Drug Therapy

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.

Acne vulgaris (AV) is a common skin disease that usually presents in adolescence and can persist into adulthood. Some cases may start in adulthood, especially in women. Acne vulgaris remains a challenge to treat successfully, both in teenagers and adults. Unrealistic expectations that therapy will rapidly clear and sustain clearance of AV completely can lead to incomplete adherence or complete cessation of treatment.^1-4 Local tolerability reactions also may decrease adherence to topical medications. Suboptimal adherence to medications for AV is one of the major reasons for treatment failure.⁵ Acne vulgaris can strongly influence psychological well-being and self-esteem.⁶ In general, severe AV causes more psychological distress, but the adverse emotional impact of AV can be independent of its severity.⁷

An effective relationship between the patient and his/her physician and staff is believed to be important in setting realistic expectations, optimizing adherence, and achieving a positive therapeutic outcome. One component related to setting reasonable expectations is the discussion about when the patient may begin to visibly perceive that the treatment regimen is working. This article evaluates the time course of a clinically meaningful response using pivotal trial data with clindamycin phosphate 1.2%–benzoyl peroxide 3.75% (clindamycin-BP 3.75%) gel for treatment of AV.

Are data available that evaluate the time course of a clinically relevant response to treatment of AV?

Unfortunately, data on what might be perceived as a clinically meaningful improvement in AV and how long it might take to achieve this treatment effect are limited. A meta-analysis of more than 4000 patients with moderate to severe AV suggested that a 10% to 20% difference in acne lesion counts from baseline as compared to a subsequent designated time point was clinically relevant.⁸ A review of 24 comparative studies of patients with mild to moderate AV used a primary outcome parameter of a 25% reduction in mean inflammatory lesion count to evaluate time to onset of action (TOA) to achieve a clinically meaningful benefit.⁹ This outcome was based on a previously identified threshold of clinical relevance and the authors’ clinical experience in a patient population with milder AV. In this same analysis, a difference of greater than 4 days between the active group and the vehicle group was considered to be relevant to the patient.⁹

A faster onset of visible improvement as perceived by the patient should be more desirable and is likely to improve treatment adherence, as long as it is not counterbalanced by an increase in adverse events.

What is meant by TOA?

Time to onset of action refers to the duration required to achieve a 25% mean lesion count reduction from baseline, which is believed to correlate with the time point at which many patients would be able to perceive visible improvement when viewing their full face. Therefore, TOA represents an attempt to correlate data that is quantitative (based on lesion count reduction) with what is likely to be the average time that a patient may qualitatively observe an initial visible improvement in their AV. This concept may be useful as a tool when communicating with AV patients but should not be used in a way that will overpromise and underdeliver; rather, it is a guide for discussion with the patient and with a parent or guardian when applicable.

Consistent with the comparative AV study analysis that evaluated TOA, a linear course of lesion reductions between the provided time intervals was assumed. In this linear model, the TOA was calculated using the 2 extracted lesion count values between which the 25% lesion reduction was achieved as well as their corresponding given time points.⁹ Differences between the results in the active and vehicle study arms were calculated for a number of determinants.

How was pivotal trial data with clindamycin-BP 3.75% gel used to assess TOA?

A total of 498 patients with moderate to severe AV were randomized (1:1) to receive clindamycin-BP 3.75% gel or vehicle in a multicenter, double-blind, controlled, 12-week, 2-arm study.¹⁰ Before randomization, patients were stratified by acne severity based on a static Evaluator’s Global Severity Score (EGSS) ranging from 0 (clear) to 5 (very severe). Specifically, moderate AV (EGSS of 3) was described as predominantly noninflammatory lesions with evidence of multiple inflammatory lesions; several to many comedones, papules, and pustules; and no more than 1 small nodulocystic lesion. Severe AV (EGSS of 4) was characterized by inflammatory lesions; numerous comedones, papules, and pustules; and possibly a few nodulocystic lesions.¹⁰

Male and female patients aged 12 to 40 years with moderate to severe AV—defined as 20 to 40 inflammatory lesions (papules, pustules, nodules), 20 to 100 noninflammatory lesions (comedones), and no more than 2 nodules—were included in the study. Standard washout periods were required for patients using prior prescription and over-the-counter acne treatments.¹⁰

Efficacy evaluations included inflammatory and noninflammatory lesion counts and EGSS at screening, baseline, and during treatment (weeks 4, 8, and 12).¹⁰ Primary efficacy end points included absolute change in mean inflammatory and noninflammatory lesion counts and the proportion of patients who achieved at least a 2-grade reduction in EGSS from baseline to week 12 (treatment success at end of study). Secondary efficacy end points included mean percentage change from baseline to week 12 in inflammatory and noninflammatory lesion counts and the proportion of patients who considered themselves clear or almost clear at week 12.¹⁰

After 12 weeks of daily treatment, inflammatory and noninflammatory lesion counts decreased by a mean of 60.4% and 51.8%, respectively, with clindamycin-BP 3.75% gel compared to 31.3% and 27.6%, respectively, with vehicle (both P<.001). At weeks 4, 8, and 12, the difference in inflammatory and noninflammatory lesion counts for the active treatment was 17.4%, 24.8%, and 29.1%, respectively, and 8.1%, 19.8%, and 24.2%, respectively, for vehicle.¹⁰

Treatment success (at least a 2-grade improvement in EGSS) was achieved by 9.1% of patients using clindamycin-BP 3.75% gel compared to 4.6% using vehicle by week 4. Additionally, 6.3% of patients considered their AV as clear or almost clear compared to 3.5% with vehicle at week 2 (Figure 1).¹⁰

This analysis represents the first attempt to evaluate and report TOA results with clindamycin-BP 3.75% gel. Time to onset of action for inflammatory lesions treated with clindamycin-BP 3.75% gel was calculated as 2.5 weeks versus 6.2 weeks for vehicle (Figure 2A). Time to onset of action for noninflammatory lesions was 3.7 weeks with clindamycin-BP 3.75% gel versus 8.6 weeks with vehicle (Figure 2B). The difference in TOA between the active and vehicle study groups was 3.7 weeks and 4.9 weeks, respectively. In addition, among actively treated patients, TOA was shorter in females (2.1 weeks) than in males (2.6 weeks) and in moderate AV (2.5 weeks) compared to severe AV (3.0 weeks).

Comment

Differences in lesion counts between clindamycin-BP 3.75% gel and vehicle suggest a clinically relevant benefit in favor of active treatment with both inflammatory and noninflammatory lesions. Nearly twice as many patients were rated as treatment successes using EGSS by week 4 or clear or almost clear as early as week 2 compared to the vehicle group.¹⁰ However, these data are suggested as an overall guide but do not provide adequate guidance on when visible improvement may start to be evident in a given patient.

The analysis reported here shows a TOA of 2.5 weeks with clindamycin-BP 3.75% gel for inflammatory lesions, approximately 4 weeks faster than with the vehicle. In most cases, a reduction in inflammatory lesions is more likely to have a greater impact on patient perception of TOA. Unless a patient is aware or focused enough to actively distinguish visibly between inflammatory and noninflammatory (comedonal) AV lesions, their eye is more likely to be drawn initially to reduction in inflammatory lesions, which are erythematous and more visible at a greater viewing distance. Although noninflammatory AV lesions usually require closer inspection to visualize them (especially closed comedones), they are often slower to respond to treatment. Analysis of the pivotal trial data reports a longer TOA with clindamycin-BP 3.75% gel for noninflammatory lesions (3.7 weeks) versus inflammatory lesions (2.5 weeks).

As expected, TOA was shorter in patients with moderate AV than severe AV (2.5 weeks vs 3.0 weeks). Time to onset of action also was shorter in females overall. It is unclear why we see gender differences in acne studies. A number of reasons have been suggested, including differences in AV pathophysiology and/or treatment adherence.^11,12 Greater efficacy of clindamycin-BP 3.75% gel in females compared with males has already been reported, and better overall efficacy leading to a shorter TOA has been noted by others.¹³

There are limitations with this analysis. First, it is not possible to assess the contributions from each of the monads to the efficacy of clindamycin-BP 3.75% gel or TOA. Also, the data extraction method used assumes a linear progression model during the provided time points and was used to provide some comparison with calculations for other combination products.⁹ Although no strong deviations from the linear model are likely, calculations of TOA using other methodologies may give different results. The definition of a clinically meaningful benefit, defined here as a 25% reduction in the mean lesion count, has been used as a guide, but it has not been validated in clinical practice. It also is important to recognize that the initial visible perception of improvement of AV is likely to differ based on interpatient variability; that is, how different individuals perceive improvement. It also may be affected by differences in baseline severity of AV among different patients. Additionally, the TOA reflects an average duration of time, so it should not be described to patients as a suggestion of when they will definitely see visible improvement in their AV.

Conclusion

Unrealistic expectations of acne therapy or poor tolerability can lead to low adherence and poor clinical outcomes.^1-4 The data on TOA reported here suggests that a clinically meaningful benefit with clindamycin-BP 3.75% gel may be seen in some patients within 2 to 3 weeks and maybe sooner in females or those with milder disease; however, longer durations may be required in some patients. This information can help clinicians and their staff in providing reasonable expectations and stress the importance of encouraging patients about the need to adhere to treatment.

Acknowledgments

The author thanks Brian Bulley, MSc (Inergy Limited, Lindfield, West Sussex, United Kingdom), for publication support. Valeant Pharmaceuticals North America, LLC, funded Inergy’s activities pertaining to this analysis. The author did not receive funding or any form of compensation for authorship of this publication.

Acne vulgaris (AV) is a common skin disease that usually presents in adolescence and can persist into adulthood. Some cases may start in adulthood, especially in women. Acne vulgaris remains a challenge to treat successfully, both in teenagers and adults. Unrealistic expectations that therapy will rapidly clear and sustain clearance of AV completely can lead to incomplete adherence or complete cessation of treatment.^1-4 Local tolerability reactions also may decrease adherence to topical medications. Suboptimal adherence to medications for AV is one of the major reasons for treatment failure.⁵ Acne vulgaris can strongly influence psychological well-being and self-esteem.⁶ In general, severe AV causes more psychological distress, but the adverse emotional impact of AV can be independent of its severity.⁷

An effective relationship between the patient and his/her physician and staff is believed to be important in setting realistic expectations, optimizing adherence, and achieving a positive therapeutic outcome. One component related to setting reasonable expectations is the discussion about when the patient may begin to visibly perceive that the treatment regimen is working. This article evaluates the time course of a clinically meaningful response using pivotal trial data with clindamycin phosphate 1.2%–benzoyl peroxide 3.75% (clindamycin-BP 3.75%) gel for treatment of AV.

Are data available that evaluate the time course of a clinically relevant response to treatment of AV?

Unfortunately, data on what might be perceived as a clinically meaningful improvement in AV and how long it might take to achieve this treatment effect are limited. A meta-analysis of more than 4000 patients with moderate to severe AV suggested that a 10% to 20% difference in acne lesion counts from baseline as compared to a subsequent designated time point was clinically relevant.⁸ A review of 24 comparative studies of patients with mild to moderate AV used a primary outcome parameter of a 25% reduction in mean inflammatory lesion count to evaluate time to onset of action (TOA) to achieve a clinically meaningful benefit.⁹ This outcome was based on a previously identified threshold of clinical relevance and the authors’ clinical experience in a patient population with milder AV. In this same analysis, a difference of greater than 4 days between the active group and the vehicle group was considered to be relevant to the patient.⁹

A faster onset of visible improvement as perceived by the patient should be more desirable and is likely to improve treatment adherence, as long as it is not counterbalanced by an increase in adverse events.

What is meant by TOA?

Time to onset of action refers to the duration required to achieve a 25% mean lesion count reduction from baseline, which is believed to correlate with the time point at which many patients would be able to perceive visible improvement when viewing their full face. Therefore, TOA represents an attempt to correlate data that is quantitative (based on lesion count reduction) with what is likely to be the average time that a patient may qualitatively observe an initial visible improvement in their AV. This concept may be useful as a tool when communicating with AV patients but should not be used in a way that will overpromise and underdeliver; rather, it is a guide for discussion with the patient and with a parent or guardian when applicable.

Consistent with the comparative AV study analysis that evaluated TOA, a linear course of lesion reductions between the provided time intervals was assumed. In this linear model, the TOA was calculated using the 2 extracted lesion count values between which the 25% lesion reduction was achieved as well as their corresponding given time points.⁹ Differences between the results in the active and vehicle study arms were calculated for a number of determinants.

How was pivotal trial data with clindamycin-BP 3.75% gel used to assess TOA?

A total of 498 patients with moderate to severe AV were randomized (1:1) to receive clindamycin-BP 3.75% gel or vehicle in a multicenter, double-blind, controlled, 12-week, 2-arm study.¹⁰ Before randomization, patients were stratified by acne severity based on a static Evaluator’s Global Severity Score (EGSS) ranging from 0 (clear) to 5 (very severe). Specifically, moderate AV (EGSS of 3) was described as predominantly noninflammatory lesions with evidence of multiple inflammatory lesions; several to many comedones, papules, and pustules; and no more than 1 small nodulocystic lesion. Severe AV (EGSS of 4) was characterized by inflammatory lesions; numerous comedones, papules, and pustules; and possibly a few nodulocystic lesions.¹⁰

Male and female patients aged 12 to 40 years with moderate to severe AV—defined as 20 to 40 inflammatory lesions (papules, pustules, nodules), 20 to 100 noninflammatory lesions (comedones), and no more than 2 nodules—were included in the study. Standard washout periods were required for patients using prior prescription and over-the-counter acne treatments.¹⁰

Efficacy evaluations included inflammatory and noninflammatory lesion counts and EGSS at screening, baseline, and during treatment (weeks 4, 8, and 12).¹⁰ Primary efficacy end points included absolute change in mean inflammatory and noninflammatory lesion counts and the proportion of patients who achieved at least a 2-grade reduction in EGSS from baseline to week 12 (treatment success at end of study). Secondary efficacy end points included mean percentage change from baseline to week 12 in inflammatory and noninflammatory lesion counts and the proportion of patients who considered themselves clear or almost clear at week 12.¹⁰

After 12 weeks of daily treatment, inflammatory and noninflammatory lesion counts decreased by a mean of 60.4% and 51.8%, respectively, with clindamycin-BP 3.75% gel compared to 31.3% and 27.6%, respectively, with vehicle (both P<.001). At weeks 4, 8, and 12, the difference in inflammatory and noninflammatory lesion counts for the active treatment was 17.4%, 24.8%, and 29.1%, respectively, and 8.1%, 19.8%, and 24.2%, respectively, for vehicle.¹⁰

Treatment success (at least a 2-grade improvement in EGSS) was achieved by 9.1% of patients using clindamycin-BP 3.75% gel compared to 4.6% using vehicle by week 4. Additionally, 6.3% of patients considered their AV as clear or almost clear compared to 3.5% with vehicle at week 2 (Figure 1).¹⁰

This analysis represents the first attempt to evaluate and report TOA results with clindamycin-BP 3.75% gel. Time to onset of action for inflammatory lesions treated with clindamycin-BP 3.75% gel was calculated as 2.5 weeks versus 6.2 weeks for vehicle (Figure 2A). Time to onset of action for noninflammatory lesions was 3.7 weeks with clindamycin-BP 3.75% gel versus 8.6 weeks with vehicle (Figure 2B). The difference in TOA between the active and vehicle study groups was 3.7 weeks and 4.9 weeks, respectively. In addition, among actively treated patients, TOA was shorter in females (2.1 weeks) than in males (2.6 weeks) and in moderate AV (2.5 weeks) compared to severe AV (3.0 weeks).

Comment

Differences in lesion counts between clindamycin-BP 3.75% gel and vehicle suggest a clinically relevant benefit in favor of active treatment with both inflammatory and noninflammatory lesions. Nearly twice as many patients were rated as treatment successes using EGSS by week 4 or clear or almost clear as early as week 2 compared to the vehicle group.¹⁰ However, these data are suggested as an overall guide but do not provide adequate guidance on when visible improvement may start to be evident in a given patient.

The analysis reported here shows a TOA of 2.5 weeks with clindamycin-BP 3.75% gel for inflammatory lesions, approximately 4 weeks faster than with the vehicle. In most cases, a reduction in inflammatory lesions is more likely to have a greater impact on patient perception of TOA. Unless a patient is aware or focused enough to actively distinguish visibly between inflammatory and noninflammatory (comedonal) AV lesions, their eye is more likely to be drawn initially to reduction in inflammatory lesions, which are erythematous and more visible at a greater viewing distance. Although noninflammatory AV lesions usually require closer inspection to visualize them (especially closed comedones), they are often slower to respond to treatment. Analysis of the pivotal trial data reports a longer TOA with clindamycin-BP 3.75% gel for noninflammatory lesions (3.7 weeks) versus inflammatory lesions (2.5 weeks).

As expected, TOA was shorter in patients with moderate AV than severe AV (2.5 weeks vs 3.0 weeks). Time to onset of action also was shorter in females overall. It is unclear why we see gender differences in acne studies. A number of reasons have been suggested, including differences in AV pathophysiology and/or treatment adherence.^11,12 Greater efficacy of clindamycin-BP 3.75% gel in females compared with males has already been reported, and better overall efficacy leading to a shorter TOA has been noted by others.¹³

There are limitations with this analysis. First, it is not possible to assess the contributions from each of the monads to the efficacy of clindamycin-BP 3.75% gel or TOA. Also, the data extraction method used assumes a linear progression model during the provided time points and was used to provide some comparison with calculations for other combination products.⁹ Although no strong deviations from the linear model are likely, calculations of TOA using other methodologies may give different results. The definition of a clinically meaningful benefit, defined here as a 25% reduction in the mean lesion count, has been used as a guide, but it has not been validated in clinical practice. It also is important to recognize that the initial visible perception of improvement of AV is likely to differ based on interpatient variability; that is, how different individuals perceive improvement. It also may be affected by differences in baseline severity of AV among different patients. Additionally, the TOA reflects an average duration of time, so it should not be described to patients as a suggestion of when they will definitely see visible improvement in their AV.

Conclusion

Unrealistic expectations of acne therapy or poor tolerability can lead to low adherence and poor clinical outcomes.^1-4 The data on TOA reported here suggests that a clinically meaningful benefit with clindamycin-BP 3.75% gel may be seen in some patients within 2 to 3 weeks and maybe sooner in females or those with milder disease; however, longer durations may be required in some patients. This information can help clinicians and their staff in providing reasonable expectations and stress the importance of encouraging patients about the need to adhere to treatment.

Acknowledgments

The author thanks Brian Bulley, MSc (Inergy Limited, Lindfield, West Sussex, United Kingdom), for publication support. Valeant Pharmaceuticals North America, LLC, funded Inergy’s activities pertaining to this analysis. The author did not receive funding or any form of compensation for authorship of this publication.

Acne vulgaris (AV) is a common skin disease that usually presents in adolescence and can persist into adulthood. Some cases may start in adulthood, especially in women. Acne vulgaris remains a challenge to treat successfully, both in teenagers and adults. Unrealistic expectations that therapy will rapidly clear and sustain clearance of AV completely can lead to incomplete adherence or complete cessation of treatment.^1-4 Local tolerability reactions also may decrease adherence to topical medications. Suboptimal adherence to medications for AV is one of the major reasons for treatment failure.⁵ Acne vulgaris can strongly influence psychological well-being and self-esteem.⁶ In general, severe AV causes more psychological distress, but the adverse emotional impact of AV can be independent of its severity.⁷

An effective relationship between the patient and his/her physician and staff is believed to be important in setting realistic expectations, optimizing adherence, and achieving a positive therapeutic outcome. One component related to setting reasonable expectations is the discussion about when the patient may begin to visibly perceive that the treatment regimen is working. This article evaluates the time course of a clinically meaningful response using pivotal trial data with clindamycin phosphate 1.2%–benzoyl peroxide 3.75% (clindamycin-BP 3.75%) gel for treatment of AV.

Are data available that evaluate the time course of a clinically relevant response to treatment of AV?

Unfortunately, data on what might be perceived as a clinically meaningful improvement in AV and how long it might take to achieve this treatment effect are limited. A meta-analysis of more than 4000 patients with moderate to severe AV suggested that a 10% to 20% difference in acne lesion counts from baseline as compared to a subsequent designated time point was clinically relevant.⁸ A review of 24 comparative studies of patients with mild to moderate AV used a primary outcome parameter of a 25% reduction in mean inflammatory lesion count to evaluate time to onset of action (TOA) to achieve a clinically meaningful benefit.⁹ This outcome was based on a previously identified threshold of clinical relevance and the authors’ clinical experience in a patient population with milder AV. In this same analysis, a difference of greater than 4 days between the active group and the vehicle group was considered to be relevant to the patient.⁹

A faster onset of visible improvement as perceived by the patient should be more desirable and is likely to improve treatment adherence, as long as it is not counterbalanced by an increase in adverse events.

What is meant by TOA?

Time to onset of action refers to the duration required to achieve a 25% mean lesion count reduction from baseline, which is believed to correlate with the time point at which many patients would be able to perceive visible improvement when viewing their full face. Therefore, TOA represents an attempt to correlate data that is quantitative (based on lesion count reduction) with what is likely to be the average time that a patient may qualitatively observe an initial visible improvement in their AV. This concept may be useful as a tool when communicating with AV patients but should not be used in a way that will overpromise and underdeliver; rather, it is a guide for discussion with the patient and with a parent or guardian when applicable.

Consistent with the comparative AV study analysis that evaluated TOA, a linear course of lesion reductions between the provided time intervals was assumed. In this linear model, the TOA was calculated using the 2 extracted lesion count values between which the 25% lesion reduction was achieved as well as their corresponding given time points.⁹ Differences between the results in the active and vehicle study arms were calculated for a number of determinants.

How was pivotal trial data with clindamycin-BP 3.75% gel used to assess TOA?

A total of 498 patients with moderate to severe AV were randomized (1:1) to receive clindamycin-BP 3.75% gel or vehicle in a multicenter, double-blind, controlled, 12-week, 2-arm study.¹⁰ Before randomization, patients were stratified by acne severity based on a static Evaluator’s Global Severity Score (EGSS) ranging from 0 (clear) to 5 (very severe). Specifically, moderate AV (EGSS of 3) was described as predominantly noninflammatory lesions with evidence of multiple inflammatory lesions; several to many comedones, papules, and pustules; and no more than 1 small nodulocystic lesion. Severe AV (EGSS of 4) was characterized by inflammatory lesions; numerous comedones, papules, and pustules; and possibly a few nodulocystic lesions.¹⁰

Male and female patients aged 12 to 40 years with moderate to severe AV—defined as 20 to 40 inflammatory lesions (papules, pustules, nodules), 20 to 100 noninflammatory lesions (comedones), and no more than 2 nodules—were included in the study. Standard washout periods were required for patients using prior prescription and over-the-counter acne treatments.¹⁰

Efficacy evaluations included inflammatory and noninflammatory lesion counts and EGSS at screening, baseline, and during treatment (weeks 4, 8, and 12).¹⁰ Primary efficacy end points included absolute change in mean inflammatory and noninflammatory lesion counts and the proportion of patients who achieved at least a 2-grade reduction in EGSS from baseline to week 12 (treatment success at end of study). Secondary efficacy end points included mean percentage change from baseline to week 12 in inflammatory and noninflammatory lesion counts and the proportion of patients who considered themselves clear or almost clear at week 12.¹⁰

After 12 weeks of daily treatment, inflammatory and noninflammatory lesion counts decreased by a mean of 60.4% and 51.8%, respectively, with clindamycin-BP 3.75% gel compared to 31.3% and 27.6%, respectively, with vehicle (both P<.001). At weeks 4, 8, and 12, the difference in inflammatory and noninflammatory lesion counts for the active treatment was 17.4%, 24.8%, and 29.1%, respectively, and 8.1%, 19.8%, and 24.2%, respectively, for vehicle.¹⁰

Treatment success (at least a 2-grade improvement in EGSS) was achieved by 9.1% of patients using clindamycin-BP 3.75% gel compared to 4.6% using vehicle by week 4. Additionally, 6.3% of patients considered their AV as clear or almost clear compared to 3.5% with vehicle at week 2 (Figure 1).¹⁰

This analysis represents the first attempt to evaluate and report TOA results with clindamycin-BP 3.75% gel. Time to onset of action for inflammatory lesions treated with clindamycin-BP 3.75% gel was calculated as 2.5 weeks versus 6.2 weeks for vehicle (Figure 2A). Time to onset of action for noninflammatory lesions was 3.7 weeks with clindamycin-BP 3.75% gel versus 8.6 weeks with vehicle (Figure 2B). The difference in TOA between the active and vehicle study groups was 3.7 weeks and 4.9 weeks, respectively. In addition, among actively treated patients, TOA was shorter in females (2.1 weeks) than in males (2.6 weeks) and in moderate AV (2.5 weeks) compared to severe AV (3.0 weeks).

Comment

Differences in lesion counts between clindamycin-BP 3.75% gel and vehicle suggest a clinically relevant benefit in favor of active treatment with both inflammatory and noninflammatory lesions. Nearly twice as many patients were rated as treatment successes using EGSS by week 4 or clear or almost clear as early as week 2 compared to the vehicle group.¹⁰ However, these data are suggested as an overall guide but do not provide adequate guidance on when visible improvement may start to be evident in a given patient.

The analysis reported here shows a TOA of 2.5 weeks with clindamycin-BP 3.75% gel for inflammatory lesions, approximately 4 weeks faster than with the vehicle. In most cases, a reduction in inflammatory lesions is more likely to have a greater impact on patient perception of TOA. Unless a patient is aware or focused enough to actively distinguish visibly between inflammatory and noninflammatory (comedonal) AV lesions, their eye is more likely to be drawn initially to reduction in inflammatory lesions, which are erythematous and more visible at a greater viewing distance. Although noninflammatory AV lesions usually require closer inspection to visualize them (especially closed comedones), they are often slower to respond to treatment. Analysis of the pivotal trial data reports a longer TOA with clindamycin-BP 3.75% gel for noninflammatory lesions (3.7 weeks) versus inflammatory lesions (2.5 weeks).

As expected, TOA was shorter in patients with moderate AV than severe AV (2.5 weeks vs 3.0 weeks). Time to onset of action also was shorter in females overall. It is unclear why we see gender differences in acne studies. A number of reasons have been suggested, including differences in AV pathophysiology and/or treatment adherence.^11,12 Greater efficacy of clindamycin-BP 3.75% gel in females compared with males has already been reported, and better overall efficacy leading to a shorter TOA has been noted by others.¹³

There are limitations with this analysis. First, it is not possible to assess the contributions from each of the monads to the efficacy of clindamycin-BP 3.75% gel or TOA. Also, the data extraction method used assumes a linear progression model during the provided time points and was used to provide some comparison with calculations for other combination products.⁹ Although no strong deviations from the linear model are likely, calculations of TOA using other methodologies may give different results. The definition of a clinically meaningful benefit, defined here as a 25% reduction in the mean lesion count, has been used as a guide, but it has not been validated in clinical practice. It also is important to recognize that the initial visible perception of improvement of AV is likely to differ based on interpatient variability; that is, how different individuals perceive improvement. It also may be affected by differences in baseline severity of AV among different patients. Additionally, the TOA reflects an average duration of time, so it should not be described to patients as a suggestion of when they will definitely see visible improvement in their AV.

Conclusion

Unrealistic expectations of acne therapy or poor tolerability can lead to low adherence and poor clinical outcomes.^1-4 The data on TOA reported here suggests that a clinically meaningful benefit with clindamycin-BP 3.75% gel may be seen in some patients within 2 to 3 weeks and maybe sooner in females or those with milder disease; however, longer durations may be required in some patients. This information can help clinicians and their staff in providing reasonable expectations and stress the importance of encouraging patients about the need to adhere to treatment.

Acknowledgments

The author thanks Brian Bulley, MSc (Inergy Limited, Lindfield, West Sussex, United Kingdom), for publication support. Valeant Pharmaceuticals North America, LLC, funded Inergy’s activities pertaining to this analysis. The author did not receive funding or any form of compensation for authorship of this publication.

Selection of oral agents for treatment of AV in adult women is dependent on multiple factors including the patient’s age, medication history, child-bearing potential, clinical presentation, and treatment preference following a discussion of the anticipated benefits versus potential risks.^1,2 In patients with the mixed inflammatory and comedonal clinical pattern of AV, oral antibiotics can be used concurrently with topical therapies when moderate to severe inflammatory lesions are noted.^3,4 However, many adult women who had AV as teenagers have already utilized oral antibiotic therapies in the past and often are interested in alternative options, express concerns regarding antibiotic resistance, report a history of antibiotic-associated yeast infections or other side effects, and/or encounter issues related to drug-drug interactions.^3,5-8 Oral hormonal therapies such as combination oral contraceptives (COCs) or spironolactone often are utilized to treat adult women with AV, sometimes in combination with each other or other agents. Combination oral contraceptives appear to be especially effective in the management of the U-shaped clinical pattern or predominantly inflammatory, late-onset AV.^1,5,9,10 Potential warnings, contraindications, adverse effects, and drug-drug interactions are important to keep in mind when considering the use of oral hormonal therapies.^8-10 Oral isotretinoin, which should be prescribed with strict adherence to the iPLEDGE™ program (https://www.ipledgeprogram.com/), remains a viable option for cases of severe nodular AV and selected cases of refractory inflammatory AV, especially when scarring and/or marked psychosocial distress are noted.^1,2,5,11 Although it is recognized that adult women with AV typically present with either a mixed inflammatory and comedonal or U-shaped clinical pattern predominantly involving the lower face and anterolateral neck, the available data do not adequately differentiate the relative responsiveness of these clinical patterns to specific therapeutic agents.

Combination Oral Contraceptives

Combination oral contraceptives are commonly used to treat AV in adult women, including those without and those with measurable androgen excess (eg, polycystic ovary syndrome [PCOS]). Combination oral contraceptives contain ethinyl estradiol and a progestational agent (eg, progestin); the latter varies in terms of its nonselective receptor interactions and the relative magnitude or absence of androgenic effects.^10,12,13 Although some COCs are approved by the US Food and Drug Administration (FDA) for AV, there is little data available to determine the comparative efficacy among these and other COCs.^10,14 When choosing a COC for treatment of AV, it is best to select an agent whose effectiveness is supported by evidence from clinical studies.^10,15

Mechanisms of Action

The reported mechanisms of action for COCs include inhibition of ovarian androgen production and ovulation through gonadotropin suppression; upregulated synthesis of sex hormone–binding globulin, which decreases free testosterone levels through receptor binding; and inhibition of 5α-reductase (by some progestins), which reduces conversion of testosterone to dihydrotestosterone, the active derivative that induces androgenic effects at peripheral target tissues.^10,13,16,17

Therapeutic Benefits

Use of COCs to treat AV in adult women who do not have measurable androgen excess is most rational in patients who also desire a method of contraception. Multiple monotherapy studies have demonstrated the efficacy of COCs in the treatment of AV on the face and trunk.^{4,10,12,15,17,18} It may take a minimum of 3 monthly cycles of use before acne lesion counts begin to appreciably decrease.^12,15,19-21 Initiating COC therapy during menstruation ensures the absence of pregnancy. Combination oral contraceptives may be used with other topical and oral therapies for AV.^2,3,9,10 Potential ancillary benefits of COCs include normalization of the menstrual cycle; reduced premenstrual dysphoric disorder symptoms; and reduced risk of endometrial cancer (approximately 50%), ovarian cancer (approximately 40%), and colorectal cancer.^22-24

Risks and Contraindications

It is important to consider the potential risks associated with the use of COCs, especially in women with AV who are not seeking a method of contraception. Side effects of COCs can include nausea, breast tenderness, breakthrough bleeding, and weight gain.^25,26 Potential adverse associations of COCs are described in the Table. The major potential vascular associations include venous thromboembolism, myocardial infarction, and cerebrovascular accident, all of which are influenced by concurrent factors such as a history of smoking, age (≥35 years), and hypertension.^27-32 It is recommended that blood pressure be measured before initiating COC therapy as part of the general examination.³³

The potential increase in breast cancer risk appears to be low, while the cervical cancer risk is reported to increase relative to the duration of use.^34-37 This latter observation may be due to the greater likelihood of unprotected sex in women using a COC and exposure to multiple sexual partners in some cases, which may increase the likelihood of oncogenic human papillomavirus infection of the cervix. If a dermatologist elects to prescribe a COC to treat AV, it has been suggested that the patient also consult with her general practitioner or gynecologist to undergo pelvic and breast examinations and a Papanicolaou test.³³ The recommendation for initial screening for cervical cancer is within 3 years of initiation of sexual intercourse or by 21 years of age, whichever is first.^33,38,39

Combination oral contraceptives are not ideal for all adult women with AV. Absolute contraindications are pregnancy and history of thromboembolic, cardiac, or hepatic disease; in women aged 35 years and older who smoke, relative contraindications include hypertension, diabetes, migraines, breastfeeding, and current breast or liver cancer.³³ In adult women with AV who have relative contra-indications but are likely to benefit from the use of a COC when other options are limited or not viable, consultation with a gynecologist is prudent. Other than rifamycin antibiotics (eg, rifampin) and griseofulvin, there is no definitive evidence that oral antibiotics (eg, tetracycline) or oral antifungal agents reduce the contraceptive efficacy of COCs, although cautions remain in print within some approved package inserts.⁸

Spironolactone

Available since 1957, spironolactone is an oral aldos-terone antagonist and potassium-sparing diuretic used to treat hypertension and congestive heart failure.⁹ Recognition of its antiandrogenic effects led to its use in dermatology to treat certain dermatologic disorders in women (eg, hirsutism, alopecia, AV).^1,4,5,9,10 Spironolactone is not approved for AV by the FDA; therefore, available data from multiple independent studies and retrospective analyses that have been collectively reviewed support its efficacy when used as both monotherapy or in combination with other agents in adult women with AV, especially those with a U-shaped pattern and/or late-onset AV.^9,40-43

Mechanism of Action

Spironolactone inhibits sebaceous gland activity through peripheral androgen receptor blockade, inhibition of 5α-reductase, decrease in androgen production, and increase in sex hormone–binding globulin.^9,10,40

Therapeutic Benefits

Good to excellent improvement of AV in women, many of whom are postadolescent, has ranged from 66% to 100% in published reports^9,40-43; however, inclusion and exclusion criteria, dosing regimens, and concomitant therapies were not usually controlled. Spironolactone has been used to treat AV in adult women as monotherapy or in combination with topical agents, oral antibiotics, and COCs.^9,40-42 Additionally, dose-ranging studies have not been completed with spironolactone for AV.^9,40 The suggested dose range is 50 mg to 200 mg daily; however, it usually is best to start at 50 mg daily and increase to 100 mg daily if clinical response is not adequate after 2 to 3 months. The gastrointestinal (GI) absorption of spironolactone is increased when ingested with a high-fat meal.^9,10

Once effective control of AV is achieved, it is optimal to use the lowest dose needed to continue reasonable suppression of new AV lesions. There is no defined end point for spironolactone use in AV, with or without concurrent PCOS, as many adult women usually continue treatment with low-dose therapy because they experience marked flaring shortly after the drug is stopped.⁹

Risks and Contraindications

Side effects associated with spironolactone are dose related and include increased diuresis, migraines, menstrual irregularities, breast tenderness, gynecomastia, fatigue, and dizziness.^9,10,40-44 Side effects (particularly menstrual irregularities and breast tenderness) are more common at doses higher than 100 mg daily, especially when used as monotherapy without concurrent use of a COC.^9,40

Spironolactone-associated hyperkalemia is most clinically relevant in patients on higher doses (eg, 100–200 mg daily), in those with renal impairment and/or congestive heart failure, and when used concurrently with certain other medications. In any patient on spironolactone, the risk of clinically relevant hyperkalemia may be increased by coingestion of potassium supplements, potassium-based salt substitutes, potassium-sparing diuretics (eg, amiloride, triamterene); aldosterone antagonists and angiotensin-converting enzyme inhibitors (eg, lisinopril, benazepril); angiotensin II receptor blockers (eg, losartan, valsartan); and tri-methoprim (with or without sulfamethoxazole).^8,9,40,45 Spironolactone may also increase serum levels of lithium or digoxin.^9,40,45,46 For management of AV, it is best that spironolactone be avoided in patients taking any of these medications.⁹

In healthy adult women with AV who are not on medications or supplements that interact adversely with spironolactone, there is no definitive recommendation regarding monitoring of serum potassium levels during treatment with spironolactone, and it has been suggested that monitoring serum potassium levels in this subgroup is not necessary.⁴⁷ However, each clinician is advised to choose whether or not they wish to obtain baseline and/or periodic serum potassium levels when prescribing spironolactone for AV based on their degree of comfort and the patient’s history. Baseline and periodic blood testing to evaluate serum electrolytes and renal function are reasonable, especially as adult women with AV are usually treated with spironolactone over a prolonged period of time.⁹

The FDA black box warning for spironolactone states that it is tumorigenic in chronic toxicity studies in rats and refers to exposures 25- to 100-fold higher than those administered to humans.^9,48 Although continued vigilance is warranted, evaluation of large populations of women treated with spironolactone do not suggest an association with increased risk of breast cancer.^49,50

Spironolactone is a category C drug and thus should be avoided during pregnancy, primarily due to animal data suggesting risks of hypospadias and feminization in male fetuses.⁹ Importantly, there is an absence of reports linking exposure during pregnancy with congenital defects in humans, including in 2 known cases of high-dose exposures for maternal Bartter syndrome.⁹

The active metabolite, canrenone, is known to be present in breast milk at 0.2% of the maternal daily dose, but breastfeeding is generally believed to be safe with spironolactone based on evidence to date.⁹

Oral Antibiotics

Oral antibiotic therapy may be used in combination with a topical regimen to treat AV in adult women, keeping in mind some important caveats.^1-7 For instance, monotherapy with oral antibiotics should be avoided, and concomitant use of benzoyl peroxide is suggested to reduce emergence of antibiotic-resistant Propionibacterium acnes strains.^3,4 A therapeutic exit plan also is suggested when prescribing oral antibiotics to limit treatment to 3 to 4 months, if possible, to help mitigate the emergence of antibiotic-resistant bacteria (eg, staphylococci and streptococci).^3-5,51

Tetracyclines, especially doxycycline and minocycline, are the most commonly prescribed agents. Doxycycline use warrants patient education on measures to limit the risks of esophageal and GI side effects and phototoxicity; enteric-coated and small tablet formulations have been shown to reduce GI side effects, especially when administered with food.^3,52-55 In addition to vestibular side effects and hyperpigmentation, minocycline may be associated with rare but potentially severe adverse reactions such as drug hypersensitivity syndrome, autoimmune hepatitis, and lupus-like syndrome, which are reported more commonly in women.^5,52,54 Vestibular side effects have been shown to decrease with use of extended-release tablets with weight-based dosing.⁵³

Oral Isotretinoin

Oral isotretinoin is well established as highly effective for treatment of severe, recalcitrant AV, including nodular acne on the face and trunk.^4,56 Currently available oral isotretinoins are branded generic formulations based on the pharmacokinetic profile of the original brand (Accutane [Roche Pharmaceuticals]) and with the use of Lidose Technology (Absorica [Cipher Pharmaceuticals]), which substantially increases GI absorption of isotretinoin in the absence of ingestion with a high-calorie, high-fat meal.⁵⁷ The short- and long-term efficacy, dosing regimens, safety considerations, and serious teratogenic risks for oral isotretinoin are well published.^4,56-58 Importantly, oral isotretinoin must be prescribed with strict adherence to the federally mandated iPLEDGE risk management program.

Low-dose oral isotretinoin therapy (<0.5 mg/kg–1 mg/kg daily) administered over several months longer than conventional regimens (ie, 16–20 weeks) has been suggested with demonstrated efficacy.⁵⁷ However, this approach is not optimal due to the lack of established sustained clearance of AV after discontinuation of therapy and the greater potential for exposure to isotretinoin during pregnancy. Recurrences of AV do occur after completion of isotretinoin therapy, especially if cumulative systemic exposure to the drug during the initial course of treatment was inadequate.^56,57

Oral isotretinoin has been shown to be effective in AV in adult women with or without PCOS with 0.5 mg/kg to 1 mg/kg daily and a total cumulative exposure of 120 mg/kg to 150 mg/kg.⁵⁹ In one study, the presence of PCOS and greater number of nodules at baseline were predictive of a higher risk of relapse during the second year posttreatment.⁵⁹

Conclusion

All oral therapies that are used to treat AV in adult women warrant individual consideration of possible benefits versus risks. Careful attention to possible side effects, patient-related risk factors, and potential drug-drug interactions is important. End points of therapy are not well established, with the exception of oral isotretinoin therapy. Clinicians must use their judgment in each case along with obtaining feedback from patients regarding the selection of therapy after a discussion of the available options.

Selection of oral agents for treatment of AV in adult women is dependent on multiple factors including the patient’s age, medication history, child-bearing potential, clinical presentation, and treatment preference following a discussion of the anticipated benefits versus potential risks.^1,2 In patients with the mixed inflammatory and comedonal clinical pattern of AV, oral antibiotics can be used concurrently with topical therapies when moderate to severe inflammatory lesions are noted.^3,4 However, many adult women who had AV as teenagers have already utilized oral antibiotic therapies in the past and often are interested in alternative options, express concerns regarding antibiotic resistance, report a history of antibiotic-associated yeast infections or other side effects, and/or encounter issues related to drug-drug interactions.^3,5-8 Oral hormonal therapies such as combination oral contraceptives (COCs) or spironolactone often are utilized to treat adult women with AV, sometimes in combination with each other or other agents. Combination oral contraceptives appear to be especially effective in the management of the U-shaped clinical pattern or predominantly inflammatory, late-onset AV.^1,5,9,10 Potential warnings, contraindications, adverse effects, and drug-drug interactions are important to keep in mind when considering the use of oral hormonal therapies.^8-10 Oral isotretinoin, which should be prescribed with strict adherence to the iPLEDGE™ program (https://www.ipledgeprogram.com/), remains a viable option for cases of severe nodular AV and selected cases of refractory inflammatory AV, especially when scarring and/or marked psychosocial distress are noted.^1,2,5,11 Although it is recognized that adult women with AV typically present with either a mixed inflammatory and comedonal or U-shaped clinical pattern predominantly involving the lower face and anterolateral neck, the available data do not adequately differentiate the relative responsiveness of these clinical patterns to specific therapeutic agents.

Combination Oral Contraceptives

Combination oral contraceptives are commonly used to treat AV in adult women, including those without and those with measurable androgen excess (eg, polycystic ovary syndrome [PCOS]). Combination oral contraceptives contain ethinyl estradiol and a progestational agent (eg, progestin); the latter varies in terms of its nonselective receptor interactions and the relative magnitude or absence of androgenic effects.^10,12,13 Although some COCs are approved by the US Food and Drug Administration (FDA) for AV, there is little data available to determine the comparative efficacy among these and other COCs.^10,14 When choosing a COC for treatment of AV, it is best to select an agent whose effectiveness is supported by evidence from clinical studies.^10,15

Mechanisms of Action

The reported mechanisms of action for COCs include inhibition of ovarian androgen production and ovulation through gonadotropin suppression; upregulated synthesis of sex hormone–binding globulin, which decreases free testosterone levels through receptor binding; and inhibition of 5α-reductase (by some progestins), which reduces conversion of testosterone to dihydrotestosterone, the active derivative that induces androgenic effects at peripheral target tissues.^10,13,16,17

Therapeutic Benefits

Use of COCs to treat AV in adult women who do not have measurable androgen excess is most rational in patients who also desire a method of contraception. Multiple monotherapy studies have demonstrated the efficacy of COCs in the treatment of AV on the face and trunk.^{4,10,12,15,17,18} It may take a minimum of 3 monthly cycles of use before acne lesion counts begin to appreciably decrease.^12,15,19-21 Initiating COC therapy during menstruation ensures the absence of pregnancy. Combination oral contraceptives may be used with other topical and oral therapies for AV.^2,3,9,10 Potential ancillary benefits of COCs include normalization of the menstrual cycle; reduced premenstrual dysphoric disorder symptoms; and reduced risk of endometrial cancer (approximately 50%), ovarian cancer (approximately 40%), and colorectal cancer.^22-24

Risks and Contraindications

It is important to consider the potential risks associated with the use of COCs, especially in women with AV who are not seeking a method of contraception. Side effects of COCs can include nausea, breast tenderness, breakthrough bleeding, and weight gain.^25,26 Potential adverse associations of COCs are described in the Table. The major potential vascular associations include venous thromboembolism, myocardial infarction, and cerebrovascular accident, all of which are influenced by concurrent factors such as a history of smoking, age (≥35 years), and hypertension.^27-32 It is recommended that blood pressure be measured before initiating COC therapy as part of the general examination.³³

The potential increase in breast cancer risk appears to be low, while the cervical cancer risk is reported to increase relative to the duration of use.^34-37 This latter observation may be due to the greater likelihood of unprotected sex in women using a COC and exposure to multiple sexual partners in some cases, which may increase the likelihood of oncogenic human papillomavirus infection of the cervix. If a dermatologist elects to prescribe a COC to treat AV, it has been suggested that the patient also consult with her general practitioner or gynecologist to undergo pelvic and breast examinations and a Papanicolaou test.³³ The recommendation for initial screening for cervical cancer is within 3 years of initiation of sexual intercourse or by 21 years of age, whichever is first.^33,38,39

Combination oral contraceptives are not ideal for all adult women with AV. Absolute contraindications are pregnancy and history of thromboembolic, cardiac, or hepatic disease; in women aged 35 years and older who smoke, relative contraindications include hypertension, diabetes, migraines, breastfeeding, and current breast or liver cancer.³³ In adult women with AV who have relative contra-indications but are likely to benefit from the use of a COC when other options are limited or not viable, consultation with a gynecologist is prudent. Other than rifamycin antibiotics (eg, rifampin) and griseofulvin, there is no definitive evidence that oral antibiotics (eg, tetracycline) or oral antifungal agents reduce the contraceptive efficacy of COCs, although cautions remain in print within some approved package inserts.⁸

Spironolactone

Available since 1957, spironolactone is an oral aldos-terone antagonist and potassium-sparing diuretic used to treat hypertension and congestive heart failure.⁹ Recognition of its antiandrogenic effects led to its use in dermatology to treat certain dermatologic disorders in women (eg, hirsutism, alopecia, AV).^1,4,5,9,10 Spironolactone is not approved for AV by the FDA; therefore, available data from multiple independent studies and retrospective analyses that have been collectively reviewed support its efficacy when used as both monotherapy or in combination with other agents in adult women with AV, especially those with a U-shaped pattern and/or late-onset AV.^9,40-43

Mechanism of Action

Spironolactone inhibits sebaceous gland activity through peripheral androgen receptor blockade, inhibition of 5α-reductase, decrease in androgen production, and increase in sex hormone–binding globulin.^9,10,40

Therapeutic Benefits

Good to excellent improvement of AV in women, many of whom are postadolescent, has ranged from 66% to 100% in published reports^9,40-43; however, inclusion and exclusion criteria, dosing regimens, and concomitant therapies were not usually controlled. Spironolactone has been used to treat AV in adult women as monotherapy or in combination with topical agents, oral antibiotics, and COCs.^9,40-42 Additionally, dose-ranging studies have not been completed with spironolactone for AV.^9,40 The suggested dose range is 50 mg to 200 mg daily; however, it usually is best to start at 50 mg daily and increase to 100 mg daily if clinical response is not adequate after 2 to 3 months. The gastrointestinal (GI) absorption of spironolactone is increased when ingested with a high-fat meal.^9,10

Once effective control of AV is achieved, it is optimal to use the lowest dose needed to continue reasonable suppression of new AV lesions. There is no defined end point for spironolactone use in AV, with or without concurrent PCOS, as many adult women usually continue treatment with low-dose therapy because they experience marked flaring shortly after the drug is stopped.⁹

Risks and Contraindications

Side effects associated with spironolactone are dose related and include increased diuresis, migraines, menstrual irregularities, breast tenderness, gynecomastia, fatigue, and dizziness.^9,10,40-44 Side effects (particularly menstrual irregularities and breast tenderness) are more common at doses higher than 100 mg daily, especially when used as monotherapy without concurrent use of a COC.^9,40

Spironolactone-associated hyperkalemia is most clinically relevant in patients on higher doses (eg, 100–200 mg daily), in those with renal impairment and/or congestive heart failure, and when used concurrently with certain other medications. In any patient on spironolactone, the risk of clinically relevant hyperkalemia may be increased by coingestion of potassium supplements, potassium-based salt substitutes, potassium-sparing diuretics (eg, amiloride, triamterene); aldosterone antagonists and angiotensin-converting enzyme inhibitors (eg, lisinopril, benazepril); angiotensin II receptor blockers (eg, losartan, valsartan); and tri-methoprim (with or without sulfamethoxazole).^8,9,40,45 Spironolactone may also increase serum levels of lithium or digoxin.^9,40,45,46 For management of AV, it is best that spironolactone be avoided in patients taking any of these medications.⁹

In healthy adult women with AV who are not on medications or supplements that interact adversely with spironolactone, there is no definitive recommendation regarding monitoring of serum potassium levels during treatment with spironolactone, and it has been suggested that monitoring serum potassium levels in this subgroup is not necessary.⁴⁷ However, each clinician is advised to choose whether or not they wish to obtain baseline and/or periodic serum potassium levels when prescribing spironolactone for AV based on their degree of comfort and the patient’s history. Baseline and periodic blood testing to evaluate serum electrolytes and renal function are reasonable, especially as adult women with AV are usually treated with spironolactone over a prolonged period of time.⁹

The FDA black box warning for spironolactone states that it is tumorigenic in chronic toxicity studies in rats and refers to exposures 25- to 100-fold higher than those administered to humans.^9,48 Although continued vigilance is warranted, evaluation of large populations of women treated with spironolactone do not suggest an association with increased risk of breast cancer.^49,50

Spironolactone is a category C drug and thus should be avoided during pregnancy, primarily due to animal data suggesting risks of hypospadias and feminization in male fetuses.⁹ Importantly, there is an absence of reports linking exposure during pregnancy with congenital defects in humans, including in 2 known cases of high-dose exposures for maternal Bartter syndrome.⁹

The active metabolite, canrenone, is known to be present in breast milk at 0.2% of the maternal daily dose, but breastfeeding is generally believed to be safe with spironolactone based on evidence to date.⁹

Oral Antibiotics

Oral antibiotic therapy may be used in combination with a topical regimen to treat AV in adult women, keeping in mind some important caveats.^1-7 For instance, monotherapy with oral antibiotics should be avoided, and concomitant use of benzoyl peroxide is suggested to reduce emergence of antibiotic-resistant Propionibacterium acnes strains.^3,4 A therapeutic exit plan also is suggested when prescribing oral antibiotics to limit treatment to 3 to 4 months, if possible, to help mitigate the emergence of antibiotic-resistant bacteria (eg, staphylococci and streptococci).^3-5,51

Tetracyclines, especially doxycycline and minocycline, are the most commonly prescribed agents. Doxycycline use warrants patient education on measures to limit the risks of esophageal and GI side effects and phototoxicity; enteric-coated and small tablet formulations have been shown to reduce GI side effects, especially when administered with food.^3,52-55 In addition to vestibular side effects and hyperpigmentation, minocycline may be associated with rare but potentially severe adverse reactions such as drug hypersensitivity syndrome, autoimmune hepatitis, and lupus-like syndrome, which are reported more commonly in women.^5,52,54 Vestibular side effects have been shown to decrease with use of extended-release tablets with weight-based dosing.⁵³

Oral Isotretinoin

Oral isotretinoin is well established as highly effective for treatment of severe, recalcitrant AV, including nodular acne on the face and trunk.^4,56 Currently available oral isotretinoins are branded generic formulations based on the pharmacokinetic profile of the original brand (Accutane [Roche Pharmaceuticals]) and with the use of Lidose Technology (Absorica [Cipher Pharmaceuticals]), which substantially increases GI absorption of isotretinoin in the absence of ingestion with a high-calorie, high-fat meal.⁵⁷ The short- and long-term efficacy, dosing regimens, safety considerations, and serious teratogenic risks for oral isotretinoin are well published.^4,56-58 Importantly, oral isotretinoin must be prescribed with strict adherence to the federally mandated iPLEDGE risk management program.

Low-dose oral isotretinoin therapy (<0.5 mg/kg–1 mg/kg daily) administered over several months longer than conventional regimens (ie, 16–20 weeks) has been suggested with demonstrated efficacy.⁵⁷ However, this approach is not optimal due to the lack of established sustained clearance of AV after discontinuation of therapy and the greater potential for exposure to isotretinoin during pregnancy. Recurrences of AV do occur after completion of isotretinoin therapy, especially if cumulative systemic exposure to the drug during the initial course of treatment was inadequate.^56,57

Oral isotretinoin has been shown to be effective in AV in adult women with or without PCOS with 0.5 mg/kg to 1 mg/kg daily and a total cumulative exposure of 120 mg/kg to 150 mg/kg.⁵⁹ In one study, the presence of PCOS and greater number of nodules at baseline were predictive of a higher risk of relapse during the second year posttreatment.⁵⁹

Conclusion

All oral therapies that are used to treat AV in adult women warrant individual consideration of possible benefits versus risks. Careful attention to possible side effects, patient-related risk factors, and potential drug-drug interactions is important. End points of therapy are not well established, with the exception of oral isotretinoin therapy. Clinicians must use their judgment in each case along with obtaining feedback from patients regarding the selection of therapy after a discussion of the available options.

Selection of oral agents for treatment of AV in adult women is dependent on multiple factors including the patient’s age, medication history, child-bearing potential, clinical presentation, and treatment preference following a discussion of the anticipated benefits versus potential risks.^1,2 In patients with the mixed inflammatory and comedonal clinical pattern of AV, oral antibiotics can be used concurrently with topical therapies when moderate to severe inflammatory lesions are noted.^3,4 However, many adult women who had AV as teenagers have already utilized oral antibiotic therapies in the past and often are interested in alternative options, express concerns regarding antibiotic resistance, report a history of antibiotic-associated yeast infections or other side effects, and/or encounter issues related to drug-drug interactions.^3,5-8 Oral hormonal therapies such as combination oral contraceptives (COCs) or spironolactone often are utilized to treat adult women with AV, sometimes in combination with each other or other agents. Combination oral contraceptives appear to be especially effective in the management of the U-shaped clinical pattern or predominantly inflammatory, late-onset AV.^1,5,9,10 Potential warnings, contraindications, adverse effects, and drug-drug interactions are important to keep in mind when considering the use of oral hormonal therapies.^8-10 Oral isotretinoin, which should be prescribed with strict adherence to the iPLEDGE™ program (https://www.ipledgeprogram.com/), remains a viable option for cases of severe nodular AV and selected cases of refractory inflammatory AV, especially when scarring and/or marked psychosocial distress are noted.^1,2,5,11 Although it is recognized that adult women with AV typically present with either a mixed inflammatory and comedonal or U-shaped clinical pattern predominantly involving the lower face and anterolateral neck, the available data do not adequately differentiate the relative responsiveness of these clinical patterns to specific therapeutic agents.

Combination Oral Contraceptives

Combination oral contraceptives are commonly used to treat AV in adult women, including those without and those with measurable androgen excess (eg, polycystic ovary syndrome [PCOS]). Combination oral contraceptives contain ethinyl estradiol and a progestational agent (eg, progestin); the latter varies in terms of its nonselective receptor interactions and the relative magnitude or absence of androgenic effects.^10,12,13 Although some COCs are approved by the US Food and Drug Administration (FDA) for AV, there is little data available to determine the comparative efficacy among these and other COCs.^10,14 When choosing a COC for treatment of AV, it is best to select an agent whose effectiveness is supported by evidence from clinical studies.^10,15

Mechanisms of Action

The reported mechanisms of action for COCs include inhibition of ovarian androgen production and ovulation through gonadotropin suppression; upregulated synthesis of sex hormone–binding globulin, which decreases free testosterone levels through receptor binding; and inhibition of 5α-reductase (by some progestins), which reduces conversion of testosterone to dihydrotestosterone, the active derivative that induces androgenic effects at peripheral target tissues.^10,13,16,17

Therapeutic Benefits

Use of COCs to treat AV in adult women who do not have measurable androgen excess is most rational in patients who also desire a method of contraception. Multiple monotherapy studies have demonstrated the efficacy of COCs in the treatment of AV on the face and trunk.^{4,10,12,15,17,18} It may take a minimum of 3 monthly cycles of use before acne lesion counts begin to appreciably decrease.^12,15,19-21 Initiating COC therapy during menstruation ensures the absence of pregnancy. Combination oral contraceptives may be used with other topical and oral therapies for AV.^2,3,9,10 Potential ancillary benefits of COCs include normalization of the menstrual cycle; reduced premenstrual dysphoric disorder symptoms; and reduced risk of endometrial cancer (approximately 50%), ovarian cancer (approximately 40%), and colorectal cancer.^22-24

Risks and Contraindications

It is important to consider the potential risks associated with the use of COCs, especially in women with AV who are not seeking a method of contraception. Side effects of COCs can include nausea, breast tenderness, breakthrough bleeding, and weight gain.^25,26 Potential adverse associations of COCs are described in the Table. The major potential vascular associations include venous thromboembolism, myocardial infarction, and cerebrovascular accident, all of which are influenced by concurrent factors such as a history of smoking, age (≥35 years), and hypertension.^27-32 It is recommended that blood pressure be measured before initiating COC therapy as part of the general examination.³³

The potential increase in breast cancer risk appears to be low, while the cervical cancer risk is reported to increase relative to the duration of use.^34-37 This latter observation may be due to the greater likelihood of unprotected sex in women using a COC and exposure to multiple sexual partners in some cases, which may increase the likelihood of oncogenic human papillomavirus infection of the cervix. If a dermatologist elects to prescribe a COC to treat AV, it has been suggested that the patient also consult with her general practitioner or gynecologist to undergo pelvic and breast examinations and a Papanicolaou test.³³ The recommendation for initial screening for cervical cancer is within 3 years of initiation of sexual intercourse or by 21 years of age, whichever is first.^33,38,39

Combination oral contraceptives are not ideal for all adult women with AV. Absolute contraindications are pregnancy and history of thromboembolic, cardiac, or hepatic disease; in women aged 35 years and older who smoke, relative contraindications include hypertension, diabetes, migraines, breastfeeding, and current breast or liver cancer.³³ In adult women with AV who have relative contra-indications but are likely to benefit from the use of a COC when other options are limited or not viable, consultation with a gynecologist is prudent. Other than rifamycin antibiotics (eg, rifampin) and griseofulvin, there is no definitive evidence that oral antibiotics (eg, tetracycline) or oral antifungal agents reduce the contraceptive efficacy of COCs, although cautions remain in print within some approved package inserts.⁸

Spironolactone

Available since 1957, spironolactone is an oral aldos-terone antagonist and potassium-sparing diuretic used to treat hypertension and congestive heart failure.⁹ Recognition of its antiandrogenic effects led to its use in dermatology to treat certain dermatologic disorders in women (eg, hirsutism, alopecia, AV).^1,4,5,9,10 Spironolactone is not approved for AV by the FDA; therefore, available data from multiple independent studies and retrospective analyses that have been collectively reviewed support its efficacy when used as both monotherapy or in combination with other agents in adult women with AV, especially those with a U-shaped pattern and/or late-onset AV.^9,40-43

Mechanism of Action

Spironolactone inhibits sebaceous gland activity through peripheral androgen receptor blockade, inhibition of 5α-reductase, decrease in androgen production, and increase in sex hormone–binding globulin.^9,10,40

Therapeutic Benefits

Good to excellent improvement of AV in women, many of whom are postadolescent, has ranged from 66% to 100% in published reports^9,40-43; however, inclusion and exclusion criteria, dosing regimens, and concomitant therapies were not usually controlled. Spironolactone has been used to treat AV in adult women as monotherapy or in combination with topical agents, oral antibiotics, and COCs.^9,40-42 Additionally, dose-ranging studies have not been completed with spironolactone for AV.^9,40 The suggested dose range is 50 mg to 200 mg daily; however, it usually is best to start at 50 mg daily and increase to 100 mg daily if clinical response is not adequate after 2 to 3 months. The gastrointestinal (GI) absorption of spironolactone is increased when ingested with a high-fat meal.^9,10

Once effective control of AV is achieved, it is optimal to use the lowest dose needed to continue reasonable suppression of new AV lesions. There is no defined end point for spironolactone use in AV, with or without concurrent PCOS, as many adult women usually continue treatment with low-dose therapy because they experience marked flaring shortly after the drug is stopped.⁹

Risks and Contraindications

Side effects associated with spironolactone are dose related and include increased diuresis, migraines, menstrual irregularities, breast tenderness, gynecomastia, fatigue, and dizziness.^9,10,40-44 Side effects (particularly menstrual irregularities and breast tenderness) are more common at doses higher than 100 mg daily, especially when used as monotherapy without concurrent use of a COC.^9,40

Spironolactone-associated hyperkalemia is most clinically relevant in patients on higher doses (eg, 100–200 mg daily), in those with renal impairment and/or congestive heart failure, and when used concurrently with certain other medications. In any patient on spironolactone, the risk of clinically relevant hyperkalemia may be increased by coingestion of potassium supplements, potassium-based salt substitutes, potassium-sparing diuretics (eg, amiloride, triamterene); aldosterone antagonists and angiotensin-converting enzyme inhibitors (eg, lisinopril, benazepril); angiotensin II receptor blockers (eg, losartan, valsartan); and tri-methoprim (with or without sulfamethoxazole).^8,9,40,45 Spironolactone may also increase serum levels of lithium or digoxin.^9,40,45,46 For management of AV, it is best that spironolactone be avoided in patients taking any of these medications.⁹

In healthy adult women with AV who are not on medications or supplements that interact adversely with spironolactone, there is no definitive recommendation regarding monitoring of serum potassium levels during treatment with spironolactone, and it has been suggested that monitoring serum potassium levels in this subgroup is not necessary.⁴⁷ However, each clinician is advised to choose whether or not they wish to obtain baseline and/or periodic serum potassium levels when prescribing spironolactone for AV based on their degree of comfort and the patient’s history. Baseline and periodic blood testing to evaluate serum electrolytes and renal function are reasonable, especially as adult women with AV are usually treated with spironolactone over a prolonged period of time.⁹

The FDA black box warning for spironolactone states that it is tumorigenic in chronic toxicity studies in rats and refers to exposures 25- to 100-fold higher than those administered to humans.^9,48 Although continued vigilance is warranted, evaluation of large populations of women treated with spironolactone do not suggest an association with increased risk of breast cancer.^49,50

Spironolactone is a category C drug and thus should be avoided during pregnancy, primarily due to animal data suggesting risks of hypospadias and feminization in male fetuses.⁹ Importantly, there is an absence of reports linking exposure during pregnancy with congenital defects in humans, including in 2 known cases of high-dose exposures for maternal Bartter syndrome.⁹

The active metabolite, canrenone, is known to be present in breast milk at 0.2% of the maternal daily dose, but breastfeeding is generally believed to be safe with spironolactone based on evidence to date.⁹

Oral Antibiotics

Oral antibiotic therapy may be used in combination with a topical regimen to treat AV in adult women, keeping in mind some important caveats.^1-7 For instance, monotherapy with oral antibiotics should be avoided, and concomitant use of benzoyl peroxide is suggested to reduce emergence of antibiotic-resistant Propionibacterium acnes strains.^3,4 A therapeutic exit plan also is suggested when prescribing oral antibiotics to limit treatment to 3 to 4 months, if possible, to help mitigate the emergence of antibiotic-resistant bacteria (eg, staphylococci and streptococci).^3-5,51

Tetracyclines, especially doxycycline and minocycline, are the most commonly prescribed agents. Doxycycline use warrants patient education on measures to limit the risks of esophageal and GI side effects and phototoxicity; enteric-coated and small tablet formulations have been shown to reduce GI side effects, especially when administered with food.^3,52-55 In addition to vestibular side effects and hyperpigmentation, minocycline may be associated with rare but potentially severe adverse reactions such as drug hypersensitivity syndrome, autoimmune hepatitis, and lupus-like syndrome, which are reported more commonly in women.^5,52,54 Vestibular side effects have been shown to decrease with use of extended-release tablets with weight-based dosing.⁵³

Oral Isotretinoin

Oral isotretinoin is well established as highly effective for treatment of severe, recalcitrant AV, including nodular acne on the face and trunk.^4,56 Currently available oral isotretinoins are branded generic formulations based on the pharmacokinetic profile of the original brand (Accutane [Roche Pharmaceuticals]) and with the use of Lidose Technology (Absorica [Cipher Pharmaceuticals]), which substantially increases GI absorption of isotretinoin in the absence of ingestion with a high-calorie, high-fat meal.⁵⁷ The short- and long-term efficacy, dosing regimens, safety considerations, and serious teratogenic risks for oral isotretinoin are well published.^4,56-58 Importantly, oral isotretinoin must be prescribed with strict adherence to the federally mandated iPLEDGE risk management program.

Low-dose oral isotretinoin therapy (<0.5 mg/kg–1 mg/kg daily) administered over several months longer than conventional regimens (ie, 16–20 weeks) has been suggested with demonstrated efficacy.⁵⁷ However, this approach is not optimal due to the lack of established sustained clearance of AV after discontinuation of therapy and the greater potential for exposure to isotretinoin during pregnancy. Recurrences of AV do occur after completion of isotretinoin therapy, especially if cumulative systemic exposure to the drug during the initial course of treatment was inadequate.^56,57

Oral isotretinoin has been shown to be effective in AV in adult women with or without PCOS with 0.5 mg/kg to 1 mg/kg daily and a total cumulative exposure of 120 mg/kg to 150 mg/kg.⁵⁹ In one study, the presence of PCOS and greater number of nodules at baseline were predictive of a higher risk of relapse during the second year posttreatment.⁵⁹

Conclusion

All oral therapies that are used to treat AV in adult women warrant individual consideration of possible benefits versus risks. Careful attention to possible side effects, patient-related risk factors, and potential drug-drug interactions is important. End points of therapy are not well established, with the exception of oral isotretinoin therapy. Clinicians must use their judgment in each case along with obtaining feedback from patients regarding the selection of therapy after a discussion of the available options.

It seems intuitive that clinicians in dermatology would automatically recognize the importance of proper selection and integration of skin care products and techniques in the management of acne vulgaris (AV). However, an understanding of the fundamental importance of skin care in AV management and the scientific basis for maintaining epidermal barrier (EpB) function and repair cannot be assumed. In fact, there is limited scientific information about EpB dysfunction and AV or the adjunctive benefits of specific skin care products. However, some data have emerged that can be successfully applied by clinicians.^1-9

In part 2 of this series, emphasis is placed on skin care and topical therapies for the treatment of AV in adult women. In addition to the plethora of cleanser and moisturizer formulations that exist in the marketplace, there are many over-the-counter (OTC) products marketed to treat AV that contain benzoyl peroxide (BP) and salicylic acid. Importantly, women tend to be selective about what they use to cleanse and moisturize their skin, and use of OTC products to treat AV is common among adult women.^10,11

A thorough discussion of EpB impairment, related inflammatory cascades, and potential relevance to AV are beyond the scope of this article. In short, appropriate skin care products can reduce the inflammation and sensitivity associated with increased transepidermal water loss and reduced stratum corneum hydration and can mitigate EpB impairments induced by certain acne medications or vehicles.^1,12 Available data support the adjunctive benefit of proper skin care in the management of AV by mitigating cutaneous irritation and potentially contributing to a reduction in AV lesions.^2-4,7,13 Use of a formulation that also provides broad-spectrum photoprotection also is helpful.^3,4

Another challenge is the myriad of cosmeceuticals that are heavily marketed to adult women with AV.^13,14 Unfortunately, the scientific evidence supporting these products for treatment of AV is limited, resulting in the clinician’s inability to make specific recommendations. The core message is to incorporate skin care products that can reduce EpB impairment and mitigate cutaneous irritation associated with some AV therapies.^1-4,7-9,12

OTC Topical Therapies

The marketplace is replete with several OTC products for treatment of AV, most of which contain BP and salicylic acid.^15,16 There is a lack of efficacy data for OTC products for AV, including cleansers and topical medications, although some may be beneficial for milder cases. A variety of formulations are available to choose from, usually without the advice of a clinician. Additionally, heavy marketing is directed at adult women with AV, which may promote the use of therapies that may not be optimal for their respective AV severity or may cause facial skin irritation. Self-treatment may also cause delay in seeking dermatologic care, increasing the risk of persistent or permanent sequelae. Delay in adequate treatment is a major risk factor for the development of acne scars.¹⁷

Prescription Topical Therapies

Despite the high prevalence of AV in adult women, there is a paucity of studies evaluating topical therapies for AV in this subset.^18-24 Reports in the literature on AV in adult women have focused on systemic hormonal agents (eg, oral contraceptives, spironolactone); however, more recent reports have addressed the use of topical therapies in this subpopulation.^11,25-30 Published data on topical formulations are predominantly post hoc analyses from pivotal randomized controlled trials (RCTs) that included adolescents and adults of both genders with facial AV located above the jawline and predominantly moderate in severity.^11,26,28,30 Participants in all of these studies presented with non-nodular, mixed inflammatory, and comedonal facial AV above the jawline, with inclusion criteria that required a minimum of 20 comedonal lesions and 20 papulopustular lesions at baseline. An important differentiating factor among these various post hoc analyses evaluating adult women versus adolescent girls with AV are the ages used to separate adults from adolescents. A dividing line of 18 years and older was used in some reports (eg, adapalene gel 0.3%, dapsone gel 5%), while other reports used 25 years and older to separate adolescent girls from adult women (ie, clindamycin phosphate [CP] 1.2%– BP 3.75% gel, adapalene 0.1%–BP 2.5% gel).^11,26,28,30

Importantly, these studies included adult women with AV who presented with mixed comedonal and inflammatory AV (mixed pattern AV) similar to adolescents. None of the studies included women with a U-shaped AV pattern or lower facial AV characterized by deep inflammatory lesions that are often tender and few in number. Unfortunately, there is a lack of data evaluating topical therapies for these patterns of AV in adult women, including AV below the jawline and on the trunk. Although mixed pattern AV has been reported to affect 75% to 90% of adult women with AV, epidemiologic data quantifying the clinical AV patterns affecting adult women are limited.^{11,22,29,31,32} More well-designed studies are needed.

The treatment of AV in adult women may incorporate any of the topical therapies used to treat AV in adolescents, especially as studies encompass both the adolescent and adult age ranges. This is especially true with mixed pattern AV, which is the predominant presentation in participants enrolled in clinical trials with topical therapies, especially of moderate severity.

Herein we provide a summary of the topical therapies that have been evaluated by post hoc analyses of data from pivotal studies in adult women with AV.

Adapalene Gel 0.3%

Adapalene exhibits retinoid activity with efficacy in reducing inflammatory and comedonal AV lesions shown with both 0.1% and 0.3% concentrations.^33-35 Post hoc analyses of 2 pivotal RCTs of patients with facial AV showed that adapalene gel 0.3% once daily (n=74; mean age, 27.2 years) was superior to vehicle once daily (n=43; mean age, 25.2 years) in both mean and median percentage reductions of comedonal, inflammatory, and total lesions in women 18 years and older who were treated for 12 weeks; the difference in mean percentage lesion reduction from vehicle for total AV lesions was statistically significant at 12 weeks (P=.045).²⁶ Adapalene gel 0.3% produced a favorable skin tolerability profile similar to adapalene gel 0.1%, with the most common adverse reactions being discomfort and dryness.

Advantages of topical retinoid therapy in adult women with facial AV are reduction in postinflammatory hyperpigmentation and therapeutic modulation of chronic photodamage (eg, fine lines, rough texture, dyschromia).^29,36,37 Disadvantages include signs and symptoms of cutaneous irritation, although this tends to occur less frequently on facial skin with adapalene gel 0.3% as compared to other topical retinoids that exhibit comparable efficacy.^33-37 Topical retinoid therapy on the anterior neck and upper chest should be used cautiously, as these anatomic sites appear to be more prone to cutaneous irritation.

Dapsone Gel 5%

Dapsone is a sulfone antimicrobial and anti-inflammatory agent that has been shown to be effective, safe, and well tolerated in the treatment of AV in a topical 5% formulation.^38,39 A post hoc analysis of pivotal 12-week trial data suggested that dapsone gel 5% twice daily produced greater AV reductions in females compared to males; no gender differences were noted in adverse effects, which were low in frequency.³⁹ A separate subgroup analysis compared outcomes among adult women (≥18 years of age; n=434) and adolescent girls (12–17 years of age; n=347) treated with dapsone gel 5%.¹¹ The proportion with no or minimal acne based on the Global Acne Assessment Score at week 12 was greater in adult women (53.5%) versus adolescent girls (45.3%, P=.022), with significantly greater percentage reductions in both noninflammatory (P<.0001) and total lesion counts (P=.0008) observed in the adult group. Percentage reductions in inflammatory lesions were similar in both groups. No major safety or tolerability issues or new safety signals were noted. Advantages of dapsone gel 5% are highly favorable tolerability and the perception of decreased oily skin in some participants.^38,39

Clindamycin Phosphate 1.2%–Benzoyl Peroxide 3.75% Gel

The combination formulation of CP 1.2%– BP 3.75% gel applied once daily has been shown to be effective, well tolerated, and safe for the treatment of facial AV, with a gender analysis noting an apparent greater efficacy in females.^40,41 A post hoc analysis from the 12-week pivotal study data in adult women aged 25 years and older showed a mean percentage change from baseline in inflammatory and noninflammatory lesion counts and the percentage of participants who achieved a 2-grade improvement by global assessment to be 68.7%, 60.4%, and 52.7% in actively treated participants (n=29), respectively, which was significantly superior to vehicle applied once daily (n=43; P=.019, P=.020, and P=.074, respectively).⁴² No relevant differences in tolerability were noted among treatment groups, and no participants discontinued therapy due to adverse events. Advantages of CP 1.2%–BP 3.75% gel are highly favorable skin tolerability and the perception of decreased oily skin in some participants.^41-43

Adapalene 0.1%–Benzoyl Peroxide 2.5% Gel

A meta-analysis of pooled data from 3 RCTs evaluated use of adapalene 0.1%–BP 2.5% gel applied once daily in adult women aged 25 years and older with facial AV (n=130) versus vehicle gel applied once daily (n=124).³⁰ The percentage of participants who achieved investigator global assessment ratings of clear or almost clear was 39.2% in actively treated participants versus 18.5% with vehicle (P<.001), and median percentage lesion reduction was approximately 30% greater in those treated with adapalene 0.1%–BP 2.5% gel versus vehicle gel. Tolerability and safety were favorable.

Other Agents

Topical azelaic acid (20% cream formulation, 15% gel formulation) has been suggested as a treatment option for adult women with AV, including patients with darker skin who are more prone to persistent hyperpigmentation.²⁹

Conclusion

Proper skin care is an important component in the management of AV in adult women. Data for topical therapies in this subpopulation are limited; however, post hoc analyses provide some information regarding their efficacy in treating mixed pattern AV. More well-designed studies are needed to better evaluate the use of topical agents in adult women with AV. Although most topical AV therapies appear to be safe for use during pregnancy when properly used and limited to facial application, their use in women of childbearing potential and during pregnancy warrants individual consideration; topical retinoids are best avoided during pregnancy, especially tazarotene, which is rated category X.⁴⁴ In part 3 of this series, oral therapies used to treat AV in adult women will be discussed.

It seems intuitive that clinicians in dermatology would automatically recognize the importance of proper selection and integration of skin care products and techniques in the management of acne vulgaris (AV). However, an understanding of the fundamental importance of skin care in AV management and the scientific basis for maintaining epidermal barrier (EpB) function and repair cannot be assumed. In fact, there is limited scientific information about EpB dysfunction and AV or the adjunctive benefits of specific skin care products. However, some data have emerged that can be successfully applied by clinicians.^1-9

In part 2 of this series, emphasis is placed on skin care and topical therapies for the treatment of AV in adult women. In addition to the plethora of cleanser and moisturizer formulations that exist in the marketplace, there are many over-the-counter (OTC) products marketed to treat AV that contain benzoyl peroxide (BP) and salicylic acid. Importantly, women tend to be selective about what they use to cleanse and moisturize their skin, and use of OTC products to treat AV is common among adult women.^10,11

A thorough discussion of EpB impairment, related inflammatory cascades, and potential relevance to AV are beyond the scope of this article. In short, appropriate skin care products can reduce the inflammation and sensitivity associated with increased transepidermal water loss and reduced stratum corneum hydration and can mitigate EpB impairments induced by certain acne medications or vehicles.^1,12 Available data support the adjunctive benefit of proper skin care in the management of AV by mitigating cutaneous irritation and potentially contributing to a reduction in AV lesions.^2-4,7,13 Use of a formulation that also provides broad-spectrum photoprotection also is helpful.^3,4

Another challenge is the myriad of cosmeceuticals that are heavily marketed to adult women with AV.^13,14 Unfortunately, the scientific evidence supporting these products for treatment of AV is limited, resulting in the clinician’s inability to make specific recommendations. The core message is to incorporate skin care products that can reduce EpB impairment and mitigate cutaneous irritation associated with some AV therapies.^1-4,7-9,12

OTC Topical Therapies

The marketplace is replete with several OTC products for treatment of AV, most of which contain BP and salicylic acid.^15,16 There is a lack of efficacy data for OTC products for AV, including cleansers and topical medications, although some may be beneficial for milder cases. A variety of formulations are available to choose from, usually without the advice of a clinician. Additionally, heavy marketing is directed at adult women with AV, which may promote the use of therapies that may not be optimal for their respective AV severity or may cause facial skin irritation. Self-treatment may also cause delay in seeking dermatologic care, increasing the risk of persistent or permanent sequelae. Delay in adequate treatment is a major risk factor for the development of acne scars.¹⁷

Prescription Topical Therapies

Despite the high prevalence of AV in adult women, there is a paucity of studies evaluating topical therapies for AV in this subset.^18-24 Reports in the literature on AV in adult women have focused on systemic hormonal agents (eg, oral contraceptives, spironolactone); however, more recent reports have addressed the use of topical therapies in this subpopulation.^11,25-30 Published data on topical formulations are predominantly post hoc analyses from pivotal randomized controlled trials (RCTs) that included adolescents and adults of both genders with facial AV located above the jawline and predominantly moderate in severity.^11,26,28,30 Participants in all of these studies presented with non-nodular, mixed inflammatory, and comedonal facial AV above the jawline, with inclusion criteria that required a minimum of 20 comedonal lesions and 20 papulopustular lesions at baseline. An important differentiating factor among these various post hoc analyses evaluating adult women versus adolescent girls with AV are the ages used to separate adults from adolescents. A dividing line of 18 years and older was used in some reports (eg, adapalene gel 0.3%, dapsone gel 5%), while other reports used 25 years and older to separate adolescent girls from adult women (ie, clindamycin phosphate [CP] 1.2%– BP 3.75% gel, adapalene 0.1%–BP 2.5% gel).^11,26,28,30

Importantly, these studies included adult women with AV who presented with mixed comedonal and inflammatory AV (mixed pattern AV) similar to adolescents. None of the studies included women with a U-shaped AV pattern or lower facial AV characterized by deep inflammatory lesions that are often tender and few in number. Unfortunately, there is a lack of data evaluating topical therapies for these patterns of AV in adult women, including AV below the jawline and on the trunk. Although mixed pattern AV has been reported to affect 75% to 90% of adult women with AV, epidemiologic data quantifying the clinical AV patterns affecting adult women are limited.^{11,22,29,31,32} More well-designed studies are needed.

The treatment of AV in adult women may incorporate any of the topical therapies used to treat AV in adolescents, especially as studies encompass both the adolescent and adult age ranges. This is especially true with mixed pattern AV, which is the predominant presentation in participants enrolled in clinical trials with topical therapies, especially of moderate severity.

Herein we provide a summary of the topical therapies that have been evaluated by post hoc analyses of data from pivotal studies in adult women with AV.

Adapalene Gel 0.3%

Adapalene exhibits retinoid activity with efficacy in reducing inflammatory and comedonal AV lesions shown with both 0.1% and 0.3% concentrations.^33-35 Post hoc analyses of 2 pivotal RCTs of patients with facial AV showed that adapalene gel 0.3% once daily (n=74; mean age, 27.2 years) was superior to vehicle once daily (n=43; mean age, 25.2 years) in both mean and median percentage reductions of comedonal, inflammatory, and total lesions in women 18 years and older who were treated for 12 weeks; the difference in mean percentage lesion reduction from vehicle for total AV lesions was statistically significant at 12 weeks (P=.045).²⁶ Adapalene gel 0.3% produced a favorable skin tolerability profile similar to adapalene gel 0.1%, with the most common adverse reactions being discomfort and dryness.

Advantages of topical retinoid therapy in adult women with facial AV are reduction in postinflammatory hyperpigmentation and therapeutic modulation of chronic photodamage (eg, fine lines, rough texture, dyschromia).^29,36,37 Disadvantages include signs and symptoms of cutaneous irritation, although this tends to occur less frequently on facial skin with adapalene gel 0.3% as compared to other topical retinoids that exhibit comparable efficacy.^33-37 Topical retinoid therapy on the anterior neck and upper chest should be used cautiously, as these anatomic sites appear to be more prone to cutaneous irritation.

Dapsone Gel 5%

Dapsone is a sulfone antimicrobial and anti-inflammatory agent that has been shown to be effective, safe, and well tolerated in the treatment of AV in a topical 5% formulation.^38,39 A post hoc analysis of pivotal 12-week trial data suggested that dapsone gel 5% twice daily produced greater AV reductions in females compared to males; no gender differences were noted in adverse effects, which were low in frequency.³⁹ A separate subgroup analysis compared outcomes among adult women (≥18 years of age; n=434) and adolescent girls (12–17 years of age; n=347) treated with dapsone gel 5%.¹¹ The proportion with no or minimal acne based on the Global Acne Assessment Score at week 12 was greater in adult women (53.5%) versus adolescent girls (45.3%, P=.022), with significantly greater percentage reductions in both noninflammatory (P<.0001) and total lesion counts (P=.0008) observed in the adult group. Percentage reductions in inflammatory lesions were similar in both groups. No major safety or tolerability issues or new safety signals were noted. Advantages of dapsone gel 5% are highly favorable tolerability and the perception of decreased oily skin in some participants.^38,39

Clindamycin Phosphate 1.2%–Benzoyl Peroxide 3.75% Gel

The combination formulation of CP 1.2%– BP 3.75% gel applied once daily has been shown to be effective, well tolerated, and safe for the treatment of facial AV, with a gender analysis noting an apparent greater efficacy in females.^40,41 A post hoc analysis from the 12-week pivotal study data in adult women aged 25 years and older showed a mean percentage change from baseline in inflammatory and noninflammatory lesion counts and the percentage of participants who achieved a 2-grade improvement by global assessment to be 68.7%, 60.4%, and 52.7% in actively treated participants (n=29), respectively, which was significantly superior to vehicle applied once daily (n=43; P=.019, P=.020, and P=.074, respectively).⁴² No relevant differences in tolerability were noted among treatment groups, and no participants discontinued therapy due to adverse events. Advantages of CP 1.2%–BP 3.75% gel are highly favorable skin tolerability and the perception of decreased oily skin in some participants.^41-43

Adapalene 0.1%–Benzoyl Peroxide 2.5% Gel

A meta-analysis of pooled data from 3 RCTs evaluated use of adapalene 0.1%–BP 2.5% gel applied once daily in adult women aged 25 years and older with facial AV (n=130) versus vehicle gel applied once daily (n=124).³⁰ The percentage of participants who achieved investigator global assessment ratings of clear or almost clear was 39.2% in actively treated participants versus 18.5% with vehicle (P<.001), and median percentage lesion reduction was approximately 30% greater in those treated with adapalene 0.1%–BP 2.5% gel versus vehicle gel. Tolerability and safety were favorable.

Other Agents

Topical azelaic acid (20% cream formulation, 15% gel formulation) has been suggested as a treatment option for adult women with AV, including patients with darker skin who are more prone to persistent hyperpigmentation.²⁹

Conclusion

Proper skin care is an important component in the management of AV in adult women. Data for topical therapies in this subpopulation are limited; however, post hoc analyses provide some information regarding their efficacy in treating mixed pattern AV. More well-designed studies are needed to better evaluate the use of topical agents in adult women with AV. Although most topical AV therapies appear to be safe for use during pregnancy when properly used and limited to facial application, their use in women of childbearing potential and during pregnancy warrants individual consideration; topical retinoids are best avoided during pregnancy, especially tazarotene, which is rated category X.⁴⁴ In part 3 of this series, oral therapies used to treat AV in adult women will be discussed.

It seems intuitive that clinicians in dermatology would automatically recognize the importance of proper selection and integration of skin care products and techniques in the management of acne vulgaris (AV). However, an understanding of the fundamental importance of skin care in AV management and the scientific basis for maintaining epidermal barrier (EpB) function and repair cannot be assumed. In fact, there is limited scientific information about EpB dysfunction and AV or the adjunctive benefits of specific skin care products. However, some data have emerged that can be successfully applied by clinicians.^1-9

In part 2 of this series, emphasis is placed on skin care and topical therapies for the treatment of AV in adult women. In addition to the plethora of cleanser and moisturizer formulations that exist in the marketplace, there are many over-the-counter (OTC) products marketed to treat AV that contain benzoyl peroxide (BP) and salicylic acid. Importantly, women tend to be selective about what they use to cleanse and moisturize their skin, and use of OTC products to treat AV is common among adult women.^10,11

A thorough discussion of EpB impairment, related inflammatory cascades, and potential relevance to AV are beyond the scope of this article. In short, appropriate skin care products can reduce the inflammation and sensitivity associated with increased transepidermal water loss and reduced stratum corneum hydration and can mitigate EpB impairments induced by certain acne medications or vehicles.^1,12 Available data support the adjunctive benefit of proper skin care in the management of AV by mitigating cutaneous irritation and potentially contributing to a reduction in AV lesions.^2-4,7,13 Use of a formulation that also provides broad-spectrum photoprotection also is helpful.^3,4

Another challenge is the myriad of cosmeceuticals that are heavily marketed to adult women with AV.^13,14 Unfortunately, the scientific evidence supporting these products for treatment of AV is limited, resulting in the clinician’s inability to make specific recommendations. The core message is to incorporate skin care products that can reduce EpB impairment and mitigate cutaneous irritation associated with some AV therapies.^1-4,7-9,12

OTC Topical Therapies

The marketplace is replete with several OTC products for treatment of AV, most of which contain BP and salicylic acid.^15,16 There is a lack of efficacy data for OTC products for AV, including cleansers and topical medications, although some may be beneficial for milder cases. A variety of formulations are available to choose from, usually without the advice of a clinician. Additionally, heavy marketing is directed at adult women with AV, which may promote the use of therapies that may not be optimal for their respective AV severity or may cause facial skin irritation. Self-treatment may also cause delay in seeking dermatologic care, increasing the risk of persistent or permanent sequelae. Delay in adequate treatment is a major risk factor for the development of acne scars.¹⁷

Prescription Topical Therapies

Despite the high prevalence of AV in adult women, there is a paucity of studies evaluating topical therapies for AV in this subset.^18-24 Reports in the literature on AV in adult women have focused on systemic hormonal agents (eg, oral contraceptives, spironolactone); however, more recent reports have addressed the use of topical therapies in this subpopulation.^11,25-30 Published data on topical formulations are predominantly post hoc analyses from pivotal randomized controlled trials (RCTs) that included adolescents and adults of both genders with facial AV located above the jawline and predominantly moderate in severity.^11,26,28,30 Participants in all of these studies presented with non-nodular, mixed inflammatory, and comedonal facial AV above the jawline, with inclusion criteria that required a minimum of 20 comedonal lesions and 20 papulopustular lesions at baseline. An important differentiating factor among these various post hoc analyses evaluating adult women versus adolescent girls with AV are the ages used to separate adults from adolescents. A dividing line of 18 years and older was used in some reports (eg, adapalene gel 0.3%, dapsone gel 5%), while other reports used 25 years and older to separate adolescent girls from adult women (ie, clindamycin phosphate [CP] 1.2%– BP 3.75% gel, adapalene 0.1%–BP 2.5% gel).^11,26,28,30

Importantly, these studies included adult women with AV who presented with mixed comedonal and inflammatory AV (mixed pattern AV) similar to adolescents. None of the studies included women with a U-shaped AV pattern or lower facial AV characterized by deep inflammatory lesions that are often tender and few in number. Unfortunately, there is a lack of data evaluating topical therapies for these patterns of AV in adult women, including AV below the jawline and on the trunk. Although mixed pattern AV has been reported to affect 75% to 90% of adult women with AV, epidemiologic data quantifying the clinical AV patterns affecting adult women are limited.^{11,22,29,31,32} More well-designed studies are needed.

The treatment of AV in adult women may incorporate any of the topical therapies used to treat AV in adolescents, especially as studies encompass both the adolescent and adult age ranges. This is especially true with mixed pattern AV, which is the predominant presentation in participants enrolled in clinical trials with topical therapies, especially of moderate severity.

Herein we provide a summary of the topical therapies that have been evaluated by post hoc analyses of data from pivotal studies in adult women with AV.

Adapalene Gel 0.3%

Adapalene exhibits retinoid activity with efficacy in reducing inflammatory and comedonal AV lesions shown with both 0.1% and 0.3% concentrations.^33-35 Post hoc analyses of 2 pivotal RCTs of patients with facial AV showed that adapalene gel 0.3% once daily (n=74; mean age, 27.2 years) was superior to vehicle once daily (n=43; mean age, 25.2 years) in both mean and median percentage reductions of comedonal, inflammatory, and total lesions in women 18 years and older who were treated for 12 weeks; the difference in mean percentage lesion reduction from vehicle for total AV lesions was statistically significant at 12 weeks (P=.045).²⁶ Adapalene gel 0.3% produced a favorable skin tolerability profile similar to adapalene gel 0.1%, with the most common adverse reactions being discomfort and dryness.

Advantages of topical retinoid therapy in adult women with facial AV are reduction in postinflammatory hyperpigmentation and therapeutic modulation of chronic photodamage (eg, fine lines, rough texture, dyschromia).^29,36,37 Disadvantages include signs and symptoms of cutaneous irritation, although this tends to occur less frequently on facial skin with adapalene gel 0.3% as compared to other topical retinoids that exhibit comparable efficacy.^33-37 Topical retinoid therapy on the anterior neck and upper chest should be used cautiously, as these anatomic sites appear to be more prone to cutaneous irritation.

Dapsone Gel 5%

Dapsone is a sulfone antimicrobial and anti-inflammatory agent that has been shown to be effective, safe, and well tolerated in the treatment of AV in a topical 5% formulation.^38,39 A post hoc analysis of pivotal 12-week trial data suggested that dapsone gel 5% twice daily produced greater AV reductions in females compared to males; no gender differences were noted in adverse effects, which were low in frequency.³⁹ A separate subgroup analysis compared outcomes among adult women (≥18 years of age; n=434) and adolescent girls (12–17 years of age; n=347) treated with dapsone gel 5%.¹¹ The proportion with no or minimal acne based on the Global Acne Assessment Score at week 12 was greater in adult women (53.5%) versus adolescent girls (45.3%, P=.022), with significantly greater percentage reductions in both noninflammatory (P<.0001) and total lesion counts (P=.0008) observed in the adult group. Percentage reductions in inflammatory lesions were similar in both groups. No major safety or tolerability issues or new safety signals were noted. Advantages of dapsone gel 5% are highly favorable tolerability and the perception of decreased oily skin in some participants.^38,39

Clindamycin Phosphate 1.2%–Benzoyl Peroxide 3.75% Gel

The combination formulation of CP 1.2%– BP 3.75% gel applied once daily has been shown to be effective, well tolerated, and safe for the treatment of facial AV, with a gender analysis noting an apparent greater efficacy in females.^40,41 A post hoc analysis from the 12-week pivotal study data in adult women aged 25 years and older showed a mean percentage change from baseline in inflammatory and noninflammatory lesion counts and the percentage of participants who achieved a 2-grade improvement by global assessment to be 68.7%, 60.4%, and 52.7% in actively treated participants (n=29), respectively, which was significantly superior to vehicle applied once daily (n=43; P=.019, P=.020, and P=.074, respectively).⁴² No relevant differences in tolerability were noted among treatment groups, and no participants discontinued therapy due to adverse events. Advantages of CP 1.2%–BP 3.75% gel are highly favorable skin tolerability and the perception of decreased oily skin in some participants.^41-43

Adapalene 0.1%–Benzoyl Peroxide 2.5% Gel

A meta-analysis of pooled data from 3 RCTs evaluated use of adapalene 0.1%–BP 2.5% gel applied once daily in adult women aged 25 years and older with facial AV (n=130) versus vehicle gel applied once daily (n=124).³⁰ The percentage of participants who achieved investigator global assessment ratings of clear or almost clear was 39.2% in actively treated participants versus 18.5% with vehicle (P<.001), and median percentage lesion reduction was approximately 30% greater in those treated with adapalene 0.1%–BP 2.5% gel versus vehicle gel. Tolerability and safety were favorable.

Other Agents

Topical azelaic acid (20% cream formulation, 15% gel formulation) has been suggested as a treatment option for adult women with AV, including patients with darker skin who are more prone to persistent hyperpigmentation.²⁹

Conclusion

Proper skin care is an important component in the management of AV in adult women. Data for topical therapies in this subpopulation are limited; however, post hoc analyses provide some information regarding their efficacy in treating mixed pattern AV. More well-designed studies are needed to better evaluate the use of topical agents in adult women with AV. Although most topical AV therapies appear to be safe for use during pregnancy when properly used and limited to facial application, their use in women of childbearing potential and during pregnancy warrants individual consideration; topical retinoids are best avoided during pregnancy, especially tazarotene, which is rated category X.⁴⁴ In part 3 of this series, oral therapies used to treat AV in adult women will be discussed.

It was not long ago that acne vulgaris (AV) was commonly considered to be a skin disease that affected teenagers with little attention given to preadolescent and postadolescent AV. This perspective has changed, with more attention being given to AV across a broad range of affected 
age groups, including preadolescent, adolescent, and postadolescent subgroups.^1-5 Earlier onset of adrenarche has led to earlier development of AV in many young girls, with a higher range of dehydroepiandrosterone sulfate (DHEAS) levels observed overall in those with AV as compared to a normal age-matched population.^3,4 At the other end of the age spectrum, AV is a common phenomenon in adult females, with at least half of women estimated to exhibit some form of AV.^1,2,5-8 Based on a 
large survey of females and males (N=1013), the prevalence of AV in adult females has been reported to be 50.9%, 35.2%, 26.3%, and 15.3% among women aged 20 to 29 years, 30 to 39 years, 40 to 49 years, and 50 years and older, respectively.² Acne vulgaris that persists beyond adolescence into adulthood is termed persistent acne, or early-onset acne, and the development of AV in women 25 years and older who have not previously been affected by AV has been termed late-onset acne.^6,8,9 Publications on the management of AV in adult women have focused primarily on systemic hormonal therapies; however, topical therapies more recently have received greater attention in this subpopulation^9-12 and will be discussed in part 2 of this series. Because data on AV in women are 
limited primarily to involvement of the face and neck region, this article does not address truncal AV unless otherwise specified. Table 1 depicts factors that can influence the management of AV in adult women.

Visible Patterns and Considerations for Clinical Evaluation 


Clinical Patterns

Although epidemiologic and demographic data are limited in the subpopulation of women with AV, it is reported that females account for up to 82% of adults with AV, with approximately 75% presenting with AV that is clinically similar to their disease course in adolescence.^2,5,13 Among those women with persistent AV, some state that their AV is worse compared to adolescence, while others report it is not as severe. The pattern of AV often is similar to that seen in adolescence, presenting as mixed comedonal and inflammatory papular/pustular lesions diffusely distributed on the face; in other cases, a more selectively distributed U-shaped pattern is noted, characterized predominantly by inflammatory papules and/or nodules involving the lower cheeks and jawline margin, with lesions also commonly noted on the anterior and lateral neck.^5,8,9,13-16 A U-shaped pattern is believed to be more common in late-onset AV, often with persistence into the mid-40s.^1,15,17 It is important to emphasize the need for additional studies on the demographics and clinical characteristics of AV in adult females, especially correlations between onset, age, and clinical patterns of AV.

An international, prospective, observational study assessed the clinical characteristics of AV in adults (aged ≥25 years) at a dermatology visit for acne (N=374).¹⁶ Participants who were under management for their AV showed severity grades of mild (clear/almost clear) in 47.3% of cases. Involvement of multiple facial sites—cheeks, forehead, mandibular region, and temples—was noted in 89.8% of women, often with both inflammatory and comedonal lesions, which is a pattern similar to adolescent AV. Inflammatory lesions alone were observed in 6.4% of women, 17.1% had comedonal AV only, 
and truncal AV was present in 48.4%.¹⁶ Additional well-designed studies are needed to determine if this study reflects an accurate qualitative and 
quantitative depiction of the spectrum of AV in adult females.

Mandibular Pattern

In the observational study of AV in adults, AV localized to the mandibular area was noted in only 11.2% of participants.¹⁶ Women with localized mandibular AV were more likely than women without localized AV to be employed, noted greater daily stress levels, and tended to report more psychologically stressful jobs. Interestingly, the subgroup with mandibular acne alone was much less likely 
to exhibit a global severity grade of moderate or higher (7.1% vs 50.1%), truncal acne 
(19.0% vs 51.9%), postinflammatory hyperpigmentation (23.8% vs 51.9%), and erythema (19.0% vs 48.4%), suggesting a unique subset of AV presentation.¹⁶

Ethnicity/Skin Color

Women of all ethnicities and skin types may be affected by AV.^1,18-20 Earlier age of onset of AV has been suggested in white women; however, earlier onset of adrenarche may be more frequent in black girls, which supports an earlier age of onset of AV in this subpopulation.^15-17 Women with skin of color usually express greater concern with persistent dyschromia at sites where lesions have resolved, and presence of acne scars is a concern among women regardless of skin color, ethnicity, or race.^18,20-22

Scarring

Acne scarring has been noted to affect up to 
three-fourths of adult women in one report¹⁷ and 
often is stated by patients to be a cause of concern 
and frustration.^1,5,17

Perimenstrual Flaring

Flaring associated with menses is commonly reported in adult females with AV, with 56%, 17%, and 
3% of women in one study (n=230) reporting worsening before, during, or after menses, respectively.²¹

External Factors

Comedogenic products used for skin care, cover-up makeup, or hair care may be important to consider in selected cases as potential etiologic or exacerbating factors in adult females with AV; they also may be used in the management of AV.^23-25 Adult females often are perplexed and frustrated by the presence of AV after their 
teenaged years and anxiously wonder about or search for the potential causes. Many women use cosmetic products to cover up facial AV.^5,23-25 Therefore, even if skin care or personal hygiene products or makeup are not believed to be an etiologic factor, many patients appreciate that their dermatologist addressed skin care and cosmetics as a component of AV management and provided appropriate recommendations.^5,13

Ingestion of dietary supplements containing whey protein have been associated with precipitation of AV.^26,27 Diets with specific content characteristics have been implicated as potential etiologic or exacerbating factors for AV; however, data are limited and specific recommendations remain elusive at present. Individual cases may warrant consideration of dietary factors, especially when treatment resistance is noted.²⁸ Importantly, progestin-only contraceptives (ie, injectables, intrauterine devices) also can exacerbate or induce AV.²⁹

Hyperandrogenism

Although most adult females with AV are reported to have normal serum androgen levels when tested, it is important to explore potential signs and symptoms that are suggestive of underlying hyperandrogenism through both the patient’s history and physical examination.^{9-11,21,29-33} Some investigators have suggested that underlying peripheral hyperandrogenism is the leading cause of AV in adult females, 
with or without concurrent polycystic ovarian syndrome (PCOS), though it is believed that most women with AV exhibit normal results when 
undergoing laboratory testing for androgen excess.^{10,11,21,29,30} Nevertheless, it is important to consider the possibility of underlying causes of androgen excess (Table 2), the most common being PCOS and late-onset congenital adrenal hyperplasia; an androgen-secreting tumor is less common.^11,29-33 It is suggested that screening for underlying endocrinopathy should be conducted in women presenting with (1) AV recalcitrant to conventional treatment, (2) sudden emergence of severe AV, 
(3) concurrent signs/symptoms of androgen 
excess, and/or (4) AV relapse shortly after isotretinoin therapy.^7,11,16,33

Hirsutism and acanthosis nigricans have been reported to be more reliable predictors of hyperandrogenism than androgenic alopecia.²¹ Although it may be subtle in some cases, acanthosis nigricans is harder to camouflage, so the clinician can usually detect it if a thorough physical examination is performed. However, a patient may not voluntarily report to the clinician and their staff that she has hair removed, so despite a thorough examination, the clinician may not detect hirsutism. Therefore, it is important to inquire directly about the presence of hairs (pigmented terminal vs “peach fuzz” hairs), their anatomic location, and any hair removal practices the patient has used. The absence of androgenic alopecia does not exclude underlying hyperandrogenism; however, its presence, especially in younger women, may serve as a clinical marker for underlying hyperandrogenism.⁵ Some women may camouflage more subtle alopecia through hairstyling, but obtaining this history usually is not problematic, as most women are distressed by any degree of hair loss.

Laboratory Evaluation—A relatively straightforward approach to the workup of androgen excess includes assessment of serum DHEAS, free testosterone, and total testosterone levels.^10,30 Elevation of serum DHEAS levels indicates an adrenal source of androgen production. Elevation of testosterone is associated with excess androgens 
produced by the ovaries. Modest elevations of 
DHEAS are most commonly associated with late-onset congenital adrenal hyperplasia that may not have been previously diagnosed. Modest elevation 
of testosterone is most commonly associated with PCOS, which also can be accompanied by an 
elevated luteinizing hormone:follicle-stimulating hormone ratio of 2.5:1 to 3:1.^10,30 Marked elevations of DHEAS or testosterone can be indicative of adrenal or ovarian tumors, respectively.³⁰

In some cases, a woman might have 
elevated DHEAS and testosterone levels. A 17-hydroxyprogesterone test can help discriminate between an adrenal or ovarian source of 
androgen excess in these cases, as elevated 
17-hydroxyprogesterone levels indicate that the androgens are coming from the adrenal gland.^10,30

It is important that laboratory evaluation be performed when ovulation is not occurring. Blood tests can be drawn just prior to or during menses. It is important that a woman is not taking an oral contraceptive at the time of testing, which can mask an underlying endocrine abnormality.^10,11,29,30 Generally, testing can be performed at least 4 to 6 weeks after stopping the oral contraceptive.

Psychosocial Impact

Facial AV exhibits a broad range of adverse psychological and social effects on many adult females.^2,5,13,18 It can be associated with depression, anxiety, psychological stress, and suicidal ideation; therefore, thorough screening for these comorbidities may be warranted in some patients.^2,18

Conclusion

The epidemiology, clinical presentation, and clinical and laboratory evaluation of AV in adult females was reviewed in part 1 of this 3-part series. It is important for the clinician to assess the clinical presentation, psychosocial effects, and the possibility of underlying causes of androgen excess. In part 2, skin care 
and topical management of AV in adult females will be discussed.

It was not long ago that acne vulgaris (AV) was commonly considered to be a skin disease that affected teenagers with little attention given to preadolescent and postadolescent AV. This perspective has changed, with more attention being given to AV across a broad range of affected 
age groups, including preadolescent, adolescent, and postadolescent subgroups.^1-5 Earlier onset of adrenarche has led to earlier development of AV in many young girls, with a higher range of dehydroepiandrosterone sulfate (DHEAS) levels observed overall in those with AV as compared to a normal age-matched population.^3,4 At the other end of the age spectrum, AV is a common phenomenon in adult females, with at least half of women estimated to exhibit some form of AV.^1,2,5-8 Based on a 
large survey of females and males (N=1013), the prevalence of AV in adult females has been reported to be 50.9%, 35.2%, 26.3%, and 15.3% among women aged 20 to 29 years, 30 to 39 years, 40 to 49 years, and 50 years and older, respectively.² Acne vulgaris that persists beyond adolescence into adulthood is termed persistent acne, or early-onset acne, and the development of AV in women 25 years and older who have not previously been affected by AV has been termed late-onset acne.^6,8,9 Publications on the management of AV in adult women have focused primarily on systemic hormonal therapies; however, topical therapies more recently have received greater attention in this subpopulation^9-12 and will be discussed in part 2 of this series. Because data on AV in women are 
limited primarily to involvement of the face and neck region, this article does not address truncal AV unless otherwise specified. Table 1 depicts factors that can influence the management of AV in adult women.

Visible Patterns and Considerations for Clinical Evaluation 


Clinical Patterns

Although epidemiologic and demographic data are limited in the subpopulation of women with AV, it is reported that females account for up to 82% of adults with AV, with approximately 75% presenting with AV that is clinically similar to their disease course in adolescence.^2,5,13 Among those women with persistent AV, some state that their AV is worse compared to adolescence, while others report it is not as severe. The pattern of AV often is similar to that seen in adolescence, presenting as mixed comedonal and inflammatory papular/pustular lesions diffusely distributed on the face; in other cases, a more selectively distributed U-shaped pattern is noted, characterized predominantly by inflammatory papules and/or nodules involving the lower cheeks and jawline margin, with lesions also commonly noted on the anterior and lateral neck.^5,8,9,13-16 A U-shaped pattern is believed to be more common in late-onset AV, often with persistence into the mid-40s.^1,15,17 It is important to emphasize the need for additional studies on the demographics and clinical characteristics of AV in adult females, especially correlations between onset, age, and clinical patterns of AV.

An international, prospective, observational study assessed the clinical characteristics of AV in adults (aged ≥25 years) at a dermatology visit for acne (N=374).¹⁶ Participants who were under management for their AV showed severity grades of mild (clear/almost clear) in 47.3% of cases. Involvement of multiple facial sites—cheeks, forehead, mandibular region, and temples—was noted in 89.8% of women, often with both inflammatory and comedonal lesions, which is a pattern similar to adolescent AV. Inflammatory lesions alone were observed in 6.4% of women, 17.1% had comedonal AV only, 
and truncal AV was present in 48.4%.¹⁶ Additional well-designed studies are needed to determine if this study reflects an accurate qualitative and 
quantitative depiction of the spectrum of AV in adult females.

Mandibular Pattern

In the observational study of AV in adults, AV localized to the mandibular area was noted in only 11.2% of participants.¹⁶ Women with localized mandibular AV were more likely than women without localized AV to be employed, noted greater daily stress levels, and tended to report more psychologically stressful jobs. Interestingly, the subgroup with mandibular acne alone was much less likely 
to exhibit a global severity grade of moderate or higher (7.1% vs 50.1%), truncal acne 
(19.0% vs 51.9%), postinflammatory hyperpigmentation (23.8% vs 51.9%), and erythema (19.0% vs 48.4%), suggesting a unique subset of AV presentation.¹⁶

Ethnicity/Skin Color

Women of all ethnicities and skin types may be affected by AV.^1,18-20 Earlier age of onset of AV has been suggested in white women; however, earlier onset of adrenarche may be more frequent in black girls, which supports an earlier age of onset of AV in this subpopulation.^15-17 Women with skin of color usually express greater concern with persistent dyschromia at sites where lesions have resolved, and presence of acne scars is a concern among women regardless of skin color, ethnicity, or race.^18,20-22

Scarring

Acne scarring has been noted to affect up to 
three-fourths of adult women in one report¹⁷ and 
often is stated by patients to be a cause of concern 
and frustration.^1,5,17

Perimenstrual Flaring

Flaring associated with menses is commonly reported in adult females with AV, with 56%, 17%, and 
3% of women in one study (n=230) reporting worsening before, during, or after menses, respectively.²¹

External Factors

Comedogenic products used for skin care, cover-up makeup, or hair care may be important to consider in selected cases as potential etiologic or exacerbating factors in adult females with AV; they also may be used in the management of AV.^23-25 Adult females often are perplexed and frustrated by the presence of AV after their 
teenaged years and anxiously wonder about or search for the potential causes. Many women use cosmetic products to cover up facial AV.^5,23-25 Therefore, even if skin care or personal hygiene products or makeup are not believed to be an etiologic factor, many patients appreciate that their dermatologist addressed skin care and cosmetics as a component of AV management and provided appropriate recommendations.^5,13

Ingestion of dietary supplements containing whey protein have been associated with precipitation of AV.^26,27 Diets with specific content characteristics have been implicated as potential etiologic or exacerbating factors for AV; however, data are limited and specific recommendations remain elusive at present. Individual cases may warrant consideration of dietary factors, especially when treatment resistance is noted.²⁸ Importantly, progestin-only contraceptives (ie, injectables, intrauterine devices) also can exacerbate or induce AV.²⁹

Hyperandrogenism

Although most adult females with AV are reported to have normal serum androgen levels when tested, it is important to explore potential signs and symptoms that are suggestive of underlying hyperandrogenism through both the patient’s history and physical examination.^{9-11,21,29-33} Some investigators have suggested that underlying peripheral hyperandrogenism is the leading cause of AV in adult females, 
with or without concurrent polycystic ovarian syndrome (PCOS), though it is believed that most women with AV exhibit normal results when 
undergoing laboratory testing for androgen excess.^{10,11,21,29,30} Nevertheless, it is important to consider the possibility of underlying causes of androgen excess (Table 2), the most common being PCOS and late-onset congenital adrenal hyperplasia; an androgen-secreting tumor is less common.^11,29-33 It is suggested that screening for underlying endocrinopathy should be conducted in women presenting with (1) AV recalcitrant to conventional treatment, (2) sudden emergence of severe AV, 
(3) concurrent signs/symptoms of androgen 
excess, and/or (4) AV relapse shortly after isotretinoin therapy.^7,11,16,33

Hirsutism and acanthosis nigricans have been reported to be more reliable predictors of hyperandrogenism than androgenic alopecia.²¹ Although it may be subtle in some cases, acanthosis nigricans is harder to camouflage, so the clinician can usually detect it if a thorough physical examination is performed. However, a patient may not voluntarily report to the clinician and their staff that she has hair removed, so despite a thorough examination, the clinician may not detect hirsutism. Therefore, it is important to inquire directly about the presence of hairs (pigmented terminal vs “peach fuzz” hairs), their anatomic location, and any hair removal practices the patient has used. The absence of androgenic alopecia does not exclude underlying hyperandrogenism; however, its presence, especially in younger women, may serve as a clinical marker for underlying hyperandrogenism.⁵ Some women may camouflage more subtle alopecia through hairstyling, but obtaining this history usually is not problematic, as most women are distressed by any degree of hair loss.

Laboratory Evaluation—A relatively straightforward approach to the workup of androgen excess includes assessment of serum DHEAS, free testosterone, and total testosterone levels.^10,30 Elevation of serum DHEAS levels indicates an adrenal source of androgen production. Elevation of testosterone is associated with excess androgens 
produced by the ovaries. Modest elevations of 
DHEAS are most commonly associated with late-onset congenital adrenal hyperplasia that may not have been previously diagnosed. Modest elevation 
of testosterone is most commonly associated with PCOS, which also can be accompanied by an 
elevated luteinizing hormone:follicle-stimulating hormone ratio of 2.5:1 to 3:1.^10,30 Marked elevations of DHEAS or testosterone can be indicative of adrenal or ovarian tumors, respectively.³⁰

In some cases, a woman might have 
elevated DHEAS and testosterone levels. A 17-hydroxyprogesterone test can help discriminate between an adrenal or ovarian source of 
androgen excess in these cases, as elevated 
17-hydroxyprogesterone levels indicate that the androgens are coming from the adrenal gland.^10,30

It is important that laboratory evaluation be performed when ovulation is not occurring. Blood tests can be drawn just prior to or during menses. It is important that a woman is not taking an oral contraceptive at the time of testing, which can mask an underlying endocrine abnormality.^10,11,29,30 Generally, testing can be performed at least 4 to 6 weeks after stopping the oral contraceptive.

Psychosocial Impact

Facial AV exhibits a broad range of adverse psychological and social effects on many adult females.^2,5,13,18 It can be associated with depression, anxiety, psychological stress, and suicidal ideation; therefore, thorough screening for these comorbidities may be warranted in some patients.^2,18

Conclusion

The epidemiology, clinical presentation, and clinical and laboratory evaluation of AV in adult females was reviewed in part 1 of this 3-part series. It is important for the clinician to assess the clinical presentation, psychosocial effects, and the possibility of underlying causes of androgen excess. In part 2, skin care 
and topical management of AV in adult females will be discussed.

It was not long ago that acne vulgaris (AV) was commonly considered to be a skin disease that affected teenagers with little attention given to preadolescent and postadolescent AV. This perspective has changed, with more attention being given to AV across a broad range of affected 
age groups, including preadolescent, adolescent, and postadolescent subgroups.^1-5 Earlier onset of adrenarche has led to earlier development of AV in many young girls, with a higher range of dehydroepiandrosterone sulfate (DHEAS) levels observed overall in those with AV as compared to a normal age-matched population.^3,4 At the other end of the age spectrum, AV is a common phenomenon in adult females, with at least half of women estimated to exhibit some form of AV.^1,2,5-8 Based on a 
large survey of females and males (N=1013), the prevalence of AV in adult females has been reported to be 50.9%, 35.2%, 26.3%, and 15.3% among women aged 20 to 29 years, 30 to 39 years, 40 to 49 years, and 50 years and older, respectively.² Acne vulgaris that persists beyond adolescence into adulthood is termed persistent acne, or early-onset acne, and the development of AV in women 25 years and older who have not previously been affected by AV has been termed late-onset acne.^6,8,9 Publications on the management of AV in adult women have focused primarily on systemic hormonal therapies; however, topical therapies more recently have received greater attention in this subpopulation^9-12 and will be discussed in part 2 of this series. Because data on AV in women are 
limited primarily to involvement of the face and neck region, this article does not address truncal AV unless otherwise specified. Table 1 depicts factors that can influence the management of AV in adult women.

Visible Patterns and Considerations for Clinical Evaluation 


Clinical Patterns

Although epidemiologic and demographic data are limited in the subpopulation of women with AV, it is reported that females account for up to 82% of adults with AV, with approximately 75% presenting with AV that is clinically similar to their disease course in adolescence.^2,5,13 Among those women with persistent AV, some state that their AV is worse compared to adolescence, while others report it is not as severe. The pattern of AV often is similar to that seen in adolescence, presenting as mixed comedonal and inflammatory papular/pustular lesions diffusely distributed on the face; in other cases, a more selectively distributed U-shaped pattern is noted, characterized predominantly by inflammatory papules and/or nodules involving the lower cheeks and jawline margin, with lesions also commonly noted on the anterior and lateral neck.^5,8,9,13-16 A U-shaped pattern is believed to be more common in late-onset AV, often with persistence into the mid-40s.^1,15,17 It is important to emphasize the need for additional studies on the demographics and clinical characteristics of AV in adult females, especially correlations between onset, age, and clinical patterns of AV.

An international, prospective, observational study assessed the clinical characteristics of AV in adults (aged ≥25 years) at a dermatology visit for acne (N=374).¹⁶ Participants who were under management for their AV showed severity grades of mild (clear/almost clear) in 47.3% of cases. Involvement of multiple facial sites—cheeks, forehead, mandibular region, and temples—was noted in 89.8% of women, often with both inflammatory and comedonal lesions, which is a pattern similar to adolescent AV. Inflammatory lesions alone were observed in 6.4% of women, 17.1% had comedonal AV only, 
and truncal AV was present in 48.4%.¹⁶ Additional well-designed studies are needed to determine if this study reflects an accurate qualitative and 
quantitative depiction of the spectrum of AV in adult females.

Mandibular Pattern

In the observational study of AV in adults, AV localized to the mandibular area was noted in only 11.2% of participants.¹⁶ Women with localized mandibular AV were more likely than women without localized AV to be employed, noted greater daily stress levels, and tended to report more psychologically stressful jobs. Interestingly, the subgroup with mandibular acne alone was much less likely 
to exhibit a global severity grade of moderate or higher (7.1% vs 50.1%), truncal acne 
(19.0% vs 51.9%), postinflammatory hyperpigmentation (23.8% vs 51.9%), and erythema (19.0% vs 48.4%), suggesting a unique subset of AV presentation.¹⁶

Ethnicity/Skin Color

Women of all ethnicities and skin types may be affected by AV.^1,18-20 Earlier age of onset of AV has been suggested in white women; however, earlier onset of adrenarche may be more frequent in black girls, which supports an earlier age of onset of AV in this subpopulation.^15-17 Women with skin of color usually express greater concern with persistent dyschromia at sites where lesions have resolved, and presence of acne scars is a concern among women regardless of skin color, ethnicity, or race.^18,20-22

Scarring

Acne scarring has been noted to affect up to 
three-fourths of adult women in one report¹⁷ and 
often is stated by patients to be a cause of concern 
and frustration.^1,5,17

Perimenstrual Flaring

Flaring associated with menses is commonly reported in adult females with AV, with 56%, 17%, and 
3% of women in one study (n=230) reporting worsening before, during, or after menses, respectively.²¹

External Factors

Comedogenic products used for skin care, cover-up makeup, or hair care may be important to consider in selected cases as potential etiologic or exacerbating factors in adult females with AV; they also may be used in the management of AV.^23-25 Adult females often are perplexed and frustrated by the presence of AV after their 
teenaged years and anxiously wonder about or search for the potential causes. Many women use cosmetic products to cover up facial AV.^5,23-25 Therefore, even if skin care or personal hygiene products or makeup are not believed to be an etiologic factor, many patients appreciate that their dermatologist addressed skin care and cosmetics as a component of AV management and provided appropriate recommendations.^5,13

Ingestion of dietary supplements containing whey protein have been associated with precipitation of AV.^26,27 Diets with specific content characteristics have been implicated as potential etiologic or exacerbating factors for AV; however, data are limited and specific recommendations remain elusive at present. Individual cases may warrant consideration of dietary factors, especially when treatment resistance is noted.²⁸ Importantly, progestin-only contraceptives (ie, injectables, intrauterine devices) also can exacerbate or induce AV.²⁹

Hyperandrogenism

Although most adult females with AV are reported to have normal serum androgen levels when tested, it is important to explore potential signs and symptoms that are suggestive of underlying hyperandrogenism through both the patient’s history and physical examination.^{9-11,21,29-33} Some investigators have suggested that underlying peripheral hyperandrogenism is the leading cause of AV in adult females, 
with or without concurrent polycystic ovarian syndrome (PCOS), though it is believed that most women with AV exhibit normal results when 
undergoing laboratory testing for androgen excess.^{10,11,21,29,30} Nevertheless, it is important to consider the possibility of underlying causes of androgen excess (Table 2), the most common being PCOS and late-onset congenital adrenal hyperplasia; an androgen-secreting tumor is less common.^11,29-33 It is suggested that screening for underlying endocrinopathy should be conducted in women presenting with (1) AV recalcitrant to conventional treatment, (2) sudden emergence of severe AV, 
(3) concurrent signs/symptoms of androgen 
excess, and/or (4) AV relapse shortly after isotretinoin therapy.^7,11,16,33

Hirsutism and acanthosis nigricans have been reported to be more reliable predictors of hyperandrogenism than androgenic alopecia.²¹ Although it may be subtle in some cases, acanthosis nigricans is harder to camouflage, so the clinician can usually detect it if a thorough physical examination is performed. However, a patient may not voluntarily report to the clinician and their staff that she has hair removed, so despite a thorough examination, the clinician may not detect hirsutism. Therefore, it is important to inquire directly about the presence of hairs (pigmented terminal vs “peach fuzz” hairs), their anatomic location, and any hair removal practices the patient has used. The absence of androgenic alopecia does not exclude underlying hyperandrogenism; however, its presence, especially in younger women, may serve as a clinical marker for underlying hyperandrogenism.⁵ Some women may camouflage more subtle alopecia through hairstyling, but obtaining this history usually is not problematic, as most women are distressed by any degree of hair loss.

Laboratory Evaluation—A relatively straightforward approach to the workup of androgen excess includes assessment of serum DHEAS, free testosterone, and total testosterone levels.^10,30 Elevation of serum DHEAS levels indicates an adrenal source of androgen production. Elevation of testosterone is associated with excess androgens 
produced by the ovaries. Modest elevations of 
DHEAS are most commonly associated with late-onset congenital adrenal hyperplasia that may not have been previously diagnosed. Modest elevation 
of testosterone is most commonly associated with PCOS, which also can be accompanied by an 
elevated luteinizing hormone:follicle-stimulating hormone ratio of 2.5:1 to 3:1.^10,30 Marked elevations of DHEAS or testosterone can be indicative of adrenal or ovarian tumors, respectively.³⁰

In some cases, a woman might have 
elevated DHEAS and testosterone levels. A 17-hydroxyprogesterone test can help discriminate between an adrenal or ovarian source of 
androgen excess in these cases, as elevated 
17-hydroxyprogesterone levels indicate that the androgens are coming from the adrenal gland.^10,30

It is important that laboratory evaluation be performed when ovulation is not occurring. Blood tests can be drawn just prior to or during menses. It is important that a woman is not taking an oral contraceptive at the time of testing, which can mask an underlying endocrine abnormality.^10,11,29,30 Generally, testing can be performed at least 4 to 6 weeks after stopping the oral contraceptive.

Psychosocial Impact

Facial AV exhibits a broad range of adverse psychological and social effects on many adult females.^2,5,13,18 It can be associated with depression, anxiety, psychological stress, and suicidal ideation; therefore, thorough screening for these comorbidities may be warranted in some patients.^2,18

Conclusion

The epidemiology, clinical presentation, and clinical and laboratory evaluation of AV in adult females was reviewed in part 1 of this 3-part series. It is important for the clinician to assess the clinical presentation, psychosocial effects, and the possibility of underlying causes of androgen excess. In part 2, skin care 
and topical management of AV in adult females will be discussed.

The management of acne vulgaris (AV) in women has been the subject of considerable attention over the last few years. It has become increasingly recognized that a greater number of patient encounters in dermatology offices involve women with AV who are beyond their adolescent years. Overall, it is estimated that up to approximately 22% of women in the United States are affected by AV, with approximately half of women in their 20s and one-third of women in their 30s reporting some degree of AV.^1-4 Among women, the disease shows no predilection for certain skin types or ethnicities, can start during the preteenaged or adolescent years, can persist or recur in adulthood (persistent acne, 75%), or can start in adulthood (late-onset acne, 25%) in females with minimal or no history of AV occurring earlier in life.^3,5-7 In the subpopulation of adult women, AV occurs at a time when many expect to be far beyond this “teenage affliction.” Women who are affected commonly express feeling embarrassed and frustrated.^5-8

Most of the emphasis in the literature and in presentations at dermatology meetings regarding the management of AV in adult women has focused on excluding underlying disorders that cause excess androgens (eg, polycystic ovary syndrome, congenital adrenal hyperplasia, tumors, exogenous sources) as well as the use of systemic therapies such as oral contraceptives (OCs) and spironolactone.^5-7,9,10 Little attention has been given to the selection of topical therapies in this patient population, especially with regard to evidence from clinical studies. To date, results from published study analyses using topical agents specifically for adult females with facial AV have only included adapalene gel 0.3% applied once daily and dapsone gel 5% applied twice daily.^11-13 Both agents have been evaluated in subset analysis comparisons of outcomes in women aged 18 years and older versus adolescents aged 12 to 17 years based on data from 12-week phase 3 pivotal trials.^14-16

Are there clinically relevant differences between AV in adult versus adolescent females?

Although much has been written about AV in women, epidemiology, demographics, assessment of clinical presentation, and correlation of clinical presentation with excess androgens have not been emphasized,^1-3,5-10,17 likely due to marketing campaigns that emphasize AV as a disorder that predominantly affects teenagers as well as the focus on optimal use of oral spironolactone and/or OCs in the management of AV in the adult female population. Attention to spironolactone use is important because it is not approved by the US Food and Drug Administration for the treatment of AV. Spironolactone carries certain black-box warnings that may not be clinically relevant in all patients but still require attention. It also is associated with risks if taken during pregnancy, and it is a potassium-sparing diuretic with potential for hyperkalemia, especially in patients with reduced renal function or those who are taking potassium supplements or certain other medications.^6,9,11,17 Use of OCs to treat AV also is not without potential risks, with specific warnings and relative contraindications reported, especially in relation to increased risks for cardiac complications, stroke, and thromboembolism.^6,9,11,12 Because adult females are in a different stage of life than teenagers, there are defined psychosocial and medical considerations in managing AV in these patients compared with adolescents.^5-8,17 Importantly for both clinicians and patients, addressing these differences and considerations can have a major impact on whether or not women with AV experience successful treatment outcomes.^{1-3,5,6,8,10,13} Skin color and ethnicity also can affect the psychosocial and physical factors that influence the overall management of adult female patients with AV, including selection of therapies and handling long-term visible sequelae that occur in some AV patients, such as dyschromia (eg, persistent or postinflammatory erythema or hyperpigmentation) and acne scarring.^5-8,13,17-20

Psychosocial Considerations

With regard to psychosocial, emotional, and attitudinal considerations in women with AV, common findings include concern or frustration regarding the presence of AV beyond adolescence; anxiety; symptoms of depression; decreased self-confidence; increased self-consciousness, especially during public interactions or intimate situations; and interference with steady concentration at work or school.^5,6,8,13 Long-term complications of AV, such as dyschromia and acne scarring, are more likely to be encountered in adult patients, especially if they had AV as a teenager, with women reporting that they remain conscious of these adverse sequelae.⁸ It is estimated that approximately three-fourths of women with AV also had AV as teenagers; therefore, most of them have already used many over-the-counter and prescription therapies and are likely to want treatments that are newer, well-tolerated, safe, and known to be effective in adult women.^8,16,17 Convenience and simplicity are vital components of treatment selection and regimen design, as many women with AV frequently face time constraints in their daily routines due to family, social, employment, and home-related demands and responsibilities.^6-8,17

Medical Considerations

It is apparent from reports in the literature as well as from clinical experience that some women with AV present with a U-shaped pattern of involvement on the face,^5-7,10,13,17 which refers to the presence of predominantly inflammatory papules (many of them deep) and some nodules on the lower face, jawline, and anterolateral neck region, with comedones often sparse or absent.^5-7 It often is perceived and may be true that women who present with this pattern of distribution are more androgen sensitive despite having normal serum androgen levels or in some cases exhibit detectable excess androgens (eg, in the setting of polycystic ovary syndrome) and may be more likely to respond to hormonal therapies (eg, spironolactone, OCs) than those with mixed facial AV (ie, multiple comedonal and inflammatory acne lesions, not limited to a U-shaped pattern, similar to adolescent AV), but data are limited to support differentiation between the U-shaped pattern group and the conventional mixed facial AV group.^5-7,17 Adult and adolescent females in both groups sometimes report perimenstrual flares and frequent persistent papular AV that tends to concentrate on the perioral and chin area.

It is also important to consider that the current literature suggests approximately three-fourths of women with AV report that they also had AV as a teenager, with many indicating the same clinical pattern of AV and approximately one-third reporting AV that is more severe in adulthood than adolescence.^5-8,17 The available literature on topical and oral therapies used to treat AV in both adolescent and adult females predominantly focuses on inclusion of both inflammatory and noninflammatory (comedonal) facial AV lesions, does not specifically address or include the U-shaped pattern of AV in adult women for inclusion in studies that evaluate efficacy in this subgroup, and does not include AV involving the neck region and below the jawline margin as part of any study protocols and/or discussions about therapy.^{5-7,9-12,17,21-26} Involvement of the neck and lower jawline is common in women presenting with the U-shaped pattern of AV, and available studies only evaluate AV involving the face and do not include AV lesions present below the jawline margin. As a result, there is a considerable need for well-designed studies with laboratory assessments to include or exclude underlying detectable excess androgens and to assess the efficacy, tolerability, and safety of specific therapeutic agents both alone and in combination in adult women who present with a U-shaped pattern of AV.¹⁷

Other medical considerations that can influence treatment selection and are more likely to be present in adult versus adolescent females include underlying chronic medical disorders; concomitant medications that may interact with other oral agents; potential for pregnancy; age, particularly when prescribing OCs; and the  potential desire to stop taking OCs if already used over a prolonged period.^6,7

Age-Related Differentiation of Female Subgroups With AV

The age-based dividing line that defines AV in adults versus adolescent females has been described in the literature; however, the basis for published definitions of female subgroups with AV is not well-supported by strong scientific evidence.^1-3,5-7,17 The conventional dividing line that was originally selected to define adult females with AV was 25 years of age or older; persistent acne is present both during adolescence and at or after 25 years of age, while late-onset acne is described as AV that first presents at 25 years of age or older.^3,5-7

More recently, a range of 18 years or older has been used to classify adult female AV and a range of 12 to 17 years for adolescent female AV in subset analyses that evaluated treatment outcomes in both patient populations from phase 3 pivotal trials completed with adapalene gel 0.3% applied once daily and dapsone gel 5% applied twice daily.^14-16 These subanalyses included participants with facial AV that was predominantly moderate in severity, mandated specific lesion count ranges for both comedonal and inflammatory lesions, and included only facial AV that was above the mandibular (jawline) margin.^15,16,21,26 Therefore, patients with AV presenting in a U-shaped pattern with involvement below the jawline and on the neck were not included in these study analyses, as these patients were excluded from the phase 3 trials on which the analyses were based. The outcomes of these analyses apply to treatment in women who present with both inflammatory and noninflammatory facial AV lesions, which supports the observation that AV in this patient population is not always predominantly inflammatory and does not always present in a U-shaped distribution.^14-16 In fact, a U-shaped pattern of distribution appears to be less common in women with AV than a mixed inflammatory and comedonal distribution that involves the face more diffusely, though more data are needed from well-designed and large-scale epidemiologic and demographic studies.^5,14,17

Are there data available on the use of benzoyl peroxide with or without a topical antibiotic in women with AV?

There is a conspicuous absence of prospective clinical trials and retrospective analyses evaluating the specific use of individual AV therapies in adult females, with a particular lack of studies with topical agents (eg, benzoyl peroxide [BP]).¹⁴ Subset analyses have been completed for adapalene gel 0.3% and dapsone gel 5%.^15,16 Additionally, an age-based subset analysis in females with facial AV also has been completed with clindamycin phosphate (CP) 1.2%–BP 2.5% gel once daily, with data presented but not yet fully published.¹⁴

Two identical phase 3, double-blind, randomized, 12-week, 4-arm trials compared treatment outcomes in groups treated with an aqueous-based combination gel formulation containing BP 2.5% and CP 1.2% (n=797), active monad gels (BP [n=809] or CP [n=812]), or vehicle gel (n=395), all applied once daily in patients with facial AV.²² Participants were 12 years or older (mean age range, 19.1–19.6 years; age range, 12.1–70.2 years), were of either gender (approximately 50% split in each study arm), and presented with moderate (approximately 80% of participants) or severe AV (approximately 20% of participants) at baseline. The entry criteria for lesion types and number of lesions were 17 to 40 inflammatory lesions (ie, papules, pustules, <2 nodules)(range of mean number of lesions, 25.8–26.4) and 20 to 100 noninflammatory lesions (ie, closed comedones, open comedones)(range of mean number of lesions, 44.0–47.4). Participant demographics included white (73.9%–77.5%), black/African American (16.1%–20.4%), and Asian (2.1%–3.3%), with the remaining participants distributed among a variety of other ethnic groups such as Native Hawaiian/Native Pacific Islander and Native American Indian/Native Alaskan (collectively <5% in each study arm). Therefore, approximately 1 of every 4 patients had skin of color, which provided good diversity of patients considering the large study size (N=2813). Data analysis included dichotomization of participants by severity rating (moderate or severe based on evaluator global severity score) and skin phototype (Fitzpatrick skin types I–III or IV–VI).²²

The pooled results from both studies completed at 68 investigative sites demonstrated that CP 1.2%–BP 2.5% gel was superior in efficacy to each individual monad and to the vehicle in inflammatory, noninflammatory, and total lesion reductions as early as week 4 (P<.001) and at week 12, which was the study end point (P<.001), with superiority also demonstrated in achieving treatment success (defined as a >2 grade improvement according to the evaluator global severity score) compared to the 3 other study arms (P<.001).²² Subject assessments also were consistent with outcomes noted by the investigators. Cutaneous tolerability was favorable and comparable in all 4 study arms with less than 1% of participants discontinuing treatment due to adverse events.²²

A subset analysis of the data from the phase 3 pivotal trials with CP 1.2%–BP 2.5% gel was completed to compare reductions in both inflammatory and noninflammatory lesions in female participants who were younger than 25 years and 25 years of age or older in all 4 study arms. This information has been presented^14,17 but has not been previously published. Based on the overall results reported in the phase 3 studies, there were no differentiations in skin tolerability or safety based on participant age, gender, or skin type.²² The subanalysis included a total of 1080 females who were younger than 25 years and 395 females who were 25 years of age or older. The lesion reduction outcomes of this subanalysis are presented in the Table. Statistical analyses of the results among these age groups in the 4 study arms were not completed because the objective was to determine if there were any major or obvious differences in reduction of AV lesions based on the conventional dividing line of 25 years of age in adult women as compared to adolescent females treated with CP 1.2%–BP 2.5% gel. In addition, the large difference in numbers of female participants between the 2 age groups (>25 years of age, n=395; <25 years of age, n=1080) at least partially confounds both statistical and observational analysis. Among the women who were 25 years of age or older who were included in the subanalysis, 67.0% and 25.8% were between the ages of 25 to 35 years and 36 to 45 years, respectively. Based on the outcomes reported in the phase 3 trials and in this subgroup analysis, CP 1.2%–BP 2.5% gel applied once daily over a 12-week period appeared overall to be comparably effective in females regardless of age and with no apparent adverse events regarding differences in skin tolerability or safety.^14,22 One observation that was noted was the possible trend of greater reduction in both lesion types in women older than 35 years versus younger females with the use of the combination gel or BP alone; however, the number of female participants who were older than 35 years of age was substantially less (n=102) than those who were 35 years of age or younger (n=1345), thus precluding support for any definitive conclusions about this possible trend.²²

How can CP 1.2%–BP 2.5% gel be incorporated into a treatment regimen for women with facial AV?

The incorporation of CP 1.2%–BP 2.5% gel into a treatment regimen for women with facial AV is similar to the general use of BP-containing formulations in the overall management of AV.^9,14,27,28 Because women with AV commonly present with facial inflammatory lesions and many also with facial comedones, CP 1.2%–BP 2.5% gel is best used once daily in the morning in combination with a topical retinoid in the evening,^9,27 which can be achieved with use of CP 1.2%–BP 2.5% gel in the morning and a topical retinoid (ie, tretinoin, adapalene, tazarotene) in the evening or CP 1.2%–tretinoin 0.025% gel in the evening. It is important to note that cutaneous irritation may be more likely if neck lesions are present; the potential for bleaching of colored fabric by BP also is a practical concern.²⁸ In addition, CP 1.2%–BP 2.5% gel may also be used in combination with topical dapsone, but both products should be applied separately at different times of the day to avoid temporary orange discoloration of the skin, which appears to be an uncommon side effect but remains a possibility based on the product information for dapsone gel 5% with regard to its concomitant use with BP.^29,30

The management of acne vulgaris (AV) in women has been the subject of considerable attention over the last few years. It has become increasingly recognized that a greater number of patient encounters in dermatology offices involve women with AV who are beyond their adolescent years. Overall, it is estimated that up to approximately 22% of women in the United States are affected by AV, with approximately half of women in their 20s and one-third of women in their 30s reporting some degree of AV.^1-4 Among women, the disease shows no predilection for certain skin types or ethnicities, can start during the preteenaged or adolescent years, can persist or recur in adulthood (persistent acne, 75%), or can start in adulthood (late-onset acne, 25%) in females with minimal or no history of AV occurring earlier in life.^3,5-7 In the subpopulation of adult women, AV occurs at a time when many expect to be far beyond this “teenage affliction.” Women who are affected commonly express feeling embarrassed and frustrated.^5-8

Most of the emphasis in the literature and in presentations at dermatology meetings regarding the management of AV in adult women has focused on excluding underlying disorders that cause excess androgens (eg, polycystic ovary syndrome, congenital adrenal hyperplasia, tumors, exogenous sources) as well as the use of systemic therapies such as oral contraceptives (OCs) and spironolactone.^5-7,9,10 Little attention has been given to the selection of topical therapies in this patient population, especially with regard to evidence from clinical studies. To date, results from published study analyses using topical agents specifically for adult females with facial AV have only included adapalene gel 0.3% applied once daily and dapsone gel 5% applied twice daily.^11-13 Both agents have been evaluated in subset analysis comparisons of outcomes in women aged 18 years and older versus adolescents aged 12 to 17 years based on data from 12-week phase 3 pivotal trials.^14-16

Are there clinically relevant differences between AV in adult versus adolescent females?

Although much has been written about AV in women, epidemiology, demographics, assessment of clinical presentation, and correlation of clinical presentation with excess androgens have not been emphasized,^1-3,5-10,17 likely due to marketing campaigns that emphasize AV as a disorder that predominantly affects teenagers as well as the focus on optimal use of oral spironolactone and/or OCs in the management of AV in the adult female population. Attention to spironolactone use is important because it is not approved by the US Food and Drug Administration for the treatment of AV. Spironolactone carries certain black-box warnings that may not be clinically relevant in all patients but still require attention. It also is associated with risks if taken during pregnancy, and it is a potassium-sparing diuretic with potential for hyperkalemia, especially in patients with reduced renal function or those who are taking potassium supplements or certain other medications.^6,9,11,17 Use of OCs to treat AV also is not without potential risks, with specific warnings and relative contraindications reported, especially in relation to increased risks for cardiac complications, stroke, and thromboembolism.^6,9,11,12 Because adult females are in a different stage of life than teenagers, there are defined psychosocial and medical considerations in managing AV in these patients compared with adolescents.^5-8,17 Importantly for both clinicians and patients, addressing these differences and considerations can have a major impact on whether or not women with AV experience successful treatment outcomes.^{1-3,5,6,8,10,13} Skin color and ethnicity also can affect the psychosocial and physical factors that influence the overall management of adult female patients with AV, including selection of therapies and handling long-term visible sequelae that occur in some AV patients, such as dyschromia (eg, persistent or postinflammatory erythema or hyperpigmentation) and acne scarring.^5-8,13,17-20

Psychosocial Considerations

With regard to psychosocial, emotional, and attitudinal considerations in women with AV, common findings include concern or frustration regarding the presence of AV beyond adolescence; anxiety; symptoms of depression; decreased self-confidence; increased self-consciousness, especially during public interactions or intimate situations; and interference with steady concentration at work or school.^5,6,8,13 Long-term complications of AV, such as dyschromia and acne scarring, are more likely to be encountered in adult patients, especially if they had AV as a teenager, with women reporting that they remain conscious of these adverse sequelae.⁸ It is estimated that approximately three-fourths of women with AV also had AV as teenagers; therefore, most of them have already used many over-the-counter and prescription therapies and are likely to want treatments that are newer, well-tolerated, safe, and known to be effective in adult women.^8,16,17 Convenience and simplicity are vital components of treatment selection and regimen design, as many women with AV frequently face time constraints in their daily routines due to family, social, employment, and home-related demands and responsibilities.^6-8,17

Medical Considerations

It is apparent from reports in the literature as well as from clinical experience that some women with AV present with a U-shaped pattern of involvement on the face,^5-7,10,13,17 which refers to the presence of predominantly inflammatory papules (many of them deep) and some nodules on the lower face, jawline, and anterolateral neck region, with comedones often sparse or absent.^5-7 It often is perceived and may be true that women who present with this pattern of distribution are more androgen sensitive despite having normal serum androgen levels or in some cases exhibit detectable excess androgens (eg, in the setting of polycystic ovary syndrome) and may be more likely to respond to hormonal therapies (eg, spironolactone, OCs) than those with mixed facial AV (ie, multiple comedonal and inflammatory acne lesions, not limited to a U-shaped pattern, similar to adolescent AV), but data are limited to support differentiation between the U-shaped pattern group and the conventional mixed facial AV group.^5-7,17 Adult and adolescent females in both groups sometimes report perimenstrual flares and frequent persistent papular AV that tends to concentrate on the perioral and chin area.

It is also important to consider that the current literature suggests approximately three-fourths of women with AV report that they also had AV as a teenager, with many indicating the same clinical pattern of AV and approximately one-third reporting AV that is more severe in adulthood than adolescence.^5-8,17 The available literature on topical and oral therapies used to treat AV in both adolescent and adult females predominantly focuses on inclusion of both inflammatory and noninflammatory (comedonal) facial AV lesions, does not specifically address or include the U-shaped pattern of AV in adult women for inclusion in studies that evaluate efficacy in this subgroup, and does not include AV involving the neck region and below the jawline margin as part of any study protocols and/or discussions about therapy.^{5-7,9-12,17,21-26} Involvement of the neck and lower jawline is common in women presenting with the U-shaped pattern of AV, and available studies only evaluate AV involving the face and do not include AV lesions present below the jawline margin. As a result, there is a considerable need for well-designed studies with laboratory assessments to include or exclude underlying detectable excess androgens and to assess the efficacy, tolerability, and safety of specific therapeutic agents both alone and in combination in adult women who present with a U-shaped pattern of AV.¹⁷

Other medical considerations that can influence treatment selection and are more likely to be present in adult versus adolescent females include underlying chronic medical disorders; concomitant medications that may interact with other oral agents; potential for pregnancy; age, particularly when prescribing OCs; and the  potential desire to stop taking OCs if already used over a prolonged period.^6,7

Age-Related Differentiation of Female Subgroups With AV

The age-based dividing line that defines AV in adults versus adolescent females has been described in the literature; however, the basis for published definitions of female subgroups with AV is not well-supported by strong scientific evidence.^1-3,5-7,17 The conventional dividing line that was originally selected to define adult females with AV was 25 years of age or older; persistent acne is present both during adolescence and at or after 25 years of age, while late-onset acne is described as AV that first presents at 25 years of age or older.^3,5-7

More recently, a range of 18 years or older has been used to classify adult female AV and a range of 12 to 17 years for adolescent female AV in subset analyses that evaluated treatment outcomes in both patient populations from phase 3 pivotal trials completed with adapalene gel 0.3% applied once daily and dapsone gel 5% applied twice daily.^14-16 These subanalyses included participants with facial AV that was predominantly moderate in severity, mandated specific lesion count ranges for both comedonal and inflammatory lesions, and included only facial AV that was above the mandibular (jawline) margin.^15,16,21,26 Therefore, patients with AV presenting in a U-shaped pattern with involvement below the jawline and on the neck were not included in these study analyses, as these patients were excluded from the phase 3 trials on which the analyses were based. The outcomes of these analyses apply to treatment in women who present with both inflammatory and noninflammatory facial AV lesions, which supports the observation that AV in this patient population is not always predominantly inflammatory and does not always present in a U-shaped distribution.^14-16 In fact, a U-shaped pattern of distribution appears to be less common in women with AV than a mixed inflammatory and comedonal distribution that involves the face more diffusely, though more data are needed from well-designed and large-scale epidemiologic and demographic studies.^5,14,17

Are there data available on the use of benzoyl peroxide with or without a topical antibiotic in women with AV?

There is a conspicuous absence of prospective clinical trials and retrospective analyses evaluating the specific use of individual AV therapies in adult females, with a particular lack of studies with topical agents (eg, benzoyl peroxide [BP]).¹⁴ Subset analyses have been completed for adapalene gel 0.3% and dapsone gel 5%.^15,16 Additionally, an age-based subset analysis in females with facial AV also has been completed with clindamycin phosphate (CP) 1.2%–BP 2.5% gel once daily, with data presented but not yet fully published.¹⁴

Two identical phase 3, double-blind, randomized, 12-week, 4-arm trials compared treatment outcomes in groups treated with an aqueous-based combination gel formulation containing BP 2.5% and CP 1.2% (n=797), active monad gels (BP [n=809] or CP [n=812]), or vehicle gel (n=395), all applied once daily in patients with facial AV.²² Participants were 12 years or older (mean age range, 19.1–19.6 years; age range, 12.1–70.2 years), were of either gender (approximately 50% split in each study arm), and presented with moderate (approximately 80% of participants) or severe AV (approximately 20% of participants) at baseline. The entry criteria for lesion types and number of lesions were 17 to 40 inflammatory lesions (ie, papules, pustules, <2 nodules)(range of mean number of lesions, 25.8–26.4) and 20 to 100 noninflammatory lesions (ie, closed comedones, open comedones)(range of mean number of lesions, 44.0–47.4). Participant demographics included white (73.9%–77.5%), black/African American (16.1%–20.4%), and Asian (2.1%–3.3%), with the remaining participants distributed among a variety of other ethnic groups such as Native Hawaiian/Native Pacific Islander and Native American Indian/Native Alaskan (collectively <5% in each study arm). Therefore, approximately 1 of every 4 patients had skin of color, which provided good diversity of patients considering the large study size (N=2813). Data analysis included dichotomization of participants by severity rating (moderate or severe based on evaluator global severity score) and skin phototype (Fitzpatrick skin types I–III or IV–VI).²²

The pooled results from both studies completed at 68 investigative sites demonstrated that CP 1.2%–BP 2.5% gel was superior in efficacy to each individual monad and to the vehicle in inflammatory, noninflammatory, and total lesion reductions as early as week 4 (P<.001) and at week 12, which was the study end point (P<.001), with superiority also demonstrated in achieving treatment success (defined as a >2 grade improvement according to the evaluator global severity score) compared to the 3 other study arms (P<.001).²² Subject assessments also were consistent with outcomes noted by the investigators. Cutaneous tolerability was favorable and comparable in all 4 study arms with less than 1% of participants discontinuing treatment due to adverse events.²²

A subset analysis of the data from the phase 3 pivotal trials with CP 1.2%–BP 2.5% gel was completed to compare reductions in both inflammatory and noninflammatory lesions in female participants who were younger than 25 years and 25 years of age or older in all 4 study arms. This information has been presented^14,17 but has not been previously published. Based on the overall results reported in the phase 3 studies, there were no differentiations in skin tolerability or safety based on participant age, gender, or skin type.²² The subanalysis included a total of 1080 females who were younger than 25 years and 395 females who were 25 years of age or older. The lesion reduction outcomes of this subanalysis are presented in the Table. Statistical analyses of the results among these age groups in the 4 study arms were not completed because the objective was to determine if there were any major or obvious differences in reduction of AV lesions based on the conventional dividing line of 25 years of age in adult women as compared to adolescent females treated with CP 1.2%–BP 2.5% gel. In addition, the large difference in numbers of female participants between the 2 age groups (>25 years of age, n=395; <25 years of age, n=1080) at least partially confounds both statistical and observational analysis. Among the women who were 25 years of age or older who were included in the subanalysis, 67.0% and 25.8% were between the ages of 25 to 35 years and 36 to 45 years, respectively. Based on the outcomes reported in the phase 3 trials and in this subgroup analysis, CP 1.2%–BP 2.5% gel applied once daily over a 12-week period appeared overall to be comparably effective in females regardless of age and with no apparent adverse events regarding differences in skin tolerability or safety.^14,22 One observation that was noted was the possible trend of greater reduction in both lesion types in women older than 35 years versus younger females with the use of the combination gel or BP alone; however, the number of female participants who were older than 35 years of age was substantially less (n=102) than those who were 35 years of age or younger (n=1345), thus precluding support for any definitive conclusions about this possible trend.²²

How can CP 1.2%–BP 2.5% gel be incorporated into a treatment regimen for women with facial AV?

The incorporation of CP 1.2%–BP 2.5% gel into a treatment regimen for women with facial AV is similar to the general use of BP-containing formulations in the overall management of AV.^9,14,27,28 Because women with AV commonly present with facial inflammatory lesions and many also with facial comedones, CP 1.2%–BP 2.5% gel is best used once daily in the morning in combination with a topical retinoid in the evening,^9,27 which can be achieved with use of CP 1.2%–BP 2.5% gel in the morning and a topical retinoid (ie, tretinoin, adapalene, tazarotene) in the evening or CP 1.2%–tretinoin 0.025% gel in the evening. It is important to note that cutaneous irritation may be more likely if neck lesions are present; the potential for bleaching of colored fabric by BP also is a practical concern.²⁸ In addition, CP 1.2%–BP 2.5% gel may also be used in combination with topical dapsone, but both products should be applied separately at different times of the day to avoid temporary orange discoloration of the skin, which appears to be an uncommon side effect but remains a possibility based on the product information for dapsone gel 5% with regard to its concomitant use with BP.^29,30

The management of acne vulgaris (AV) in women has been the subject of considerable attention over the last few years. It has become increasingly recognized that a greater number of patient encounters in dermatology offices involve women with AV who are beyond their adolescent years. Overall, it is estimated that up to approximately 22% of women in the United States are affected by AV, with approximately half of women in their 20s and one-third of women in their 30s reporting some degree of AV.^1-4 Among women, the disease shows no predilection for certain skin types or ethnicities, can start during the preteenaged or adolescent years, can persist or recur in adulthood (persistent acne, 75%), or can start in adulthood (late-onset acne, 25%) in females with minimal or no history of AV occurring earlier in life.^3,5-7 In the subpopulation of adult women, AV occurs at a time when many expect to be far beyond this “teenage affliction.” Women who are affected commonly express feeling embarrassed and frustrated.^5-8

Most of the emphasis in the literature and in presentations at dermatology meetings regarding the management of AV in adult women has focused on excluding underlying disorders that cause excess androgens (eg, polycystic ovary syndrome, congenital adrenal hyperplasia, tumors, exogenous sources) as well as the use of systemic therapies such as oral contraceptives (OCs) and spironolactone.^5-7,9,10 Little attention has been given to the selection of topical therapies in this patient population, especially with regard to evidence from clinical studies. To date, results from published study analyses using topical agents specifically for adult females with facial AV have only included adapalene gel 0.3% applied once daily and dapsone gel 5% applied twice daily.^11-13 Both agents have been evaluated in subset analysis comparisons of outcomes in women aged 18 years and older versus adolescents aged 12 to 17 years based on data from 12-week phase 3 pivotal trials.^14-16

Are there clinically relevant differences between AV in adult versus adolescent females?

Although much has been written about AV in women, epidemiology, demographics, assessment of clinical presentation, and correlation of clinical presentation with excess androgens have not been emphasized,^1-3,5-10,17 likely due to marketing campaigns that emphasize AV as a disorder that predominantly affects teenagers as well as the focus on optimal use of oral spironolactone and/or OCs in the management of AV in the adult female population. Attention to spironolactone use is important because it is not approved by the US Food and Drug Administration for the treatment of AV. Spironolactone carries certain black-box warnings that may not be clinically relevant in all patients but still require attention. It also is associated with risks if taken during pregnancy, and it is a potassium-sparing diuretic with potential for hyperkalemia, especially in patients with reduced renal function or those who are taking potassium supplements or certain other medications.^6,9,11,17 Use of OCs to treat AV also is not without potential risks, with specific warnings and relative contraindications reported, especially in relation to increased risks for cardiac complications, stroke, and thromboembolism.^6,9,11,12 Because adult females are in a different stage of life than teenagers, there are defined psychosocial and medical considerations in managing AV in these patients compared with adolescents.^5-8,17 Importantly for both clinicians and patients, addressing these differences and considerations can have a major impact on whether or not women with AV experience successful treatment outcomes.^{1-3,5,6,8,10,13} Skin color and ethnicity also can affect the psychosocial and physical factors that influence the overall management of adult female patients with AV, including selection of therapies and handling long-term visible sequelae that occur in some AV patients, such as dyschromia (eg, persistent or postinflammatory erythema or hyperpigmentation) and acne scarring.^5-8,13,17-20

Psychosocial Considerations

With regard to psychosocial, emotional, and attitudinal considerations in women with AV, common findings include concern or frustration regarding the presence of AV beyond adolescence; anxiety; symptoms of depression; decreased self-confidence; increased self-consciousness, especially during public interactions or intimate situations; and interference with steady concentration at work or school.^5,6,8,13 Long-term complications of AV, such as dyschromia and acne scarring, are more likely to be encountered in adult patients, especially if they had AV as a teenager, with women reporting that they remain conscious of these adverse sequelae.⁸ It is estimated that approximately three-fourths of women with AV also had AV as teenagers; therefore, most of them have already used many over-the-counter and prescription therapies and are likely to want treatments that are newer, well-tolerated, safe, and known to be effective in adult women.^8,16,17 Convenience and simplicity are vital components of treatment selection and regimen design, as many women with AV frequently face time constraints in their daily routines due to family, social, employment, and home-related demands and responsibilities.^6-8,17

Medical Considerations

It is apparent from reports in the literature as well as from clinical experience that some women with AV present with a U-shaped pattern of involvement on the face,^5-7,10,13,17 which refers to the presence of predominantly inflammatory papules (many of them deep) and some nodules on the lower face, jawline, and anterolateral neck region, with comedones often sparse or absent.^5-7 It often is perceived and may be true that women who present with this pattern of distribution are more androgen sensitive despite having normal serum androgen levels or in some cases exhibit detectable excess androgens (eg, in the setting of polycystic ovary syndrome) and may be more likely to respond to hormonal therapies (eg, spironolactone, OCs) than those with mixed facial AV (ie, multiple comedonal and inflammatory acne lesions, not limited to a U-shaped pattern, similar to adolescent AV), but data are limited to support differentiation between the U-shaped pattern group and the conventional mixed facial AV group.^5-7,17 Adult and adolescent females in both groups sometimes report perimenstrual flares and frequent persistent papular AV that tends to concentrate on the perioral and chin area.

It is also important to consider that the current literature suggests approximately three-fourths of women with AV report that they also had AV as a teenager, with many indicating the same clinical pattern of AV and approximately one-third reporting AV that is more severe in adulthood than adolescence.^5-8,17 The available literature on topical and oral therapies used to treat AV in both adolescent and adult females predominantly focuses on inclusion of both inflammatory and noninflammatory (comedonal) facial AV lesions, does not specifically address or include the U-shaped pattern of AV in adult women for inclusion in studies that evaluate efficacy in this subgroup, and does not include AV involving the neck region and below the jawline margin as part of any study protocols and/or discussions about therapy.^{5-7,9-12,17,21-26} Involvement of the neck and lower jawline is common in women presenting with the U-shaped pattern of AV, and available studies only evaluate AV involving the face and do not include AV lesions present below the jawline margin. As a result, there is a considerable need for well-designed studies with laboratory assessments to include or exclude underlying detectable excess androgens and to assess the efficacy, tolerability, and safety of specific therapeutic agents both alone and in combination in adult women who present with a U-shaped pattern of AV.¹⁷

Other medical considerations that can influence treatment selection and are more likely to be present in adult versus adolescent females include underlying chronic medical disorders; concomitant medications that may interact with other oral agents; potential for pregnancy; age, particularly when prescribing OCs; and the  potential desire to stop taking OCs if already used over a prolonged period.^6,7

Age-Related Differentiation of Female Subgroups With AV

The age-based dividing line that defines AV in adults versus adolescent females has been described in the literature; however, the basis for published definitions of female subgroups with AV is not well-supported by strong scientific evidence.^1-3,5-7,17 The conventional dividing line that was originally selected to define adult females with AV was 25 years of age or older; persistent acne is present both during adolescence and at or after 25 years of age, while late-onset acne is described as AV that first presents at 25 years of age or older.^3,5-7

More recently, a range of 18 years or older has been used to classify adult female AV and a range of 12 to 17 years for adolescent female AV in subset analyses that evaluated treatment outcomes in both patient populations from phase 3 pivotal trials completed with adapalene gel 0.3% applied once daily and dapsone gel 5% applied twice daily.^14-16 These subanalyses included participants with facial AV that was predominantly moderate in severity, mandated specific lesion count ranges for both comedonal and inflammatory lesions, and included only facial AV that was above the mandibular (jawline) margin.^15,16,21,26 Therefore, patients with AV presenting in a U-shaped pattern with involvement below the jawline and on the neck were not included in these study analyses, as these patients were excluded from the phase 3 trials on which the analyses were based. The outcomes of these analyses apply to treatment in women who present with both inflammatory and noninflammatory facial AV lesions, which supports the observation that AV in this patient population is not always predominantly inflammatory and does not always present in a U-shaped distribution.^14-16 In fact, a U-shaped pattern of distribution appears to be less common in women with AV than a mixed inflammatory and comedonal distribution that involves the face more diffusely, though more data are needed from well-designed and large-scale epidemiologic and demographic studies.^5,14,17

Are there data available on the use of benzoyl peroxide with or without a topical antibiotic in women with AV?

There is a conspicuous absence of prospective clinical trials and retrospective analyses evaluating the specific use of individual AV therapies in adult females, with a particular lack of studies with topical agents (eg, benzoyl peroxide [BP]).¹⁴ Subset analyses have been completed for adapalene gel 0.3% and dapsone gel 5%.^15,16 Additionally, an age-based subset analysis in females with facial AV also has been completed with clindamycin phosphate (CP) 1.2%–BP 2.5% gel once daily, with data presented but not yet fully published.¹⁴

Two identical phase 3, double-blind, randomized, 12-week, 4-arm trials compared treatment outcomes in groups treated with an aqueous-based combination gel formulation containing BP 2.5% and CP 1.2% (n=797), active monad gels (BP [n=809] or CP [n=812]), or vehicle gel (n=395), all applied once daily in patients with facial AV.²² Participants were 12 years or older (mean age range, 19.1–19.6 years; age range, 12.1–70.2 years), were of either gender (approximately 50% split in each study arm), and presented with moderate (approximately 80% of participants) or severe AV (approximately 20% of participants) at baseline. The entry criteria for lesion types and number of lesions were 17 to 40 inflammatory lesions (ie, papules, pustules, <2 nodules)(range of mean number of lesions, 25.8–26.4) and 20 to 100 noninflammatory lesions (ie, closed comedones, open comedones)(range of mean number of lesions, 44.0–47.4). Participant demographics included white (73.9%–77.5%), black/African American (16.1%–20.4%), and Asian (2.1%–3.3%), with the remaining participants distributed among a variety of other ethnic groups such as Native Hawaiian/Native Pacific Islander and Native American Indian/Native Alaskan (collectively <5% in each study arm). Therefore, approximately 1 of every 4 patients had skin of color, which provided good diversity of patients considering the large study size (N=2813). Data analysis included dichotomization of participants by severity rating (moderate or severe based on evaluator global severity score) and skin phototype (Fitzpatrick skin types I–III or IV–VI).²²

The pooled results from both studies completed at 68 investigative sites demonstrated that CP 1.2%–BP 2.5% gel was superior in efficacy to each individual monad and to the vehicle in inflammatory, noninflammatory, and total lesion reductions as early as week 4 (P<.001) and at week 12, which was the study end point (P<.001), with superiority also demonstrated in achieving treatment success (defined as a >2 grade improvement according to the evaluator global severity score) compared to the 3 other study arms (P<.001).²² Subject assessments also were consistent with outcomes noted by the investigators. Cutaneous tolerability was favorable and comparable in all 4 study arms with less than 1% of participants discontinuing treatment due to adverse events.²²

A subset analysis of the data from the phase 3 pivotal trials with CP 1.2%–BP 2.5% gel was completed to compare reductions in both inflammatory and noninflammatory lesions in female participants who were younger than 25 years and 25 years of age or older in all 4 study arms. This information has been presented^14,17 but has not been previously published. Based on the overall results reported in the phase 3 studies, there were no differentiations in skin tolerability or safety based on participant age, gender, or skin type.²² The subanalysis included a total of 1080 females who were younger than 25 years and 395 females who were 25 years of age or older. The lesion reduction outcomes of this subanalysis are presented in the Table. Statistical analyses of the results among these age groups in the 4 study arms were not completed because the objective was to determine if there were any major or obvious differences in reduction of AV lesions based on the conventional dividing line of 25 years of age in adult women as compared to adolescent females treated with CP 1.2%–BP 2.5% gel. In addition, the large difference in numbers of female participants between the 2 age groups (>25 years of age, n=395; <25 years of age, n=1080) at least partially confounds both statistical and observational analysis. Among the women who were 25 years of age or older who were included in the subanalysis, 67.0% and 25.8% were between the ages of 25 to 35 years and 36 to 45 years, respectively. Based on the outcomes reported in the phase 3 trials and in this subgroup analysis, CP 1.2%–BP 2.5% gel applied once daily over a 12-week period appeared overall to be comparably effective in females regardless of age and with no apparent adverse events regarding differences in skin tolerability or safety.^14,22 One observation that was noted was the possible trend of greater reduction in both lesion types in women older than 35 years versus younger females with the use of the combination gel or BP alone; however, the number of female participants who were older than 35 years of age was substantially less (n=102) than those who were 35 years of age or younger (n=1345), thus precluding support for any definitive conclusions about this possible trend.²²

How can CP 1.2%–BP 2.5% gel be incorporated into a treatment regimen for women with facial AV?

The incorporation of CP 1.2%–BP 2.5% gel into a treatment regimen for women with facial AV is similar to the general use of BP-containing formulations in the overall management of AV.^9,14,27,28 Because women with AV commonly present with facial inflammatory lesions and many also with facial comedones, CP 1.2%–BP 2.5% gel is best used once daily in the morning in combination with a topical retinoid in the evening,^9,27 which can be achieved with use of CP 1.2%–BP 2.5% gel in the morning and a topical retinoid (ie, tretinoin, adapalene, tazarotene) in the evening or CP 1.2%–tretinoin 0.025% gel in the evening. It is important to note that cutaneous irritation may be more likely if neck lesions are present; the potential for bleaching of colored fabric by BP also is a practical concern.²⁸ In addition, CP 1.2%–BP 2.5% gel may also be used in combination with topical dapsone, but both products should be applied separately at different times of the day to avoid temporary orange discoloration of the skin, which appears to be an uncommon side effect but remains a possibility based on the product information for dapsone gel 5% with regard to its concomitant use with BP.^29,30

Psoriasis is a common inflammatory skin disorder that appears to be induced by multifactorial pathophysiologic processes associated with immunologic dysregulation.¹ It can affect patients of any age, gender, and ethnicity, and it presents clinically with a variety of visible manifestations. The disease course and severity of psoriasis varies among affected patients.¹ Chronic plaque psoriasis (PP), also referred to as psoriasis vulgaris, is the most common clinical presentation.^1,2 Although many patients are affected by psoriasis that is widespread and in some cases severe, the majority of affected patients exhibit localized involvement that usually affects less than 2% to 5% of the body surface area. Although the skin at any anatomic location can be affected, commonly involved sites are described by the mnemonic term SNAKES (scalp, nails, anogenital region, knees, elbows, sacral region).^2,3

Because the majority of patients with PP present with localized disease, topical therapy is the foundation of treatment in most cases. Topical corticosteroids (TCs) are the most commonly utilized agents, supported by a long track record of favorable efficacy and safety over approximately 6 decades.^4,5 However, optimal management of PP with TCs requires use of a formulation that is of adequate potency, is adaptable for application to the affected body sites, and is properly monitored and adjusted to avoid potential TC-induced adverse effects.^4-6 Nonsteroidal topical therapies such as vitamin D analogues (eg, calcipotriene) and retinoids (eg, tazarotene) are commonly integrated into topical regimens to reduce the application frequency and duration of TC use as well as to sustain efficacy.^5,7,8 Plaque psoriasis is characteristically a chronic disease associated with periods of persistence and episodes of flaring; therefore, intermittent use of TC therapy along with concurrent or sequential use of a nonsteroidal topical agent are commonly employed to achieve and sustain control of the disorder.^7-9

In the last decade, several advances have revolutionized the management of psoriasis, especially for PP patients with extensive involvement who require systemic therapy and/or phototherapy as well as for those with psoriatic arthritis.^10,11 The availability of biologic agents such as tumor necrosis factor a inhibitors and certain interleukin inhibitors (eg, IL-12/IL-23) have been at the forefront of major advances in PP treatment, with some agents also blocking the progression of joint destruction associated with psoriatic arthritis.^10-12 However, even when patients with PP respond favorably to biologic therapy, it is not uncommon for them to still be affected by some persistent PP. In these cases, although much of the chronic PP may clear with use of the biologic agent, persistence of psoriatic plaques may involve the lower extremities, scalp, and/or trunk, with topical therapy often added to augment the therapeutic response.^13-15

This article provides a review of a patented topical suspension combination formulation that contains calcipotriene hydrate 0.005%, a vitamin D analogue, and betamethasone dipropio-nate (Bd) 0.064%, a high-potency TC. In 2008, the US Food and Drug Administration approved the once-daily application of calcipotriene 0.005%–Bd 0.064% topical suspension (C/Bd-TS) for the treatment of PP; this formulation is approved for use on the scalp and body in patients 18 years of age and older. According to the product insert, the recommended maximum duration of treatment with C/Bd-TS once daily is 8 weeks, and patients may not exceed a maximum weekly dose of 100 g.¹⁶ It is important to note that the terms calcipotriene and calcipotriol refer to the same molecule and are used interchangeably in the literature. Formulation characteristics of C/Bd-TS, perspectives on modes of action, outcomes from pivotal trials, and efficacy and safety data reported from additional studies are discussed in this article.

What are the formulation characteristics of C/Bd-TS?

Each gram of C/Bd-TS contains 52.18 mg of calcipotriene hydrate (equivalent to 50 µg of calcipotriene) and 0.643 µg of Bd (equivalent to 0.5 mg of betamethasone), formulated together in a viscous, nearly odorless, almost clear to slightly off-white suspension. The excipients are hydrogenated castor oil, polypropylene glycol 11 stearyl ether, α-tocopherol, butylhydroxytoluene, and mineral oil, collectively producing a gel base in which both active ingredients are suspended.¹⁶ Although the viscous quality of the suspension warrants some additional effort for removal during hair washing, the tenacious gel-like viscosity assists in removing scale on psoriatic plaques, which is often adherent, especially on the scalp. Additionally, it is important that C/Bd-TS be shaken well before use.¹⁶ Initially, C/Bd-TS was studied and marketed in the United States for treatment of scalp psoriasis; however, the indication was expanded to include treatment of PP on the rest of the body, supported by evidence from randomized controlled trials (RCTs).^16-23

Vitamin D analogues (eg, calcipotriene/calcitriol) have been shown to be photolabile when exposed to UV light, especially UVA. They also have been shown to be chemically incompatible and less stable when admixed with a variety of other active ingredients and/or vehicles used to treat PP, including hydrocortisone valerate ointment 0.2%, ammonium lactate lotion 12%, and salicylic acid compound ointment 6%.^24-26 As a result, it is important for clinicians to consider avoidance of concomitant topical calcipotriene application with use of a TC unless the stability of the active ingredients has been tested when the formulations are combined. Calcipotriene 0.005%/Bd 0.064% topical suspension utilizes vehicle technology that maintains the stability and activity of both calcipotriene and Bd within the suspension formulation.^16,26

What is the rationale behind combining calcipotriene and Bd in a single formulation for the treatment of PP?

The potential advantages of C/Bd-TS include the combined modes of action of 2 different active ingredients used for treatment of PP, complementary immunomodulatory effects as compared to use of a TC or vitamin D analogue alone, ease of use with a single product applied once daily, adaptability of the vehicle for use on scalp and/or body skin, and improvement in quality-of-life (QOL) measures.^27-34

Combined Modes of Action

Calcipotriene 0.005%–Bd 0.064% topical suspension combines the modes of action of a high-potency topical suspension and a vitamin D analogue for the treatment of PP in a single stable gel formulation that is approved in the United States for treatment of PP in adults.¹⁶ The multiple anti-inflammatory properties of corticosteroids as well as the efficacy and safety of TC therapy for psoriasis have been well described.^4,6,7,9,27 The antiproliferative and anti-inflammatory properties of vitamin D analogues that appear to correlate with therapeutic effects in the treatment of PP also have been discussed in the literature.²⁸

Complementary Immunomodulatory Effects

More recent studies using various research assays have provided further evidence supporting relevant immunomodulatory properties of calcipotriene alone and in combination with Bd that favorably modify immune dysregulation pathways described more recently in the pathogenesis of PP.^1,29,30 Treatment of psoriatic plaques with calcipotriene has been shown to suppress the increased production of peptide alarmins (psoriasin and koebnerisin) in psoriatic skin and their T_H17-mediated regulation in epidermal ke-ratinocytes, thus interfering with the S100 amplification loop that appears to produce inflammation in psoriasis.²⁹ In T-lymphocyte cultures evaluating exposure to calcipotriene and Bd both alone and as a combined therapy, calcipotriene inhibited IFN-g, IL-8, IL-17, and IL-22 expression, and it reversed the corticosteroid-induced suppression of IL-4, IL-5, IL-10, and IL-13; Bd inhibited both IL-6 and tumor necrosis factor α expression. The outcomes demonstrated that the combination of calcipotriene and Bd inhibited the endogenous release of T_H1- and T_H17-associated cytokines that are associated with psoriatic inflammation and together induced a more favorable anti-inflammatory cytokine profile.³⁰ Although the broad range of anti-inflammatory effects provided by a TC of adequate potency, such as Bd, can clear or markedly improve PP, the concurrent use of calcipotriene was shown to provide additional immunomodulatory effects that suppressed the key T_H17/T_H1 pathophysiologic mediators of psoriatic inflammation and simultaneously induced a T_H2/T regulatory response that is believed to provide therapeutic benefit.^29,30

Ease of Use and Vehicle Adaptability

A once-daily regimen and a vehicle formulation adaptable for use on both the scalp and body are advantageous in enhancing the potential for greater patient adherence.^31,32 The adaptability of the C/Bd-TS for use on the scalp and/or body is supported by several studies encompassing a large number of actively treated subjects. Calcipotriene 0.005%–Bd 0.064% topical suspension has been extensively studied in patients with PP on the scalp and/or body as evidenced by a pooled analysis of 9 eight-week RCTs (scalp, n=6; body, n=3) that encompassed 2777 total subjects treated once daily for PP (scalp, n=1953; body, n=824).²³ Additionally, C/Bd-TS applied once daily was evaluated in an open-label, single-arm, 8-week, phase 2 study of adolescents (N=78; age range, 12–17 years [mean age, 14.6 years]) with scalp psoriasis (mean affected scalp area, 43.7%). The investigator global assessment of treatment success (clear or almost clear) and the patient global assessment of treatment success (clear or very mild) were essentially identical among participants and investigators with 85% and 87% reported after 8 weeks, respectively; approximately 50% of participants achieved treatment success after 2 weeks based on both the investigator global assessment and patient global assessment.³³

Improvement in QOL Measures

Quality-of-life measures were compared in an 8-week RCT of participants with at least moderate scalp psoriasis treated with C/Bd-TS once daily (n=207) or calcipotriene solution twice daily (n=107). Significantly greater improvement in QOL scores compared to baseline were noted at all time points using the Skindex-16 questionnaire in participants treated with C/Bd-TS compared to calcipotriene solution (total score, P<.001 at weeks 2 and 4 and P=.008 at week 8; symptoms score, P<.001 at weeks 2 and 4 and P=.004 at week 8; emotions score, P<.001 at weeks 2 and 4 and P=.005 at week 8).³⁴ A 4-week, open-label, noninterventional cohort, postmarketing (“real life”) study of 721 patients treated at 333 dermatology centers with C/Bd-TS showed a 69.5% improvement in the scalp life quality index score compared to baseline (P<.0001), with 89.5% and 90.4% of participants reporting that C/Bd-TS was better/much better than previously used therapies for scalp psoriasis and easy/very easy to use, respectively.³⁵ An 8-week RCT trial evaluated C/Bd-TS once daily compared to calcipotriene alone, betamethasone dipropionate alone, and vehicle in 1152 participants with mild to moderate PP involving the trunk and extremities. Participants treated with C/Bd-TS (n=442) demonstrated superior reductions in QOL scores using the dermatology life quality index at weeks 4 and 8 compared to those treated with Bd alone (n=418) or vehicle (n=77) but not compared to calcipotriene alone (n=80).¹⁹

What data are available on the efficacy and safety of C/Bd-TS?

Several clinical studies have evaluated the efficacy, tolerability, and safety of C/Bd-TS applied once daily for PP of the scalp and body (ie, trunk, extremities). Most studies were completed over a duration of 8 weeks in adults^16-23; however, studies also have been performed in adolescents,³³ in adults treated for up to 52 weeks,³⁶ and in a subgroup of Hispanic/Latino and black/African American patients with scalp psoriasis.³⁷ The Table provides a detailed summary of primary efficacy data along with important tolerability and safety considerations based on study outcomes.

What practical recommendations can be made regarding the use of C/Bd-TS for PP?

Calcipotriene 0.005%–Bd 0.064% topical suspension applied once daily provides a formulation that allows for treatment of PP involving both the scalp and body using a single product, which provides an element of convenience and is likely to enhance compliance and reduce costs compared with the use of 2 separate products. The efficacy and safety of C/Bd-TS has been well established in several studies,^16-23,37 including a 52-week trial in patients with scalp psoriasis.³⁶ The combination of calcipotriene and Bd appears to favorably address the pathophysiologic pathways involved in psoriasis.^29,30 Calcipotriene 0.005%–Bd 0.064% topical suspension is a rational option for the treatment of PP in patients with localized disease or in patients treated systemically or with phototherapy for more extensive disease who exhibit persistence or recurrence of scattered areas of PP.^6-9,14,15 Appropriate use of C/Bd-TS is likely to achieve favorable efficacy with a low risk of tolerability reactions and a very low risk of major adverse drug reactions.^16-23,36-38

Psoriasis is a common inflammatory skin disorder that appears to be induced by multifactorial pathophysiologic processes associated with immunologic dysregulation.¹ It can affect patients of any age, gender, and ethnicity, and it presents clinically with a variety of visible manifestations. The disease course and severity of psoriasis varies among affected patients.¹ Chronic plaque psoriasis (PP), also referred to as psoriasis vulgaris, is the most common clinical presentation.^1,2 Although many patients are affected by psoriasis that is widespread and in some cases severe, the majority of affected patients exhibit localized involvement that usually affects less than 2% to 5% of the body surface area. Although the skin at any anatomic location can be affected, commonly involved sites are described by the mnemonic term SNAKES (scalp, nails, anogenital region, knees, elbows, sacral region).^2,3

Because the majority of patients with PP present with localized disease, topical therapy is the foundation of treatment in most cases. Topical corticosteroids (TCs) are the most commonly utilized agents, supported by a long track record of favorable efficacy and safety over approximately 6 decades.^4,5 However, optimal management of PP with TCs requires use of a formulation that is of adequate potency, is adaptable for application to the affected body sites, and is properly monitored and adjusted to avoid potential TC-induced adverse effects.^4-6 Nonsteroidal topical therapies such as vitamin D analogues (eg, calcipotriene) and retinoids (eg, tazarotene) are commonly integrated into topical regimens to reduce the application frequency and duration of TC use as well as to sustain efficacy.^5,7,8 Plaque psoriasis is characteristically a chronic disease associated with periods of persistence and episodes of flaring; therefore, intermittent use of TC therapy along with concurrent or sequential use of a nonsteroidal topical agent are commonly employed to achieve and sustain control of the disorder.^7-9

In the last decade, several advances have revolutionized the management of psoriasis, especially for PP patients with extensive involvement who require systemic therapy and/or phototherapy as well as for those with psoriatic arthritis.^10,11 The availability of biologic agents such as tumor necrosis factor a inhibitors and certain interleukin inhibitors (eg, IL-12/IL-23) have been at the forefront of major advances in PP treatment, with some agents also blocking the progression of joint destruction associated with psoriatic arthritis.^10-12 However, even when patients with PP respond favorably to biologic therapy, it is not uncommon for them to still be affected by some persistent PP. In these cases, although much of the chronic PP may clear with use of the biologic agent, persistence of psoriatic plaques may involve the lower extremities, scalp, and/or trunk, with topical therapy often added to augment the therapeutic response.^13-15

This article provides a review of a patented topical suspension combination formulation that contains calcipotriene hydrate 0.005%, a vitamin D analogue, and betamethasone dipropio-nate (Bd) 0.064%, a high-potency TC. In 2008, the US Food and Drug Administration approved the once-daily application of calcipotriene 0.005%–Bd 0.064% topical suspension (C/Bd-TS) for the treatment of PP; this formulation is approved for use on the scalp and body in patients 18 years of age and older. According to the product insert, the recommended maximum duration of treatment with C/Bd-TS once daily is 8 weeks, and patients may not exceed a maximum weekly dose of 100 g.¹⁶ It is important to note that the terms calcipotriene and calcipotriol refer to the same molecule and are used interchangeably in the literature. Formulation characteristics of C/Bd-TS, perspectives on modes of action, outcomes from pivotal trials, and efficacy and safety data reported from additional studies are discussed in this article.

What are the formulation characteristics of C/Bd-TS?

Each gram of C/Bd-TS contains 52.18 mg of calcipotriene hydrate (equivalent to 50 µg of calcipotriene) and 0.643 µg of Bd (equivalent to 0.5 mg of betamethasone), formulated together in a viscous, nearly odorless, almost clear to slightly off-white suspension. The excipients are hydrogenated castor oil, polypropylene glycol 11 stearyl ether, α-tocopherol, butylhydroxytoluene, and mineral oil, collectively producing a gel base in which both active ingredients are suspended.¹⁶ Although the viscous quality of the suspension warrants some additional effort for removal during hair washing, the tenacious gel-like viscosity assists in removing scale on psoriatic plaques, which is often adherent, especially on the scalp. Additionally, it is important that C/Bd-TS be shaken well before use.¹⁶ Initially, C/Bd-TS was studied and marketed in the United States for treatment of scalp psoriasis; however, the indication was expanded to include treatment of PP on the rest of the body, supported by evidence from randomized controlled trials (RCTs).^16-23

Vitamin D analogues (eg, calcipotriene/calcitriol) have been shown to be photolabile when exposed to UV light, especially UVA. They also have been shown to be chemically incompatible and less stable when admixed with a variety of other active ingredients and/or vehicles used to treat PP, including hydrocortisone valerate ointment 0.2%, ammonium lactate lotion 12%, and salicylic acid compound ointment 6%.^24-26 As a result, it is important for clinicians to consider avoidance of concomitant topical calcipotriene application with use of a TC unless the stability of the active ingredients has been tested when the formulations are combined. Calcipotriene 0.005%/Bd 0.064% topical suspension utilizes vehicle technology that maintains the stability and activity of both calcipotriene and Bd within the suspension formulation.^16,26

What is the rationale behind combining calcipotriene and Bd in a single formulation for the treatment of PP?

The potential advantages of C/Bd-TS include the combined modes of action of 2 different active ingredients used for treatment of PP, complementary immunomodulatory effects as compared to use of a TC or vitamin D analogue alone, ease of use with a single product applied once daily, adaptability of the vehicle for use on scalp and/or body skin, and improvement in quality-of-life (QOL) measures.^27-34

Combined Modes of Action

Calcipotriene 0.005%–Bd 0.064% topical suspension combines the modes of action of a high-potency topical suspension and a vitamin D analogue for the treatment of PP in a single stable gel formulation that is approved in the United States for treatment of PP in adults.¹⁶ The multiple anti-inflammatory properties of corticosteroids as well as the efficacy and safety of TC therapy for psoriasis have been well described.^4,6,7,9,27 The antiproliferative and anti-inflammatory properties of vitamin D analogues that appear to correlate with therapeutic effects in the treatment of PP also have been discussed in the literature.²⁸

Complementary Immunomodulatory Effects

More recent studies using various research assays have provided further evidence supporting relevant immunomodulatory properties of calcipotriene alone and in combination with Bd that favorably modify immune dysregulation pathways described more recently in the pathogenesis of PP.^1,29,30 Treatment of psoriatic plaques with calcipotriene has been shown to suppress the increased production of peptide alarmins (psoriasin and koebnerisin) in psoriatic skin and their T_H17-mediated regulation in epidermal ke-ratinocytes, thus interfering with the S100 amplification loop that appears to produce inflammation in psoriasis.²⁹ In T-lymphocyte cultures evaluating exposure to calcipotriene and Bd both alone and as a combined therapy, calcipotriene inhibited IFN-g, IL-8, IL-17, and IL-22 expression, and it reversed the corticosteroid-induced suppression of IL-4, IL-5, IL-10, and IL-13; Bd inhibited both IL-6 and tumor necrosis factor α expression. The outcomes demonstrated that the combination of calcipotriene and Bd inhibited the endogenous release of T_H1- and T_H17-associated cytokines that are associated with psoriatic inflammation and together induced a more favorable anti-inflammatory cytokine profile.³⁰ Although the broad range of anti-inflammatory effects provided by a TC of adequate potency, such as Bd, can clear or markedly improve PP, the concurrent use of calcipotriene was shown to provide additional immunomodulatory effects that suppressed the key T_H17/T_H1 pathophysiologic mediators of psoriatic inflammation and simultaneously induced a T_H2/T regulatory response that is believed to provide therapeutic benefit.^29,30

Ease of Use and Vehicle Adaptability

A once-daily regimen and a vehicle formulation adaptable for use on both the scalp and body are advantageous in enhancing the potential for greater patient adherence.^31,32 The adaptability of the C/Bd-TS for use on the scalp and/or body is supported by several studies encompassing a large number of actively treated subjects. Calcipotriene 0.005%–Bd 0.064% topical suspension has been extensively studied in patients with PP on the scalp and/or body as evidenced by a pooled analysis of 9 eight-week RCTs (scalp, n=6; body, n=3) that encompassed 2777 total subjects treated once daily for PP (scalp, n=1953; body, n=824).²³ Additionally, C/Bd-TS applied once daily was evaluated in an open-label, single-arm, 8-week, phase 2 study of adolescents (N=78; age range, 12–17 years [mean age, 14.6 years]) with scalp psoriasis (mean affected scalp area, 43.7%). The investigator global assessment of treatment success (clear or almost clear) and the patient global assessment of treatment success (clear or very mild) were essentially identical among participants and investigators with 85% and 87% reported after 8 weeks, respectively; approximately 50% of participants achieved treatment success after 2 weeks based on both the investigator global assessment and patient global assessment.³³

Improvement in QOL Measures

Quality-of-life measures were compared in an 8-week RCT of participants with at least moderate scalp psoriasis treated with C/Bd-TS once daily (n=207) or calcipotriene solution twice daily (n=107). Significantly greater improvement in QOL scores compared to baseline were noted at all time points using the Skindex-16 questionnaire in participants treated with C/Bd-TS compared to calcipotriene solution (total score, P<.001 at weeks 2 and 4 and P=.008 at week 8; symptoms score, P<.001 at weeks 2 and 4 and P=.004 at week 8; emotions score, P<.001 at weeks 2 and 4 and P=.005 at week 8).³⁴ A 4-week, open-label, noninterventional cohort, postmarketing (“real life”) study of 721 patients treated at 333 dermatology centers with C/Bd-TS showed a 69.5% improvement in the scalp life quality index score compared to baseline (P<.0001), with 89.5% and 90.4% of participants reporting that C/Bd-TS was better/much better than previously used therapies for scalp psoriasis and easy/very easy to use, respectively.³⁵ An 8-week RCT trial evaluated C/Bd-TS once daily compared to calcipotriene alone, betamethasone dipropionate alone, and vehicle in 1152 participants with mild to moderate PP involving the trunk and extremities. Participants treated with C/Bd-TS (n=442) demonstrated superior reductions in QOL scores using the dermatology life quality index at weeks 4 and 8 compared to those treated with Bd alone (n=418) or vehicle (n=77) but not compared to calcipotriene alone (n=80).¹⁹

What data are available on the efficacy and safety of C/Bd-TS?

Several clinical studies have evaluated the efficacy, tolerability, and safety of C/Bd-TS applied once daily for PP of the scalp and body (ie, trunk, extremities). Most studies were completed over a duration of 8 weeks in adults^16-23; however, studies also have been performed in adolescents,³³ in adults treated for up to 52 weeks,³⁶ and in a subgroup of Hispanic/Latino and black/African American patients with scalp psoriasis.³⁷ The Table provides a detailed summary of primary efficacy data along with important tolerability and safety considerations based on study outcomes.

What practical recommendations can be made regarding the use of C/Bd-TS for PP?

Calcipotriene 0.005%–Bd 0.064% topical suspension applied once daily provides a formulation that allows for treatment of PP involving both the scalp and body using a single product, which provides an element of convenience and is likely to enhance compliance and reduce costs compared with the use of 2 separate products. The efficacy and safety of C/Bd-TS has been well established in several studies,^16-23,37 including a 52-week trial in patients with scalp psoriasis.³⁶ The combination of calcipotriene and Bd appears to favorably address the pathophysiologic pathways involved in psoriasis.^29,30 Calcipotriene 0.005%–Bd 0.064% topical suspension is a rational option for the treatment of PP in patients with localized disease or in patients treated systemically or with phototherapy for more extensive disease who exhibit persistence or recurrence of scattered areas of PP.^6-9,14,15 Appropriate use of C/Bd-TS is likely to achieve favorable efficacy with a low risk of tolerability reactions and a very low risk of major adverse drug reactions.^16-23,36-38

Psoriasis is a common inflammatory skin disorder that appears to be induced by multifactorial pathophysiologic processes associated with immunologic dysregulation.¹ It can affect patients of any age, gender, and ethnicity, and it presents clinically with a variety of visible manifestations. The disease course and severity of psoriasis varies among affected patients.¹ Chronic plaque psoriasis (PP), also referred to as psoriasis vulgaris, is the most common clinical presentation.^1,2 Although many patients are affected by psoriasis that is widespread and in some cases severe, the majority of affected patients exhibit localized involvement that usually affects less than 2% to 5% of the body surface area. Although the skin at any anatomic location can be affected, commonly involved sites are described by the mnemonic term SNAKES (scalp, nails, anogenital region, knees, elbows, sacral region).^2,3

Because the majority of patients with PP present with localized disease, topical therapy is the foundation of treatment in most cases. Topical corticosteroids (TCs) are the most commonly utilized agents, supported by a long track record of favorable efficacy and safety over approximately 6 decades.^4,5 However, optimal management of PP with TCs requires use of a formulation that is of adequate potency, is adaptable for application to the affected body sites, and is properly monitored and adjusted to avoid potential TC-induced adverse effects.^4-6 Nonsteroidal topical therapies such as vitamin D analogues (eg, calcipotriene) and retinoids (eg, tazarotene) are commonly integrated into topical regimens to reduce the application frequency and duration of TC use as well as to sustain efficacy.^5,7,8 Plaque psoriasis is characteristically a chronic disease associated with periods of persistence and episodes of flaring; therefore, intermittent use of TC therapy along with concurrent or sequential use of a nonsteroidal topical agent are commonly employed to achieve and sustain control of the disorder.^7-9

In the last decade, several advances have revolutionized the management of psoriasis, especially for PP patients with extensive involvement who require systemic therapy and/or phototherapy as well as for those with psoriatic arthritis.^10,11 The availability of biologic agents such as tumor necrosis factor a inhibitors and certain interleukin inhibitors (eg, IL-12/IL-23) have been at the forefront of major advances in PP treatment, with some agents also blocking the progression of joint destruction associated with psoriatic arthritis.^10-12 However, even when patients with PP respond favorably to biologic therapy, it is not uncommon for them to still be affected by some persistent PP. In these cases, although much of the chronic PP may clear with use of the biologic agent, persistence of psoriatic plaques may involve the lower extremities, scalp, and/or trunk, with topical therapy often added to augment the therapeutic response.^13-15

This article provides a review of a patented topical suspension combination formulation that contains calcipotriene hydrate 0.005%, a vitamin D analogue, and betamethasone dipropio-nate (Bd) 0.064%, a high-potency TC. In 2008, the US Food and Drug Administration approved the once-daily application of calcipotriene 0.005%–Bd 0.064% topical suspension (C/Bd-TS) for the treatment of PP; this formulation is approved for use on the scalp and body in patients 18 years of age and older. According to the product insert, the recommended maximum duration of treatment with C/Bd-TS once daily is 8 weeks, and patients may not exceed a maximum weekly dose of 100 g.¹⁶ It is important to note that the terms calcipotriene and calcipotriol refer to the same molecule and are used interchangeably in the literature. Formulation characteristics of C/Bd-TS, perspectives on modes of action, outcomes from pivotal trials, and efficacy and safety data reported from additional studies are discussed in this article.

What are the formulation characteristics of C/Bd-TS?

Each gram of C/Bd-TS contains 52.18 mg of calcipotriene hydrate (equivalent to 50 µg of calcipotriene) and 0.643 µg of Bd (equivalent to 0.5 mg of betamethasone), formulated together in a viscous, nearly odorless, almost clear to slightly off-white suspension. The excipients are hydrogenated castor oil, polypropylene glycol 11 stearyl ether, α-tocopherol, butylhydroxytoluene, and mineral oil, collectively producing a gel base in which both active ingredients are suspended.¹⁶ Although the viscous quality of the suspension warrants some additional effort for removal during hair washing, the tenacious gel-like viscosity assists in removing scale on psoriatic plaques, which is often adherent, especially on the scalp. Additionally, it is important that C/Bd-TS be shaken well before use.¹⁶ Initially, C/Bd-TS was studied and marketed in the United States for treatment of scalp psoriasis; however, the indication was expanded to include treatment of PP on the rest of the body, supported by evidence from randomized controlled trials (RCTs).^16-23

Vitamin D analogues (eg, calcipotriene/calcitriol) have been shown to be photolabile when exposed to UV light, especially UVA. They also have been shown to be chemically incompatible and less stable when admixed with a variety of other active ingredients and/or vehicles used to treat PP, including hydrocortisone valerate ointment 0.2%, ammonium lactate lotion 12%, and salicylic acid compound ointment 6%.^24-26 As a result, it is important for clinicians to consider avoidance of concomitant topical calcipotriene application with use of a TC unless the stability of the active ingredients has been tested when the formulations are combined. Calcipotriene 0.005%/Bd 0.064% topical suspension utilizes vehicle technology that maintains the stability and activity of both calcipotriene and Bd within the suspension formulation.^16,26

What is the rationale behind combining calcipotriene and Bd in a single formulation for the treatment of PP?

The potential advantages of C/Bd-TS include the combined modes of action of 2 different active ingredients used for treatment of PP, complementary immunomodulatory effects as compared to use of a TC or vitamin D analogue alone, ease of use with a single product applied once daily, adaptability of the vehicle for use on scalp and/or body skin, and improvement in quality-of-life (QOL) measures.^27-34

Combined Modes of Action

Calcipotriene 0.005%–Bd 0.064% topical suspension combines the modes of action of a high-potency topical suspension and a vitamin D analogue for the treatment of PP in a single stable gel formulation that is approved in the United States for treatment of PP in adults.¹⁶ The multiple anti-inflammatory properties of corticosteroids as well as the efficacy and safety of TC therapy for psoriasis have been well described.^4,6,7,9,27 The antiproliferative and anti-inflammatory properties of vitamin D analogues that appear to correlate with therapeutic effects in the treatment of PP also have been discussed in the literature.²⁸

Complementary Immunomodulatory Effects

More recent studies using various research assays have provided further evidence supporting relevant immunomodulatory properties of calcipotriene alone and in combination with Bd that favorably modify immune dysregulation pathways described more recently in the pathogenesis of PP.^1,29,30 Treatment of psoriatic plaques with calcipotriene has been shown to suppress the increased production of peptide alarmins (psoriasin and koebnerisin) in psoriatic skin and their T_H17-mediated regulation in epidermal ke-ratinocytes, thus interfering with the S100 amplification loop that appears to produce inflammation in psoriasis.²⁹ In T-lymphocyte cultures evaluating exposure to calcipotriene and Bd both alone and as a combined therapy, calcipotriene inhibited IFN-g, IL-8, IL-17, and IL-22 expression, and it reversed the corticosteroid-induced suppression of IL-4, IL-5, IL-10, and IL-13; Bd inhibited both IL-6 and tumor necrosis factor α expression. The outcomes demonstrated that the combination of calcipotriene and Bd inhibited the endogenous release of T_H1- and T_H17-associated cytokines that are associated with psoriatic inflammation and together induced a more favorable anti-inflammatory cytokine profile.³⁰ Although the broad range of anti-inflammatory effects provided by a TC of adequate potency, such as Bd, can clear or markedly improve PP, the concurrent use of calcipotriene was shown to provide additional immunomodulatory effects that suppressed the key T_H17/T_H1 pathophysiologic mediators of psoriatic inflammation and simultaneously induced a T_H2/T regulatory response that is believed to provide therapeutic benefit.^29,30

Ease of Use and Vehicle Adaptability

A once-daily regimen and a vehicle formulation adaptable for use on both the scalp and body are advantageous in enhancing the potential for greater patient adherence.^31,32 The adaptability of the C/Bd-TS for use on the scalp and/or body is supported by several studies encompassing a large number of actively treated subjects. Calcipotriene 0.005%–Bd 0.064% topical suspension has been extensively studied in patients with PP on the scalp and/or body as evidenced by a pooled analysis of 9 eight-week RCTs (scalp, n=6; body, n=3) that encompassed 2777 total subjects treated once daily for PP (scalp, n=1953; body, n=824).²³ Additionally, C/Bd-TS applied once daily was evaluated in an open-label, single-arm, 8-week, phase 2 study of adolescents (N=78; age range, 12–17 years [mean age, 14.6 years]) with scalp psoriasis (mean affected scalp area, 43.7%). The investigator global assessment of treatment success (clear or almost clear) and the patient global assessment of treatment success (clear or very mild) were essentially identical among participants and investigators with 85% and 87% reported after 8 weeks, respectively; approximately 50% of participants achieved treatment success after 2 weeks based on both the investigator global assessment and patient global assessment.³³

Improvement in QOL Measures

Quality-of-life measures were compared in an 8-week RCT of participants with at least moderate scalp psoriasis treated with C/Bd-TS once daily (n=207) or calcipotriene solution twice daily (n=107). Significantly greater improvement in QOL scores compared to baseline were noted at all time points using the Skindex-16 questionnaire in participants treated with C/Bd-TS compared to calcipotriene solution (total score, P<.001 at weeks 2 and 4 and P=.008 at week 8; symptoms score, P<.001 at weeks 2 and 4 and P=.004 at week 8; emotions score, P<.001 at weeks 2 and 4 and P=.005 at week 8).³⁴ A 4-week, open-label, noninterventional cohort, postmarketing (“real life”) study of 721 patients treated at 333 dermatology centers with C/Bd-TS showed a 69.5% improvement in the scalp life quality index score compared to baseline (P<.0001), with 89.5% and 90.4% of participants reporting that C/Bd-TS was better/much better than previously used therapies for scalp psoriasis and easy/very easy to use, respectively.³⁵ An 8-week RCT trial evaluated C/Bd-TS once daily compared to calcipotriene alone, betamethasone dipropionate alone, and vehicle in 1152 participants with mild to moderate PP involving the trunk and extremities. Participants treated with C/Bd-TS (n=442) demonstrated superior reductions in QOL scores using the dermatology life quality index at weeks 4 and 8 compared to those treated with Bd alone (n=418) or vehicle (n=77) but not compared to calcipotriene alone (n=80).¹⁹

What data are available on the efficacy and safety of C/Bd-TS?

Several clinical studies have evaluated the efficacy, tolerability, and safety of C/Bd-TS applied once daily for PP of the scalp and body (ie, trunk, extremities). Most studies were completed over a duration of 8 weeks in adults^16-23; however, studies also have been performed in adolescents,³³ in adults treated for up to 52 weeks,³⁶ and in a subgroup of Hispanic/Latino and black/African American patients with scalp psoriasis.³⁷ The Table provides a detailed summary of primary efficacy data along with important tolerability and safety considerations based on study outcomes.

What practical recommendations can be made regarding the use of C/Bd-TS for PP?

Calcipotriene 0.005%–Bd 0.064% topical suspension applied once daily provides a formulation that allows for treatment of PP involving both the scalp and body using a single product, which provides an element of convenience and is likely to enhance compliance and reduce costs compared with the use of 2 separate products. The efficacy and safety of C/Bd-TS has been well established in several studies,^16-23,37 including a 52-week trial in patients with scalp psoriasis.³⁶ The combination of calcipotriene and Bd appears to favorably address the pathophysiologic pathways involved in psoriasis.^29,30 Calcipotriene 0.005%–Bd 0.064% topical suspension is a rational option for the treatment of PP in patients with localized disease or in patients treated systemically or with phototherapy for more extensive disease who exhibit persistence or recurrence of scattered areas of PP.^6-9,14,15 Appropriate use of C/Bd-TS is likely to achieve favorable efficacy with a low risk of tolerability reactions and a very low risk of major adverse drug reactions.^16-23,36-38