Cutis

Practice Gap

Perioperative anxiety is common in patients undergoing nail surgery. Patients might worry about seeing blood; about the procedure itself, including nail avulsion; and about associated pain and disfigurement. Nail surgery causes a high level of anxiety that correlates positively with postoperative pain¹ and overall patient dissatisfaction. Furthermore, surgery-related anxiety is a predictor of increased postoperative analgesic use² and delayed recovery.³

Therefore, implementing strategies that reduce perioperative anxiety may help minimize postoperative pain. Squeezing a stress ball, hand-holding, virtual reality, and music are tools that have been studied to reduce anxiety in the context of Mohs micrographic surgery; these strategies have not been studied for nail surgery.

The Technique

Using a sleep mask is a practical solution to reduce patient anxiety during nail surgery. A minority of patients will choose to watch their surgical procedure; most become unnerved observing their nail surgery. Using a sleep mask diverts visual attention from the surgical field without physically interfering with the nail surgeon. Utilizing a sleep mask is cost-effective, with disposable sleep masks available online for less than $0.30 each. Patients can bring their own mask, or a mask can be offered prior to surgery.

If desired, patients are instructed to wear the sleep mask during the entirety of the procedure, starting from anesthetic infiltration until wound closure and dressing application. Any adjustments can be made with the patient’s free hand. The sleep mask can be offered to patients of all ages undergoing nail surgery under local anesthesia, except babies and young children, who require general anesthesia.

Practical Implications

Distraction is an important strategy to reduce anxiety and pain in patients undergoing surgical procedures. In an observational study of 3087 surgical patients, 36% reported that self-distraction was the most helpful strategy for coping with preoperative anxiety.⁴ In a randomized, open-label clinical trial of 72 patients undergoing peripheral venous catheterization, asking the patients simple questions during the procedure was more effective than local anesthesia in reducing the perception of pain.⁵

It is crucial to implement strategies to reduce anxiety in patients undergoing nail surgery. Using a sleep mask impedes direct visualization of the surgical field, thus distracting the patient’s sight and attention from the procedure. Furthermore, this technique is safe and cost-effective.

Controlled clinical trials are necessary to assess the efficacy of this method in reducing nail surgery–related anxiety in comparison to other techniques.

Practice Gap

Perioperative anxiety is common in patients undergoing nail surgery. Patients might worry about seeing blood; about the procedure itself, including nail avulsion; and about associated pain and disfigurement. Nail surgery causes a high level of anxiety that correlates positively with postoperative pain¹ and overall patient dissatisfaction. Furthermore, surgery-related anxiety is a predictor of increased postoperative analgesic use² and delayed recovery.³

Therefore, implementing strategies that reduce perioperative anxiety may help minimize postoperative pain. Squeezing a stress ball, hand-holding, virtual reality, and music are tools that have been studied to reduce anxiety in the context of Mohs micrographic surgery; these strategies have not been studied for nail surgery.

The Technique

Using a sleep mask is a practical solution to reduce patient anxiety during nail surgery. A minority of patients will choose to watch their surgical procedure; most become unnerved observing their nail surgery. Using a sleep mask diverts visual attention from the surgical field without physically interfering with the nail surgeon. Utilizing a sleep mask is cost-effective, with disposable sleep masks available online for less than $0.30 each. Patients can bring their own mask, or a mask can be offered prior to surgery.

If desired, patients are instructed to wear the sleep mask during the entirety of the procedure, starting from anesthetic infiltration until wound closure and dressing application. Any adjustments can be made with the patient’s free hand. The sleep mask can be offered to patients of all ages undergoing nail surgery under local anesthesia, except babies and young children, who require general anesthesia.

Practical Implications

Distraction is an important strategy to reduce anxiety and pain in patients undergoing surgical procedures. In an observational study of 3087 surgical patients, 36% reported that self-distraction was the most helpful strategy for coping with preoperative anxiety.⁴ In a randomized, open-label clinical trial of 72 patients undergoing peripheral venous catheterization, asking the patients simple questions during the procedure was more effective than local anesthesia in reducing the perception of pain.⁵

It is crucial to implement strategies to reduce anxiety in patients undergoing nail surgery. Using a sleep mask impedes direct visualization of the surgical field, thus distracting the patient’s sight and attention from the procedure. Furthermore, this technique is safe and cost-effective.

Controlled clinical trials are necessary to assess the efficacy of this method in reducing nail surgery–related anxiety in comparison to other techniques.

Practice Gap

Perioperative anxiety is common in patients undergoing nail surgery. Patients might worry about seeing blood; about the procedure itself, including nail avulsion; and about associated pain and disfigurement. Nail surgery causes a high level of anxiety that correlates positively with postoperative pain¹ and overall patient dissatisfaction. Furthermore, surgery-related anxiety is a predictor of increased postoperative analgesic use² and delayed recovery.³

Therefore, implementing strategies that reduce perioperative anxiety may help minimize postoperative pain. Squeezing a stress ball, hand-holding, virtual reality, and music are tools that have been studied to reduce anxiety in the context of Mohs micrographic surgery; these strategies have not been studied for nail surgery.

The Technique

Using a sleep mask is a practical solution to reduce patient anxiety during nail surgery. A minority of patients will choose to watch their surgical procedure; most become unnerved observing their nail surgery. Using a sleep mask diverts visual attention from the surgical field without physically interfering with the nail surgeon. Utilizing a sleep mask is cost-effective, with disposable sleep masks available online for less than $0.30 each. Patients can bring their own mask, or a mask can be offered prior to surgery.

If desired, patients are instructed to wear the sleep mask during the entirety of the procedure, starting from anesthetic infiltration until wound closure and dressing application. Any adjustments can be made with the patient’s free hand. The sleep mask can be offered to patients of all ages undergoing nail surgery under local anesthesia, except babies and young children, who require general anesthesia.

Practical Implications

Distraction is an important strategy to reduce anxiety and pain in patients undergoing surgical procedures. In an observational study of 3087 surgical patients, 36% reported that self-distraction was the most helpful strategy for coping with preoperative anxiety.⁴ In a randomized, open-label clinical trial of 72 patients undergoing peripheral venous catheterization, asking the patients simple questions during the procedure was more effective than local anesthesia in reducing the perception of pain.⁵

It is crucial to implement strategies to reduce anxiety in patients undergoing nail surgery. Using a sleep mask impedes direct visualization of the surgical field, thus distracting the patient’s sight and attention from the procedure. Furthermore, this technique is safe and cost-effective.

Controlled clinical trials are necessary to assess the efficacy of this method in reducing nail surgery–related anxiety in comparison to other techniques.

Congenital onychodysplasia of the index finger (COIF), or Iso-Kikuchi syndrome, is a rare disorder characterized by malformation of one or both nails of the index fingers. The various anomalies described are anonychia, micronychia, polyonychia, malalignment, or hemi-onychogryphosis. It may be associated with abnormalities of the underlying phalangeal bone, the most masked being bifurcation of the terminal phalange.¹ Initially thought to be nonhereditary and nonfamilial,² it is now known that COIF can be inherited in an autosomal-dominant fashion.³ Millman and Strier³ described a family of 9 patients with COIF. It rarely is described outside of Japan. Padmavathy et al⁴ described a case in an Indian patient with COIF that was associated with the absence of a ring finger in addition to anomalies of the metacarpal bones.

Congenital onychodysplasia of the index finger has a broad spectrum regarding its etiology and clinical features.⁵ The pathogenesis of COIF still is poorly understood. Deficient circulation in digital arteries is thought to be a putative mechanism for developing a deformed nail. The nail is affected on the radial side of the index finger, likely because of the smaller caliber of the artery on that side.⁵ Hereditary as well as nonhereditary sporadic cases have been reported. In addition to the various fingernail anomalies, skeletal abnormalities also have been reported. Baran and Stroud⁶ have reported deformed lunulae as a manifestation of COIF.

The Diagnosis: Congenital Onychodysplasia of the Index Finger

The differential diagnosis of COIF includes hidrotic ectodermal dysplasia, nail-patella syndrome, Poland syndrome, and DOOR syndrome. Hidrotic ectodermal dysplasia exhibits onychodystrophy, generalized hypotrichosis, palmoplantar keratoderma, and dental anomalies.⁷ Nail-patella syndrome presents with hypoplasia of the fingernails and toenails, triangular nail lunulae, absent or hypoplastic patellae, and elbow and iliac horn dysplasia. Poland syndrome is distinguished from COIF by the congenital absence of the pectoralis major muscle on the ipsilateral side of the involved digits. The DOOR syndrome tetrad is comprised of deafness, onychodystrophy, osteodystrophy, and mental retardation.⁸ Unlike these conditions, COIF does not involve systems other than the nails and phalanges.

Treatment of this condition is mainly conservative, as patients typically do not have symptoms.⁹ Surgical interventions can be considered for cosmetic concerns. Knowledge of this congenital entity and its clinical findings is essential to prevent unnecessary procedures and workup.

Congenital onychodysplasia of the index finger (COIF), or Iso-Kikuchi syndrome, is a rare disorder characterized by malformation of one or both nails of the index fingers. The various anomalies described are anonychia, micronychia, polyonychia, malalignment, or hemi-onychogryphosis. It may be associated with abnormalities of the underlying phalangeal bone, the most masked being bifurcation of the terminal phalange.¹ Initially thought to be nonhereditary and nonfamilial,² it is now known that COIF can be inherited in an autosomal-dominant fashion.³ Millman and Strier³ described a family of 9 patients with COIF. It rarely is described outside of Japan. Padmavathy et al⁴ described a case in an Indian patient with COIF that was associated with the absence of a ring finger in addition to anomalies of the metacarpal bones.

Congenital onychodysplasia of the index finger has a broad spectrum regarding its etiology and clinical features.⁵ The pathogenesis of COIF still is poorly understood. Deficient circulation in digital arteries is thought to be a putative mechanism for developing a deformed nail. The nail is affected on the radial side of the index finger, likely because of the smaller caliber of the artery on that side.⁵ Hereditary as well as nonhereditary sporadic cases have been reported. In addition to the various fingernail anomalies, skeletal abnormalities also have been reported. Baran and Stroud⁶ have reported deformed lunulae as a manifestation of COIF.

The Diagnosis: Congenital Onychodysplasia of the Index Finger

The differential diagnosis of COIF includes hidrotic ectodermal dysplasia, nail-patella syndrome, Poland syndrome, and DOOR syndrome. Hidrotic ectodermal dysplasia exhibits onychodystrophy, generalized hypotrichosis, palmoplantar keratoderma, and dental anomalies.⁷ Nail-patella syndrome presents with hypoplasia of the fingernails and toenails, triangular nail lunulae, absent or hypoplastic patellae, and elbow and iliac horn dysplasia. Poland syndrome is distinguished from COIF by the congenital absence of the pectoralis major muscle on the ipsilateral side of the involved digits. The DOOR syndrome tetrad is comprised of deafness, onychodystrophy, osteodystrophy, and mental retardation.⁸ Unlike these conditions, COIF does not involve systems other than the nails and phalanges.

Treatment of this condition is mainly conservative, as patients typically do not have symptoms.⁹ Surgical interventions can be considered for cosmetic concerns. Knowledge of this congenital entity and its clinical findings is essential to prevent unnecessary procedures and workup.

Congenital onychodysplasia of the index finger (COIF), or Iso-Kikuchi syndrome, is a rare disorder characterized by malformation of one or both nails of the index fingers. The various anomalies described are anonychia, micronychia, polyonychia, malalignment, or hemi-onychogryphosis. It may be associated with abnormalities of the underlying phalangeal bone, the most masked being bifurcation of the terminal phalange.¹ Initially thought to be nonhereditary and nonfamilial,² it is now known that COIF can be inherited in an autosomal-dominant fashion.³ Millman and Strier³ described a family of 9 patients with COIF. It rarely is described outside of Japan. Padmavathy et al⁴ described a case in an Indian patient with COIF that was associated with the absence of a ring finger in addition to anomalies of the metacarpal bones.

Congenital onychodysplasia of the index finger has a broad spectrum regarding its etiology and clinical features.⁵ The pathogenesis of COIF still is poorly understood. Deficient circulation in digital arteries is thought to be a putative mechanism for developing a deformed nail. The nail is affected on the radial side of the index finger, likely because of the smaller caliber of the artery on that side.⁵ Hereditary as well as nonhereditary sporadic cases have been reported. In addition to the various fingernail anomalies, skeletal abnormalities also have been reported. Baran and Stroud⁶ have reported deformed lunulae as a manifestation of COIF.

The Diagnosis: Congenital Onychodysplasia of the Index Finger

The differential diagnosis of COIF includes hidrotic ectodermal dysplasia, nail-patella syndrome, Poland syndrome, and DOOR syndrome. Hidrotic ectodermal dysplasia exhibits onychodystrophy, generalized hypotrichosis, palmoplantar keratoderma, and dental anomalies.⁷ Nail-patella syndrome presents with hypoplasia of the fingernails and toenails, triangular nail lunulae, absent or hypoplastic patellae, and elbow and iliac horn dysplasia. Poland syndrome is distinguished from COIF by the congenital absence of the pectoralis major muscle on the ipsilateral side of the involved digits. The DOOR syndrome tetrad is comprised of deafness, onychodystrophy, osteodystrophy, and mental retardation.⁸ Unlike these conditions, COIF does not involve systems other than the nails and phalanges.

Treatment of this condition is mainly conservative, as patients typically do not have symptoms.⁹ Surgical interventions can be considered for cosmetic concerns. Knowledge of this congenital entity and its clinical findings is essential to prevent unnecessary procedures and workup.

Professional appearance of servicemembers has been a long-standing custom in the US Military. Specific standards are determined by each branch. Initially, men dominated the military.^1,2 As the number of women as well as racial diversity increased in the military, modifications to grooming standards were slow to change and resulted in female hair standards requiring a uniform tight and sleek style or short haircut. Clinicians can be attuned to these occupational standards and their implications on the diagnosis and management of common diseases of the hair and scalp.

History of Hairstyle Standards for Female Servicemembers

For half a century, female servicemembers had limited hairstyle choices. They were not authorized to have hair shorter than one-quarter inch in length. They could choose either short hair worn down or long hair with neatly secured loose ends in the form of a bun or a tucked braid—both of which could not extend past the bottom edge of the uniform collar.^3-5 Female navy sailors and air force airmen with long hair were only allowed to wear ponytails during physical training; however, army soldiers previously were limited to wearing a bun.^3,6,7 Cornrows and microbraids were authorized in the mid-1990s for the US Air Force, but policy stated that locs were prohibited due to their “unkempt” and “matted” nature. Furthermore, the size of hair bulk in the air force was restricted to no more than 3 inches and could not obstruct wear of the uniform cap.⁵ Based on these regulations, female servicemembers with longer hair had to utilize tight hairstyles that caused prolonged traction and pressure along the scalp, which contributed to headaches, a sore scalp, and alopecia over time. Normalization of these symptoms led to underreporting, as women lived with the consequences or turned to shorter hairstyles.

In the last decade alone, female servicemembers have witnessed the greatest number of changes in authorized hairstyles despite being part of the military for more than 50 years (Figure 1).^1-11 In 2014, the language used in the air force instructions to describe locs was revised to remove ethnically offensive terms.^4,5 This same year, the army allowed female soldiers to wear ponytails during physical training, a privilege that had been authorized by other services years prior.^3,6,7 By the end of 2018, locs were authorized by all services, and female sailors could wear a ponytail in all navy uniforms as long as it did not extend 3 inches below the collar.^3,4,6-8 In 2018, the air force increased authorized hair bulk up to 3.5 inches from the previous mandate of 3 inches and approved female buzz cuts^6,9; in 2020, it allowed hair bulk up to 4 inches. As of 2021, female airmen can wear a ponytail and/or braid(s) as long as it starts below the crown of the head and the length does not extend below a horizontal line running between the top of each sleeve inseam at the underarm (Figures 2–4).⁶ In an ongoing effort to be more inclusive of hair density differences, female airmen will be authorized to wear a ponytail not exceeding a maximum width bulk of 1 ft starting June 25, 2021, so long as they can comply with the above regulations.¹¹ The army now allows ponytails and braids across all uniforms, as long they do not extend past the bottom of the shoulder blades. This change came just months after authorizing the wearing of ponytails tucked under the uniform blouse with tactical headgear.¹⁰ These changes allow for a variety of hairstyles for members to practice while avoiding the physical consequences that develop from repetitive traction and pressure along the same areas of the hair and scalp.

Common Hair Disorders in Female Servicemembers

Herein, we discuss 3 of the most common hair and scalp disorders linked to grooming practices utilized by women to meet prior military regulations: trichorrhexis nodosa (TN), extracranial headaches, and traction alopecia (TA). It is essential that health care providers are able to promptly recognize these conditions, understand their risk factors, and be familiar with first-line treatment options. With these new standards, the hope is that the incidence of the following conditions decreases, thus improving servicemembers’ medical readiness and overall quality of life.

Trichorrhexis Nodosa
Acquired TN is a defect in the hair shaft that causes the hair to break easily secondary to chemical, thermal, or mechanical trauma. This can include but is not limited to chemical relaxers, blow-dryers, excessive brushing or styling, flat irons, and tightly packed hairstyles. The condition is characterized by a thickened hair diameter and splitting at the tip. Clinically, it may present as brittle, lusterless, broken hair with split ends, as well as a positive tug test.¹⁴ Management includes gentle hair care and avoidance of harsh hair care practices and treatments.

Extracranial Headaches
Headaches are a common concern among military servicemembers¹⁵ and generally are classified as primary or secondary. A less commonly discussed primary headache disorder includes external-pressure headaches, which result from either sustained compression or traction of the soft tissues of the scalp, usually from wearing headbands, helmets, or tight hairstyles.¹⁶ Additional at-risk groups include those who chronically wear surgical scrub caps or flight caps, especially if clipped or pinned to the hair. In our 38 years of combined military clinical experience, we can attest that these types of headaches are common among female servicemembers. The diagnostic criteria for an external-pressure headache, commonly referred to by patients as a “ponytail headache,” includes at least 2 headache episodes triggered within 1 hour of sustained traction on the scalp, maximal at the site of traction and resolving within 1 hour after relieving the traction.¹⁶ Management includes removal of the pressure-causing source, usually a tight ponytail or bun.

Traction Alopecia
Traction alopecia is hair loss caused by repetitive or prolonged tension on the hair secondary to tight hairstyles. It can be clinically classified into 2 types: marginal and nonmarginal patchy alopecia (Figure 5).^13,17,18 Traction alopecia most commonly is found in individuals with ethnic hair, predominantly Black women. Hairstyles with the highest risk for causing TA include tight buns, ponytails, cornrows, weaves, and locs—all of which are utilized by female servicemembers to maintain a professional appearance and adhere to grooming regulations.^13,18 Other groups at risk include athletes (eg, ballerinas, gymnasts) and those with chronic headwear use (eg, turbans, helmets, nurse caps, wigs).¹⁸ Early TA typically presents with perifollicular erythema followed by follicular-based papules or pustules.^13,18 Marginal TA classically includes frontotemporal hair loss or thinning with or without a fringe sign.^17,18 Nonmarginal TA includes patchy alopecia most commonly involving the parietal or occipital scalp, seen with chignons, buns, ponytails, or the use of clips, extensions, or bobby pins.¹⁸ The first line in management is avoidance of traction-causing hairstyles or headgear. Medical therapy may be warranted and consists of a single agent or combination regimen to include oral or topical antibiotics, topical or intralesional steroids, and topical minoxidil.^13,18

Final Thoughts

Military hair-grooming standards have evolved over time. Recent changes show that the US Department of Defense is seriously evaluating policies that may be inherently exclusive. Prior grooming standards resulted in the widespread use of tight hairstyles and harsh hair treatments among female servicemembers with long hair. These practices resulted in TN, extracranial headaches, and TA, among other hair and scalp disorders. These occupational-related hair conditions impact female servicemembers’ mental and physical well-being and thus impact military readiness. Physicians should recognize that these conditions can be related to occupational grooming standards that may impact hair care practices.

The challenge that remains is a lack of standardized documentation for hair and scalp symptoms in the medical record. Due to a paucity in reporting and documentation, limited objective data exist to guide future recommendations for military grooming standards. Another obstacle is the lack of knowledge of hair diseases among primary care providers and patients, especially due to the underrepresentation of ethnic hair in medical textbooks.¹⁹ As a result, women frequently accept their hair symptoms as normal and either suffer through them, cut their hair short, or wear wigs before considering a visit to the doctor. Furthermore, hair-grooming standards can expose racial disparities, which are the driving force behind the current policy changes. Clinicians can strive to ask about hair and scalp symptoms and document the following in relation to hair and scalp disorders: occupational grooming requirements; skin and hair type; location, number, and size of scalp lesion(s); onset; duration; current and prior hair care practices; history of treatment; and clinical course accompanied with photographic documentation. Ultimately, improved awareness in patients, collaboration between physicians, and consistent clinical documentation can help create positive change and continued improvement in hair-grooming standards within the military. Improved reporting and documentation will facilitate further study into the effectiveness of the updated hair-grooming standards in female servicemembers.

Professional appearance of servicemembers has been a long-standing custom in the US Military. Specific standards are determined by each branch. Initially, men dominated the military.^1,2 As the number of women as well as racial diversity increased in the military, modifications to grooming standards were slow to change and resulted in female hair standards requiring a uniform tight and sleek style or short haircut. Clinicians can be attuned to these occupational standards and their implications on the diagnosis and management of common diseases of the hair and scalp.

History of Hairstyle Standards for Female Servicemembers

For half a century, female servicemembers had limited hairstyle choices. They were not authorized to have hair shorter than one-quarter inch in length. They could choose either short hair worn down or long hair with neatly secured loose ends in the form of a bun or a tucked braid—both of which could not extend past the bottom edge of the uniform collar.^3-5 Female navy sailors and air force airmen with long hair were only allowed to wear ponytails during physical training; however, army soldiers previously were limited to wearing a bun.^3,6,7 Cornrows and microbraids were authorized in the mid-1990s for the US Air Force, but policy stated that locs were prohibited due to their “unkempt” and “matted” nature. Furthermore, the size of hair bulk in the air force was restricted to no more than 3 inches and could not obstruct wear of the uniform cap.⁵ Based on these regulations, female servicemembers with longer hair had to utilize tight hairstyles that caused prolonged traction and pressure along the scalp, which contributed to headaches, a sore scalp, and alopecia over time. Normalization of these symptoms led to underreporting, as women lived with the consequences or turned to shorter hairstyles.

In the last decade alone, female servicemembers have witnessed the greatest number of changes in authorized hairstyles despite being part of the military for more than 50 years (Figure 1).^1-11 In 2014, the language used in the air force instructions to describe locs was revised to remove ethnically offensive terms.^4,5 This same year, the army allowed female soldiers to wear ponytails during physical training, a privilege that had been authorized by other services years prior.^3,6,7 By the end of 2018, locs were authorized by all services, and female sailors could wear a ponytail in all navy uniforms as long as it did not extend 3 inches below the collar.^3,4,6-8 In 2018, the air force increased authorized hair bulk up to 3.5 inches from the previous mandate of 3 inches and approved female buzz cuts^6,9; in 2020, it allowed hair bulk up to 4 inches. As of 2021, female airmen can wear a ponytail and/or braid(s) as long as it starts below the crown of the head and the length does not extend below a horizontal line running between the top of each sleeve inseam at the underarm (Figures 2–4).⁶ In an ongoing effort to be more inclusive of hair density differences, female airmen will be authorized to wear a ponytail not exceeding a maximum width bulk of 1 ft starting June 25, 2021, so long as they can comply with the above regulations.¹¹ The army now allows ponytails and braids across all uniforms, as long they do not extend past the bottom of the shoulder blades. This change came just months after authorizing the wearing of ponytails tucked under the uniform blouse with tactical headgear.¹⁰ These changes allow for a variety of hairstyles for members to practice while avoiding the physical consequences that develop from repetitive traction and pressure along the same areas of the hair and scalp.

Common Hair Disorders in Female Servicemembers

Herein, we discuss 3 of the most common hair and scalp disorders linked to grooming practices utilized by women to meet prior military regulations: trichorrhexis nodosa (TN), extracranial headaches, and traction alopecia (TA). It is essential that health care providers are able to promptly recognize these conditions, understand their risk factors, and be familiar with first-line treatment options. With these new standards, the hope is that the incidence of the following conditions decreases, thus improving servicemembers’ medical readiness and overall quality of life.

Trichorrhexis Nodosa
Acquired TN is a defect in the hair shaft that causes the hair to break easily secondary to chemical, thermal, or mechanical trauma. This can include but is not limited to chemical relaxers, blow-dryers, excessive brushing or styling, flat irons, and tightly packed hairstyles. The condition is characterized by a thickened hair diameter and splitting at the tip. Clinically, it may present as brittle, lusterless, broken hair with split ends, as well as a positive tug test.¹⁴ Management includes gentle hair care and avoidance of harsh hair care practices and treatments.

Extracranial Headaches
Headaches are a common concern among military servicemembers¹⁵ and generally are classified as primary or secondary. A less commonly discussed primary headache disorder includes external-pressure headaches, which result from either sustained compression or traction of the soft tissues of the scalp, usually from wearing headbands, helmets, or tight hairstyles.¹⁶ Additional at-risk groups include those who chronically wear surgical scrub caps or flight caps, especially if clipped or pinned to the hair. In our 38 years of combined military clinical experience, we can attest that these types of headaches are common among female servicemembers. The diagnostic criteria for an external-pressure headache, commonly referred to by patients as a “ponytail headache,” includes at least 2 headache episodes triggered within 1 hour of sustained traction on the scalp, maximal at the site of traction and resolving within 1 hour after relieving the traction.¹⁶ Management includes removal of the pressure-causing source, usually a tight ponytail or bun.

Traction Alopecia
Traction alopecia is hair loss caused by repetitive or prolonged tension on the hair secondary to tight hairstyles. It can be clinically classified into 2 types: marginal and nonmarginal patchy alopecia (Figure 5).^13,17,18 Traction alopecia most commonly is found in individuals with ethnic hair, predominantly Black women. Hairstyles with the highest risk for causing TA include tight buns, ponytails, cornrows, weaves, and locs—all of which are utilized by female servicemembers to maintain a professional appearance and adhere to grooming regulations.^13,18 Other groups at risk include athletes (eg, ballerinas, gymnasts) and those with chronic headwear use (eg, turbans, helmets, nurse caps, wigs).¹⁸ Early TA typically presents with perifollicular erythema followed by follicular-based papules or pustules.^13,18 Marginal TA classically includes frontotemporal hair loss or thinning with or without a fringe sign.^17,18 Nonmarginal TA includes patchy alopecia most commonly involving the parietal or occipital scalp, seen with chignons, buns, ponytails, or the use of clips, extensions, or bobby pins.¹⁸ The first line in management is avoidance of traction-causing hairstyles or headgear. Medical therapy may be warranted and consists of a single agent or combination regimen to include oral or topical antibiotics, topical or intralesional steroids, and topical minoxidil.^13,18

Final Thoughts

Military hair-grooming standards have evolved over time. Recent changes show that the US Department of Defense is seriously evaluating policies that may be inherently exclusive. Prior grooming standards resulted in the widespread use of tight hairstyles and harsh hair treatments among female servicemembers with long hair. These practices resulted in TN, extracranial headaches, and TA, among other hair and scalp disorders. These occupational-related hair conditions impact female servicemembers’ mental and physical well-being and thus impact military readiness. Physicians should recognize that these conditions can be related to occupational grooming standards that may impact hair care practices.

The challenge that remains is a lack of standardized documentation for hair and scalp symptoms in the medical record. Due to a paucity in reporting and documentation, limited objective data exist to guide future recommendations for military grooming standards. Another obstacle is the lack of knowledge of hair diseases among primary care providers and patients, especially due to the underrepresentation of ethnic hair in medical textbooks.¹⁹ As a result, women frequently accept their hair symptoms as normal and either suffer through them, cut their hair short, or wear wigs before considering a visit to the doctor. Furthermore, hair-grooming standards can expose racial disparities, which are the driving force behind the current policy changes. Clinicians can strive to ask about hair and scalp symptoms and document the following in relation to hair and scalp disorders: occupational grooming requirements; skin and hair type; location, number, and size of scalp lesion(s); onset; duration; current and prior hair care practices; history of treatment; and clinical course accompanied with photographic documentation. Ultimately, improved awareness in patients, collaboration between physicians, and consistent clinical documentation can help create positive change and continued improvement in hair-grooming standards within the military. Improved reporting and documentation will facilitate further study into the effectiveness of the updated hair-grooming standards in female servicemembers.

Professional appearance of servicemembers has been a long-standing custom in the US Military. Specific standards are determined by each branch. Initially, men dominated the military.^1,2 As the number of women as well as racial diversity increased in the military, modifications to grooming standards were slow to change and resulted in female hair standards requiring a uniform tight and sleek style or short haircut. Clinicians can be attuned to these occupational standards and their implications on the diagnosis and management of common diseases of the hair and scalp.

History of Hairstyle Standards for Female Servicemembers

For half a century, female servicemembers had limited hairstyle choices. They were not authorized to have hair shorter than one-quarter inch in length. They could choose either short hair worn down or long hair with neatly secured loose ends in the form of a bun or a tucked braid—both of which could not extend past the bottom edge of the uniform collar.^3-5 Female navy sailors and air force airmen with long hair were only allowed to wear ponytails during physical training; however, army soldiers previously were limited to wearing a bun.^3,6,7 Cornrows and microbraids were authorized in the mid-1990s for the US Air Force, but policy stated that locs were prohibited due to their “unkempt” and “matted” nature. Furthermore, the size of hair bulk in the air force was restricted to no more than 3 inches and could not obstruct wear of the uniform cap.⁵ Based on these regulations, female servicemembers with longer hair had to utilize tight hairstyles that caused prolonged traction and pressure along the scalp, which contributed to headaches, a sore scalp, and alopecia over time. Normalization of these symptoms led to underreporting, as women lived with the consequences or turned to shorter hairstyles.

In the last decade alone, female servicemembers have witnessed the greatest number of changes in authorized hairstyles despite being part of the military for more than 50 years (Figure 1).^1-11 In 2014, the language used in the air force instructions to describe locs was revised to remove ethnically offensive terms.^4,5 This same year, the army allowed female soldiers to wear ponytails during physical training, a privilege that had been authorized by other services years prior.^3,6,7 By the end of 2018, locs were authorized by all services, and female sailors could wear a ponytail in all navy uniforms as long as it did not extend 3 inches below the collar.^3,4,6-8 In 2018, the air force increased authorized hair bulk up to 3.5 inches from the previous mandate of 3 inches and approved female buzz cuts^6,9; in 2020, it allowed hair bulk up to 4 inches. As of 2021, female airmen can wear a ponytail and/or braid(s) as long as it starts below the crown of the head and the length does not extend below a horizontal line running between the top of each sleeve inseam at the underarm (Figures 2–4).⁶ In an ongoing effort to be more inclusive of hair density differences, female airmen will be authorized to wear a ponytail not exceeding a maximum width bulk of 1 ft starting June 25, 2021, so long as they can comply with the above regulations.¹¹ The army now allows ponytails and braids across all uniforms, as long they do not extend past the bottom of the shoulder blades. This change came just months after authorizing the wearing of ponytails tucked under the uniform blouse with tactical headgear.¹⁰ These changes allow for a variety of hairstyles for members to practice while avoiding the physical consequences that develop from repetitive traction and pressure along the same areas of the hair and scalp.

Common Hair Disorders in Female Servicemembers

Herein, we discuss 3 of the most common hair and scalp disorders linked to grooming practices utilized by women to meet prior military regulations: trichorrhexis nodosa (TN), extracranial headaches, and traction alopecia (TA). It is essential that health care providers are able to promptly recognize these conditions, understand their risk factors, and be familiar with first-line treatment options. With these new standards, the hope is that the incidence of the following conditions decreases, thus improving servicemembers’ medical readiness and overall quality of life.

Trichorrhexis Nodosa
Acquired TN is a defect in the hair shaft that causes the hair to break easily secondary to chemical, thermal, or mechanical trauma. This can include but is not limited to chemical relaxers, blow-dryers, excessive brushing or styling, flat irons, and tightly packed hairstyles. The condition is characterized by a thickened hair diameter and splitting at the tip. Clinically, it may present as brittle, lusterless, broken hair with split ends, as well as a positive tug test.¹⁴ Management includes gentle hair care and avoidance of harsh hair care practices and treatments.

Extracranial Headaches
Headaches are a common concern among military servicemembers¹⁵ and generally are classified as primary or secondary. A less commonly discussed primary headache disorder includes external-pressure headaches, which result from either sustained compression or traction of the soft tissues of the scalp, usually from wearing headbands, helmets, or tight hairstyles.¹⁶ Additional at-risk groups include those who chronically wear surgical scrub caps or flight caps, especially if clipped or pinned to the hair. In our 38 years of combined military clinical experience, we can attest that these types of headaches are common among female servicemembers. The diagnostic criteria for an external-pressure headache, commonly referred to by patients as a “ponytail headache,” includes at least 2 headache episodes triggered within 1 hour of sustained traction on the scalp, maximal at the site of traction and resolving within 1 hour after relieving the traction.¹⁶ Management includes removal of the pressure-causing source, usually a tight ponytail or bun.

Traction Alopecia
Traction alopecia is hair loss caused by repetitive or prolonged tension on the hair secondary to tight hairstyles. It can be clinically classified into 2 types: marginal and nonmarginal patchy alopecia (Figure 5).^13,17,18 Traction alopecia most commonly is found in individuals with ethnic hair, predominantly Black women. Hairstyles with the highest risk for causing TA include tight buns, ponytails, cornrows, weaves, and locs—all of which are utilized by female servicemembers to maintain a professional appearance and adhere to grooming regulations.^13,18 Other groups at risk include athletes (eg, ballerinas, gymnasts) and those with chronic headwear use (eg, turbans, helmets, nurse caps, wigs).¹⁸ Early TA typically presents with perifollicular erythema followed by follicular-based papules or pustules.^13,18 Marginal TA classically includes frontotemporal hair loss or thinning with or without a fringe sign.^17,18 Nonmarginal TA includes patchy alopecia most commonly involving the parietal or occipital scalp, seen with chignons, buns, ponytails, or the use of clips, extensions, or bobby pins.¹⁸ The first line in management is avoidance of traction-causing hairstyles or headgear. Medical therapy may be warranted and consists of a single agent or combination regimen to include oral or topical antibiotics, topical or intralesional steroids, and topical minoxidil.^13,18

Final Thoughts

Military hair-grooming standards have evolved over time. Recent changes show that the US Department of Defense is seriously evaluating policies that may be inherently exclusive. Prior grooming standards resulted in the widespread use of tight hairstyles and harsh hair treatments among female servicemembers with long hair. These practices resulted in TN, extracranial headaches, and TA, among other hair and scalp disorders. These occupational-related hair conditions impact female servicemembers’ mental and physical well-being and thus impact military readiness. Physicians should recognize that these conditions can be related to occupational grooming standards that may impact hair care practices.

The challenge that remains is a lack of standardized documentation for hair and scalp symptoms in the medical record. Due to a paucity in reporting and documentation, limited objective data exist to guide future recommendations for military grooming standards. Another obstacle is the lack of knowledge of hair diseases among primary care providers and patients, especially due to the underrepresentation of ethnic hair in medical textbooks.¹⁹ As a result, women frequently accept their hair symptoms as normal and either suffer through them, cut their hair short, or wear wigs before considering a visit to the doctor. Furthermore, hair-grooming standards can expose racial disparities, which are the driving force behind the current policy changes. Clinicians can strive to ask about hair and scalp symptoms and document the following in relation to hair and scalp disorders: occupational grooming requirements; skin and hair type; location, number, and size of scalp lesion(s); onset; duration; current and prior hair care practices; history of treatment; and clinical course accompanied with photographic documentation. Ultimately, improved awareness in patients, collaboration between physicians, and consistent clinical documentation can help create positive change and continued improvement in hair-grooming standards within the military. Improved reporting and documentation will facilitate further study into the effectiveness of the updated hair-grooming standards in female servicemembers.

The world is an increasingly diverse place, which has particular relevance for the dermatologist. Skin color plays a significant role in diagnostic approach, as there are important differences in how cutaneous disease presents in patients with skin of color (SOC). Therefore, education about these differences is imperative. In this review, we focus on allergic contact dermatitis (ACD) and patch testing in patients with SOC. We discuss allergens common to this demographic and challenges encountered in patch testing patients with SOC. We also identify key health care disparities in the evaluation and management of ACD in this population.

Has contact allergy in SOC populations been studied in North America?

Over the last 2 decades, there have been only a handful of North American studies that address contact allergy in SOC populations. Patch test results from 114 Black patients and 877 White patients at the Cleveland Clinic from 1988 to 1991 showed that overall allergy frequency was relatively similar (43.0% vs 43.6%). There were notable differences in allergen sensitization. Paraphenylenediamine (PPD), which is used in hair dye, had more positive patch test reactions in Black patients (10.6% vs 4.5%), and both PPD (21.2% vs 4.2%) and imidazolidinyl urea, a formaldehyde-releasing preservative (9.1% vs 2.6%), were more frequently allergenic in Black men compared to White men.¹ Patch test results from the North American Contact Dermatitis Group from 1992 to 1998 described similar results, with minimal variation in the prevalence of ACD among 1014 Black and 8610 White patients (47%–49% vs 46%–49%).² Positive patch test reactions to PPD were higher in Black patients for 2 of 3 test cycles (13.5% vs 5.8% [1994-1996] and 10.3% vs 5.3% [1996-1998]). Positive patch test reactions were higher in White patients for dimethylol dimethyl hydantoin, a formaldehyde-releasing preservative, also for 2 of 3 test cycles (1.8% vs 0% [1992-1994] and 2.8% vs 0.3% [1994-1996]). Finally, positive patch test reactions to thioureas (rubber accelerators) had a mixed picture: 2 test cycles were higher in Black patients (1.9% vs 1.0% [1992-1994] and 1.3% vs 0.7% [1994-1996]), but the third cycle (1996-1998) was lower (0.7% vs 1.4%). Positive patch test reactions to the metal cobalt chloride were higher in Black patients in just 1 test cycle (9.2% vs 6.6% [1992-1994]). The authors suggested that the use of darker hair dyes in the Black community may lead to more sensitization to PPD. They also theorized that this population’s more frequent use of ointment-based skin care products may make them less susceptible to sensitization to preservatives such as formaldehyde, which more commonly are found in water-based products such as creams. They concluded that differences in sensitization patterns likely were driven by cultural practices affecting exposures.²

In 2016, the North American Contact Dermatitis Group reported patch test results in 434 Black and 6634 White patients (1998-2006).³ Again, ACD prevalence was about the same in both groups (45.9% vs 43.6%). However, they reported several allergens with different reaction patterns. Black patients had higher risk ratios (RRs) for 3 rubber accelerators: mercaptobenzothiazole (RR, 2.10), mercapto mix (RR, 2.27), and thiuram mix (RR, 1.44). They also reacted to PPD (RR, 1.56) and the antibiotic bacitracin (RR, 1.34) at higher frequencies than White patients, who more frequently reacted to formaldehyde (RR, 0.58); the formaldehyde-releasing preservatives quaternium-15 (RR, 0.63) and diazolidinyl urea (in petrolatum: RR, 0.44; aqueous: RR, 0.47); the clothing finish ethylene urea melamine formalin resin (RR, 0.45); and the fragrances fragrance mix 1 (RR, 0.65) and balsam of Peru (RR, 0.55).³

Patch testing of 139 African American or Black patients at the Cleveland Clinic (2003-2012) revealed that this population most commonly had positive reactions to nickel (27.5%), fragrance mix (18.1%), bacitracin (13.0%), balsam of Peru (12.3%), and PPD (10.9%). The authors highlighted unique features of physical examination in patients with darker skin types, including lichenification and/or hyperpigmentation in those with ACD and the potential for lack of erythema and/or a papular reaction with patch test readings.⁴ Recently, data was presented at the American Contact Dermatitis Society Annual Meeting (March 2021) on patterns of ACD in Black and White patch tested patients in Philadelphia (2009-2019).⁵ Using the North American 80 comprehensive series, the researchers documented statistically significant differences in allergen sensitivity between the 2 groups. Black patients reacted to disperse blue dye (P=.019) and textile dye mix (P=.001) at higher frequencies. There was a nonsignificant trend of more frequent positive reactions to PPD in Black patients (11% vs 6%).⁵

Notably, all of these studies examined only 1 or 2 racial groups with a focus on Black patients. Some authors commented that this was due to low numbers of Hispanic, Asian and Pacific Islander, and Native American patients in tested populations.^2,3,5 With approximately 13% of the US population self-identifying as Black,⁶ these patients and other minority races typically are underrepresented in large patch test studies. More data on patch test results for these groups is necessary for a complete understanding of patch testing in patients with SOC.

What are the challenges in patch testing SOC populations?

Patch testing in patients with SOC requires additional skills and experience. Darker skin does not reveal erythema as strikingly as lighter skin, making it more difficult to appreciate subtle color changes. Moreover, multiple studies have shown that ACD can have different presentations in Black patients.^4,7,8 Lichenification and hyperpigmentation may be early signs of ACD in comparison to bright erythema and vesicles that can be seen in lighter skin types. It also has been reported that scalp ACD can be mistaken for seborrheic dermatitis due to lack of erythema.⁷ Without a high degree of clinical suspicion, a diagnosis of ACD can be missed in this patient population.

Patch test interpretation also can be challenging in patients with SOC. An early papular or follicular eruption with minimal erythema can signal a positive reaction.^4,7 Because of these potentially subtle changes, patch testers should exercise care and attention when reading results for SOC populations. We recommend ample side lighting, palpation for adequate identification of positive reactions, and double-checking for positives that may have been overlooked on the initial review of findings.^4,7

What health care disparities impact the evaluation and management of ACD?

There are many factors at play in this dialogue. The challenges we identified in diagnosing ACD in darker skin types are important to consider. Lack of familiarity with these unique features can lead to a delay in diagnosis and ultimately a delay in referral for patch testing. This is where dermatology training can help fill in the gap, but are the majority of programs equipped to do so? Inadequate education and exposure to patients with SOC is an issue for many dermatology residency programs. Surveys of residents and program directors in geographically less diverse regions may not receive adequate education or exposure to patients with SOC.⁹ Further, there is a lack of representation of SOC images for general dermatologic conditions in textbooks,^10,11 which has a profound impact on the dermatologist’s ability to recognize common diseases in darker skin types. A 2019 survey of more than 5000 images from 2 dermatology textbooks showed SOC images comprised 22% to 32% of the total images.¹¹ However, SOC images are overrepresented in textbooks for sexually transmitted infections, constituting 47% to 58% of the images; they made up 28% of images for nonvenereal infections.¹¹ Why is that? In this article, we have shown the prevalence of ACD to be nearly equivalent in Black and White patients, yet a perusal of ACD images in dermatology textbooks will tell a different story. This trend deserves our attention; perhaps it is highlighting patterns of systemic racism seen in medicine. If our primary teaching materials are perpetuating stereotypes, we must consider the impact this can have on our personal implicit biases and the health care disparities that can ensue.

Additional factors impact time to diagnosis of ACD and referral for patch testing. A retrospective study examining distance to a North Carolina patch test referral clinic showed that patients living further from the clinic experienced a longer duration of dermatitis prior to patch test consultation and tended to live in areas with a higher county poverty rate.¹² Specifically, a 17.9% increase (P<.001) in the median duration of dermatitis was observed for every 50-mile increase in distance to the patch test clinic. County poverty rate was measured by the percentage of residents living below the poverty threshold; for every 5% increase in county poverty rate, a 16.3% increase (P<.032) in duration of dermatitis was found.¹²

These data highlight a relationship with which many dermatologists are familiar and underscore a need for dermatologists to practice in areas that are more geographically accessible. The recently increased utilization of telehealth modalities can potentially help to bridge this gap by decreasing delays in diagnosis and providing more affordable options for evaluation by a dermatologist for patients with socioeconomic obstacles.

Final Interpretation

The prevalence of ACD among Black and White patients is similar; however, there are important differences in patch test reaction frequencies that may be related to the diverse exposure patterns for each group. Additionally, patients with SOC may have unique clinical presentations of ACD, such as lichenification and hyperpigmentation. Darker skin types also may require specialized techniques for accurate patch test readings. It is imperative that dermatologists are trained to recognize all of these features. Health care disparities come in many forms and, in this setting, can result in delayed referral for patch testing. Additional studies are needed to further examine these health care disparities and identify potential solutions.

The world is an increasingly diverse place, which has particular relevance for the dermatologist. Skin color plays a significant role in diagnostic approach, as there are important differences in how cutaneous disease presents in patients with skin of color (SOC). Therefore, education about these differences is imperative. In this review, we focus on allergic contact dermatitis (ACD) and patch testing in patients with SOC. We discuss allergens common to this demographic and challenges encountered in patch testing patients with SOC. We also identify key health care disparities in the evaluation and management of ACD in this population.

Has contact allergy in SOC populations been studied in North America?

Over the last 2 decades, there have been only a handful of North American studies that address contact allergy in SOC populations. Patch test results from 114 Black patients and 877 White patients at the Cleveland Clinic from 1988 to 1991 showed that overall allergy frequency was relatively similar (43.0% vs 43.6%). There were notable differences in allergen sensitization. Paraphenylenediamine (PPD), which is used in hair dye, had more positive patch test reactions in Black patients (10.6% vs 4.5%), and both PPD (21.2% vs 4.2%) and imidazolidinyl urea, a formaldehyde-releasing preservative (9.1% vs 2.6%), were more frequently allergenic in Black men compared to White men.¹ Patch test results from the North American Contact Dermatitis Group from 1992 to 1998 described similar results, with minimal variation in the prevalence of ACD among 1014 Black and 8610 White patients (47%–49% vs 46%–49%).² Positive patch test reactions to PPD were higher in Black patients for 2 of 3 test cycles (13.5% vs 5.8% [1994-1996] and 10.3% vs 5.3% [1996-1998]). Positive patch test reactions were higher in White patients for dimethylol dimethyl hydantoin, a formaldehyde-releasing preservative, also for 2 of 3 test cycles (1.8% vs 0% [1992-1994] and 2.8% vs 0.3% [1994-1996]). Finally, positive patch test reactions to thioureas (rubber accelerators) had a mixed picture: 2 test cycles were higher in Black patients (1.9% vs 1.0% [1992-1994] and 1.3% vs 0.7% [1994-1996]), but the third cycle (1996-1998) was lower (0.7% vs 1.4%). Positive patch test reactions to the metal cobalt chloride were higher in Black patients in just 1 test cycle (9.2% vs 6.6% [1992-1994]). The authors suggested that the use of darker hair dyes in the Black community may lead to more sensitization to PPD. They also theorized that this population’s more frequent use of ointment-based skin care products may make them less susceptible to sensitization to preservatives such as formaldehyde, which more commonly are found in water-based products such as creams. They concluded that differences in sensitization patterns likely were driven by cultural practices affecting exposures.²

In 2016, the North American Contact Dermatitis Group reported patch test results in 434 Black and 6634 White patients (1998-2006).³ Again, ACD prevalence was about the same in both groups (45.9% vs 43.6%). However, they reported several allergens with different reaction patterns. Black patients had higher risk ratios (RRs) for 3 rubber accelerators: mercaptobenzothiazole (RR, 2.10), mercapto mix (RR, 2.27), and thiuram mix (RR, 1.44). They also reacted to PPD (RR, 1.56) and the antibiotic bacitracin (RR, 1.34) at higher frequencies than White patients, who more frequently reacted to formaldehyde (RR, 0.58); the formaldehyde-releasing preservatives quaternium-15 (RR, 0.63) and diazolidinyl urea (in petrolatum: RR, 0.44; aqueous: RR, 0.47); the clothing finish ethylene urea melamine formalin resin (RR, 0.45); and the fragrances fragrance mix 1 (RR, 0.65) and balsam of Peru (RR, 0.55).³

Patch testing of 139 African American or Black patients at the Cleveland Clinic (2003-2012) revealed that this population most commonly had positive reactions to nickel (27.5%), fragrance mix (18.1%), bacitracin (13.0%), balsam of Peru (12.3%), and PPD (10.9%). The authors highlighted unique features of physical examination in patients with darker skin types, including lichenification and/or hyperpigmentation in those with ACD and the potential for lack of erythema and/or a papular reaction with patch test readings.⁴ Recently, data was presented at the American Contact Dermatitis Society Annual Meeting (March 2021) on patterns of ACD in Black and White patch tested patients in Philadelphia (2009-2019).⁵ Using the North American 80 comprehensive series, the researchers documented statistically significant differences in allergen sensitivity between the 2 groups. Black patients reacted to disperse blue dye (P=.019) and textile dye mix (P=.001) at higher frequencies. There was a nonsignificant trend of more frequent positive reactions to PPD in Black patients (11% vs 6%).⁵

Notably, all of these studies examined only 1 or 2 racial groups with a focus on Black patients. Some authors commented that this was due to low numbers of Hispanic, Asian and Pacific Islander, and Native American patients in tested populations.^2,3,5 With approximately 13% of the US population self-identifying as Black,⁶ these patients and other minority races typically are underrepresented in large patch test studies. More data on patch test results for these groups is necessary for a complete understanding of patch testing in patients with SOC.

What are the challenges in patch testing SOC populations?

Patch testing in patients with SOC requires additional skills and experience. Darker skin does not reveal erythema as strikingly as lighter skin, making it more difficult to appreciate subtle color changes. Moreover, multiple studies have shown that ACD can have different presentations in Black patients.^4,7,8 Lichenification and hyperpigmentation may be early signs of ACD in comparison to bright erythema and vesicles that can be seen in lighter skin types. It also has been reported that scalp ACD can be mistaken for seborrheic dermatitis due to lack of erythema.⁷ Without a high degree of clinical suspicion, a diagnosis of ACD can be missed in this patient population.

Patch test interpretation also can be challenging in patients with SOC. An early papular or follicular eruption with minimal erythema can signal a positive reaction.^4,7 Because of these potentially subtle changes, patch testers should exercise care and attention when reading results for SOC populations. We recommend ample side lighting, palpation for adequate identification of positive reactions, and double-checking for positives that may have been overlooked on the initial review of findings.^4,7

What health care disparities impact the evaluation and management of ACD?

There are many factors at play in this dialogue. The challenges we identified in diagnosing ACD in darker skin types are important to consider. Lack of familiarity with these unique features can lead to a delay in diagnosis and ultimately a delay in referral for patch testing. This is where dermatology training can help fill in the gap, but are the majority of programs equipped to do so? Inadequate education and exposure to patients with SOC is an issue for many dermatology residency programs. Surveys of residents and program directors in geographically less diverse regions may not receive adequate education or exposure to patients with SOC.⁹ Further, there is a lack of representation of SOC images for general dermatologic conditions in textbooks,^10,11 which has a profound impact on the dermatologist’s ability to recognize common diseases in darker skin types. A 2019 survey of more than 5000 images from 2 dermatology textbooks showed SOC images comprised 22% to 32% of the total images.¹¹ However, SOC images are overrepresented in textbooks for sexually transmitted infections, constituting 47% to 58% of the images; they made up 28% of images for nonvenereal infections.¹¹ Why is that? In this article, we have shown the prevalence of ACD to be nearly equivalent in Black and White patients, yet a perusal of ACD images in dermatology textbooks will tell a different story. This trend deserves our attention; perhaps it is highlighting patterns of systemic racism seen in medicine. If our primary teaching materials are perpetuating stereotypes, we must consider the impact this can have on our personal implicit biases and the health care disparities that can ensue.

Additional factors impact time to diagnosis of ACD and referral for patch testing. A retrospective study examining distance to a North Carolina patch test referral clinic showed that patients living further from the clinic experienced a longer duration of dermatitis prior to patch test consultation and tended to live in areas with a higher county poverty rate.¹² Specifically, a 17.9% increase (P<.001) in the median duration of dermatitis was observed for every 50-mile increase in distance to the patch test clinic. County poverty rate was measured by the percentage of residents living below the poverty threshold; for every 5% increase in county poverty rate, a 16.3% increase (P<.032) in duration of dermatitis was found.¹²

These data highlight a relationship with which many dermatologists are familiar and underscore a need for dermatologists to practice in areas that are more geographically accessible. The recently increased utilization of telehealth modalities can potentially help to bridge this gap by decreasing delays in diagnosis and providing more affordable options for evaluation by a dermatologist for patients with socioeconomic obstacles.

Final Interpretation

The prevalence of ACD among Black and White patients is similar; however, there are important differences in patch test reaction frequencies that may be related to the diverse exposure patterns for each group. Additionally, patients with SOC may have unique clinical presentations of ACD, such as lichenification and hyperpigmentation. Darker skin types also may require specialized techniques for accurate patch test readings. It is imperative that dermatologists are trained to recognize all of these features. Health care disparities come in many forms and, in this setting, can result in delayed referral for patch testing. Additional studies are needed to further examine these health care disparities and identify potential solutions.

The world is an increasingly diverse place, which has particular relevance for the dermatologist. Skin color plays a significant role in diagnostic approach, as there are important differences in how cutaneous disease presents in patients with skin of color (SOC). Therefore, education about these differences is imperative. In this review, we focus on allergic contact dermatitis (ACD) and patch testing in patients with SOC. We discuss allergens common to this demographic and challenges encountered in patch testing patients with SOC. We also identify key health care disparities in the evaluation and management of ACD in this population.

Has contact allergy in SOC populations been studied in North America?

Over the last 2 decades, there have been only a handful of North American studies that address contact allergy in SOC populations. Patch test results from 114 Black patients and 877 White patients at the Cleveland Clinic from 1988 to 1991 showed that overall allergy frequency was relatively similar (43.0% vs 43.6%). There were notable differences in allergen sensitization. Paraphenylenediamine (PPD), which is used in hair dye, had more positive patch test reactions in Black patients (10.6% vs 4.5%), and both PPD (21.2% vs 4.2%) and imidazolidinyl urea, a formaldehyde-releasing preservative (9.1% vs 2.6%), were more frequently allergenic in Black men compared to White men.¹ Patch test results from the North American Contact Dermatitis Group from 1992 to 1998 described similar results, with minimal variation in the prevalence of ACD among 1014 Black and 8610 White patients (47%–49% vs 46%–49%).² Positive patch test reactions to PPD were higher in Black patients for 2 of 3 test cycles (13.5% vs 5.8% [1994-1996] and 10.3% vs 5.3% [1996-1998]). Positive patch test reactions were higher in White patients for dimethylol dimethyl hydantoin, a formaldehyde-releasing preservative, also for 2 of 3 test cycles (1.8% vs 0% [1992-1994] and 2.8% vs 0.3% [1994-1996]). Finally, positive patch test reactions to thioureas (rubber accelerators) had a mixed picture: 2 test cycles were higher in Black patients (1.9% vs 1.0% [1992-1994] and 1.3% vs 0.7% [1994-1996]), but the third cycle (1996-1998) was lower (0.7% vs 1.4%). Positive patch test reactions to the metal cobalt chloride were higher in Black patients in just 1 test cycle (9.2% vs 6.6% [1992-1994]). The authors suggested that the use of darker hair dyes in the Black community may lead to more sensitization to PPD. They also theorized that this population’s more frequent use of ointment-based skin care products may make them less susceptible to sensitization to preservatives such as formaldehyde, which more commonly are found in water-based products such as creams. They concluded that differences in sensitization patterns likely were driven by cultural practices affecting exposures.²

In 2016, the North American Contact Dermatitis Group reported patch test results in 434 Black and 6634 White patients (1998-2006).³ Again, ACD prevalence was about the same in both groups (45.9% vs 43.6%). However, they reported several allergens with different reaction patterns. Black patients had higher risk ratios (RRs) for 3 rubber accelerators: mercaptobenzothiazole (RR, 2.10), mercapto mix (RR, 2.27), and thiuram mix (RR, 1.44). They also reacted to PPD (RR, 1.56) and the antibiotic bacitracin (RR, 1.34) at higher frequencies than White patients, who more frequently reacted to formaldehyde (RR, 0.58); the formaldehyde-releasing preservatives quaternium-15 (RR, 0.63) and diazolidinyl urea (in petrolatum: RR, 0.44; aqueous: RR, 0.47); the clothing finish ethylene urea melamine formalin resin (RR, 0.45); and the fragrances fragrance mix 1 (RR, 0.65) and balsam of Peru (RR, 0.55).³

Patch testing of 139 African American or Black patients at the Cleveland Clinic (2003-2012) revealed that this population most commonly had positive reactions to nickel (27.5%), fragrance mix (18.1%), bacitracin (13.0%), balsam of Peru (12.3%), and PPD (10.9%). The authors highlighted unique features of physical examination in patients with darker skin types, including lichenification and/or hyperpigmentation in those with ACD and the potential for lack of erythema and/or a papular reaction with patch test readings.⁴ Recently, data was presented at the American Contact Dermatitis Society Annual Meeting (March 2021) on patterns of ACD in Black and White patch tested patients in Philadelphia (2009-2019).⁵ Using the North American 80 comprehensive series, the researchers documented statistically significant differences in allergen sensitivity between the 2 groups. Black patients reacted to disperse blue dye (P=.019) and textile dye mix (P=.001) at higher frequencies. There was a nonsignificant trend of more frequent positive reactions to PPD in Black patients (11% vs 6%).⁵

Notably, all of these studies examined only 1 or 2 racial groups with a focus on Black patients. Some authors commented that this was due to low numbers of Hispanic, Asian and Pacific Islander, and Native American patients in tested populations.^2,3,5 With approximately 13% of the US population self-identifying as Black,⁶ these patients and other minority races typically are underrepresented in large patch test studies. More data on patch test results for these groups is necessary for a complete understanding of patch testing in patients with SOC.

What are the challenges in patch testing SOC populations?

Patch testing in patients with SOC requires additional skills and experience. Darker skin does not reveal erythema as strikingly as lighter skin, making it more difficult to appreciate subtle color changes. Moreover, multiple studies have shown that ACD can have different presentations in Black patients.^4,7,8 Lichenification and hyperpigmentation may be early signs of ACD in comparison to bright erythema and vesicles that can be seen in lighter skin types. It also has been reported that scalp ACD can be mistaken for seborrheic dermatitis due to lack of erythema.⁷ Without a high degree of clinical suspicion, a diagnosis of ACD can be missed in this patient population.

Patch test interpretation also can be challenging in patients with SOC. An early papular or follicular eruption with minimal erythema can signal a positive reaction.^4,7 Because of these potentially subtle changes, patch testers should exercise care and attention when reading results for SOC populations. We recommend ample side lighting, palpation for adequate identification of positive reactions, and double-checking for positives that may have been overlooked on the initial review of findings.^4,7

What health care disparities impact the evaluation and management of ACD?

There are many factors at play in this dialogue. The challenges we identified in diagnosing ACD in darker skin types are important to consider. Lack of familiarity with these unique features can lead to a delay in diagnosis and ultimately a delay in referral for patch testing. This is where dermatology training can help fill in the gap, but are the majority of programs equipped to do so? Inadequate education and exposure to patients with SOC is an issue for many dermatology residency programs. Surveys of residents and program directors in geographically less diverse regions may not receive adequate education or exposure to patients with SOC.⁹ Further, there is a lack of representation of SOC images for general dermatologic conditions in textbooks,^10,11 which has a profound impact on the dermatologist’s ability to recognize common diseases in darker skin types. A 2019 survey of more than 5000 images from 2 dermatology textbooks showed SOC images comprised 22% to 32% of the total images.¹¹ However, SOC images are overrepresented in textbooks for sexually transmitted infections, constituting 47% to 58% of the images; they made up 28% of images for nonvenereal infections.¹¹ Why is that? In this article, we have shown the prevalence of ACD to be nearly equivalent in Black and White patients, yet a perusal of ACD images in dermatology textbooks will tell a different story. This trend deserves our attention; perhaps it is highlighting patterns of systemic racism seen in medicine. If our primary teaching materials are perpetuating stereotypes, we must consider the impact this can have on our personal implicit biases and the health care disparities that can ensue.

Additional factors impact time to diagnosis of ACD and referral for patch testing. A retrospective study examining distance to a North Carolina patch test referral clinic showed that patients living further from the clinic experienced a longer duration of dermatitis prior to patch test consultation and tended to live in areas with a higher county poverty rate.¹² Specifically, a 17.9% increase (P<.001) in the median duration of dermatitis was observed for every 50-mile increase in distance to the patch test clinic. County poverty rate was measured by the percentage of residents living below the poverty threshold; for every 5% increase in county poverty rate, a 16.3% increase (P<.032) in duration of dermatitis was found.¹²

These data highlight a relationship with which many dermatologists are familiar and underscore a need for dermatologists to practice in areas that are more geographically accessible. The recently increased utilization of telehealth modalities can potentially help to bridge this gap by decreasing delays in diagnosis and providing more affordable options for evaluation by a dermatologist for patients with socioeconomic obstacles.

Final Interpretation

The prevalence of ACD among Black and White patients is similar; however, there are important differences in patch test reaction frequencies that may be related to the diverse exposure patterns for each group. Additionally, patients with SOC may have unique clinical presentations of ACD, such as lichenification and hyperpigmentation. Darker skin types also may require specialized techniques for accurate patch test readings. It is imperative that dermatologists are trained to recognize all of these features. Health care disparities come in many forms and, in this setting, can result in delayed referral for patch testing. Additional studies are needed to further examine these health care disparities and identify potential solutions.

We cannot solve our problems with the same thinking we used when we created them.
Albert Einstein

Amidst the myriad of disruptions and corollary solutions budding from the ongoing global COVID-19 pandemic, management of acne with isotretinoin underwent a makeover. Firstly, as with any pharmaceutical prescribed in the last 1 to 2 years, patients asked the compelling question, “Will this prescription put me at higher risk for COVID-19?”, resulting in a complex set of answers from both clinical and basic science perspectives. Further, the practical use of telemedicine for clinical visits and pregnancy test reporting altered the shape of isotretinoin physician-patient communication and follow-up. Finally, the combination of these circumstances spurred us to revisit common quandaries in prescribing this drug: Can we trust what patients tell us when they are taking isotretinoin? Do we need to monitor laboratory values and follow patients on isotretinoin as closely and as frequently as we have in the past? Does the Risk Evaluation and Mitigation Strategy (REMS) program of iPLEDGE hold true utility?

Impact of COVID-19 on Isotretinoin Use

Isotretinoin may have varying influence on the ease of host entry and virulence of COVID-19. Because the majority of patients experience some degree of mucous membrane desiccation on isotretinoin, it originally was postulated that disruption of the nasal mucosa, thereby uncovering the basal epithelial layer where angiotensin-converting enzyme 2 (ACE2) receptors are expressed, could increase the risk for viral invasion, as ACE2 is the host receptor for COVID-19 entry.^1,2 On the other hand, a study of 672 medications and their effect on regulation of ACE2 levels stratified isotretinoin in the highest category of ACE2 downregulators, therefore theoretically preventing cellular entry and replication of the virus.³ In conferring with many of my colleagues and reviewing available literature, I found that these data did not summarily deter providers from initiating or continuing isotretinoin during the pandemic, and research is ongoing to particularly earmark isotretinoin as a possible COVID-19 therapy option.^4,5 Despite this, and despite the lower risk for COVID-19 in the customary isotretinoin adolescent and young adult age range, an Italian study reported that 14.7% of patients (5/34) prematurely interrupted isotretinoin therapy during lockdown because of fear of COVID-19 infection.⁶ Data also suggest that college towns (akin to where I practice, rife with isotretinoin-eligible patients) reflected higher COVID-19 infection and death rates, likely due to dense cohabitation and intermittent migration of students and staff to and from campuses and within their communities.⁷ Approximately 30% of my patients on isotretinoin in the last 18 months reported having COVID-19 at some point during the pandemic, though no data exist to guide us on whether isotretinoin should be discontinued in this scenario; my patients typically continued the drug unless their primary health care team discouraged it, and in those cases, all of them resumed it after COVID-19 symptomatology resolved.

Last spring, the US Department of Health and Human Services and the US Food and Drug Administration announced that health care professionals who prescribe and/or dispense drugs subject to REMS with laboratory testing or imaging requirements should consider whether there are compelling reasons not to complete the required testing/imaging during the current public health emergency and use their best medical judgment in weighing the benefits and risks of continuing treatment in the absence of these tests. It also was stressed that prescribers should effectively communicate with their patients regarding these benefits, risks, and altered protocols.⁸ Further, the iPLEDGE program concurred that telemedicine was an acceptable visit type for both initiating and maintaining isotretinoin, and home pregnancy tests were valid for females of childbearing potential if an accurate testing date and results were communicated by patients to the prescriber in the required reporting windows.⁹ This allowed dermatologists to foster what was one of our most important roles as outpatient clinicians during the pandemic: to maintain normalcy, continuity, and support for as many patients as possible.

Isotretinoin and Telemedicine

During the pandemic, continuation of isotretinoin therapy proved easier than initiating it, given that patients could access and maintain a clear connection to the online visit platform, display understanding of the REMS mandates (along with a guardian present for a minor), perform a home pregnancy test and report the result followed by the quiz (for females), and collect the prescription in the allotted window. For new patients, the absence of a detailed in-person examination and rapport with the patient (and guardians when applicable) as well as misalignment of the date of iPLEDGE registration with the timing of the pregnancy test results and prescribing window were more onerous using digital or mailed versions of consent forms and photodocumentation of urine pregnancy test results. This tangle of requirements perpetuated missed prescribing windows, increased patient portal and phone messages, resulted in more time on the phone with the iPLEDGE help desk, and intensified angst for clinical staff.

These telemedicine visits also required validation of the patient’s geographic location to verify the billability of the visit and whether the patient was in a secure location to have a US Health Insurance Portability and Accountability Act–compliant conversation as well as the abstract notion that the timing and result of the pregnancy tests for females reflected a true nonpregnant state.^10,11 Verification of the pregnancy tests in these situations was approached by either the patient reporting the outcome verbally or displaying the pregnancy test kit result in a video or photograph form for the medical record, all of which leave room for error, doubt, and lower sensitivity than laboratory-based collection. That being said, the increased implementation of telemedicine visits during the pandemic sustained patient access, decreased cost with less laboratory testing and reduced time away from work or school, and resulted in high patient satisfaction with their care.¹² Additionally, it allowed providers to continue to more comfortably inch away from frequent in-person serologic cholesterol and hepatic testing during therapy based on mounting data that it is not indicated.¹³

Accordingly, the complicated concepts of trust, practicality, and sustainability for the safe and effective management of isotretinoin patients re-emerged. For example, prior to COVID-19, we trusted patients who said they were regularly taking their oral contraceptives or were truly practicing abstinence as a form of contraception. During the pandemic, we then added a layer of trust with home pregnancy test reporting. If the patient or guardian signed the isotretinoin consent form and understood the risks of the medication, ideally the physician-patient relationship fostered the optimal goals of honest conversation, adherence to the drug, safety, and clear skin. However, there is yet another trust assay: iPLEDGE, in turn, trusts that we are reporting patient data accurately, provoking us to reiterate questions we asked ourselves before the pandemic. Is the extra provider and staff clerical work and validation necessary, compounded by prior data that iPLEDGE’s capacity to limit pregnancy-related morbidity with isotretinoin has been called into question in the last decade?¹⁴ Do males need to be followed every month? Is laboratory monitoring still necessary for all isotretinoin candidates? Will post–COVID-19 data show that during various versions of the lockdown, an increased number of isotretinoin patients developed unmonitored morbidity, including transaminitis, hypertriglyceridemia, and an increase in pregnancies? How long will telemedicine visits for isotretinoin be reimbursable beyond the pandemic? Are there other models to enhance and improve isotretinoin teledermatology and compliance?¹⁵

Final Thoughts

Dermatologists’ experience managing high volumes of isotretinoin patients paired with the creativity to maintain meaningful (and truthful) patient connections and decrease administrative burden lie front and center in 2021. Because the COVID-19 pandemic remains ambient with a dearth of data to guide us, I pose the questions above as points for commiseration and catapults for future study, discussion, collaboration, and innovation. Perhaps the neo–COVID-19 world provided us with the spark we needed to metaphorically clean up the dusty isotretinoin tenets that have frayed our time and patience so we can maintain excellent care for this worthy population.

We cannot solve our problems with the same thinking we used when we created them.
Albert Einstein

Amidst the myriad of disruptions and corollary solutions budding from the ongoing global COVID-19 pandemic, management of acne with isotretinoin underwent a makeover. Firstly, as with any pharmaceutical prescribed in the last 1 to 2 years, patients asked the compelling question, “Will this prescription put me at higher risk for COVID-19?”, resulting in a complex set of answers from both clinical and basic science perspectives. Further, the practical use of telemedicine for clinical visits and pregnancy test reporting altered the shape of isotretinoin physician-patient communication and follow-up. Finally, the combination of these circumstances spurred us to revisit common quandaries in prescribing this drug: Can we trust what patients tell us when they are taking isotretinoin? Do we need to monitor laboratory values and follow patients on isotretinoin as closely and as frequently as we have in the past? Does the Risk Evaluation and Mitigation Strategy (REMS) program of iPLEDGE hold true utility?

Impact of COVID-19 on Isotretinoin Use

Isotretinoin may have varying influence on the ease of host entry and virulence of COVID-19. Because the majority of patients experience some degree of mucous membrane desiccation on isotretinoin, it originally was postulated that disruption of the nasal mucosa, thereby uncovering the basal epithelial layer where angiotensin-converting enzyme 2 (ACE2) receptors are expressed, could increase the risk for viral invasion, as ACE2 is the host receptor for COVID-19 entry.^1,2 On the other hand, a study of 672 medications and their effect on regulation of ACE2 levels stratified isotretinoin in the highest category of ACE2 downregulators, therefore theoretically preventing cellular entry and replication of the virus.³ In conferring with many of my colleagues and reviewing available literature, I found that these data did not summarily deter providers from initiating or continuing isotretinoin during the pandemic, and research is ongoing to particularly earmark isotretinoin as a possible COVID-19 therapy option.^4,5 Despite this, and despite the lower risk for COVID-19 in the customary isotretinoin adolescent and young adult age range, an Italian study reported that 14.7% of patients (5/34) prematurely interrupted isotretinoin therapy during lockdown because of fear of COVID-19 infection.⁶ Data also suggest that college towns (akin to where I practice, rife with isotretinoin-eligible patients) reflected higher COVID-19 infection and death rates, likely due to dense cohabitation and intermittent migration of students and staff to and from campuses and within their communities.⁷ Approximately 30% of my patients on isotretinoin in the last 18 months reported having COVID-19 at some point during the pandemic, though no data exist to guide us on whether isotretinoin should be discontinued in this scenario; my patients typically continued the drug unless their primary health care team discouraged it, and in those cases, all of them resumed it after COVID-19 symptomatology resolved.

Last spring, the US Department of Health and Human Services and the US Food and Drug Administration announced that health care professionals who prescribe and/or dispense drugs subject to REMS with laboratory testing or imaging requirements should consider whether there are compelling reasons not to complete the required testing/imaging during the current public health emergency and use their best medical judgment in weighing the benefits and risks of continuing treatment in the absence of these tests. It also was stressed that prescribers should effectively communicate with their patients regarding these benefits, risks, and altered protocols.⁸ Further, the iPLEDGE program concurred that telemedicine was an acceptable visit type for both initiating and maintaining isotretinoin, and home pregnancy tests were valid for females of childbearing potential if an accurate testing date and results were communicated by patients to the prescriber in the required reporting windows.⁹ This allowed dermatologists to foster what was one of our most important roles as outpatient clinicians during the pandemic: to maintain normalcy, continuity, and support for as many patients as possible.

Isotretinoin and Telemedicine

During the pandemic, continuation of isotretinoin therapy proved easier than initiating it, given that patients could access and maintain a clear connection to the online visit platform, display understanding of the REMS mandates (along with a guardian present for a minor), perform a home pregnancy test and report the result followed by the quiz (for females), and collect the prescription in the allotted window. For new patients, the absence of a detailed in-person examination and rapport with the patient (and guardians when applicable) as well as misalignment of the date of iPLEDGE registration with the timing of the pregnancy test results and prescribing window were more onerous using digital or mailed versions of consent forms and photodocumentation of urine pregnancy test results. This tangle of requirements perpetuated missed prescribing windows, increased patient portal and phone messages, resulted in more time on the phone with the iPLEDGE help desk, and intensified angst for clinical staff.

These telemedicine visits also required validation of the patient’s geographic location to verify the billability of the visit and whether the patient was in a secure location to have a US Health Insurance Portability and Accountability Act–compliant conversation as well as the abstract notion that the timing and result of the pregnancy tests for females reflected a true nonpregnant state.^10,11 Verification of the pregnancy tests in these situations was approached by either the patient reporting the outcome verbally or displaying the pregnancy test kit result in a video or photograph form for the medical record, all of which leave room for error, doubt, and lower sensitivity than laboratory-based collection. That being said, the increased implementation of telemedicine visits during the pandemic sustained patient access, decreased cost with less laboratory testing and reduced time away from work or school, and resulted in high patient satisfaction with their care.¹² Additionally, it allowed providers to continue to more comfortably inch away from frequent in-person serologic cholesterol and hepatic testing during therapy based on mounting data that it is not indicated.¹³

Accordingly, the complicated concepts of trust, practicality, and sustainability for the safe and effective management of isotretinoin patients re-emerged. For example, prior to COVID-19, we trusted patients who said they were regularly taking their oral contraceptives or were truly practicing abstinence as a form of contraception. During the pandemic, we then added a layer of trust with home pregnancy test reporting. If the patient or guardian signed the isotretinoin consent form and understood the risks of the medication, ideally the physician-patient relationship fostered the optimal goals of honest conversation, adherence to the drug, safety, and clear skin. However, there is yet another trust assay: iPLEDGE, in turn, trusts that we are reporting patient data accurately, provoking us to reiterate questions we asked ourselves before the pandemic. Is the extra provider and staff clerical work and validation necessary, compounded by prior data that iPLEDGE’s capacity to limit pregnancy-related morbidity with isotretinoin has been called into question in the last decade?¹⁴ Do males need to be followed every month? Is laboratory monitoring still necessary for all isotretinoin candidates? Will post–COVID-19 data show that during various versions of the lockdown, an increased number of isotretinoin patients developed unmonitored morbidity, including transaminitis, hypertriglyceridemia, and an increase in pregnancies? How long will telemedicine visits for isotretinoin be reimbursable beyond the pandemic? Are there other models to enhance and improve isotretinoin teledermatology and compliance?¹⁵

Final Thoughts

Dermatologists’ experience managing high volumes of isotretinoin patients paired with the creativity to maintain meaningful (and truthful) patient connections and decrease administrative burden lie front and center in 2021. Because the COVID-19 pandemic remains ambient with a dearth of data to guide us, I pose the questions above as points for commiseration and catapults for future study, discussion, collaboration, and innovation. Perhaps the neo–COVID-19 world provided us with the spark we needed to metaphorically clean up the dusty isotretinoin tenets that have frayed our time and patience so we can maintain excellent care for this worthy population.

We cannot solve our problems with the same thinking we used when we created them.
Albert Einstein

Amidst the myriad of disruptions and corollary solutions budding from the ongoing global COVID-19 pandemic, management of acne with isotretinoin underwent a makeover. Firstly, as with any pharmaceutical prescribed in the last 1 to 2 years, patients asked the compelling question, “Will this prescription put me at higher risk for COVID-19?”, resulting in a complex set of answers from both clinical and basic science perspectives. Further, the practical use of telemedicine for clinical visits and pregnancy test reporting altered the shape of isotretinoin physician-patient communication and follow-up. Finally, the combination of these circumstances spurred us to revisit common quandaries in prescribing this drug: Can we trust what patients tell us when they are taking isotretinoin? Do we need to monitor laboratory values and follow patients on isotretinoin as closely and as frequently as we have in the past? Does the Risk Evaluation and Mitigation Strategy (REMS) program of iPLEDGE hold true utility?

Impact of COVID-19 on Isotretinoin Use

Isotretinoin may have varying influence on the ease of host entry and virulence of COVID-19. Because the majority of patients experience some degree of mucous membrane desiccation on isotretinoin, it originally was postulated that disruption of the nasal mucosa, thereby uncovering the basal epithelial layer where angiotensin-converting enzyme 2 (ACE2) receptors are expressed, could increase the risk for viral invasion, as ACE2 is the host receptor for COVID-19 entry.^1,2 On the other hand, a study of 672 medications and their effect on regulation of ACE2 levels stratified isotretinoin in the highest category of ACE2 downregulators, therefore theoretically preventing cellular entry and replication of the virus.³ In conferring with many of my colleagues and reviewing available literature, I found that these data did not summarily deter providers from initiating or continuing isotretinoin during the pandemic, and research is ongoing to particularly earmark isotretinoin as a possible COVID-19 therapy option.^4,5 Despite this, and despite the lower risk for COVID-19 in the customary isotretinoin adolescent and young adult age range, an Italian study reported that 14.7% of patients (5/34) prematurely interrupted isotretinoin therapy during lockdown because of fear of COVID-19 infection.⁶ Data also suggest that college towns (akin to where I practice, rife with isotretinoin-eligible patients) reflected higher COVID-19 infection and death rates, likely due to dense cohabitation and intermittent migration of students and staff to and from campuses and within their communities.⁷ Approximately 30% of my patients on isotretinoin in the last 18 months reported having COVID-19 at some point during the pandemic, though no data exist to guide us on whether isotretinoin should be discontinued in this scenario; my patients typically continued the drug unless their primary health care team discouraged it, and in those cases, all of them resumed it after COVID-19 symptomatology resolved.

Last spring, the US Department of Health and Human Services and the US Food and Drug Administration announced that health care professionals who prescribe and/or dispense drugs subject to REMS with laboratory testing or imaging requirements should consider whether there are compelling reasons not to complete the required testing/imaging during the current public health emergency and use their best medical judgment in weighing the benefits and risks of continuing treatment in the absence of these tests. It also was stressed that prescribers should effectively communicate with their patients regarding these benefits, risks, and altered protocols.⁸ Further, the iPLEDGE program concurred that telemedicine was an acceptable visit type for both initiating and maintaining isotretinoin, and home pregnancy tests were valid for females of childbearing potential if an accurate testing date and results were communicated by patients to the prescriber in the required reporting windows.⁹ This allowed dermatologists to foster what was one of our most important roles as outpatient clinicians during the pandemic: to maintain normalcy, continuity, and support for as many patients as possible.

Isotretinoin and Telemedicine

During the pandemic, continuation of isotretinoin therapy proved easier than initiating it, given that patients could access and maintain a clear connection to the online visit platform, display understanding of the REMS mandates (along with a guardian present for a minor), perform a home pregnancy test and report the result followed by the quiz (for females), and collect the prescription in the allotted window. For new patients, the absence of a detailed in-person examination and rapport with the patient (and guardians when applicable) as well as misalignment of the date of iPLEDGE registration with the timing of the pregnancy test results and prescribing window were more onerous using digital or mailed versions of consent forms and photodocumentation of urine pregnancy test results. This tangle of requirements perpetuated missed prescribing windows, increased patient portal and phone messages, resulted in more time on the phone with the iPLEDGE help desk, and intensified angst for clinical staff.

These telemedicine visits also required validation of the patient’s geographic location to verify the billability of the visit and whether the patient was in a secure location to have a US Health Insurance Portability and Accountability Act–compliant conversation as well as the abstract notion that the timing and result of the pregnancy tests for females reflected a true nonpregnant state.^10,11 Verification of the pregnancy tests in these situations was approached by either the patient reporting the outcome verbally or displaying the pregnancy test kit result in a video or photograph form for the medical record, all of which leave room for error, doubt, and lower sensitivity than laboratory-based collection. That being said, the increased implementation of telemedicine visits during the pandemic sustained patient access, decreased cost with less laboratory testing and reduced time away from work or school, and resulted in high patient satisfaction with their care.¹² Additionally, it allowed providers to continue to more comfortably inch away from frequent in-person serologic cholesterol and hepatic testing during therapy based on mounting data that it is not indicated.¹³

Accordingly, the complicated concepts of trust, practicality, and sustainability for the safe and effective management of isotretinoin patients re-emerged. For example, prior to COVID-19, we trusted patients who said they were regularly taking their oral contraceptives or were truly practicing abstinence as a form of contraception. During the pandemic, we then added a layer of trust with home pregnancy test reporting. If the patient or guardian signed the isotretinoin consent form and understood the risks of the medication, ideally the physician-patient relationship fostered the optimal goals of honest conversation, adherence to the drug, safety, and clear skin. However, there is yet another trust assay: iPLEDGE, in turn, trusts that we are reporting patient data accurately, provoking us to reiterate questions we asked ourselves before the pandemic. Is the extra provider and staff clerical work and validation necessary, compounded by prior data that iPLEDGE’s capacity to limit pregnancy-related morbidity with isotretinoin has been called into question in the last decade?¹⁴ Do males need to be followed every month? Is laboratory monitoring still necessary for all isotretinoin candidates? Will post–COVID-19 data show that during various versions of the lockdown, an increased number of isotretinoin patients developed unmonitored morbidity, including transaminitis, hypertriglyceridemia, and an increase in pregnancies? How long will telemedicine visits for isotretinoin be reimbursable beyond the pandemic? Are there other models to enhance and improve isotretinoin teledermatology and compliance?¹⁵

Final Thoughts

Dermatologists’ experience managing high volumes of isotretinoin patients paired with the creativity to maintain meaningful (and truthful) patient connections and decrease administrative burden lie front and center in 2021. Because the COVID-19 pandemic remains ambient with a dearth of data to guide us, I pose the questions above as points for commiseration and catapults for future study, discussion, collaboration, and innovation. Perhaps the neo–COVID-19 world provided us with the spark we needed to metaphorically clean up the dusty isotretinoin tenets that have frayed our time and patience so we can maintain excellent care for this worthy population.

Acne rosacea is a chronic inflammatory disease that may affect the facial skin, eyes, and eyelids.¹ It is characterized by transient or persistent flushing, facial erythema, and telangiectases, generally located on the central portion of the face, and may progress to papules and pustules.^2,3 At the late stage of the disease, dermal edema or fibroplasia and sebaceous gland hypertrophy may cause phymatous alterations in the skin. In 2004, the National Rosacea Society Expert Committee developed a classification system for rosacea to standardize subtypes and variants that has since been widely accepted and continues to aid in research and epidemiologic studies.⁴ The committee defined 4 subtypes based on clinical characteristics: erythematotelangiectatic (ETR), papulopustular (PPR), phymatous, and ocular rosacea.^2,3

Ocular rosacea may accompany mild, moderate, and severe dermatologic disease or may occur in the absence of diagnostic skin disease.⁵ Ocular signs include eyelid margin telangiectasia, spade-shaped infiltrates in the cornea, scleritis, and sclerokeratitis. Common symptoms include burning, stinging, light sensitivity, and foreign-body sensation. Ocular signs commonly seen in rosacea are meibomian gland dysfunction characterized by inspissation and inflammation of the meibomian glands (chalazia), conjunctivitis, honey crust and cylindrical collarette accumulation at the base of the eyelashes, irregularity of the eyelid margin architecture, and evaporative tear dysfunction.^5,6

The physiopathology of rosacea is still unknown. Potential factors include genetic predisposition, abnormal inflammation, vascular dysfunction, and involvement of several microbial agents, such as commensal Demodex mites. The number of Demodex mites on normal skin flora is less than 5/cm²; however, the increased vascular dilation and capillary permeability associated with rosacea that result from sunlight and heat exposure increase the density of Demodex folliculorum.⁷ Elevated Demodex mite density has been observed in the lumens of the sebaceous follicles in patients with rosacea. However, because the severity of the clinical manifestations of the disease is not directly associated with the density of D folliculorum, it generally is accepted that D folliculorum is not a pathogenetic but rather an exacerbating factor.⁸ It has been reported that this species of mite is mostly found on the face and around the eyelashes and scalp of patients and that it can cause ocular surface inflammation.⁸

Most studies have researched ocular manifestations of rosacea but not ocular involvement in rosacea patients with and without Demodex mite infestation. In our study, we sought to compare the ocular surface, meibomian gland characteristics, and tear film abnormalities among patients with cutaneous rosacea with and without Demodex infestation.

Materials and Methods

We conducted a retrospective study of 60 patients with cutaneous rosacea. This study was approved by the ethics committee of the local hospital (2018/002-003), and all patients provided verbal and written informed consent before participating in the study. The study was carried out according to the guidelines of the Declaration of Helsinki.

Patient Selection and Evaluation
Patients diagnosed with rosacea by a dermatologist within 6 months were included in the study. Diagnosis of the disease was made after a detailed anamnesis and dermatologic examination. Rosacea was diagnosed if patients had an itching sensation, erythema and/or erythema attacks, and papules and pustules, and fulfilled the diagnostic criteria according to the National Rosacea Society. The skin disease was classified according to the subtypes as ETR, PPR, phymatous rosacea, or ocular rosacea.

The standard skin surface biopsy method was used in 60 patients for detecting Demodex density. When more than 5 mites were detected per square centimeter, the result was recorded as positive. Thirty consecutive, newly diagnosed patients with cutaneous acne rosacea with Demodex infestation and 30 consecutive, newly diagnosed sex- and age-matched patients with acne rosacea without Demodex infestation admitted to the dermatology outpatient clinic were included to this study. The patients who did not have any known dermatologic, systemic, or ocular diseases were included in the study. Patients who met any of the following criteria were excluded from the study: prior anti-inflammatory topical and/or systemic treatment for rosacea during the last 3 months, contact lens wear, eyelid surgery, or autoimmune disease requiring treatment.

Microscopic Demodex Examination
Demodex count was determined using a standardized skin surface biopsy, which is a noninvasive method. Every patient gave samples from the cheeks. This biopsy was repeated from the same site. A drop of cyanoacrylate was placed on a clean slide, pressed against a skin lesion, held in place for 1 minute, and removed. The obtained samples were evaluated under a light microscope (Nikon E200) with oil immersion. When more than 5 mites were detected per square centimeter, the result was recorded as positive.

Ophthalmologic Examination
A complete ophthalmologic examination including visual acuity assessment, standardized slit lamp examination, and fundus examination was done for all patients. Ocular rosacea was diagnosed on detection of 1 or more of the following: watery or bloodshot appearance, foreign-body sensation, burning or stinging, dryness, itching, light sensitivity, blurred vision, telangiectases of the conjunctiva and eyelid margin, eyelid lid and periocular erythema, anterior blepharitis, meibomian gland dysfunction, or irregularity of eyelid margins. All patients were screened for the signs and symptoms of ocular rosacea and underwent other ophthalmologic examinations, including tear function tests. Tear functions were evaluated with Schirmer tests without anesthesia and fluorescein tear breakup time (TBUT). Tear film breakup time was assessed after instillation of 2% fluorescein staining under a cobalt blue filter. The time interval between the last complete blink and the appearance of the first dry spot was recorded. The mean of 3 consecutive measurements was obtained. The Schirmer test was performed without topical anesthesia using a standardized filter strip (Bio-Tech Vision Care). The amount of wetting was measured after 5 minutes. Meibomian gland expressibility was assessed by applying digital pressure to the eyelid margin.

Statistical Analysis
Statistical analysis of the study was performed with SPSS Statistics Version 22.0 (SPSS Inc). Continuous variables were reported as mean (SD), and categorical variables were reported as percentages and counts. Descriptive statistics for numerical variables were created. An independent sample t test was used for normally distributed continuous variables. The Kolmogorov-Smirnov test was used to determine normality. The Schirmer test without anesthesia and TBUT values among groups were compared using one-way analysis of variance. The differences were calculated using the multiple comparison Tukey test. P<.05 was considered statistically significant.

Results

Demographic Characteristics of Rosacea Patients
Sixty eyes of 30 newly diagnosed patients with acne rosacea with Demodex infestation and 60 eyes of 30 newly diagnosed patients with acne rosacea without Demodex infestation were enrolled in this study. The mean age (SD) of the 60 patients was 37.63 (10.01) years. The mean TBUT (SD) of the 120 eyes was 6.65 (3.44) seconds, and the mean Schirmer score (SD) was 12.59 (6.71) mm (Table 1).

Meibomian Gland Dysfunction vs Subgroup of Rosacea Patients
Thirty-four (57%) patients had blepharitis, and 18 (30%) patients had meibomitis. Thirty-five (58.3%) patients had ETR, 5 (8.3%) patients had phymatous rosacea, and 20 (33.4%) patients had PPR (Table 2). Of the Demodex-negative patients, 73.3% (22/30) had ETR, 20% (6/30) had PPR, and 6.7% (2/30) had phymatous rosacea. Of the Demodex-positive patients, 43.3% (13/30) had ETR, 46.7% (14/30) had PPR, and 10% (3/30) had phymatous rosacea (Table 3). Papulopustular rosacea was found to be significantly associated with Demodex positivity (P=.003); neither ETR nor phymatous rosacea was found to be significantly associated with Demodex infestation (P=.66 and P=.13, respectively)(Table 3).

Sixteen (53.3%) patients (32 eyes) in the Demodex-negative group and 21 (70%) patients (42 eyes) in the Demodex-positive group had TBUT values less than 10 seconds. Eighteen (60%) patients (36 eyes) in the Demodex-negative group and 25 (83.3%) patients (50 eyes) in the Demodex-positive group had Schirmer scores less than 10 mm (Table 3). The 2 groups were not significantly different in dry eye findings (P=.25 and P=.29, respectively).

Comment

Inflammation in Rosacea
It is known that the density of nonfloral bacteria as well as D folliculorum and Demodex brevis increases in skin affected by rosacea compared to normal skin. Vascular dilation associated with rosacea that results from sunlight and heat causes increased capillary permeability and creates the ideal environment for the proliferation of D folliculorum. Demodex is thought to act as a vector for the activity of certain other microorganisms, particularly Bacillus oleronius, and thus initiates the inflammatory response associated with rosacea.⁹

One study reported that the inflammation associated with rosacea that was caused by Demodex and other environmental stimuli occurred through toll-like receptor 2 and various cytokines.¹⁰ It has been reported that the abnormal function of toll-like receptor 2 in the epidermis leads to the increased production of cathelicidin. Cathelicidin is an antimicrobial peptide with both vasoactive and proinflammatory activity and has been used as a basis to explain the pathogenesis of facial erythema, flushing, and telangiectasia in the context of rosacea.^11,12 In addition, it has been reported that the increased secretion of proinflammatory cytokines such as IL-1 and gelatinase B in ocular rosacea leads to tearing film abnormalities that result from increased bacterial flora in the eyelids, which subsequently leads to decreased tear drainage and dry eyes.¹³ In addition, B oleronius isolated from a D folliculorum mite from patients with PPR produced proteins that induced an inflammatory immune response in 73% (16/22) of patients with rosacea.¹⁴

Ocular Findings in Rosacea Patients
In our study, PPR was found to be significantly associated with Demodex positivity compared to ETR and phymatous rosacea (P=.003). However, ocular inflammation findings such as blepharitis and meibomitis were not significantly different between Demodex-positive and Demodex-negative patients. Although the mean Schirmer score of Demodex-positive patients was lower than Demodex-negative patients, this difference was not statistically significant. We evaluated a TBUT of less than 10 seconds and a Schirmer score less than 10 mm as dry eye. Accordingly, the number of patients with dry eye was higher in the Demodex-positive group, but this difference was not statistically significant.

Chronic blepharitis, conjunctival inflammation, and meibomian gland dysfunction are among the most common findings of ocular rosacea.^15,16 Patients with ocular rosacea commonly have dry eye and abnormal TBUT and Schirmer scores.¹⁷ In our study, we found that the fluorescein TBUT and Schirmer scores were more likely to be abnormal in the Demodex-positive group, but the difference between the 2 groups was not statistically significant.

It has been reported that proinflammatory cytokines due to a weakened immune system in rosacea patients were increased. The weakened immune system was further supported by the increased concentrations of proinflammatory cytokines such as IL-1 and matrix metalloproteinase 9 in these patients’ tears and the improvement of symptoms after the inhibition of these cytokines.¹¹ Luo et al¹⁸ reported that Demodex inflammation causes dry eye, particularly with D brevis. Ayyildiz and Sezgin¹⁹ reported that Schirmer scores were significantly lower and that the Ocular Surface Disease Index had significantly increased in the Demodex-positive group compared to the Demodex-negative group (P=.001 for both). A Korean study reported that Demodex density was correlated with age, sex, and TBUT results, but there was no significant relationship between Demodex density and Schirmer scores.¹⁶

Sobolewska et al²⁰ administered ivermectin cream 1% to 10 patients with cutaneous and ocular rosacea, but only to the forehead, chin, nose, cheeks, and regions close to the eyelids, and observed a significant improvement in blepharitis (P=.004). They stated that ivermectin, as applied only to the face, suppressed the proinflammatory cytokines associated with rosacea and showed anti-inflammatory effects by reducing Demodex mites.²⁰Li et al²¹ demonstrated a strong correlation between ocular Demodex inflammation and serum reactivity to these bacterial proteins in patients with ocular rosacea, and they found that eyelid margin inflammation and facial rosacea correlated with reactivity to these proteins. These studies suggest a possible role for Demodex infestation and bacterial proteins in the etiology of rosacea.

Gonzalez-Hinojosa et al²² demonstrated that even though eyelash blepharitis was more common in PPR than ETR, there was no statistically significant association between rosacea and Demodex blepharitis. In our study, we found a significant correlation between PPR and Demodex positivity. Also, meibomian gland dysfunction was more common in the Demodex-positive group; however, this result was not statistically significant. One study compared patients with primary demodicosis and patients with rosacea with Demodex-induced blepharitis to healthy controls and found that patients with primary demodicosis and patients with rosacea did not have significantly different ocular findings.²³ In contrast, Forton and De Maertelaer²⁴ reported that patients with PPR had significantly more severe ocular manifestations compared with patients with demodicosis (P=.004).

Mizuno et al²⁵ compared the normal (nonrosacea) population with and without Demodex-infested eyelashes and found that the 2 groups were not significantly different for meibomian gland dysfunction, fluorescein TBUT, or ocular surface discomfort.

Varying results have been reported regarding the association between Demodex and blepharitis or ocular surface discomfort with or without rosacea. In our study, we found that Demodex did not affect tear function tests or meibomian gland function in patients with rosacea. We believe this study is important because it demonstrates the effects of Demodex on ocular findings in patients with cutaneous rosacea.

Limitations
Our study has some limitations. The number of patients was relatively small, resulting in few significant differences between the comparison groups. A larger prospective research study is required to assess the prevalence of Demodex mites in the ocular rosacea population along with associated symptoms and findings.

Conclusion

Rosacea is a chronic disease associated with skin and ocular manifestations that range from mild to severe, that progresses in the form of attacks, and that requires long-term follow-up and treatment. Rosacea most often presents as a disease that causes ocular surface inflammation of varying degrees. Demodex infestation may increase cutaneous or ocular inflammation in rosacea. Therefore, every patient diagnosed with rosacea should be given a dermatologic examination to determine Demodex positivity and an ophthalmologic examination to determine ocular manifestations.

Acne rosacea is a chronic inflammatory disease that may affect the facial skin, eyes, and eyelids.¹ It is characterized by transient or persistent flushing, facial erythema, and telangiectases, generally located on the central portion of the face, and may progress to papules and pustules.^2,3 At the late stage of the disease, dermal edema or fibroplasia and sebaceous gland hypertrophy may cause phymatous alterations in the skin. In 2004, the National Rosacea Society Expert Committee developed a classification system for rosacea to standardize subtypes and variants that has since been widely accepted and continues to aid in research and epidemiologic studies.⁴ The committee defined 4 subtypes based on clinical characteristics: erythematotelangiectatic (ETR), papulopustular (PPR), phymatous, and ocular rosacea.^2,3

Ocular rosacea may accompany mild, moderate, and severe dermatologic disease or may occur in the absence of diagnostic skin disease.⁵ Ocular signs include eyelid margin telangiectasia, spade-shaped infiltrates in the cornea, scleritis, and sclerokeratitis. Common symptoms include burning, stinging, light sensitivity, and foreign-body sensation. Ocular signs commonly seen in rosacea are meibomian gland dysfunction characterized by inspissation and inflammation of the meibomian glands (chalazia), conjunctivitis, honey crust and cylindrical collarette accumulation at the base of the eyelashes, irregularity of the eyelid margin architecture, and evaporative tear dysfunction.^5,6

The physiopathology of rosacea is still unknown. Potential factors include genetic predisposition, abnormal inflammation, vascular dysfunction, and involvement of several microbial agents, such as commensal Demodex mites. The number of Demodex mites on normal skin flora is less than 5/cm²; however, the increased vascular dilation and capillary permeability associated with rosacea that result from sunlight and heat exposure increase the density of Demodex folliculorum.⁷ Elevated Demodex mite density has been observed in the lumens of the sebaceous follicles in patients with rosacea. However, because the severity of the clinical manifestations of the disease is not directly associated with the density of D folliculorum, it generally is accepted that D folliculorum is not a pathogenetic but rather an exacerbating factor.⁸ It has been reported that this species of mite is mostly found on the face and around the eyelashes and scalp of patients and that it can cause ocular surface inflammation.⁸

Most studies have researched ocular manifestations of rosacea but not ocular involvement in rosacea patients with and without Demodex mite infestation. In our study, we sought to compare the ocular surface, meibomian gland characteristics, and tear film abnormalities among patients with cutaneous rosacea with and without Demodex infestation.

Materials and Methods

We conducted a retrospective study of 60 patients with cutaneous rosacea. This study was approved by the ethics committee of the local hospital (2018/002-003), and all patients provided verbal and written informed consent before participating in the study. The study was carried out according to the guidelines of the Declaration of Helsinki.

Patient Selection and Evaluation
Patients diagnosed with rosacea by a dermatologist within 6 months were included in the study. Diagnosis of the disease was made after a detailed anamnesis and dermatologic examination. Rosacea was diagnosed if patients had an itching sensation, erythema and/or erythema attacks, and papules and pustules, and fulfilled the diagnostic criteria according to the National Rosacea Society. The skin disease was classified according to the subtypes as ETR, PPR, phymatous rosacea, or ocular rosacea.

The standard skin surface biopsy method was used in 60 patients for detecting Demodex density. When more than 5 mites were detected per square centimeter, the result was recorded as positive. Thirty consecutive, newly diagnosed patients with cutaneous acne rosacea with Demodex infestation and 30 consecutive, newly diagnosed sex- and age-matched patients with acne rosacea without Demodex infestation admitted to the dermatology outpatient clinic were included to this study. The patients who did not have any known dermatologic, systemic, or ocular diseases were included in the study. Patients who met any of the following criteria were excluded from the study: prior anti-inflammatory topical and/or systemic treatment for rosacea during the last 3 months, contact lens wear, eyelid surgery, or autoimmune disease requiring treatment.

Microscopic Demodex Examination
Demodex count was determined using a standardized skin surface biopsy, which is a noninvasive method. Every patient gave samples from the cheeks. This biopsy was repeated from the same site. A drop of cyanoacrylate was placed on a clean slide, pressed against a skin lesion, held in place for 1 minute, and removed. The obtained samples were evaluated under a light microscope (Nikon E200) with oil immersion. When more than 5 mites were detected per square centimeter, the result was recorded as positive.

Ophthalmologic Examination
A complete ophthalmologic examination including visual acuity assessment, standardized slit lamp examination, and fundus examination was done for all patients. Ocular rosacea was diagnosed on detection of 1 or more of the following: watery or bloodshot appearance, foreign-body sensation, burning or stinging, dryness, itching, light sensitivity, blurred vision, telangiectases of the conjunctiva and eyelid margin, eyelid lid and periocular erythema, anterior blepharitis, meibomian gland dysfunction, or irregularity of eyelid margins. All patients were screened for the signs and symptoms of ocular rosacea and underwent other ophthalmologic examinations, including tear function tests. Tear functions were evaluated with Schirmer tests without anesthesia and fluorescein tear breakup time (TBUT). Tear film breakup time was assessed after instillation of 2% fluorescein staining under a cobalt blue filter. The time interval between the last complete blink and the appearance of the first dry spot was recorded. The mean of 3 consecutive measurements was obtained. The Schirmer test was performed without topical anesthesia using a standardized filter strip (Bio-Tech Vision Care). The amount of wetting was measured after 5 minutes. Meibomian gland expressibility was assessed by applying digital pressure to the eyelid margin.

Statistical Analysis
Statistical analysis of the study was performed with SPSS Statistics Version 22.0 (SPSS Inc). Continuous variables were reported as mean (SD), and categorical variables were reported as percentages and counts. Descriptive statistics for numerical variables were created. An independent sample t test was used for normally distributed continuous variables. The Kolmogorov-Smirnov test was used to determine normality. The Schirmer test without anesthesia and TBUT values among groups were compared using one-way analysis of variance. The differences were calculated using the multiple comparison Tukey test. P<.05 was considered statistically significant.

Results

Demographic Characteristics of Rosacea Patients
Sixty eyes of 30 newly diagnosed patients with acne rosacea with Demodex infestation and 60 eyes of 30 newly diagnosed patients with acne rosacea without Demodex infestation were enrolled in this study. The mean age (SD) of the 60 patients was 37.63 (10.01) years. The mean TBUT (SD) of the 120 eyes was 6.65 (3.44) seconds, and the mean Schirmer score (SD) was 12.59 (6.71) mm (Table 1).

Meibomian Gland Dysfunction vs Subgroup of Rosacea Patients
Thirty-four (57%) patients had blepharitis, and 18 (30%) patients had meibomitis. Thirty-five (58.3%) patients had ETR, 5 (8.3%) patients had phymatous rosacea, and 20 (33.4%) patients had PPR (Table 2). Of the Demodex-negative patients, 73.3% (22/30) had ETR, 20% (6/30) had PPR, and 6.7% (2/30) had phymatous rosacea. Of the Demodex-positive patients, 43.3% (13/30) had ETR, 46.7% (14/30) had PPR, and 10% (3/30) had phymatous rosacea (Table 3). Papulopustular rosacea was found to be significantly associated with Demodex positivity (P=.003); neither ETR nor phymatous rosacea was found to be significantly associated with Demodex infestation (P=.66 and P=.13, respectively)(Table 3).

Sixteen (53.3%) patients (32 eyes) in the Demodex-negative group and 21 (70%) patients (42 eyes) in the Demodex-positive group had TBUT values less than 10 seconds. Eighteen (60%) patients (36 eyes) in the Demodex-negative group and 25 (83.3%) patients (50 eyes) in the Demodex-positive group had Schirmer scores less than 10 mm (Table 3). The 2 groups were not significantly different in dry eye findings (P=.25 and P=.29, respectively).

Comment

Inflammation in Rosacea
It is known that the density of nonfloral bacteria as well as D folliculorum and Demodex brevis increases in skin affected by rosacea compared to normal skin. Vascular dilation associated with rosacea that results from sunlight and heat causes increased capillary permeability and creates the ideal environment for the proliferation of D folliculorum. Demodex is thought to act as a vector for the activity of certain other microorganisms, particularly Bacillus oleronius, and thus initiates the inflammatory response associated with rosacea.⁹

One study reported that the inflammation associated with rosacea that was caused by Demodex and other environmental stimuli occurred through toll-like receptor 2 and various cytokines.¹⁰ It has been reported that the abnormal function of toll-like receptor 2 in the epidermis leads to the increased production of cathelicidin. Cathelicidin is an antimicrobial peptide with both vasoactive and proinflammatory activity and has been used as a basis to explain the pathogenesis of facial erythema, flushing, and telangiectasia in the context of rosacea.^11,12 In addition, it has been reported that the increased secretion of proinflammatory cytokines such as IL-1 and gelatinase B in ocular rosacea leads to tearing film abnormalities that result from increased bacterial flora in the eyelids, which subsequently leads to decreased tear drainage and dry eyes.¹³ In addition, B oleronius isolated from a D folliculorum mite from patients with PPR produced proteins that induced an inflammatory immune response in 73% (16/22) of patients with rosacea.¹⁴

Ocular Findings in Rosacea Patients
In our study, PPR was found to be significantly associated with Demodex positivity compared to ETR and phymatous rosacea (P=.003). However, ocular inflammation findings such as blepharitis and meibomitis were not significantly different between Demodex-positive and Demodex-negative patients. Although the mean Schirmer score of Demodex-positive patients was lower than Demodex-negative patients, this difference was not statistically significant. We evaluated a TBUT of less than 10 seconds and a Schirmer score less than 10 mm as dry eye. Accordingly, the number of patients with dry eye was higher in the Demodex-positive group, but this difference was not statistically significant.

Chronic blepharitis, conjunctival inflammation, and meibomian gland dysfunction are among the most common findings of ocular rosacea.^15,16 Patients with ocular rosacea commonly have dry eye and abnormal TBUT and Schirmer scores.¹⁷ In our study, we found that the fluorescein TBUT and Schirmer scores were more likely to be abnormal in the Demodex-positive group, but the difference between the 2 groups was not statistically significant.

It has been reported that proinflammatory cytokines due to a weakened immune system in rosacea patients were increased. The weakened immune system was further supported by the increased concentrations of proinflammatory cytokines such as IL-1 and matrix metalloproteinase 9 in these patients’ tears and the improvement of symptoms after the inhibition of these cytokines.¹¹ Luo et al¹⁸ reported that Demodex inflammation causes dry eye, particularly with D brevis. Ayyildiz and Sezgin¹⁹ reported that Schirmer scores were significantly lower and that the Ocular Surface Disease Index had significantly increased in the Demodex-positive group compared to the Demodex-negative group (P=.001 for both). A Korean study reported that Demodex density was correlated with age, sex, and TBUT results, but there was no significant relationship between Demodex density and Schirmer scores.¹⁶

Sobolewska et al²⁰ administered ivermectin cream 1% to 10 patients with cutaneous and ocular rosacea, but only to the forehead, chin, nose, cheeks, and regions close to the eyelids, and observed a significant improvement in blepharitis (P=.004). They stated that ivermectin, as applied only to the face, suppressed the proinflammatory cytokines associated with rosacea and showed anti-inflammatory effects by reducing Demodex mites.²⁰Li et al²¹ demonstrated a strong correlation between ocular Demodex inflammation and serum reactivity to these bacterial proteins in patients with ocular rosacea, and they found that eyelid margin inflammation and facial rosacea correlated with reactivity to these proteins. These studies suggest a possible role for Demodex infestation and bacterial proteins in the etiology of rosacea.

Gonzalez-Hinojosa et al²² demonstrated that even though eyelash blepharitis was more common in PPR than ETR, there was no statistically significant association between rosacea and Demodex blepharitis. In our study, we found a significant correlation between PPR and Demodex positivity. Also, meibomian gland dysfunction was more common in the Demodex-positive group; however, this result was not statistically significant. One study compared patients with primary demodicosis and patients with rosacea with Demodex-induced blepharitis to healthy controls and found that patients with primary demodicosis and patients with rosacea did not have significantly different ocular findings.²³ In contrast, Forton and De Maertelaer²⁴ reported that patients with PPR had significantly more severe ocular manifestations compared with patients with demodicosis (P=.004).

Mizuno et al²⁵ compared the normal (nonrosacea) population with and without Demodex-infested eyelashes and found that the 2 groups were not significantly different for meibomian gland dysfunction, fluorescein TBUT, or ocular surface discomfort.

Varying results have been reported regarding the association between Demodex and blepharitis or ocular surface discomfort with or without rosacea. In our study, we found that Demodex did not affect tear function tests or meibomian gland function in patients with rosacea. We believe this study is important because it demonstrates the effects of Demodex on ocular findings in patients with cutaneous rosacea.

Limitations
Our study has some limitations. The number of patients was relatively small, resulting in few significant differences between the comparison groups. A larger prospective research study is required to assess the prevalence of Demodex mites in the ocular rosacea population along with associated symptoms and findings.

Conclusion

Rosacea is a chronic disease associated with skin and ocular manifestations that range from mild to severe, that progresses in the form of attacks, and that requires long-term follow-up and treatment. Rosacea most often presents as a disease that causes ocular surface inflammation of varying degrees. Demodex infestation may increase cutaneous or ocular inflammation in rosacea. Therefore, every patient diagnosed with rosacea should be given a dermatologic examination to determine Demodex positivity and an ophthalmologic examination to determine ocular manifestations.

Acne rosacea is a chronic inflammatory disease that may affect the facial skin, eyes, and eyelids.¹ It is characterized by transient or persistent flushing, facial erythema, and telangiectases, generally located on the central portion of the face, and may progress to papules and pustules.^2,3 At the late stage of the disease, dermal edema or fibroplasia and sebaceous gland hypertrophy may cause phymatous alterations in the skin. In 2004, the National Rosacea Society Expert Committee developed a classification system for rosacea to standardize subtypes and variants that has since been widely accepted and continues to aid in research and epidemiologic studies.⁴ The committee defined 4 subtypes based on clinical characteristics: erythematotelangiectatic (ETR), papulopustular (PPR), phymatous, and ocular rosacea.^2,3

Ocular rosacea may accompany mild, moderate, and severe dermatologic disease or may occur in the absence of diagnostic skin disease.⁵ Ocular signs include eyelid margin telangiectasia, spade-shaped infiltrates in the cornea, scleritis, and sclerokeratitis. Common symptoms include burning, stinging, light sensitivity, and foreign-body sensation. Ocular signs commonly seen in rosacea are meibomian gland dysfunction characterized by inspissation and inflammation of the meibomian glands (chalazia), conjunctivitis, honey crust and cylindrical collarette accumulation at the base of the eyelashes, irregularity of the eyelid margin architecture, and evaporative tear dysfunction.^5,6

The physiopathology of rosacea is still unknown. Potential factors include genetic predisposition, abnormal inflammation, vascular dysfunction, and involvement of several microbial agents, such as commensal Demodex mites. The number of Demodex mites on normal skin flora is less than 5/cm²; however, the increased vascular dilation and capillary permeability associated with rosacea that result from sunlight and heat exposure increase the density of Demodex folliculorum.⁷ Elevated Demodex mite density has been observed in the lumens of the sebaceous follicles in patients with rosacea. However, because the severity of the clinical manifestations of the disease is not directly associated with the density of D folliculorum, it generally is accepted that D folliculorum is not a pathogenetic but rather an exacerbating factor.⁸ It has been reported that this species of mite is mostly found on the face and around the eyelashes and scalp of patients and that it can cause ocular surface inflammation.⁸

Most studies have researched ocular manifestations of rosacea but not ocular involvement in rosacea patients with and without Demodex mite infestation. In our study, we sought to compare the ocular surface, meibomian gland characteristics, and tear film abnormalities among patients with cutaneous rosacea with and without Demodex infestation.

Materials and Methods

We conducted a retrospective study of 60 patients with cutaneous rosacea. This study was approved by the ethics committee of the local hospital (2018/002-003), and all patients provided verbal and written informed consent before participating in the study. The study was carried out according to the guidelines of the Declaration of Helsinki.

Patient Selection and Evaluation
Patients diagnosed with rosacea by a dermatologist within 6 months were included in the study. Diagnosis of the disease was made after a detailed anamnesis and dermatologic examination. Rosacea was diagnosed if patients had an itching sensation, erythema and/or erythema attacks, and papules and pustules, and fulfilled the diagnostic criteria according to the National Rosacea Society. The skin disease was classified according to the subtypes as ETR, PPR, phymatous rosacea, or ocular rosacea.

The standard skin surface biopsy method was used in 60 patients for detecting Demodex density. When more than 5 mites were detected per square centimeter, the result was recorded as positive. Thirty consecutive, newly diagnosed patients with cutaneous acne rosacea with Demodex infestation and 30 consecutive, newly diagnosed sex- and age-matched patients with acne rosacea without Demodex infestation admitted to the dermatology outpatient clinic were included to this study. The patients who did not have any known dermatologic, systemic, or ocular diseases were included in the study. Patients who met any of the following criteria were excluded from the study: prior anti-inflammatory topical and/or systemic treatment for rosacea during the last 3 months, contact lens wear, eyelid surgery, or autoimmune disease requiring treatment.

Microscopic Demodex Examination
Demodex count was determined using a standardized skin surface biopsy, which is a noninvasive method. Every patient gave samples from the cheeks. This biopsy was repeated from the same site. A drop of cyanoacrylate was placed on a clean slide, pressed against a skin lesion, held in place for 1 minute, and removed. The obtained samples were evaluated under a light microscope (Nikon E200) with oil immersion. When more than 5 mites were detected per square centimeter, the result was recorded as positive.

Ophthalmologic Examination
A complete ophthalmologic examination including visual acuity assessment, standardized slit lamp examination, and fundus examination was done for all patients. Ocular rosacea was diagnosed on detection of 1 or more of the following: watery or bloodshot appearance, foreign-body sensation, burning or stinging, dryness, itching, light sensitivity, blurred vision, telangiectases of the conjunctiva and eyelid margin, eyelid lid and periocular erythema, anterior blepharitis, meibomian gland dysfunction, or irregularity of eyelid margins. All patients were screened for the signs and symptoms of ocular rosacea and underwent other ophthalmologic examinations, including tear function tests. Tear functions were evaluated with Schirmer tests without anesthesia and fluorescein tear breakup time (TBUT). Tear film breakup time was assessed after instillation of 2% fluorescein staining under a cobalt blue filter. The time interval between the last complete blink and the appearance of the first dry spot was recorded. The mean of 3 consecutive measurements was obtained. The Schirmer test was performed without topical anesthesia using a standardized filter strip (Bio-Tech Vision Care). The amount of wetting was measured after 5 minutes. Meibomian gland expressibility was assessed by applying digital pressure to the eyelid margin.

Statistical Analysis
Statistical analysis of the study was performed with SPSS Statistics Version 22.0 (SPSS Inc). Continuous variables were reported as mean (SD), and categorical variables were reported as percentages and counts. Descriptive statistics for numerical variables were created. An independent sample t test was used for normally distributed continuous variables. The Kolmogorov-Smirnov test was used to determine normality. The Schirmer test without anesthesia and TBUT values among groups were compared using one-way analysis of variance. The differences were calculated using the multiple comparison Tukey test. P<.05 was considered statistically significant.

Results

Demographic Characteristics of Rosacea Patients
Sixty eyes of 30 newly diagnosed patients with acne rosacea with Demodex infestation and 60 eyes of 30 newly diagnosed patients with acne rosacea without Demodex infestation were enrolled in this study. The mean age (SD) of the 60 patients was 37.63 (10.01) years. The mean TBUT (SD) of the 120 eyes was 6.65 (3.44) seconds, and the mean Schirmer score (SD) was 12.59 (6.71) mm (Table 1).

Meibomian Gland Dysfunction vs Subgroup of Rosacea Patients
Thirty-four (57%) patients had blepharitis, and 18 (30%) patients had meibomitis. Thirty-five (58.3%) patients had ETR, 5 (8.3%) patients had phymatous rosacea, and 20 (33.4%) patients had PPR (Table 2). Of the Demodex-negative patients, 73.3% (22/30) had ETR, 20% (6/30) had PPR, and 6.7% (2/30) had phymatous rosacea. Of the Demodex-positive patients, 43.3% (13/30) had ETR, 46.7% (14/30) had PPR, and 10% (3/30) had phymatous rosacea (Table 3). Papulopustular rosacea was found to be significantly associated with Demodex positivity (P=.003); neither ETR nor phymatous rosacea was found to be significantly associated with Demodex infestation (P=.66 and P=.13, respectively)(Table 3).

Sixteen (53.3%) patients (32 eyes) in the Demodex-negative group and 21 (70%) patients (42 eyes) in the Demodex-positive group had TBUT values less than 10 seconds. Eighteen (60%) patients (36 eyes) in the Demodex-negative group and 25 (83.3%) patients (50 eyes) in the Demodex-positive group had Schirmer scores less than 10 mm (Table 3). The 2 groups were not significantly different in dry eye findings (P=.25 and P=.29, respectively).

Comment

Inflammation in Rosacea
It is known that the density of nonfloral bacteria as well as D folliculorum and Demodex brevis increases in skin affected by rosacea compared to normal skin. Vascular dilation associated with rosacea that results from sunlight and heat causes increased capillary permeability and creates the ideal environment for the proliferation of D folliculorum. Demodex is thought to act as a vector for the activity of certain other microorganisms, particularly Bacillus oleronius, and thus initiates the inflammatory response associated with rosacea.⁹

One study reported that the inflammation associated with rosacea that was caused by Demodex and other environmental stimuli occurred through toll-like receptor 2 and various cytokines.¹⁰ It has been reported that the abnormal function of toll-like receptor 2 in the epidermis leads to the increased production of cathelicidin. Cathelicidin is an antimicrobial peptide with both vasoactive and proinflammatory activity and has been used as a basis to explain the pathogenesis of facial erythema, flushing, and telangiectasia in the context of rosacea.^11,12 In addition, it has been reported that the increased secretion of proinflammatory cytokines such as IL-1 and gelatinase B in ocular rosacea leads to tearing film abnormalities that result from increased bacterial flora in the eyelids, which subsequently leads to decreased tear drainage and dry eyes.¹³ In addition, B oleronius isolated from a D folliculorum mite from patients with PPR produced proteins that induced an inflammatory immune response in 73% (16/22) of patients with rosacea.¹⁴

Ocular Findings in Rosacea Patients
In our study, PPR was found to be significantly associated with Demodex positivity compared to ETR and phymatous rosacea (P=.003). However, ocular inflammation findings such as blepharitis and meibomitis were not significantly different between Demodex-positive and Demodex-negative patients. Although the mean Schirmer score of Demodex-positive patients was lower than Demodex-negative patients, this difference was not statistically significant. We evaluated a TBUT of less than 10 seconds and a Schirmer score less than 10 mm as dry eye. Accordingly, the number of patients with dry eye was higher in the Demodex-positive group, but this difference was not statistically significant.

Chronic blepharitis, conjunctival inflammation, and meibomian gland dysfunction are among the most common findings of ocular rosacea.^15,16 Patients with ocular rosacea commonly have dry eye and abnormal TBUT and Schirmer scores.¹⁷ In our study, we found that the fluorescein TBUT and Schirmer scores were more likely to be abnormal in the Demodex-positive group, but the difference between the 2 groups was not statistically significant.

It has been reported that proinflammatory cytokines due to a weakened immune system in rosacea patients were increased. The weakened immune system was further supported by the increased concentrations of proinflammatory cytokines such as IL-1 and matrix metalloproteinase 9 in these patients’ tears and the improvement of symptoms after the inhibition of these cytokines.¹¹ Luo et al¹⁸ reported that Demodex inflammation causes dry eye, particularly with D brevis. Ayyildiz and Sezgin¹⁹ reported that Schirmer scores were significantly lower and that the Ocular Surface Disease Index had significantly increased in the Demodex-positive group compared to the Demodex-negative group (P=.001 for both). A Korean study reported that Demodex density was correlated with age, sex, and TBUT results, but there was no significant relationship between Demodex density and Schirmer scores.¹⁶

Sobolewska et al²⁰ administered ivermectin cream 1% to 10 patients with cutaneous and ocular rosacea, but only to the forehead, chin, nose, cheeks, and regions close to the eyelids, and observed a significant improvement in blepharitis (P=.004). They stated that ivermectin, as applied only to the face, suppressed the proinflammatory cytokines associated with rosacea and showed anti-inflammatory effects by reducing Demodex mites.²⁰Li et al²¹ demonstrated a strong correlation between ocular Demodex inflammation and serum reactivity to these bacterial proteins in patients with ocular rosacea, and they found that eyelid margin inflammation and facial rosacea correlated with reactivity to these proteins. These studies suggest a possible role for Demodex infestation and bacterial proteins in the etiology of rosacea.

Gonzalez-Hinojosa et al²² demonstrated that even though eyelash blepharitis was more common in PPR than ETR, there was no statistically significant association between rosacea and Demodex blepharitis. In our study, we found a significant correlation between PPR and Demodex positivity. Also, meibomian gland dysfunction was more common in the Demodex-positive group; however, this result was not statistically significant. One study compared patients with primary demodicosis and patients with rosacea with Demodex-induced blepharitis to healthy controls and found that patients with primary demodicosis and patients with rosacea did not have significantly different ocular findings.²³ In contrast, Forton and De Maertelaer²⁴ reported that patients with PPR had significantly more severe ocular manifestations compared with patients with demodicosis (P=.004).

Mizuno et al²⁵ compared the normal (nonrosacea) population with and without Demodex-infested eyelashes and found that the 2 groups were not significantly different for meibomian gland dysfunction, fluorescein TBUT, or ocular surface discomfort.

Varying results have been reported regarding the association between Demodex and blepharitis or ocular surface discomfort with or without rosacea. In our study, we found that Demodex did not affect tear function tests or meibomian gland function in patients with rosacea. We believe this study is important because it demonstrates the effects of Demodex on ocular findings in patients with cutaneous rosacea.

Limitations
Our study has some limitations. The number of patients was relatively small, resulting in few significant differences between the comparison groups. A larger prospective research study is required to assess the prevalence of Demodex mites in the ocular rosacea population along with associated symptoms and findings.

Conclusion

Rosacea is a chronic disease associated with skin and ocular manifestations that range from mild to severe, that progresses in the form of attacks, and that requires long-term follow-up and treatment. Rosacea most often presents as a disease that causes ocular surface inflammation of varying degrees. Demodex infestation may increase cutaneous or ocular inflammation in rosacea. Therefore, every patient diagnosed with rosacea should be given a dermatologic examination to determine Demodex positivity and an ophthalmologic examination to determine ocular manifestations.

Introduced in 1982, isotretinoin is a retinoid derivative that has been widely used to treat various dermatologic conditions such as acne vulgaris, rosacea, hidradenitis suppurativa, and hair folliculitis. ¹ It remains one of the most effective drugs for the treatment of all forms of acne vulgaris, especially the nodulocystic type, and exerts its effects via different mechanisms that affect the major domains involved in the pathogenesis of acne. ² One month after treatment initiation, isotretinoin suppresses sebum production by decreasing the size and activity of sebaceous glands. In addition, it notably stabilizes keratinization of the skin and decreases the number of Propionibacterium acnes, which will minimize the inflammation associated with acne. ^3,4 Despite its beneficial effects, isotretinoin therapy has been associated with several complications. The most commonly reported adverse effects include fissured lips, dry skin, eczema, epistaxis, dry eyes, gastrointestinal tract upset, angular stomatitis, and back pain. Less frequent systemic adverse effects have been reported and relate mainly to teratogenicity, pancreatitis, drug-induced hepatotoxicity, leukopenia, and thrombocytopenia. ⁵

Isotretinoin use has been associated with alterations in hepatic and lipid profiles; elevations of serum liver enzymes and triglycerides (TGs) following isotretinoin treatment have been reported.⁴ Consequently, different protocols for laboratory monitoring during isotretinoin therapy have been established and utilized by various health care institutes.⁶ Despite the time and economic investment involved, certain protocols recommend repetition of liver function tests and several other laboratory parameters following a baseline test.⁷ The aim of this study was to determine the prevalence of laboratory changes in alanine aminotransferase (ALT), aspartate aminotransferase (AST), cholesterol, and TGs among patients with acne receiving isotretinoin therapy, as well as to link the initial and second laboratory readings of the aforementioned parameters following initiation of isotretinoin treatment.

Materials and Methods

This retrospective cohort design study obtained patient data, including laboratory test results, from the Electronic System for Integrated Health Information at King Khalid University Hospital (KKUH)(Riyadh, Saudi Arabia). All patients older than 16 years who presented with acne vulgaris to the dermatology department at KKUH; who received a course of isotretinoin for at least 4 weeks between 2011 and 2016; and who had available baseline readings of ALT, AST, cholesterol, and TGs, as well as 2 concurrent follow-up readings after isotretinoin treatment initiation, were included in this study. Patients with only 1 reading following treatment initiation and those receiving isotretinoin treatment for reasons other than acne were excluded. This study was approved by the institutional review board of the College of Medicine at King Saud University (Riyadh, Saudi Arabia)(E-18-3310).

Statistical Analysis
Data were entered into a Microsoft Excel document, and statistical analysis was performed using SPSS (version 22.0). Data were represented as numbers and percentages. Repeated measures analysis was performed using the Cochran Q test to compare proportions of abnormal laboratory values among 3 groups: baseline, first reading, and second reading. When test results were significant, a post hoc test was used to compare proportions between any 2 groups. Moreover, a Spearman rank correlation was performed to investigate the association between the daily isotretinoin dose and the laboratory parameters. Results with P<.05 were considered statistically significant.

Results

During the study period, treatment with oral isotretinoin was undertaken by 386 patients at KKUH. Several of these patients were excluded due to incomplete medical records. The age of the studied patients ranged from 17 to 60 years, with a median age of 24 years (interquartile range, 20−28 years). The daily administered dose ranged from 10 to 80 mg, with a median dose of 30 mg (interquartile range, 20−40 mg), as illustrated in the Table. Repeated-measures analysis of liver enzymes (AST and ALT), total cholesterol, and TGs is detailed in eTable 1. Eight (2.2%) of 371 patients showed abnormal baseline AST levels. The first follow-up measurements of AST revealed high levels in 7 (1.9%) patients. This figure doubled (14 [3.8%] patients) at the second follow-up, with no statistically significant differences (P>.05). Likewise, ALT showed abnormally high levels at baseline and at both the first and second follow-ups (47/371 [12.7%], 49/371 [13.2%], and 37/371 [10.0%], respectively) with no significant differences (P>.05). Furthermore, the proportions of high cholesterol levels at baseline and at both the first and second follow-ups (40/331 [12.1%], 72/331 [21.8%], and 62/331 [18.7%], respectively) showed a statistically significant difference (P=.001). The proportions of high cholesterol levels in both the first and second follow-ups were significantly higher than the baseline proportions (P=.001 and P=.002, respectively). However, the percentages of high cholesterol were reduced at the second reading relative to the first but with no significant differences. Regarding TGs, there was a statistically significant difference in the proportions of high levels over time (5/320 [1.6%], 12/320 [3.8%], and 14/320 [4.4%] at baseline and at the first and second readings, respectively). Moreover, pairwise comparison among the 3 readings revealed a significant difference between the second follow-up and the baseline levels (P=.048). eTable 2 demonstrates statistically significant positive weak associations between the daily administered isotretinoin dose and each of the cholesterol and TG levels, both at the first and second follow-up readings (P<.05).

Comment

Evaluation of the effects of isotretinoin on liver enzymes and lipids has suggested that oral isotretinoin may cause alterations in liver aminotransferases (AST and ALT) and lipid profiles to various degrees.⁸ Furthermore, there are controversies regarding the routine laboratory monitoring of these patients. Some studies have reported severe alterations in serum liver transaminase and lipid levels, and they support the need for careful monitoring when treating patients with isotretinoin. However, other studies have reported that adverse effects are minimal, with no need for costly laboratory monitoring.⁹

Our study explored the profile of changes in liver aminotransferases (AST and ALT), cholesterol, and TGs in patients with acne who had been treated with oral isotretinoin. The cholesterol levels showed a nonprogressive increase, with a prevalence rate of 21.8% and 18.7% at the first and second follow-ups, respectively. Likewise, the frequency of high TG levels was 3.8% and 4.4%, respectively, with significant differences from the baseline levels (P=.041). However, liver enzymes were less affected by isotretinoin therapy than lipid profiles. Both AST and ALT showed nonsignificant minimal elevations during follow-up of the patients.

Similar to our findings, Zane et al⁶ at the University of California, San Francisco, studied 13,772 patients with acne who underwent oral isotretinoin therapy between 1995 and 2002. They reported a cumulative incidence of new abnormalities in patients with normal values at baseline at a frequency of 44% for TG levels, 31% for total cholesterol levels, and 11% for transaminase levels. Moreover, they suggested that these abnormalities generally were transient and reversible.⁶ Another retrospective study in Brazil included 130 patients who were treated with isotretinoin for 3 months and reported that TG levels had increased beyond the normal range in 11% of patients, whereas 8.6% had elevated AST levels and 7.3% had elevated ALT levels.⁸ Comparable to our findings, Kizilyel et al¹⁰ concluded that isotretinoin appeared to have a greater effect on lipids than on liver enzymes, and they recommended its use with careful monitoring.

The transient effects of isotretinoin therapy on lipid profiles were highlighted in an earlier study. It has been reported that the changes in low-density lipoprotein and TGs returned to baseline levels 2 months following termination of treatment.¹¹ Although many studies have reported alterations in serum transaminase and lipid levels, other studies fail to report any such effects. Alcalay et al⁷ investigated 907 patients who completed a treatment course lasting 5 to 9 months. They reported that only 1.5% of patients had serum TG levels above 400 mg. Additionally, serum levels of liver enzymes were not elevated to a degree necessitating discontinuation of treatment. They concluded that isotretinoin is a safe therapeutic drug and suggested that there is no need for routine laboratory follow-up in young healthy patients apart from a pregnancy test for females.⁷ In addition, Brito et al¹² conducted a prospective clinical and laboratory evaluation of 150 patients being treated with oral isotretinoin prior to the start of therapy, 1 month after therapy initiation, and every 3 months thereafter until the completion of treatment. They found no statistically significant changes in liver transaminase, TG, or cholesterol levels.¹² In another study of 30 participants, Baxter et al¹³ also reported no significant changes in TG or cholesterol levels measured at baseline or during treatment with isotretinoin. Furthermore, a systematic review and meta-analysis has estimated the laboratory changes that occur during isotretinoin therapy of acne vulgaris.¹⁴ The evidence revealed in this study does not support monthly laboratory testing for use of standard doses of oral isotretinoin for the typical patient with acne.

Conclusion

In our study, liver enzymes were less affected than lipids in patients who were treated with isotretinoin. Additionally, laboratory alterations in lipid profiles were nonprogressive and nonsevere. Consequently, isotretinoin may be administered with minimal concern for changes in serum transaminase and lipid profile. However, physicians should exercise caution when administering isotretinoin in patients with a history of abnormal findings.

Introduced in 1982, isotretinoin is a retinoid derivative that has been widely used to treat various dermatologic conditions such as acne vulgaris, rosacea, hidradenitis suppurativa, and hair folliculitis. ¹ It remains one of the most effective drugs for the treatment of all forms of acne vulgaris, especially the nodulocystic type, and exerts its effects via different mechanisms that affect the major domains involved in the pathogenesis of acne. ² One month after treatment initiation, isotretinoin suppresses sebum production by decreasing the size and activity of sebaceous glands. In addition, it notably stabilizes keratinization of the skin and decreases the number of Propionibacterium acnes, which will minimize the inflammation associated with acne. ^3,4 Despite its beneficial effects, isotretinoin therapy has been associated with several complications. The most commonly reported adverse effects include fissured lips, dry skin, eczema, epistaxis, dry eyes, gastrointestinal tract upset, angular stomatitis, and back pain. Less frequent systemic adverse effects have been reported and relate mainly to teratogenicity, pancreatitis, drug-induced hepatotoxicity, leukopenia, and thrombocytopenia. ⁵

Isotretinoin use has been associated with alterations in hepatic and lipid profiles; elevations of serum liver enzymes and triglycerides (TGs) following isotretinoin treatment have been reported.⁴ Consequently, different protocols for laboratory monitoring during isotretinoin therapy have been established and utilized by various health care institutes.⁶ Despite the time and economic investment involved, certain protocols recommend repetition of liver function tests and several other laboratory parameters following a baseline test.⁷ The aim of this study was to determine the prevalence of laboratory changes in alanine aminotransferase (ALT), aspartate aminotransferase (AST), cholesterol, and TGs among patients with acne receiving isotretinoin therapy, as well as to link the initial and second laboratory readings of the aforementioned parameters following initiation of isotretinoin treatment.

Materials and Methods

This retrospective cohort design study obtained patient data, including laboratory test results, from the Electronic System for Integrated Health Information at King Khalid University Hospital (KKUH)(Riyadh, Saudi Arabia). All patients older than 16 years who presented with acne vulgaris to the dermatology department at KKUH; who received a course of isotretinoin for at least 4 weeks between 2011 and 2016; and who had available baseline readings of ALT, AST, cholesterol, and TGs, as well as 2 concurrent follow-up readings after isotretinoin treatment initiation, were included in this study. Patients with only 1 reading following treatment initiation and those receiving isotretinoin treatment for reasons other than acne were excluded. This study was approved by the institutional review board of the College of Medicine at King Saud University (Riyadh, Saudi Arabia)(E-18-3310).

Statistical Analysis
Data were entered into a Microsoft Excel document, and statistical analysis was performed using SPSS (version 22.0). Data were represented as numbers and percentages. Repeated measures analysis was performed using the Cochran Q test to compare proportions of abnormal laboratory values among 3 groups: baseline, first reading, and second reading. When test results were significant, a post hoc test was used to compare proportions between any 2 groups. Moreover, a Spearman rank correlation was performed to investigate the association between the daily isotretinoin dose and the laboratory parameters. Results with P<.05 were considered statistically significant.

Results

During the study period, treatment with oral isotretinoin was undertaken by 386 patients at KKUH. Several of these patients were excluded due to incomplete medical records. The age of the studied patients ranged from 17 to 60 years, with a median age of 24 years (interquartile range, 20−28 years). The daily administered dose ranged from 10 to 80 mg, with a median dose of 30 mg (interquartile range, 20−40 mg), as illustrated in the Table. Repeated-measures analysis of liver enzymes (AST and ALT), total cholesterol, and TGs is detailed in eTable 1. Eight (2.2%) of 371 patients showed abnormal baseline AST levels. The first follow-up measurements of AST revealed high levels in 7 (1.9%) patients. This figure doubled (14 [3.8%] patients) at the second follow-up, with no statistically significant differences (P>.05). Likewise, ALT showed abnormally high levels at baseline and at both the first and second follow-ups (47/371 [12.7%], 49/371 [13.2%], and 37/371 [10.0%], respectively) with no significant differences (P>.05). Furthermore, the proportions of high cholesterol levels at baseline and at both the first and second follow-ups (40/331 [12.1%], 72/331 [21.8%], and 62/331 [18.7%], respectively) showed a statistically significant difference (P=.001). The proportions of high cholesterol levels in both the first and second follow-ups were significantly higher than the baseline proportions (P=.001 and P=.002, respectively). However, the percentages of high cholesterol were reduced at the second reading relative to the first but with no significant differences. Regarding TGs, there was a statistically significant difference in the proportions of high levels over time (5/320 [1.6%], 12/320 [3.8%], and 14/320 [4.4%] at baseline and at the first and second readings, respectively). Moreover, pairwise comparison among the 3 readings revealed a significant difference between the second follow-up and the baseline levels (P=.048). eTable 2 demonstrates statistically significant positive weak associations between the daily administered isotretinoin dose and each of the cholesterol and TG levels, both at the first and second follow-up readings (P<.05).

Comment

Evaluation of the effects of isotretinoin on liver enzymes and lipids has suggested that oral isotretinoin may cause alterations in liver aminotransferases (AST and ALT) and lipid profiles to various degrees.⁸ Furthermore, there are controversies regarding the routine laboratory monitoring of these patients. Some studies have reported severe alterations in serum liver transaminase and lipid levels, and they support the need for careful monitoring when treating patients with isotretinoin. However, other studies have reported that adverse effects are minimal, with no need for costly laboratory monitoring.⁹

Our study explored the profile of changes in liver aminotransferases (AST and ALT), cholesterol, and TGs in patients with acne who had been treated with oral isotretinoin. The cholesterol levels showed a nonprogressive increase, with a prevalence rate of 21.8% and 18.7% at the first and second follow-ups, respectively. Likewise, the frequency of high TG levels was 3.8% and 4.4%, respectively, with significant differences from the baseline levels (P=.041). However, liver enzymes were less affected by isotretinoin therapy than lipid profiles. Both AST and ALT showed nonsignificant minimal elevations during follow-up of the patients.

Similar to our findings, Zane et al⁶ at the University of California, San Francisco, studied 13,772 patients with acne who underwent oral isotretinoin therapy between 1995 and 2002. They reported a cumulative incidence of new abnormalities in patients with normal values at baseline at a frequency of 44% for TG levels, 31% for total cholesterol levels, and 11% for transaminase levels. Moreover, they suggested that these abnormalities generally were transient and reversible.⁶ Another retrospective study in Brazil included 130 patients who were treated with isotretinoin for 3 months and reported that TG levels had increased beyond the normal range in 11% of patients, whereas 8.6% had elevated AST levels and 7.3% had elevated ALT levels.⁸ Comparable to our findings, Kizilyel et al¹⁰ concluded that isotretinoin appeared to have a greater effect on lipids than on liver enzymes, and they recommended its use with careful monitoring.

The transient effects of isotretinoin therapy on lipid profiles were highlighted in an earlier study. It has been reported that the changes in low-density lipoprotein and TGs returned to baseline levels 2 months following termination of treatment.¹¹ Although many studies have reported alterations in serum transaminase and lipid levels, other studies fail to report any such effects. Alcalay et al⁷ investigated 907 patients who completed a treatment course lasting 5 to 9 months. They reported that only 1.5% of patients had serum TG levels above 400 mg. Additionally, serum levels of liver enzymes were not elevated to a degree necessitating discontinuation of treatment. They concluded that isotretinoin is a safe therapeutic drug and suggested that there is no need for routine laboratory follow-up in young healthy patients apart from a pregnancy test for females.⁷ In addition, Brito et al¹² conducted a prospective clinical and laboratory evaluation of 150 patients being treated with oral isotretinoin prior to the start of therapy, 1 month after therapy initiation, and every 3 months thereafter until the completion of treatment. They found no statistically significant changes in liver transaminase, TG, or cholesterol levels.¹² In another study of 30 participants, Baxter et al¹³ also reported no significant changes in TG or cholesterol levels measured at baseline or during treatment with isotretinoin. Furthermore, a systematic review and meta-analysis has estimated the laboratory changes that occur during isotretinoin therapy of acne vulgaris.¹⁴ The evidence revealed in this study does not support monthly laboratory testing for use of standard doses of oral isotretinoin for the typical patient with acne.

Conclusion

In our study, liver enzymes were less affected than lipids in patients who were treated with isotretinoin. Additionally, laboratory alterations in lipid profiles were nonprogressive and nonsevere. Consequently, isotretinoin may be administered with minimal concern for changes in serum transaminase and lipid profile. However, physicians should exercise caution when administering isotretinoin in patients with a history of abnormal findings.

Introduced in 1982, isotretinoin is a retinoid derivative that has been widely used to treat various dermatologic conditions such as acne vulgaris, rosacea, hidradenitis suppurativa, and hair folliculitis. ¹ It remains one of the most effective drugs for the treatment of all forms of acne vulgaris, especially the nodulocystic type, and exerts its effects via different mechanisms that affect the major domains involved in the pathogenesis of acne. ² One month after treatment initiation, isotretinoin suppresses sebum production by decreasing the size and activity of sebaceous glands. In addition, it notably stabilizes keratinization of the skin and decreases the number of Propionibacterium acnes, which will minimize the inflammation associated with acne. ^3,4 Despite its beneficial effects, isotretinoin therapy has been associated with several complications. The most commonly reported adverse effects include fissured lips, dry skin, eczema, epistaxis, dry eyes, gastrointestinal tract upset, angular stomatitis, and back pain. Less frequent systemic adverse effects have been reported and relate mainly to teratogenicity, pancreatitis, drug-induced hepatotoxicity, leukopenia, and thrombocytopenia. ⁵

Isotretinoin use has been associated with alterations in hepatic and lipid profiles; elevations of serum liver enzymes and triglycerides (TGs) following isotretinoin treatment have been reported.⁴ Consequently, different protocols for laboratory monitoring during isotretinoin therapy have been established and utilized by various health care institutes.⁶ Despite the time and economic investment involved, certain protocols recommend repetition of liver function tests and several other laboratory parameters following a baseline test.⁷ The aim of this study was to determine the prevalence of laboratory changes in alanine aminotransferase (ALT), aspartate aminotransferase (AST), cholesterol, and TGs among patients with acne receiving isotretinoin therapy, as well as to link the initial and second laboratory readings of the aforementioned parameters following initiation of isotretinoin treatment.

Materials and Methods

This retrospective cohort design study obtained patient data, including laboratory test results, from the Electronic System for Integrated Health Information at King Khalid University Hospital (KKUH)(Riyadh, Saudi Arabia). All patients older than 16 years who presented with acne vulgaris to the dermatology department at KKUH; who received a course of isotretinoin for at least 4 weeks between 2011 and 2016; and who had available baseline readings of ALT, AST, cholesterol, and TGs, as well as 2 concurrent follow-up readings after isotretinoin treatment initiation, were included in this study. Patients with only 1 reading following treatment initiation and those receiving isotretinoin treatment for reasons other than acne were excluded. This study was approved by the institutional review board of the College of Medicine at King Saud University (Riyadh, Saudi Arabia)(E-18-3310).

Statistical Analysis
Data were entered into a Microsoft Excel document, and statistical analysis was performed using SPSS (version 22.0). Data were represented as numbers and percentages. Repeated measures analysis was performed using the Cochran Q test to compare proportions of abnormal laboratory values among 3 groups: baseline, first reading, and second reading. When test results were significant, a post hoc test was used to compare proportions between any 2 groups. Moreover, a Spearman rank correlation was performed to investigate the association between the daily isotretinoin dose and the laboratory parameters. Results with P<.05 were considered statistically significant.

Results

During the study period, treatment with oral isotretinoin was undertaken by 386 patients at KKUH. Several of these patients were excluded due to incomplete medical records. The age of the studied patients ranged from 17 to 60 years, with a median age of 24 years (interquartile range, 20−28 years). The daily administered dose ranged from 10 to 80 mg, with a median dose of 30 mg (interquartile range, 20−40 mg), as illustrated in the Table. Repeated-measures analysis of liver enzymes (AST and ALT), total cholesterol, and TGs is detailed in eTable 1. Eight (2.2%) of 371 patients showed abnormal baseline AST levels. The first follow-up measurements of AST revealed high levels in 7 (1.9%) patients. This figure doubled (14 [3.8%] patients) at the second follow-up, with no statistically significant differences (P>.05). Likewise, ALT showed abnormally high levels at baseline and at both the first and second follow-ups (47/371 [12.7%], 49/371 [13.2%], and 37/371 [10.0%], respectively) with no significant differences (P>.05). Furthermore, the proportions of high cholesterol levels at baseline and at both the first and second follow-ups (40/331 [12.1%], 72/331 [21.8%], and 62/331 [18.7%], respectively) showed a statistically significant difference (P=.001). The proportions of high cholesterol levels in both the first and second follow-ups were significantly higher than the baseline proportions (P=.001 and P=.002, respectively). However, the percentages of high cholesterol were reduced at the second reading relative to the first but with no significant differences. Regarding TGs, there was a statistically significant difference in the proportions of high levels over time (5/320 [1.6%], 12/320 [3.8%], and 14/320 [4.4%] at baseline and at the first and second readings, respectively). Moreover, pairwise comparison among the 3 readings revealed a significant difference between the second follow-up and the baseline levels (P=.048). eTable 2 demonstrates statistically significant positive weak associations between the daily administered isotretinoin dose and each of the cholesterol and TG levels, both at the first and second follow-up readings (P<.05).

Comment

Evaluation of the effects of isotretinoin on liver enzymes and lipids has suggested that oral isotretinoin may cause alterations in liver aminotransferases (AST and ALT) and lipid profiles to various degrees.⁸ Furthermore, there are controversies regarding the routine laboratory monitoring of these patients. Some studies have reported severe alterations in serum liver transaminase and lipid levels, and they support the need for careful monitoring when treating patients with isotretinoin. However, other studies have reported that adverse effects are minimal, with no need for costly laboratory monitoring.⁹

Our study explored the profile of changes in liver aminotransferases (AST and ALT), cholesterol, and TGs in patients with acne who had been treated with oral isotretinoin. The cholesterol levels showed a nonprogressive increase, with a prevalence rate of 21.8% and 18.7% at the first and second follow-ups, respectively. Likewise, the frequency of high TG levels was 3.8% and 4.4%, respectively, with significant differences from the baseline levels (P=.041). However, liver enzymes were less affected by isotretinoin therapy than lipid profiles. Both AST and ALT showed nonsignificant minimal elevations during follow-up of the patients.

Similar to our findings, Zane et al⁶ at the University of California, San Francisco, studied 13,772 patients with acne who underwent oral isotretinoin therapy between 1995 and 2002. They reported a cumulative incidence of new abnormalities in patients with normal values at baseline at a frequency of 44% for TG levels, 31% for total cholesterol levels, and 11% for transaminase levels. Moreover, they suggested that these abnormalities generally were transient and reversible.⁶ Another retrospective study in Brazil included 130 patients who were treated with isotretinoin for 3 months and reported that TG levels had increased beyond the normal range in 11% of patients, whereas 8.6% had elevated AST levels and 7.3% had elevated ALT levels.⁸ Comparable to our findings, Kizilyel et al¹⁰ concluded that isotretinoin appeared to have a greater effect on lipids than on liver enzymes, and they recommended its use with careful monitoring.

The transient effects of isotretinoin therapy on lipid profiles were highlighted in an earlier study. It has been reported that the changes in low-density lipoprotein and TGs returned to baseline levels 2 months following termination of treatment.¹¹ Although many studies have reported alterations in serum transaminase and lipid levels, other studies fail to report any such effects. Alcalay et al⁷ investigated 907 patients who completed a treatment course lasting 5 to 9 months. They reported that only 1.5% of patients had serum TG levels above 400 mg. Additionally, serum levels of liver enzymes were not elevated to a degree necessitating discontinuation of treatment. They concluded that isotretinoin is a safe therapeutic drug and suggested that there is no need for routine laboratory follow-up in young healthy patients apart from a pregnancy test for females.⁷ In addition, Brito et al¹² conducted a prospective clinical and laboratory evaluation of 150 patients being treated with oral isotretinoin prior to the start of therapy, 1 month after therapy initiation, and every 3 months thereafter until the completion of treatment. They found no statistically significant changes in liver transaminase, TG, or cholesterol levels.¹² In another study of 30 participants, Baxter et al¹³ also reported no significant changes in TG or cholesterol levels measured at baseline or during treatment with isotretinoin. Furthermore, a systematic review and meta-analysis has estimated the laboratory changes that occur during isotretinoin therapy of acne vulgaris.¹⁴ The evidence revealed in this study does not support monthly laboratory testing for use of standard doses of oral isotretinoin for the typical patient with acne.

Conclusion

In our study, liver enzymes were less affected than lipids in patients who were treated with isotretinoin. Additionally, laboratory alterations in lipid profiles were nonprogressive and nonsevere. Consequently, isotretinoin may be administered with minimal concern for changes in serum transaminase and lipid profile. However, physicians should exercise caution when administering isotretinoin in patients with a history of abnormal findings.

To the Editor:

Etanercept is an immune-modulating drug used for the treatment of a variety of diseases including psoriasis, rheumatoid arthritis, and ankylosing spondylitis. It is an anti–tumor necrosis factor (TNF) fusion protein consisting of an extracellular domain of the p75 TNF receptor and the Fc portion of human IgG.¹ Etanercept is well known for its immunosuppressive side effects. A handful of case reports have provided evidence of squamous cell cancers in the setting of etanercept therapy. The most comprehensive description was a case series by Brewer et al² describing 4 patients with squamous cell carcinoma (SCC) that developed 1 to 17 months after the initiation of etanercept therapy. We present a case of a patient diagnosed with psoriasis and concomitant porokeratosis who developed multiple SCCs and squamous proliferations after initiation of etanercept therapy.

A 66-year-old man was referred to our clinic for treatment of psoriasis, as noted on a biopsy of the right ankle diagnosed several years prior. He was being treated with etanercept 50 mg twice weekly. Other treatments included calcipotriene–betamethasone dipropionate, salicylic acid gel, intralesional triamcinolone, clobetasol, and urea 40%. Physical examination revealed multiple erythematous tender nodules with hyperkeratotic scale distributed on the right arm and leg (Figure 1) that were concerning for SCC. Biopsies from 6 lesions revealed multiple SCC/keratoacanthomas (KAs) with verrucous features (Figure 2). Primers for human papillomavirus (HPV) 6, 11, 16, 18, 31, 33, and 51 were all negative. At that time, etanercept was discontinued. The patient was referred for Mohs micrographic surgery and underwent excision of several SCC lesions including an approximately 7-cm SCC on the right ankle (Figure 1B). Positron emission tomography/computed tomography found hypermetabolic lymphadenopathy. A follow-up biopsy of the inguinal nodes identified no malignant cells. Given their multiplicity, the patient was initiated on a prolonged course of a retinoid with acitretin 35 mg daily. The clearance of the large 7-cm lesion with a single stage of Mohs micrographic surgery directed suspicion to a pseudoepitheliomatous or HPV-induced cause for the lesions. Rereview of the original 6 biopsies indicated 1 definitive SCC on the right wrist, 2 KAs, and 3 that were most consistent with verruca vulgaris. At 1-year follow-up, most of the hyperkeratotic lesions had resolved with continued acitretin. Baseline porokeratosis lesions that were abundantly present on the arms and legs resolved by 1-year follow-up (Figure 3A).

The link between classic porokeratosis and the development of squamous cell proliferations is well established. Ninomiya et al³ noted a possible mechanism of p53 overexpression in the epidermis of porokeratotic lesions that may make the lesions particularly susceptible to the development of immunosuppression-induced SCC. Etanercept is an immune-modulating drug with well-known immunosuppressive side effects including reactivation of HPV as well as the development of SCCs.

Our patient initially was diagnosed with psoriasis and etanercept was initiated. The presence of coexistent porokeratosis likely predisposed him to etanercept-induced squamous proliferations including 2 SCCs and verrucous lesions, with histologic features suggesting SCC/KA. Histopathology revealed a cornoid lamella in SCC (Figure 3B), suggesting development of malignancy within epithelial clones, as noted by Lee et al.⁴

Targeted systemic therapies may lead to the formation of SCCs. The association between epidermal growth factor receptor (EGFR) kinase inhibitors and SCC formation is well known. For instance, sorafenib—a multikinase inhibitor that is downstream in the EGFR pathway—has been noted to induce epidermal growths including KAs and SCCs.⁵ There has been no definitive causal relationship identified between the development of SCC and TNF-α inhibitors. It has been suggested that perhaps there is an unmasking effect, as subclinical SCC manifests after TNF-α inhibition that leads to SCC development. Discontinuation of etanercept and resolution of lesions highlights a potential role of TNF-α inhibition and tumorigenesis of SCCs, especially in the background of porokeratosis. Vigilance for development of immunosuppression-induced malignancy, especially squamous cell proliferations, has become exceedingly important with exponentially increasing use of biologic therapies in medicine.

To the Editor:

Etanercept is an immune-modulating drug used for the treatment of a variety of diseases including psoriasis, rheumatoid arthritis, and ankylosing spondylitis. It is an anti–tumor necrosis factor (TNF) fusion protein consisting of an extracellular domain of the p75 TNF receptor and the Fc portion of human IgG.¹ Etanercept is well known for its immunosuppressive side effects. A handful of case reports have provided evidence of squamous cell cancers in the setting of etanercept therapy. The most comprehensive description was a case series by Brewer et al² describing 4 patients with squamous cell carcinoma (SCC) that developed 1 to 17 months after the initiation of etanercept therapy. We present a case of a patient diagnosed with psoriasis and concomitant porokeratosis who developed multiple SCCs and squamous proliferations after initiation of etanercept therapy.

A 66-year-old man was referred to our clinic for treatment of psoriasis, as noted on a biopsy of the right ankle diagnosed several years prior. He was being treated with etanercept 50 mg twice weekly. Other treatments included calcipotriene–betamethasone dipropionate, salicylic acid gel, intralesional triamcinolone, clobetasol, and urea 40%. Physical examination revealed multiple erythematous tender nodules with hyperkeratotic scale distributed on the right arm and leg (Figure 1) that were concerning for SCC. Biopsies from 6 lesions revealed multiple SCC/keratoacanthomas (KAs) with verrucous features (Figure 2). Primers for human papillomavirus (HPV) 6, 11, 16, 18, 31, 33, and 51 were all negative. At that time, etanercept was discontinued. The patient was referred for Mohs micrographic surgery and underwent excision of several SCC lesions including an approximately 7-cm SCC on the right ankle (Figure 1B). Positron emission tomography/computed tomography found hypermetabolic lymphadenopathy. A follow-up biopsy of the inguinal nodes identified no malignant cells. Given their multiplicity, the patient was initiated on a prolonged course of a retinoid with acitretin 35 mg daily. The clearance of the large 7-cm lesion with a single stage of Mohs micrographic surgery directed suspicion to a pseudoepitheliomatous or HPV-induced cause for the lesions. Rereview of the original 6 biopsies indicated 1 definitive SCC on the right wrist, 2 KAs, and 3 that were most consistent with verruca vulgaris. At 1-year follow-up, most of the hyperkeratotic lesions had resolved with continued acitretin. Baseline porokeratosis lesions that were abundantly present on the arms and legs resolved by 1-year follow-up (Figure 3A).

The link between classic porokeratosis and the development of squamous cell proliferations is well established. Ninomiya et al³ noted a possible mechanism of p53 overexpression in the epidermis of porokeratotic lesions that may make the lesions particularly susceptible to the development of immunosuppression-induced SCC. Etanercept is an immune-modulating drug with well-known immunosuppressive side effects including reactivation of HPV as well as the development of SCCs.

Our patient initially was diagnosed with psoriasis and etanercept was initiated. The presence of coexistent porokeratosis likely predisposed him to etanercept-induced squamous proliferations including 2 SCCs and verrucous lesions, with histologic features suggesting SCC/KA. Histopathology revealed a cornoid lamella in SCC (Figure 3B), suggesting development of malignancy within epithelial clones, as noted by Lee et al.⁴

Targeted systemic therapies may lead to the formation of SCCs. The association between epidermal growth factor receptor (EGFR) kinase inhibitors and SCC formation is well known. For instance, sorafenib—a multikinase inhibitor that is downstream in the EGFR pathway—has been noted to induce epidermal growths including KAs and SCCs.⁵ There has been no definitive causal relationship identified between the development of SCC and TNF-α inhibitors. It has been suggested that perhaps there is an unmasking effect, as subclinical SCC manifests after TNF-α inhibition that leads to SCC development. Discontinuation of etanercept and resolution of lesions highlights a potential role of TNF-α inhibition and tumorigenesis of SCCs, especially in the background of porokeratosis. Vigilance for development of immunosuppression-induced malignancy, especially squamous cell proliferations, has become exceedingly important with exponentially increasing use of biologic therapies in medicine.

To the Editor:

Etanercept is an immune-modulating drug used for the treatment of a variety of diseases including psoriasis, rheumatoid arthritis, and ankylosing spondylitis. It is an anti–tumor necrosis factor (TNF) fusion protein consisting of an extracellular domain of the p75 TNF receptor and the Fc portion of human IgG.¹ Etanercept is well known for its immunosuppressive side effects. A handful of case reports have provided evidence of squamous cell cancers in the setting of etanercept therapy. The most comprehensive description was a case series by Brewer et al² describing 4 patients with squamous cell carcinoma (SCC) that developed 1 to 17 months after the initiation of etanercept therapy. We present a case of a patient diagnosed with psoriasis and concomitant porokeratosis who developed multiple SCCs and squamous proliferations after initiation of etanercept therapy.

A 66-year-old man was referred to our clinic for treatment of psoriasis, as noted on a biopsy of the right ankle diagnosed several years prior. He was being treated with etanercept 50 mg twice weekly. Other treatments included calcipotriene–betamethasone dipropionate, salicylic acid gel, intralesional triamcinolone, clobetasol, and urea 40%. Physical examination revealed multiple erythematous tender nodules with hyperkeratotic scale distributed on the right arm and leg (Figure 1) that were concerning for SCC. Biopsies from 6 lesions revealed multiple SCC/keratoacanthomas (KAs) with verrucous features (Figure 2). Primers for human papillomavirus (HPV) 6, 11, 16, 18, 31, 33, and 51 were all negative. At that time, etanercept was discontinued. The patient was referred for Mohs micrographic surgery and underwent excision of several SCC lesions including an approximately 7-cm SCC on the right ankle (Figure 1B). Positron emission tomography/computed tomography found hypermetabolic lymphadenopathy. A follow-up biopsy of the inguinal nodes identified no malignant cells. Given their multiplicity, the patient was initiated on a prolonged course of a retinoid with acitretin 35 mg daily. The clearance of the large 7-cm lesion with a single stage of Mohs micrographic surgery directed suspicion to a pseudoepitheliomatous or HPV-induced cause for the lesions. Rereview of the original 6 biopsies indicated 1 definitive SCC on the right wrist, 2 KAs, and 3 that were most consistent with verruca vulgaris. At 1-year follow-up, most of the hyperkeratotic lesions had resolved with continued acitretin. Baseline porokeratosis lesions that were abundantly present on the arms and legs resolved by 1-year follow-up (Figure 3A).

The link between classic porokeratosis and the development of squamous cell proliferations is well established. Ninomiya et al³ noted a possible mechanism of p53 overexpression in the epidermis of porokeratotic lesions that may make the lesions particularly susceptible to the development of immunosuppression-induced SCC. Etanercept is an immune-modulating drug with well-known immunosuppressive side effects including reactivation of HPV as well as the development of SCCs.

Our patient initially was diagnosed with psoriasis and etanercept was initiated. The presence of coexistent porokeratosis likely predisposed him to etanercept-induced squamous proliferations including 2 SCCs and verrucous lesions, with histologic features suggesting SCC/KA. Histopathology revealed a cornoid lamella in SCC (Figure 3B), suggesting development of malignancy within epithelial clones, as noted by Lee et al.⁴

Targeted systemic therapies may lead to the formation of SCCs. The association between epidermal growth factor receptor (EGFR) kinase inhibitors and SCC formation is well known. For instance, sorafenib—a multikinase inhibitor that is downstream in the EGFR pathway—has been noted to induce epidermal growths including KAs and SCCs.⁵ There has been no definitive causal relationship identified between the development of SCC and TNF-α inhibitors. It has been suggested that perhaps there is an unmasking effect, as subclinical SCC manifests after TNF-α inhibition that leads to SCC development. Discontinuation of etanercept and resolution of lesions highlights a potential role of TNF-α inhibition and tumorigenesis of SCCs, especially in the background of porokeratosis. Vigilance for development of immunosuppression-induced malignancy, especially squamous cell proliferations, has become exceedingly important with exponentially increasing use of biologic therapies in medicine.

To the Editor:

A 56-year-old man with a history of stage IV metastatic penile squamous cell carcinoma treated with penectomy and chemotherapy with 5-fluorouracil and cisplatin presented with several painful ulcerations in the groin, abdomen, and thighs. The lesions initially appeared in the groin and were treated as bacterial abscesses with antibiotics. Over the next few weeks, new lesions appeared on the abdomen and thighs. An additional cycle of chemotherapy led to a reduction in number; however, they again increased within a few weeks. Medications included enoxaparin followed by 3 weeks of warfarin use due to a right leg deep vein thrombosis.

Physical examination revealed multiple 1- to 4-cm, firm, ulcerated nodules on the bilateral inguinal folds, abdomen, and upper thighs, as well as areas of livedo racemosa and noninflammatory retiform purpura with central ulceration (Figures 1 and 2). This retiform purpura was both perilesional and in areas without ulcerations. Laboratory values included the following: sodium, 127 mmol/L (reference range, 136–145 mmol/L); prothrombin time, 16.1 seconds (reference range, 11–15 seconds); white blood cell count, 20.69×10⁹/L (reference range, 4.5–11.0×10⁹/L) with 87% neutrophils (reference range, 54%–62%); hemoglobin, 6.1 g/dL (reference range, 13.5–17.5 g/dL); hematocrit, 18.8% (reference range, 41%–53%); platelets, 474×10⁹/L (reference range, 150–400×10⁹/L); D-dimer, 0.77 mg/L (reference range, ≤0.50 mg/L); fibrinogen, 489 mg/dL (reference range, 150–400 mg/dL); prior urine culture positive for Pseudomonas aeruginosa. He was negative for hepatitis B and hepatitis C viruses as well as HIV, and the lesions were not clinically consistent with herpes simplex virus, as they were not scalloped or circinate. Punch biopsies were obtained from a nodule on the left leg and a purpuric patch on the right leg.

Ischemic cutaneous lesions less commonly occur in the setting of malignancy and can be the result of both direct and indirect systemic effects from the cancer. Malignancies are known to directly trigger vasculopathies in other organs, most commonly the lungs, through 2 primary mechanisms. First, in carcinomatous arteriopathy, metastatic cells promote fibrocellular intimal proliferation of small pulmonary arteries and arterioles leading to stenosis, thrombosis, and obliteration. This mechanism has been described in pulmonary thrombotic microangiopathy secondary to lung carcinoma.⁴ This pathophysiology likely is also what underlies paraneoplastic acral vascular syndromes, which culminate in digital ischemia. Hypothesized mechanisms for this ischemia also range from vasospasm to thromboembolism.⁵ Secondly, in vasculitis carcinomatosa, metastatic tumor cells damage or block vessel walls, resulting in end-organ ischemia. Vasculitis carcinomatosa is a well-known phenomenon in angiocentric and intravascular lymphoid malignancies (typically of B-T or natural killer/T-cell origin) but also has been reported in a case of gastric adenocarcinoma with arterial invasion.⁶ This process is different than carcinoma telangiectoides where malignant cells may be present in the vasculature on histopathology but not trigger thrombosis and ischemic skin necrosis.

Systemic coagulopathies such as disseminated intravascular coagulation (DIC), thrombotic thrombocytopenia purpura, and catastrophic antiphospholipid antibody syndrome can occur in the setting of malignancies.⁷ Clinically, all may present with livedo racemosa, noninflammatory retiform purpura, and widespread skin necrosis. In adult patients, purpura fulminans most often is seen in the setting of sepsis and DIC, with accompanying evidence of microangiopathy.⁸ Catastrophic antiphospholipid antibody syndrome can be triggered by malignancy and is characterized by central nervous system, renal, pulmonary, and gastrointestinal complications. Skin involvement such as ulcers, livedo reticularis, and gangrene have been reported.⁹ Other causes of thrombotic vasculopathy include warfarin necrosis, heparin-induced thrombotic thrombocytopenia, calciphylaxis, and angioinvasive infections.⁸ Warfarin necrosis and heparin-induced thrombotic thrombocytopenia typically present days after initiating therapy with the respective medication. Calciphylaxis typically occurs in patients on dialysis, though it may occur in nonuremic patients including those with malignancy.⁸ Patients with malignancies on chemotherapy can become neutropenic and are at risk for ecthyma gangrenosum due to P aeruginosa and other gram-negative rods, Staphylococcus aureus, and angioinvasive fungi.¹⁰

Based on clinical, histopathological, and laboratory data, we favored a diagnosis of cutaneous carcinomatous arteriopathy. Vasculitis carcinomatosa was a possibility despite the lack of vasculotropism on histopathology, which may have been due to biopsy site selection. Systemic coagulopathies such as DIC, thrombotic thrombocytopenia purpura, and catastrophic antiphospholipid antibody syndrome were unlikely, as the ischemic skin lesions and livedo racemosa were limited to areas adjacent to cutaneous metastases, and the patient lacked other common multiorgan manifestations or laboratory findings. Although our patient was on warfarin, he was on a stable dose for weeks and histopathologic features of subcutaneous thrombosis were not seen. The biopsy also was not consistent with calciphylaxis. Ecthyma gangrenosum was unlikely given the lack of organisms on histopathology and negative skin and blood cultures. Although additional laboratory testing in this patient may have included cryoglobulins and cryofibrinogens, both entities were unlikely due to a lack of ischemic acral lesions.

In conclusion, we present a case of localized thrombotic vasculopathy that likely was secondary to cutaneous carcinomatous arteriopathy in the setting of cutaneous metastatic penile squamous cell carcinoma. The differential diagnosis of retiform purpura, livedo racemosa, and other signs of cutaneous ischemia in patients with metastatic cancer is broad and can be the result of both direct and indirect systemic effects from the cancer. Appropriate workup in these cases should include skin biopsies for histopathology and culture, medication review, and laboratory evaluation for systemic coagulopathies.

To the Editor:

A 56-year-old man with a history of stage IV metastatic penile squamous cell carcinoma treated with penectomy and chemotherapy with 5-fluorouracil and cisplatin presented with several painful ulcerations in the groin, abdomen, and thighs. The lesions initially appeared in the groin and were treated as bacterial abscesses with antibiotics. Over the next few weeks, new lesions appeared on the abdomen and thighs. An additional cycle of chemotherapy led to a reduction in number; however, they again increased within a few weeks. Medications included enoxaparin followed by 3 weeks of warfarin use due to a right leg deep vein thrombosis.

Physical examination revealed multiple 1- to 4-cm, firm, ulcerated nodules on the bilateral inguinal folds, abdomen, and upper thighs, as well as areas of livedo racemosa and noninflammatory retiform purpura with central ulceration (Figures 1 and 2). This retiform purpura was both perilesional and in areas without ulcerations. Laboratory values included the following: sodium, 127 mmol/L (reference range, 136–145 mmol/L); prothrombin time, 16.1 seconds (reference range, 11–15 seconds); white blood cell count, 20.69×10⁹/L (reference range, 4.5–11.0×10⁹/L) with 87% neutrophils (reference range, 54%–62%); hemoglobin, 6.1 g/dL (reference range, 13.5–17.5 g/dL); hematocrit, 18.8% (reference range, 41%–53%); platelets, 474×10⁹/L (reference range, 150–400×10⁹/L); D-dimer, 0.77 mg/L (reference range, ≤0.50 mg/L); fibrinogen, 489 mg/dL (reference range, 150–400 mg/dL); prior urine culture positive for Pseudomonas aeruginosa. He was negative for hepatitis B and hepatitis C viruses as well as HIV, and the lesions were not clinically consistent with herpes simplex virus, as they were not scalloped or circinate. Punch biopsies were obtained from a nodule on the left leg and a purpuric patch on the right leg.

Ischemic cutaneous lesions less commonly occur in the setting of malignancy and can be the result of both direct and indirect systemic effects from the cancer. Malignancies are known to directly trigger vasculopathies in other organs, most commonly the lungs, through 2 primary mechanisms. First, in carcinomatous arteriopathy, metastatic cells promote fibrocellular intimal proliferation of small pulmonary arteries and arterioles leading to stenosis, thrombosis, and obliteration. This mechanism has been described in pulmonary thrombotic microangiopathy secondary to lung carcinoma.⁴ This pathophysiology likely is also what underlies paraneoplastic acral vascular syndromes, which culminate in digital ischemia. Hypothesized mechanisms for this ischemia also range from vasospasm to thromboembolism.⁵ Secondly, in vasculitis carcinomatosa, metastatic tumor cells damage or block vessel walls, resulting in end-organ ischemia. Vasculitis carcinomatosa is a well-known phenomenon in angiocentric and intravascular lymphoid malignancies (typically of B-T or natural killer/T-cell origin) but also has been reported in a case of gastric adenocarcinoma with arterial invasion.⁶ This process is different than carcinoma telangiectoides where malignant cells may be present in the vasculature on histopathology but not trigger thrombosis and ischemic skin necrosis.

Systemic coagulopathies such as disseminated intravascular coagulation (DIC), thrombotic thrombocytopenia purpura, and catastrophic antiphospholipid antibody syndrome can occur in the setting of malignancies.⁷ Clinically, all may present with livedo racemosa, noninflammatory retiform purpura, and widespread skin necrosis. In adult patients, purpura fulminans most often is seen in the setting of sepsis and DIC, with accompanying evidence of microangiopathy.⁸ Catastrophic antiphospholipid antibody syndrome can be triggered by malignancy and is characterized by central nervous system, renal, pulmonary, and gastrointestinal complications. Skin involvement such as ulcers, livedo reticularis, and gangrene have been reported.⁹ Other causes of thrombotic vasculopathy include warfarin necrosis, heparin-induced thrombotic thrombocytopenia, calciphylaxis, and angioinvasive infections.⁸ Warfarin necrosis and heparin-induced thrombotic thrombocytopenia typically present days after initiating therapy with the respective medication. Calciphylaxis typically occurs in patients on dialysis, though it may occur in nonuremic patients including those with malignancy.⁸ Patients with malignancies on chemotherapy can become neutropenic and are at risk for ecthyma gangrenosum due to P aeruginosa and other gram-negative rods, Staphylococcus aureus, and angioinvasive fungi.¹⁰

Based on clinical, histopathological, and laboratory data, we favored a diagnosis of cutaneous carcinomatous arteriopathy. Vasculitis carcinomatosa was a possibility despite the lack of vasculotropism on histopathology, which may have been due to biopsy site selection. Systemic coagulopathies such as DIC, thrombotic thrombocytopenia purpura, and catastrophic antiphospholipid antibody syndrome were unlikely, as the ischemic skin lesions and livedo racemosa were limited to areas adjacent to cutaneous metastases, and the patient lacked other common multiorgan manifestations or laboratory findings. Although our patient was on warfarin, he was on a stable dose for weeks and histopathologic features of subcutaneous thrombosis were not seen. The biopsy also was not consistent with calciphylaxis. Ecthyma gangrenosum was unlikely given the lack of organisms on histopathology and negative skin and blood cultures. Although additional laboratory testing in this patient may have included cryoglobulins and cryofibrinogens, both entities were unlikely due to a lack of ischemic acral lesions.

In conclusion, we present a case of localized thrombotic vasculopathy that likely was secondary to cutaneous carcinomatous arteriopathy in the setting of cutaneous metastatic penile squamous cell carcinoma. The differential diagnosis of retiform purpura, livedo racemosa, and other signs of cutaneous ischemia in patients with metastatic cancer is broad and can be the result of both direct and indirect systemic effects from the cancer. Appropriate workup in these cases should include skin biopsies for histopathology and culture, medication review, and laboratory evaluation for systemic coagulopathies.

To the Editor:

A 56-year-old man with a history of stage IV metastatic penile squamous cell carcinoma treated with penectomy and chemotherapy with 5-fluorouracil and cisplatin presented with several painful ulcerations in the groin, abdomen, and thighs. The lesions initially appeared in the groin and were treated as bacterial abscesses with antibiotics. Over the next few weeks, new lesions appeared on the abdomen and thighs. An additional cycle of chemotherapy led to a reduction in number; however, they again increased within a few weeks. Medications included enoxaparin followed by 3 weeks of warfarin use due to a right leg deep vein thrombosis.

Physical examination revealed multiple 1- to 4-cm, firm, ulcerated nodules on the bilateral inguinal folds, abdomen, and upper thighs, as well as areas of livedo racemosa and noninflammatory retiform purpura with central ulceration (Figures 1 and 2). This retiform purpura was both perilesional and in areas without ulcerations. Laboratory values included the following: sodium, 127 mmol/L (reference range, 136–145 mmol/L); prothrombin time, 16.1 seconds (reference range, 11–15 seconds); white blood cell count, 20.69×10⁹/L (reference range, 4.5–11.0×10⁹/L) with 87% neutrophils (reference range, 54%–62%); hemoglobin, 6.1 g/dL (reference range, 13.5–17.5 g/dL); hematocrit, 18.8% (reference range, 41%–53%); platelets, 474×10⁹/L (reference range, 150–400×10⁹/L); D-dimer, 0.77 mg/L (reference range, ≤0.50 mg/L); fibrinogen, 489 mg/dL (reference range, 150–400 mg/dL); prior urine culture positive for Pseudomonas aeruginosa. He was negative for hepatitis B and hepatitis C viruses as well as HIV, and the lesions were not clinically consistent with herpes simplex virus, as they were not scalloped or circinate. Punch biopsies were obtained from a nodule on the left leg and a purpuric patch on the right leg.

Ischemic cutaneous lesions less commonly occur in the setting of malignancy and can be the result of both direct and indirect systemic effects from the cancer. Malignancies are known to directly trigger vasculopathies in other organs, most commonly the lungs, through 2 primary mechanisms. First, in carcinomatous arteriopathy, metastatic cells promote fibrocellular intimal proliferation of small pulmonary arteries and arterioles leading to stenosis, thrombosis, and obliteration. This mechanism has been described in pulmonary thrombotic microangiopathy secondary to lung carcinoma.⁴ This pathophysiology likely is also what underlies paraneoplastic acral vascular syndromes, which culminate in digital ischemia. Hypothesized mechanisms for this ischemia also range from vasospasm to thromboembolism.⁵ Secondly, in vasculitis carcinomatosa, metastatic tumor cells damage or block vessel walls, resulting in end-organ ischemia. Vasculitis carcinomatosa is a well-known phenomenon in angiocentric and intravascular lymphoid malignancies (typically of B-T or natural killer/T-cell origin) but also has been reported in a case of gastric adenocarcinoma with arterial invasion.⁶ This process is different than carcinoma telangiectoides where malignant cells may be present in the vasculature on histopathology but not trigger thrombosis and ischemic skin necrosis.

Systemic coagulopathies such as disseminated intravascular coagulation (DIC), thrombotic thrombocytopenia purpura, and catastrophic antiphospholipid antibody syndrome can occur in the setting of malignancies.⁷ Clinically, all may present with livedo racemosa, noninflammatory retiform purpura, and widespread skin necrosis. In adult patients, purpura fulminans most often is seen in the setting of sepsis and DIC, with accompanying evidence of microangiopathy.⁸ Catastrophic antiphospholipid antibody syndrome can be triggered by malignancy and is characterized by central nervous system, renal, pulmonary, and gastrointestinal complications. Skin involvement such as ulcers, livedo reticularis, and gangrene have been reported.⁹ Other causes of thrombotic vasculopathy include warfarin necrosis, heparin-induced thrombotic thrombocytopenia, calciphylaxis, and angioinvasive infections.⁸ Warfarin necrosis and heparin-induced thrombotic thrombocytopenia typically present days after initiating therapy with the respective medication. Calciphylaxis typically occurs in patients on dialysis, though it may occur in nonuremic patients including those with malignancy.⁸ Patients with malignancies on chemotherapy can become neutropenic and are at risk for ecthyma gangrenosum due to P aeruginosa and other gram-negative rods, Staphylococcus aureus, and angioinvasive fungi.¹⁰

Based on clinical, histopathological, and laboratory data, we favored a diagnosis of cutaneous carcinomatous arteriopathy. Vasculitis carcinomatosa was a possibility despite the lack of vasculotropism on histopathology, which may have been due to biopsy site selection. Systemic coagulopathies such as DIC, thrombotic thrombocytopenia purpura, and catastrophic antiphospholipid antibody syndrome were unlikely, as the ischemic skin lesions and livedo racemosa were limited to areas adjacent to cutaneous metastases, and the patient lacked other common multiorgan manifestations or laboratory findings. Although our patient was on warfarin, he was on a stable dose for weeks and histopathologic features of subcutaneous thrombosis were not seen. The biopsy also was not consistent with calciphylaxis. Ecthyma gangrenosum was unlikely given the lack of organisms on histopathology and negative skin and blood cultures. Although additional laboratory testing in this patient may have included cryoglobulins and cryofibrinogens, both entities were unlikely due to a lack of ischemic acral lesions.

In conclusion, we present a case of localized thrombotic vasculopathy that likely was secondary to cutaneous carcinomatous arteriopathy in the setting of cutaneous metastatic penile squamous cell carcinoma. The differential diagnosis of retiform purpura, livedo racemosa, and other signs of cutaneous ischemia in patients with metastatic cancer is broad and can be the result of both direct and indirect systemic effects from the cancer. Appropriate workup in these cases should include skin biopsies for histopathology and culture, medication review, and laboratory evaluation for systemic coagulopathies.