk factors for hyperlipidemia, such as abdominal obesity and familial hyperlipidemia, do not require further follow-up if there is no increase in serum lipids in the first month of treatment.¹ The presence of grade 1 or 2 hypertriglyceridemia at baseline in all our patients with grade 3 TG elevation may suggest that periodic laboratory follow-up during isotretinoin treatment is necessary to detect patients with grade 3 and higher TG levels.

The lack of knowledge of other risk factors (eg, familial hyperlipidemia, insulin resistance) for hyperlipidemia in all patients at baseline may be a limitation of our study. Although hypercholesterolemia persisted in the follow-up of our patients with initial LDL-C abnormalities, hypercholesterolemia over 250 mg/dL was very rare (1 patient). Possible complications associated with serum lipid abnormalities are pancreatitis and metabolic syndrome.⁴ In our study, none of the patients with lipid abnormalities had any relevant clinical sequelae. The dose-dependent elevation of the changes in LDL-C and TG (Table 3) may be important to predict the significant elevation of lipids and the associated complications in patients with a high total cumulative dose target that may require a long treatment duration. However, considering the short follow-up periods in our patients, the absence of clinical sequelae may be misleading. There are differences in recommendations between the US and European guidelines for isotretinoin dosage. Although the US guidelines recommend a total cumulative dose target, the European guidelines recommend low-dose isotretinoin daily for at least 6 months instead of a cumulative dose.^5,6 The relationship between change in lipids and total cumulative dose in our study may not be similar in patients treated with the dosing regimen recommended by the European guidelines, as our patients received a total cumulative dose instead of a daily low-dose isotretinoin regimen, unlike the European guidelines.⁵

Most liver transaminase abnormalities were detected in the second month. Abnormalities in GGT were seen in the second month and remained elevated at the next follow-up. However, clinically important grade 3 transaminase and GGT elevations were rare. It has been reported that GGT levels are more specific than transaminases in measuring hepatotoxicity.⁷ The fact that our patient with hepatotoxicity had a grade 3 GGT elevation in addition to grade 3 transaminase elevations supports that GGT elevation is more specific than transaminase levels in measuring hepatotoxicity. When these parameters were rechecked in our patients with grade 3 transaminase elevations, except in the case of hepatotoxicity, transaminase elevations did not recur, and GGT elevations did not accompany elevated transaminases, which suggested that transaminases may be elevated due to an extrahepatic origin (eg, hemolysis, exercise).

Rhabdomyolysis secondary to isotretinoin is rare in the literature of acne studies. In addition to clinical findings such as myalgia and fatigue, increased CK and abnormal liver enzymes, specifically AST, suggest the development of rhabdomyolysis.⁸ Our patient who developed rhabdomyolysis also had a recent history of vigorous exercise, grade 4 CK, and AST elevations. Other patients with isolated grade 3 CK elevations were informed about possible clinical signs of rhabdomyolysis, and they were able to complete their courses without any incident. According to a study by Landau et al,⁹ isotretinoin-associated hyperCKemia has been reported as benign. Similarly, our study found that isolated CK elevation during isotretinoin treatment may be misleading as a sign of rhabdomyolysis. Instead, CK monitoring may be more appropriate and cost-effective in patients with suspected clinical signs of rhabdomyolysis or in those with major elevations in transaminases, especially AST.

Conclusion

According to our study, hyperlipidemia was the most common complication in acne patients using isotretinoin. It may be appropriate to monitor the TG level at 2-month intervals in patients with grade 1 or 2 TG elevation at baseline to detect the possible risk for developing grade 3 hyperlipidemia. Periodic monitoring of LDL-C and TG levels may be appropriate, especially in patients who require a high total cumulative dose of isotretinoin. Clinically important liver enzyme abnormalities were rare in our study. Our findings support the idea that routine monthly monitoring of normal laboratory parameters is unnecessary and wasteful. Additionally, periodic monitoring of abnormal laboratory parameters should be considered on an individual basis.

Isotretinoin is used in the treatment of nodulocystic and severe papulopustular acne. During the treatment period, laboratory monitoring is recommended to identify the risk for complications such as hepatotoxicity, teratogenicity, rhabdomyolysis, hyperlipidemia, and pancreatitis.¹ There is a lack of consensus of the frequency of follow-up of laboratory parameters during isotretinoin treatment. This study evaluated the changes in laboratory parameters used in daily practice for patients with acne who were treated with isotretinoin to determine the optimum test repetition frequency.

Materials and Methods

We conducted a retrospective study of data from patients who received oral isotretinoin therapy for acne between January 2021 and July 2022 via the electronic medical records at Konya Numune Hospital and Konya Private Medova Hospital (both in Konya, Turkey). Patients who received an oral isotretinoin total cumulative dose greater than 120 mg/kg were included in the study. Patient demographic data; cumulative isotretinoin doses; and alanine transaminase (ALT), aspartate transaminase (AST), γ-glutamyltransferase (GGT), creatinine kinase (CK), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) levels during treatment were recorded. Baseline laboratory levels of those parameters were compared with levels of the same parameters from the second and fourth months of treatment. Comparisons for all parameters were made between the second- and fourth-month levels. Reference ranges are shown in Table 1. Abnormalities were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events v3.0 grading system.² This study was approved by the Karatay University (Konya, Turkey) ethical committee.

Statistical Analysis—The descriptive statistics of the measurements were presented as means, standard deviations, or medians (first and third quartiles). With respect to the normal distribution, the consistency of the measurements was evaluated with the Kolmogorov-Smirnov test, and small deviations from the normal distribution were observed. Changes in laboratory measurements were evaluated with simple repeated-measures analysis of variance, and changes that differed significantly were determined by a Holm-Sidak post hoc test. Relationships between total cumulative doses and laboratory measurements at second visits were evaluated by the Pearson correlation analysis. The statistical significance level was P<.05. SPSS Statistics 23 (IBM) was used in the calculations.

Results

Consecutive Data at Baseline and Follow-up—A total of 415 patients with a mean age (SD) of 21.49 (7.25) years (range, 12–53 years) were included in our study. The mean total cumulative dose (SD) of the patients was 7267.27 (1878.4) mg. The consecutive data of the means of the laboratory parameters are shown in Table 1 and Figure 1. There was no significant change in the ALT levels between baseline and the fourth month as well as between the second- and fourth-month assessments (both P=.311). When comparing the differences among AST, GGT, and LDL-C measurements, the levels increased significantly between baseline and the second month and between baseline and the fourth month (all P<.001). There was no significant difference in CK levels at all assessments (all P=.304). When the differences between TG measurements were compared, the changes between baseline and the second month (P<.001), baseline and the fourth month (P<.001), and the second and fourth months (P=.013) were significant (Figure 1).

Abnormal Laboratory Measurements—The distribution of abnormal laboratory measurements during treatment is shown in Table 2 and Figure 2. Grade 3 or higher elevations of liver transaminases (ALT, AST) and GGT were observed in fewer than 2% of patients during treatment compared with baseline (grade 3 elevations of ALT and AST together in 2 patients; grade 4 AST elevation in 1 patient; grade 3 elevations of ALT, AST, and GGT combined in 1 patient; isolated grade 3 GGT elevation in 1 patient). All of the patients who developed grade 3 liver transaminases and isolated grade 3 GGT elevation had improved values when these were rechecked within 2 weeks.

In the patient who developed hepatotoxicity in the second month, the ALT level rose from a baseline of 19 U/L to 169 U/L, the AST level from a baseline of 19 U/L to 61 U/L, and the GGT level from a baseline of 24 U/L to 124 U/L. The patient was asymptomatic. Liver function test levels returned to reference range 4 weeks after discontinuation of therapy. Hepatotoxicity did not recur after treatment was re-administered.

The patient who developed grade 4 AST elevation (364 U/L) experienced fatigue and myalgia. He had done vigorous exercise up to 2 days before the test and also had a grade 4 CK elevation (12,310 U/L). He was thought to have isotretinoin-related rhabdomyolysis. His treatment was discontinued, and he was advised to hydrate and rest. Treatment was re-started after 2 weeks. With frequent laboratory monitoring and avoidance of vigorous physical activity, the patient completed the remaining course of isotretinoin without any laboratory abnormalities or symptoms.

Creatinine kinase abnormalities in the second and fourth months compared with baseline were not statistically significant. The patients with grade 3 or higher CK elevations, except for the case with rhabdomyolysis, had no clinical signs or other characteristic laboratory findings of rhabdomyolysis.

Hypercholesterolemia (LDL-C ≥130 mg/dL) occurred most frequently, with a maximum of 280 mg/dL in 1 patient (in the fourth month) and less than 250 mg/dL in all other patients. Hypercholesterolemia occurred in 183 (44.1%) patients in the second month and in 166 (40.0%) patients in the fourth month. However, baseline abnormalities also were frequent (86 [20.7%]), and hypercholesterolemia persisted in the second and fourth months in all of these patients.

It was observed that the patients with TG abnormalities increased continuously in the second (99 [23.9%]) and fourth (113 [27.2%]) months compared with baseline (49 [11.8%]). Grade 3 TG elevations were observed in 2.2% of patients (n=9; 5 patients in the second month, 4 patients in the fourth month) during treatment compared with baseline, and all patients had grade 1 or 2 hypertriglyceridemia at baseline. Of the patients with grade 3 TG elevation, 3 patients in the second month and 2 patients in the fourth month were obese at baseline. No grade 4 TG elevations were observed. Complications related to hyperlipidemia, such as pancreatitis, were observed in 1 patient. No patient terminated treatment because of lipid abnormalities. The treatment of our patients with major hypercholesterolemia and/or grade 3 hypertriglyceridemia was interrupted. The hyperlipidemia of these patients was controlled by a low-fat diet and a short-term dose reduction.

Relationship Between Total Cumulative Dose and Laboratory Parameters—The relationships between the total cumulative dose and changes up to the fourth month are presented in Table 3. As the total dose increased, the changes in TG and LDL-C levels significantly increased in the fourth month (both P=.001). However, the degree of these relationships was weak. No significant correlation was found between the periodic changes of other laboratory parameters and the total dose.

Comment

The parameters followed in our study show that TG levels tend to increase continuously from baseline during isotretinoin treatment, while ALT, AST, GGT, and LDL-C levels increase in the second month and decrease at 4 months. Although this same trend occurs with CK levels, the change was not statistically significant. The most common laboratory abnormality in our study was hyperlipidemia. Levels of LDL-C and TG were both found to be statistically elevated in the second and fourth months of treatment compared with baseline. Parthasarathy et al³ reported that obesity had an important role in the increase of lipid levels in patients using isotretinoin at baseline. In our study, 5 of 9 patients (55.6%) with grade 3 TG elevation were obese, which supports the theory that obesity plays an important role in the increase in lipid levels. Up-to-date laboratory follow-up of lipids suggests that there is no need to follow up serum lipids after the second month of treatment. Patients with risk factors for hyperlipidemia, such as abdominal obesity and familial hyperlipidemia, do not require further follow-up if there is no increase in serum lipids in the first month of treatment.¹ The presence of grade 1 or 2 hypertriglyceridemia at baseline in all our patients with grade 3 TG elevation may suggest that periodic laboratory follow-up during isotretinoin treatment is necessary to detect patients with grade 3 and higher TG levels.

The lack of knowledge of other risk factors (eg, familial hyperlipidemia, insulin resistance) for hyperlipidemia in all patients at baseline may be a limitation of our study. Although hypercholesterolemia persisted in the follow-up of our patients with initial LDL-C abnormalities, hypercholesterolemia over 250 mg/dL was very rare (1 patient). Possible complications associated with serum lipid abnormalities are pancreatitis and metabolic syndrome.⁴ In our study, none of the patients with lipid abnormalities had any relevant clinical sequelae. The dose-dependent elevation of the changes in LDL-C and TG (Table 3) may be important to predict the significant elevation of lipids and the associated complications in patients with a high total cumulative dose target that may require a long treatment duration. However, considering the short follow-up periods in our patients, the absence of clinical sequelae may be misleading. There are differences in recommendations between the US and European guidelines for isotretinoin dosage. Although the US guidelines recommend a total cumulative dose target, the European guidelines recommend low-dose isotretinoin daily for at least 6 months instead of a cumulative dose.^5,6 The relationship between change in lipids and total cumulative dose in our study may not be similar in patients treated with the dosing regimen recommended by the European guidelines, as our patients received a total cumulative dose instead of a daily low-dose isotretinoin regimen, unlike the European guidelines.⁵

Most liver transaminase abnormalities were detected in the second month. Abnormalities in GGT were seen in the second month and remained elevated at the next follow-up. However, clinically important grade 3 transaminase and GGT elevations were rare. It has been reported that GGT levels are more specific than transaminases in measuring hepatotoxicity.⁷ The fact that our patient with hepatotoxicity had a grade 3 GGT elevation in addition to grade 3 transaminase elevations supports that GGT elevation is more specific than transaminase levels in measuring hepatotoxicity. When these parameters were rechecked in our patients with grade 3 transaminase elevations, except in the case of hepatotoxicity, transaminase elevations did not recur, and GGT elevations did not accompany elevated transaminases, which suggested that transaminases may be elevated due to an extrahepatic origin (eg, hemolysis, exercise).

Rhabdomyolysis secondary to isotretinoin is rare in the literature of acne studies. In addition to clinical findings such as myalgia and fatigue, increased CK and abnormal liver enzymes, specifically AST, suggest the development of rhabdomyolysis.⁸ Our patient who developed rhabdomyolysis also had a recent history of vigorous exercise, grade 4 CK, and AST elevations. Other patients with isolated grade 3 CK elevations were informed about possible clinical signs of rhabdomyolysis, and they were able to complete their courses without any incident. According to a study by Landau et al,⁹ isotretinoin-associated hyperCKemia has been reported as benign. Similarly, our study found that isolated CK elevation during isotretinoin treatment may be misleading as a sign of rhabdomyolysis. Instead, CK monitoring may be more appropriate and cost-effective in patients with suspected clinical signs of rhabdomyolysis or in those with major elevations in transaminases, especially AST.

Conclusion

According to our study, hyperlipidemia was the most common complication in acne patients using isotretinoin. It may be appropriate to monitor the TG level at 2-month intervals in patients with grade 1 or 2 TG elevation at baseline to detect the possible risk for developing grade 3 hyperlipidemia. Periodic monitoring of LDL-C and TG levels may be appropriate, especially in patients who require a high total cumulative dose of isotretinoin. Clinically important liver enzyme abnormalities were rare in our study. Our findings support the idea that routine monthly monitoring of normal laboratory parameters is unnecessary and wasteful. Additionally, periodic monitoring of abnormal laboratory parameters should be considered on an individual basis.

Isotretinoin is used in the treatment of nodulocystic and severe papulopustular acne. During the treatment period, laboratory monitoring is recommended to identify the risk for complications such as hepatotoxicity, teratogenicity, rhabdomyolysis, hyperlipidemia, and pancreatitis.¹ There is a lack of consensus of the frequency of follow-up of laboratory parameters during isotretinoin treatment. This study evaluated the changes in laboratory parameters used in daily practice for patients with acne who were treated with isotretinoin to determine the optimum test repetition frequency.

Materials and Methods

We conducted a retrospective study of data from patients who received oral isotretinoin therapy for acne between January 2021 and July 2022 via the electronic medical records at Konya Numune Hospital and Konya Private Medova Hospital (both in Konya, Turkey). Patients who received an oral isotretinoin total cumulative dose greater than 120 mg/kg were included in the study. Patient demographic data; cumulative isotretinoin doses; and alanine transaminase (ALT), aspartate transaminase (AST), γ-glutamyltransferase (GGT), creatinine kinase (CK), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) levels during treatment were recorded. Baseline laboratory levels of those parameters were compared with levels of the same parameters from the second and fourth months of treatment. Comparisons for all parameters were made between the second- and fourth-month levels. Reference ranges are shown in Table 1. Abnormalities were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events v3.0 grading system.² This study was approved by the Karatay University (Konya, Turkey) ethical committee.

Statistical Analysis—The descriptive statistics of the measurements were presented as means, standard deviations, or medians (first and third quartiles). With respect to the normal distribution, the consistency of the measurements was evaluated with the Kolmogorov-Smirnov test, and small deviations from the normal distribution were observed. Changes in laboratory measurements were evaluated with simple repeated-measures analysis of variance, and changes that differed significantly were determined by a Holm-Sidak post hoc test. Relationships between total cumulative doses and laboratory measurements at second visits were evaluated by the Pearson correlation analysis. The statistical significance level was P<.05. SPSS Statistics 23 (IBM) was used in the calculations.

Results

Consecutive Data at Baseline and Follow-up—A total of 415 patients with a mean age (SD) of 21.49 (7.25) years (range, 12–53 years) were included in our study. The mean total cumulative dose (SD) of the patients was 7267.27 (1878.4) mg. The consecutive data of the means of the laboratory parameters are shown in Table 1 and Figure 1. There was no significant change in the ALT levels between baseline and the fourth month as well as between the second- and fourth-month assessments (both P=.311). When comparing the differences among AST, GGT, and LDL-C measurements, the levels increased significantly between baseline and the second month and between baseline and the fourth month (all P<.001). There was no significant difference in CK levels at all assessments (all P=.304). When the differences between TG measurements were compared, the changes between baseline and the second month (P<.001), baseline and the fourth month (P<.001), and the second and fourth months (P=.013) were significant (Figure 1).

Abnormal Laboratory Measurements—The distribution of abnormal laboratory measurements during treatment is shown in Table 2 and Figure 2. Grade 3 or higher elevations of liver transaminases (ALT, AST) and GGT were observed in fewer than 2% of patients during treatment compared with baseline (grade 3 elevations of ALT and AST together in 2 patients; grade 4 AST elevation in 1 patient; grade 3 elevations of ALT, AST, and GGT combined in 1 patient; isolated grade 3 GGT elevation in 1 patient). All of the patients who developed grade 3 liver transaminases and isolated grade 3 GGT elevation had improved values when these were rechecked within 2 weeks.

In the patient who developed hepatotoxicity in the second month, the ALT level rose from a baseline of 19 U/L to 169 U/L, the AST level from a baseline of 19 U/L to 61 U/L, and the GGT level from a baseline of 24 U/L to 124 U/L. The patient was asymptomatic. Liver function test levels returned to reference range 4 weeks after discontinuation of therapy. Hepatotoxicity did not recur after treatment was re-administered.

The patient who developed grade 4 AST elevation (364 U/L) experienced fatigue and myalgia. He had done vigorous exercise up to 2 days before the test and also had a grade 4 CK elevation (12,310 U/L). He was thought to have isotretinoin-related rhabdomyolysis. His treatment was discontinued, and he was advised to hydrate and rest. Treatment was re-started after 2 weeks. With frequent laboratory monitoring and avoidance of vigorous physical activity, the patient completed the remaining course of isotretinoin without any laboratory abnormalities or symptoms.

Creatinine kinase abnormalities in the second and fourth months compared with baseline were not statistically significant. The patients with grade 3 or higher CK elevations, except for the case with rhabdomyolysis, had no clinical signs or other characteristic laboratory findings of rhabdomyolysis.

Hypercholesterolemia (LDL-C ≥130 mg/dL) occurred most frequently, with a maximum of 280 mg/dL in 1 patient (in the fourth month) and less than 250 mg/dL in all other patients. Hypercholesterolemia occurred in 183 (44.1%) patients in the second month and in 166 (40.0%) patients in the fourth month. However, baseline abnormalities also were frequent (86 [20.7%]), and hypercholesterolemia persisted in the second and fourth months in all of these patients.

It was observed that the patients with TG abnormalities increased continuously in the second (99 [23.9%]) and fourth (113 [27.2%]) months compared with baseline (49 [11.8%]). Grade 3 TG elevations were observed in 2.2% of patients (n=9; 5 patients in the second month, 4 patients in the fourth month) during treatment compared with baseline, and all patients had grade 1 or 2 hypertriglyceridemia at baseline. Of the patients with grade 3 TG elevation, 3 patients in the second month and 2 patients in the fourth month were obese at baseline. No grade 4 TG elevations were observed. Complications related to hyperlipidemia, such as pancreatitis, were observed in 1 patient. No patient terminated treatment because of lipid abnormalities. The treatment of our patients with major hypercholesterolemia and/or grade 3 hypertriglyceridemia was interrupted. The hyperlipidemia of these patients was controlled by a low-fat diet and a short-term dose reduction.

Relationship Between Total Cumulative Dose and Laboratory Parameters—The relationships between the total cumulative dose and changes up to the fourth month are presented in Table 3. As the total dose increased, the changes in TG and LDL-C levels significantly increased in the fourth month (both P=.001). However, the degree of these relationships was weak. No significant correlation was found between the periodic changes of other laboratory parameters and the total dose.

Comment

The parameters followed in our study show that TG levels tend to increase continuously from baseline during isotretinoin treatment, while ALT, AST, GGT, and LDL-C levels increase in the second month and decrease at 4 months. Although this same trend occurs with CK levels, the change was not statistically significant. The most common laboratory abnormality in our study was hyperlipidemia. Levels of LDL-C and TG were both found to be statistically elevated in the second and fourth months of treatment compared with baseline. Parthasarathy et al³ reported that obesity had an important role in the increase of lipid levels in patients using isotretinoin at baseline. In our study, 5 of 9 patients (55.6%) with grade 3 TG elevation were obese, which supports the theory that obesity plays an important role in the increase in lipid levels. Up-to-date laboratory follow-up of lipids suggests that there is no need to follow up serum lipids after the second month of treatment. Patients with risk factors for hyperlipidemia, such as abdominal obesity and familial hyperlipidemia, do not require further follow-up if there is no increase in serum lipids in the first month of treatment.¹ The presence of grade 1 or 2 hypertriglyceridemia at baseline in all our patients with grade 3 TG elevation may suggest that periodic laboratory follow-up during isotretinoin treatment is necessary to detect patients with grade 3 and higher TG levels.

The lack of knowledge of other risk factors (eg, familial hyperlipidemia, insulin resistance) for hyperlipidemia in all patients at baseline may be a limitation of our study. Although hypercholesterolemia persisted in the follow-up of our patients with initial LDL-C abnormalities, hypercholesterolemia over 250 mg/dL was very rare (1 patient). Possible complications associated with serum lipid abnormalities are pancreatitis and metabolic syndrome.⁴ In our study, none of the patients with lipid abnormalities had any relevant clinical sequelae. The dose-dependent elevation of the changes in LDL-C and TG (Table 3) may be important to predict the significant elevation of lipids and the associated complications in patients with a high total cumulative dose target that may require a long treatment duration. However, considering the short follow-up periods in our patients, the absence of clinical sequelae may be misleading. There are differences in recommendations between the US and European guidelines for isotretinoin dosage. Although the US guidelines recommend a total cumulative dose target, the European guidelines recommend low-dose isotretinoin daily for at least 6 months instead of a cumulative dose.^5,6 The relationship between change in lipids and total cumulative dose in our study may not be similar in patients treated with the dosing regimen recommended by the European guidelines, as our patients received a total cumulative dose instead of a daily low-dose isotretinoin regimen, unlike the European guidelines.⁵

Most liver transaminase abnormalities were detected in the second month. Abnormalities in GGT were seen in the second month and remained elevated at the next follow-up. However, clinically important grade 3 transaminase and GGT elevations were rare. It has been reported that GGT levels are more specific than transaminases in measuring hepatotoxicity.⁷ The fact that our patient with hepatotoxicity had a grade 3 GGT elevation in addition to grade 3 transaminase elevations supports that GGT elevation is more specific than transaminase levels in measuring hepatotoxicity. When these parameters were rechecked in our patients with grade 3 transaminase elevations, except in the case of hepatotoxicity, transaminase elevations did not recur, and GGT elevations did not accompany elevated transaminases, which suggested that transaminases may be elevated due to an extrahepatic origin (eg, hemolysis, exercise).

Rhabdomyolysis secondary to isotretinoin is rare in the literature of acne studies. In addition to clinical findings such as myalgia and fatigue, increased CK and abnormal liver enzymes, specifically AST, suggest the development of rhabdomyolysis.⁸ Our patient who developed rhabdomyolysis also had a recent history of vigorous exercise, grade 4 CK, and AST elevations. Other patients with isolated grade 3 CK elevations were informed about possible clinical signs of rhabdomyolysis, and they were able to complete their courses without any incident. According to a study by Landau et al,⁹ isotretinoin-associated hyperCKemia has been reported as benign. Similarly, our study found that isolated CK elevation during isotretinoin treatment may be misleading as a sign of rhabdomyolysis. Instead, CK monitoring may be more appropriate and cost-effective in patients with suspected clinical signs of rhabdomyolysis or in those with major elevations in transaminases, especially AST.

Conclusion

According to our study, hyperlipidemia was the most common complication in acne patients using isotretinoin. It may be appropriate to monitor the TG level at 2-month intervals in patients with grade 1 or 2 TG elevation at baseline to detect the possible risk for developing grade 3 hyperlipidemia. Periodic monitoring of LDL-C and TG levels may be appropriate, especially in patients who require a high total cumulative dose of isotretinoin. Clinically important liver enzyme abnormalities were rare in our study. Our findings support the idea that routine monthly monitoring of normal laboratory parameters is unnecessary and wasteful. Additionally, periodic monitoring of abnormal laboratory parameters should be considered on an individual basis.

It is interesting to observe the changes in dermatology that have occurred over the last 1 to 2 decades, especially as major advances in basic science research techniques have rapidly expanded our current understanding of the pathophysiology of many disease states—psoriasis, psoriatic arthritis, atopic dermatitis, alopecia areata, vitiligo, hidradenitis suppurativa, and lichen planus.¹ Although acne vulgaris (AV) and rosacea do not make front-page news quite as often as some of these other aforementioned disease states in the pathophysiology arena, advances still have been made in understanding the pathophysiology, albeit slower and often less popularized in dermatology publications and other forms of media.^2-4

If one looks at our fundamental understanding of AV, most of the discussion over multiple decades has been driven by new treatments and in some cases new formulations and packaging differences with topical agents. Although we understood that adrenarche, a subsequent increase in androgen synthesis, and the ensuing sebocyte development with formation of sebum were prerequisites for the development of AV, the absence of therapeutic options to address these vital components of AV—especially US Food and Drug Administration (FDA)–approved therapies—resulted in limited discussion about this specific area.⁵ Rather, the discussion was dominated by the notable role of Propionibacterium acnes (now called Cutibacterium acnes) in AV pathophysiology, as we had therapies such as benzoyl peroxide and antibiotics that improved AV in direct correlation with reductions in P acnes.⁶ This was soon coupled with an advanced understanding of how to reduce follicular hyperkeratinization with the development of topical tretinoin, followed by 3 other topical retinoids over time—adapalene, tazarotene, and trifarotene. Over subsequent years, slowly emerging basic science developments and collective data reviews added to our understanding of AV and how different therapies appear to work, including the role of toll-like receptors, anti-inflammatory properties of tetracyclines, and inflammasomes.^7-9 Without a doubt, the availability of oral isotretinoin revolutionized AV therapy, especially in patients with severe refractory disease, with advanced formulations allowing for optimization of sustained remission without the need for high dietary fat intake.^10-12

Progress in the pathophysiology of rosacea has been slower to develop, with the first true discussion of specific clinical presentations published after the new millennium.¹³ This was followed by more advanced basic science and clinical research, which led to an improved ability to understand modes of action of various therapies and to correlate treatment selection with specific visible manifestations of rosacea, including incorporation of physical devices.^14-16 A newer perspective on evaluation and management of rosacea moved away from the “buckets” of rosacea subtypes to phenotypes observed at the time of clinical presentation.^17,18

I could elaborate on research advancements with both diseases, but the bottom line is that information, developments, and current perspectives change over time. Keeping up is a challenge for all who study and practice dermatology. It is human nature to revert to what we already believe and do, which sometimes remains valid and other times is quite outdated and truly replaced by more optimal approaches. With AV and rosacea, progress is much slower in availability of newer agents. With AV, new agents have included topical dapsone, oral sarecycline, and topical clascoterone, with the latter being the first FDA-approved topical agent to mitigate the effects of androgens and sebum in both males and females. For rosacea, the 2 most recent FDA-approved therapies are minocycline foam and microencapsulated benzoyl peroxide. All of these therapies are proven to be effective for the modes of action and skin manifestations they specifically manage. Over the upcoming year, we are hoping to see the first triple-combination topical product come to market for AV, which will prompt our minds to consider if and how 3 established agents can work together to further augment treatment efficacy with favorable tolerability and safety.

Where will all of this end up? It is hard to say. We still have several other areas to tackle with both disease states, including establishing a well-substantiated understanding of the pathophysiologic role of the microbiome, sorting out the role of antibiotic use due to concerns about bacterial resistance, integration of FDA-approved physical devices in AV, and data on both diet and optimized skin care, to name a few.^19-21

There is a lot on the plate to accomplish and digest. I have remained very involved in this subject matter for almost 3 decades and am still feeling the growing pains. Fortunately, the satisfaction of being part of a process so important to the lives of millions of patients makes this worth every moment. Stay tuned—more valuable information is to come.

It is interesting to observe the changes in dermatology that have occurred over the last 1 to 2 decades, especially as major advances in basic science research techniques have rapidly expanded our current understanding of the pathophysiology of many disease states—psoriasis, psoriatic arthritis, atopic dermatitis, alopecia areata, vitiligo, hidradenitis suppurativa, and lichen planus.¹ Although acne vulgaris (AV) and rosacea do not make front-page news quite as often as some of these other aforementioned disease states in the pathophysiology arena, advances still have been made in understanding the pathophysiology, albeit slower and often less popularized in dermatology publications and other forms of media.^2-4

If one looks at our fundamental understanding of AV, most of the discussion over multiple decades has been driven by new treatments and in some cases new formulations and packaging differences with topical agents. Although we understood that adrenarche, a subsequent increase in androgen synthesis, and the ensuing sebocyte development with formation of sebum were prerequisites for the development of AV, the absence of therapeutic options to address these vital components of AV—especially US Food and Drug Administration (FDA)–approved therapies—resulted in limited discussion about this specific area.⁵ Rather, the discussion was dominated by the notable role of Propionibacterium acnes (now called Cutibacterium acnes) in AV pathophysiology, as we had therapies such as benzoyl peroxide and antibiotics that improved AV in direct correlation with reductions in P acnes.⁶ This was soon coupled with an advanced understanding of how to reduce follicular hyperkeratinization with the development of topical tretinoin, followed by 3 other topical retinoids over time—adapalene, tazarotene, and trifarotene. Over subsequent years, slowly emerging basic science developments and collective data reviews added to our understanding of AV and how different therapies appear to work, including the role of toll-like receptors, anti-inflammatory properties of tetracyclines, and inflammasomes.^7-9 Without a doubt, the availability of oral isotretinoin revolutionized AV therapy, especially in patients with severe refractory disease, with advanced formulations allowing for optimization of sustained remission without the need for high dietary fat intake.^10-12

Progress in the pathophysiology of rosacea has been slower to develop, with the first true discussion of specific clinical presentations published after the new millennium.¹³ This was followed by more advanced basic science and clinical research, which led to an improved ability to understand modes of action of various therapies and to correlate treatment selection with specific visible manifestations of rosacea, including incorporation of physical devices.^14-16 A newer perspective on evaluation and management of rosacea moved away from the “buckets” of rosacea subtypes to phenotypes observed at the time of clinical presentation.^17,18

I could elaborate on research advancements with both diseases, but the bottom line is that information, developments, and current perspectives change over time. Keeping up is a challenge for all who study and practice dermatology. It is human nature to revert to what we already believe and do, which sometimes remains valid and other times is quite outdated and truly replaced by more optimal approaches. With AV and rosacea, progress is much slower in availability of newer agents. With AV, new agents have included topical dapsone, oral sarecycline, and topical clascoterone, with the latter being the first FDA-approved topical agent to mitigate the effects of androgens and sebum in both males and females. For rosacea, the 2 most recent FDA-approved therapies are minocycline foam and microencapsulated benzoyl peroxide. All of these therapies are proven to be effective for the modes of action and skin manifestations they specifically manage. Over the upcoming year, we are hoping to see the first triple-combination topical product come to market for AV, which will prompt our minds to consider if and how 3 established agents can work together to further augment treatment efficacy with favorable tolerability and safety.

Where will all of this end up? It is hard to say. We still have several other areas to tackle with both disease states, including establishing a well-substantiated understanding of the pathophysiologic role of the microbiome, sorting out the role of antibiotic use due to concerns about bacterial resistance, integration of FDA-approved physical devices in AV, and data on both diet and optimized skin care, to name a few.^19-21

There is a lot on the plate to accomplish and digest. I have remained very involved in this subject matter for almost 3 decades and am still feeling the growing pains. Fortunately, the satisfaction of being part of a process so important to the lives of millions of patients makes this worth every moment. Stay tuned—more valuable information is to come.

It is interesting to observe the changes in dermatology that have occurred over the last 1 to 2 decades, especially as major advances in basic science research techniques have rapidly expanded our current understanding of the pathophysiology of many disease states—psoriasis, psoriatic arthritis, atopic dermatitis, alopecia areata, vitiligo, hidradenitis suppurativa, and lichen planus.¹ Although acne vulgaris (AV) and rosacea do not make front-page news quite as often as some of these other aforementioned disease states in the pathophysiology arena, advances still have been made in understanding the pathophysiology, albeit slower and often less popularized in dermatology publications and other forms of media.^2-4

If one looks at our fundamental understanding of AV, most of the discussion over multiple decades has been driven by new treatments and in some cases new formulations and packaging differences with topical agents. Although we understood that adrenarche, a subsequent increase in androgen synthesis, and the ensuing sebocyte development with formation of sebum were prerequisites for the development of AV, the absence of therapeutic options to address these vital components of AV—especially US Food and Drug Administration (FDA)–approved therapies—resulted in limited discussion about this specific area.⁵ Rather, the discussion was dominated by the notable role of Propionibacterium acnes (now called Cutibacterium acnes) in AV pathophysiology, as we had therapies such as benzoyl peroxide and antibiotics that improved AV in direct correlation with reductions in P acnes.⁶ This was soon coupled with an advanced understanding of how to reduce follicular hyperkeratinization with the development of topical tretinoin, followed by 3 other topical retinoids over time—adapalene, tazarotene, and trifarotene. Over subsequent years, slowly emerging basic science developments and collective data reviews added to our understanding of AV and how different therapies appear to work, including the role of toll-like receptors, anti-inflammatory properties of tetracyclines, and inflammasomes.^7-9 Without a doubt, the availability of oral isotretinoin revolutionized AV therapy, especially in patients with severe refractory disease, with advanced formulations allowing for optimization of sustained remission without the need for high dietary fat intake.^10-12

Progress in the pathophysiology of rosacea has been slower to develop, with the first true discussion of specific clinical presentations published after the new millennium.¹³ This was followed by more advanced basic science and clinical research, which led to an improved ability to understand modes of action of various therapies and to correlate treatment selection with specific visible manifestations of rosacea, including incorporation of physical devices.^14-16 A newer perspective on evaluation and management of rosacea moved away from the “buckets” of rosacea subtypes to phenotypes observed at the time of clinical presentation.^17,18

I could elaborate on research advancements with both diseases, but the bottom line is that information, developments, and current perspectives change over time. Keeping up is a challenge for all who study and practice dermatology. It is human nature to revert to what we already believe and do, which sometimes remains valid and other times is quite outdated and truly replaced by more optimal approaches. With AV and rosacea, progress is much slower in availability of newer agents. With AV, new agents have included topical dapsone, oral sarecycline, and topical clascoterone, with the latter being the first FDA-approved topical agent to mitigate the effects of androgens and sebum in both males and females. For rosacea, the 2 most recent FDA-approved therapies are minocycline foam and microencapsulated benzoyl peroxide. All of these therapies are proven to be effective for the modes of action and skin manifestations they specifically manage. Over the upcoming year, we are hoping to see the first triple-combination topical product come to market for AV, which will prompt our minds to consider if and how 3 established agents can work together to further augment treatment efficacy with favorable tolerability and safety.

Where will all of this end up? It is hard to say. We still have several other areas to tackle with both disease states, including establishing a well-substantiated understanding of the pathophysiologic role of the microbiome, sorting out the role of antibiotic use due to concerns about bacterial resistance, integration of FDA-approved physical devices in AV, and data on both diet and optimized skin care, to name a few.^19-21

There is a lot on the plate to accomplish and digest. I have remained very involved in this subject matter for almost 3 decades and am still feeling the growing pains. Fortunately, the satisfaction of being part of a process so important to the lives of millions of patients makes this worth every moment. Stay tuned—more valuable information is to come.

Pyoderma gangrenosum (PG), acne, and hidradenitis suppurativa (HS)(PASH) syndrome is a recently identified disease process within the spectrum of autoinflammatory diseases (AIDs), which are distinct from autoimmune, infectious, and allergic syndromes and are gaining increasing interest given their complex pathophysiology and therapeutic resistance.¹ Autoinflammatory diseases are defined by a dysregulation of the innate immune system in the absence of typical autoimmune features, including autoantibodies and antigen-specific T lymphocytes.² Mutations affecting proteins of the inflammasome or proteins involved in regulating inflammasome function have been associated with these AIDs.²

Many AIDs have cutaneous involvement, as seen in PASH syndrome. Pyoderma gangrenosum is a neutrophilic dermatosis presenting as skin ulcers with undermined, erythematous, violaceous borders. It can be isolated, syndromic, or associated with inflammatory conditions (eg, inflammatory bowel disease, rheumatologic disorders, hematologic disorders).¹ Acne vulgaris develops because of chronic obstruction of hair follicles as a result of disordered keratinization and abnormal sebaceous stem cell differentiation.²Propionibacterium acnes can reside and replicate within the biofilm community of the hair follicle and activate the inflammasome.^2,3 Hidradenitis suppurativa, a chronic relapsing neutrophilic dermatosis, is a debilitating inflammatory disease of the hair follicles involving apocrine gland–bearing skin (ie, the axillary, inguinal, and anogenital regions).² Onset often occurs between the ages of 20 and 40 years, with a 3-fold higher incidence in women compared to men.³ Patients experience painful, deep-seated nodules that drain into sinus tracts and abscesses. The condition can be isolated or associated with inflammatory conditions, such as inflammatory bowel disease.⁴

PASH syndrome has been described as a polygenic autoinflammatory condition that most commonly presents in young adults, with onset of acne beginning years prior to other manifestations. A study analyzing 5 patients with PASH syndrome reported an average age of 32.2 years at diagnosis with a disease duration of 3 to 7 years.⁵ Pathophysiology of this condition is not well understood, with many hypotheses calling upon dysregulation of the innate immune system, a commonality this syndrome may share with other AIDs. Given its poorly understood pathophysiology, treating PASH syndrome can be especially difficult. We report a novel case of disease remission lasting more than 4 years using adalimumab and cyclosporine. We also discuss prior treatment successes and hypotheses regarding etiologic factors in PASH syndrome.

Case Report

A 36-year-old woman presented for evaluation of open draining ulcerations on the back of 18 months’ duration. She had a 16-year history of scarring cystic acne of the face and HS of the groin. The patient’s family history was remarkable for severe cystic acne in her brother and son as well as HS in her mother and another brother. Her treatment history included isotretinoin, doxycycline, and topical steroids.

Physical examination revealed 2 ulcerations with violaceous borders involving the left upper back (greatest diameter, 5×7 cm)(Figure 1). Evidence of papular and cystic acne with residual scarring was noted on the cheeks. Scarring from HS was noted in the axillae and right groin. A biopsy from the edge of an ulceration on the back demonstrated epidermal spongiosis with acute and chronic inflammation and fibrosis (Figure 2). The clinicopathologic findings were most consistent with PG, and the patient was diagnosed with PASH syndrome, given the constellation of cutaneous lesions.

After treatment with topical and systemic antibiotics for acne and HS for more than 1 year failed, the patient was started on adalimumab. The initial dose was 160 mg subcutaneously, then 80 mg 2 weeks later, then 40 mg weekly thereafter. Doxycycline was continued for treatment of the acne and HS. After 6 weeks of adalimumab, the PG worsened and prednisone was added. She developed tender furuncles on the back, and cultures grew Pseudomonas aeruginosa and methicillin-sensitive Staphylococcus aureus that responded to ciprofloxacin and cephalexin.

Due to progression of PG on adalimumab, switching to an infliximab infusion or anakinra was considered, but these options were not covered by the patient’s health insurance. Three months after the initial presentation, the patient was started on cyclosporine 100 mg 3 times daily (5 mg/kg/d) while adalimumab was continued; the ulcers started to improve within 2.5 weeks. After 3 months (Figure 3), the cyclosporine was reduced to 100 mg twice daily, and adalimumab was continued. She had a slight flare of PG after 8 months of treatment when adalimumab was unavailable to her for 2 months. After 8 months on cyclosporine, the dosage was tapered to 100 mg/d and then completely discontinued after 12 months.

The patient has continued on adalimumab 40 mg weekly with excellent control of the PG (Figure 4), although she did have one HS flare in the left axilla 11 months after the initial treatment. The patient’s cystic acne has intermittently flared and has been managed with spironolactone 100 mg/d for 3 years. After 4 years of management, the patient’s PG and HS remain well controlled on adalimumab.

Comment

Our case represents a major step in refining long-term treatment approaches for PASH syndrome due to the 4-year remission. Prior cases have reported use of anakinra, anakinra-cyclosporine combination, prednisone, azathioprine, topical tacrolimus, etanercept, and dapsone without sustainable success.^1-6 The case studies discussed below have achieved remission via alternative drug combinations.

Staub et al⁴ found greatest success with a combination of infliximab, dapsone, and cyclosporine, and their patient had been in remission for 20 months at time of publication. Their hypothesis proposed that multiple inflammatory signaling pathways are involved in PASH syndrome, and this is why combination therapy is required for remission.⁴ In 2018, Lamiaux et al⁷ demonstrated successful treatment with rifampicin and clindamycin. Their patient had been in remission for 22 months at the time of publication—this time frame included 12 months of combination therapy and 10 months without medication. The authors hypothesized that, because of the autoinflammatory nature of these antibiotics, this pharmacologic combination could eradicate pathogenic bacteria from host microbiota while also inhibiting neutrophil function and synthesis of chemokines and cytokines.⁷

More recently, reports have been published regarding the success of tildrakizumab, an IL-23 antagonist, and ixekizumab, an IL-17 antagonist, in the treatment of PASH syndrome.^6,8 Ixekizumab was used in combination with doxycycline, and remission was achieved in 12 months.⁸ However, tildrakizumab was used alone and achieved greater than 75% improvement in disease manifestations within 2 months.

Marzano et al⁵ conducted protein arrays and enzyme-linked immunosorbent assay to analyze the expression of cytokine, chemokine, and effector molecule profiles in PASH syndrome. It was determined that serum analysis displayed a normal cytokine/chemokine profile, with the only abnormalities being anemia and elevated C-reactive protein. There were no statistically significant differences in serum levels of IL-1β, tumor necrosis factor (TNF) α, or IL-17 between PASH syndrome and healthy controls. However, cutaneous analysis revealed extensive cytokine and chemokine hyperactivity for IL-1β and IL-1β receptor; TNF-α; C-X-C motif ligands 1, 2, and 3; C-X-C motif ligand 16; regulated on activation, normal T cell expressed and secreted; IL-17 and IL-17R; Fas/Fas ligand; and CD40/CD40L. This cutaneous profile of elevated cytokines and chemokines mirrors that of nonsyndromic PG and many other AIDs. These results demonstrate that the inflammation in PASH syndrome is localized mainly to the skin and further support the hypothesis that possibilities for alternative treatment options are diverse.⁵

Ead et al³ presented a unique perspective focusing on cutaneous biofilm involvement in PASH syndrome. Microbes within these biofilms induce the migration and proliferation of inflammatory cells that consume factors normally utilized for tissue catabolism. These organisms deplete necessary biochemical cofactors used during healing. This lack of nutrients needed for healing not only slows the process but also promotes favorable conditions for the growth of anerobic species. In conjunction, biofilm formation restricts bacterial access to oxygen and nutrients, thus decreasing the bacterial metabolic rate and preventing the effects of antibiotic therapy. These features of biofilm communities contribute to inflammation and possibly the troubling resistance to many therapeutic options for PASH syndrome.

Each component of PASH syndrome has been associated with biofilm formation. As previously described, PG manifests in the skin as painful ulcerations, often with slough. This slough is hypothesized to be a consequence of increased vascular permeability and exudative byproducts that accompany the inflammatory nature of biofilms.³ Acne vulgaris has well-described associations with P acnes. Ead et al³ described P acnes as a component of the biofilm community within the microcomedone of hair follicles. This biofilm allows for antibiotic resistance occasionally seen in the treatment of acne and is potentially the pathogenic factor that both impedes healing and enhances the inflammatory state. Hidradenitis suppurativa has been associated with biofilm formation.³

In further pursuit of PASH syndrome pathophysiology, many experts have sought to uncover the relationship between PASH syndrome and the previously described pyogenic arthritis, PG, and acne (PAPA) syndrome, another entity within the AIDs spectrum (Table). This condition was first recognized in 1997 in a 3-generation family with 10 affected members.¹ It is characterized by PG and acne, similar to PASH; however, PAPA syndrome includes PG arthritis and lacks HS. Pyogenic arthritis manifests as recurrent aseptic inflammation of the joints, mainly the elbows, knees, and ankles. Pyogenic arthritis commonly is the presenting symptom of PAPA syndrome, with onset in childhood.² As patients age, the arthritic symptoms decrease, and skin manifestations become more prominent.

PAPA syndrome has autosomal-dominant inheritance with mutations on chromosome 15 in the proline-serine-threonine phosphatase interacting protein 1 (PSTPIP1) gene.¹ This mutation induces hyperphosphorylation of PSTPIP1, allowing for increased binding affinity to pyrin. Both PSTPIP1 and pyrin are co-expressed as parts of the NLRP3 inflammasome in granulocytes and monocytes.¹ As a result, pyrin is more highly bound and loses its inhibitory effect on the NLRP3 inflammasome pathway. This lack of inhibition allows for uninhibited cleavage of pro–IL-1β to active IL-1β by the inflammasome.¹

Elevated concentrations of IL-1β in patients with PAPA syndrome result in a dysregulation of the innate immune system. IL-1β induces the release of proinflammatory cytokines, namely TNF-α; interferon γ; IL-8; and regulated on activation, normal T cell expressed and secreted (RANTES), all of which activate neutrophils and induce neutrophilic inflammation.² IL-1β not only initiates this entire cascade but also acts as an antiapoptotic signal for neutrophils.² When IL-1β reaches a critical threshold, it induces enough inflammation to cause severe tissue damage, thus causing joint and cutaneous disease in PAPA syndrome. IL-1 inhibitors (anakinra) or TNF-α inhibitors (etanercept, adalimumab, infliximab) have been used many times to successfully treat PAPA syndrome, with TNF-α inhibitors providing the most consistent results.

Another AIDs entity with similarities to both PAPA syndrome and PASH syndrome is pyogenic arthritis, PG, acne, and HS (PA-PASH) syndrome. First identified in 2012 by Bruzzese,⁹ genetic analyses revealed a p.E277D missense mutation in PSTPIP1 in PA-PASH syndrome. Research has suggested that the key molecular feature is neutrophil activation by T_H17 cells and the TNF-α axis.⁹ This syndrome has not been further characterized, and little is known regarding adequate treatment for PA-PASH syndrome.

Although it is similar in phenotype to aspects of PAPA and PA-PASH syndromes, PASH syndrome has distinct genotypic and immunologic abnormalities. Genetic analysis of this condition has shown an increased number of CCTG repeats in proximity to the PSTPIP1 promoter. It is hypothesized that these additional repeats predispose patients to neutrophilic inflammation in a similar manner to a condition described in France, termed aseptic abscess syndrome.^1,5 Other mutations have been identified, including those in IL-1N, PSMB8, MEFV, NOD2, NCSTN, and more.^2,7 However, it has been determined that the majority of these variants have already been filed in the Single Nucleotide Polymorphism Database or in the Registry of Hereditary Auto-inflammatory Disorders Mutations.² The question remains regarding the origin of inflammation seen in PASH syndrome; the potential role of biofilms; and the relationship between PASH, PAPA, and PA-PASH syndromes. Much work remains to be done in refining therapeutic options for PASH syndrome. Continued biochemical research is necessary, as well as collaboration among dermatologists worldwide who find success in treating this condition.

Conclusion

There are genotypic and phenotypic similarities between PASH, PAPA, and PA-PASH syndromes, with various mutations within or near the PSTPIP1 gene; however, their genetic discrepancies seem to play a major role in the pathophysiology of each syndrome. Much work remains to be done in PA-PASH syndrome, which has not yet been well described. Meanwhile, PAPA syndrome has been well characterized with mutations affecting proteins of the NLRP3 inflammasome, resulting in elevated IL-1β and excess neutrophilic inflammation. In PASH syndrome, the importance of increased repeats near the PSTPIP1 promoter is yet to be elucidated. It has been shown that these abnormalities predispose individuals to neutrophilic inflammation, but the mechanism by which they do so is unknown. In addition, consideration of biofilms and their predisposition to inflammation within the pathophysiology of PASH syndrome is a possibility that must be considered when discussing therapeutic options. Based on our case study and previous successes in treating PASH syndrome, it is clear that a multidrug approach is necessary for remission. It is likely that the etiology of PASH syndrome is multifaceted and involves hyperactivity in multiple arms of the innate immune system.

Patients with PASH syndrome have severely impaired quality of life and often experience social withdrawal due to the disfiguring sequelae and limited treatment options available. To improve patient outcomes, it is essential for physicians and scientists to report on successful treatment strategies and advances in immunologic understanding. Improved understanding of PASH syndrome calls for further genetic exploration into the role of additional genomic repeats and how these affect the PSTPIP1 gene and inflammasome activity. As medical advances improve understanding of the pathophysiology of this disease entity, it will likely become clear which mechanisms are most important in disease progression and how clinicians can best optimize treatment.

Pyoderma gangrenosum (PG), acne, and hidradenitis suppurativa (HS)(PASH) syndrome is a recently identified disease process within the spectrum of autoinflammatory diseases (AIDs), which are distinct from autoimmune, infectious, and allergic syndromes and are gaining increasing interest given their complex pathophysiology and therapeutic resistance.¹ Autoinflammatory diseases are defined by a dysregulation of the innate immune system in the absence of typical autoimmune features, including autoantibodies and antigen-specific T lymphocytes.² Mutations affecting proteins of the inflammasome or proteins involved in regulating inflammasome function have been associated with these AIDs.²

Many AIDs have cutaneous involvement, as seen in PASH syndrome. Pyoderma gangrenosum is a neutrophilic dermatosis presenting as skin ulcers with undermined, erythematous, violaceous borders. It can be isolated, syndromic, or associated with inflammatory conditions (eg, inflammatory bowel disease, rheumatologic disorders, hematologic disorders).¹ Acne vulgaris develops because of chronic obstruction of hair follicles as a result of disordered keratinization and abnormal sebaceous stem cell differentiation.²Propionibacterium acnes can reside and replicate within the biofilm community of the hair follicle and activate the inflammasome.^2,3 Hidradenitis suppurativa, a chronic relapsing neutrophilic dermatosis, is a debilitating inflammatory disease of the hair follicles involving apocrine gland–bearing skin (ie, the axillary, inguinal, and anogenital regions).² Onset often occurs between the ages of 20 and 40 years, with a 3-fold higher incidence in women compared to men.³ Patients experience painful, deep-seated nodules that drain into sinus tracts and abscesses. The condition can be isolated or associated with inflammatory conditions, such as inflammatory bowel disease.⁴

PASH syndrome has been described as a polygenic autoinflammatory condition that most commonly presents in young adults, with onset of acne beginning years prior to other manifestations. A study analyzing 5 patients with PASH syndrome reported an average age of 32.2 years at diagnosis with a disease duration of 3 to 7 years.⁵ Pathophysiology of this condition is not well understood, with many hypotheses calling upon dysregulation of the innate immune system, a commonality this syndrome may share with other AIDs. Given its poorly understood pathophysiology, treating PASH syndrome can be especially difficult. We report a novel case of disease remission lasting more than 4 years using adalimumab and cyclosporine. We also discuss prior treatment successes and hypotheses regarding etiologic factors in PASH syndrome.

Case Report

A 36-year-old woman presented for evaluation of open draining ulcerations on the back of 18 months’ duration. She had a 16-year history of scarring cystic acne of the face and HS of the groin. The patient’s family history was remarkable for severe cystic acne in her brother and son as well as HS in her mother and another brother. Her treatment history included isotretinoin, doxycycline, and topical steroids.

Physical examination revealed 2 ulcerations with violaceous borders involving the left upper back (greatest diameter, 5×7 cm)(Figure 1). Evidence of papular and cystic acne with residual scarring was noted on the cheeks. Scarring from HS was noted in the axillae and right groin. A biopsy from the edge of an ulceration on the back demonstrated epidermal spongiosis with acute and chronic inflammation and fibrosis (Figure 2). The clinicopathologic findings were most consistent with PG, and the patient was diagnosed with PASH syndrome, given the constellation of cutaneous lesions.

After treatment with topical and systemic antibiotics for acne and HS for more than 1 year failed, the patient was started on adalimumab. The initial dose was 160 mg subcutaneously, then 80 mg 2 weeks later, then 40 mg weekly thereafter. Doxycycline was continued for treatment of the acne and HS. After 6 weeks of adalimumab, the PG worsened and prednisone was added. She developed tender furuncles on the back, and cultures grew Pseudomonas aeruginosa and methicillin-sensitive Staphylococcus aureus that responded to ciprofloxacin and cephalexin.

Due to progression of PG on adalimumab, switching to an infliximab infusion or anakinra was considered, but these options were not covered by the patient’s health insurance. Three months after the initial presentation, the patient was started on cyclosporine 100 mg 3 times daily (5 mg/kg/d) while adalimumab was continued; the ulcers started to improve within 2.5 weeks. After 3 months (Figure 3), the cyclosporine was reduced to 100 mg twice daily, and adalimumab was continued. She had a slight flare of PG after 8 months of treatment when adalimumab was unavailable to her for 2 months. After 8 months on cyclosporine, the dosage was tapered to 100 mg/d and then completely discontinued after 12 months.

The patient has continued on adalimumab 40 mg weekly with excellent control of the PG (Figure 4), although she did have one HS flare in the left axilla 11 months after the initial treatment. The patient’s cystic acne has intermittently flared and has been managed with spironolactone 100 mg/d for 3 years. After 4 years of management, the patient’s PG and HS remain well controlled on adalimumab.

Comment

Our case represents a major step in refining long-term treatment approaches for PASH syndrome due to the 4-year remission. Prior cases have reported use of anakinra, anakinra-cyclosporine combination, prednisone, azathioprine, topical tacrolimus, etanercept, and dapsone without sustainable success.^1-6 The case studies discussed below have achieved remission via alternative drug combinations.

Staub et al⁴ found greatest success with a combination of infliximab, dapsone, and cyclosporine, and their patient had been in remission for 20 months at time of publication. Their hypothesis proposed that multiple inflammatory signaling pathways are involved in PASH syndrome, and this is why combination therapy is required for remission.⁴ In 2018, Lamiaux et al⁷ demonstrated successful treatment with rifampicin and clindamycin. Their patient had been in remission for 22 months at the time of publication—this time frame included 12 months of combination therapy and 10 months without medication. The authors hypothesized that, because of the autoinflammatory nature of these antibiotics, this pharmacologic combination could eradicate pathogenic bacteria from host microbiota while also inhibiting neutrophil function and synthesis of chemokines and cytokines.⁷

More recently, reports have been published regarding the success of tildrakizumab, an IL-23 antagonist, and ixekizumab, an IL-17 antagonist, in the treatment of PASH syndrome.^6,8 Ixekizumab was used in combination with doxycycline, and remission was achieved in 12 months.⁸ However, tildrakizumab was used alone and achieved greater than 75% improvement in disease manifestations within 2 months.

Marzano et al⁵ conducted protein arrays and enzyme-linked immunosorbent assay to analyze the expression of cytokine, chemokine, and effector molecule profiles in PASH syndrome. It was determined that serum analysis displayed a normal cytokine/chemokine profile, with the only abnormalities being anemia and elevated C-reactive protein. There were no statistically significant differences in serum levels of IL-1β, tumor necrosis factor (TNF) α, or IL-17 between PASH syndrome and healthy controls. However, cutaneous analysis revealed extensive cytokine and chemokine hyperactivity for IL-1β and IL-1β receptor; TNF-α; C-X-C motif ligands 1, 2, and 3; C-X-C motif ligand 16; regulated on activation, normal T cell expressed and secreted; IL-17 and IL-17R; Fas/Fas ligand; and CD40/CD40L. This cutaneous profile of elevated cytokines and chemokines mirrors that of nonsyndromic PG and many other AIDs. These results demonstrate that the inflammation in PASH syndrome is localized mainly to the skin and further support the hypothesis that possibilities for alternative treatment options are diverse.⁵

Ead et al³ presented a unique perspective focusing on cutaneous biofilm involvement in PASH syndrome. Microbes within these biofilms induce the migration and proliferation of inflammatory cells that consume factors normally utilized for tissue catabolism. These organisms deplete necessary biochemical cofactors used during healing. This lack of nutrients needed for healing not only slows the process but also promotes favorable conditions for the growth of anerobic species. In conjunction, biofilm formation restricts bacterial access to oxygen and nutrients, thus decreasing the bacterial metabolic rate and preventing the effects of antibiotic therapy. These features of biofilm communities contribute to inflammation and possibly the troubling resistance to many therapeutic options for PASH syndrome.

Each component of PASH syndrome has been associated with biofilm formation. As previously described, PG manifests in the skin as painful ulcerations, often with slough. This slough is hypothesized to be a consequence of increased vascular permeability and exudative byproducts that accompany the inflammatory nature of biofilms.³ Acne vulgaris has well-described associations with P acnes. Ead et al³ described P acnes as a component of the biofilm community within the microcomedone of hair follicles. This biofilm allows for antibiotic resistance occasionally seen in the treatment of acne and is potentially the pathogenic factor that both impedes healing and enhances the inflammatory state. Hidradenitis suppurativa has been associated with biofilm formation.³

In further pursuit of PASH syndrome pathophysiology, many experts have sought to uncover the relationship between PASH syndrome and the previously described pyogenic arthritis, PG, and acne (PAPA) syndrome, another entity within the AIDs spectrum (Table). This condition was first recognized in 1997 in a 3-generation family with 10 affected members.¹ It is characterized by PG and acne, similar to PASH; however, PAPA syndrome includes PG arthritis and lacks HS. Pyogenic arthritis manifests as recurrent aseptic inflammation of the joints, mainly the elbows, knees, and ankles. Pyogenic arthritis commonly is the presenting symptom of PAPA syndrome, with onset in childhood.² As patients age, the arthritic symptoms decrease, and skin manifestations become more prominent.

PAPA syndrome has autosomal-dominant inheritance with mutations on chromosome 15 in the proline-serine-threonine phosphatase interacting protein 1 (PSTPIP1) gene.¹ This mutation induces hyperphosphorylation of PSTPIP1, allowing for increased binding affinity to pyrin. Both PSTPIP1 and pyrin are co-expressed as parts of the NLRP3 inflammasome in granulocytes and monocytes.¹ As a result, pyrin is more highly bound and loses its inhibitory effect on the NLRP3 inflammasome pathway. This lack of inhibition allows for uninhibited cleavage of pro–IL-1β to active IL-1β by the inflammasome.¹

Elevated concentrations of IL-1β in patients with PAPA syndrome result in a dysregulation of the innate immune system. IL-1β induces the release of proinflammatory cytokines, namely TNF-α; interferon γ; IL-8; and regulated on activation, normal T cell expressed and secreted (RANTES), all of which activate neutrophils and induce neutrophilic inflammation.² IL-1β not only initiates this entire cascade but also acts as an antiapoptotic signal for neutrophils.² When IL-1β reaches a critical threshold, it induces enough inflammation to cause severe tissue damage, thus causing joint and cutaneous disease in PAPA syndrome. IL-1 inhibitors (anakinra) or TNF-α inhibitors (etanercept, adalimumab, infliximab) have been used many times to successfully treat PAPA syndrome, with TNF-α inhibitors providing the most consistent results.

Another AIDs entity with similarities to both PAPA syndrome and PASH syndrome is pyogenic arthritis, PG, acne, and HS (PA-PASH) syndrome. First identified in 2012 by Bruzzese,⁹ genetic analyses revealed a p.E277D missense mutation in PSTPIP1 in PA-PASH syndrome. Research has suggested that the key molecular feature is neutrophil activation by T_H17 cells and the TNF-α axis.⁹ This syndrome has not been further characterized, and little is known regarding adequate treatment for PA-PASH syndrome.

Although it is similar in phenotype to aspects of PAPA and PA-PASH syndromes, PASH syndrome has distinct genotypic and immunologic abnormalities. Genetic analysis of this condition has shown an increased number of CCTG repeats in proximity to the PSTPIP1 promoter. It is hypothesized that these additional repeats predispose patients to neutrophilic inflammation in a similar manner to a condition described in France, termed aseptic abscess syndrome.^1,5 Other mutations have been identified, including those in IL-1N, PSMB8, MEFV, NOD2, NCSTN, and more.^2,7 However, it has been determined that the majority of these variants have already been filed in the Single Nucleotide Polymorphism Database or in the Registry of Hereditary Auto-inflammatory Disorders Mutations.² The question remains regarding the origin of inflammation seen in PASH syndrome; the potential role of biofilms; and the relationship between PASH, PAPA, and PA-PASH syndromes. Much work remains to be done in refining therapeutic options for PASH syndrome. Continued biochemical research is necessary, as well as collaboration among dermatologists worldwide who find success in treating this condition.

Conclusion

There are genotypic and phenotypic similarities between PASH, PAPA, and PA-PASH syndromes, with various mutations within or near the PSTPIP1 gene; however, their genetic discrepancies seem to play a major role in the pathophysiology of each syndrome. Much work remains to be done in PA-PASH syndrome, which has not yet been well described. Meanwhile, PAPA syndrome has been well characterized with mutations affecting proteins of the NLRP3 inflammasome, resulting in elevated IL-1β and excess neutrophilic inflammation. In PASH syndrome, the importance of increased repeats near the PSTPIP1 promoter is yet to be elucidated. It has been shown that these abnormalities predispose individuals to neutrophilic inflammation, but the mechanism by which they do so is unknown. In addition, consideration of biofilms and their predisposition to inflammation within the pathophysiology of PASH syndrome is a possibility that must be considered when discussing therapeutic options. Based on our case study and previous successes in treating PASH syndrome, it is clear that a multidrug approach is necessary for remission. It is likely that the etiology of PASH syndrome is multifaceted and involves hyperactivity in multiple arms of the innate immune system.

Patients with PASH syndrome have severely impaired quality of life and often experience social withdrawal due to the disfiguring sequelae and limited treatment options available. To improve patient outcomes, it is essential for physicians and scientists to report on successful treatment strategies and advances in immunologic understanding. Improved understanding of PASH syndrome calls for further genetic exploration into the role of additional genomic repeats and how these affect the PSTPIP1 gene and inflammasome activity. As medical advances improve understanding of the pathophysiology of this disease entity, it will likely become clear which mechanisms are most important in disease progression and how clinicians can best optimize treatment.

Pyoderma gangrenosum (PG), acne, and hidradenitis suppurativa (HS)(PASH) syndrome is a recently identified disease process within the spectrum of autoinflammatory diseases (AIDs), which are distinct from autoimmune, infectious, and allergic syndromes and are gaining increasing interest given their complex pathophysiology and therapeutic resistance.¹ Autoinflammatory diseases are defined by a dysregulation of the innate immune system in the absence of typical autoimmune features, including autoantibodies and antigen-specific T lymphocytes.² Mutations affecting proteins of the inflammasome or proteins involved in regulating inflammasome function have been associated with these AIDs.²

Many AIDs have cutaneous involvement, as seen in PASH syndrome. Pyoderma gangrenosum is a neutrophilic dermatosis presenting as skin ulcers with undermined, erythematous, violaceous borders. It can be isolated, syndromic, or associated with inflammatory conditions (eg, inflammatory bowel disease, rheumatologic disorders, hematologic disorders).¹ Acne vulgaris develops because of chronic obstruction of hair follicles as a result of disordered keratinization and abnormal sebaceous stem cell differentiation.²Propionibacterium acnes can reside and replicate within the biofilm community of the hair follicle and activate the inflammasome.^2,3 Hidradenitis suppurativa, a chronic relapsing neutrophilic dermatosis, is a debilitating inflammatory disease of the hair follicles involving apocrine gland–bearing skin (ie, the axillary, inguinal, and anogenital regions).² Onset often occurs between the ages of 20 and 40 years, with a 3-fold higher incidence in women compared to men.³ Patients experience painful, deep-seated nodules that drain into sinus tracts and abscesses. The condition can be isolated or associated with inflammatory conditions, such as inflammatory bowel disease.⁴

PASH syndrome has been described as a polygenic autoinflammatory condition that most commonly presents in young adults, with onset of acne beginning years prior to other manifestations. A study analyzing 5 patients with PASH syndrome reported an average age of 32.2 years at diagnosis with a disease duration of 3 to 7 years.⁵ Pathophysiology of this condition is not well understood, with many hypotheses calling upon dysregulation of the innate immune system, a commonality this syndrome may share with other AIDs. Given its poorly understood pathophysiology, treating PASH syndrome can be especially difficult. We report a novel case of disease remission lasting more than 4 years using adalimumab and cyclosporine. We also discuss prior treatment successes and hypotheses regarding etiologic factors in PASH syndrome.

Case Report

A 36-year-old woman presented for evaluation of open draining ulcerations on the back of 18 months’ duration. She had a 16-year history of scarring cystic acne of the face and HS of the groin. The patient’s family history was remarkable for severe cystic acne in her brother and son as well as HS in her mother and another brother. Her treatment history included isotretinoin, doxycycline, and topical steroids.

Physical examination revealed 2 ulcerations with violaceous borders involving the left upper back (greatest diameter, 5×7 cm)(Figure 1). Evidence of papular and cystic acne with residual scarring was noted on the cheeks. Scarring from HS was noted in the axillae and right groin. A biopsy from the edge of an ulceration on the back demonstrated epidermal spongiosis with acute and chronic inflammation and fibrosis (Figure 2). The clinicopathologic findings were most consistent with PG, and the patient was diagnosed with PASH syndrome, given the constellation of cutaneous lesions.

After treatment with topical and systemic antibiotics for acne and HS for more than 1 year failed, the patient was started on adalimumab. The initial dose was 160 mg subcutaneously, then 80 mg 2 weeks later, then 40 mg weekly thereafter. Doxycycline was continued for treatment of the acne and HS. After 6 weeks of adalimumab, the PG worsened and prednisone was added. She developed tender furuncles on the back, and cultures grew Pseudomonas aeruginosa and methicillin-sensitive Staphylococcus aureus that responded to ciprofloxacin and cephalexin.

Due to progression of PG on adalimumab, switching to an infliximab infusion or anakinra was considered, but these options were not covered by the patient’s health insurance. Three months after the initial presentation, the patient was started on cyclosporine 100 mg 3 times daily (5 mg/kg/d) while adalimumab was continued; the ulcers started to improve within 2.5 weeks. After 3 months (Figure 3), the cyclosporine was reduced to 100 mg twice daily, and adalimumab was continued. She had a slight flare of PG after 8 months of treatment when adalimumab was unavailable to her for 2 months. After 8 months on cyclosporine, the dosage was tapered to 100 mg/d and then completely discontinued after 12 months.

The patient has continued on adalimumab 40 mg weekly with excellent control of the PG (Figure 4), although she did have one HS flare in the left axilla 11 months after the initial treatment. The patient’s cystic acne has intermittently flared and has been managed with spironolactone 100 mg/d for 3 years. After 4 years of management, the patient’s PG and HS remain well controlled on adalimumab.

Comment

Our case represents a major step in refining long-term treatment approaches for PASH syndrome due to the 4-year remission. Prior cases have reported use of anakinra, anakinra-cyclosporine combination, prednisone, azathioprine, topical tacrolimus, etanercept, and dapsone without sustainable success.^1-6 The case studies discussed below have achieved remission via alternative drug combinations.

Staub et al⁴ found greatest success with a combination of infliximab, dapsone, and cyclosporine, and their patient had been in remission for 20 months at time of publication. Their hypothesis proposed that multiple inflammatory signaling pathways are involved in PASH syndrome, and this is why combination therapy is required for remission.⁴ In 2018, Lamiaux et al⁷ demonstrated successful treatment with rifampicin and clindamycin. Their patient had been in remission for 22 months at the time of publication—this time frame included 12 months of combination therapy and 10 months without medication. The authors hypothesized that, because of the autoinflammatory nature of these antibiotics, this pharmacologic combination could eradicate pathogenic bacteria from host microbiota while also inhibiting neutrophil function and synthesis of chemokines and cytokines.⁷

More recently, reports have been published regarding the success of tildrakizumab, an IL-23 antagonist, and ixekizumab, an IL-17 antagonist, in the treatment of PASH syndrome.^6,8 Ixekizumab was used in combination with doxycycline, and remission was achieved in 12 months.⁸ However, tildrakizumab was used alone and achieved greater than 75% improvement in disease manifestations within 2 months.

Marzano et al⁵ conducted protein arrays and enzyme-linked immunosorbent assay to analyze the expression of cytokine, chemokine, and effector molecule profiles in PASH syndrome. It was determined that serum analysis displayed a normal cytokine/chemokine profile, with the only abnormalities being anemia and elevated C-reactive protein. There were no statistically significant differences in serum levels of IL-1β, tumor necrosis factor (TNF) α, or IL-17 between PASH syndrome and healthy controls. However, cutaneous analysis revealed extensive cytokine and chemokine hyperactivity for IL-1β and IL-1β receptor; TNF-α; C-X-C motif ligands 1, 2, and 3; C-X-C motif ligand 16; regulated on activation, normal T cell expressed and secreted; IL-17 and IL-17R; Fas/Fas ligand; and CD40/CD40L. This cutaneous profile of elevated cytokines and chemokines mirrors that of nonsyndromic PG and many other AIDs. These results demonstrate that the inflammation in PASH syndrome is localized mainly to the skin and further support the hypothesis that possibilities for alternative treatment options are diverse.⁵

Ead et al³ presented a unique perspective focusing on cutaneous biofilm involvement in PASH syndrome. Microbes within these biofilms induce the migration and proliferation of inflammatory cells that consume factors normally utilized for tissue catabolism. These organisms deplete necessary biochemical cofactors used during healing. This lack of nutrients needed for healing not only slows the process but also promotes favorable conditions for the growth of anerobic species. In conjunction, biofilm formation restricts bacterial access to oxygen and nutrients, thus decreasing the bacterial metabolic rate and preventing the effects of antibiotic therapy. These features of biofilm communities contribute to inflammation and possibly the troubling resistance to many therapeutic options for PASH syndrome.

Each component of PASH syndrome has been associated with biofilm formation. As previously described, PG manifests in the skin as painful ulcerations, often with slough. This slough is hypothesized to be a consequence of increased vascular permeability and exudative byproducts that accompany the inflammatory nature of biofilms.³ Acne vulgaris has well-described associations with P acnes. Ead et al³ described P acnes as a component of the biofilm community within the microcomedone of hair follicles. This biofilm allows for antibiotic resistance occasionally seen in the treatment of acne and is potentially the pathogenic factor that both impedes healing and enhances the inflammatory state. Hidradenitis suppurativa has been associated with biofilm formation.³

In further pursuit of PASH syndrome pathophysiology, many experts have sought to uncover the relationship between PASH syndrome and the previously described pyogenic arthritis, PG, and acne (PAPA) syndrome, another entity within the AIDs spectrum (Table). This condition was first recognized in 1997 in a 3-generation family with 10 affected members.¹ It is characterized by PG and acne, similar to PASH; however, PAPA syndrome includes PG arthritis and lacks HS. Pyogenic arthritis manifests as recurrent aseptic inflammation of the joints, mainly the elbows, knees, and ankles. Pyogenic arthritis commonly is the presenting symptom of PAPA syndrome, with onset in childhood.² As patients age, the arthritic symptoms decrease, and skin manifestations become more prominent.

PAPA syndrome has autosomal-dominant inheritance with mutations on chromosome 15 in the proline-serine-threonine phosphatase interacting protein 1 (PSTPIP1) gene.¹ This mutation induces hyperphosphorylation of PSTPIP1, allowing for increased binding affinity to pyrin. Both PSTPIP1 and pyrin are co-expressed as parts of the NLRP3 inflammasome in granulocytes and monocytes.¹ As a result, pyrin is more highly bound and loses its inhibitory effect on the NLRP3 inflammasome pathway. This lack of inhibition allows for uninhibited cleavage of pro–IL-1β to active IL-1β by the inflammasome.¹

Elevated concentrations of IL-1β in patients with PAPA syndrome result in a dysregulation of the innate immune system. IL-1β induces the release of proinflammatory cytokines, namely TNF-α; interferon γ; IL-8; and regulated on activation, normal T cell expressed and secreted (RANTES), all of which activate neutrophils and induce neutrophilic inflammation.² IL-1β not only initiates this entire cascade but also acts as an antiapoptotic signal for neutrophils.² When IL-1β reaches a critical threshold, it induces enough inflammation to cause severe tissue damage, thus causing joint and cutaneous disease in PAPA syndrome. IL-1 inhibitors (anakinra) or TNF-α inhibitors (etanercept, adalimumab, infliximab) have been used many times to successfully treat PAPA syndrome, with TNF-α inhibitors providing the most consistent results.

Another AIDs entity with similarities to both PAPA syndrome and PASH syndrome is pyogenic arthritis, PG, acne, and HS (PA-PASH) syndrome. First identified in 2012 by Bruzzese,⁹ genetic analyses revealed a p.E277D missense mutation in PSTPIP1 in PA-PASH syndrome. Research has suggested that the key molecular feature is neutrophil activation by T_H17 cells and the TNF-α axis.⁹ This syndrome has not been further characterized, and little is known regarding adequate treatment for PA-PASH syndrome.

Although it is similar in phenotype to aspects of PAPA and PA-PASH syndromes, PASH syndrome has distinct genotypic and immunologic abnormalities. Genetic analysis of this condition has shown an increased number of CCTG repeats in proximity to the PSTPIP1 promoter. It is hypothesized that these additional repeats predispose patients to neutrophilic inflammation in a similar manner to a condition described in France, termed aseptic abscess syndrome.^1,5 Other mutations have been identified, including those in IL-1N, PSMB8, MEFV, NOD2, NCSTN, and more.^2,7 However, it has been determined that the majority of these variants have already been filed in the Single Nucleotide Polymorphism Database or in the Registry of Hereditary Auto-inflammatory Disorders Mutations.² The question remains regarding the origin of inflammation seen in PASH syndrome; the potential role of biofilms; and the relationship between PASH, PAPA, and PA-PASH syndromes. Much work remains to be done in refining therapeutic options for PASH syndrome. Continued biochemical research is necessary, as well as collaboration among dermatologists worldwide who find success in treating this condition.

Conclusion

There are genotypic and phenotypic similarities between PASH, PAPA, and PA-PASH syndromes, with various mutations within or near the PSTPIP1 gene; however, their genetic discrepancies seem to play a major role in the pathophysiology of each syndrome. Much work remains to be done in PA-PASH syndrome, which has not yet been well described. Meanwhile, PAPA syndrome has been well characterized with mutations affecting proteins of the NLRP3 inflammasome, resulting in elevated IL-1β and excess neutrophilic inflammation. In PASH syndrome, the importance of increased repeats near the PSTPIP1 promoter is yet to be elucidated. It has been shown that these abnormalities predispose individuals to neutrophilic inflammation, but the mechanism by which they do so is unknown. In addition, consideration of biofilms and their predisposition to inflammation within the pathophysiology of PASH syndrome is a possibility that must be considered when discussing therapeutic options. Based on our case study and previous successes in treating PASH syndrome, it is clear that a multidrug approach is necessary for remission. It is likely that the etiology of PASH syndrome is multifaceted and involves hyperactivity in multiple arms of the innate immune system.

Patients with PASH syndrome have severely impaired quality of life and often experience social withdrawal due to the disfiguring sequelae and limited treatment options available. To improve patient outcomes, it is essential for physicians and scientists to report on successful treatment strategies and advances in immunologic understanding. Improved understanding of PASH syndrome calls for further genetic exploration into the role of additional genomic repeats and how these affect the PSTPIP1 gene and inflammasome activity. As medical advances improve understanding of the pathophysiology of this disease entity, it will likely become clear which mechanisms are most important in disease progression and how clinicians can best optimize treatment.

The Diagnosis: Syphilis

Histopathology revealed psoriasiform hyperplasia, endothelial cell swelling, and a brisk lichenoid inflammation with plasma cells (Figure, A). There also was pustular folliculitis in association with well-formed granulomatous inflammation and a prominent number of plasma cells (Figure, B). Treponema pallidum immunostaining showed numerous organisms in the epidermal and follicular epithelium. Rapid plasma reagin was found to be positive with a titer of 1:128. Evaluation for neurosyphilis through lumbar puncture was negative; the patient also was HIV negative. All of our patient’s skin lesions cleared after a 3-week course of weekly intramuscular benzathine G injections. Due to his substantial clinical improvement, the patient was subsequently lost to follow-up.

Syphilis, an infectious disease caused by the spirochete bacterium T pallidum, has a well-known natural history defined by various stages classically categorized as primary, secondary, latent, or late (tertiary).¹ The classic lesion in primary syphilis is the chancre, a painless ulcer with raised borders that develops within approximately 3 weeks following the initial inoculation.² Secondary syphilis manifests with mucocutaneous findings in up to 97% of patients, and untreated patients develop secondary syphilis at a rate of approximately 25%.³ Although mucocutaneous findings in secondary syphilis can vary widely, patients most commonly develop a diffuse maculopapular exanthem, and 40% develop mucosal findings including genital ulcers, mucous patches, and condylomata lata.¹ In latent syphilis, there is seroreactivity, but otherwise there are no clinical symptoms. A clear symptomatic history of prior primary or secondary syphilis may be known or unknown. Latent syphilis is divided into early and late phases, and the World Health Organization designates 2 years after the first suspected exposure as the cutoff point for early and late latency.⁴ During the first 4 years of latent syphilis, patients may exhibit mucocutaneous relapses. Our patient denied any sexual activity for more than 3 years prior to presentation. Because of the start of iatrogenic immunosuppression during this period, this case was classified as late latent syphilis with mucocutaneous reactivation.

Behçet disease was included within the differential diagnosis but is characterized by multiorgan systemic vasculitis that causes various mucocutaneous findings including aphthous ulcers, papulopustular lesions, and genital ulcers.⁵ Histopathologic features are nonspecific, and the clinical finding of recurrent genital and oral ulceration should be present for diagnosis. This disease predominantly occurs in East Asian or Mediterranean populations and is otherwise rare in White individuals.

SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) syndrome is a rare disorder consisting of skin, joint, and bone manifestations.⁶ Severe acne generally is accompanied by palmoplantar pustulosis along with pain and joint tenderness involving the anterior chest and axial skeleton, both of which were absent in our patient.

Pustular psoriasis can be localized or generalized. Localized presentations frequently are acral and may be associated with a variable degree of nail dystrophy and arthritis. Generalized presentations are characterized by hyperemic, well-defined patches with variable numbers of pustules.⁷ The pustules are the consequence of exuberate neutrophilic exocytosis into the epidermis and are nonfollicular.

Steroid-induced acne may be considered in the proper clinical setting of an acneform eruption with a prior history of systemic steroid treatment. However, additional findings of mucositis would not be expected, and although our patient was prescribed prednisone from his primary care physician prior to presentation to our clinic, this medication was given after the onset of the cutaneous eruption.

Syphilis commonly is referred to as the great mimicker due to its potential diverse morphologic presentations, which can involve acneform eruptions, though rare.⁸ In the setting of mucositis, generalized acneform eruptions should raise suspicion for the possibility of syphilis, even in the absence of other more classic cutaneous features.

The Diagnosis: Syphilis

Histopathology revealed psoriasiform hyperplasia, endothelial cell swelling, and a brisk lichenoid inflammation with plasma cells (Figure, A). There also was pustular folliculitis in association with well-formed granulomatous inflammation and a prominent number of plasma cells (Figure, B). Treponema pallidum immunostaining showed numerous organisms in the epidermal and follicular epithelium. Rapid plasma reagin was found to be positive with a titer of 1:128. Evaluation for neurosyphilis through lumbar puncture was negative; the patient also was HIV negative. All of our patient’s skin lesions cleared after a 3-week course of weekly intramuscular benzathine G injections. Due to his substantial clinical improvement, the patient was subsequently lost to follow-up.

Syphilis, an infectious disease caused by the spirochete bacterium T pallidum, has a well-known natural history defined by various stages classically categorized as primary, secondary, latent, or late (tertiary).¹ The classic lesion in primary syphilis is the chancre, a painless ulcer with raised borders that develops within approximately 3 weeks following the initial inoculation.² Secondary syphilis manifests with mucocutaneous findings in up to 97% of patients, and untreated patients develop secondary syphilis at a rate of approximately 25%.³ Although mucocutaneous findings in secondary syphilis can vary widely, patients most commonly develop a diffuse maculopapular exanthem, and 40% develop mucosal findings including genital ulcers, mucous patches, and condylomata lata.¹ In latent syphilis, there is seroreactivity, but otherwise there are no clinical symptoms. A clear symptomatic history of prior primary or secondary syphilis may be known or unknown. Latent syphilis is divided into early and late phases, and the World Health Organization designates 2 years after the first suspected exposure as the cutoff point for early and late latency.⁴ During the first 4 years of latent syphilis, patients may exhibit mucocutaneous relapses. Our patient denied any sexual activity for more than 3 years prior to presentation. Because of the start of iatrogenic immunosuppression during this period, this case was classified as late latent syphilis with mucocutaneous reactivation.

Behçet disease was included within the differential diagnosis but is characterized by multiorgan systemic vasculitis that causes various mucocutaneous findings including aphthous ulcers, papulopustular lesions, and genital ulcers.⁵ Histopathologic features are nonspecific, and the clinical finding of recurrent genital and oral ulceration should be present for diagnosis. This disease predominantly occurs in East Asian or Mediterranean populations and is otherwise rare in White individuals.

SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) syndrome is a rare disorder consisting of skin, joint, and bone manifestations.⁶ Severe acne generally is accompanied by palmoplantar pustulosis along with pain and joint tenderness involving the anterior chest and axial skeleton, both of which were absent in our patient.

Pustular psoriasis can be localized or generalized. Localized presentations frequently are acral and may be associated with a variable degree of nail dystrophy and arthritis. Generalized presentations are characterized by hyperemic, well-defined patches with variable numbers of pustules.⁷ The pustules are the consequence of exuberate neutrophilic exocytosis into the epidermis and are nonfollicular.

Steroid-induced acne may be considered in the proper clinical setting of an acneform eruption with a prior history of systemic steroid treatment. However, additional findings of mucositis would not be expected, and although our patient was prescribed prednisone from his primary care physician prior to presentation to our clinic, this medication was given after the onset of the cutaneous eruption.

Syphilis commonly is referred to as the great mimicker due to its potential diverse morphologic presentations, which can involve acneform eruptions, though rare.⁸ In the setting of mucositis, generalized acneform eruptions should raise suspicion for the possibility of syphilis, even in the absence of other more classic cutaneous features.

The Diagnosis: Syphilis

Histopathology revealed psoriasiform hyperplasia, endothelial cell swelling, and a brisk lichenoid inflammation with plasma cells (Figure, A). There also was pustular folliculitis in association with well-formed granulomatous inflammation and a prominent number of plasma cells (Figure, B). Treponema pallidum immunostaining showed numerous organisms in the epidermal and follicular epithelium. Rapid plasma reagin was found to be positive with a titer of 1:128. Evaluation for neurosyphilis through lumbar puncture was negative; the patient also was HIV negative. All of our patient’s skin lesions cleared after a 3-week course of weekly intramuscular benzathine G injections. Due to his substantial clinical improvement, the patient was subsequently lost to follow-up.

Syphilis, an infectious disease caused by the spirochete bacterium T pallidum, has a well-known natural history defined by various stages classically categorized as primary, secondary, latent, or late (tertiary).¹ The classic lesion in primary syphilis is the chancre, a painless ulcer with raised borders that develops within approximately 3 weeks following the initial inoculation.² Secondary syphilis manifests with mucocutaneous findings in up to 97% of patients, and untreated patients develop secondary syphilis at a rate of approximately 25%.³ Although mucocutaneous findings in secondary syphilis can vary widely, patients most commonly develop a diffuse maculopapular exanthem, and 40% develop mucosal findings including genital ulcers, mucous patches, and condylomata lata.¹ In latent syphilis, there is seroreactivity, but otherwise there are no clinical symptoms. A clear symptomatic history of prior primary or secondary syphilis may be known or unknown. Latent syphilis is divided into early and late phases, and the World Health Organization designates 2 years after the first suspected exposure as the cutoff point for early and late latency.⁴ During the first 4 years of latent syphilis, patients may exhibit mucocutaneous relapses. Our patient denied any sexual activity for more than 3 years prior to presentation. Because of the start of iatrogenic immunosuppression during this period, this case was classified as late latent syphilis with mucocutaneous reactivation.

Behçet disease was included within the differential diagnosis but is characterized by multiorgan systemic vasculitis that causes various mucocutaneous findings including aphthous ulcers, papulopustular lesions, and genital ulcers.⁵ Histopathologic features are nonspecific, and the clinical finding of recurrent genital and oral ulceration should be present for diagnosis. This disease predominantly occurs in East Asian or Mediterranean populations and is otherwise rare in White individuals.

SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) syndrome is a rare disorder consisting of skin, joint, and bone manifestations.⁶ Severe acne generally is accompanied by palmoplantar pustulosis along with pain and joint tenderness involving the anterior chest and axial skeleton, both of which were absent in our patient.

Pustular psoriasis can be localized or generalized. Localized presentations frequently are acral and may be associated with a variable degree of nail dystrophy and arthritis. Generalized presentations are characterized by hyperemic, well-defined patches with variable numbers of pustules.⁷ The pustules are the consequence of exuberate neutrophilic exocytosis into the epidermis and are nonfollicular.

Steroid-induced acne may be considered in the proper clinical setting of an acneform eruption with a prior history of systemic steroid treatment. However, additional findings of mucositis would not be expected, and although our patient was prescribed prednisone from his primary care physician prior to presentation to our clinic, this medication was given after the onset of the cutaneous eruption.

Syphilis commonly is referred to as the great mimicker due to its potential diverse morphologic presentations, which can involve acneform eruptions, though rare.⁸ In the setting of mucositis, generalized acneform eruptions should raise suspicion for the possibility of syphilis, even in the absence of other more classic cutaneous features.

The Diagnosis: PASH (Pyoderma Gangrenosum, Acne, Hidradenitis Suppurativa) Syndrome

Obtaining our patient’s history of hidradenitis suppurativa (HS), a hallmark sterile neutrophilic dermatosis, was key to making the correct diagnosis of PASH (pyoderma gangrenosum, acne, HS) syndrome. In our patient, the history of HS increased the consideration of pyoderma gangrenosum (PG) due to the persistent breast and leg wounds. Additionally, it was important to consider a diagnosis of PG in lesions that were not responding to broad-spectrum antimicrobial treatment. In our patient, the concurrent presentation of draining abscesses in the axillae (Figure, A) and inflammatory nodulocystic facial acne (Figure, B) were additional diagnostic clues that suggested the triad of PASH syndrome.

Although SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) syndrome also can present with cutaneous features of acne and HS, the lack of bone and joint involvement in our patient made this diagnosis less likely. Calciphylaxis can present as ulcerations on the lower extremities, but it usually presents with a livedolike pattern with overlying black eschar and is unlikely in the absence of underlying metabolic or renal disease. PAPA (pyogenic arthritis, PG, acne) syndrome is characterized by recurrent joint involvement and lacks features of HS. Lastly, our patient was immunocompetent with no risk factors for mycobacterial infection.

PASH syndrome is a rare inherited syndrome, but its constituent inflammatory conditions are ubiquitous. They share a common underlying mechanism consisting of overactivation of the innate immune systems driven by increased production of the inflammatory cytokines IL-1, IL-17, and tumor necrosis factor α, resulting in sterile neutrophilic dermatoses.¹ The diagnosis is based on the clinical presentation, as laboratory investigations are nondiagnostic. Biopsies and cultures can be performed to rule out infectious etiologies. Additionally, PASH syndrome is considered part of a larger spectrum of syndromes including PAPA and PAPASH (pyogenic arthritis, acne, PG, HS) syndromes. The absence of pyogenic arthritis distinguishes PASH syndrome from PAPA and PAPASH syndromes.² Clinically, PASH syndrome and the related sterile neutrophilic dermatoses share the characteristic of pronounced cutaneous involvement that substantially alters the patient’s quality of life. Cigarette smoking is an exacerbating factor and has a well-established association with HS.³ Therefore, smoking cessation should be encouraged in these patients to avoid exacerbation of the disease process.

Maintaining adequate immunosuppression is key to managing the underlying disease processes. Classic immunosuppressive agents such as systemic glucocorticoids and methotrexate may fail to satisfactorily control the disease.⁴ Treatment options currently are somewhat limited and are aimed at targeting the inflammatory cytokines that propagate the disease. The most consistent responses have been observed with anti–tumor necrosis factor α antagonists such as adalimumab, infliximab, and etanercept.⁵ Additionally, there is varied response to anakinra, suggesting the importance of selectively targeting IL-1β.⁶ Unfortunately, misdiagnosis for an infectious etiology is common, and antibiotics and debridement are of limited use for the underlying pathophysiology of PASH syndrome. Importantly, biopsy and debridement often are discouraged due to the risk of pathergy.⁷

Our case demonstrates the importance of maintaining a high clinical suspicion for immune-mediated lesions that are refractory to antimicrobial agents. Additionally, prior history of multiple neutrophilic dermatoses should prompt consideration for the PASH/PAPA/PAPASH disease spectrum. Early and accurate identification of neutrophilic dermatoses such as PG and HS are crucial to initiating proper cytokine-targeting treatment and achieving disease remission.

The Diagnosis: PASH (Pyoderma Gangrenosum, Acne, Hidradenitis Suppurativa) Syndrome

Obtaining our patient’s history of hidradenitis suppurativa (HS), a hallmark sterile neutrophilic dermatosis, was key to making the correct diagnosis of PASH (pyoderma gangrenosum, acne, HS) syndrome. In our patient, the history of HS increased the consideration of pyoderma gangrenosum (PG) due to the persistent breast and leg wounds. Additionally, it was important to consider a diagnosis of PG in lesions that were not responding to broad-spectrum antimicrobial treatment. In our patient, the concurrent presentation of draining abscesses in the axillae (Figure, A) and inflammatory nodulocystic facial acne (Figure, B) were additional diagnostic clues that suggested the triad of PASH syndrome.

Although SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) syndrome also can present with cutaneous features of acne and HS, the lack of bone and joint involvement in our patient made this diagnosis less likely. Calciphylaxis can present as ulcerations on the lower extremities, but it usually presents with a livedolike pattern with overlying black eschar and is unlikely in the absence of underlying metabolic or renal disease. PAPA (pyogenic arthritis, PG, acne) syndrome is characterized by recurrent joint involvement and lacks features of HS. Lastly, our patient was immunocompetent with no risk factors for mycobacterial infection.

PASH syndrome is a rare inherited syndrome, but its constituent inflammatory conditions are ubiquitous. They share a common underlying mechanism consisting of overactivation of the innate immune systems driven by increased production of the inflammatory cytokines IL-1, IL-17, and tumor necrosis factor α, resulting in sterile neutrophilic dermatoses.¹ The diagnosis is based on the clinical presentation, as laboratory investigations are nondiagnostic. Biopsies and cultures can be performed to rule out infectious etiologies. Additionally, PASH syndrome is considered part of a larger spectrum of syndromes including PAPA and PAPASH (pyogenic arthritis, acne, PG, HS) syndromes. The absence of pyogenic arthritis distinguishes PASH syndrome from PAPA and PAPASH syndromes.² Clinically, PASH syndrome and the related sterile neutrophilic dermatoses share the characteristic of pronounced cutaneous involvement that substantially alters the patient’s quality of life. Cigarette smoking is an exacerbating factor and has a well-established association with HS.³ Therefore, smoking cessation should be encouraged in these patients to avoid exacerbation of the disease process.

Maintaining adequate immunosuppression is key to managing the underlying disease processes. Classic immunosuppressive agents such as systemic glucocorticoids and methotrexate may fail to satisfactorily control the disease.⁴ Treatment options currently are somewhat limited and are aimed at targeting the inflammatory cytokines that propagate the disease. The most consistent responses have been observed with anti–tumor necrosis factor α antagonists such as adalimumab, infliximab, and etanercept.⁵ Additionally, there is varied response to anakinra, suggesting the importance of selectively targeting IL-1β.⁶ Unfortunately, misdiagnosis for an infectious etiology is common, and antibiotics and debridement are of limited use for the underlying pathophysiology of PASH syndrome. Importantly, biopsy and debridement often are discouraged due to the risk of pathergy.⁷

Our case demonstrates the importance of maintaining a high clinical suspicion for immune-mediated lesions that are refractory to antimicrobial agents. Additionally, prior history of multiple neutrophilic dermatoses should prompt consideration for the PASH/PAPA/PAPASH disease spectrum. Early and accurate identification of neutrophilic dermatoses such as PG and HS are crucial to initiating proper cytokine-targeting treatment and achieving disease remission.

The Diagnosis: PASH (Pyoderma Gangrenosum, Acne, Hidradenitis Suppurativa) Syndrome

Obtaining our patient’s history of hidradenitis suppurativa (HS), a hallmark sterile neutrophilic dermatosis, was key to making the correct diagnosis of PASH (pyoderma gangrenosum, acne, HS) syndrome. In our patient, the history of HS increased the consideration of pyoderma gangrenosum (PG) due to the persistent breast and leg wounds. Additionally, it was important to consider a diagnosis of PG in lesions that were not responding to broad-spectrum antimicrobial treatment. In our patient, the concurrent presentation of draining abscesses in the axillae (Figure, A) and inflammatory nodulocystic facial acne (Figure, B) were additional diagnostic clues that suggested the triad of PASH syndrome.

Although SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) syndrome also can present with cutaneous features of acne and HS, the lack of bone and joint involvement in our patient made this diagnosis less likely. Calciphylaxis can present as ulcerations on the lower extremities, but it usually presents with a livedolike pattern with overlying black eschar and is unlikely in the absence of underlying metabolic or renal disease. PAPA (pyogenic arthritis, PG, acne) syndrome is characterized by recurrent joint involvement and lacks features of HS. Lastly, our patient was immunocompetent with no risk factors for mycobacterial infection.

PASH syndrome is a rare inherited syndrome, but its constituent inflammatory conditions are ubiquitous. They share a common underlying mechanism consisting of overactivation of the innate immune systems driven by increased production of the inflammatory cytokines IL-1, IL-17, and tumor necrosis factor α, resulting in sterile neutrophilic dermatoses.¹ The diagnosis is based on the clinical presentation, as laboratory investigations are nondiagnostic. Biopsies and cultures can be performed to rule out infectious etiologies. Additionally, PASH syndrome is considered part of a larger spectrum of syndromes including PAPA and PAPASH (pyogenic arthritis, acne, PG, HS) syndromes. The absence of pyogenic arthritis distinguishes PASH syndrome from PAPA and PAPASH syndromes.² Clinically, PASH syndrome and the related sterile neutrophilic dermatoses share the characteristic of pronounced cutaneous involvement that substantially alters the patient’s quality of life. Cigarette smoking is an exacerbating factor and has a well-established association with HS.³ Therefore, smoking cessation should be encouraged in these patients to avoid exacerbation of the disease process.

Maintaining adequate immunosuppression is key to managing the underlying disease processes. Classic immunosuppressive agents such as systemic glucocorticoids and methotrexate may fail to satisfactorily control the disease.⁴ Treatment options currently are somewhat limited and are aimed at targeting the inflammatory cytokines that propagate the disease. The most consistent responses have been observed with anti–tumor necrosis factor α antagonists such as adalimumab, infliximab, and etanercept.⁵ Additionally, there is varied response to anakinra, suggesting the importance of selectively targeting IL-1β.⁶ Unfortunately, misdiagnosis for an infectious etiology is common, and antibiotics and debridement are of limited use for the underlying pathophysiology of PASH syndrome. Importantly, biopsy and debridement often are discouraged due to the risk of pathergy.⁷

Our case demonstrates the importance of maintaining a high clinical suspicion for immune-mediated lesions that are refractory to antimicrobial agents. Additionally, prior history of multiple neutrophilic dermatoses should prompt consideration for the PASH/PAPA/PAPASH disease spectrum. Early and accurate identification of neutrophilic dermatoses such as PG and HS are crucial to initiating proper cytokine-targeting treatment and achieving disease remission.

PHOENIX – Ever since PicoSure became the first picosecond laser cleared by the Food and Drug Administration for the treatment of unwanted tattoos and pigmented lesions in 2012, new uses for this technology continue to expand.

Now, several different FDA-cleared picosecond devices are used for treating conditions ranging from nevus of Ota, café-au-lait macules, and lentigines to melasma, photoaging, yellow tattoos, and recalcitrant tattoos. These include PicoWay, PicoSure, Enlighten, PicoPlus, PiQo4, and Quanta Pico, among others.

“PicoWay technology has integrated nicely into my practice in Houston, the most ethnically diverse city in the country, with its ability to safely treat a number of various benign, congenital, and acquired epidermal and dermal pigmented lesions with ultrashort pulse duration and low thermal impact, which greatly reduces the risk of postinflammatory hyperpigmentation even in darker skin types,” Paul M. Friedman, MD, director of the Dermatology and Laser Surgery Center, Houston, said at the annual conference of the American Society for Laser Medicine and Surgery.

Dr. Friedman

He emphasized the importance of therapeutic clinical endpoints, noting that with q-switched lasers, “you’re looking for immediate whitening, whereas with picosecond lasers, your endpoint is slight whitening or slight darkening depending on wavelength, indication, and skin type. The ability to fractionate picosecond pulses has also allowed us to utilize this technology for photoaging as well as acne scarring.”

The PicoWay system includes a 730-nm picosecond titanium sapphire handpiece, which is FDA cleared for treatment of benign pigmented lesions and blue and green tattoo removal. Dr. Friedman said that he has seen good clinical results using the handpiece for café-au-lait macules, particularly in skin of color.

In an abstract presented at the ASLMS meeting, he and his colleagues presented a retrospective review of 12 patients with café-au-lait macules with Fitzpatrick skin types III-VI who were treated with the PicoWay 730 nm handpiece between April 2021 and January 2023. Patients received a mean of 3.1 treatments at intervals that ranged from 5 to 40 weeks. Clinical photographs were graded by three board-certified dermatologists using a 5-point visual analogue scale.

Overall, patients were rated to have a mean improvement of 26%-50%. Two patients achieved 100% clearance after four to five treatment sessions. “Café-au-lait macules with smooth borders responded less well to laser treatment, confirming prior studies at our center,” he said. “We often educate parents that café-au-lait macules may recur over time, especially with repeated sun exposure.”
 

Treating melasma

Dr. Friedman’s go-to devices for melasma include the low-density, low-energy 1,927-nm fractional diode laser; the 1,064 nm picosecond Nd:YAG, the low-fluence 1,064 nm Q-switched Nd:YAG with a nanosecond pulse duration, and the 595-nm pulsed dye laser for lesions exhibiting underlying vascularity. He said that combining therapies that target pigment and vasculature may be ideal to prevent relapses. “Melasma is a multifactorial condition so by improving patient education and expectation alongside advances in laser treatment of melasma, we have ultimately improved our ability to treat this condition,” he said.

“We’re approaching it from all angles, with ultraviolet photography and spectrocolorimetry, behavioral modifications, topical skin-lightening agents, broad spectrum sunscreens with protection against visible light, and oral tranexamic acid in advanced cases. Then, we intervene with these energy-based modalities, and the bottom line is, less energy and density is more, with lengthened treatment intervals. In 2023, we’re better than we’ve ever been in terms of our ability to safely and effectively improve melasma.”

Novel lasers

Dr. Friedman also described the UltraClear, a novel ablative fractional 2,910-nm erbium-doped glass fiber laser that delivers a customized blend of ablation and coagulation based on the patient’s condition, skin type, and tolerability for down time. He provided an overview of the versatility of what he described as highly customizable technology for conditions such as photoaging and dyschromia in patients of various skin types, making it a very versatile platform in his practice.

The AVAVA MIRIA system is a “next generation” laser “where you’re able to use a focal point. Basically, you’re treating the skin from the inside out in a 3D manner and you’re able to focus intradermally up to 1 mm with high energy 1,064 nm or 1,550 nm,” he said. “It’s a unique conical geometry that spares the epidermis, combined with sapphire tip cooling and images the skin at the same time with the potential for personalized treatments of dyschromia and photoaging in all skin types. It’s truly remarkable where the technology is heading.”

Dr. Friedman disclosed that he has received consulting fees from Allergan, Galderma, Acclaro, Merz Aesthetics, Solta Medical, and Cytrellis. He has conducted contracted research for Sofwave and is a member of the speakers bureau for Solta Medical and Candela.

PHOENIX – Ever since PicoSure became the first picosecond laser cleared by the Food and Drug Administration for the treatment of unwanted tattoos and pigmented lesions in 2012, new uses for this technology continue to expand.

Now, several different FDA-cleared picosecond devices are used for treating conditions ranging from nevus of Ota, café-au-lait macules, and lentigines to melasma, photoaging, yellow tattoos, and recalcitrant tattoos. These include PicoWay, PicoSure, Enlighten, PicoPlus, PiQo4, and Quanta Pico, among others.

“PicoWay technology has integrated nicely into my practice in Houston, the most ethnically diverse city in the country, with its ability to safely treat a number of various benign, congenital, and acquired epidermal and dermal pigmented lesions with ultrashort pulse duration and low thermal impact, which greatly reduces the risk of postinflammatory hyperpigmentation even in darker skin types,” Paul M. Friedman, MD, director of the Dermatology and Laser Surgery Center, Houston, said at the annual conference of the American Society for Laser Medicine and Surgery.

Dr. Friedman

He emphasized the importance of therapeutic clinical endpoints, noting that with q-switched lasers, “you’re looking for immediate whitening, whereas with picosecond lasers, your endpoint is slight whitening or slight darkening depending on wavelength, indication, and skin type. The ability to fractionate picosecond pulses has also allowed us to utilize this technology for photoaging as well as acne scarring.”

The PicoWay system includes a 730-nm picosecond titanium sapphire handpiece, which is FDA cleared for treatment of benign pigmented lesions and blue and green tattoo removal. Dr. Friedman said that he has seen good clinical results using the handpiece for café-au-lait macules, particularly in skin of color.

In an abstract presented at the ASLMS meeting, he and his colleagues presented a retrospective review of 12 patients with café-au-lait macules with Fitzpatrick skin types III-VI who were treated with the PicoWay 730 nm handpiece between April 2021 and January 2023. Patients received a mean of 3.1 treatments at intervals that ranged from 5 to 40 weeks. Clinical photographs were graded by three board-certified dermatologists using a 5-point visual analogue scale.

Overall, patients were rated to have a mean improvement of 26%-50%. Two patients achieved 100% clearance after four to five treatment sessions. “Café-au-lait macules with smooth borders responded less well to laser treatment, confirming prior studies at our center,” he said. “We often educate parents that café-au-lait macules may recur over time, especially with repeated sun exposure.”
 

Treating melasma

Dr. Friedman’s go-to devices for melasma include the low-density, low-energy 1,927-nm fractional diode laser; the 1,064 nm picosecond Nd:YAG, the low-fluence 1,064 nm Q-switched Nd:YAG with a nanosecond pulse duration, and the 595-nm pulsed dye laser for lesions exhibiting underlying vascularity. He said that combining therapies that target pigment and vasculature may be ideal to prevent relapses. “Melasma is a multifactorial condition so by improving patient education and expectation alongside advances in laser treatment of melasma, we have ultimately improved our ability to treat this condition,” he said.

“We’re approaching it from all angles, with ultraviolet photography and spectrocolorimetry, behavioral modifications, topical skin-lightening agents, broad spectrum sunscreens with protection against visible light, and oral tranexamic acid in advanced cases. Then, we intervene with these energy-based modalities, and the bottom line is, less energy and density is more, with lengthened treatment intervals. In 2023, we’re better than we’ve ever been in terms of our ability to safely and effectively improve melasma.”

Novel lasers

Dr. Friedman also described the UltraClear, a novel ablative fractional 2,910-nm erbium-doped glass fiber laser that delivers a customized blend of ablation and coagulation based on the patient’s condition, skin type, and tolerability for down time. He provided an overview of the versatility of what he described as highly customizable technology for conditions such as photoaging and dyschromia in patients of various skin types, making it a very versatile platform in his practice.

The AVAVA MIRIA system is a “next generation” laser “where you’re able to use a focal point. Basically, you’re treating the skin from the inside out in a 3D manner and you’re able to focus intradermally up to 1 mm with high energy 1,064 nm or 1,550 nm,” he said. “It’s a unique conical geometry that spares the epidermis, combined with sapphire tip cooling and images the skin at the same time with the potential for personalized treatments of dyschromia and photoaging in all skin types. It’s truly remarkable where the technology is heading.”

Dr. Friedman disclosed that he has received consulting fees from Allergan, Galderma, Acclaro, Merz Aesthetics, Solta Medical, and Cytrellis. He has conducted contracted research for Sofwave and is a member of the speakers bureau for Solta Medical and Candela.

PHOENIX – Ever since PicoSure became the first picosecond laser cleared by the Food and Drug Administration for the treatment of unwanted tattoos and pigmented lesions in 2012, new uses for this technology continue to expand.

Now, several different FDA-cleared picosecond devices are used for treating conditions ranging from nevus of Ota, café-au-lait macules, and lentigines to melasma, photoaging, yellow tattoos, and recalcitrant tattoos. These include PicoWay, PicoSure, Enlighten, PicoPlus, PiQo4, and Quanta Pico, among others.

“PicoWay technology has integrated nicely into my practice in Houston, the most ethnically diverse city in the country, with its ability to safely treat a number of various benign, congenital, and acquired epidermal and dermal pigmented lesions with ultrashort pulse duration and low thermal impact, which greatly reduces the risk of postinflammatory hyperpigmentation even in darker skin types,” Paul M. Friedman, MD, director of the Dermatology and Laser Surgery Center, Houston, said at the annual conference of the American Society for Laser Medicine and Surgery.

Dr. Friedman

He emphasized the importance of therapeutic clinical endpoints, noting that with q-switched lasers, “you’re looking for immediate whitening, whereas with picosecond lasers, your endpoint is slight whitening or slight darkening depending on wavelength, indication, and skin type. The ability to fractionate picosecond pulses has also allowed us to utilize this technology for photoaging as well as acne scarring.”

The PicoWay system includes a 730-nm picosecond titanium sapphire handpiece, which is FDA cleared for treatment of benign pigmented lesions and blue and green tattoo removal. Dr. Friedman said that he has seen good clinical results using the handpiece for café-au-lait macules, particularly in skin of color.

In an abstract presented at the ASLMS meeting, he and his colleagues presented a retrospective review of 12 patients with café-au-lait macules with Fitzpatrick skin types III-VI who were treated with the PicoWay 730 nm handpiece between April 2021 and January 2023. Patients received a mean of 3.1 treatments at intervals that ranged from 5 to 40 weeks. Clinical photographs were graded by three board-certified dermatologists using a 5-point visual analogue scale.

Overall, patients were rated to have a mean improvement of 26%-50%. Two patients achieved 100% clearance after four to five treatment sessions. “Café-au-lait macules with smooth borders responded less well to laser treatment, confirming prior studies at our center,” he said. “We often educate parents that café-au-lait macules may recur over time, especially with repeated sun exposure.”
 

Treating melasma

Dr. Friedman’s go-to devices for melasma include the low-density, low-energy 1,927-nm fractional diode laser; the 1,064 nm picosecond Nd:YAG, the low-fluence 1,064 nm Q-switched Nd:YAG with a nanosecond pulse duration, and the 595-nm pulsed dye laser for lesions exhibiting underlying vascularity. He said that combining therapies that target pigment and vasculature may be ideal to prevent relapses. “Melasma is a multifactorial condition so by improving patient education and expectation alongside advances in laser treatment of melasma, we have ultimately improved our ability to treat this condition,” he said.

“We’re approaching it from all angles, with ultraviolet photography and spectrocolorimetry, behavioral modifications, topical skin-lightening agents, broad spectrum sunscreens with protection against visible light, and oral tranexamic acid in advanced cases. Then, we intervene with these energy-based modalities, and the bottom line is, less energy and density is more, with lengthened treatment intervals. In 2023, we’re better than we’ve ever been in terms of our ability to safely and effectively improve melasma.”

Novel lasers

Dr. Friedman also described the UltraClear, a novel ablative fractional 2,910-nm erbium-doped glass fiber laser that delivers a customized blend of ablation and coagulation based on the patient’s condition, skin type, and tolerability for down time. He provided an overview of the versatility of what he described as highly customizable technology for conditions such as photoaging and dyschromia in patients of various skin types, making it a very versatile platform in his practice.

The AVAVA MIRIA system is a “next generation” laser “where you’re able to use a focal point. Basically, you’re treating the skin from the inside out in a 3D manner and you’re able to focus intradermally up to 1 mm with high energy 1,064 nm or 1,550 nm,” he said. “It’s a unique conical geometry that spares the epidermis, combined with sapphire tip cooling and images the skin at the same time with the potential for personalized treatments of dyschromia and photoaging in all skin types. It’s truly remarkable where the technology is heading.”

Dr. Friedman disclosed that he has received consulting fees from Allergan, Galderma, Acclaro, Merz Aesthetics, Solta Medical, and Cytrellis. He has conducted contracted research for Sofwave and is a member of the speakers bureau for Solta Medical and Candela.

PHOENIX – When Jeffrey Dover, MD, addressed audience members gathered for a session on cutting-edge technologies at the annual conference of the American Society for Laser Medicine and Surgery, he reflected on a conversation he had with R. Rox Anderson, MD, almost 40 years ago, about eventually finding a cure for acne.

“Despite the fact that we have over-the-counter therapies, prescription therapies, and all kinds of devices available to treat acne, there are still barriers to care that get in the way of treatment,” said Dr. Dover, director of SkinCare Physicians in Chestnut Hill, Mass. “If we had a device based on innovative light science that could meet the needs of the acne patient to get rid of these barriers, wouldn’t that be something wonderful?”

Dr. Jeffrey Dover

The answer to this question, he said, is now “yes,” because of advances in lasers that target sebaceous glands.

In a seminal paper published in 2012, Fernanda H. Sakamoto, MD, PhD, Dr. Anderson, and colleagues demonstrated the potential for a free electron laser to target sebaceous glands . Following several years of refinement, there are now two 1,726-nm laser devices – the AviClear and the Accure Laser System – cleared by the Food and Drug Administration for the treatment of mild to severe acne, which have “very impressive results,” Dr. Dover said.

“With the 1,726-nm laser, there is some selective absorption in sebum in skin, which beats out absorption in the other chromophores,” he said. “But it’s not a big difference like it is, for example, for pulsed-dye lasers and vascular targets. ... This means that the therapeutic window is relatively small and protecting the rest of the epidermis and dermis is crucial to be able to target these lesions or the sebaceous gland without unnecessary damage. If we can protect the epidermis and heat just the sebaceous glands, we should be able to get Accutane-like results if we get durability [by] shrinking sebaceous glands.”

Effective cooling, whether contact cooling, bulk cooling, or air cooling, is crucial to success, he continued. “It’s got to be robust and highly specific to protect the skin, so you don’t end up with side effects that are worse than the disease.”

The AviClear laser delivers seven 3-mm spots, which takes into account the thermal relaxation times of the sebaceous glands. The algorithm delivers a treatment imprint at roughly 0.3 Hz and a 1.5-mm depth of penetration, and the device relies on contact cooling. In pivotal data submitted to the FDA, 104 individuals with moderate to severe acne received three treatments with the AviClear 1 month apart, with follow-up at 1, 3, 6, and 12 months post treatment. They had no other treatment regimens, and the primary endpoint was the percentage of patients who achieved a 50% reduction in inflammatory lesion count 3 months after the final treatment. The secondary endpoint was an Investigator’s Global Assessment (IGA) improvement of 2 or greater.

Dr. Dover, who helped design the study, said that, at 3 months, 80% of those treated achieved a 50% or greater reduction in inflammatory lesion count (P < .001). As for secondary endpoints, 36% of individuals were assessed as having clear or almost clear skin; 47% achieved a 2-point or greater improvement in IGA score, compared with baseline, and 87% achieved a 1-point or greater improvement in IGA score, compared with baseline. By 6 months, 88% of individuals achieved a 50% or greater reduction in inflammatory lesion count; this improved to 92% by 12 months (P < .001).

“All of these procedures were done with no topical anesthetic, no intralesional anesthetic, and they tolerated these quite well,” he said. “There was no down time that required medical intervention after the treatments. All posttreatment erythema and swelling resolved quickly,” and 75% of the patients were “very satisfied” with the treatments.

The Accure Laser System features a proprietary technology that precisely controls thermal gradient depth. “So instead of guessing whether you are delivering the correct amount of heat, it actually tells you,” said Dr. Dover, a past president of the ASLMS and the American Society for Dermatologic Surgery. “It correlates surface and at-depth temperatures, and there’s an infrared camera for real-time accurate temperature monitoring.” The device features highly controlled air cooling and a pulsing pattern that ensures treatment of sebaceous glands of all sizes and at all depths. The clinical end marker is peak epidermal temperature.

In a study supported by Accure, the manufacturer, researchers evaluated the efficacy of the Accure Laser System in 35 subjects with types I to VI skin, who received four monthly treatments 30-45 minutes each, and were followed 12, 26, 39, and 52 weeks following their last treatment. To date, data out to 52 weeks is available for 17 study participants. According to Dr. Dover, the researchers found 80% clearance at 12 weeks following the last treatment, with continued improvement at 52 weeks. One hundred percent of subjects responded. Side effects included erythema, edema, crusting, blisters, and inflammatory papules. “None of these were medically significant,” he said.

As dermatologists begin to incorporate the AviClear and Accure devices into their practices, Dr. Dover said that he is reminded of the conversation he had some 40 years ago with Dr. Anderson about finding a cure for acne, and he feels a bit awestruck. “These 1,726-nm lasers are effective for treating acne. I personally think they are going to revolutionize the way we treat at least some of our patients with acne. They may both be effective for treating facial acne scars. Time will tell. Further study of both scarring and acne are needed to fully categorize the benefit and to optimize treatments.”

To date no direct clinical comparisons have been made between the AviClear and Accure devices.

Dr. Dover reported that he is a consultant for Cutera, the manufacturer for AviClear. He also performs research for the company.





 

PHOENIX – When Jeffrey Dover, MD, addressed audience members gathered for a session on cutting-edge technologies at the annual conference of the American Society for Laser Medicine and Surgery, he reflected on a conversation he had with R. Rox Anderson, MD, almost 40 years ago, about eventually finding a cure for acne.

“Despite the fact that we have over-the-counter therapies, prescription therapies, and all kinds of devices available to treat acne, there are still barriers to care that get in the way of treatment,” said Dr. Dover, director of SkinCare Physicians in Chestnut Hill, Mass. “If we had a device based on innovative light science that could meet the needs of the acne patient to get rid of these barriers, wouldn’t that be something wonderful?”

Dr. Jeffrey Dover

The answer to this question, he said, is now “yes,” because of advances in lasers that target sebaceous glands.

In a seminal paper published in 2012, Fernanda H. Sakamoto, MD, PhD, Dr. Anderson, and colleagues demonstrated the potential for a free electron laser to target sebaceous glands . Following several years of refinement, there are now two 1,726-nm laser devices – the AviClear and the Accure Laser System – cleared by the Food and Drug Administration for the treatment of mild to severe acne, which have “very impressive results,” Dr. Dover said.

“With the 1,726-nm laser, there is some selective absorption in sebum in skin, which beats out absorption in the other chromophores,” he said. “But it’s not a big difference like it is, for example, for pulsed-dye lasers and vascular targets. ... This means that the therapeutic window is relatively small and protecting the rest of the epidermis and dermis is crucial to be able to target these lesions or the sebaceous gland without unnecessary damage. If we can protect the epidermis and heat just the sebaceous glands, we should be able to get Accutane-like results if we get durability [by] shrinking sebaceous glands.”

Effective cooling, whether contact cooling, bulk cooling, or air cooling, is crucial to success, he continued. “It’s got to be robust and highly specific to protect the skin, so you don’t end up with side effects that are worse than the disease.”

The AviClear laser delivers seven 3-mm spots, which takes into account the thermal relaxation times of the sebaceous glands. The algorithm delivers a treatment imprint at roughly 0.3 Hz and a 1.5-mm depth of penetration, and the device relies on contact cooling. In pivotal data submitted to the FDA, 104 individuals with moderate to severe acne received three treatments with the AviClear 1 month apart, with follow-up at 1, 3, 6, and 12 months post treatment. They had no other treatment regimens, and the primary endpoint was the percentage of patients who achieved a 50% reduction in inflammatory lesion count 3 months after the final treatment. The secondary endpoint was an Investigator’s Global Assessment (IGA) improvement of 2 or greater.

Dr. Dover, who helped design the study, said that, at 3 months, 80% of those treated achieved a 50% or greater reduction in inflammatory lesion count (P < .001). As for secondary endpoints, 36% of individuals were assessed as having clear or almost clear skin; 47% achieved a 2-point or greater improvement in IGA score, compared with baseline, and 87% achieved a 1-point or greater improvement in IGA score, compared with baseline. By 6 months, 88% of individuals achieved a 50% or greater reduction in inflammatory lesion count; this improved to 92% by 12 months (P < .001).

“All of these procedures were done with no topical anesthetic, no intralesional anesthetic, and they tolerated these quite well,” he said. “There was no down time that required medical intervention after the treatments. All posttreatment erythema and swelling resolved quickly,” and 75% of the patients were “very satisfied” with the treatments.

The Accure Laser System features a proprietary technology that precisely controls thermal gradient depth. “So instead of guessing whether you are delivering the correct amount of heat, it actually tells you,” said Dr. Dover, a past president of the ASLMS and the American Society for Dermatologic Surgery. “It correlates surface and at-depth temperatures, and there’s an infrared camera for real-time accurate temperature monitoring.” The device features highly controlled air cooling and a pulsing pattern that ensures treatment of sebaceous glands of all sizes and at all depths. The clinical end marker is peak epidermal temperature.

In a study supported by Accure, the manufacturer, researchers evaluated the efficacy of the Accure Laser System in 35 subjects with types I to VI skin, who received four monthly treatments 30-45 minutes each, and were followed 12, 26, 39, and 52 weeks following their last treatment. To date, data out to 52 weeks is available for 17 study participants. According to Dr. Dover, the researchers found 80% clearance at 12 weeks following the last treatment, with continued improvement at 52 weeks. One hundred percent of subjects responded. Side effects included erythema, edema, crusting, blisters, and inflammatory papules. “None of these were medically significant,” he said.

As dermatologists begin to incorporate the AviClear and Accure devices into their practices, Dr. Dover said that he is reminded of the conversation he had some 40 years ago with Dr. Anderson about finding a cure for acne, and he feels a bit awestruck. “These 1,726-nm lasers are effective for treating acne. I personally think they are going to revolutionize the way we treat at least some of our patients with acne. They may both be effective for treating facial acne scars. Time will tell. Further study of both scarring and acne are needed to fully categorize the benefit and to optimize treatments.”

To date no direct clinical comparisons have been made between the AviClear and Accure devices.

Dr. Dover reported that he is a consultant for Cutera, the manufacturer for AviClear. He also performs research for the company.





 

PHOENIX – When Jeffrey Dover, MD, addressed audience members gathered for a session on cutting-edge technologies at the annual conference of the American Society for Laser Medicine and Surgery, he reflected on a conversation he had with R. Rox Anderson, MD, almost 40 years ago, about eventually finding a cure for acne.

“Despite the fact that we have over-the-counter therapies, prescription therapies, and all kinds of devices available to treat acne, there are still barriers to care that get in the way of treatment,” said Dr. Dover, director of SkinCare Physicians in Chestnut Hill, Mass. “If we had a device based on innovative light science that could meet the needs of the acne patient to get rid of these barriers, wouldn’t that be something wonderful?”

Dr. Jeffrey Dover

The answer to this question, he said, is now “yes,” because of advances in lasers that target sebaceous glands.

In a seminal paper published in 2012, Fernanda H. Sakamoto, MD, PhD, Dr. Anderson, and colleagues demonstrated the potential for a free electron laser to target sebaceous glands . Following several years of refinement, there are now two 1,726-nm laser devices – the AviClear and the Accure Laser System – cleared by the Food and Drug Administration for the treatment of mild to severe acne, which have “very impressive results,” Dr. Dover said.

“With the 1,726-nm laser, there is some selective absorption in sebum in skin, which beats out absorption in the other chromophores,” he said. “But it’s not a big difference like it is, for example, for pulsed-dye lasers and vascular targets. ... This means that the therapeutic window is relatively small and protecting the rest of the epidermis and dermis is crucial to be able to target these lesions or the sebaceous gland without unnecessary damage. If we can protect the epidermis and heat just the sebaceous glands, we should be able to get Accutane-like results if we get durability [by] shrinking sebaceous glands.”

Effective cooling, whether contact cooling, bulk cooling, or air cooling, is crucial to success, he continued. “It’s got to be robust and highly specific to protect the skin, so you don’t end up with side effects that are worse than the disease.”

The AviClear laser delivers seven 3-mm spots, which takes into account the thermal relaxation times of the sebaceous glands. The algorithm delivers a treatment imprint at roughly 0.3 Hz and a 1.5-mm depth of penetration, and the device relies on contact cooling. In pivotal data submitted to the FDA, 104 individuals with moderate to severe acne received three treatments with the AviClear 1 month apart, with follow-up at 1, 3, 6, and 12 months post treatment. They had no other treatment regimens, and the primary endpoint was the percentage of patients who achieved a 50% reduction in inflammatory lesion count 3 months after the final treatment. The secondary endpoint was an Investigator’s Global Assessment (IGA) improvement of 2 or greater.

Dr. Dover, who helped design the study, said that, at 3 months, 80% of those treated achieved a 50% or greater reduction in inflammatory lesion count (P < .001). As for secondary endpoints, 36% of individuals were assessed as having clear or almost clear skin; 47% achieved a 2-point or greater improvement in IGA score, compared with baseline, and 87% achieved a 1-point or greater improvement in IGA score, compared with baseline. By 6 months, 88% of individuals achieved a 50% or greater reduction in inflammatory lesion count; this improved to 92% by 12 months (P < .001).

“All of these procedures were done with no topical anesthetic, no intralesional anesthetic, and they tolerated these quite well,” he said. “There was no down time that required medical intervention after the treatments. All posttreatment erythema and swelling resolved quickly,” and 75% of the patients were “very satisfied” with the treatments.

The Accure Laser System features a proprietary technology that precisely controls thermal gradient depth. “So instead of guessing whether you are delivering the correct amount of heat, it actually tells you,” said Dr. Dover, a past president of the ASLMS and the American Society for Dermatologic Surgery. “It correlates surface and at-depth temperatures, and there’s an infrared camera for real-time accurate temperature monitoring.” The device features highly controlled air cooling and a pulsing pattern that ensures treatment of sebaceous glands of all sizes and at all depths. The clinical end marker is peak epidermal temperature.

In a study supported by Accure, the manufacturer, researchers evaluated the efficacy of the Accure Laser System in 35 subjects with types I to VI skin, who received four monthly treatments 30-45 minutes each, and were followed 12, 26, 39, and 52 weeks following their last treatment. To date, data out to 52 weeks is available for 17 study participants. According to Dr. Dover, the researchers found 80% clearance at 12 weeks following the last treatment, with continued improvement at 52 weeks. One hundred percent of subjects responded. Side effects included erythema, edema, crusting, blisters, and inflammatory papules. “None of these were medically significant,” he said.

As dermatologists begin to incorporate the AviClear and Accure devices into their practices, Dr. Dover said that he is reminded of the conversation he had some 40 years ago with Dr. Anderson about finding a cure for acne, and he feels a bit awestruck. “These 1,726-nm lasers are effective for treating acne. I personally think they are going to revolutionize the way we treat at least some of our patients with acne. They may both be effective for treating facial acne scars. Time will tell. Further study of both scarring and acne are needed to fully categorize the benefit and to optimize treatments.”

To date no direct clinical comparisons have been made between the AviClear and Accure devices.

Dr. Dover reported that he is a consultant for Cutera, the manufacturer for AviClear. He also performs research for the company.





 

PHOENIX – Combining a serum containing silymarin with nonablative laser therapy could serve as a promising solution for decreasing inflammation, postinflammatory erythema (PIE), and postinflammatory hyperpigmentation (PIH) associated with acne lesions, results from a prospective, single-center study showed.

“Acne vulgaris is the most common inflammatory dermatosis worldwide, often resulting in sequelae such as scarring, PIE, and PIH,” presenting author Jamie Hu, MD, said at the annual conference of the American Society for Laser Medicine and Surgery, where the study results were presented during an abstract session. “This dyschromia can cause greater psychological distress than the original acne lesions, and disproportionately affects skin of color patients.”

Blemish-prone skin is known to have higher levels of sebum and lower levels of antioxidants, leading to lipid peroxidation and oxidative stress, resulting in proliferation of Cutibacterium acnes and an inflammatory cascade that has recently been implicated in postinflammatory dyschromia and the development of PIE and PIH, noted Dr. Hu, a dermatology resident at the University of Miami. “Therefore, the use of antioxidants presents an opportunity to disrupt blemish and dyschromia,” she said.

One such antioxidant is silymarin, which is derived from the milk thistle plant. Recent studies have demonstrated that silymarin reduces proinflammatory mediators, prevents lipid peroxidation, and presents a new way to target the treatment of both acne and postinflammatory dyschromia.

Dr. Hu’s mentor, Jill S. Waibel, MD, owner and medical director of the Miami Dermatology and Laser Institute, hypothesized that nonablative laser therapy followed by topical application of silymarin would improve acne-associated postinflammatory dyschromia. To test her hunch, she conducted a 12-week, prospective trial in which 24 patients with PIE and/or PIH were randomized to one of two treatment arms: laser treatment with topical antioxidants or laser treatment with vehicle control. Patients received three laser treatments, each 1 month apart. The topical antioxidant used was Silymarin CF, a serum that contains 0.5% silymarin, 0.5% salicylic acid, 15% L-ascorbic acid, and 0.5% ferulic acid. (The study was sponsored by SkinCeuticals, the manufacturer of the serum.)

Laser selection was made primarily on the type of dyschromia, with PIE patients receiving treatment with the pulsed dye laser and PIH patients receiving treatment with the 1,927-nm thulium laser. Patients were treated on days 0, 28, and 56 of the 12-week study, followed by immediate application of topical antioxidants or vehicle control. They were also instructed to apply the assigned topical twice daily for the duration of the study. Patients ranged in age from 21 to 61 years, and 20 had skin types III-IV.

To evaluate efficacy, the researchers conducted blinded clinical assessments with the postacne hyperpigmentation index (PAHPI) and the Global Aesthetic Improvement Scale (GAIS), instrumentation with the Mexameter, a device that captures erythema and melanin index values, and visual diagnostics with optical coherence tomography (OCT).

Dr. Hu reported that at week 12, the PAHPI in the silymarin-plus-laser treatment group fell from an average of 3.18 to 1.74 (a decrease of 1.44), which suggested an improvement trend, compared with the laser treatment–only group, whose PAHPI fell from an average of 3.25 to 1.97 (a decrease of 1.28).

As for the GAIS, a one-time score assessed at the end of the trial, the average score for all patients was 3.24, which translated to “much improved/very much improved.” Patients in the silymarin-plus-laser treatment group had higher average scores compared with patients in the laser treatment–only group (3.35 vs. 3.10, respectively), but the differences did not reach statistical significance.

According to results of the Mexameter assessment, paired t-tests showed that the levels of intralesional melanin decreased significantly for patients in the silymarin-plus-laser treatment group, compared with the laser treatment–only group (P < .05). OCT assessments demonstrated an increase in dermal brightness in both groups, corresponding to an increase in dermal collagen, as well as an increase in blood vessel density.

In an interview at the meeting, Dr. Waibel, subsection chief of dermatology at Baptist Hospital of Miami, said that future studies will focus on long-term follow-up to determine if acne scars can be prevented by combining silymarin with lasers to prevent PIH and PIE. “That would be priceless,” she said. “I believe that the PIH is what causes damage to the collagen, and that damage to the collagen is what causes the scarring. So, if we can prevent or treat PIH, we may be able to prevent scarring.”

This approach, she added, “would decrease the pharmaceutical cost because I think there are many dermatologists who are treating PEI and PIH as active acne. You really have to have a keen eye for understanding the differences and you really have to be looking, because PIE and PIH are flat, whereas active acne consists of either comedones or nodules.”

She noted that in skin of color patients, she has seen PIH persist for 9 or 10 months after treatment with isotretinoin. “It’s not the isotretinoin causing the scars, or even the acne, it’s the prolonged inflammation,” she said.

Catherine M. DiGiorgio, MD, a Boston-based laser and cosmetic dermatologist who was asked to comment on the study, said that patients and dermatologists frequently seek alternatives to hydroquinone for unwanted hyperpigmentation.

Dr. DiGiorgio

Dr. Jalian

“While the study failed to show statistically significant improvement in postinflammatory erythema with concomitant laser and topical therapy versus laser alone, the promising data supporting concurrent use of topicals and fractional lasers for treatment of PIH, particularly in dark skin phototypes, is a clinically impactful contribution to our daily practice,” he said.

Dr. Waibel disclosed that she has conducted clinical trials for many device and pharmaceutical companies including SkinCeuticals. Dr. Hu, Dr. DiGiorgio, and Dr. Jalian were not involved with the study and reported having no relevant disclosures.

PHOENIX – Combining a serum containing silymarin with nonablative laser therapy could serve as a promising solution for decreasing inflammation, postinflammatory erythema (PIE), and postinflammatory hyperpigmentation (PIH) associated with acne lesions, results from a prospective, single-center study showed.

“Acne vulgaris is the most common inflammatory dermatosis worldwide, often resulting in sequelae such as scarring, PIE, and PIH,” presenting author Jamie Hu, MD, said at the annual conference of the American Society for Laser Medicine and Surgery, where the study results were presented during an abstract session. “This dyschromia can cause greater psychological distress than the original acne lesions, and disproportionately affects skin of color patients.”

Blemish-prone skin is known to have higher levels of sebum and lower levels of antioxidants, leading to lipid peroxidation and oxidative stress, resulting in proliferation of Cutibacterium acnes and an inflammatory cascade that has recently been implicated in postinflammatory dyschromia and the development of PIE and PIH, noted Dr. Hu, a dermatology resident at the University of Miami. “Therefore, the use of antioxidants presents an opportunity to disrupt blemish and dyschromia,” she said.

One such antioxidant is silymarin, which is derived from the milk thistle plant. Recent studies have demonstrated that silymarin reduces proinflammatory mediators, prevents lipid peroxidation, and presents a new way to target the treatment of both acne and postinflammatory dyschromia.

Dr. Hu’s mentor, Jill S. Waibel, MD, owner and medical director of the Miami Dermatology and Laser Institute, hypothesized that nonablative laser therapy followed by topical application of silymarin would improve acne-associated postinflammatory dyschromia. To test her hunch, she conducted a 12-week, prospective trial in which 24 patients with PIE and/or PIH were randomized to one of two treatment arms: laser treatment with topical antioxidants or laser treatment with vehicle control. Patients received three laser treatments, each 1 month apart. The topical antioxidant used was Silymarin CF, a serum that contains 0.5% silymarin, 0.5% salicylic acid, 15% L-ascorbic acid, and 0.5% ferulic acid. (The study was sponsored by SkinCeuticals, the manufacturer of the serum.)

Laser selection was made primarily on the type of dyschromia, with PIE patients receiving treatment with the pulsed dye laser and PIH patients receiving treatment with the 1,927-nm thulium laser. Patients were treated on days 0, 28, and 56 of the 12-week study, followed by immediate application of topical antioxidants or vehicle control. They were also instructed to apply the assigned topical twice daily for the duration of the study. Patients ranged in age from 21 to 61 years, and 20 had skin types III-IV.

To evaluate efficacy, the researchers conducted blinded clinical assessments with the postacne hyperpigmentation index (PAHPI) and the Global Aesthetic Improvement Scale (GAIS), instrumentation with the Mexameter, a device that captures erythema and melanin index values, and visual diagnostics with optical coherence tomography (OCT).

Dr. Hu reported that at week 12, the PAHPI in the silymarin-plus-laser treatment group fell from an average of 3.18 to 1.74 (a decrease of 1.44), which suggested an improvement trend, compared with the laser treatment–only group, whose PAHPI fell from an average of 3.25 to 1.97 (a decrease of 1.28).

As for the GAIS, a one-time score assessed at the end of the trial, the average score for all patients was 3.24, which translated to “much improved/very much improved.” Patients in the silymarin-plus-laser treatment group had higher average scores compared with patients in the laser treatment–only group (3.35 vs. 3.10, respectively), but the differences did not reach statistical significance.

According to results of the Mexameter assessment, paired t-tests showed that the levels of intralesional melanin decreased significantly for patients in the silymarin-plus-laser treatment group, compared with the laser treatment–only group (P < .05). OCT assessments demonstrated an increase in dermal brightness in both groups, corresponding to an increase in dermal collagen, as well as an increase in blood vessel density.

In an interview at the meeting, Dr. Waibel, subsection chief of dermatology at Baptist Hospital of Miami, said that future studies will focus on long-term follow-up to determine if acne scars can be prevented by combining silymarin with lasers to prevent PIH and PIE. “That would be priceless,” she said. “I believe that the PIH is what causes damage to the collagen, and that damage to the collagen is what causes the scarring. So, if we can prevent or treat PIH, we may be able to prevent scarring.”

This approach, she added, “would decrease the pharmaceutical cost because I think there are many dermatologists who are treating PEI and PIH as active acne. You really have to have a keen eye for understanding the differences and you really have to be looking, because PIE and PIH are flat, whereas active acne consists of either comedones or nodules.”

She noted that in skin of color patients, she has seen PIH persist for 9 or 10 months after treatment with isotretinoin. “It’s not the isotretinoin causing the scars, or even the acne, it’s the prolonged inflammation,” she said.

Catherine M. DiGiorgio, MD, a Boston-based laser and cosmetic dermatologist who was asked to comment on the study, said that patients and dermatologists frequently seek alternatives to hydroquinone for unwanted hyperpigmentation.

Dr. DiGiorgio

Dr. Jalian

“While the study failed to show statistically significant improvement in postinflammatory erythema with concomitant laser and topical therapy versus laser alone, the promising data supporting concurrent use of topicals and fractional lasers for treatment of PIH, particularly in dark skin phototypes, is a clinically impactful contribution to our daily practice,” he said.

Dr. Waibel disclosed that she has conducted clinical trials for many device and pharmaceutical companies including SkinCeuticals. Dr. Hu, Dr. DiGiorgio, and Dr. Jalian were not involved with the study and reported having no relevant disclosures.

PHOENIX – Combining a serum containing silymarin with nonablative laser therapy could serve as a promising solution for decreasing inflammation, postinflammatory erythema (PIE), and postinflammatory hyperpigmentation (PIH) associated with acne lesions, results from a prospective, single-center study showed.

“Acne vulgaris is the most common inflammatory dermatosis worldwide, often resulting in sequelae such as scarring, PIE, and PIH,” presenting author Jamie Hu, MD, said at the annual conference of the American Society for Laser Medicine and Surgery, where the study results were presented during an abstract session. “This dyschromia can cause greater psychological distress than the original acne lesions, and disproportionately affects skin of color patients.”

Blemish-prone skin is known to have higher levels of sebum and lower levels of antioxidants, leading to lipid peroxidation and oxidative stress, resulting in proliferation of Cutibacterium acnes and an inflammatory cascade that has recently been implicated in postinflammatory dyschromia and the development of PIE and PIH, noted Dr. Hu, a dermatology resident at the University of Miami. “Therefore, the use of antioxidants presents an opportunity to disrupt blemish and dyschromia,” she said.

One such antioxidant is silymarin, which is derived from the milk thistle plant. Recent studies have demonstrated that silymarin reduces proinflammatory mediators, prevents lipid peroxidation, and presents a new way to target the treatment of both acne and postinflammatory dyschromia.

Dr. Hu’s mentor, Jill S. Waibel, MD, owner and medical director of the Miami Dermatology and Laser Institute, hypothesized that nonablative laser therapy followed by topical application of silymarin would improve acne-associated postinflammatory dyschromia. To test her hunch, she conducted a 12-week, prospective trial in which 24 patients with PIE and/or PIH were randomized to one of two treatment arms: laser treatment with topical antioxidants or laser treatment with vehicle control. Patients received three laser treatments, each 1 month apart. The topical antioxidant used was Silymarin CF, a serum that contains 0.5% silymarin, 0.5% salicylic acid, 15% L-ascorbic acid, and 0.5% ferulic acid. (The study was sponsored by SkinCeuticals, the manufacturer of the serum.)

Laser selection was made primarily on the type of dyschromia, with PIE patients receiving treatment with the pulsed dye laser and PIH patients receiving treatment with the 1,927-nm thulium laser. Patients were treated on days 0, 28, and 56 of the 12-week study, followed by immediate application of topical antioxidants or vehicle control. They were also instructed to apply the assigned topical twice daily for the duration of the study. Patients ranged in age from 21 to 61 years, and 20 had skin types III-IV.

To evaluate efficacy, the researchers conducted blinded clinical assessments with the postacne hyperpigmentation index (PAHPI) and the Global Aesthetic Improvement Scale (GAIS), instrumentation with the Mexameter, a device that captures erythema and melanin index values, and visual diagnostics with optical coherence tomography (OCT).

Dr. Hu reported that at week 12, the PAHPI in the silymarin-plus-laser treatment group fell from an average of 3.18 to 1.74 (a decrease of 1.44), which suggested an improvement trend, compared with the laser treatment–only group, whose PAHPI fell from an average of 3.25 to 1.97 (a decrease of 1.28).

As for the GAIS, a one-time score assessed at the end of the trial, the average score for all patients was 3.24, which translated to “much improved/very much improved.” Patients in the silymarin-plus-laser treatment group had higher average scores compared with patients in the laser treatment–only group (3.35 vs. 3.10, respectively), but the differences did not reach statistical significance.

According to results of the Mexameter assessment, paired t-tests showed that the levels of intralesional melanin decreased significantly for patients in the silymarin-plus-laser treatment group, compared with the laser treatment–only group (P < .05). OCT assessments demonstrated an increase in dermal brightness in both groups, corresponding to an increase in dermal collagen, as well as an increase in blood vessel density.

In an interview at the meeting, Dr. Waibel, subsection chief of dermatology at Baptist Hospital of Miami, said that future studies will focus on long-term follow-up to determine if acne scars can be prevented by combining silymarin with lasers to prevent PIH and PIE. “That would be priceless,” she said. “I believe that the PIH is what causes damage to the collagen, and that damage to the collagen is what causes the scarring. So, if we can prevent or treat PIH, we may be able to prevent scarring.”

This approach, she added, “would decrease the pharmaceutical cost because I think there are many dermatologists who are treating PEI and PIH as active acne. You really have to have a keen eye for understanding the differences and you really have to be looking, because PIE and PIH are flat, whereas active acne consists of either comedones or nodules.”

She noted that in skin of color patients, she has seen PIH persist for 9 or 10 months after treatment with isotretinoin. “It’s not the isotretinoin causing the scars, or even the acne, it’s the prolonged inflammation,” she said.

Catherine M. DiGiorgio, MD, a Boston-based laser and cosmetic dermatologist who was asked to comment on the study, said that patients and dermatologists frequently seek alternatives to hydroquinone for unwanted hyperpigmentation.

Dr. DiGiorgio

Dr. Jalian

“While the study failed to show statistically significant improvement in postinflammatory erythema with concomitant laser and topical therapy versus laser alone, the promising data supporting concurrent use of topicals and fractional lasers for treatment of PIH, particularly in dark skin phototypes, is a clinically impactful contribution to our daily practice,” he said.

Dr. Waibel disclosed that she has conducted clinical trials for many device and pharmaceutical companies including SkinCeuticals. Dr. Hu, Dr. DiGiorgio, and Dr. Jalian were not involved with the study and reported having no relevant disclosures.

Citrus bergamia (bergamot) is a fruit tree thought to originate in the Mediterranean area; its fruit has been a part of the diet in that region since the early 18th century.¹ Bergamot is known to confer antioxidant as well as anti-inflammatory activity, and yields proapoptotic effects in the sebaceous gland.^2,3 The plant contains the natural furocoumarin bergapten, which is also known as 5-methoxypsoralen.⁴

Antibacterial, anti-inflammatory, hypolipemic, and anticancer properties have been associated with bergapten, which is primarily found in bergamot essential oil and used effectively as a photosensitizing agent.⁵ In this capacity, bergamot oil has been used for photodynamic therapy of cutaneous conditions such as vitiligo.⁶ In fact, for several years 5-methoxypsoralen and 8-methoxypsoralen have been used to achieve acceptable clearance rates of psoriasis and vitiligo.⁷ This column focuses on bergapten, as well as the cutaneous conditions for which bergamot has been shown to have some benefits warranting application or further investigation.
 

Bergapten

In a 2021 literature review, Liang et al. cited the anti-inflammatory, antimicrobial, anticancer, and other salutary effects associated with bergapten. Based on numerous citations, they also cautioned about the phototoxicity of the compound combined with ultraviolet (UV) light while noting the photoactivation of bergapten for anticancer uses.⁴

The following year, Quetglas-Llabrés et al. acknowledged, in another literature review, the numerous preclinical and in vitro studies demonstrating the therapeutic activity of bergapten and highlighted clinical trials revealing notable lesion clearance rates of psoriasis or vitiligo imparted by oral or topical bergapten along with UV irradiation. Bergapten was also found to be effective as hypolipemic therapy.⁵

Anti-inflammatory topical uses

In a 2017 study by Han et al. of 10 essential oils, bergamot was among the investigated oils, all of which exhibited significant anti-proliferative activity in a preinflamed human dermal fibroblast system simulating chronic inflammation. Bergamot was among three essential oils that also suppressed protein molecules involved with inflammation, immune responses, and tissue remodeling, indicating anti-inflammatory and wound healing characteristics.⁸

More recently, Cristiano et al. reported that ultradeformable nanocarriers containing bergamot essential oil and ammonium glycyrrhizinate were demonstrated in healthy human volunteers to be characterized by the appropriate mean size, size distribution, surface charge, and long-term stability for topical administration. Topical administration on human volunteers also revealed greater activity of the combined agents as compared with a nanosystem loaded only with ammonium glycyrrhizinate. The researchers concluded that this combination of ingredients in ultradeformable vesicles shows potential as topical anti-inflammatory treatment.³

Acne

In a 2020 study using golden hamsters, Sun et al. assessed the effects of the juice and essential oils of bergamot and sweet orange on acne vulgaris engendered by excessive androgen secretion. Among 80 male hamsters randomly divided into 10 groups ranging from low to high doses, all results demonstrated improvement with treatment as seen by decreased growth rates of sebaceous glands, suppressed triglyceride accumulation, lowered inflammatory cytokine release, and apoptosis promotion in sebaceous glands. The authors noted that the essential oils yielded better dose-dependent effects than the juices.²

Psoriasis

In 2019, Perna et al. conducted a literature review on the effects of bergamot essential oil, extract, juice, and polyphenolic fraction on various health metrics. Thirty-one studies (20 involving humans with 1,709 subjects and 11 in rats and mice) were identified. Animal models indicated that bergamot essential oil (10 mg/kg or 20 mg/kg daily for 20 weeks) reduced psoriatic plaques, increased skin collagen content, and fostered hair growth and that bergamot juice (20 mg/kg) diminished proinflammatory cytokines. Human studies showed that bergamot extract and essential oil may reduce blood pressure and improve mental conditions.⁹

Vitiligo

In 2019, Shaaban et al. prepared elastic nanocarriers (spanlastics) to deliver psoralen-containing bergamot oil along with PUVB with the intention of harnessing melanogenic activity to treat vitiligo. Histopathologic assessment on rat skin was conducted before clinical treatment in patients with vitiligo. The spanlastics were deemed to be of suitable nanosize and deformable, yielding consistent bergamot oil release. The bergamot oil included in the nanocarrier was found to enhance photostability and photodynamic activity, with the researchers concluding that bergamot oil nanospanlastics with psoralen-UVB therapy shows potential as a vitiligo therapy.¹⁰

Two years later, Shaaban evaluated bergamot oil formulated in nanostructured lipid carriers as a photosensitizer for photodynamic treatment of vitiligo. The botanical oil was effectively used in the nanostructured lipid carriers with a gel consistency that delivered sustained release of the oil for 24 hours. Preclinical and clinical results in patients were encouraging for the topical photodynamic treatment of vitiligo, with the nanostructured lipid carriers improving the photostability and photodynamic activity of bergamot oil.⁶

Photoaging, photoprotection, and safety concerns

Three decades ago, an international cooperative study of the photophysical, photomutagenic, and photocarcinogenic characteristics of bergamot oil and the effect of UVA and UVB sunscreens found that UVB and UVA sunscreens at low concentration (0.5%-1%) in perfumes could not inhibit the phototoxicity of bergamot oil on human skin.¹¹

In a 2015 study assessing the impact of 38% bergamot polyphenolic fraction (a highly concentrated Citrus bergamia fruit extract) on UVB-generated photoaging, Nisticò et al. found that the bergamot compound dose-dependently protected HaCaT cells against UVB-caused oxidative stress and photoaging markers. Suggesting that the high-antioxidant bergamot polyphenolic fraction has potential for use in skin care formulations, the researchers added that the extract seems to induce antiproliferative, immune-modulating, and antiaging activity.¹²In 2022, Alexa et al. performed in vitro tests and found that natural preparations containing bergamot, orange, and clove essential oils do not significantly alter physiological skin parameters and were deemed safe for topical use. An emulsion with bergamot essential oil was also found to reduce the viability of oral squamous cell carcinoma cells.¹³

Conclusion

As a photosensitizing agent, bergamot has an established role in skin care. Beyond its niche role in treatments for vitiligo and psoriasis, this botanical product appears to show potential as an anti-inflammatory agent as well as an ingredient to combat photoaging and skin cancer. Much more research is needed to elucidate the possible wider benefits of this Mediterranean staple.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur in Miami. She founded the division of cosmetic dermatology at the University of Miami in 1997. The third edition of her bestselling textbook, “Cosmetic Dermatology,” was published in 2022. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Johnson & Johnson, and Burt’s Bees. She is the CEO of Skin Type Solutions Inc., a SaaS company used to generate skin care routines in office and as an ecommerce solution. Write to her at dermnews@mdedge.com.

References

1. Juber M. Health benefits of bergamot. WebMD. November 29, 2022. Accessed March 21, 2023.

2. Sun P et al. Mediators Inflamm. 2020 Oct 6;2020:8868107.

3. Cristiano MC et al. Biomedicines. 2022 Apr 30;10(5):1039.

4. Liang Y et al. Phytother Res. 2021 Nov;35(11):6131-47.

5. Quetglas-Llabrés MM et al. Oxid Med Cell Longev. 2022 Apr 25;2022:8615242.

6. Shaaban M et al. Expert Opin Drug Deliv. 2021 Jan;18(1):139-50.

7. McNeely W, Goa KL. Drugs. 1998 Oct;56(4):667-90.

8. Han X, Beaumont C, Stevens N. Biochim Open. 2017 Apr 26;5:1-7.

9. Perna S et al. Food Sci Nutr. 2019 Jan 25;7(2):369-84.

10. Shaaban M et al. Drug Deliv Transl Res. 2019 Dec;9(6):1106-16.

11. Dubertret L et al. J Photochem Photobiol B. 1990 Nov;7(2-4):251-9.

12. Nisticò S et al. J Biol Regul Homeost Agents. 2015 Jul-Sep;29(3):723-8.

13. Alexa VT et al. Molecules. 2022 Feb 1;27(3):990.

Citrus bergamia (bergamot) is a fruit tree thought to originate in the Mediterranean area; its fruit has been a part of the diet in that region since the early 18th century.¹ Bergamot is known to confer antioxidant as well as anti-inflammatory activity, and yields proapoptotic effects in the sebaceous gland.^2,3 The plant contains the natural furocoumarin bergapten, which is also known as 5-methoxypsoralen.⁴

Antibacterial, anti-inflammatory, hypolipemic, and anticancer properties have been associated with bergapten, which is primarily found in bergamot essential oil and used effectively as a photosensitizing agent.⁵ In this capacity, bergamot oil has been used for photodynamic therapy of cutaneous conditions such as vitiligo.⁶ In fact, for several years 5-methoxypsoralen and 8-methoxypsoralen have been used to achieve acceptable clearance rates of psoriasis and vitiligo.⁷ This column focuses on bergapten, as well as the cutaneous conditions for which bergamot has been shown to have some benefits warranting application or further investigation.
 

Bergapten

In a 2021 literature review, Liang et al. cited the anti-inflammatory, antimicrobial, anticancer, and other salutary effects associated with bergapten. Based on numerous citations, they also cautioned about the phototoxicity of the compound combined with ultraviolet (UV) light while noting the photoactivation of bergapten for anticancer uses.⁴

The following year, Quetglas-Llabrés et al. acknowledged, in another literature review, the numerous preclinical and in vitro studies demonstrating the therapeutic activity of bergapten and highlighted clinical trials revealing notable lesion clearance rates of psoriasis or vitiligo imparted by oral or topical bergapten along with UV irradiation. Bergapten was also found to be effective as hypolipemic therapy.⁵

Anti-inflammatory topical uses

In a 2017 study by Han et al. of 10 essential oils, bergamot was among the investigated oils, all of which exhibited significant anti-proliferative activity in a preinflamed human dermal fibroblast system simulating chronic inflammation. Bergamot was among three essential oils that also suppressed protein molecules involved with inflammation, immune responses, and tissue remodeling, indicating anti-inflammatory and wound healing characteristics.⁸

More recently, Cristiano et al. reported that ultradeformable nanocarriers containing bergamot essential oil and ammonium glycyrrhizinate were demonstrated in healthy human volunteers to be characterized by the appropriate mean size, size distribution, surface charge, and long-term stability for topical administration. Topical administration on human volunteers also revealed greater activity of the combined agents as compared with a nanosystem loaded only with ammonium glycyrrhizinate. The researchers concluded that this combination of ingredients in ultradeformable vesicles shows potential as topical anti-inflammatory treatment.³

Acne

In a 2020 study using golden hamsters, Sun et al. assessed the effects of the juice and essential oils of bergamot and sweet orange on acne vulgaris engendered by excessive androgen secretion. Among 80 male hamsters randomly divided into 10 groups ranging from low to high doses, all results demonstrated improvement with treatment as seen by decreased growth rates of sebaceous glands, suppressed triglyceride accumulation, lowered inflammatory cytokine release, and apoptosis promotion in sebaceous glands. The authors noted that the essential oils yielded better dose-dependent effects than the juices.²

Psoriasis

In 2019, Perna et al. conducted a literature review on the effects of bergamot essential oil, extract, juice, and polyphenolic fraction on various health metrics. Thirty-one studies (20 involving humans with 1,709 subjects and 11 in rats and mice) were identified. Animal models indicated that bergamot essential oil (10 mg/kg or 20 mg/kg daily for 20 weeks) reduced psoriatic plaques, increased skin collagen content, and fostered hair growth and that bergamot juice (20 mg/kg) diminished proinflammatory cytokines. Human studies showed that bergamot extract and essential oil may reduce blood pressure and improve mental conditions.⁹

Vitiligo

In 2019, Shaaban et al. prepared elastic nanocarriers (spanlastics) to deliver psoralen-containing bergamot oil along with PUVB with the intention of harnessing melanogenic activity to treat vitiligo. Histopathologic assessment on rat skin was conducted before clinical treatment in patients with vitiligo. The spanlastics were deemed to be of suitable nanosize and deformable, yielding consistent bergamot oil release. The bergamot oil included in the nanocarrier was found to enhance photostability and photodynamic activity, with the researchers concluding that bergamot oil nanospanlastics with psoralen-UVB therapy shows potential as a vitiligo therapy.¹⁰

Two years later, Shaaban evaluated bergamot oil formulated in nanostructured lipid carriers as a photosensitizer for photodynamic treatment of vitiligo. The botanical oil was effectively used in the nanostructured lipid carriers with a gel consistency that delivered sustained release of the oil for 24 hours. Preclinical and clinical results in patients were encouraging for the topical photodynamic treatment of vitiligo, with the nanostructured lipid carriers improving the photostability and photodynamic activity of bergamot oil.⁶

Photoaging, photoprotection, and safety concerns

Three decades ago, an international cooperative study of the photophysical, photomutagenic, and photocarcinogenic characteristics of bergamot oil and the effect of UVA and UVB sunscreens found that UVB and UVA sunscreens at low concentration (0.5%-1%) in perfumes could not inhibit the phototoxicity of bergamot oil on human skin.¹¹

In a 2015 study assessing the impact of 38% bergamot polyphenolic fraction (a highly concentrated Citrus bergamia fruit extract) on UVB-generated photoaging, Nisticò et al. found that the bergamot compound dose-dependently protected HaCaT cells against UVB-caused oxidative stress and photoaging markers. Suggesting that the high-antioxidant bergamot polyphenolic fraction has potential for use in skin care formulations, the researchers added that the extract seems to induce antiproliferative, immune-modulating, and antiaging activity.¹²In 2022, Alexa et al. performed in vitro tests and found that natural preparations containing bergamot, orange, and clove essential oils do not significantly alter physiological skin parameters and were deemed safe for topical use. An emulsion with bergamot essential oil was also found to reduce the viability of oral squamous cell carcinoma cells.¹³

Conclusion

As a photosensitizing agent, bergamot has an established role in skin care. Beyond its niche role in treatments for vitiligo and psoriasis, this botanical product appears to show potential as an anti-inflammatory agent as well as an ingredient to combat photoaging and skin cancer. Much more research is needed to elucidate the possible wider benefits of this Mediterranean staple.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur in Miami. She founded the division of cosmetic dermatology at the University of Miami in 1997. The third edition of her bestselling textbook, “Cosmetic Dermatology,” was published in 2022. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Johnson & Johnson, and Burt’s Bees. She is the CEO of Skin Type Solutions Inc., a SaaS company used to generate skin care routines in office and as an ecommerce solution. Write to her at dermnews@mdedge.com.

References

1. Juber M. Health benefits of bergamot. WebMD. November 29, 2022. Accessed March 21, 2023.

2. Sun P et al. Mediators Inflamm. 2020 Oct 6;2020:8868107.

3. Cristiano MC et al. Biomedicines. 2022 Apr 30;10(5):1039.

4. Liang Y et al. Phytother Res. 2021 Nov;35(11):6131-47.

5. Quetglas-Llabrés MM et al. Oxid Med Cell Longev. 2022 Apr 25;2022:8615242.

6. Shaaban M et al. Expert Opin Drug Deliv. 2021 Jan;18(1):139-50.

7. McNeely W, Goa KL. Drugs. 1998 Oct;56(4):667-90.

8. Han X, Beaumont C, Stevens N. Biochim Open. 2017 Apr 26;5:1-7.

9. Perna S et al. Food Sci Nutr. 2019 Jan 25;7(2):369-84.

10. Shaaban M et al. Drug Deliv Transl Res. 2019 Dec;9(6):1106-16.

11. Dubertret L et al. J Photochem Photobiol B. 1990 Nov;7(2-4):251-9.

12. Nisticò S et al. J Biol Regul Homeost Agents. 2015 Jul-Sep;29(3):723-8.

13. Alexa VT et al. Molecules. 2022 Feb 1;27(3):990.

Citrus bergamia (bergamot) is a fruit tree thought to originate in the Mediterranean area; its fruit has been a part of the diet in that region since the early 18th century.¹ Bergamot is known to confer antioxidant as well as anti-inflammatory activity, and yields proapoptotic effects in the sebaceous gland.^2,3 The plant contains the natural furocoumarin bergapten, which is also known as 5-methoxypsoralen.⁴

Antibacterial, anti-inflammatory, hypolipemic, and anticancer properties have been associated with bergapten, which is primarily found in bergamot essential oil and used effectively as a photosensitizing agent.⁵ In this capacity, bergamot oil has been used for photodynamic therapy of cutaneous conditions such as vitiligo.⁶ In fact, for several years 5-methoxypsoralen and 8-methoxypsoralen have been used to achieve acceptable clearance rates of psoriasis and vitiligo.⁷ This column focuses on bergapten, as well as the cutaneous conditions for which bergamot has been shown to have some benefits warranting application or further investigation.
 

Bergapten

In a 2021 literature review, Liang et al. cited the anti-inflammatory, antimicrobial, anticancer, and other salutary effects associated with bergapten. Based on numerous citations, they also cautioned about the phototoxicity of the compound combined with ultraviolet (UV) light while noting the photoactivation of bergapten for anticancer uses.⁴

The following year, Quetglas-Llabrés et al. acknowledged, in another literature review, the numerous preclinical and in vitro studies demonstrating the therapeutic activity of bergapten and highlighted clinical trials revealing notable lesion clearance rates of psoriasis or vitiligo imparted by oral or topical bergapten along with UV irradiation. Bergapten was also found to be effective as hypolipemic therapy.⁵

Anti-inflammatory topical uses

In a 2017 study by Han et al. of 10 essential oils, bergamot was among the investigated oils, all of which exhibited significant anti-proliferative activity in a preinflamed human dermal fibroblast system simulating chronic inflammation. Bergamot was among three essential oils that also suppressed protein molecules involved with inflammation, immune responses, and tissue remodeling, indicating anti-inflammatory and wound healing characteristics.⁸

More recently, Cristiano et al. reported that ultradeformable nanocarriers containing bergamot essential oil and ammonium glycyrrhizinate were demonstrated in healthy human volunteers to be characterized by the appropriate mean size, size distribution, surface charge, and long-term stability for topical administration. Topical administration on human volunteers also revealed greater activity of the combined agents as compared with a nanosystem loaded only with ammonium glycyrrhizinate. The researchers concluded that this combination of ingredients in ultradeformable vesicles shows potential as topical anti-inflammatory treatment.³

Acne

In a 2020 study using golden hamsters, Sun et al. assessed the effects of the juice and essential oils of bergamot and sweet orange on acne vulgaris engendered by excessive androgen secretion. Among 80 male hamsters randomly divided into 10 groups ranging from low to high doses, all results demonstrated improvement with treatment as seen by decreased growth rates of sebaceous glands, suppressed triglyceride accumulation, lowered inflammatory cytokine release, and apoptosis promotion in sebaceous glands. The authors noted that the essential oils yielded better dose-dependent effects than the juices.²

Psoriasis

In 2019, Perna et al. conducted a literature review on the effects of bergamot essential oil, extract, juice, and polyphenolic fraction on various health metrics. Thirty-one studies (20 involving humans with 1,709 subjects and 11 in rats and mice) were identified. Animal models indicated that bergamot essential oil (10 mg/kg or 20 mg/kg daily for 20 weeks) reduced psoriatic plaques, increased skin collagen content, and fostered hair growth and that bergamot juice (20 mg/kg) diminished proinflammatory cytokines. Human studies showed that bergamot extract and essential oil may reduce blood pressure and improve mental conditions.⁹

Vitiligo

In 2019, Shaaban et al. prepared elastic nanocarriers (spanlastics) to deliver psoralen-containing bergamot oil along with PUVB with the intention of harnessing melanogenic activity to treat vitiligo. Histopathologic assessment on rat skin was conducted before clinical treatment in patients with vitiligo. The spanlastics were deemed to be of suitable nanosize and deformable, yielding consistent bergamot oil release. The bergamot oil included in the nanocarrier was found to enhance photostability and photodynamic activity, with the researchers concluding that bergamot oil nanospanlastics with psoralen-UVB therapy shows potential as a vitiligo therapy.¹⁰

Two years later, Shaaban evaluated bergamot oil formulated in nanostructured lipid carriers as a photosensitizer for photodynamic treatment of vitiligo. The botanical oil was effectively used in the nanostructured lipid carriers with a gel consistency that delivered sustained release of the oil for 24 hours. Preclinical and clinical results in patients were encouraging for the topical photodynamic treatment of vitiligo, with the nanostructured lipid carriers improving the photostability and photodynamic activity of bergamot oil.⁶

Photoaging, photoprotection, and safety concerns

Three decades ago, an international cooperative study of the photophysical, photomutagenic, and photocarcinogenic characteristics of bergamot oil and the effect of UVA and UVB sunscreens found that UVB and UVA sunscreens at low concentration (0.5%-1%) in perfumes could not inhibit the phototoxicity of bergamot oil on human skin.¹¹

In a 2015 study assessing the impact of 38% bergamot polyphenolic fraction (a highly concentrated Citrus bergamia fruit extract) on UVB-generated photoaging, Nisticò et al. found that the bergamot compound dose-dependently protected HaCaT cells against UVB-caused oxidative stress and photoaging markers. Suggesting that the high-antioxidant bergamot polyphenolic fraction has potential for use in skin care formulations, the researchers added that the extract seems to induce antiproliferative, immune-modulating, and antiaging activity.¹²In 2022, Alexa et al. performed in vitro tests and found that natural preparations containing bergamot, orange, and clove essential oils do not significantly alter physiological skin parameters and were deemed safe for topical use. An emulsion with bergamot essential oil was also found to reduce the viability of oral squamous cell carcinoma cells.¹³

Conclusion

As a photosensitizing agent, bergamot has an established role in skin care. Beyond its niche role in treatments for vitiligo and psoriasis, this botanical product appears to show potential as an anti-inflammatory agent as well as an ingredient to combat photoaging and skin cancer. Much more research is needed to elucidate the possible wider benefits of this Mediterranean staple.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur in Miami. She founded the division of cosmetic dermatology at the University of Miami in 1997. The third edition of her bestselling textbook, “Cosmetic Dermatology,” was published in 2022. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Johnson & Johnson, and Burt’s Bees. She is the CEO of Skin Type Solutions Inc., a SaaS company used to generate skin care routines in office and as an ecommerce solution. Write to her at dermnews@mdedge.com.

References

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4. Liang Y et al. Phytother Res. 2021 Nov;35(11):6131-47.

5. Quetglas-Llabrés MM et al. Oxid Med Cell Longev. 2022 Apr 25;2022:8615242.

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8. Han X, Beaumont C, Stevens N. Biochim Open. 2017 Apr 26;5:1-7.

9. Perna S et al. Food Sci Nutr. 2019 Jan 25;7(2):369-84.

10. Shaaban M et al. Drug Deliv Transl Res. 2019 Dec;9(6):1106-16.

11. Dubertret L et al. J Photochem Photobiol B. 1990 Nov;7(2-4):251-9.

12. Nisticò S et al. J Biol Regul Homeost Agents. 2015 Jul-Sep;29(3):723-8.

13. Alexa VT et al. Molecules. 2022 Feb 1;27(3):990.