Cutis

The Diagnosis: Verrucous Hemangioma

Verrucous hemangioma (VH) is a rare vascular anomaly that has not been definitively delineated as a malformation or a tumor, as it has features of both. Verrucous hemangioma presents at birth as a compressible soft mass with a red violaceous hue favoring the legs.^1,2 Over time VH will develop a warty, friable, and keratotic surface that can begin to evolve as early as 6 months or as late as 34 years of age.³ Verrucous hemangioma does not involute and tends to grow proportionally with the patient. Thus, VH classically has been considered a vascular malformation.

On histopathology VH shows collections of uniform, thin-walled vessels with a multilamellated basement membrane throughout the dermis, similar to an infantile hemangioma (IH). These lesions extend deep into the subcutaneous tissue and often involve the underlying fascia. The papillary dermis has large ectatic vessels, while the epidermis displays verrucous hyperkeratosis, papillomatosis, and irregular acanthosis without viral change (Figure).^4,5 The superficial component can resemble an angiokeratoma; however, VH is differentiated by a deeper component that is often larger in size and has a more protracted clinical course.

Similar to IH, immunohistochemical studies have shown that VH expresses Wilms tumor 1 and glucose transporter 1 but is negative for D2-40.⁴ These findings suggest that VH is a vascular tumor rather than a vascular malformation, as was previously reported.⁶ Additional research has shown that the immunohistochemical staining profile of VH is nearly identical to IH, which has led to postulation that VH may be of placental mesodermal origin, as has been hypothesized for IH.⁵

Due to its deep infiltration and tendency for recurrence, VH is most effectively treated with wide local excision.^3,6-8 Preoperative planning with magnetic resonance imaging may be indicated. Although laser monotherapy and other local destructive therapies have been largely unsuccessful, postsurgical laser therapy with CO2 lasers as well as dual pulsed dye laser and Nd:YAG laser have shown promise in preventing recurrence.³

The Diagnosis: Verrucous Hemangioma

Verrucous hemangioma (VH) is a rare vascular anomaly that has not been definitively delineated as a malformation or a tumor, as it has features of both. Verrucous hemangioma presents at birth as a compressible soft mass with a red violaceous hue favoring the legs.^1,2 Over time VH will develop a warty, friable, and keratotic surface that can begin to evolve as early as 6 months or as late as 34 years of age.³ Verrucous hemangioma does not involute and tends to grow proportionally with the patient. Thus, VH classically has been considered a vascular malformation.

On histopathology VH shows collections of uniform, thin-walled vessels with a multilamellated basement membrane throughout the dermis, similar to an infantile hemangioma (IH). These lesions extend deep into the subcutaneous tissue and often involve the underlying fascia. The papillary dermis has large ectatic vessels, while the epidermis displays verrucous hyperkeratosis, papillomatosis, and irregular acanthosis without viral change (Figure).^4,5 The superficial component can resemble an angiokeratoma; however, VH is differentiated by a deeper component that is often larger in size and has a more protracted clinical course.

Similar to IH, immunohistochemical studies have shown that VH expresses Wilms tumor 1 and glucose transporter 1 but is negative for D2-40.⁴ These findings suggest that VH is a vascular tumor rather than a vascular malformation, as was previously reported.⁶ Additional research has shown that the immunohistochemical staining profile of VH is nearly identical to IH, which has led to postulation that VH may be of placental mesodermal origin, as has been hypothesized for IH.⁵

Due to its deep infiltration and tendency for recurrence, VH is most effectively treated with wide local excision.^3,6-8 Preoperative planning with magnetic resonance imaging may be indicated. Although laser monotherapy and other local destructive therapies have been largely unsuccessful, postsurgical laser therapy with CO2 lasers as well as dual pulsed dye laser and Nd:YAG laser have shown promise in preventing recurrence.³

The Diagnosis: Verrucous Hemangioma

Verrucous hemangioma (VH) is a rare vascular anomaly that has not been definitively delineated as a malformation or a tumor, as it has features of both. Verrucous hemangioma presents at birth as a compressible soft mass with a red violaceous hue favoring the legs.^1,2 Over time VH will develop a warty, friable, and keratotic surface that can begin to evolve as early as 6 months or as late as 34 years of age.³ Verrucous hemangioma does not involute and tends to grow proportionally with the patient. Thus, VH classically has been considered a vascular malformation.

On histopathology VH shows collections of uniform, thin-walled vessels with a multilamellated basement membrane throughout the dermis, similar to an infantile hemangioma (IH). These lesions extend deep into the subcutaneous tissue and often involve the underlying fascia. The papillary dermis has large ectatic vessels, while the epidermis displays verrucous hyperkeratosis, papillomatosis, and irregular acanthosis without viral change (Figure).^4,5 The superficial component can resemble an angiokeratoma; however, VH is differentiated by a deeper component that is often larger in size and has a more protracted clinical course.

Similar to IH, immunohistochemical studies have shown that VH expresses Wilms tumor 1 and glucose transporter 1 but is negative for D2-40.⁴ These findings suggest that VH is a vascular tumor rather than a vascular malformation, as was previously reported.⁶ Additional research has shown that the immunohistochemical staining profile of VH is nearly identical to IH, which has led to postulation that VH may be of placental mesodermal origin, as has been hypothesized for IH.⁵

Due to its deep infiltration and tendency for recurrence, VH is most effectively treated with wide local excision.^3,6-8 Preoperative planning with magnetic resonance imaging may be indicated. Although laser monotherapy and other local destructive therapies have been largely unsuccessful, postsurgical laser therapy with CO2 lasers as well as dual pulsed dye laser and Nd:YAG laser have shown promise in preventing recurrence.³

Varicella-zoster virus (VZV) causes varicella as a primary infection. It is a highly contagious disease characterized by a widespread papulovesicular eruption with fever and malaise.^1,2 After the primary infection, the virus remains latent within the sensory dorsal root ganglia and can reactivate as herpes zoster (HZ).^1-5 Herpes zoster is characterized by unilateral radicular pain and a vesicular rash in a dermatomal pattern.^1,2 It is most common in adults, especially elderly and immunocompromised patients, but rarely occurs in children. Herpes zoster is most often seen in individuals previously infected with VZV, but it also has occurred in individuals without known varicella infection,^1-17 possibly because these individuals had a prior subclinical VZV infection.

A live attenuated VZV vaccine was created after isolation of the virus from a child in Japan.² Since the introduction of the vaccine in 1995 in the United States, the incidence of VZV and HZ has declined.⁵ Herpes zoster rates after vaccination vary from 14 to 19 per 100,000 individuals.^3,5 Breakthrough disease with the wild-type strain does occur in vaccinated children, but vaccine-strain HZ also has been reported.^1-5 The risk for HZ caused by reactivated VZV vaccine in healthy children is unknown. We present a case of HZ in an otherwise healthy 19-month-old boy with no known varicella exposure who received the VZV vaccine at 13 months of age.

Case Report

An otherwise healthy 19-month-old boy presented to the dermatology clinic with a rash that began 2 days prior on the right groin and spread to the right leg. The patient’s mother denied that the child had been febrile and noted that the rash did not appear to bother him in any way. The patient was up-to-date on his vaccinations and received the first dose of the varicella series 6 months prior to presentation. He had no personal history of varicella, no exposure to sick contacts with varicella, and no known exposure to the virus. He was otherwise completely healthy with no signs or symptoms of immunocompromise.

Physical examination revealed grouped vesicles on an erythematous base on the right thigh, right sacrum, and lower abdomen that did not cross the midline (Figure). There were no other pertinent physical examination findings. The eruption was most consistent with HZ but concern remained for herpes simplex virus (HSV) or impetigo. A bacterial culture and polymerase chain reaction assay for VZV and HSV from skin swabs was ordered. The patient was prescribed acyclovir 20 mg/kg every 6 hours for 5 days. Laboratory testing revealed a positive result for VZV on polymerase chain reaction and a negative result for HSV. The majority of the patient’s lesions had crusted after 2 days of treatment with acyclovir, and the rash had nearly resolved 1 week after presentation. Subsequent evaluation with a complete blood cell count with differential and basic metabolic profile was normal. Levels of IgG, IgA, and IgM also were normal; IgE was slightly elevated.

Comment

Herpes zoster in children is an uncommon clinical entity. Most children with HZ are immunocompromised, have a history of varicella, or were exposed to varicella during gestation.⁸ With the introduction of the live VZV vaccine, the incidence of HZ has declined, but reactivation of the live vaccine leading to HZ infection is possible. The vaccine is 90% effective, and breakthrough varicella has been reported in 15% to 20% of vaccinated patients.^1-17 The cause of HZ in vaccinated children is unclear due to the potential for either wild-type or vaccine-strain VZV to induce HZ.

Twenty-two cases of HZ in healthy children after vaccination were identified with a PubMed search of articles indexed for MEDLINE using the search terms herpes zoster infection after vaccination and herpes zoster infection AND immunocompetent AND vaccination in separate searches for all English-language studies (Table). The search was limited to immunocompetent children and adolescents who were 18 years or younger with no history of varicella or exposure to varicella during gestation.

The mean age for HZ infection was 5.3 years. The average time between vaccination and HZ infection was 3.3 years. There was a spread of dermatomal patterns with cases in the first division of the trigeminal nerve, cervical, thoracic, lumbar, and sacral distributions. Of the 22 cases of HZ we reviewed, 16 underwent genotype testing to determine the source of the infection. The Oka vaccine strain virus was identified in 8 (50%) cases, while wild-type virus was found in 8 (50%) cases.^{1,2,4,5,7,8,10,11,13,14,16} Twelve cases were treated with acyclovir.^{2,3,5,6,9-12,14-17} The method of delivery, either oral or intravenous, and the length of treatment depended on the severity of the disease. Patients with meningoencephalitis and HZ ophthalmicus received intravenous acyclovir more often and also had a longer course of acyclovir compared to those individuals with involvement limited to the skin.

This review found HZ occurs from reactivation of wild-type or Oka vaccine-strain VZV in immunocompetent children.^1-17 It shows that subclinical varicella infection is not the only explanation for HZ in a healthy vaccinated child. It is currently not clear why some healthy children experience HZ from vaccine-strain VZV. When HZ presents in a vaccinated immunocompetent child without a history of varicella infection or exposure, the possibility for vaccine strain–induced HZ should be considered.

Varicella-zoster virus (VZV) causes varicella as a primary infection. It is a highly contagious disease characterized by a widespread papulovesicular eruption with fever and malaise.^1,2 After the primary infection, the virus remains latent within the sensory dorsal root ganglia and can reactivate as herpes zoster (HZ).^1-5 Herpes zoster is characterized by unilateral radicular pain and a vesicular rash in a dermatomal pattern.^1,2 It is most common in adults, especially elderly and immunocompromised patients, but rarely occurs in children. Herpes zoster is most often seen in individuals previously infected with VZV, but it also has occurred in individuals without known varicella infection,^1-17 possibly because these individuals had a prior subclinical VZV infection.

A live attenuated VZV vaccine was created after isolation of the virus from a child in Japan.² Since the introduction of the vaccine in 1995 in the United States, the incidence of VZV and HZ has declined.⁵ Herpes zoster rates after vaccination vary from 14 to 19 per 100,000 individuals.^3,5 Breakthrough disease with the wild-type strain does occur in vaccinated children, but vaccine-strain HZ also has been reported.^1-5 The risk for HZ caused by reactivated VZV vaccine in healthy children is unknown. We present a case of HZ in an otherwise healthy 19-month-old boy with no known varicella exposure who received the VZV vaccine at 13 months of age.

Case Report

An otherwise healthy 19-month-old boy presented to the dermatology clinic with a rash that began 2 days prior on the right groin and spread to the right leg. The patient’s mother denied that the child had been febrile and noted that the rash did not appear to bother him in any way. The patient was up-to-date on his vaccinations and received the first dose of the varicella series 6 months prior to presentation. He had no personal history of varicella, no exposure to sick contacts with varicella, and no known exposure to the virus. He was otherwise completely healthy with no signs or symptoms of immunocompromise.

Physical examination revealed grouped vesicles on an erythematous base on the right thigh, right sacrum, and lower abdomen that did not cross the midline (Figure). There were no other pertinent physical examination findings. The eruption was most consistent with HZ but concern remained for herpes simplex virus (HSV) or impetigo. A bacterial culture and polymerase chain reaction assay for VZV and HSV from skin swabs was ordered. The patient was prescribed acyclovir 20 mg/kg every 6 hours for 5 days. Laboratory testing revealed a positive result for VZV on polymerase chain reaction and a negative result for HSV. The majority of the patient’s lesions had crusted after 2 days of treatment with acyclovir, and the rash had nearly resolved 1 week after presentation. Subsequent evaluation with a complete blood cell count with differential and basic metabolic profile was normal. Levels of IgG, IgA, and IgM also were normal; IgE was slightly elevated.

Comment

Herpes zoster in children is an uncommon clinical entity. Most children with HZ are immunocompromised, have a history of varicella, or were exposed to varicella during gestation.⁸ With the introduction of the live VZV vaccine, the incidence of HZ has declined, but reactivation of the live vaccine leading to HZ infection is possible. The vaccine is 90% effective, and breakthrough varicella has been reported in 15% to 20% of vaccinated patients.^1-17 The cause of HZ in vaccinated children is unclear due to the potential for either wild-type or vaccine-strain VZV to induce HZ.

Twenty-two cases of HZ in healthy children after vaccination were identified with a PubMed search of articles indexed for MEDLINE using the search terms herpes zoster infection after vaccination and herpes zoster infection AND immunocompetent AND vaccination in separate searches for all English-language studies (Table). The search was limited to immunocompetent children and adolescents who were 18 years or younger with no history of varicella or exposure to varicella during gestation.

The mean age for HZ infection was 5.3 years. The average time between vaccination and HZ infection was 3.3 years. There was a spread of dermatomal patterns with cases in the first division of the trigeminal nerve, cervical, thoracic, lumbar, and sacral distributions. Of the 22 cases of HZ we reviewed, 16 underwent genotype testing to determine the source of the infection. The Oka vaccine strain virus was identified in 8 (50%) cases, while wild-type virus was found in 8 (50%) cases.^{1,2,4,5,7,8,10,11,13,14,16} Twelve cases were treated with acyclovir.^{2,3,5,6,9-12,14-17} The method of delivery, either oral or intravenous, and the length of treatment depended on the severity of the disease. Patients with meningoencephalitis and HZ ophthalmicus received intravenous acyclovir more often and also had a longer course of acyclovir compared to those individuals with involvement limited to the skin.

This review found HZ occurs from reactivation of wild-type or Oka vaccine-strain VZV in immunocompetent children.^1-17 It shows that subclinical varicella infection is not the only explanation for HZ in a healthy vaccinated child. It is currently not clear why some healthy children experience HZ from vaccine-strain VZV. When HZ presents in a vaccinated immunocompetent child without a history of varicella infection or exposure, the possibility for vaccine strain–induced HZ should be considered.

Varicella-zoster virus (VZV) causes varicella as a primary infection. It is a highly contagious disease characterized by a widespread papulovesicular eruption with fever and malaise.^1,2 After the primary infection, the virus remains latent within the sensory dorsal root ganglia and can reactivate as herpes zoster (HZ).^1-5 Herpes zoster is characterized by unilateral radicular pain and a vesicular rash in a dermatomal pattern.^1,2 It is most common in adults, especially elderly and immunocompromised patients, but rarely occurs in children. Herpes zoster is most often seen in individuals previously infected with VZV, but it also has occurred in individuals without known varicella infection,^1-17 possibly because these individuals had a prior subclinical VZV infection.

A live attenuated VZV vaccine was created after isolation of the virus from a child in Japan.² Since the introduction of the vaccine in 1995 in the United States, the incidence of VZV and HZ has declined.⁵ Herpes zoster rates after vaccination vary from 14 to 19 per 100,000 individuals.^3,5 Breakthrough disease with the wild-type strain does occur in vaccinated children, but vaccine-strain HZ also has been reported.^1-5 The risk for HZ caused by reactivated VZV vaccine in healthy children is unknown. We present a case of HZ in an otherwise healthy 19-month-old boy with no known varicella exposure who received the VZV vaccine at 13 months of age.

Case Report

An otherwise healthy 19-month-old boy presented to the dermatology clinic with a rash that began 2 days prior on the right groin and spread to the right leg. The patient’s mother denied that the child had been febrile and noted that the rash did not appear to bother him in any way. The patient was up-to-date on his vaccinations and received the first dose of the varicella series 6 months prior to presentation. He had no personal history of varicella, no exposure to sick contacts with varicella, and no known exposure to the virus. He was otherwise completely healthy with no signs or symptoms of immunocompromise.

Physical examination revealed grouped vesicles on an erythematous base on the right thigh, right sacrum, and lower abdomen that did not cross the midline (Figure). There were no other pertinent physical examination findings. The eruption was most consistent with HZ but concern remained for herpes simplex virus (HSV) or impetigo. A bacterial culture and polymerase chain reaction assay for VZV and HSV from skin swabs was ordered. The patient was prescribed acyclovir 20 mg/kg every 6 hours for 5 days. Laboratory testing revealed a positive result for VZV on polymerase chain reaction and a negative result for HSV. The majority of the patient’s lesions had crusted after 2 days of treatment with acyclovir, and the rash had nearly resolved 1 week after presentation. Subsequent evaluation with a complete blood cell count with differential and basic metabolic profile was normal. Levels of IgG, IgA, and IgM also were normal; IgE was slightly elevated.

Comment

Herpes zoster in children is an uncommon clinical entity. Most children with HZ are immunocompromised, have a history of varicella, or were exposed to varicella during gestation.⁸ With the introduction of the live VZV vaccine, the incidence of HZ has declined, but reactivation of the live vaccine leading to HZ infection is possible. The vaccine is 90% effective, and breakthrough varicella has been reported in 15% to 20% of vaccinated patients.^1-17 The cause of HZ in vaccinated children is unclear due to the potential for either wild-type or vaccine-strain VZV to induce HZ.

Twenty-two cases of HZ in healthy children after vaccination were identified with a PubMed search of articles indexed for MEDLINE using the search terms herpes zoster infection after vaccination and herpes zoster infection AND immunocompetent AND vaccination in separate searches for all English-language studies (Table). The search was limited to immunocompetent children and adolescents who were 18 years or younger with no history of varicella or exposure to varicella during gestation.

The mean age for HZ infection was 5.3 years. The average time between vaccination and HZ infection was 3.3 years. There was a spread of dermatomal patterns with cases in the first division of the trigeminal nerve, cervical, thoracic, lumbar, and sacral distributions. Of the 22 cases of HZ we reviewed, 16 underwent genotype testing to determine the source of the infection. The Oka vaccine strain virus was identified in 8 (50%) cases, while wild-type virus was found in 8 (50%) cases.^{1,2,4,5,7,8,10,11,13,14,16} Twelve cases were treated with acyclovir.^{2,3,5,6,9-12,14-17} The method of delivery, either oral or intravenous, and the length of treatment depended on the severity of the disease. Patients with meningoencephalitis and HZ ophthalmicus received intravenous acyclovir more often and also had a longer course of acyclovir compared to those individuals with involvement limited to the skin.

This review found HZ occurs from reactivation of wild-type or Oka vaccine-strain VZV in immunocompetent children.^1-17 It shows that subclinical varicella infection is not the only explanation for HZ in a healthy vaccinated child. It is currently not clear why some healthy children experience HZ from vaccine-strain VZV. When HZ presents in a vaccinated immunocompetent child without a history of varicella infection or exposure, the possibility for vaccine strain–induced HZ should be considered.

Topical management of acne vulgaris (AV) incorporates a variety of agents with diverse modes of action (MOAs), including retinoids and antibiotics.^1-3 The first topical retinoid developed for acne therapy was tretinoin, available in the United States since 1971.^2,4 Topical retinoids, including tretinoin, exhibit multiple pharmacologic effects that are believed to correlate with efficacy for acne treatment,^1,2,4,5 such as the reduction of inflammatory and comedonal lesions and contribution to dermal matrix remodeling.^1,2,4-9 The predominant topical antibiotic used for acne treatment, often in combination with benzoyl peroxide (BP) and/or a topical retinoid, is clindamycin. Clindamycin is a lincosamide antibiotic that is closely related to erythromycin, a member of the macrolide antibiotic category.^1,3,10 Available data support that over time topical clindamycin has sustained greater efficacy in reducing AV lesions than topical erythromycin; the latter also has been shown to exhibit a greater prevalence of Propionibacterium acnes resistance than clindamycin.^1,3,10-12

Combination gel formulations of clindamycin phosphate 1.2%–tretinoin 0.025% (CP-Tret) are approved by the US Food and Drug Administration and available in the United States for once-daily treatment of AV in patients 12 years of age and older.^13-15 Large-scale randomized controlled trials (RCTs) have demonstrated both efficacy and safety for these formulations.^16,17 This article reviews important considerations related to both individual active ingredients (clindamycin phosphate [CP] and tretinoin [Tret]), formulation characteristics, and data from pivotal RCTs with a CP-Tret gel that has more recently been reintroduced into the US marketplace for acne therapy (Veltin, Aqua Pharmaceuticals).

What is the rationale behind combining CP and Tret in a single combination formulation?

Clindamycin is a lincosamide antibiotic that has been used for the treatment of AV for approximately 5 decades.^1,3,10,17 The main MOA of clindamycin in the treatment of AV is believed to be reduction of P acnes; however, anti-inflammatory effects maypotentially play some role in AV lesion reduction.^{3,10,12,17-19} Multiple RCTs completed over approximately 3 decades and inclusive of more than 2000 participants treated topically with clindamycin as monotherapy have shown that the efficacy of this agent in reducing AV lesions has remained consistent overall,^3,20-24 unlike topical erythromycin, which did not sustain its efficacy over a similar comparative time period.²⁰ Importantly, these data are based on RCTs designed to evaluate the efficacy and safety of individual agents, including topical clindamycin; however, topical antibiotic therapy is not recommended as monotherapy for AV treatment due to emergence of antibiotic-resistant bacterial strains.^{1,3,11,12,25-28} Although the prevalence of resistant strains of P acnes is lower in the United States and many other countries for clindamycin versus erythromycin, the magnitude of clindamycin-resistant P acnes strains increases and response to clindamycin therapy may decrease when this agent is used alone.^{12,25-27,29,30} Therefore, it is recommended that a BP formulation that exhibits the ability to adequately reduce P acnes counts be used concurrently with antibiotic therapy for AV to reduce the emergence and proliferation of antibiotic-resistant P acnes organisms; short-contact BP therapy using a high-concentration (9.8%) emollient foam formulation and sufficient contact time (ie, 2 minutes) prior to washing off also has been shown to markedly reduce truncal P acnes organism counts.^{1,3,10-12,25-33} The Table depicts the major characteristics of clindamycin related to its use for treatment of AV.

Tretinoin has been used extensively for the treatment of AV since its introduction in the United States in 1971.^1,2,4,5 The proposed MOAs of topical retinoids, including tretinoin, based on available data include a variety of pharmacologic effects such as inhibition of follicular hyperkeratosis (decreased microcomedone formation), modulation of keratinocyte differentiation, anti-inflammatory properties, and inhibition of dermal matrix degradation (Figure).^{1,2,4,5,14,34,35} Topical retinoids, including tretinoin, have been shown to reduce both inflammatory and comedonal acne lesions, likely due to multiple MOAs, and are devoid of antibiotic properties.^2,4-8,16 Available data support that topical combination therapy for AV with a retinoid and a topical antimicrobial agent augments the therapeutic benefit as compared to use of either agent alone.^{1-4,12,15,16,28,31,32}

The rationale for incorporating both clindamycin and tretinoin together into one topical formulation includes combining different MOAs that appear to correlate with suppression of AV lesion formation and to improve patient adherence through once-daily application of a single topical product.^16,31,32,36 Importantly, formulation researchers were able to combine CP-Tret into a specific aqueous gel formulation that maintained the stability of both active ingredients and proved to be effective and safe in preliminary studies completed in participants with AV.^16,23,37-39 This aqueous formulation incorporated a limited number of excipients with low to negligible potential for cutaneous irritation or allergenicity, including anhydrous citric acid (chelating agent, preservative, emulsifier, acidulent), butylated hydroxytoluene (antioxidant), carbomer homopolymer type C (thickening agent, dispersing agent, biocompatible gel matrix), edetate disodium (chelating agent), laureth 4 (emulsifier, dissolution agent), methylparaben (preservative), propylene glycol (low-concentration humectant), purified water (diluent), and tromethamine (buffer, permeability enhancer).¹⁴

What are the clinical data evaluating the efficacy and tolerability/safety of the specific aqueous-based gel formulation of CP-Tret?

An aqueous-based gel formulation (referred to in the literature as a hydrogel) of CP-Tret is devoid of alcohol and contains the excipients described above.¹⁴ This formulation was shown to be efficacious, well tolerated, and safe in smaller clinical studies of participants with AV.^23,37-39 Two large-scale phase 3 studies were completed (N=2219), powered to compare the efficacy and tolerability/safety of CP-Tret hydrogel (n=634) versus CP hydrogel (n=635), Tret hydrogel (n=635), and vehicle hydrogel (n=315) in participants with facial AV. All 4 study drug formulations in both studies—CP-Tret, CP, Tret, vehicle—used the same hydrogel vehicle, hereafter referred to simply as gel.¹⁶

In both trials, participants 12 years of age and older with AV were randomized to active drug groups versus vehicle (2:2:2:1 randomization), each applied once daily at bedtime for 12 weeks.¹⁶ The baseline demographics among all 4 study groups were well matched, with approximately two-thirds of white participants and one-third Asian (2%–3%), black (19%–21%), or Hispanic (9%–10%). Approximately half of enrolled participants were 16 years of age or younger (mean age [range], 19.0–20.2 years). Enrolled participants in each study group presented at baseline predominantly with facial AV of mild (grade 2 [20%–23% of enrolled participants]) or moderate (grade 3 [60%–62% of enrolled participants]) severity based on a protocol-mandated, 6-point investigator static global assessment scale. Investigator static global assessment scores and acne lesion counts, including noninflammatory (comedonal), inflammatory (papules, pustules), and total AV lesions, were evaluated at baseline and weeks 2, 4, 8, and 12 (end of study [EOS]). Among the 4 study groups at baseline, the range of mean lesion counts was 27.7 to 29.3 for noninflammatory lesions, 26.0 to 26.4 for inflammatory lesions, and 76.4 to 78.3 for total lesions. All enrolled participants met protocol-mandated, standardized, inclusion, exclusion, and prestudy washout period criteria.¹⁶

The primary efficacy end points determined based on intention-to-treat analysis were the percentage reduction in all 3 lesion counts at EOS compared to baseline and the proportion of participants who achieved scores of clear (grade 0) or almost clear (grade 1) at EOS. The secondary end point parameter was time to 50% reduction in total lesion counts.¹⁶

The study efficacy outcomes were as follows: The mean percentage reduction in inflammatory lesions at EOS versus baseline was significantly higher in the CP-Tret group than in each of the other 3 groups (CP-Tret, 53.4%; CP, 47.5%; Tret, 43.3%; vehicle, 30.3%)(P<.005).¹⁶ The mean percentage reduction in noninflammatory lesions at EOS versus baseline was significantly higher in the CP-Tret group than in each of the other 3 groups (CP-Tret, 45.2%; CP, 31.6%; Tret, 37.9%; vehicle, 18.5%)(P≤.0004). The mean percentage reduction in total AV lesions at EOS versus baseline was significantly higher in the CP-Tret group than in each of the other 3 groups (CP-Tret, 48.7%; CP, 38.3%; Tret, 40.3%; vehicle, 23.2%)(P≤.0001). The median time to 50% reduction in total AV lesion counts was significantly faster with CP-Tret (8 weeks) compared to the other 3 groups (CP, 12 weeks [P<.0001]; Tret, 12 weeks [P<.001]; vehicle, not reached by EOS [P<.0001]). The consistency of results, methodologies, and overall study characteristics between the 2 phase 3 RCTs allowed for accurate pooling of data.¹⁶

Tolerability and safety assessments were completed at each visit for all enrolled participants. No adverse events (AEs) were noted in approximately 90% of enrolled participants.¹⁶ The most common AEs noted over the course of the study were mild to moderate application-site reactions (eg, dryness, erythema, burning, pruritus, desquamation), mostly correlated with the 2 groups containing tretinoin—CP-Tret and Tret—which is not unanticipated with topical retinoid use; 1.2% of these participants withdrew from the study due to such application-site AEs. No serious AEs or systemic safety signals emerged during the study.¹⁶

What summarizing statements can be made about CP-Tret gel from these study results that may be helpful to clinicians treating patients with AV?

The gel formulation of CP-Tret incorporates active ingredients that target different pathophysiologic cascades in AV, providing antimicrobial, anti-inflammatory, and anticomedonal effects.

Applied once daily, CP-Tret gel demonstrated the ability to achieve complete or near-complete clearance of comedonal and papulopustular facial AV lesions of mild to moderate severity in approximately 40% of participants within 12 weeks of use in 2 large-scale RCTs.¹⁶ The ability to achieve a median 50% reduction in total lesions by 8 weeks of use provides relevant information for patients regarding reasonable expectations with therapy.

The favorable cutaneous tolerability profile and low number of AEs demonstrated with CP-Tret gel are major considerations, especially as skin tolerability reactions can impede patient adherence with treatment. Any issues that interfere with achieving a favorable therapeutic outcome can lead to patients giving up with their therapy.

The large number of patients with skin of color treated with CP-Tret gel (n=209) in the 2 phase 3 RCTs is important, as the spectrum of racial origins, skin types, and skin colors seen in dermatology practices is diversifying across the United States. Both clinicians and patients with skin of color are often concerned about the sequelae of medication-induced skin irritation, which can lead to ensuing dyschromia.

Concerns related to potential development of clindamycin-resistant P acnes with CP-Tret gel may be addressed by concurrent use of BP, including with leave-on or short-contact therapy.

Although phase 3 RCTs evaluate therapeutic agents as monotherapy, in real world clinical practice, combination topical regimens using different individual products are common to optimize therapeutic outcomes. Advantages of the CP-Tret gel formulation, if a clinician desires to use it along with another topical product, are once-daily use and the low risk for cutaneous irritation.

Topical management of acne vulgaris (AV) incorporates a variety of agents with diverse modes of action (MOAs), including retinoids and antibiotics.^1-3 The first topical retinoid developed for acne therapy was tretinoin, available in the United States since 1971.^2,4 Topical retinoids, including tretinoin, exhibit multiple pharmacologic effects that are believed to correlate with efficacy for acne treatment,^1,2,4,5 such as the reduction of inflammatory and comedonal lesions and contribution to dermal matrix remodeling.^1,2,4-9 The predominant topical antibiotic used for acne treatment, often in combination with benzoyl peroxide (BP) and/or a topical retinoid, is clindamycin. Clindamycin is a lincosamide antibiotic that is closely related to erythromycin, a member of the macrolide antibiotic category.^1,3,10 Available data support that over time topical clindamycin has sustained greater efficacy in reducing AV lesions than topical erythromycin; the latter also has been shown to exhibit a greater prevalence of Propionibacterium acnes resistance than clindamycin.^1,3,10-12

Combination gel formulations of clindamycin phosphate 1.2%–tretinoin 0.025% (CP-Tret) are approved by the US Food and Drug Administration and available in the United States for once-daily treatment of AV in patients 12 years of age and older.^13-15 Large-scale randomized controlled trials (RCTs) have demonstrated both efficacy and safety for these formulations.^16,17 This article reviews important considerations related to both individual active ingredients (clindamycin phosphate [CP] and tretinoin [Tret]), formulation characteristics, and data from pivotal RCTs with a CP-Tret gel that has more recently been reintroduced into the US marketplace for acne therapy (Veltin, Aqua Pharmaceuticals).

What is the rationale behind combining CP and Tret in a single combination formulation?

Clindamycin is a lincosamide antibiotic that has been used for the treatment of AV for approximately 5 decades.^1,3,10,17 The main MOA of clindamycin in the treatment of AV is believed to be reduction of P acnes; however, anti-inflammatory effects maypotentially play some role in AV lesion reduction.^{3,10,12,17-19} Multiple RCTs completed over approximately 3 decades and inclusive of more than 2000 participants treated topically with clindamycin as monotherapy have shown that the efficacy of this agent in reducing AV lesions has remained consistent overall,^3,20-24 unlike topical erythromycin, which did not sustain its efficacy over a similar comparative time period.²⁰ Importantly, these data are based on RCTs designed to evaluate the efficacy and safety of individual agents, including topical clindamycin; however, topical antibiotic therapy is not recommended as monotherapy for AV treatment due to emergence of antibiotic-resistant bacterial strains.^{1,3,11,12,25-28} Although the prevalence of resistant strains of P acnes is lower in the United States and many other countries for clindamycin versus erythromycin, the magnitude of clindamycin-resistant P acnes strains increases and response to clindamycin therapy may decrease when this agent is used alone.^{12,25-27,29,30} Therefore, it is recommended that a BP formulation that exhibits the ability to adequately reduce P acnes counts be used concurrently with antibiotic therapy for AV to reduce the emergence and proliferation of antibiotic-resistant P acnes organisms; short-contact BP therapy using a high-concentration (9.8%) emollient foam formulation and sufficient contact time (ie, 2 minutes) prior to washing off also has been shown to markedly reduce truncal P acnes organism counts.^{1,3,10-12,25-33} The Table depicts the major characteristics of clindamycin related to its use for treatment of AV.

Tretinoin has been used extensively for the treatment of AV since its introduction in the United States in 1971.^1,2,4,5 The proposed MOAs of topical retinoids, including tretinoin, based on available data include a variety of pharmacologic effects such as inhibition of follicular hyperkeratosis (decreased microcomedone formation), modulation of keratinocyte differentiation, anti-inflammatory properties, and inhibition of dermal matrix degradation (Figure).^{1,2,4,5,14,34,35} Topical retinoids, including tretinoin, have been shown to reduce both inflammatory and comedonal acne lesions, likely due to multiple MOAs, and are devoid of antibiotic properties.^2,4-8,16 Available data support that topical combination therapy for AV with a retinoid and a topical antimicrobial agent augments the therapeutic benefit as compared to use of either agent alone.^{1-4,12,15,16,28,31,32}

The rationale for incorporating both clindamycin and tretinoin together into one topical formulation includes combining different MOAs that appear to correlate with suppression of AV lesion formation and to improve patient adherence through once-daily application of a single topical product.^16,31,32,36 Importantly, formulation researchers were able to combine CP-Tret into a specific aqueous gel formulation that maintained the stability of both active ingredients and proved to be effective and safe in preliminary studies completed in participants with AV.^16,23,37-39 This aqueous formulation incorporated a limited number of excipients with low to negligible potential for cutaneous irritation or allergenicity, including anhydrous citric acid (chelating agent, preservative, emulsifier, acidulent), butylated hydroxytoluene (antioxidant), carbomer homopolymer type C (thickening agent, dispersing agent, biocompatible gel matrix), edetate disodium (chelating agent), laureth 4 (emulsifier, dissolution agent), methylparaben (preservative), propylene glycol (low-concentration humectant), purified water (diluent), and tromethamine (buffer, permeability enhancer).¹⁴

What are the clinical data evaluating the efficacy and tolerability/safety of the specific aqueous-based gel formulation of CP-Tret?

An aqueous-based gel formulation (referred to in the literature as a hydrogel) of CP-Tret is devoid of alcohol and contains the excipients described above.¹⁴ This formulation was shown to be efficacious, well tolerated, and safe in smaller clinical studies of participants with AV.^23,37-39 Two large-scale phase 3 studies were completed (N=2219), powered to compare the efficacy and tolerability/safety of CP-Tret hydrogel (n=634) versus CP hydrogel (n=635), Tret hydrogel (n=635), and vehicle hydrogel (n=315) in participants with facial AV. All 4 study drug formulations in both studies—CP-Tret, CP, Tret, vehicle—used the same hydrogel vehicle, hereafter referred to simply as gel.¹⁶

In both trials, participants 12 years of age and older with AV were randomized to active drug groups versus vehicle (2:2:2:1 randomization), each applied once daily at bedtime for 12 weeks.¹⁶ The baseline demographics among all 4 study groups were well matched, with approximately two-thirds of white participants and one-third Asian (2%–3%), black (19%–21%), or Hispanic (9%–10%). Approximately half of enrolled participants were 16 years of age or younger (mean age [range], 19.0–20.2 years). Enrolled participants in each study group presented at baseline predominantly with facial AV of mild (grade 2 [20%–23% of enrolled participants]) or moderate (grade 3 [60%–62% of enrolled participants]) severity based on a protocol-mandated, 6-point investigator static global assessment scale. Investigator static global assessment scores and acne lesion counts, including noninflammatory (comedonal), inflammatory (papules, pustules), and total AV lesions, were evaluated at baseline and weeks 2, 4, 8, and 12 (end of study [EOS]). Among the 4 study groups at baseline, the range of mean lesion counts was 27.7 to 29.3 for noninflammatory lesions, 26.0 to 26.4 for inflammatory lesions, and 76.4 to 78.3 for total lesions. All enrolled participants met protocol-mandated, standardized, inclusion, exclusion, and prestudy washout period criteria.¹⁶

The primary efficacy end points determined based on intention-to-treat analysis were the percentage reduction in all 3 lesion counts at EOS compared to baseline and the proportion of participants who achieved scores of clear (grade 0) or almost clear (grade 1) at EOS. The secondary end point parameter was time to 50% reduction in total lesion counts.¹⁶

The study efficacy outcomes were as follows: The mean percentage reduction in inflammatory lesions at EOS versus baseline was significantly higher in the CP-Tret group than in each of the other 3 groups (CP-Tret, 53.4%; CP, 47.5%; Tret, 43.3%; vehicle, 30.3%)(P<.005).¹⁶ The mean percentage reduction in noninflammatory lesions at EOS versus baseline was significantly higher in the CP-Tret group than in each of the other 3 groups (CP-Tret, 45.2%; CP, 31.6%; Tret, 37.9%; vehicle, 18.5%)(P≤.0004). The mean percentage reduction in total AV lesions at EOS versus baseline was significantly higher in the CP-Tret group than in each of the other 3 groups (CP-Tret, 48.7%; CP, 38.3%; Tret, 40.3%; vehicle, 23.2%)(P≤.0001). The median time to 50% reduction in total AV lesion counts was significantly faster with CP-Tret (8 weeks) compared to the other 3 groups (CP, 12 weeks [P<.0001]; Tret, 12 weeks [P<.001]; vehicle, not reached by EOS [P<.0001]). The consistency of results, methodologies, and overall study characteristics between the 2 phase 3 RCTs allowed for accurate pooling of data.¹⁶

Tolerability and safety assessments were completed at each visit for all enrolled participants. No adverse events (AEs) were noted in approximately 90% of enrolled participants.¹⁶ The most common AEs noted over the course of the study were mild to moderate application-site reactions (eg, dryness, erythema, burning, pruritus, desquamation), mostly correlated with the 2 groups containing tretinoin—CP-Tret and Tret—which is not unanticipated with topical retinoid use; 1.2% of these participants withdrew from the study due to such application-site AEs. No serious AEs or systemic safety signals emerged during the study.¹⁶

What summarizing statements can be made about CP-Tret gel from these study results that may be helpful to clinicians treating patients with AV?

The gel formulation of CP-Tret incorporates active ingredients that target different pathophysiologic cascades in AV, providing antimicrobial, anti-inflammatory, and anticomedonal effects.

Applied once daily, CP-Tret gel demonstrated the ability to achieve complete or near-complete clearance of comedonal and papulopustular facial AV lesions of mild to moderate severity in approximately 40% of participants within 12 weeks of use in 2 large-scale RCTs.¹⁶ The ability to achieve a median 50% reduction in total lesions by 8 weeks of use provides relevant information for patients regarding reasonable expectations with therapy.

The favorable cutaneous tolerability profile and low number of AEs demonstrated with CP-Tret gel are major considerations, especially as skin tolerability reactions can impede patient adherence with treatment. Any issues that interfere with achieving a favorable therapeutic outcome can lead to patients giving up with their therapy.

The large number of patients with skin of color treated with CP-Tret gel (n=209) in the 2 phase 3 RCTs is important, as the spectrum of racial origins, skin types, and skin colors seen in dermatology practices is diversifying across the United States. Both clinicians and patients with skin of color are often concerned about the sequelae of medication-induced skin irritation, which can lead to ensuing dyschromia.

Concerns related to potential development of clindamycin-resistant P acnes with CP-Tret gel may be addressed by concurrent use of BP, including with leave-on or short-contact therapy.

Although phase 3 RCTs evaluate therapeutic agents as monotherapy, in real world clinical practice, combination topical regimens using different individual products are common to optimize therapeutic outcomes. Advantages of the CP-Tret gel formulation, if a clinician desires to use it along with another topical product, are once-daily use and the low risk for cutaneous irritation.

Topical management of acne vulgaris (AV) incorporates a variety of agents with diverse modes of action (MOAs), including retinoids and antibiotics.^1-3 The first topical retinoid developed for acne therapy was tretinoin, available in the United States since 1971.^2,4 Topical retinoids, including tretinoin, exhibit multiple pharmacologic effects that are believed to correlate with efficacy for acne treatment,^1,2,4,5 such as the reduction of inflammatory and comedonal lesions and contribution to dermal matrix remodeling.^1,2,4-9 The predominant topical antibiotic used for acne treatment, often in combination with benzoyl peroxide (BP) and/or a topical retinoid, is clindamycin. Clindamycin is a lincosamide antibiotic that is closely related to erythromycin, a member of the macrolide antibiotic category.^1,3,10 Available data support that over time topical clindamycin has sustained greater efficacy in reducing AV lesions than topical erythromycin; the latter also has been shown to exhibit a greater prevalence of Propionibacterium acnes resistance than clindamycin.^1,3,10-12

Combination gel formulations of clindamycin phosphate 1.2%–tretinoin 0.025% (CP-Tret) are approved by the US Food and Drug Administration and available in the United States for once-daily treatment of AV in patients 12 years of age and older.^13-15 Large-scale randomized controlled trials (RCTs) have demonstrated both efficacy and safety for these formulations.^16,17 This article reviews important considerations related to both individual active ingredients (clindamycin phosphate [CP] and tretinoin [Tret]), formulation characteristics, and data from pivotal RCTs with a CP-Tret gel that has more recently been reintroduced into the US marketplace for acne therapy (Veltin, Aqua Pharmaceuticals).

What is the rationale behind combining CP and Tret in a single combination formulation?

Clindamycin is a lincosamide antibiotic that has been used for the treatment of AV for approximately 5 decades.^1,3,10,17 The main MOA of clindamycin in the treatment of AV is believed to be reduction of P acnes; however, anti-inflammatory effects maypotentially play some role in AV lesion reduction.^{3,10,12,17-19} Multiple RCTs completed over approximately 3 decades and inclusive of more than 2000 participants treated topically with clindamycin as monotherapy have shown that the efficacy of this agent in reducing AV lesions has remained consistent overall,^3,20-24 unlike topical erythromycin, which did not sustain its efficacy over a similar comparative time period.²⁰ Importantly, these data are based on RCTs designed to evaluate the efficacy and safety of individual agents, including topical clindamycin; however, topical antibiotic therapy is not recommended as monotherapy for AV treatment due to emergence of antibiotic-resistant bacterial strains.^{1,3,11,12,25-28} Although the prevalence of resistant strains of P acnes is lower in the United States and many other countries for clindamycin versus erythromycin, the magnitude of clindamycin-resistant P acnes strains increases and response to clindamycin therapy may decrease when this agent is used alone.^{12,25-27,29,30} Therefore, it is recommended that a BP formulation that exhibits the ability to adequately reduce P acnes counts be used concurrently with antibiotic therapy for AV to reduce the emergence and proliferation of antibiotic-resistant P acnes organisms; short-contact BP therapy using a high-concentration (9.8%) emollient foam formulation and sufficient contact time (ie, 2 minutes) prior to washing off also has been shown to markedly reduce truncal P acnes organism counts.^{1,3,10-12,25-33} The Table depicts the major characteristics of clindamycin related to its use for treatment of AV.

Tretinoin has been used extensively for the treatment of AV since its introduction in the United States in 1971.^1,2,4,5 The proposed MOAs of topical retinoids, including tretinoin, based on available data include a variety of pharmacologic effects such as inhibition of follicular hyperkeratosis (decreased microcomedone formation), modulation of keratinocyte differentiation, anti-inflammatory properties, and inhibition of dermal matrix degradation (Figure).^{1,2,4,5,14,34,35} Topical retinoids, including tretinoin, have been shown to reduce both inflammatory and comedonal acne lesions, likely due to multiple MOAs, and are devoid of antibiotic properties.^2,4-8,16 Available data support that topical combination therapy for AV with a retinoid and a topical antimicrobial agent augments the therapeutic benefit as compared to use of either agent alone.^{1-4,12,15,16,28,31,32}

The rationale for incorporating both clindamycin and tretinoin together into one topical formulation includes combining different MOAs that appear to correlate with suppression of AV lesion formation and to improve patient adherence through once-daily application of a single topical product.^16,31,32,36 Importantly, formulation researchers were able to combine CP-Tret into a specific aqueous gel formulation that maintained the stability of both active ingredients and proved to be effective and safe in preliminary studies completed in participants with AV.^16,23,37-39 This aqueous formulation incorporated a limited number of excipients with low to negligible potential for cutaneous irritation or allergenicity, including anhydrous citric acid (chelating agent, preservative, emulsifier, acidulent), butylated hydroxytoluene (antioxidant), carbomer homopolymer type C (thickening agent, dispersing agent, biocompatible gel matrix), edetate disodium (chelating agent), laureth 4 (emulsifier, dissolution agent), methylparaben (preservative), propylene glycol (low-concentration humectant), purified water (diluent), and tromethamine (buffer, permeability enhancer).¹⁴

What are the clinical data evaluating the efficacy and tolerability/safety of the specific aqueous-based gel formulation of CP-Tret?

An aqueous-based gel formulation (referred to in the literature as a hydrogel) of CP-Tret is devoid of alcohol and contains the excipients described above.¹⁴ This formulation was shown to be efficacious, well tolerated, and safe in smaller clinical studies of participants with AV.^23,37-39 Two large-scale phase 3 studies were completed (N=2219), powered to compare the efficacy and tolerability/safety of CP-Tret hydrogel (n=634) versus CP hydrogel (n=635), Tret hydrogel (n=635), and vehicle hydrogel (n=315) in participants with facial AV. All 4 study drug formulations in both studies—CP-Tret, CP, Tret, vehicle—used the same hydrogel vehicle, hereafter referred to simply as gel.¹⁶

In both trials, participants 12 years of age and older with AV were randomized to active drug groups versus vehicle (2:2:2:1 randomization), each applied once daily at bedtime for 12 weeks.¹⁶ The baseline demographics among all 4 study groups were well matched, with approximately two-thirds of white participants and one-third Asian (2%–3%), black (19%–21%), or Hispanic (9%–10%). Approximately half of enrolled participants were 16 years of age or younger (mean age [range], 19.0–20.2 years). Enrolled participants in each study group presented at baseline predominantly with facial AV of mild (grade 2 [20%–23% of enrolled participants]) or moderate (grade 3 [60%–62% of enrolled participants]) severity based on a protocol-mandated, 6-point investigator static global assessment scale. Investigator static global assessment scores and acne lesion counts, including noninflammatory (comedonal), inflammatory (papules, pustules), and total AV lesions, were evaluated at baseline and weeks 2, 4, 8, and 12 (end of study [EOS]). Among the 4 study groups at baseline, the range of mean lesion counts was 27.7 to 29.3 for noninflammatory lesions, 26.0 to 26.4 for inflammatory lesions, and 76.4 to 78.3 for total lesions. All enrolled participants met protocol-mandated, standardized, inclusion, exclusion, and prestudy washout period criteria.¹⁶

The primary efficacy end points determined based on intention-to-treat analysis were the percentage reduction in all 3 lesion counts at EOS compared to baseline and the proportion of participants who achieved scores of clear (grade 0) or almost clear (grade 1) at EOS. The secondary end point parameter was time to 50% reduction in total lesion counts.¹⁶

The study efficacy outcomes were as follows: The mean percentage reduction in inflammatory lesions at EOS versus baseline was significantly higher in the CP-Tret group than in each of the other 3 groups (CP-Tret, 53.4%; CP, 47.5%; Tret, 43.3%; vehicle, 30.3%)(P<.005).¹⁶ The mean percentage reduction in noninflammatory lesions at EOS versus baseline was significantly higher in the CP-Tret group than in each of the other 3 groups (CP-Tret, 45.2%; CP, 31.6%; Tret, 37.9%; vehicle, 18.5%)(P≤.0004). The mean percentage reduction in total AV lesions at EOS versus baseline was significantly higher in the CP-Tret group than in each of the other 3 groups (CP-Tret, 48.7%; CP, 38.3%; Tret, 40.3%; vehicle, 23.2%)(P≤.0001). The median time to 50% reduction in total AV lesion counts was significantly faster with CP-Tret (8 weeks) compared to the other 3 groups (CP, 12 weeks [P<.0001]; Tret, 12 weeks [P<.001]; vehicle, not reached by EOS [P<.0001]). The consistency of results, methodologies, and overall study characteristics between the 2 phase 3 RCTs allowed for accurate pooling of data.¹⁶

Tolerability and safety assessments were completed at each visit for all enrolled participants. No adverse events (AEs) were noted in approximately 90% of enrolled participants.¹⁶ The most common AEs noted over the course of the study were mild to moderate application-site reactions (eg, dryness, erythema, burning, pruritus, desquamation), mostly correlated with the 2 groups containing tretinoin—CP-Tret and Tret—which is not unanticipated with topical retinoid use; 1.2% of these participants withdrew from the study due to such application-site AEs. No serious AEs or systemic safety signals emerged during the study.¹⁶

What summarizing statements can be made about CP-Tret gel from these study results that may be helpful to clinicians treating patients with AV?

The gel formulation of CP-Tret incorporates active ingredients that target different pathophysiologic cascades in AV, providing antimicrobial, anti-inflammatory, and anticomedonal effects.

Applied once daily, CP-Tret gel demonstrated the ability to achieve complete or near-complete clearance of comedonal and papulopustular facial AV lesions of mild to moderate severity in approximately 40% of participants within 12 weeks of use in 2 large-scale RCTs.¹⁶ The ability to achieve a median 50% reduction in total lesions by 8 weeks of use provides relevant information for patients regarding reasonable expectations with therapy.

The favorable cutaneous tolerability profile and low number of AEs demonstrated with CP-Tret gel are major considerations, especially as skin tolerability reactions can impede patient adherence with treatment. Any issues that interfere with achieving a favorable therapeutic outcome can lead to patients giving up with their therapy.

The large number of patients with skin of color treated with CP-Tret gel (n=209) in the 2 phase 3 RCTs is important, as the spectrum of racial origins, skin types, and skin colors seen in dermatology practices is diversifying across the United States. Both clinicians and patients with skin of color are often concerned about the sequelae of medication-induced skin irritation, which can lead to ensuing dyschromia.

Concerns related to potential development of clindamycin-resistant P acnes with CP-Tret gel may be addressed by concurrent use of BP, including with leave-on or short-contact therapy.

Although phase 3 RCTs evaluate therapeutic agents as monotherapy, in real world clinical practice, combination topical regimens using different individual products are common to optimize therapeutic outcomes. Advantages of the CP-Tret gel formulation, if a clinician desires to use it along with another topical product, are once-daily use and the low risk for cutaneous irritation.

What does your patient need to know?

When a patient presents with a history of genital warts (GWs), find out when and where the lesions started; where the lesions are currently located; what new lesions have developed; what treatments have been administered (eg, physician applied, prescription) and which one(s) worked; what side effects to treatments have been experienced and at what dose; does a partner(s) have similar lesions; is there a history of other sexually transmitted diseases or genital cancer; is he/she immunocompromised (eg, human immunodeficiency virus, transplant, medications); and what is his/her sexual orientation.

Once all of the information has been gathered and the entire anogenital region has been examined, a treatment plan can be formulated. If the patient is immunocompromised or is a man who has sex with men, the risk for anogenital malignancy due to human papillomavirus (HPV) is higher, and GWs, which can be coinfected with oncogenic HPV types, should be treated more aggressively. If the patient is still getting new lesions, use of only a destructive method such as cryotherapy will likely lead to suboptimal results.

Any patients with GWs in the anal region but particularly those in high-risk groups such as men who have sex with men and human immunodeficiency virus–infected patients should have an anoscopy to evaluate for lesions on the anal mucosa and in the rectum.

What are your go-to treatments?

Prior treatments need to be taken into account; make sure to understand any side effects and how he/she applied the prior treatment before eliminating it as a viable option. Treatment usually depends on the number of lesions, surface area, anatomic locations involved, and size of the lesions. I start with a 2-pronged approach—a debulking therapy and a patient-applied topical therapy—which allows me to physically remove some of the lesions, typically the larger ones, and then have the patient apply a topical medication at home that will treat the smaller lesions as well as help to clear or decrease the burden of HPV virus on the skin. I use cryotherapy as a debulking agent, but curettage or podophyllin 25% also can be used in the office. I use imiquimod cream 5% as a first-line topical agent at the recommended dose of 3 times weekly; however, if after the first 2 weeks the patient has little response or too much irritation, I titrate the dose so that the patient has mild inflammation on the skin. The dose ultimately can range from daily to once weekly. Some patients who can only tolerate imiquimod once or twice weekly may require zinc oxide paste for the inguinal folds and scrotum to protect from irritation. Alternate topical medications for GWs include sinecatechins ointment 15% or cidofovir ointment 2%.

How do you keep patients compliant?

Start the visit with open communication about the disease, where it came from, what the risks are if it is not treated, and how we can best treat it to make sure we minimize those risks. I explain all of the treatment options as well as our role in treating these lesions and minimizing the risk for disease progression.

What do you do if they refuse treatment?

Most patients with GWs are motivated to be treated. If pain is a concern, such as with cryotherapy, I recommend topical treatments.

What patient resources do you recommend?

The American Academy of Dermatology (https://www.aad.org/public/diseases/contagious-skin-diseases/genital-warts), Harvard Medical School patient education center (Boston, Massachusetts)(http://www.patienteducationcenter.org/articles/genital-warts/), and American Family Physician (http://www.aafp.org/afp/2004/1215/p2345.html) provide patient materials that I recommend.

What does your patient need to know?

When a patient presents with a history of genital warts (GWs), find out when and where the lesions started; where the lesions are currently located; what new lesions have developed; what treatments have been administered (eg, physician applied, prescription) and which one(s) worked; what side effects to treatments have been experienced and at what dose; does a partner(s) have similar lesions; is there a history of other sexually transmitted diseases or genital cancer; is he/she immunocompromised (eg, human immunodeficiency virus, transplant, medications); and what is his/her sexual orientation.

Once all of the information has been gathered and the entire anogenital region has been examined, a treatment plan can be formulated. If the patient is immunocompromised or is a man who has sex with men, the risk for anogenital malignancy due to human papillomavirus (HPV) is higher, and GWs, which can be coinfected with oncogenic HPV types, should be treated more aggressively. If the patient is still getting new lesions, use of only a destructive method such as cryotherapy will likely lead to suboptimal results.

Any patients with GWs in the anal region but particularly those in high-risk groups such as men who have sex with men and human immunodeficiency virus–infected patients should have an anoscopy to evaluate for lesions on the anal mucosa and in the rectum.

What are your go-to treatments?

Prior treatments need to be taken into account; make sure to understand any side effects and how he/she applied the prior treatment before eliminating it as a viable option. Treatment usually depends on the number of lesions, surface area, anatomic locations involved, and size of the lesions. I start with a 2-pronged approach—a debulking therapy and a patient-applied topical therapy—which allows me to physically remove some of the lesions, typically the larger ones, and then have the patient apply a topical medication at home that will treat the smaller lesions as well as help to clear or decrease the burden of HPV virus on the skin. I use cryotherapy as a debulking agent, but curettage or podophyllin 25% also can be used in the office. I use imiquimod cream 5% as a first-line topical agent at the recommended dose of 3 times weekly; however, if after the first 2 weeks the patient has little response or too much irritation, I titrate the dose so that the patient has mild inflammation on the skin. The dose ultimately can range from daily to once weekly. Some patients who can only tolerate imiquimod once or twice weekly may require zinc oxide paste for the inguinal folds and scrotum to protect from irritation. Alternate topical medications for GWs include sinecatechins ointment 15% or cidofovir ointment 2%.

How do you keep patients compliant?

Start the visit with open communication about the disease, where it came from, what the risks are if it is not treated, and how we can best treat it to make sure we minimize those risks. I explain all of the treatment options as well as our role in treating these lesions and minimizing the risk for disease progression.

What do you do if they refuse treatment?

Most patients with GWs are motivated to be treated. If pain is a concern, such as with cryotherapy, I recommend topical treatments.

What patient resources do you recommend?

The American Academy of Dermatology (https://www.aad.org/public/diseases/contagious-skin-diseases/genital-warts), Harvard Medical School patient education center (Boston, Massachusetts)(http://www.patienteducationcenter.org/articles/genital-warts/), and American Family Physician (http://www.aafp.org/afp/2004/1215/p2345.html) provide patient materials that I recommend.

What does your patient need to know?

When a patient presents with a history of genital warts (GWs), find out when and where the lesions started; where the lesions are currently located; what new lesions have developed; what treatments have been administered (eg, physician applied, prescription) and which one(s) worked; what side effects to treatments have been experienced and at what dose; does a partner(s) have similar lesions; is there a history of other sexually transmitted diseases or genital cancer; is he/she immunocompromised (eg, human immunodeficiency virus, transplant, medications); and what is his/her sexual orientation.

Once all of the information has been gathered and the entire anogenital region has been examined, a treatment plan can be formulated. If the patient is immunocompromised or is a man who has sex with men, the risk for anogenital malignancy due to human papillomavirus (HPV) is higher, and GWs, which can be coinfected with oncogenic HPV types, should be treated more aggressively. If the patient is still getting new lesions, use of only a destructive method such as cryotherapy will likely lead to suboptimal results.

Any patients with GWs in the anal region but particularly those in high-risk groups such as men who have sex with men and human immunodeficiency virus–infected patients should have an anoscopy to evaluate for lesions on the anal mucosa and in the rectum.

What are your go-to treatments?

Prior treatments need to be taken into account; make sure to understand any side effects and how he/she applied the prior treatment before eliminating it as a viable option. Treatment usually depends on the number of lesions, surface area, anatomic locations involved, and size of the lesions. I start with a 2-pronged approach—a debulking therapy and a patient-applied topical therapy—which allows me to physically remove some of the lesions, typically the larger ones, and then have the patient apply a topical medication at home that will treat the smaller lesions as well as help to clear or decrease the burden of HPV virus on the skin. I use cryotherapy as a debulking agent, but curettage or podophyllin 25% also can be used in the office. I use imiquimod cream 5% as a first-line topical agent at the recommended dose of 3 times weekly; however, if after the first 2 weeks the patient has little response or too much irritation, I titrate the dose so that the patient has mild inflammation on the skin. The dose ultimately can range from daily to once weekly. Some patients who can only tolerate imiquimod once or twice weekly may require zinc oxide paste for the inguinal folds and scrotum to protect from irritation. Alternate topical medications for GWs include sinecatechins ointment 15% or cidofovir ointment 2%.

How do you keep patients compliant?

Start the visit with open communication about the disease, where it came from, what the risks are if it is not treated, and how we can best treat it to make sure we minimize those risks. I explain all of the treatment options as well as our role in treating these lesions and minimizing the risk for disease progression.

What do you do if they refuse treatment?

Most patients with GWs are motivated to be treated. If pain is a concern, such as with cryotherapy, I recommend topical treatments.

What patient resources do you recommend?

The American Academy of Dermatology (https://www.aad.org/public/diseases/contagious-skin-diseases/genital-warts), Harvard Medical School patient education center (Boston, Massachusetts)(http://www.patienteducationcenter.org/articles/genital-warts/), and American Family Physician (http://www.aafp.org/afp/2004/1215/p2345.html) provide patient materials that I recommend.

An established patient comes into your office with a painful new lesion on the hand. He thinks it may be a wart. You take a focused history of the lesion, do a physical examination, and confirm the diagnosis of verruca vulgaris. You discuss treatment options, risks, and the benefits of treatment, as well as the pathophysiology of warts. The decision is made to proceed that same day with cryosurgical destruction, which is performed. You feel that billing both an office visit with an appended modifier -25 and the benign destruction code 17110 is warranted, but your biller says only the procedure should be reported. Who is correct?

Modifier -25 use has come under increased scrutiny by insurers and regulators. There is a perception that this modifier is frequently used inappropriately or unnecessarily. In fact, the Office of Inspector General reported that 35% of claims using modifier -25 that Medicare allowed did not meet the requirements. The Office of Inspector General has recommended that the “[Centers for Medicare & Medicaid Services] should work with carriers to reduce the number of claims submitted using modifier -25” and “include modifier -25 reviews in their medical review strategies.”¹ Translation: More chart reviews and audits! In my discussions with insurer medical directors, they point to the single diagnosis modifier -25 as likely abused and feel that its use in this context is almost never appropriate. Their audits have been focused on this aspect of dermatologists’ coding. In addition, some private insurers have started to discount reimbursement for office visits billed with modifier -25 by 50% to account for the level of perceived overuse.²

The Current Procedural Terminology description of modifier -25 is relatively clear: Modifier -25 is used to facilitate billing of evaluation and management (E/M) services on the day of a procedure for which separate payment may be made.³ This modifier indicates that a significant, separately identifiable E/M service was performed by the same physician on the day of a procedure. To appropriately bill both the E/M service and the procedure, the physician must indicate that the patient’s condition required an E/M service “above and beyond the usual pre- and post-operative work of a procedure.”⁴ However, it is largely left up to the physician to decide what constitutes the significant, separately identifiable E/M service.

As dermatologists, we all report modifier -25 appropriately as part of our daily practice. Performance of a medically necessary procedure on the same day as an E/M service generally is done to facilitate a prompt diagnosis or streamline treatment of a complex condition. Providing distinct medically necessary services on the same date allows physicians to provide effective and efficient high-quality care, in many cases saving patients a return visit. The most common scenario for using modifier -25 involves multiple concerns and multiple diagnoses, some of which are not associated with a procedure(s) that is performed on the same date of service. With multiple diagnoses, it is straightforward to demonstrate the separate E/M service associated with the nonprocedure-related diagnosis code(s); however, with one diagnosis for both the office visit and the procedure, clear documentation of the separate and identifiable E/M service is critical and is dependent on understanding what is included in the global surgical package.

Insurer payment for procedures includes local or topical anesthesia, the surgical service/procedure itself, immediate postoperative care including dictating the operative note, meeting/discussing the patient’s procedure with family and other physicians, evaluating the patient in postanesthesia/recovery area, and writing orders for the patient. This group of services is called the global surgical package. For minor procedures (ie, those with either 0- or 10-day global periods), the surgical package also includes same-day E/M associated with the decision to perform surgery. An appropriate history and physical examination, as well as the discussion of differential diagnosis, treatment options, and risk and benefits of treatments, are all included in the payment of a minor procedure itself. Therefore, if an E/M service is performed on the same day as a minor procedure to decide whether to proceed with the minor surgical procedure, this E/M service cannot be separately reported. Moreover, the fact that the patient is new to the physician is not sufficient to allow reporting of an E/M service with such a minor procedure. For major procedures (ie, those with 90-day postoperative periods), the decision for surgery is excluded from the global surgical package.

Therefore, it is clear that the clinical scenario for verruca vulgaris treatment as described at the start of this article does not meet criteria for an office visit billed in addition to the destruction. The E/M services performed prior to the patient’s verruca vulgaris treatment are integral to and necessary for the decision to perform the procedure. Making and confirming the diagnosis of a condition or lesion prior to a procedure either by physical evaluation or by interpretation of a pathology report is part of the evaluation required to make the decision to proceed with a particular procedure.

There are clinical scenarios in which a physician can support additional E/M services beyond that of the procedure with just one diagnosis. If a patient presents with warts on the hand and face with resultant cryosurgical destruction done on the hand and a prescription for imiquimod to be used on the face to induce immunologic clearance of viral infection and decrease the risk of scarring, it is clear that a significant and separately identifiable E/M service exists. The evaluation of the facial warts and the prescription of medication and discussion of the risks, benefits, and therapeutic effects of that prescription is definitely distinct from the procedure. Similarly, if an evaluation of a patient with a rash results in only a diagnostic biopsy with no separate cognitive services other than the decision to perform the biopsy, an office visit charge in addition to the biopsy charge would not be warranted. However, if in addition to the biopsy the rash also is treated with topical or systemic steroids because of pruritus or a more extensive evaluation for systemic complications is required, an office visit charge is appropriate.

The frequent use of modifier -25 is a critical part of a high-quality and cost-effective dermatology practice. Same-day performance of E/M services and minor procedures allows for more rapid and efficient diagnosis and treatment of various conditions as well as minimizing unnecessary office visits. However, modifier -25 use, particularly in the context of the same diagnosis for the office visit and the procedure, is under intense insurer scrutiny. Careful and complete documentation of the additional E/M service provided, including the additional history, physical examination results, and treatment considerations above and beyond those typically required by the minor procedure, will reduce the likelihood of redeterminations from reviews and audits. Understanding Medicare guidelines and National Correct Coding Initiative recommendations will help keep the dermatologist out of hot water.⁵

An established patient comes into your office with a painful new lesion on the hand. He thinks it may be a wart. You take a focused history of the lesion, do a physical examination, and confirm the diagnosis of verruca vulgaris. You discuss treatment options, risks, and the benefits of treatment, as well as the pathophysiology of warts. The decision is made to proceed that same day with cryosurgical destruction, which is performed. You feel that billing both an office visit with an appended modifier -25 and the benign destruction code 17110 is warranted, but your biller says only the procedure should be reported. Who is correct?

Modifier -25 use has come under increased scrutiny by insurers and regulators. There is a perception that this modifier is frequently used inappropriately or unnecessarily. In fact, the Office of Inspector General reported that 35% of claims using modifier -25 that Medicare allowed did not meet the requirements. The Office of Inspector General has recommended that the “[Centers for Medicare & Medicaid Services] should work with carriers to reduce the number of claims submitted using modifier -25” and “include modifier -25 reviews in their medical review strategies.”¹ Translation: More chart reviews and audits! In my discussions with insurer medical directors, they point to the single diagnosis modifier -25 as likely abused and feel that its use in this context is almost never appropriate. Their audits have been focused on this aspect of dermatologists’ coding. In addition, some private insurers have started to discount reimbursement for office visits billed with modifier -25 by 50% to account for the level of perceived overuse.²

The Current Procedural Terminology description of modifier -25 is relatively clear: Modifier -25 is used to facilitate billing of evaluation and management (E/M) services on the day of a procedure for which separate payment may be made.³ This modifier indicates that a significant, separately identifiable E/M service was performed by the same physician on the day of a procedure. To appropriately bill both the E/M service and the procedure, the physician must indicate that the patient’s condition required an E/M service “above and beyond the usual pre- and post-operative work of a procedure.”⁴ However, it is largely left up to the physician to decide what constitutes the significant, separately identifiable E/M service.

As dermatologists, we all report modifier -25 appropriately as part of our daily practice. Performance of a medically necessary procedure on the same day as an E/M service generally is done to facilitate a prompt diagnosis or streamline treatment of a complex condition. Providing distinct medically necessary services on the same date allows physicians to provide effective and efficient high-quality care, in many cases saving patients a return visit. The most common scenario for using modifier -25 involves multiple concerns and multiple diagnoses, some of which are not associated with a procedure(s) that is performed on the same date of service. With multiple diagnoses, it is straightforward to demonstrate the separate E/M service associated with the nonprocedure-related diagnosis code(s); however, with one diagnosis for both the office visit and the procedure, clear documentation of the separate and identifiable E/M service is critical and is dependent on understanding what is included in the global surgical package.

Insurer payment for procedures includes local or topical anesthesia, the surgical service/procedure itself, immediate postoperative care including dictating the operative note, meeting/discussing the patient’s procedure with family and other physicians, evaluating the patient in postanesthesia/recovery area, and writing orders for the patient. This group of services is called the global surgical package. For minor procedures (ie, those with either 0- or 10-day global periods), the surgical package also includes same-day E/M associated with the decision to perform surgery. An appropriate history and physical examination, as well as the discussion of differential diagnosis, treatment options, and risk and benefits of treatments, are all included in the payment of a minor procedure itself. Therefore, if an E/M service is performed on the same day as a minor procedure to decide whether to proceed with the minor surgical procedure, this E/M service cannot be separately reported. Moreover, the fact that the patient is new to the physician is not sufficient to allow reporting of an E/M service with such a minor procedure. For major procedures (ie, those with 90-day postoperative periods), the decision for surgery is excluded from the global surgical package.

Therefore, it is clear that the clinical scenario for verruca vulgaris treatment as described at the start of this article does not meet criteria for an office visit billed in addition to the destruction. The E/M services performed prior to the patient’s verruca vulgaris treatment are integral to and necessary for the decision to perform the procedure. Making and confirming the diagnosis of a condition or lesion prior to a procedure either by physical evaluation or by interpretation of a pathology report is part of the evaluation required to make the decision to proceed with a particular procedure.

There are clinical scenarios in which a physician can support additional E/M services beyond that of the procedure with just one diagnosis. If a patient presents with warts on the hand and face with resultant cryosurgical destruction done on the hand and a prescription for imiquimod to be used on the face to induce immunologic clearance of viral infection and decrease the risk of scarring, it is clear that a significant and separately identifiable E/M service exists. The evaluation of the facial warts and the prescription of medication and discussion of the risks, benefits, and therapeutic effects of that prescription is definitely distinct from the procedure. Similarly, if an evaluation of a patient with a rash results in only a diagnostic biopsy with no separate cognitive services other than the decision to perform the biopsy, an office visit charge in addition to the biopsy charge would not be warranted. However, if in addition to the biopsy the rash also is treated with topical or systemic steroids because of pruritus or a more extensive evaluation for systemic complications is required, an office visit charge is appropriate.

The frequent use of modifier -25 is a critical part of a high-quality and cost-effective dermatology practice. Same-day performance of E/M services and minor procedures allows for more rapid and efficient diagnosis and treatment of various conditions as well as minimizing unnecessary office visits. However, modifier -25 use, particularly in the context of the same diagnosis for the office visit and the procedure, is under intense insurer scrutiny. Careful and complete documentation of the additional E/M service provided, including the additional history, physical examination results, and treatment considerations above and beyond those typically required by the minor procedure, will reduce the likelihood of redeterminations from reviews and audits. Understanding Medicare guidelines and National Correct Coding Initiative recommendations will help keep the dermatologist out of hot water.⁵

An established patient comes into your office with a painful new lesion on the hand. He thinks it may be a wart. You take a focused history of the lesion, do a physical examination, and confirm the diagnosis of verruca vulgaris. You discuss treatment options, risks, and the benefits of treatment, as well as the pathophysiology of warts. The decision is made to proceed that same day with cryosurgical destruction, which is performed. You feel that billing both an office visit with an appended modifier -25 and the benign destruction code 17110 is warranted, but your biller says only the procedure should be reported. Who is correct?

Modifier -25 use has come under increased scrutiny by insurers and regulators. There is a perception that this modifier is frequently used inappropriately or unnecessarily. In fact, the Office of Inspector General reported that 35% of claims using modifier -25 that Medicare allowed did not meet the requirements. The Office of Inspector General has recommended that the “[Centers for Medicare & Medicaid Services] should work with carriers to reduce the number of claims submitted using modifier -25” and “include modifier -25 reviews in their medical review strategies.”¹ Translation: More chart reviews and audits! In my discussions with insurer medical directors, they point to the single diagnosis modifier -25 as likely abused and feel that its use in this context is almost never appropriate. Their audits have been focused on this aspect of dermatologists’ coding. In addition, some private insurers have started to discount reimbursement for office visits billed with modifier -25 by 50% to account for the level of perceived overuse.²

The Current Procedural Terminology description of modifier -25 is relatively clear: Modifier -25 is used to facilitate billing of evaluation and management (E/M) services on the day of a procedure for which separate payment may be made.³ This modifier indicates that a significant, separately identifiable E/M service was performed by the same physician on the day of a procedure. To appropriately bill both the E/M service and the procedure, the physician must indicate that the patient’s condition required an E/M service “above and beyond the usual pre- and post-operative work of a procedure.”⁴ However, it is largely left up to the physician to decide what constitutes the significant, separately identifiable E/M service.

As dermatologists, we all report modifier -25 appropriately as part of our daily practice. Performance of a medically necessary procedure on the same day as an E/M service generally is done to facilitate a prompt diagnosis or streamline treatment of a complex condition. Providing distinct medically necessary services on the same date allows physicians to provide effective and efficient high-quality care, in many cases saving patients a return visit. The most common scenario for using modifier -25 involves multiple concerns and multiple diagnoses, some of which are not associated with a procedure(s) that is performed on the same date of service. With multiple diagnoses, it is straightforward to demonstrate the separate E/M service associated with the nonprocedure-related diagnosis code(s); however, with one diagnosis for both the office visit and the procedure, clear documentation of the separate and identifiable E/M service is critical and is dependent on understanding what is included in the global surgical package.

Insurer payment for procedures includes local or topical anesthesia, the surgical service/procedure itself, immediate postoperative care including dictating the operative note, meeting/discussing the patient’s procedure with family and other physicians, evaluating the patient in postanesthesia/recovery area, and writing orders for the patient. This group of services is called the global surgical package. For minor procedures (ie, those with either 0- or 10-day global periods), the surgical package also includes same-day E/M associated with the decision to perform surgery. An appropriate history and physical examination, as well as the discussion of differential diagnosis, treatment options, and risk and benefits of treatments, are all included in the payment of a minor procedure itself. Therefore, if an E/M service is performed on the same day as a minor procedure to decide whether to proceed with the minor surgical procedure, this E/M service cannot be separately reported. Moreover, the fact that the patient is new to the physician is not sufficient to allow reporting of an E/M service with such a minor procedure. For major procedures (ie, those with 90-day postoperative periods), the decision for surgery is excluded from the global surgical package.

Therefore, it is clear that the clinical scenario for verruca vulgaris treatment as described at the start of this article does not meet criteria for an office visit billed in addition to the destruction. The E/M services performed prior to the patient’s verruca vulgaris treatment are integral to and necessary for the decision to perform the procedure. Making and confirming the diagnosis of a condition or lesion prior to a procedure either by physical evaluation or by interpretation of a pathology report is part of the evaluation required to make the decision to proceed with a particular procedure.

There are clinical scenarios in which a physician can support additional E/M services beyond that of the procedure with just one diagnosis. If a patient presents with warts on the hand and face with resultant cryosurgical destruction done on the hand and a prescription for imiquimod to be used on the face to induce immunologic clearance of viral infection and decrease the risk of scarring, it is clear that a significant and separately identifiable E/M service exists. The evaluation of the facial warts and the prescription of medication and discussion of the risks, benefits, and therapeutic effects of that prescription is definitely distinct from the procedure. Similarly, if an evaluation of a patient with a rash results in only a diagnostic biopsy with no separate cognitive services other than the decision to perform the biopsy, an office visit charge in addition to the biopsy charge would not be warranted. However, if in addition to the biopsy the rash also is treated with topical or systemic steroids because of pruritus or a more extensive evaluation for systemic complications is required, an office visit charge is appropriate.

The frequent use of modifier -25 is a critical part of a high-quality and cost-effective dermatology practice. Same-day performance of E/M services and minor procedures allows for more rapid and efficient diagnosis and treatment of various conditions as well as minimizing unnecessary office visits. However, modifier -25 use, particularly in the context of the same diagnosis for the office visit and the procedure, is under intense insurer scrutiny. Careful and complete documentation of the additional E/M service provided, including the additional history, physical examination results, and treatment considerations above and beyond those typically required by the minor procedure, will reduce the likelihood of redeterminations from reviews and audits. Understanding Medicare guidelines and National Correct Coding Initiative recommendations will help keep the dermatologist out of hot water.⁵

Primary Cutaneous B-cell Lymphoma

Cutaneous B-cell lymphomas (CBCLs) are a diverse but rare group of cutaneous lympho­proliferative neoplasms that make up approximately 20% of the total number of hematolymphoid neoplasms primary to the skin.¹ These lymphomas are comprised of neoplastic B cells in various stages of differentiation. As a whole, they are rare neoplasms that primarily involve the head, neck, trunk, arms, or legs.¹ Clinically, patients present with nontender, compressible, solitary, red to violaceous papules or nodules. Most CBCLs are considered low-grade malignancies with nonaggressive behavior and excellent prognosis; however, the diffuse large B-cell lymphomas, including but not limited to intravascular and leg type; lymphomatoid granulomatosis; and B-cell lymphoblastic lymphoma can act more aggressively.¹

Histopathologic examination of primary CBCL generally reveals a relatively normal epidermis accompanied by a nodular to diffuse monomorphic lymphocytic cellular infiltrate in the dermis that can occasionally extend into the subcutaneous tissue (quiz image). Although not specific for CBCLs, oftentimes there is an acellular portion of the superficial papillary dermis known as a grenz zone that can serve as a histopathologic clue to the diagnosis of a cutaneous lymphoproliferative disorder. The list of malignant B-cell neoplasms is extensive (eg, cutaneous marginal zone B-cell lymphoma, primary cutaneous follicle center lymphoma, diffuse large B-cell lymphoma, intravascular large B-cell lymphoma), and few are seen in the skin.

The most common type of CBCL is marginal zone B-cell lymphoma, which is considered to be a tumor of mucosa-associated (or skin-associated) lymphoid tissue. It is characterized by a monomorphous population of small mature lymphocytes showing characteristics of the B cells of the marginal zone of the lymph node. Some cells have the features of centrocytes/centroblasts (Figure 1) demonstrated by slightly irregular or indented nuclei and generous amounts of cytoplasm. Larger and more pleomorphic cells such as immunoblasts are similarly noted (Figure 1). The quiz image and Figure 1 demonstrate a cutaneous marginal zone B-cell lymphoma. A histomorphologic clue supporting a diagnosis of marginal zone B-cell lymphoma over reactive lymphoid hyperplasia is a B-cell predominate (B- to T-cell ratio of at least 3 to 1) infiltrate that is comprised of marginal zone-type cells. Immunohistochemistry demonstrating fewer differentiated B cells with light chain restriction may provide additional evidence that supports a clonal and potentially malignant process.

Erythematous to violaceous nodules on the head and neck of older individuals are characteristic of both granuloma faciale and CBCL. Histologically, granuloma faciale is characterized by a dense cellular infiltrate, often with a nodular outline, occupying the mid dermis.² Granuloma faciale typically spares the immediate subepidermis and hair follicles, forming a grenz zone. The cellular infiltrate is polymorphic and consists of eosinophils and neutrophils with scattered plasma cells, mast cells, and lymphocytes in a vasculocentric distribution, eventually with chronic concentric fibrosis (Figure 2).

Leukemia cutis demonstrates a dermal infiltrate that contains atypical mononuclear cells (myeloblasts and myelocytes)(Figure 3).³ These markedly atypical mononuclear cells can have kidney bean-shaped nuclei and percolate through the dermal collagen, resembling single-file cells. They have increased nuclear to cytoplasmic ratios and occasionally have prominent nucleoli. Correlation with immunophenotypic and cytochemical studies is required for specific typing of the leukemic infiltrate.

Similar to primary CBCL, lymphomatoid papulosis (LyP) consists of erythematous papules or nodules that can occur anywhere on the body. In contrast to CBCL, the lesions of LyP classically self-resolve. However, approximately 10% to 20% of patients develop a malignant lymphoma, with mycosis fungoides, Hodgkin disease, and anaplastic large cell lymphoma being the most commonly associated.

Histologic examination of lesions of LyP classically demonstrates a wedge-shaped dermal infiltrate with variable epidermal changes (Figure 4). The wedge-shaped infiltrate is composed of large atypical cells. Three main types of lesions have been delineated: types A, B, and C. Type A is characterized by an increased number of cells with large vesicular nuclei with clumped chromatin, prominent nucleoli, and pronounced cytoplasm. Reed-Sternberg-like cells with an admixture of inflammatory cells including small lymphocytes, macrophages, neutrophils, and eosinophils also are present. Type B neoplastic cells vary in size and feature hyperchromatic, convoluted, or cerebriform nuclei. The infiltrate can be dense and bandlike with fewer cells resembling mycosis fungoides; type B LyP has neoplastic cells, not inflammatory cells. Finally, type C demonstrates solid sheets of large atypical cells resembling anaplastic large cell lymphoma. Immunohistochemically, the atypical cells often are CD4⁺ and CD8^- with variable loss of pan-T-cell antigens. The atypical cells of types A and C express CD30 reactivity.⁴

Merkel cell carcinoma (MCC) is a primary neuroendocrine carcinoma of the skin that usually arises on sun-exposed skin in elderly patients with lesions that histologically and clinically resemble cutaneous lymphoma.⁵ It classically is composed of small, round to oval, basophilic cells with a vesicular nucleus and multiple small nucleoli. Apoptotic cells and mitoses often are present.⁶ One key finding that helps to differentiate MCC from lymphoma is the presence of finely dispersed salt-and-pepper chromatin and molded nuclear contour in MCC (Figure 5).

Immunophenotyping is important in the differentiation of these diagnoses. The atypical cells of LyP are positive for CD3, CD4, and CD30 but are negative for CD8. However, in type B LyP, the large CD30⁺ cells seen in the other types are not commonly seen. In contrast, MCC expresses reactivity with cytokeratins, in particular cytokeratin 20 and CAM5.2, classically in a paranuclear dotlike pattern. In keeping with MCC's neuroendocrine differentiation, the tumor cells will demonstrate reactivity with synaptophysin, chromogranin, and CD56. The immunohistochemistry for leukemia cutis varies depending on the type of leukemia. Acute myelomonocytic leukemia is positive for myeloperoxidase, CD13, CD33, and CD68. The immunophenotype of these marginal zone lymphoma cells is as follows: positive for CD20, CD79a, and Bcl-2; negative for Bcl-6, CD5, CD10, CD23, and cyclin D1 (Bcl-1).⁷ 

Primary Cutaneous B-cell Lymphoma

Cutaneous B-cell lymphomas (CBCLs) are a diverse but rare group of cutaneous lympho­proliferative neoplasms that make up approximately 20% of the total number of hematolymphoid neoplasms primary to the skin.¹ These lymphomas are comprised of neoplastic B cells in various stages of differentiation. As a whole, they are rare neoplasms that primarily involve the head, neck, trunk, arms, or legs.¹ Clinically, patients present with nontender, compressible, solitary, red to violaceous papules or nodules. Most CBCLs are considered low-grade malignancies with nonaggressive behavior and excellent prognosis; however, the diffuse large B-cell lymphomas, including but not limited to intravascular and leg type; lymphomatoid granulomatosis; and B-cell lymphoblastic lymphoma can act more aggressively.¹

Histopathologic examination of primary CBCL generally reveals a relatively normal epidermis accompanied by a nodular to diffuse monomorphic lymphocytic cellular infiltrate in the dermis that can occasionally extend into the subcutaneous tissue (quiz image). Although not specific for CBCLs, oftentimes there is an acellular portion of the superficial papillary dermis known as a grenz zone that can serve as a histopathologic clue to the diagnosis of a cutaneous lymphoproliferative disorder. The list of malignant B-cell neoplasms is extensive (eg, cutaneous marginal zone B-cell lymphoma, primary cutaneous follicle center lymphoma, diffuse large B-cell lymphoma, intravascular large B-cell lymphoma), and few are seen in the skin.

The most common type of CBCL is marginal zone B-cell lymphoma, which is considered to be a tumor of mucosa-associated (or skin-associated) lymphoid tissue. It is characterized by a monomorphous population of small mature lymphocytes showing characteristics of the B cells of the marginal zone of the lymph node. Some cells have the features of centrocytes/centroblasts (Figure 1) demonstrated by slightly irregular or indented nuclei and generous amounts of cytoplasm. Larger and more pleomorphic cells such as immunoblasts are similarly noted (Figure 1). The quiz image and Figure 1 demonstrate a cutaneous marginal zone B-cell lymphoma. A histomorphologic clue supporting a diagnosis of marginal zone B-cell lymphoma over reactive lymphoid hyperplasia is a B-cell predominate (B- to T-cell ratio of at least 3 to 1) infiltrate that is comprised of marginal zone-type cells. Immunohistochemistry demonstrating fewer differentiated B cells with light chain restriction may provide additional evidence that supports a clonal and potentially malignant process.

Erythematous to violaceous nodules on the head and neck of older individuals are characteristic of both granuloma faciale and CBCL. Histologically, granuloma faciale is characterized by a dense cellular infiltrate, often with a nodular outline, occupying the mid dermis.² Granuloma faciale typically spares the immediate subepidermis and hair follicles, forming a grenz zone. The cellular infiltrate is polymorphic and consists of eosinophils and neutrophils with scattered plasma cells, mast cells, and lymphocytes in a vasculocentric distribution, eventually with chronic concentric fibrosis (Figure 2).

Leukemia cutis demonstrates a dermal infiltrate that contains atypical mononuclear cells (myeloblasts and myelocytes)(Figure 3).³ These markedly atypical mononuclear cells can have kidney bean-shaped nuclei and percolate through the dermal collagen, resembling single-file cells. They have increased nuclear to cytoplasmic ratios and occasionally have prominent nucleoli. Correlation with immunophenotypic and cytochemical studies is required for specific typing of the leukemic infiltrate.

Similar to primary CBCL, lymphomatoid papulosis (LyP) consists of erythematous papules or nodules that can occur anywhere on the body. In contrast to CBCL, the lesions of LyP classically self-resolve. However, approximately 10% to 20% of patients develop a malignant lymphoma, with mycosis fungoides, Hodgkin disease, and anaplastic large cell lymphoma being the most commonly associated.

Histologic examination of lesions of LyP classically demonstrates a wedge-shaped dermal infiltrate with variable epidermal changes (Figure 4). The wedge-shaped infiltrate is composed of large atypical cells. Three main types of lesions have been delineated: types A, B, and C. Type A is characterized by an increased number of cells with large vesicular nuclei with clumped chromatin, prominent nucleoli, and pronounced cytoplasm. Reed-Sternberg-like cells with an admixture of inflammatory cells including small lymphocytes, macrophages, neutrophils, and eosinophils also are present. Type B neoplastic cells vary in size and feature hyperchromatic, convoluted, or cerebriform nuclei. The infiltrate can be dense and bandlike with fewer cells resembling mycosis fungoides; type B LyP has neoplastic cells, not inflammatory cells. Finally, type C demonstrates solid sheets of large atypical cells resembling anaplastic large cell lymphoma. Immunohistochemically, the atypical cells often are CD4⁺ and CD8^- with variable loss of pan-T-cell antigens. The atypical cells of types A and C express CD30 reactivity.⁴

Merkel cell carcinoma (MCC) is a primary neuroendocrine carcinoma of the skin that usually arises on sun-exposed skin in elderly patients with lesions that histologically and clinically resemble cutaneous lymphoma.⁵ It classically is composed of small, round to oval, basophilic cells with a vesicular nucleus and multiple small nucleoli. Apoptotic cells and mitoses often are present.⁶ One key finding that helps to differentiate MCC from lymphoma is the presence of finely dispersed salt-and-pepper chromatin and molded nuclear contour in MCC (Figure 5).

Immunophenotyping is important in the differentiation of these diagnoses. The atypical cells of LyP are positive for CD3, CD4, and CD30 but are negative for CD8. However, in type B LyP, the large CD30⁺ cells seen in the other types are not commonly seen. In contrast, MCC expresses reactivity with cytokeratins, in particular cytokeratin 20 and CAM5.2, classically in a paranuclear dotlike pattern. In keeping with MCC's neuroendocrine differentiation, the tumor cells will demonstrate reactivity with synaptophysin, chromogranin, and CD56. The immunohistochemistry for leukemia cutis varies depending on the type of leukemia. Acute myelomonocytic leukemia is positive for myeloperoxidase, CD13, CD33, and CD68. The immunophenotype of these marginal zone lymphoma cells is as follows: positive for CD20, CD79a, and Bcl-2; negative for Bcl-6, CD5, CD10, CD23, and cyclin D1 (Bcl-1).⁷ 

Primary Cutaneous B-cell Lymphoma

Cutaneous B-cell lymphomas (CBCLs) are a diverse but rare group of cutaneous lympho­proliferative neoplasms that make up approximately 20% of the total number of hematolymphoid neoplasms primary to the skin.¹ These lymphomas are comprised of neoplastic B cells in various stages of differentiation. As a whole, they are rare neoplasms that primarily involve the head, neck, trunk, arms, or legs.¹ Clinically, patients present with nontender, compressible, solitary, red to violaceous papules or nodules. Most CBCLs are considered low-grade malignancies with nonaggressive behavior and excellent prognosis; however, the diffuse large B-cell lymphomas, including but not limited to intravascular and leg type; lymphomatoid granulomatosis; and B-cell lymphoblastic lymphoma can act more aggressively.¹

Histopathologic examination of primary CBCL generally reveals a relatively normal epidermis accompanied by a nodular to diffuse monomorphic lymphocytic cellular infiltrate in the dermis that can occasionally extend into the subcutaneous tissue (quiz image). Although not specific for CBCLs, oftentimes there is an acellular portion of the superficial papillary dermis known as a grenz zone that can serve as a histopathologic clue to the diagnosis of a cutaneous lymphoproliferative disorder. The list of malignant B-cell neoplasms is extensive (eg, cutaneous marginal zone B-cell lymphoma, primary cutaneous follicle center lymphoma, diffuse large B-cell lymphoma, intravascular large B-cell lymphoma), and few are seen in the skin.

The most common type of CBCL is marginal zone B-cell lymphoma, which is considered to be a tumor of mucosa-associated (or skin-associated) lymphoid tissue. It is characterized by a monomorphous population of small mature lymphocytes showing characteristics of the B cells of the marginal zone of the lymph node. Some cells have the features of centrocytes/centroblasts (Figure 1) demonstrated by slightly irregular or indented nuclei and generous amounts of cytoplasm. Larger and more pleomorphic cells such as immunoblasts are similarly noted (Figure 1). The quiz image and Figure 1 demonstrate a cutaneous marginal zone B-cell lymphoma. A histomorphologic clue supporting a diagnosis of marginal zone B-cell lymphoma over reactive lymphoid hyperplasia is a B-cell predominate (B- to T-cell ratio of at least 3 to 1) infiltrate that is comprised of marginal zone-type cells. Immunohistochemistry demonstrating fewer differentiated B cells with light chain restriction may provide additional evidence that supports a clonal and potentially malignant process.

Erythematous to violaceous nodules on the head and neck of older individuals are characteristic of both granuloma faciale and CBCL. Histologically, granuloma faciale is characterized by a dense cellular infiltrate, often with a nodular outline, occupying the mid dermis.² Granuloma faciale typically spares the immediate subepidermis and hair follicles, forming a grenz zone. The cellular infiltrate is polymorphic and consists of eosinophils and neutrophils with scattered plasma cells, mast cells, and lymphocytes in a vasculocentric distribution, eventually with chronic concentric fibrosis (Figure 2).

Leukemia cutis demonstrates a dermal infiltrate that contains atypical mononuclear cells (myeloblasts and myelocytes)(Figure 3).³ These markedly atypical mononuclear cells can have kidney bean-shaped nuclei and percolate through the dermal collagen, resembling single-file cells. They have increased nuclear to cytoplasmic ratios and occasionally have prominent nucleoli. Correlation with immunophenotypic and cytochemical studies is required for specific typing of the leukemic infiltrate.

Similar to primary CBCL, lymphomatoid papulosis (LyP) consists of erythematous papules or nodules that can occur anywhere on the body. In contrast to CBCL, the lesions of LyP classically self-resolve. However, approximately 10% to 20% of patients develop a malignant lymphoma, with mycosis fungoides, Hodgkin disease, and anaplastic large cell lymphoma being the most commonly associated.

Histologic examination of lesions of LyP classically demonstrates a wedge-shaped dermal infiltrate with variable epidermal changes (Figure 4). The wedge-shaped infiltrate is composed of large atypical cells. Three main types of lesions have been delineated: types A, B, and C. Type A is characterized by an increased number of cells with large vesicular nuclei with clumped chromatin, prominent nucleoli, and pronounced cytoplasm. Reed-Sternberg-like cells with an admixture of inflammatory cells including small lymphocytes, macrophages, neutrophils, and eosinophils also are present. Type B neoplastic cells vary in size and feature hyperchromatic, convoluted, or cerebriform nuclei. The infiltrate can be dense and bandlike with fewer cells resembling mycosis fungoides; type B LyP has neoplastic cells, not inflammatory cells. Finally, type C demonstrates solid sheets of large atypical cells resembling anaplastic large cell lymphoma. Immunohistochemically, the atypical cells often are CD4⁺ and CD8^- with variable loss of pan-T-cell antigens. The atypical cells of types A and C express CD30 reactivity.⁴

Merkel cell carcinoma (MCC) is a primary neuroendocrine carcinoma of the skin that usually arises on sun-exposed skin in elderly patients with lesions that histologically and clinically resemble cutaneous lymphoma.⁵ It classically is composed of small, round to oval, basophilic cells with a vesicular nucleus and multiple small nucleoli. Apoptotic cells and mitoses often are present.⁶ One key finding that helps to differentiate MCC from lymphoma is the presence of finely dispersed salt-and-pepper chromatin and molded nuclear contour in MCC (Figure 5).

Immunophenotyping is important in the differentiation of these diagnoses. The atypical cells of LyP are positive for CD3, CD4, and CD30 but are negative for CD8. However, in type B LyP, the large CD30⁺ cells seen in the other types are not commonly seen. In contrast, MCC expresses reactivity with cytokeratins, in particular cytokeratin 20 and CAM5.2, classically in a paranuclear dotlike pattern. In keeping with MCC's neuroendocrine differentiation, the tumor cells will demonstrate reactivity with synaptophysin, chromogranin, and CD56. The immunohistochemistry for leukemia cutis varies depending on the type of leukemia. Acute myelomonocytic leukemia is positive for myeloperoxidase, CD13, CD33, and CD68. The immunophenotype of these marginal zone lymphoma cells is as follows: positive for CD20, CD79a, and Bcl-2; negative for Bcl-6, CD5, CD10, CD23, and cyclin D1 (Bcl-1).⁷ 

With great pleasure we announce a collaboration between Cutis^® and the Skin of Color Society (SOCS) to increase the knowledge available to dermatologists to help improve delivery of care to this underserved population.

Established in 2004 by Susan C. Taylor, MD (who also serves on the Cutis Editorial Board), SOCS (http://www.skinofcolorsociety.org) promotes, supports, and stimulates the development of information related to all aspects of skin of color within the specialty of dermatology, making this information readily available to the general population.

“Although a relatively new organization, SOCS has been essential in supporting and encouraging research and scholarly activity to increase our understanding of the ethnic differences that occur in problems related to hair, skin, and nails of the growing population of darker-skinned individuals in our country,” said Vincent A. DeLeo, MD, Editor-in-Chief of Cutis and a founding member of SOCS. “In addition, SOCS has been essential in mentoring young students and increasing minority participation in dermatology, and Cutis will strive to assist in those endeavors.”

The society also seeks to increase the body of dermatologic literature related to skin of color. To achieve this goal, SOCS will be collaborating with the editors of Cutis to publish quarterly Skin of Color columns to educate dermatologists and residents on basic science and clinical, surgical, and cosmetic research relevant to this patient population.

“SOCS is very excited to collaborate with Cutis in our mutual academic pursuits,” said Seemal R. Desai, MD, current secretary/treasurer of SOCS and president-elect. “It is vitally important to the mission of SOCS that dermatologists and patients be educated with the most up-to-date objective data, studies, and information that is available to most effectively help those suffering from skin disease in the skin of color population.”

Look for Skin of Color columns in upcoming issues of Cutis.

With great pleasure we announce a collaboration between Cutis^® and the Skin of Color Society (SOCS) to increase the knowledge available to dermatologists to help improve delivery of care to this underserved population.

Established in 2004 by Susan C. Taylor, MD (who also serves on the Cutis Editorial Board), SOCS (http://www.skinofcolorsociety.org) promotes, supports, and stimulates the development of information related to all aspects of skin of color within the specialty of dermatology, making this information readily available to the general population.

“Although a relatively new organization, SOCS has been essential in supporting and encouraging research and scholarly activity to increase our understanding of the ethnic differences that occur in problems related to hair, skin, and nails of the growing population of darker-skinned individuals in our country,” said Vincent A. DeLeo, MD, Editor-in-Chief of Cutis and a founding member of SOCS. “In addition, SOCS has been essential in mentoring young students and increasing minority participation in dermatology, and Cutis will strive to assist in those endeavors.”

The society also seeks to increase the body of dermatologic literature related to skin of color. To achieve this goal, SOCS will be collaborating with the editors of Cutis to publish quarterly Skin of Color columns to educate dermatologists and residents on basic science and clinical, surgical, and cosmetic research relevant to this patient population.

“SOCS is very excited to collaborate with Cutis in our mutual academic pursuits,” said Seemal R. Desai, MD, current secretary/treasurer of SOCS and president-elect. “It is vitally important to the mission of SOCS that dermatologists and patients be educated with the most up-to-date objective data, studies, and information that is available to most effectively help those suffering from skin disease in the skin of color population.”

Look for Skin of Color columns in upcoming issues of Cutis.

With great pleasure we announce a collaboration between Cutis^® and the Skin of Color Society (SOCS) to increase the knowledge available to dermatologists to help improve delivery of care to this underserved population.

Established in 2004 by Susan C. Taylor, MD (who also serves on the Cutis Editorial Board), SOCS (http://www.skinofcolorsociety.org) promotes, supports, and stimulates the development of information related to all aspects of skin of color within the specialty of dermatology, making this information readily available to the general population.

“Although a relatively new organization, SOCS has been essential in supporting and encouraging research and scholarly activity to increase our understanding of the ethnic differences that occur in problems related to hair, skin, and nails of the growing population of darker-skinned individuals in our country,” said Vincent A. DeLeo, MD, Editor-in-Chief of Cutis and a founding member of SOCS. “In addition, SOCS has been essential in mentoring young students and increasing minority participation in dermatology, and Cutis will strive to assist in those endeavors.”

The society also seeks to increase the body of dermatologic literature related to skin of color. To achieve this goal, SOCS will be collaborating with the editors of Cutis to publish quarterly Skin of Color columns to educate dermatologists and residents on basic science and clinical, surgical, and cosmetic research relevant to this patient population.

“SOCS is very excited to collaborate with Cutis in our mutual academic pursuits,” said Seemal R. Desai, MD, current secretary/treasurer of SOCS and president-elect. “It is vitally important to the mission of SOCS that dermatologists and patients be educated with the most up-to-date objective data, studies, and information that is available to most effectively help those suffering from skin disease in the skin of color population.”

Look for Skin of Color columns in upcoming issues of Cutis.

The incidence of acne in adult females is rising,¹ and treatment with combined oral contraceptive pills (OCPs) is becoming an increasingly important therapy for women with acne. Prior reports have indicated that OCPs were as effective as systemic antibiotics in reducing inflammatory, noninflammatory, and total facial acne lesions after 6 months of treatment.^2,3 The acne management guidelines of the American Academy of Dermatology confer OCPs a grade A recommendation based on consistent and good-quality patient-oriented evidence.⁴

The US Food and Drug Administration (FDA) has approved 3 OCPs for the treatment of acne in adult women: norgestimate–ethinyl estradiol in 1997, norethindrone acetate–ethinyl estradiol in 2001, and drospirenone–ethinyl estradiol in 2007.⁵ However, the use of these OCPs is poorly understood by many dermatologists. One study showed that dermatologists prescribed OCPs in only 2% of visits with female patients aged 12 to 55 years who presented for acne treatment, which is less often than obstetrician/gynecologists (36%) and internists (11%),⁶ perhaps due to perceived risks or unfamiliarity with OCP formulations and guidelines among dermatologists.⁷ Adverse effects of OCPs include venous thromboembolism (VTE), myocardial infarction, and hypertension,⁸ but they generally are well tolerated.⁹

Even less is known about dermatologists’ use of drospirenone-containing OCPs (DCOCPs), which contain the only FDA-approved progestin that blocks androgen receptors. In prior studies, treatment with DCOCPs was associated with greater reductions in total lesion count and investigator-graded acne severity compared to early-generation OCPs.^10,11 However, DCOCPs have been associated with a greater risk for VTE (4.0–6.3 times higher than OCP nonuse; 1.0–3.3 times higher than levonorgestrel-containing OCPs),¹² which may explain the decline in DCOCP prescriptions among gynecologists in Germany from 23.8% of OCP prescriptions in 2007 to 11.4% in 2011.¹³

In this study, we surveyed US dermatologists about their knowledge, comfort, and prescribing practices pertaining to the use of OCPs. We compare OCP-prescribing to nonprescribing dermatologists, and those frequently prescribing DCOCPs to those who infrequently prescribe DCOCPs.

Methods

Survey Design

We performed a cross-sectional survey study using convenience sampling. The instrument was designed based on primary literature on OCPs in acne treatment and questionnaires assessing the use of OCPs in other specialties. Topics included prescribing practices, contraindications for OCPs defined by the Centers for Disease Control and Prevention (CDC),¹⁴ VTE risk, patient selection for hormonal acne therapy, comfort with prescribing OCP therapy, and participant demographics.

Skip logic was employed (ie, subsequent questions depended on prior answers). A pilot study surveyed 9 board-certified dermatologists at our home institution (Weill Cornell Medical College, New York, New York).

Data Collection

Eligible participants were board-certified US dermatologists. Data were collected and managed using an electronic data capture tool through the Weill Cornell Medical College Clinical & Translational Science Center. Surveys were distributed electronically to dermatologic society members, university alumni networks, investigators’ professional contacts, and dermatologists whose contact information was purchased from an email marketing company. Chain-referral sampling (ie, participants’ recruitment among their colleagues) was used. Surveys were distributed at a regional dermatology meeting. Responses were collected from November 2014 to April 2015. This study was approved by the institutional review board.

Statistical Analysis

For the descriptive data, all responses including pilot study participants were analyzed regardless of survey completion and were summarized using frequency counts and percentages (N=130).

For the analysis of OCP prescription predictors, the sample included all respondents answering the demographic questions and indicating if they prescribe OCPs (N=116). One respondent was excluded for answering other for current practice setting. Demographic predictors of OCP prescription were physician characteristics, geographic region, practice location population density, practice attributes, time spent on medical versus pediatric dermatology, number of weekly acne patients, and percentage of total patients who are female. Medical school graduation year was a categorical variable and was categorized as prior to 1997 (when norgestimate–ethinyl estradiol was FDA approved for acne⁵) versus 1997 or later. Respondents’ practice states were analyzed according to US regions—Northeast, Midwest, South, West/Pacific—and population density (persons per square mile) using US Census Bureau data.^15,16

Univariate logistic regressions modeling OCP prescribing probability were performed for each demographic variable; a multivariable logistic model was constructed including all variables significant at α=.20 from univariate modeling.

To compare frequent prescribers versus infrequent prescribers of DCOCPs, we included all respondents answering whether they frequently prescribe DCOCPs and whether they believed the risk for VTE associated with DCOCPs differed from other OCPs (n=68). A univariate logistic regression was performed to model the probability of responding “Yes, they pose a greater risk” versus any of the other 3 responses by whether or not the respondent frequently prescribed DCOCPs for acne, and an unadjusted odds ratio was obtained. All P values were 2-tailed with statistical significance evaluated at α=.05. Ninety-five percent confidence intervals were calculated to assess precision of obtained estimates. Analyses were performed using SAS software version 9.4.

Results

Demographics

Participant demographics as predictors of OCP prescription practices are described in Table 1.

Knowledge

Oral contraceptive pills were endorsed as effective in the treatment of acne in women by 95.4% (124/130) of respondents. Among prescribers of OCPs for acne, 94.2% (65/69) believed OCPs were associated with an increased risk for VTE, no respondents thought OCPs were associated with a decreased VTE risk, 2.9% (2/69) believed OCPs did not affect VTE risk, and 2.9% (2/69) were unsure.

Among prescribers of OCPs for acne, 46.4% (32/69) believed DCOCPs posed a greater VTE risk than other OCPs. Odds of this response did not differ with frequent DCOCP prescribers versus infrequent prescribers (odds ratio, 0.731 [95% confidence interval, 0.272-1.964]; P=.5342). Participant responses on VTE risk and DCOCPs are provided in Table 2.

Dermatologists prescribing OCPs for acne endorsed greater likelihood of doing so in cases of cyclical flares with menstrual cycle (94.2% [65/69]), acne unresponsive to conventional therapy (87.0% [60/69]), acne on the lower half of the face (78.3% [54/69]), diagnosis of polycystic ovary syndrome (PCOS)(76.8% [53/69]), clinical suspicion of PCOS (71.0% [49/69]), concomitant hirsutism (71.0% [49/69]), late- or adult-onset acne (66.7% [46/69]), laboratory evidence of hyperandrogenism (60.9% [42/69]), and concomitant androgenetic alopecia (49.3% [34/69]).

Among dermatologists who prescribed OCPs for acne, CDC-defined absolute contraindications identified correctly were blood pressure of 160/100 mm Hg (59.4% [41/69]) and history of migraine with focal neurologic symptoms (49.3% [34/69]). The CDC-defined relative contraindications identified correctly were history of deep vein thrombosis or pulmonary embolism (1.4% [1/69]), breast cancer history with 5 years of no disease (15.9% [11/69]), hyperlipidemia (42.0% [29/69]), and 36 years or older smoking fewer than 15 cigarettes per day (21.7% [15/69]).

Comfort

Dermatologist self-reported comfort levels in prescribing OCPs for acne are shown in Table 3.

Prescribing Practices

Among all respondents, acne medications prescribed often included oral antibiotics (76.9% [100/130]), isotretinoin (41.5% [54/130]), and spironolactone (40.8% [53/130]).

Overall, 55.4% (72/130) of respondents prescribed OCPs for the following uses: acne (95.8% [69/72]), concomitant treatment with teratogenic medication (48.6% [35/72]), PCOS (34.7% [25/72]), hirsutism (26.4% [19/72]), androgenetic alopecia (19.4% [14/72]), SAHA (seborrhea, acne, hirsutism, alopecia) syndrome (12.5% [9/72]), and HAIR-AN (hyperandrogenism, insulin resistance, acanthosis nigricans) syndrome (11.1% [8/72]). For teratogenic medications, dermatologists prescribing OCPs did so with isotretinoin (77.8% [56/72]), spironolactone (73.6% [53/72]), tetracycline antibiotics (37.5% [27/72]), and other (34.7% [25/72]).

Of dermatologists prescribing OCPs for acne, frequency included often (19% [13/69]), sometimes (45% [31/69]), and rarely (36% [25/69]). The most frequently prescribed OCPs included Ortho Tri-Cyclen (Janssen Pharmaceuticals, Inc)(80% [55/69]), Yaz (Bayer)(64% [44/69]), and Estrostep (Warner Chilcott)(19% [13/69]). Fill-in responses included Desogen (Merck & Co, Inc)(3/69 [4%]), Alesse (Wyeth Pharmaceuticals, Inc)(3/69 [4%]), Lutera (Watson Pharma, Inc)(1/69 [1%]), Loestrin (Warner Chilcott)(1/69 [1%]), and Yasmin (Bayer)(1/69 [1%]).

In univariate regressions, graduation from medical school in 1997 or later (P=.0416), academic practice setting (P=.0130), and low-density practice setting (P=.0034) were significant predictors of prescribing OCPs. In multivariable regression, only academic practice setting (P=.0295) and low-density practice setting (P=.0050) remained significant predictors. Demographic predictors are summarized in Table 1.

Comment

Our results suggest that most dermatologists (95.4%) believe OCPs effectively treat acne; however, only 54% of respondents reported prescribing them. Academic dermatologists were more likely to prescribe OCPs than nonacademic dermatologists, possibly indicating that academic dermatologists are more familiar with the literature on the efficacy and use of OCPs. Nearly half of respondents seeing 25 or more acne patients weekly did not prescribe OCPs, suggesting a notable practice gap. Dermatologists in less dense US regions were more likely to prescribe OCPs, perhaps because dermatologists may be more likely to prescribe OCPs than refer patients in health care access–limited areas, just as primary care providers treat a broader range of conditions in low-density rural areas than urban ones.¹⁷ Exploring all dermatologists’ referral patterns for OCPs is warranted.

A strong knowledge area revealed from this study was hormonal treatment of acne in women, a vital area because appropriate patient selection is key to treatment success.⁸ Weaker knowledge areas included OCP contraindications and differences in VTE risk between formulations containing drospirenone and those not containing drospirenone. Only half the sample identified CDC-defined absolute contraindications, suggesting an education target for dermatologists to ensure patient safety. In contrast, respondents were conservative about relative contraindications, with most identifying deep vein thrombosis or pulmonary embolism, remote breast cancer history, and light smoking at 36 years or older as absolute contraindications. These results could reflect weighing the risk of relative contraindications against the benefit in acne, resulting in appropriately more conservative management than overall guidelines suggest. If so, it may suggest that dermatologists are adapting overall guidelines appropriately for use of OCPs in skin conditions.

Nearly all respondents knew that OCPs are associated with an increased risk for VTE. Approximately half understood that DCOCPs are associated with a greater VTE risk than other OCPs, with no difference between frequent and infrequent prescribers. Comparing these results to the findings on OCP prescribing overall, some dermatologists’ risk-benefit calculation for VTE differs from other specialties because DCOCPs have superior efficacy in acne, whereas DCOCPs have similar contraceptive efficacy to other OCPs.¹⁸ The fact that more dermatologists believed VTE to be an absolute contraindication than hypertension suggests dermatologists have a heightened awareness of VTE risk but prescribe DCOCPs for acne despite it.

Most OCP prescribers felt very comfortable selecting good candidates for OCPs (55.5%) and counseling on treatment initiation (45.8%) and side effects (48.6%). Only 22.2%, by contrast, were very comfortable managing side effects. This finding likely reflects the notion that VTEs are not most appropriately managed by a dermatologist. Exploring if a greater comfort level in managing side effects would make dermatologists more likely to prescribe OCPs is worthwhile. Additionally, exploring why many dermatologists do not prescribe OCPs despite believing they are effective for acne is warranted.

Study limitations included the use of convenience sampling. Additionally, our study did not investigate dermatologists’ reasons for not prescribing OCPs.

Conclusion

This study demonstrates that dermatologists believe OCPs effectively treat acne in women and that most dermatologists prescribing OCPs do so for acne treatment. Academic practice setting was associated with higher odds of prescribing OCPs than a nonacademic setting, but the number of weekly acne patients did not impact the likelihood of prescribing OCPs, which suggests a treatment gap warranting education efforts for dermatologists in nonacademic settings seeing many acne patients. Our study also suggests that awareness of the increased risk for VTE associated with DCOCPs is not associated with lower likelihood of prescribing DCOCPs, suggesting dermatologists may find greater treatment efficacy to be worth the higher risk.

Acknowledgments

We are grateful to the Department of Dermatology at the Weill Cornell College of Medicine (New York, New York) for providing funding to complete this study. We also acknowledge Paul Christos, DrPH, MS (New York, New York), and Xuming Sun, MS (New York, New York), for their assistance with the survey design. We also are indebted to numerous dermatologic professional societies for allowing the survey to be distributed to their membership.

The incidence of acne in adult females is rising,¹ and treatment with combined oral contraceptive pills (OCPs) is becoming an increasingly important therapy for women with acne. Prior reports have indicated that OCPs were as effective as systemic antibiotics in reducing inflammatory, noninflammatory, and total facial acne lesions after 6 months of treatment.^2,3 The acne management guidelines of the American Academy of Dermatology confer OCPs a grade A recommendation based on consistent and good-quality patient-oriented evidence.⁴

The US Food and Drug Administration (FDA) has approved 3 OCPs for the treatment of acne in adult women: norgestimate–ethinyl estradiol in 1997, norethindrone acetate–ethinyl estradiol in 2001, and drospirenone–ethinyl estradiol in 2007.⁵ However, the use of these OCPs is poorly understood by many dermatologists. One study showed that dermatologists prescribed OCPs in only 2% of visits with female patients aged 12 to 55 years who presented for acne treatment, which is less often than obstetrician/gynecologists (36%) and internists (11%),⁶ perhaps due to perceived risks or unfamiliarity with OCP formulations and guidelines among dermatologists.⁷ Adverse effects of OCPs include venous thromboembolism (VTE), myocardial infarction, and hypertension,⁸ but they generally are well tolerated.⁹

Even less is known about dermatologists’ use of drospirenone-containing OCPs (DCOCPs), which contain the only FDA-approved progestin that blocks androgen receptors. In prior studies, treatment with DCOCPs was associated with greater reductions in total lesion count and investigator-graded acne severity compared to early-generation OCPs.^10,11 However, DCOCPs have been associated with a greater risk for VTE (4.0–6.3 times higher than OCP nonuse; 1.0–3.3 times higher than levonorgestrel-containing OCPs),¹² which may explain the decline in DCOCP prescriptions among gynecologists in Germany from 23.8% of OCP prescriptions in 2007 to 11.4% in 2011.¹³

In this study, we surveyed US dermatologists about their knowledge, comfort, and prescribing practices pertaining to the use of OCPs. We compare OCP-prescribing to nonprescribing dermatologists, and those frequently prescribing DCOCPs to those who infrequently prescribe DCOCPs.

Methods

Survey Design

We performed a cross-sectional survey study using convenience sampling. The instrument was designed based on primary literature on OCPs in acne treatment and questionnaires assessing the use of OCPs in other specialties. Topics included prescribing practices, contraindications for OCPs defined by the Centers for Disease Control and Prevention (CDC),¹⁴ VTE risk, patient selection for hormonal acne therapy, comfort with prescribing OCP therapy, and participant demographics.

Skip logic was employed (ie, subsequent questions depended on prior answers). A pilot study surveyed 9 board-certified dermatologists at our home institution (Weill Cornell Medical College, New York, New York).

Data Collection

Eligible participants were board-certified US dermatologists. Data were collected and managed using an electronic data capture tool through the Weill Cornell Medical College Clinical & Translational Science Center. Surveys were distributed electronically to dermatologic society members, university alumni networks, investigators’ professional contacts, and dermatologists whose contact information was purchased from an email marketing company. Chain-referral sampling (ie, participants’ recruitment among their colleagues) was used. Surveys were distributed at a regional dermatology meeting. Responses were collected from November 2014 to April 2015. This study was approved by the institutional review board.

Statistical Analysis

For the descriptive data, all responses including pilot study participants were analyzed regardless of survey completion and were summarized using frequency counts and percentages (N=130).

For the analysis of OCP prescription predictors, the sample included all respondents answering the demographic questions and indicating if they prescribe OCPs (N=116). One respondent was excluded for answering other for current practice setting. Demographic predictors of OCP prescription were physician characteristics, geographic region, practice location population density, practice attributes, time spent on medical versus pediatric dermatology, number of weekly acne patients, and percentage of total patients who are female. Medical school graduation year was a categorical variable and was categorized as prior to 1997 (when norgestimate–ethinyl estradiol was FDA approved for acne⁵) versus 1997 or later. Respondents’ practice states were analyzed according to US regions—Northeast, Midwest, South, West/Pacific—and population density (persons per square mile) using US Census Bureau data.^15,16

Univariate logistic regressions modeling OCP prescribing probability were performed for each demographic variable; a multivariable logistic model was constructed including all variables significant at α=.20 from univariate modeling.

To compare frequent prescribers versus infrequent prescribers of DCOCPs, we included all respondents answering whether they frequently prescribe DCOCPs and whether they believed the risk for VTE associated with DCOCPs differed from other OCPs (n=68). A univariate logistic regression was performed to model the probability of responding “Yes, they pose a greater risk” versus any of the other 3 responses by whether or not the respondent frequently prescribed DCOCPs for acne, and an unadjusted odds ratio was obtained. All P values were 2-tailed with statistical significance evaluated at α=.05. Ninety-five percent confidence intervals were calculated to assess precision of obtained estimates. Analyses were performed using SAS software version 9.4.

Results

Demographics

Participant demographics as predictors of OCP prescription practices are described in Table 1.

Knowledge

Oral contraceptive pills were endorsed as effective in the treatment of acne in women by 95.4% (124/130) of respondents. Among prescribers of OCPs for acne, 94.2% (65/69) believed OCPs were associated with an increased risk for VTE, no respondents thought OCPs were associated with a decreased VTE risk, 2.9% (2/69) believed OCPs did not affect VTE risk, and 2.9% (2/69) were unsure.

Among prescribers of OCPs for acne, 46.4% (32/69) believed DCOCPs posed a greater VTE risk than other OCPs. Odds of this response did not differ with frequent DCOCP prescribers versus infrequent prescribers (odds ratio, 0.731 [95% confidence interval, 0.272-1.964]; P=.5342). Participant responses on VTE risk and DCOCPs are provided in Table 2.

Dermatologists prescribing OCPs for acne endorsed greater likelihood of doing so in cases of cyclical flares with menstrual cycle (94.2% [65/69]), acne unresponsive to conventional therapy (87.0% [60/69]), acne on the lower half of the face (78.3% [54/69]), diagnosis of polycystic ovary syndrome (PCOS)(76.8% [53/69]), clinical suspicion of PCOS (71.0% [49/69]), concomitant hirsutism (71.0% [49/69]), late- or adult-onset acne (66.7% [46/69]), laboratory evidence of hyperandrogenism (60.9% [42/69]), and concomitant androgenetic alopecia (49.3% [34/69]).

Among dermatologists who prescribed OCPs for acne, CDC-defined absolute contraindications identified correctly were blood pressure of 160/100 mm Hg (59.4% [41/69]) and history of migraine with focal neurologic symptoms (49.3% [34/69]). The CDC-defined relative contraindications identified correctly were history of deep vein thrombosis or pulmonary embolism (1.4% [1/69]), breast cancer history with 5 years of no disease (15.9% [11/69]), hyperlipidemia (42.0% [29/69]), and 36 years or older smoking fewer than 15 cigarettes per day (21.7% [15/69]).

Comfort

Dermatologist self-reported comfort levels in prescribing OCPs for acne are shown in Table 3.

Prescribing Practices

Among all respondents, acne medications prescribed often included oral antibiotics (76.9% [100/130]), isotretinoin (41.5% [54/130]), and spironolactone (40.8% [53/130]).

Overall, 55.4% (72/130) of respondents prescribed OCPs for the following uses: acne (95.8% [69/72]), concomitant treatment with teratogenic medication (48.6% [35/72]), PCOS (34.7% [25/72]), hirsutism (26.4% [19/72]), androgenetic alopecia (19.4% [14/72]), SAHA (seborrhea, acne, hirsutism, alopecia) syndrome (12.5% [9/72]), and HAIR-AN (hyperandrogenism, insulin resistance, acanthosis nigricans) syndrome (11.1% [8/72]). For teratogenic medications, dermatologists prescribing OCPs did so with isotretinoin (77.8% [56/72]), spironolactone (73.6% [53/72]), tetracycline antibiotics (37.5% [27/72]), and other (34.7% [25/72]).

Of dermatologists prescribing OCPs for acne, frequency included often (19% [13/69]), sometimes (45% [31/69]), and rarely (36% [25/69]). The most frequently prescribed OCPs included Ortho Tri-Cyclen (Janssen Pharmaceuticals, Inc)(80% [55/69]), Yaz (Bayer)(64% [44/69]), and Estrostep (Warner Chilcott)(19% [13/69]). Fill-in responses included Desogen (Merck & Co, Inc)(3/69 [4%]), Alesse (Wyeth Pharmaceuticals, Inc)(3/69 [4%]), Lutera (Watson Pharma, Inc)(1/69 [1%]), Loestrin (Warner Chilcott)(1/69 [1%]), and Yasmin (Bayer)(1/69 [1%]).

In univariate regressions, graduation from medical school in 1997 or later (P=.0416), academic practice setting (P=.0130), and low-density practice setting (P=.0034) were significant predictors of prescribing OCPs. In multivariable regression, only academic practice setting (P=.0295) and low-density practice setting (P=.0050) remained significant predictors. Demographic predictors are summarized in Table 1.

Comment

Our results suggest that most dermatologists (95.4%) believe OCPs effectively treat acne; however, only 54% of respondents reported prescribing them. Academic dermatologists were more likely to prescribe OCPs than nonacademic dermatologists, possibly indicating that academic dermatologists are more familiar with the literature on the efficacy and use of OCPs. Nearly half of respondents seeing 25 or more acne patients weekly did not prescribe OCPs, suggesting a notable practice gap. Dermatologists in less dense US regions were more likely to prescribe OCPs, perhaps because dermatologists may be more likely to prescribe OCPs than refer patients in health care access–limited areas, just as primary care providers treat a broader range of conditions in low-density rural areas than urban ones.¹⁷ Exploring all dermatologists’ referral patterns for OCPs is warranted.

A strong knowledge area revealed from this study was hormonal treatment of acne in women, a vital area because appropriate patient selection is key to treatment success.⁸ Weaker knowledge areas included OCP contraindications and differences in VTE risk between formulations containing drospirenone and those not containing drospirenone. Only half the sample identified CDC-defined absolute contraindications, suggesting an education target for dermatologists to ensure patient safety. In contrast, respondents were conservative about relative contraindications, with most identifying deep vein thrombosis or pulmonary embolism, remote breast cancer history, and light smoking at 36 years or older as absolute contraindications. These results could reflect weighing the risk of relative contraindications against the benefit in acne, resulting in appropriately more conservative management than overall guidelines suggest. If so, it may suggest that dermatologists are adapting overall guidelines appropriately for use of OCPs in skin conditions.

Nearly all respondents knew that OCPs are associated with an increased risk for VTE. Approximately half understood that DCOCPs are associated with a greater VTE risk than other OCPs, with no difference between frequent and infrequent prescribers. Comparing these results to the findings on OCP prescribing overall, some dermatologists’ risk-benefit calculation for VTE differs from other specialties because DCOCPs have superior efficacy in acne, whereas DCOCPs have similar contraceptive efficacy to other OCPs.¹⁸ The fact that more dermatologists believed VTE to be an absolute contraindication than hypertension suggests dermatologists have a heightened awareness of VTE risk but prescribe DCOCPs for acne despite it.

Most OCP prescribers felt very comfortable selecting good candidates for OCPs (55.5%) and counseling on treatment initiation (45.8%) and side effects (48.6%). Only 22.2%, by contrast, were very comfortable managing side effects. This finding likely reflects the notion that VTEs are not most appropriately managed by a dermatologist. Exploring if a greater comfort level in managing side effects would make dermatologists more likely to prescribe OCPs is worthwhile. Additionally, exploring why many dermatologists do not prescribe OCPs despite believing they are effective for acne is warranted.

Study limitations included the use of convenience sampling. Additionally, our study did not investigate dermatologists’ reasons for not prescribing OCPs.

Conclusion

This study demonstrates that dermatologists believe OCPs effectively treat acne in women and that most dermatologists prescribing OCPs do so for acne treatment. Academic practice setting was associated with higher odds of prescribing OCPs than a nonacademic setting, but the number of weekly acne patients did not impact the likelihood of prescribing OCPs, which suggests a treatment gap warranting education efforts for dermatologists in nonacademic settings seeing many acne patients. Our study also suggests that awareness of the increased risk for VTE associated with DCOCPs is not associated with lower likelihood of prescribing DCOCPs, suggesting dermatologists may find greater treatment efficacy to be worth the higher risk.

Acknowledgments

We are grateful to the Department of Dermatology at the Weill Cornell College of Medicine (New York, New York) for providing funding to complete this study. We also acknowledge Paul Christos, DrPH, MS (New York, New York), and Xuming Sun, MS (New York, New York), for their assistance with the survey design. We also are indebted to numerous dermatologic professional societies for allowing the survey to be distributed to their membership.

The incidence of acne in adult females is rising,¹ and treatment with combined oral contraceptive pills (OCPs) is becoming an increasingly important therapy for women with acne. Prior reports have indicated that OCPs were as effective as systemic antibiotics in reducing inflammatory, noninflammatory, and total facial acne lesions after 6 months of treatment.^2,3 The acne management guidelines of the American Academy of Dermatology confer OCPs a grade A recommendation based on consistent and good-quality patient-oriented evidence.⁴

The US Food and Drug Administration (FDA) has approved 3 OCPs for the treatment of acne in adult women: norgestimate–ethinyl estradiol in 1997, norethindrone acetate–ethinyl estradiol in 2001, and drospirenone–ethinyl estradiol in 2007.⁵ However, the use of these OCPs is poorly understood by many dermatologists. One study showed that dermatologists prescribed OCPs in only 2% of visits with female patients aged 12 to 55 years who presented for acne treatment, which is less often than obstetrician/gynecologists (36%) and internists (11%),⁶ perhaps due to perceived risks or unfamiliarity with OCP formulations and guidelines among dermatologists.⁷ Adverse effects of OCPs include venous thromboembolism (VTE), myocardial infarction, and hypertension,⁸ but they generally are well tolerated.⁹

Even less is known about dermatologists’ use of drospirenone-containing OCPs (DCOCPs), which contain the only FDA-approved progestin that blocks androgen receptors. In prior studies, treatment with DCOCPs was associated with greater reductions in total lesion count and investigator-graded acne severity compared to early-generation OCPs.^10,11 However, DCOCPs have been associated with a greater risk for VTE (4.0–6.3 times higher than OCP nonuse; 1.0–3.3 times higher than levonorgestrel-containing OCPs),¹² which may explain the decline in DCOCP prescriptions among gynecologists in Germany from 23.8% of OCP prescriptions in 2007 to 11.4% in 2011.¹³

In this study, we surveyed US dermatologists about their knowledge, comfort, and prescribing practices pertaining to the use of OCPs. We compare OCP-prescribing to nonprescribing dermatologists, and those frequently prescribing DCOCPs to those who infrequently prescribe DCOCPs.

Methods

Survey Design

We performed a cross-sectional survey study using convenience sampling. The instrument was designed based on primary literature on OCPs in acne treatment and questionnaires assessing the use of OCPs in other specialties. Topics included prescribing practices, contraindications for OCPs defined by the Centers for Disease Control and Prevention (CDC),¹⁴ VTE risk, patient selection for hormonal acne therapy, comfort with prescribing OCP therapy, and participant demographics.

Skip logic was employed (ie, subsequent questions depended on prior answers). A pilot study surveyed 9 board-certified dermatologists at our home institution (Weill Cornell Medical College, New York, New York).

Data Collection

Eligible participants were board-certified US dermatologists. Data were collected and managed using an electronic data capture tool through the Weill Cornell Medical College Clinical & Translational Science Center. Surveys were distributed electronically to dermatologic society members, university alumni networks, investigators’ professional contacts, and dermatologists whose contact information was purchased from an email marketing company. Chain-referral sampling (ie, participants’ recruitment among their colleagues) was used. Surveys were distributed at a regional dermatology meeting. Responses were collected from November 2014 to April 2015. This study was approved by the institutional review board.

Statistical Analysis

For the descriptive data, all responses including pilot study participants were analyzed regardless of survey completion and were summarized using frequency counts and percentages (N=130).

For the analysis of OCP prescription predictors, the sample included all respondents answering the demographic questions and indicating if they prescribe OCPs (N=116). One respondent was excluded for answering other for current practice setting. Demographic predictors of OCP prescription were physician characteristics, geographic region, practice location population density, practice attributes, time spent on medical versus pediatric dermatology, number of weekly acne patients, and percentage of total patients who are female. Medical school graduation year was a categorical variable and was categorized as prior to 1997 (when norgestimate–ethinyl estradiol was FDA approved for acne⁵) versus 1997 or later. Respondents’ practice states were analyzed according to US regions—Northeast, Midwest, South, West/Pacific—and population density (persons per square mile) using US Census Bureau data.^15,16

Univariate logistic regressions modeling OCP prescribing probability were performed for each demographic variable; a multivariable logistic model was constructed including all variables significant at α=.20 from univariate modeling.

To compare frequent prescribers versus infrequent prescribers of DCOCPs, we included all respondents answering whether they frequently prescribe DCOCPs and whether they believed the risk for VTE associated with DCOCPs differed from other OCPs (n=68). A univariate logistic regression was performed to model the probability of responding “Yes, they pose a greater risk” versus any of the other 3 responses by whether or not the respondent frequently prescribed DCOCPs for acne, and an unadjusted odds ratio was obtained. All P values were 2-tailed with statistical significance evaluated at α=.05. Ninety-five percent confidence intervals were calculated to assess precision of obtained estimates. Analyses were performed using SAS software version 9.4.

Results

Demographics

Participant demographics as predictors of OCP prescription practices are described in Table 1.

Knowledge

Oral contraceptive pills were endorsed as effective in the treatment of acne in women by 95.4% (124/130) of respondents. Among prescribers of OCPs for acne, 94.2% (65/69) believed OCPs were associated with an increased risk for VTE, no respondents thought OCPs were associated with a decreased VTE risk, 2.9% (2/69) believed OCPs did not affect VTE risk, and 2.9% (2/69) were unsure.

Among prescribers of OCPs for acne, 46.4% (32/69) believed DCOCPs posed a greater VTE risk than other OCPs. Odds of this response did not differ with frequent DCOCP prescribers versus infrequent prescribers (odds ratio, 0.731 [95% confidence interval, 0.272-1.964]; P=.5342). Participant responses on VTE risk and DCOCPs are provided in Table 2.

Dermatologists prescribing OCPs for acne endorsed greater likelihood of doing so in cases of cyclical flares with menstrual cycle (94.2% [65/69]), acne unresponsive to conventional therapy (87.0% [60/69]), acne on the lower half of the face (78.3% [54/69]), diagnosis of polycystic ovary syndrome (PCOS)(76.8% [53/69]), clinical suspicion of PCOS (71.0% [49/69]), concomitant hirsutism (71.0% [49/69]), late- or adult-onset acne (66.7% [46/69]), laboratory evidence of hyperandrogenism (60.9% [42/69]), and concomitant androgenetic alopecia (49.3% [34/69]).

Among dermatologists who prescribed OCPs for acne, CDC-defined absolute contraindications identified correctly were blood pressure of 160/100 mm Hg (59.4% [41/69]) and history of migraine with focal neurologic symptoms (49.3% [34/69]). The CDC-defined relative contraindications identified correctly were history of deep vein thrombosis or pulmonary embolism (1.4% [1/69]), breast cancer history with 5 years of no disease (15.9% [11/69]), hyperlipidemia (42.0% [29/69]), and 36 years or older smoking fewer than 15 cigarettes per day (21.7% [15/69]).

Comfort

Dermatologist self-reported comfort levels in prescribing OCPs for acne are shown in Table 3.

Prescribing Practices

Among all respondents, acne medications prescribed often included oral antibiotics (76.9% [100/130]), isotretinoin (41.5% [54/130]), and spironolactone (40.8% [53/130]).

Overall, 55.4% (72/130) of respondents prescribed OCPs for the following uses: acne (95.8% [69/72]), concomitant treatment with teratogenic medication (48.6% [35/72]), PCOS (34.7% [25/72]), hirsutism (26.4% [19/72]), androgenetic alopecia (19.4% [14/72]), SAHA (seborrhea, acne, hirsutism, alopecia) syndrome (12.5% [9/72]), and HAIR-AN (hyperandrogenism, insulin resistance, acanthosis nigricans) syndrome (11.1% [8/72]). For teratogenic medications, dermatologists prescribing OCPs did so with isotretinoin (77.8% [56/72]), spironolactone (73.6% [53/72]), tetracycline antibiotics (37.5% [27/72]), and other (34.7% [25/72]).

Of dermatologists prescribing OCPs for acne, frequency included often (19% [13/69]), sometimes (45% [31/69]), and rarely (36% [25/69]). The most frequently prescribed OCPs included Ortho Tri-Cyclen (Janssen Pharmaceuticals, Inc)(80% [55/69]), Yaz (Bayer)(64% [44/69]), and Estrostep (Warner Chilcott)(19% [13/69]). Fill-in responses included Desogen (Merck & Co, Inc)(3/69 [4%]), Alesse (Wyeth Pharmaceuticals, Inc)(3/69 [4%]), Lutera (Watson Pharma, Inc)(1/69 [1%]), Loestrin (Warner Chilcott)(1/69 [1%]), and Yasmin (Bayer)(1/69 [1%]).

In univariate regressions, graduation from medical school in 1997 or later (P=.0416), academic practice setting (P=.0130), and low-density practice setting (P=.0034) were significant predictors of prescribing OCPs. In multivariable regression, only academic practice setting (P=.0295) and low-density practice setting (P=.0050) remained significant predictors. Demographic predictors are summarized in Table 1.

Comment

Our results suggest that most dermatologists (95.4%) believe OCPs effectively treat acne; however, only 54% of respondents reported prescribing them. Academic dermatologists were more likely to prescribe OCPs than nonacademic dermatologists, possibly indicating that academic dermatologists are more familiar with the literature on the efficacy and use of OCPs. Nearly half of respondents seeing 25 or more acne patients weekly did not prescribe OCPs, suggesting a notable practice gap. Dermatologists in less dense US regions were more likely to prescribe OCPs, perhaps because dermatologists may be more likely to prescribe OCPs than refer patients in health care access–limited areas, just as primary care providers treat a broader range of conditions in low-density rural areas than urban ones.¹⁷ Exploring all dermatologists’ referral patterns for OCPs is warranted.

A strong knowledge area revealed from this study was hormonal treatment of acne in women, a vital area because appropriate patient selection is key to treatment success.⁸ Weaker knowledge areas included OCP contraindications and differences in VTE risk between formulations containing drospirenone and those not containing drospirenone. Only half the sample identified CDC-defined absolute contraindications, suggesting an education target for dermatologists to ensure patient safety. In contrast, respondents were conservative about relative contraindications, with most identifying deep vein thrombosis or pulmonary embolism, remote breast cancer history, and light smoking at 36 years or older as absolute contraindications. These results could reflect weighing the risk of relative contraindications against the benefit in acne, resulting in appropriately more conservative management than overall guidelines suggest. If so, it may suggest that dermatologists are adapting overall guidelines appropriately for use of OCPs in skin conditions.

Nearly all respondents knew that OCPs are associated with an increased risk for VTE. Approximately half understood that DCOCPs are associated with a greater VTE risk than other OCPs, with no difference between frequent and infrequent prescribers. Comparing these results to the findings on OCP prescribing overall, some dermatologists’ risk-benefit calculation for VTE differs from other specialties because DCOCPs have superior efficacy in acne, whereas DCOCPs have similar contraceptive efficacy to other OCPs.¹⁸ The fact that more dermatologists believed VTE to be an absolute contraindication than hypertension suggests dermatologists have a heightened awareness of VTE risk but prescribe DCOCPs for acne despite it.

Most OCP prescribers felt very comfortable selecting good candidates for OCPs (55.5%) and counseling on treatment initiation (45.8%) and side effects (48.6%). Only 22.2%, by contrast, were very comfortable managing side effects. This finding likely reflects the notion that VTEs are not most appropriately managed by a dermatologist. Exploring if a greater comfort level in managing side effects would make dermatologists more likely to prescribe OCPs is worthwhile. Additionally, exploring why many dermatologists do not prescribe OCPs despite believing they are effective for acne is warranted.

Study limitations included the use of convenience sampling. Additionally, our study did not investigate dermatologists’ reasons for not prescribing OCPs.

Conclusion

This study demonstrates that dermatologists believe OCPs effectively treat acne in women and that most dermatologists prescribing OCPs do so for acne treatment. Academic practice setting was associated with higher odds of prescribing OCPs than a nonacademic setting, but the number of weekly acne patients did not impact the likelihood of prescribing OCPs, which suggests a treatment gap warranting education efforts for dermatologists in nonacademic settings seeing many acne patients. Our study also suggests that awareness of the increased risk for VTE associated with DCOCPs is not associated with lower likelihood of prescribing DCOCPs, suggesting dermatologists may find greater treatment efficacy to be worth the higher risk.

Acknowledgments

We are grateful to the Department of Dermatology at the Weill Cornell College of Medicine (New York, New York) for providing funding to complete this study. We also acknowledge Paul Christos, DrPH, MS (New York, New York), and Xuming Sun, MS (New York, New York), for their assistance with the survey design. We also are indebted to numerous dermatologic professional societies for allowing the survey to be distributed to their membership.

Case Report

A recently incarcerated 34-year-old man with an 11-year history of multidrug-resistant human immunodeficiency virus/AIDS (CD4 count, 121 cells/mm³; viral load, 49,625 particles/mm³ one week prior to presentation) was admitted to the hospital for an intensely pruritic, hyperkeratotic, scaly rash involving the entire body. The rash first appeared on the feet approximately 1 year prior to admission. At that time the patient was given oral fluconazole and a steroid cream with near resolution of the rash. He was then transferred multiple times to different units with subsequent discontinuation of the medications. The rash flared and progressed to involve the knees. He was restarted on the fluconazole and steroid cream and placed in isolation by medical personnel at the prison 6 months prior to presentation. The rash continued to spread, and he was given a working diagnosis of plaque-type psoriasis by several providers after several months of nonresponse to treatment. Additional attempts at treatment at outside facilities included oral fluconazole, trimethoprim-sulfamethoxazole, and other antibiotics. He was referred to dermatology at our institution but missed the appointment and was admitted to the hospital before the appointment could be rescheduled.

On admission to the hospital, he denied similar lesions in close contacts. On review of systems he had subjective fevers and chills, decreased appetite, nausea without vomiting, dysphagia to solids, epigastric pain, and 70-lb weight loss over the last 6 months. Facial involvement of the rash impaired the ability to open the mouth, speak, and eat. He had no known drug allergies. His only medications at the time of admission were nortriptyline, trimethoprim-sulfamethoxazole, and oral combination elvitegravir-cobicistat-emtricitabine-tenofovir for hu-man immunodeficiency virus treatment.

On physical examination he was cachectic, shivering, and foul smelling. He was afebrile, slightly tachycardic (112 beats per minute), and hypertensive (144/83 mm Hg) with a respiratory rate of 18 breaths per minute. His height was 1.83 m (6 ft) and weight was 48.5 kg (107 lb) with a body mass index of 14.5. Extensive erythematous, hyperkeratotic, crusted, and fissured plaques covered the entire body including the face, hands, and feet. The tongue was covered with bilateral white-colored plaques, and he had patches of alopecia, excoriations, and scales on the scalp. The elbows were fixed in a flexed position and he had decreased range of motion in the wrists and fingers due to the severe hyperkeratosis (Figure 1A). Hyperkeratosis also was prominent on the knees and feet with associated burrows (Figure 2A). He had foot drop on the left.

The differential diagnosis included a drug eruption; fungal or parasite infestation, such as crusted scabies; psoriasis; or cutaneous lymphoma. Laboratory studies were difficult to obtain, as there were limited areas suitable for vascular access. Blood work showed leukocytosis (18.9×10⁹ cells/L [reference range, 4.8–10.8×10⁹ cells/L) with 13.3% eosinophils (reference range, 1%–6%). This eosinophilia narrowed the likely diagnoses to a drug eruption or parasite infection.

The dermatology service was consulted. A mineral oil preparation was performed and showed numerous mites and feces consistent with a diagnosis of crusted scabies (Figure 3). The patient was started on a regimen of permethrin cream 5% applied to the entire body, except the face, which was left on overnight and washed off. This regimen was repeated daily for 1 week, then twice weekly until the rash resolved after a total of 3 weeks. Due to the severity of his condition, immunocompromised status, and concern for superinfection, oral ivermectin 200 μg/kg once daily was added on days 1, 2, 8, 9, 15, 22, and 29.¹

Our patient’s hospital course was further complicated by symptomatic hypoglycemia, altered mental status, and superimposed methicillin-resistant Staphylococcus aureus bacteremia, as well as Pseudomonas aeruginosa bacteremia, pneumonia, and coffee ground emesis. He was transferred to the intensive care unit but fortunately did not require intubation. His overall condition, mental status, and rash gradually improved. Three weeks after admission he only had a few residual lesions on the feet with clearing elsewhere (Figures 1B and 2B). He was discharged with a skin moisturizer and was referred for physical and occupational therapy. On follow-up clinic visits at 3 and 6 months, he had recovered well with general improvement in his condition.

Comment

Classic (noncrusted) scabies is common worldwide, with an estimated 300 million cases per year. It is caused by the mite Sarcoptes scabiei var hominis, and transmission occurs by direct skin-to-skin contact or less commonly by fomites (eg, linens, bedsheets) and therefore is common in overcrowded environments.²Crusted scabies is a severe, highly contagious form of the disease in which the host’s immune system is overwhelmed and unable to defend against mites on the skin, resulting in hyperinfestation of the host. The mites use secretions to dissolve the epidermis and burrow through the skin, leaving feces in their tracks.³ Interestingly, the native aboriginal populations of Australia have a high incidence of crusted scabies even though they show no signs of immunosuppression. The reason remains unclear but may be due to a skewed T-cell response.⁴ Various mechanisms have been described for the symptoms of scabies, and it is believed that there is a hypersensitivity reaction to the mites and the feces. Increased IL-17 production by skin T cells may be responsible.⁵

Clinical Features

Crusted scabies is characterized by severe hyperkeratosis and plaques with desquamation and erythroderma that is worse in the acral regions and large joints, such as the elbows and the knees, as seen in our patient. Because of the deep burrows, patients are predisposed to secondary superinfections by bacteria. In our case, the patient had methicillin-resistant S aureus bacteremia, which persisted for some time despite treatment with intravenous antibiotics.

Diagnosis

Because scabies can imitate different conditions, it can be difficult to diagnose. Misdiagnosis of psoriasis in our patient led to ineffective treatment and subsequent worsening of his condition. Burrows are pathognomonic for scabies, though in severe cases, the burrows may be concealed by extreme hyperkeratosis. Diagnosis is confirmed by mineral oil preparation from the plaques showing numerous scabies mites and feces.

Treatment

It is important to control the spread of scabies, as it is highly contagious, and if the living environment is not properly cleaned, the patient can be reinfected. All clothing, bedsheets, and linens in the household must be washed in hot water and dried in a hot dryer, and nonwashable items should be placed in a closed plastic bag for 72 hours. All contacts also should be treated with 1 application of permethrin cream to the entire body including the head and neck, left on overnight, and washed off with warm water.¹ The washing also helps remove some of the skin crusts. Patients should be educated that pruritus and burning may initially worsen with permethrin treatment due to the body’s reaction to the parasite.^1,2 In addition, keratolytic agents such as topical urea or salicylic acid can be used as an adjuvant therapy to improve the efficacy of permethrin.

Permethrin is effective against both mites and eggs and works by inhibiting sodium channels, resulting in nerve signal conduction block and subsequent paralysis. Ivermectin is thought to act on glutamate-gated chloride channels, which are present in invertebrates but absent in vertebrates, causing hyperpolarization and paralysis of the adult mite.^1,6

Conclusion

Crusted scabies is a highly contagious and intensely pruritic condition. Scabies can mimic other conditions, such as psoriasis or severe dermatitis, so it is important to keep this diagnosis in mind, especially in immunocompromised patients or populations in overcrowded areas (eg, those who are incarcerated or in nursing homes). Treatment consists of isolating the patient, starting topical permethrin and oral ivermectin (in severe cases), washing all linens, and prophylactically treating contacts. A delay in diagnosis can lead to severe debilitating disease, as seen in the extreme case of our patient. However, our patient made a full recovery with appropriate treatment and care.

Case Report

A recently incarcerated 34-year-old man with an 11-year history of multidrug-resistant human immunodeficiency virus/AIDS (CD4 count, 121 cells/mm³; viral load, 49,625 particles/mm³ one week prior to presentation) was admitted to the hospital for an intensely pruritic, hyperkeratotic, scaly rash involving the entire body. The rash first appeared on the feet approximately 1 year prior to admission. At that time the patient was given oral fluconazole and a steroid cream with near resolution of the rash. He was then transferred multiple times to different units with subsequent discontinuation of the medications. The rash flared and progressed to involve the knees. He was restarted on the fluconazole and steroid cream and placed in isolation by medical personnel at the prison 6 months prior to presentation. The rash continued to spread, and he was given a working diagnosis of plaque-type psoriasis by several providers after several months of nonresponse to treatment. Additional attempts at treatment at outside facilities included oral fluconazole, trimethoprim-sulfamethoxazole, and other antibiotics. He was referred to dermatology at our institution but missed the appointment and was admitted to the hospital before the appointment could be rescheduled.

On admission to the hospital, he denied similar lesions in close contacts. On review of systems he had subjective fevers and chills, decreased appetite, nausea without vomiting, dysphagia to solids, epigastric pain, and 70-lb weight loss over the last 6 months. Facial involvement of the rash impaired the ability to open the mouth, speak, and eat. He had no known drug allergies. His only medications at the time of admission were nortriptyline, trimethoprim-sulfamethoxazole, and oral combination elvitegravir-cobicistat-emtricitabine-tenofovir for hu-man immunodeficiency virus treatment.

On physical examination he was cachectic, shivering, and foul smelling. He was afebrile, slightly tachycardic (112 beats per minute), and hypertensive (144/83 mm Hg) with a respiratory rate of 18 breaths per minute. His height was 1.83 m (6 ft) and weight was 48.5 kg (107 lb) with a body mass index of 14.5. Extensive erythematous, hyperkeratotic, crusted, and fissured plaques covered the entire body including the face, hands, and feet. The tongue was covered with bilateral white-colored plaques, and he had patches of alopecia, excoriations, and scales on the scalp. The elbows were fixed in a flexed position and he had decreased range of motion in the wrists and fingers due to the severe hyperkeratosis (Figure 1A). Hyperkeratosis also was prominent on the knees and feet with associated burrows (Figure 2A). He had foot drop on the left.

The differential diagnosis included a drug eruption; fungal or parasite infestation, such as crusted scabies; psoriasis; or cutaneous lymphoma. Laboratory studies were difficult to obtain, as there were limited areas suitable for vascular access. Blood work showed leukocytosis (18.9×10⁹ cells/L [reference range, 4.8–10.8×10⁹ cells/L) with 13.3% eosinophils (reference range, 1%–6%). This eosinophilia narrowed the likely diagnoses to a drug eruption or parasite infection.

The dermatology service was consulted. A mineral oil preparation was performed and showed numerous mites and feces consistent with a diagnosis of crusted scabies (Figure 3). The patient was started on a regimen of permethrin cream 5% applied to the entire body, except the face, which was left on overnight and washed off. This regimen was repeated daily for 1 week, then twice weekly until the rash resolved after a total of 3 weeks. Due to the severity of his condition, immunocompromised status, and concern for superinfection, oral ivermectin 200 μg/kg once daily was added on days 1, 2, 8, 9, 15, 22, and 29.¹

Our patient’s hospital course was further complicated by symptomatic hypoglycemia, altered mental status, and superimposed methicillin-resistant Staphylococcus aureus bacteremia, as well as Pseudomonas aeruginosa bacteremia, pneumonia, and coffee ground emesis. He was transferred to the intensive care unit but fortunately did not require intubation. His overall condition, mental status, and rash gradually improved. Three weeks after admission he only had a few residual lesions on the feet with clearing elsewhere (Figures 1B and 2B). He was discharged with a skin moisturizer and was referred for physical and occupational therapy. On follow-up clinic visits at 3 and 6 months, he had recovered well with general improvement in his condition.

Comment

Classic (noncrusted) scabies is common worldwide, with an estimated 300 million cases per year. It is caused by the mite Sarcoptes scabiei var hominis, and transmission occurs by direct skin-to-skin contact or less commonly by fomites (eg, linens, bedsheets) and therefore is common in overcrowded environments.²Crusted scabies is a severe, highly contagious form of the disease in which the host’s immune system is overwhelmed and unable to defend against mites on the skin, resulting in hyperinfestation of the host. The mites use secretions to dissolve the epidermis and burrow through the skin, leaving feces in their tracks.³ Interestingly, the native aboriginal populations of Australia have a high incidence of crusted scabies even though they show no signs of immunosuppression. The reason remains unclear but may be due to a skewed T-cell response.⁴ Various mechanisms have been described for the symptoms of scabies, and it is believed that there is a hypersensitivity reaction to the mites and the feces. Increased IL-17 production by skin T cells may be responsible.⁵

Clinical Features

Crusted scabies is characterized by severe hyperkeratosis and plaques with desquamation and erythroderma that is worse in the acral regions and large joints, such as the elbows and the knees, as seen in our patient. Because of the deep burrows, patients are predisposed to secondary superinfections by bacteria. In our case, the patient had methicillin-resistant S aureus bacteremia, which persisted for some time despite treatment with intravenous antibiotics.

Diagnosis

Because scabies can imitate different conditions, it can be difficult to diagnose. Misdiagnosis of psoriasis in our patient led to ineffective treatment and subsequent worsening of his condition. Burrows are pathognomonic for scabies, though in severe cases, the burrows may be concealed by extreme hyperkeratosis. Diagnosis is confirmed by mineral oil preparation from the plaques showing numerous scabies mites and feces.

Treatment

It is important to control the spread of scabies, as it is highly contagious, and if the living environment is not properly cleaned, the patient can be reinfected. All clothing, bedsheets, and linens in the household must be washed in hot water and dried in a hot dryer, and nonwashable items should be placed in a closed plastic bag for 72 hours. All contacts also should be treated with 1 application of permethrin cream to the entire body including the head and neck, left on overnight, and washed off with warm water.¹ The washing also helps remove some of the skin crusts. Patients should be educated that pruritus and burning may initially worsen with permethrin treatment due to the body’s reaction to the parasite.^1,2 In addition, keratolytic agents such as topical urea or salicylic acid can be used as an adjuvant therapy to improve the efficacy of permethrin.

Permethrin is effective against both mites and eggs and works by inhibiting sodium channels, resulting in nerve signal conduction block and subsequent paralysis. Ivermectin is thought to act on glutamate-gated chloride channels, which are present in invertebrates but absent in vertebrates, causing hyperpolarization and paralysis of the adult mite.^1,6

Conclusion

Crusted scabies is a highly contagious and intensely pruritic condition. Scabies can mimic other conditions, such as psoriasis or severe dermatitis, so it is important to keep this diagnosis in mind, especially in immunocompromised patients or populations in overcrowded areas (eg, those who are incarcerated or in nursing homes). Treatment consists of isolating the patient, starting topical permethrin and oral ivermectin (in severe cases), washing all linens, and prophylactically treating contacts. A delay in diagnosis can lead to severe debilitating disease, as seen in the extreme case of our patient. However, our patient made a full recovery with appropriate treatment and care.

Case Report

A recently incarcerated 34-year-old man with an 11-year history of multidrug-resistant human immunodeficiency virus/AIDS (CD4 count, 121 cells/mm³; viral load, 49,625 particles/mm³ one week prior to presentation) was admitted to the hospital for an intensely pruritic, hyperkeratotic, scaly rash involving the entire body. The rash first appeared on the feet approximately 1 year prior to admission. At that time the patient was given oral fluconazole and a steroid cream with near resolution of the rash. He was then transferred multiple times to different units with subsequent discontinuation of the medications. The rash flared and progressed to involve the knees. He was restarted on the fluconazole and steroid cream and placed in isolation by medical personnel at the prison 6 months prior to presentation. The rash continued to spread, and he was given a working diagnosis of plaque-type psoriasis by several providers after several months of nonresponse to treatment. Additional attempts at treatment at outside facilities included oral fluconazole, trimethoprim-sulfamethoxazole, and other antibiotics. He was referred to dermatology at our institution but missed the appointment and was admitted to the hospital before the appointment could be rescheduled.

On admission to the hospital, he denied similar lesions in close contacts. On review of systems he had subjective fevers and chills, decreased appetite, nausea without vomiting, dysphagia to solids, epigastric pain, and 70-lb weight loss over the last 6 months. Facial involvement of the rash impaired the ability to open the mouth, speak, and eat. He had no known drug allergies. His only medications at the time of admission were nortriptyline, trimethoprim-sulfamethoxazole, and oral combination elvitegravir-cobicistat-emtricitabine-tenofovir for hu-man immunodeficiency virus treatment.

On physical examination he was cachectic, shivering, and foul smelling. He was afebrile, slightly tachycardic (112 beats per minute), and hypertensive (144/83 mm Hg) with a respiratory rate of 18 breaths per minute. His height was 1.83 m (6 ft) and weight was 48.5 kg (107 lb) with a body mass index of 14.5. Extensive erythematous, hyperkeratotic, crusted, and fissured plaques covered the entire body including the face, hands, and feet. The tongue was covered with bilateral white-colored plaques, and he had patches of alopecia, excoriations, and scales on the scalp. The elbows were fixed in a flexed position and he had decreased range of motion in the wrists and fingers due to the severe hyperkeratosis (Figure 1A). Hyperkeratosis also was prominent on the knees and feet with associated burrows (Figure 2A). He had foot drop on the left.

The differential diagnosis included a drug eruption; fungal or parasite infestation, such as crusted scabies; psoriasis; or cutaneous lymphoma. Laboratory studies were difficult to obtain, as there were limited areas suitable for vascular access. Blood work showed leukocytosis (18.9×10⁹ cells/L [reference range, 4.8–10.8×10⁹ cells/L) with 13.3% eosinophils (reference range, 1%–6%). This eosinophilia narrowed the likely diagnoses to a drug eruption or parasite infection.

The dermatology service was consulted. A mineral oil preparation was performed and showed numerous mites and feces consistent with a diagnosis of crusted scabies (Figure 3). The patient was started on a regimen of permethrin cream 5% applied to the entire body, except the face, which was left on overnight and washed off. This regimen was repeated daily for 1 week, then twice weekly until the rash resolved after a total of 3 weeks. Due to the severity of his condition, immunocompromised status, and concern for superinfection, oral ivermectin 200 μg/kg once daily was added on days 1, 2, 8, 9, 15, 22, and 29.¹

Our patient’s hospital course was further complicated by symptomatic hypoglycemia, altered mental status, and superimposed methicillin-resistant Staphylococcus aureus bacteremia, as well as Pseudomonas aeruginosa bacteremia, pneumonia, and coffee ground emesis. He was transferred to the intensive care unit but fortunately did not require intubation. His overall condition, mental status, and rash gradually improved. Three weeks after admission he only had a few residual lesions on the feet with clearing elsewhere (Figures 1B and 2B). He was discharged with a skin moisturizer and was referred for physical and occupational therapy. On follow-up clinic visits at 3 and 6 months, he had recovered well with general improvement in his condition.

Comment

Classic (noncrusted) scabies is common worldwide, with an estimated 300 million cases per year. It is caused by the mite Sarcoptes scabiei var hominis, and transmission occurs by direct skin-to-skin contact or less commonly by fomites (eg, linens, bedsheets) and therefore is common in overcrowded environments.²Crusted scabies is a severe, highly contagious form of the disease in which the host’s immune system is overwhelmed and unable to defend against mites on the skin, resulting in hyperinfestation of the host. The mites use secretions to dissolve the epidermis and burrow through the skin, leaving feces in their tracks.³ Interestingly, the native aboriginal populations of Australia have a high incidence of crusted scabies even though they show no signs of immunosuppression. The reason remains unclear but may be due to a skewed T-cell response.⁴ Various mechanisms have been described for the symptoms of scabies, and it is believed that there is a hypersensitivity reaction to the mites and the feces. Increased IL-17 production by skin T cells may be responsible.⁵

Clinical Features

Crusted scabies is characterized by severe hyperkeratosis and plaques with desquamation and erythroderma that is worse in the acral regions and large joints, such as the elbows and the knees, as seen in our patient. Because of the deep burrows, patients are predisposed to secondary superinfections by bacteria. In our case, the patient had methicillin-resistant S aureus bacteremia, which persisted for some time despite treatment with intravenous antibiotics.

Diagnosis

Because scabies can imitate different conditions, it can be difficult to diagnose. Misdiagnosis of psoriasis in our patient led to ineffective treatment and subsequent worsening of his condition. Burrows are pathognomonic for scabies, though in severe cases, the burrows may be concealed by extreme hyperkeratosis. Diagnosis is confirmed by mineral oil preparation from the plaques showing numerous scabies mites and feces.

Treatment

It is important to control the spread of scabies, as it is highly contagious, and if the living environment is not properly cleaned, the patient can be reinfected. All clothing, bedsheets, and linens in the household must be washed in hot water and dried in a hot dryer, and nonwashable items should be placed in a closed plastic bag for 72 hours. All contacts also should be treated with 1 application of permethrin cream to the entire body including the head and neck, left on overnight, and washed off with warm water.¹ The washing also helps remove some of the skin crusts. Patients should be educated that pruritus and burning may initially worsen with permethrin treatment due to the body’s reaction to the parasite.^1,2 In addition, keratolytic agents such as topical urea or salicylic acid can be used as an adjuvant therapy to improve the efficacy of permethrin.

Permethrin is effective against both mites and eggs and works by inhibiting sodium channels, resulting in nerve signal conduction block and subsequent paralysis. Ivermectin is thought to act on glutamate-gated chloride channels, which are present in invertebrates but absent in vertebrates, causing hyperpolarization and paralysis of the adult mite.^1,6

Conclusion

Crusted scabies is a highly contagious and intensely pruritic condition. Scabies can mimic other conditions, such as psoriasis or severe dermatitis, so it is important to keep this diagnosis in mind, especially in immunocompromised patients or populations in overcrowded areas (eg, those who are incarcerated or in nursing homes). Treatment consists of isolating the patient, starting topical permethrin and oral ivermectin (in severe cases), washing all linens, and prophylactically treating contacts. A delay in diagnosis can lead to severe debilitating disease, as seen in the extreme case of our patient. However, our patient made a full recovery with appropriate treatment and care.