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Who’s at risk for depression on isotretinoin?
A Sanaa Butt, MD, reported at the virtual annual congress of the European Academy of Dermatology and Venereology.
This was, however, the sole identifiable risk factor for treatment-limiting depressive symptoms in acne patients on isotretinoin in the study of 3,151 consecutive acne patients taking isotretinoin. There was no significant difference between those who did or did not develop depression on the oral retinoid in terms of age, gender, or daily dose of the drug at the time it was discontinued.
“Depressive symptoms occurred at any time from the date of initiation of isotretinoin up to 6 months into therapy, with no identifiable peak time period,” said Dr. Butt, a dermatologist with the U.K. National Health Service Tayside district at Ninewells Hospital, Dundee, Scotland. “Lower doses appear not to be protective,” she added.
The Tayside district has a catchment of roughly 450,000 people. The local population tends to stay put because Tayside is an economically disadvantaged and remote part of Scotland. There are very few private practice dermatologists in the area, so Dr. Butt and coinvestigators are confident their observational study of NHS patients captured the great majority of isotretinoin users in northern Scotland.
The investigators utilized software to analyze the contents of more than 8,000 digitized letters exchanged between NHS Tayside dermatologists and general practitioners during 2005-2018, zeroing in on 3,151 consecutive patients on isotretinoin for acne and 158 on the drug for other conditions, most often rosacea or folliculitis. They then drilled down further through the letters, electronically searching for key words such as suicide, depression, and anxiety. In this way, they ultimately identified 30 patients who discontinued the drug because they developed depressive symptoms. All 30 were on the drug for acne.
The annual incidence of treatment-limiting depressive mood changes was 0.96%, a figure that remained steady over the 13-year study period, even though prescribing of isotretinoin increased over time. This flat incidence rate effectively rules out the potential for confounding because of assessor bias, especially since many different NHS dermatologists were prescribing the drug, Dr. Butt said.
Half of acne patients prescribed isotretinoin were female and 50% were male. And 15 cases of treatment discontinuation caused by development of depressive symptoms occurred in females, 15 in males. A history of past depressive illness was present in 9.3% of females who started on isotretinoin and in 4.5% of the males. The relative risk of treatment-limiting depressive mood changes was increased 790% among females with a prior history of depressive illness and 440% in males with such a history.
Dr. Butt reported having no financial conflicts regarding her NHS-funded study.
A Sanaa Butt, MD, reported at the virtual annual congress of the European Academy of Dermatology and Venereology.
This was, however, the sole identifiable risk factor for treatment-limiting depressive symptoms in acne patients on isotretinoin in the study of 3,151 consecutive acne patients taking isotretinoin. There was no significant difference between those who did or did not develop depression on the oral retinoid in terms of age, gender, or daily dose of the drug at the time it was discontinued.
“Depressive symptoms occurred at any time from the date of initiation of isotretinoin up to 6 months into therapy, with no identifiable peak time period,” said Dr. Butt, a dermatologist with the U.K. National Health Service Tayside district at Ninewells Hospital, Dundee, Scotland. “Lower doses appear not to be protective,” she added.
The Tayside district has a catchment of roughly 450,000 people. The local population tends to stay put because Tayside is an economically disadvantaged and remote part of Scotland. There are very few private practice dermatologists in the area, so Dr. Butt and coinvestigators are confident their observational study of NHS patients captured the great majority of isotretinoin users in northern Scotland.
The investigators utilized software to analyze the contents of more than 8,000 digitized letters exchanged between NHS Tayside dermatologists and general practitioners during 2005-2018, zeroing in on 3,151 consecutive patients on isotretinoin for acne and 158 on the drug for other conditions, most often rosacea or folliculitis. They then drilled down further through the letters, electronically searching for key words such as suicide, depression, and anxiety. In this way, they ultimately identified 30 patients who discontinued the drug because they developed depressive symptoms. All 30 were on the drug for acne.
The annual incidence of treatment-limiting depressive mood changes was 0.96%, a figure that remained steady over the 13-year study period, even though prescribing of isotretinoin increased over time. This flat incidence rate effectively rules out the potential for confounding because of assessor bias, especially since many different NHS dermatologists were prescribing the drug, Dr. Butt said.
Half of acne patients prescribed isotretinoin were female and 50% were male. And 15 cases of treatment discontinuation caused by development of depressive symptoms occurred in females, 15 in males. A history of past depressive illness was present in 9.3% of females who started on isotretinoin and in 4.5% of the males. The relative risk of treatment-limiting depressive mood changes was increased 790% among females with a prior history of depressive illness and 440% in males with such a history.
Dr. Butt reported having no financial conflicts regarding her NHS-funded study.
A Sanaa Butt, MD, reported at the virtual annual congress of the European Academy of Dermatology and Venereology.
This was, however, the sole identifiable risk factor for treatment-limiting depressive symptoms in acne patients on isotretinoin in the study of 3,151 consecutive acne patients taking isotretinoin. There was no significant difference between those who did or did not develop depression on the oral retinoid in terms of age, gender, or daily dose of the drug at the time it was discontinued.
“Depressive symptoms occurred at any time from the date of initiation of isotretinoin up to 6 months into therapy, with no identifiable peak time period,” said Dr. Butt, a dermatologist with the U.K. National Health Service Tayside district at Ninewells Hospital, Dundee, Scotland. “Lower doses appear not to be protective,” she added.
The Tayside district has a catchment of roughly 450,000 people. The local population tends to stay put because Tayside is an economically disadvantaged and remote part of Scotland. There are very few private practice dermatologists in the area, so Dr. Butt and coinvestigators are confident their observational study of NHS patients captured the great majority of isotretinoin users in northern Scotland.
The investigators utilized software to analyze the contents of more than 8,000 digitized letters exchanged between NHS Tayside dermatologists and general practitioners during 2005-2018, zeroing in on 3,151 consecutive patients on isotretinoin for acne and 158 on the drug for other conditions, most often rosacea or folliculitis. They then drilled down further through the letters, electronically searching for key words such as suicide, depression, and anxiety. In this way, they ultimately identified 30 patients who discontinued the drug because they developed depressive symptoms. All 30 were on the drug for acne.
The annual incidence of treatment-limiting depressive mood changes was 0.96%, a figure that remained steady over the 13-year study period, even though prescribing of isotretinoin increased over time. This flat incidence rate effectively rules out the potential for confounding because of assessor bias, especially since many different NHS dermatologists were prescribing the drug, Dr. Butt said.
Half of acne patients prescribed isotretinoin were female and 50% were male. And 15 cases of treatment discontinuation caused by development of depressive symptoms occurred in females, 15 in males. A history of past depressive illness was present in 9.3% of females who started on isotretinoin and in 4.5% of the males. The relative risk of treatment-limiting depressive mood changes was increased 790% among females with a prior history of depressive illness and 440% in males with such a history.
Dr. Butt reported having no financial conflicts regarding her NHS-funded study.
FROM THE EADV CONGRESS
For acne in darker skin, judicious use of peeling agents can speed resolution
according to an expert, who cited both published data and empirical experience at the virtual Skin of Color Update 2020.
Because of the risk of exacerbating hyperpigmentation, superficial peels must be used judiciously, but “peels do add some benefit in terms of resolving the hyperpigmentation more rapidly,” Andrew Alexis, MD, chair of the department of dermatology at Mount Sinai Morningside and Mount Sinai West, New York, said at the meeting.
Addressing hyperpigmentation in skin of color is a critical goal. For many patients, the postinflammatory hyperpigmentation (PIH) that accompanies acne in Fitzpatrick skin types IV or higher imposes a greater burden than the acne itself.
“PIH is one of the driving forces among patients with darker skin coming to a dermatologist,” said Dr. Alexis, who is also professor of dermatology at the Icahn School of Medicine at Mount Sinai, New York. “Patients often describe these hyperpigmented macules as scars, and they are concerned that they are not reversible.”
In darker skin, the combination of treatments used for acne should address the pathogenic factors that contribute to acne and PIH at the same time, according to Dr. Alexis. He advised describing the goals and the timeline of acne and PIH resolution at the very first visit.
Of these two goals, resolution of PIH is often the more challenging. First-line topical retinoids have anti-inflammatory effects, but Dr. Alexis suggested that additional agents, such as topical antibiotics, topical dapsone, and benzoyl peroxide, are commonly needed to fully control inflammation.
“Topical retinoids serve as the foundation of acne treatment, especially in skin of color due to their dual action on acne and PIH,” he said. However, he added that this needs support with a “well-rounded combination therapy to address as many pathogenic factors as possible.”
One of these factors is subclinical inflammation. Citing studies first initiated at Howard University, Washington, Dr. Alexis said there are now compelling data showing T lymphocyte infiltration and increased expression of proinflammatory cytokines even in clinically uninvolved skin in acne patients with darker skin.
In patients with significant PIH, he considers oral antibiotics for their systemic anti-inflammatory effects, singling out sarecycline as a narrow-spectrum agent with a potent effect on Cutibacterium acnes. This tetracycline, a relatively recent addition to acne treatment options, has specifically been shown to be “superior to placebo across a diverse patient population” that includes those with darker skin tones.
“Another addition that can be leveraged for anti-inflammatory effects is topical minocycline foam. This has also been studied in diverse patient populations and shown to be superior to vehicle,” Dr. Alexis said.
For acne, the response to most of these therapies is relatively rapid, but control of PIH takes longer. After resolution of acne, he considers superficial chemical peels to speed the healing of PIH.
In a small randomized trial he cited, superficial glycolic acid peel added to a modified Kligman formula (hydroquinone 2%, tretinoin 0.05%, and hydrocortisone 1%) provided significantly lower scores in the mean Hyperpigmentation Area and Severity Index at 12 weeks (P = .004) and 21 weeks (P < .001 relative to the Kligman formula alone). Dr. Alexis said he has had the same clinical experience with chemical peels
For many acne patients with darker skin, good results are achieved after four weeks on a multidrug combination with a topical retinoid backbone. One week after stopping the combination, the superficial chemical peel can be started at a very low dose on an every-other-night schedule. If tolerated, the dose can be slowly increased.
Slow up-titration of all topical agents in skin of color, not just superficial chemical peels, is prudent, according to Dr. Alexis. For patients new to retinoids, he also recommended every-other-night dosing to avoid the irritation that might exacerbate PIH. He said the risks of adverse reactions come early. “We need to hold the hands of our patients through the first 2 weeks. Warn of dryness and pealing. Recommend moisturizers and keep the doses low.”
The benefits and risks of acne treatment are different in dark relative to light skin, Dr. Alexis emphasized. He added that a measured approach that includes specific strategies for PIH delivers results.
Providing treatment with a strategy that addresses both acne and PIH, he said, “we can have excellent outcomes time and time again for acne in patients with darker skin types.”
There is an evidence basis for making effective treatment of PIH a specific goal in the treatment of acne. In a study that evaluated the psychosocial impact of PIH in 50 patients with acne, 54% responded that PIH was a source of embarrassment. The study was one of the first to evaluate the impact of PIH as a separate source of impaired quality of life in acne patients.
“To improve the patient’s quality of life, the dermatologist should treat acne and postinflammatory hyperpigmentation at the same time,” said Katlein Franca, MD, PhD, assistant professor of dermatology, University of Miami.
In particular, Dr. Franca, who led the PIH study, suggested that PIH, like acne, is a source of low self-esteem. In regard to PIH, “most patients feel embarrassed about the spots,” she said in an interview.
“Strategies to hide the hyperpigmented spots include the use of makeup and even different hairstyles to cover the affected areas,” she added, indicating that treatments provided to clear PIH as well as acne can remove a source of stress and threat to a sense of well-being.
Dr. Alexis reports financial relationships with many pharmaceutical companies, including those that make acne drugs.
according to an expert, who cited both published data and empirical experience at the virtual Skin of Color Update 2020.
Because of the risk of exacerbating hyperpigmentation, superficial peels must be used judiciously, but “peels do add some benefit in terms of resolving the hyperpigmentation more rapidly,” Andrew Alexis, MD, chair of the department of dermatology at Mount Sinai Morningside and Mount Sinai West, New York, said at the meeting.
Addressing hyperpigmentation in skin of color is a critical goal. For many patients, the postinflammatory hyperpigmentation (PIH) that accompanies acne in Fitzpatrick skin types IV or higher imposes a greater burden than the acne itself.
“PIH is one of the driving forces among patients with darker skin coming to a dermatologist,” said Dr. Alexis, who is also professor of dermatology at the Icahn School of Medicine at Mount Sinai, New York. “Patients often describe these hyperpigmented macules as scars, and they are concerned that they are not reversible.”
In darker skin, the combination of treatments used for acne should address the pathogenic factors that contribute to acne and PIH at the same time, according to Dr. Alexis. He advised describing the goals and the timeline of acne and PIH resolution at the very first visit.
Of these two goals, resolution of PIH is often the more challenging. First-line topical retinoids have anti-inflammatory effects, but Dr. Alexis suggested that additional agents, such as topical antibiotics, topical dapsone, and benzoyl peroxide, are commonly needed to fully control inflammation.
“Topical retinoids serve as the foundation of acne treatment, especially in skin of color due to their dual action on acne and PIH,” he said. However, he added that this needs support with a “well-rounded combination therapy to address as many pathogenic factors as possible.”
One of these factors is subclinical inflammation. Citing studies first initiated at Howard University, Washington, Dr. Alexis said there are now compelling data showing T lymphocyte infiltration and increased expression of proinflammatory cytokines even in clinically uninvolved skin in acne patients with darker skin.
In patients with significant PIH, he considers oral antibiotics for their systemic anti-inflammatory effects, singling out sarecycline as a narrow-spectrum agent with a potent effect on Cutibacterium acnes. This tetracycline, a relatively recent addition to acne treatment options, has specifically been shown to be “superior to placebo across a diverse patient population” that includes those with darker skin tones.
“Another addition that can be leveraged for anti-inflammatory effects is topical minocycline foam. This has also been studied in diverse patient populations and shown to be superior to vehicle,” Dr. Alexis said.
For acne, the response to most of these therapies is relatively rapid, but control of PIH takes longer. After resolution of acne, he considers superficial chemical peels to speed the healing of PIH.
In a small randomized trial he cited, superficial glycolic acid peel added to a modified Kligman formula (hydroquinone 2%, tretinoin 0.05%, and hydrocortisone 1%) provided significantly lower scores in the mean Hyperpigmentation Area and Severity Index at 12 weeks (P = .004) and 21 weeks (P < .001 relative to the Kligman formula alone). Dr. Alexis said he has had the same clinical experience with chemical peels
For many acne patients with darker skin, good results are achieved after four weeks on a multidrug combination with a topical retinoid backbone. One week after stopping the combination, the superficial chemical peel can be started at a very low dose on an every-other-night schedule. If tolerated, the dose can be slowly increased.
Slow up-titration of all topical agents in skin of color, not just superficial chemical peels, is prudent, according to Dr. Alexis. For patients new to retinoids, he also recommended every-other-night dosing to avoid the irritation that might exacerbate PIH. He said the risks of adverse reactions come early. “We need to hold the hands of our patients through the first 2 weeks. Warn of dryness and pealing. Recommend moisturizers and keep the doses low.”
The benefits and risks of acne treatment are different in dark relative to light skin, Dr. Alexis emphasized. He added that a measured approach that includes specific strategies for PIH delivers results.
Providing treatment with a strategy that addresses both acne and PIH, he said, “we can have excellent outcomes time and time again for acne in patients with darker skin types.”
There is an evidence basis for making effective treatment of PIH a specific goal in the treatment of acne. In a study that evaluated the psychosocial impact of PIH in 50 patients with acne, 54% responded that PIH was a source of embarrassment. The study was one of the first to evaluate the impact of PIH as a separate source of impaired quality of life in acne patients.
“To improve the patient’s quality of life, the dermatologist should treat acne and postinflammatory hyperpigmentation at the same time,” said Katlein Franca, MD, PhD, assistant professor of dermatology, University of Miami.
In particular, Dr. Franca, who led the PIH study, suggested that PIH, like acne, is a source of low self-esteem. In regard to PIH, “most patients feel embarrassed about the spots,” she said in an interview.
“Strategies to hide the hyperpigmented spots include the use of makeup and even different hairstyles to cover the affected areas,” she added, indicating that treatments provided to clear PIH as well as acne can remove a source of stress and threat to a sense of well-being.
Dr. Alexis reports financial relationships with many pharmaceutical companies, including those that make acne drugs.
according to an expert, who cited both published data and empirical experience at the virtual Skin of Color Update 2020.
Because of the risk of exacerbating hyperpigmentation, superficial peels must be used judiciously, but “peels do add some benefit in terms of resolving the hyperpigmentation more rapidly,” Andrew Alexis, MD, chair of the department of dermatology at Mount Sinai Morningside and Mount Sinai West, New York, said at the meeting.
Addressing hyperpigmentation in skin of color is a critical goal. For many patients, the postinflammatory hyperpigmentation (PIH) that accompanies acne in Fitzpatrick skin types IV or higher imposes a greater burden than the acne itself.
“PIH is one of the driving forces among patients with darker skin coming to a dermatologist,” said Dr. Alexis, who is also professor of dermatology at the Icahn School of Medicine at Mount Sinai, New York. “Patients often describe these hyperpigmented macules as scars, and they are concerned that they are not reversible.”
In darker skin, the combination of treatments used for acne should address the pathogenic factors that contribute to acne and PIH at the same time, according to Dr. Alexis. He advised describing the goals and the timeline of acne and PIH resolution at the very first visit.
Of these two goals, resolution of PIH is often the more challenging. First-line topical retinoids have anti-inflammatory effects, but Dr. Alexis suggested that additional agents, such as topical antibiotics, topical dapsone, and benzoyl peroxide, are commonly needed to fully control inflammation.
“Topical retinoids serve as the foundation of acne treatment, especially in skin of color due to their dual action on acne and PIH,” he said. However, he added that this needs support with a “well-rounded combination therapy to address as many pathogenic factors as possible.”
One of these factors is subclinical inflammation. Citing studies first initiated at Howard University, Washington, Dr. Alexis said there are now compelling data showing T lymphocyte infiltration and increased expression of proinflammatory cytokines even in clinically uninvolved skin in acne patients with darker skin.
In patients with significant PIH, he considers oral antibiotics for their systemic anti-inflammatory effects, singling out sarecycline as a narrow-spectrum agent with a potent effect on Cutibacterium acnes. This tetracycline, a relatively recent addition to acne treatment options, has specifically been shown to be “superior to placebo across a diverse patient population” that includes those with darker skin tones.
“Another addition that can be leveraged for anti-inflammatory effects is topical minocycline foam. This has also been studied in diverse patient populations and shown to be superior to vehicle,” Dr. Alexis said.
For acne, the response to most of these therapies is relatively rapid, but control of PIH takes longer. After resolution of acne, he considers superficial chemical peels to speed the healing of PIH.
In a small randomized trial he cited, superficial glycolic acid peel added to a modified Kligman formula (hydroquinone 2%, tretinoin 0.05%, and hydrocortisone 1%) provided significantly lower scores in the mean Hyperpigmentation Area and Severity Index at 12 weeks (P = .004) and 21 weeks (P < .001 relative to the Kligman formula alone). Dr. Alexis said he has had the same clinical experience with chemical peels
For many acne patients with darker skin, good results are achieved after four weeks on a multidrug combination with a topical retinoid backbone. One week after stopping the combination, the superficial chemical peel can be started at a very low dose on an every-other-night schedule. If tolerated, the dose can be slowly increased.
Slow up-titration of all topical agents in skin of color, not just superficial chemical peels, is prudent, according to Dr. Alexis. For patients new to retinoids, he also recommended every-other-night dosing to avoid the irritation that might exacerbate PIH. He said the risks of adverse reactions come early. “We need to hold the hands of our patients through the first 2 weeks. Warn of dryness and pealing. Recommend moisturizers and keep the doses low.”
The benefits and risks of acne treatment are different in dark relative to light skin, Dr. Alexis emphasized. He added that a measured approach that includes specific strategies for PIH delivers results.
Providing treatment with a strategy that addresses both acne and PIH, he said, “we can have excellent outcomes time and time again for acne in patients with darker skin types.”
There is an evidence basis for making effective treatment of PIH a specific goal in the treatment of acne. In a study that evaluated the psychosocial impact of PIH in 50 patients with acne, 54% responded that PIH was a source of embarrassment. The study was one of the first to evaluate the impact of PIH as a separate source of impaired quality of life in acne patients.
“To improve the patient’s quality of life, the dermatologist should treat acne and postinflammatory hyperpigmentation at the same time,” said Katlein Franca, MD, PhD, assistant professor of dermatology, University of Miami.
In particular, Dr. Franca, who led the PIH study, suggested that PIH, like acne, is a source of low self-esteem. In regard to PIH, “most patients feel embarrassed about the spots,” she said in an interview.
“Strategies to hide the hyperpigmented spots include the use of makeup and even different hairstyles to cover the affected areas,” she added, indicating that treatments provided to clear PIH as well as acne can remove a source of stress and threat to a sense of well-being.
Dr. Alexis reports financial relationships with many pharmaceutical companies, including those that make acne drugs.
FROM SOC 2020
Expert spotlights recent advances in the medical treatment of acne
During the virtual annual Masters of Aesthetics Symposium, he highlighted the following new acne treatment options:
- Trifarotene cream 0.005% (Aklief). This marks the first new retinoid indicated for acne in several decades. It is indicated for the topical treatment of acne vulgaris in patients 9 years of age and older and has been studied in acne of the face, chest, and back. “It’s nice to have in our armamentarium,” he said.
- Tazarotene lotion 0.045% (Arazlo). The 0.1% formulation of tazarotene is commonly used for acne, but it can cause skin irritation, dryness, and erythema. The new 0.045% formulation was developed in a three-dimensional mesh matrix, with ingredients from an oil-in-water emulsion. “This allows for graduated dosing on the skin without as much irritation,” said Dr. Eichenfield, who is chief of pediatric and adolescent dermatology at Rady Children’s Hospital, San Diego.
- Minocycline 4% topical foam (Amzeeq). This marks the first and only topical minocycline prescription treatment for acne. “Its hydrophobic composition allows for stable and efficient delivery of inherently unstable pharmaceutical ingredients,” he said. “There is no evidence of photosensitivity as you’d expect from a minocycline-based product, and there are low systemic levels compared with oral minocycline.”
- Clascoterone cream 1% (Winlevi). This first-in-class topical androgen receptor inhibitor has been approved for the treatment of acne in patients 12 years and older. It competes with dihydrotestosterone and selectively targets androgen receptors in sebocytes and hair papilla cells. “It has been studied on the face and trunk and has been shown to inhibit sebum production, reduce secretion of inflammatory cytokines, and inhibit inflammatory pathways,” said Dr. Eichenfield, who is also professor of dermatology and pediatrics at the University of California, San Diego.
- From a systemic standpoint, sarecycline, a new tetracycline class antibiotic, has been approved for the treatment of inflammatory lesions of nonnodular moderate to severe acne vulgaris in patients 9 years and older. The once-daily drug can be taken with or without food in a weight-based dose. “This medicine appears to have a narrow spectrum of antibacterial activity compared with other tetracyclines,” he said. “It may have less of a negative effect on gut microbiome than traditional oral antibiotics.”
As for integrating these new options into existing clinical practice, Dr. Eichenfield predicts that the general approach to acne treatment will remain the same. “We’ll have to wait to see where the topical androgens fit into the treatment algorithms,” he said. “Our goal is to minimize scarring, minimize disease, and to modulate the disease course.”
Dr. Eichenfield disclosed that he has been an investigator and/or consultant for Almirall, Cassiopea, Dermata, Foamix, Galderma, L’Oreal, and Ortho Dermatologics.
During the virtual annual Masters of Aesthetics Symposium, he highlighted the following new acne treatment options:
- Trifarotene cream 0.005% (Aklief). This marks the first new retinoid indicated for acne in several decades. It is indicated for the topical treatment of acne vulgaris in patients 9 years of age and older and has been studied in acne of the face, chest, and back. “It’s nice to have in our armamentarium,” he said.
- Tazarotene lotion 0.045% (Arazlo). The 0.1% formulation of tazarotene is commonly used for acne, but it can cause skin irritation, dryness, and erythema. The new 0.045% formulation was developed in a three-dimensional mesh matrix, with ingredients from an oil-in-water emulsion. “This allows for graduated dosing on the skin without as much irritation,” said Dr. Eichenfield, who is chief of pediatric and adolescent dermatology at Rady Children’s Hospital, San Diego.
- Minocycline 4% topical foam (Amzeeq). This marks the first and only topical minocycline prescription treatment for acne. “Its hydrophobic composition allows for stable and efficient delivery of inherently unstable pharmaceutical ingredients,” he said. “There is no evidence of photosensitivity as you’d expect from a minocycline-based product, and there are low systemic levels compared with oral minocycline.”
- Clascoterone cream 1% (Winlevi). This first-in-class topical androgen receptor inhibitor has been approved for the treatment of acne in patients 12 years and older. It competes with dihydrotestosterone and selectively targets androgen receptors in sebocytes and hair papilla cells. “It has been studied on the face and trunk and has been shown to inhibit sebum production, reduce secretion of inflammatory cytokines, and inhibit inflammatory pathways,” said Dr. Eichenfield, who is also professor of dermatology and pediatrics at the University of California, San Diego.
- From a systemic standpoint, sarecycline, a new tetracycline class antibiotic, has been approved for the treatment of inflammatory lesions of nonnodular moderate to severe acne vulgaris in patients 9 years and older. The once-daily drug can be taken with or without food in a weight-based dose. “This medicine appears to have a narrow spectrum of antibacterial activity compared with other tetracyclines,” he said. “It may have less of a negative effect on gut microbiome than traditional oral antibiotics.”
As for integrating these new options into existing clinical practice, Dr. Eichenfield predicts that the general approach to acne treatment will remain the same. “We’ll have to wait to see where the topical androgens fit into the treatment algorithms,” he said. “Our goal is to minimize scarring, minimize disease, and to modulate the disease course.”
Dr. Eichenfield disclosed that he has been an investigator and/or consultant for Almirall, Cassiopea, Dermata, Foamix, Galderma, L’Oreal, and Ortho Dermatologics.
During the virtual annual Masters of Aesthetics Symposium, he highlighted the following new acne treatment options:
- Trifarotene cream 0.005% (Aklief). This marks the first new retinoid indicated for acne in several decades. It is indicated for the topical treatment of acne vulgaris in patients 9 years of age and older and has been studied in acne of the face, chest, and back. “It’s nice to have in our armamentarium,” he said.
- Tazarotene lotion 0.045% (Arazlo). The 0.1% formulation of tazarotene is commonly used for acne, but it can cause skin irritation, dryness, and erythema. The new 0.045% formulation was developed in a three-dimensional mesh matrix, with ingredients from an oil-in-water emulsion. “This allows for graduated dosing on the skin without as much irritation,” said Dr. Eichenfield, who is chief of pediatric and adolescent dermatology at Rady Children’s Hospital, San Diego.
- Minocycline 4% topical foam (Amzeeq). This marks the first and only topical minocycline prescription treatment for acne. “Its hydrophobic composition allows for stable and efficient delivery of inherently unstable pharmaceutical ingredients,” he said. “There is no evidence of photosensitivity as you’d expect from a minocycline-based product, and there are low systemic levels compared with oral minocycline.”
- Clascoterone cream 1% (Winlevi). This first-in-class topical androgen receptor inhibitor has been approved for the treatment of acne in patients 12 years and older. It competes with dihydrotestosterone and selectively targets androgen receptors in sebocytes and hair papilla cells. “It has been studied on the face and trunk and has been shown to inhibit sebum production, reduce secretion of inflammatory cytokines, and inhibit inflammatory pathways,” said Dr. Eichenfield, who is also professor of dermatology and pediatrics at the University of California, San Diego.
- From a systemic standpoint, sarecycline, a new tetracycline class antibiotic, has been approved for the treatment of inflammatory lesions of nonnodular moderate to severe acne vulgaris in patients 9 years and older. The once-daily drug can be taken with or without food in a weight-based dose. “This medicine appears to have a narrow spectrum of antibacterial activity compared with other tetracyclines,” he said. “It may have less of a negative effect on gut microbiome than traditional oral antibiotics.”
As for integrating these new options into existing clinical practice, Dr. Eichenfield predicts that the general approach to acne treatment will remain the same. “We’ll have to wait to see where the topical androgens fit into the treatment algorithms,” he said. “Our goal is to minimize scarring, minimize disease, and to modulate the disease course.”
Dr. Eichenfield disclosed that he has been an investigator and/or consultant for Almirall, Cassiopea, Dermata, Foamix, Galderma, L’Oreal, and Ortho Dermatologics.
FROM MOA 2020
Active Comparator Trial Designs Used to Promote Development of Innovative New Medications
Spending on medications is expected to grow from $344 billion in 2018 to $420 billion in 2023, largely driven by the introduction of new branded drugs.1 These costs place substantial financial burden on patients, with nearly 30% of patients not taking their prescriptions as directed because of costs. Although many new medications have transformed how we care for patients, others may not offer meaningful benefit over existing less-costly alternatives that are supported by declining effect sizes of conventional placebo-controlled trials.2 Most medications are approved based on placebo-controlled trial data that does not include an arm comparing the new drug to standard of care, leaving clinicians and patients unable to make meaningful comparisons when deciding on the most appropriate or cost-effective treatment. We consider ways in which clinicians, patients, payers, and regulators could compel more meaningful trials from industry.
Although we often look to the US Food and Drug Administration (FDA) to ensure rigorous and appropriate testing of new medications, the primary mission of the FDA is to ensure efficacy and safety. As a result, pharmaceutical companies seeking approval in the United States have little incentive to go beyond providing the minimal level of evidence required: placebo-controlled randomized trials. Although these trials provide important data on whether a treatment works and its associated risks, they do not provide data on comparative effectiveness. When relevant inexpensive medications are already on the market for the same indication, these placebo-controlled trials provide inadequate evidence to guide clinical decision-making. This issue is particularly relevant in dermatology given how easily topical medications can be combined or reformulated to pursue additional market exclusivity. The addition of an active comparator arm represents an important opportunity to improve the value of these studies.
In the pivotal trials of clindamycin phosphate 1.2%–benzoyl peroxide 2.5% gel for the treatment of acne, the experimental group was not only compared to vehicle but also the active comparator arms of clindamycin alone and benzoyl peroxide alone. The mean percentage change in total lesions was 47.9% with clindamycin phosphate 1.2%–benzoyl peroxide 2.5% gel, 41.6% with the active comparator arm of benzoyl peroxide alone, 40.4% with the active comparator arm of clindamycin alone, and 26.2% for vehicle.3 With these data in mind, clinicians and patients can decide whether the additional benefit of this new product over benzoyl peroxide alone is worth the increased cost.
In contrast, the trials of dapsone gel 7.5% for the treatment of acne did not include an active comparator. The mean percentage change in total lesions was 48.9% for dapsone gel and 43.2% for vehicle.4 Given these data, it is possible that dapsone gel may be no more effective, or possibly less effective, than alternatives such as benzoyl peroxide or other topical antibiotics. Nevertheless, dapsone annual sales were more than $200 million in 2016,5 suggesting that effectively marketed new products can achieve high sales even without convincing evidence of their value compared to standard of care. Although dapsone may be a useful treatment, we cannot effectively make patient-centered clinical decisions given the lack of an active comparator trial design.
This issue is not limited to acne. Phase 3 trials of halobetasol propionate foam 0.05% for psoriasis and crisaborole for atopic dermatitis also did not include an active comparator arm.6,7 Given that topical steroids—and calcineurin inhibitors for atopic dermatitis—are mainstays of treatment for each condition, it is difficult to determine whether these new treatments offer meaningful advantages over existing options and how to incorporate them into our management strategies.
Unfortunately, expensive new medications that are adopted without convincing evidence of their benefit above standard of care can put patients at risk for financial toxicity, either directly through higher out-of-pocket costs or indirectly through higher premiums. Given the impact of rising medication costs on clinicians, patients, and payers, we propose several approaches these stakeholders could adopt to encourage the use of active comparator trial designs.
Clinicians and patients can encourage these trials by remaining skeptical of new treatments that were only compared to vehicle or placebo. Because new medications often are more expensive, clinicians and patients could avoid using these treatments without evidence of either increased efficacy or improved safety and tolerability. In addition, health care institutions should consider reducing pharmaceutical representatives’ access to clinicians to encourage treatment decisions based on the published literature and comparative effectiveness data rather than marketing.
Payers, such as Medicare, also could play a role by requiring active comparator trials for coverage of new medications, particularly when there are already other effective treatments available or other medications in the same class. Payers also could give preferred coverage tier or step therapy status to medications that demonstrate value over existing options.
Although regulatory approaches to increase use of active comparator designs may be more politically challenging to introduce, these options would be more administratively robust. The FDA or a novel regulatory body could require that new treatments demonstrate value in addition to safety and efficacy. This approach would be similar to the role of The National Institute for Health and Care Excellence in the United Kingdom or the recommendations of the European Medicines Agency. Such a group also could provide independent adjudication to ensure appropriate selection of a relevant active comparator. Another approach would be to give extended market exclusivity to medications that are approved based on trials including an additional active comparator arm, an approach used by the European Medicines Agency.
Any approach that encourages increased use of active comparator trials is not without potential downsides. It will be important to avoid unintended consequences of reduced research for rare diseases with smaller markets that may not be able to support the increased cost of these trials. As a result, it would be reasonable to forgo active comparator designs for mediations indicated for rare and orphan diseases or for medications with novel mechanisms of action.
Another argument against including an active comparator arm is that it may stifle innovation by driving up the cost of conducting trials; however, if a product is so marginally innovative that it cannot demonstrate superior safety or efficacy to an existing product, such a new treatment may not be worth the increased cost. In addition, patients provide a notable contribution by participating in these trials, and it is important to ensure that their efforts result in the highest-quality data possible. Furthermore, given the adverse physical and psychosocial impact of a wide variety of dermatologic diseases, the inclusion of an active comparator arm reduces the likelihood that patients will receive placebo, which will make these trials more ethical when effective treatments are available.8 By raising the bar, we can encourage pharmaceutical companies to pursue novel approaches that are more likely to have a revolutionary impact rather than minor modifications or formulations that offer little to no benefit at substantially increased cost.
Although some recent clinical trials in dermatology have included active comparators, many new medications continue to be introduced without any evidence of how they compare to existing standards of care. Until clinicians, patients, payers, and regulators demand that pharmaceutical companies conduct the necessary trials to not only demonstrate whether a treatment is effective and safe but also how it provides value, there will be continued introduction of marginal innovations rather than revolutionary treatments that improve patients’ lives. The next time a new medication is approved, as clinicians, patients, and payers, we must ask ourselves, is this treatment worth it?
- Aitken M, Kleinrock M. Medicine Use and Spending in the U.S.: A Review of 2018 and Outlook to 2023. IQVIA Institute for Human Data Science. https://www.iqvia.com/insights/the-iqvia-institute/reports/medicine-use-and-spending-in-the-us-a-review-of-2018-and-outlook-to-2023. Published May 9, 2019. Accessed August 15, 2020.
- Olfson M, Marcus SC. Decline in placebo-controlled trial results suggests new directions for comparative effectiveness research. Health Aff Proj Hope. 2019;32:1116-1125.
- Thiboutot D, Zaenglein A, Weiss J, et al. An aqueous gel fixed combination of clindamycin phosphate 1.2% and benzoyl peroxide 2.5% for the once-daily treatment of moderate to severe acne vulgaris: assessment of efficacy and safety in 2813 patients. J Am Acad Dermatol. 2008;59:792-800.
- Eichenfield LF, Lain T, Frankel EH, et al. Efficacy and safety of once-daily dapsone gel, 7.5% for treatment of adolescents and adults with acne vulgaris: second of two identically designed, large, multicenter, randomized, vehicle-controlled trials. J Drugs Dermatol. 2016;15:962-969.
- Allergan. 2017 Form 10-K. https://www.abbvie.com/content/dam/abbvie-dotcom/uploads/PDFs/allergan/allergan-annual-report-form-10K-123117.pdf. Accessed August 19, 2020.
- Paller AS, Tom WL, Lebwohl MG, et al. Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of atopic dermatitis (AD) in children and adults. J Am Acad Dermatol. 2016;75:494-503.e6.
- Bhatia N, Stein Gold L, Kircik LH, et al. Two multicenter, randomized, double-blind, parallel group comparison studies of a novel foam formulation of halobetasol propionate, 0.05% vs its vehicle in adult subjects with plaque psoriasis. J Drugs Dermatol. 2019;18:790-796.
- Temple R, Ellenberg SS. Placebo-controlled trials and active-control trials in the evaluation of new treatments. part 1: ethical and scientific issues. Ann Intern Med. 2000;133:455-463.
Spending on medications is expected to grow from $344 billion in 2018 to $420 billion in 2023, largely driven by the introduction of new branded drugs.1 These costs place substantial financial burden on patients, with nearly 30% of patients not taking their prescriptions as directed because of costs. Although many new medications have transformed how we care for patients, others may not offer meaningful benefit over existing less-costly alternatives that are supported by declining effect sizes of conventional placebo-controlled trials.2 Most medications are approved based on placebo-controlled trial data that does not include an arm comparing the new drug to standard of care, leaving clinicians and patients unable to make meaningful comparisons when deciding on the most appropriate or cost-effective treatment. We consider ways in which clinicians, patients, payers, and regulators could compel more meaningful trials from industry.
Although we often look to the US Food and Drug Administration (FDA) to ensure rigorous and appropriate testing of new medications, the primary mission of the FDA is to ensure efficacy and safety. As a result, pharmaceutical companies seeking approval in the United States have little incentive to go beyond providing the minimal level of evidence required: placebo-controlled randomized trials. Although these trials provide important data on whether a treatment works and its associated risks, they do not provide data on comparative effectiveness. When relevant inexpensive medications are already on the market for the same indication, these placebo-controlled trials provide inadequate evidence to guide clinical decision-making. This issue is particularly relevant in dermatology given how easily topical medications can be combined or reformulated to pursue additional market exclusivity. The addition of an active comparator arm represents an important opportunity to improve the value of these studies.
In the pivotal trials of clindamycin phosphate 1.2%–benzoyl peroxide 2.5% gel for the treatment of acne, the experimental group was not only compared to vehicle but also the active comparator arms of clindamycin alone and benzoyl peroxide alone. The mean percentage change in total lesions was 47.9% with clindamycin phosphate 1.2%–benzoyl peroxide 2.5% gel, 41.6% with the active comparator arm of benzoyl peroxide alone, 40.4% with the active comparator arm of clindamycin alone, and 26.2% for vehicle.3 With these data in mind, clinicians and patients can decide whether the additional benefit of this new product over benzoyl peroxide alone is worth the increased cost.
In contrast, the trials of dapsone gel 7.5% for the treatment of acne did not include an active comparator. The mean percentage change in total lesions was 48.9% for dapsone gel and 43.2% for vehicle.4 Given these data, it is possible that dapsone gel may be no more effective, or possibly less effective, than alternatives such as benzoyl peroxide or other topical antibiotics. Nevertheless, dapsone annual sales were more than $200 million in 2016,5 suggesting that effectively marketed new products can achieve high sales even without convincing evidence of their value compared to standard of care. Although dapsone may be a useful treatment, we cannot effectively make patient-centered clinical decisions given the lack of an active comparator trial design.
This issue is not limited to acne. Phase 3 trials of halobetasol propionate foam 0.05% for psoriasis and crisaborole for atopic dermatitis also did not include an active comparator arm.6,7 Given that topical steroids—and calcineurin inhibitors for atopic dermatitis—are mainstays of treatment for each condition, it is difficult to determine whether these new treatments offer meaningful advantages over existing options and how to incorporate them into our management strategies.
Unfortunately, expensive new medications that are adopted without convincing evidence of their benefit above standard of care can put patients at risk for financial toxicity, either directly through higher out-of-pocket costs or indirectly through higher premiums. Given the impact of rising medication costs on clinicians, patients, and payers, we propose several approaches these stakeholders could adopt to encourage the use of active comparator trial designs.
Clinicians and patients can encourage these trials by remaining skeptical of new treatments that were only compared to vehicle or placebo. Because new medications often are more expensive, clinicians and patients could avoid using these treatments without evidence of either increased efficacy or improved safety and tolerability. In addition, health care institutions should consider reducing pharmaceutical representatives’ access to clinicians to encourage treatment decisions based on the published literature and comparative effectiveness data rather than marketing.
Payers, such as Medicare, also could play a role by requiring active comparator trials for coverage of new medications, particularly when there are already other effective treatments available or other medications in the same class. Payers also could give preferred coverage tier or step therapy status to medications that demonstrate value over existing options.
Although regulatory approaches to increase use of active comparator designs may be more politically challenging to introduce, these options would be more administratively robust. The FDA or a novel regulatory body could require that new treatments demonstrate value in addition to safety and efficacy. This approach would be similar to the role of The National Institute for Health and Care Excellence in the United Kingdom or the recommendations of the European Medicines Agency. Such a group also could provide independent adjudication to ensure appropriate selection of a relevant active comparator. Another approach would be to give extended market exclusivity to medications that are approved based on trials including an additional active comparator arm, an approach used by the European Medicines Agency.
Any approach that encourages increased use of active comparator trials is not without potential downsides. It will be important to avoid unintended consequences of reduced research for rare diseases with smaller markets that may not be able to support the increased cost of these trials. As a result, it would be reasonable to forgo active comparator designs for mediations indicated for rare and orphan diseases or for medications with novel mechanisms of action.
Another argument against including an active comparator arm is that it may stifle innovation by driving up the cost of conducting trials; however, if a product is so marginally innovative that it cannot demonstrate superior safety or efficacy to an existing product, such a new treatment may not be worth the increased cost. In addition, patients provide a notable contribution by participating in these trials, and it is important to ensure that their efforts result in the highest-quality data possible. Furthermore, given the adverse physical and psychosocial impact of a wide variety of dermatologic diseases, the inclusion of an active comparator arm reduces the likelihood that patients will receive placebo, which will make these trials more ethical when effective treatments are available.8 By raising the bar, we can encourage pharmaceutical companies to pursue novel approaches that are more likely to have a revolutionary impact rather than minor modifications or formulations that offer little to no benefit at substantially increased cost.
Although some recent clinical trials in dermatology have included active comparators, many new medications continue to be introduced without any evidence of how they compare to existing standards of care. Until clinicians, patients, payers, and regulators demand that pharmaceutical companies conduct the necessary trials to not only demonstrate whether a treatment is effective and safe but also how it provides value, there will be continued introduction of marginal innovations rather than revolutionary treatments that improve patients’ lives. The next time a new medication is approved, as clinicians, patients, and payers, we must ask ourselves, is this treatment worth it?
Spending on medications is expected to grow from $344 billion in 2018 to $420 billion in 2023, largely driven by the introduction of new branded drugs.1 These costs place substantial financial burden on patients, with nearly 30% of patients not taking their prescriptions as directed because of costs. Although many new medications have transformed how we care for patients, others may not offer meaningful benefit over existing less-costly alternatives that are supported by declining effect sizes of conventional placebo-controlled trials.2 Most medications are approved based on placebo-controlled trial data that does not include an arm comparing the new drug to standard of care, leaving clinicians and patients unable to make meaningful comparisons when deciding on the most appropriate or cost-effective treatment. We consider ways in which clinicians, patients, payers, and regulators could compel more meaningful trials from industry.
Although we often look to the US Food and Drug Administration (FDA) to ensure rigorous and appropriate testing of new medications, the primary mission of the FDA is to ensure efficacy and safety. As a result, pharmaceutical companies seeking approval in the United States have little incentive to go beyond providing the minimal level of evidence required: placebo-controlled randomized trials. Although these trials provide important data on whether a treatment works and its associated risks, they do not provide data on comparative effectiveness. When relevant inexpensive medications are already on the market for the same indication, these placebo-controlled trials provide inadequate evidence to guide clinical decision-making. This issue is particularly relevant in dermatology given how easily topical medications can be combined or reformulated to pursue additional market exclusivity. The addition of an active comparator arm represents an important opportunity to improve the value of these studies.
In the pivotal trials of clindamycin phosphate 1.2%–benzoyl peroxide 2.5% gel for the treatment of acne, the experimental group was not only compared to vehicle but also the active comparator arms of clindamycin alone and benzoyl peroxide alone. The mean percentage change in total lesions was 47.9% with clindamycin phosphate 1.2%–benzoyl peroxide 2.5% gel, 41.6% with the active comparator arm of benzoyl peroxide alone, 40.4% with the active comparator arm of clindamycin alone, and 26.2% for vehicle.3 With these data in mind, clinicians and patients can decide whether the additional benefit of this new product over benzoyl peroxide alone is worth the increased cost.
In contrast, the trials of dapsone gel 7.5% for the treatment of acne did not include an active comparator. The mean percentage change in total lesions was 48.9% for dapsone gel and 43.2% for vehicle.4 Given these data, it is possible that dapsone gel may be no more effective, or possibly less effective, than alternatives such as benzoyl peroxide or other topical antibiotics. Nevertheless, dapsone annual sales were more than $200 million in 2016,5 suggesting that effectively marketed new products can achieve high sales even without convincing evidence of their value compared to standard of care. Although dapsone may be a useful treatment, we cannot effectively make patient-centered clinical decisions given the lack of an active comparator trial design.
This issue is not limited to acne. Phase 3 trials of halobetasol propionate foam 0.05% for psoriasis and crisaborole for atopic dermatitis also did not include an active comparator arm.6,7 Given that topical steroids—and calcineurin inhibitors for atopic dermatitis—are mainstays of treatment for each condition, it is difficult to determine whether these new treatments offer meaningful advantages over existing options and how to incorporate them into our management strategies.
Unfortunately, expensive new medications that are adopted without convincing evidence of their benefit above standard of care can put patients at risk for financial toxicity, either directly through higher out-of-pocket costs or indirectly through higher premiums. Given the impact of rising medication costs on clinicians, patients, and payers, we propose several approaches these stakeholders could adopt to encourage the use of active comparator trial designs.
Clinicians and patients can encourage these trials by remaining skeptical of new treatments that were only compared to vehicle or placebo. Because new medications often are more expensive, clinicians and patients could avoid using these treatments without evidence of either increased efficacy or improved safety and tolerability. In addition, health care institutions should consider reducing pharmaceutical representatives’ access to clinicians to encourage treatment decisions based on the published literature and comparative effectiveness data rather than marketing.
Payers, such as Medicare, also could play a role by requiring active comparator trials for coverage of new medications, particularly when there are already other effective treatments available or other medications in the same class. Payers also could give preferred coverage tier or step therapy status to medications that demonstrate value over existing options.
Although regulatory approaches to increase use of active comparator designs may be more politically challenging to introduce, these options would be more administratively robust. The FDA or a novel regulatory body could require that new treatments demonstrate value in addition to safety and efficacy. This approach would be similar to the role of The National Institute for Health and Care Excellence in the United Kingdom or the recommendations of the European Medicines Agency. Such a group also could provide independent adjudication to ensure appropriate selection of a relevant active comparator. Another approach would be to give extended market exclusivity to medications that are approved based on trials including an additional active comparator arm, an approach used by the European Medicines Agency.
Any approach that encourages increased use of active comparator trials is not without potential downsides. It will be important to avoid unintended consequences of reduced research for rare diseases with smaller markets that may not be able to support the increased cost of these trials. As a result, it would be reasonable to forgo active comparator designs for mediations indicated for rare and orphan diseases or for medications with novel mechanisms of action.
Another argument against including an active comparator arm is that it may stifle innovation by driving up the cost of conducting trials; however, if a product is so marginally innovative that it cannot demonstrate superior safety or efficacy to an existing product, such a new treatment may not be worth the increased cost. In addition, patients provide a notable contribution by participating in these trials, and it is important to ensure that their efforts result in the highest-quality data possible. Furthermore, given the adverse physical and psychosocial impact of a wide variety of dermatologic diseases, the inclusion of an active comparator arm reduces the likelihood that patients will receive placebo, which will make these trials more ethical when effective treatments are available.8 By raising the bar, we can encourage pharmaceutical companies to pursue novel approaches that are more likely to have a revolutionary impact rather than minor modifications or formulations that offer little to no benefit at substantially increased cost.
Although some recent clinical trials in dermatology have included active comparators, many new medications continue to be introduced without any evidence of how they compare to existing standards of care. Until clinicians, patients, payers, and regulators demand that pharmaceutical companies conduct the necessary trials to not only demonstrate whether a treatment is effective and safe but also how it provides value, there will be continued introduction of marginal innovations rather than revolutionary treatments that improve patients’ lives. The next time a new medication is approved, as clinicians, patients, and payers, we must ask ourselves, is this treatment worth it?
- Aitken M, Kleinrock M. Medicine Use and Spending in the U.S.: A Review of 2018 and Outlook to 2023. IQVIA Institute for Human Data Science. https://www.iqvia.com/insights/the-iqvia-institute/reports/medicine-use-and-spending-in-the-us-a-review-of-2018-and-outlook-to-2023. Published May 9, 2019. Accessed August 15, 2020.
- Olfson M, Marcus SC. Decline in placebo-controlled trial results suggests new directions for comparative effectiveness research. Health Aff Proj Hope. 2019;32:1116-1125.
- Thiboutot D, Zaenglein A, Weiss J, et al. An aqueous gel fixed combination of clindamycin phosphate 1.2% and benzoyl peroxide 2.5% for the once-daily treatment of moderate to severe acne vulgaris: assessment of efficacy and safety in 2813 patients. J Am Acad Dermatol. 2008;59:792-800.
- Eichenfield LF, Lain T, Frankel EH, et al. Efficacy and safety of once-daily dapsone gel, 7.5% for treatment of adolescents and adults with acne vulgaris: second of two identically designed, large, multicenter, randomized, vehicle-controlled trials. J Drugs Dermatol. 2016;15:962-969.
- Allergan. 2017 Form 10-K. https://www.abbvie.com/content/dam/abbvie-dotcom/uploads/PDFs/allergan/allergan-annual-report-form-10K-123117.pdf. Accessed August 19, 2020.
- Paller AS, Tom WL, Lebwohl MG, et al. Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of atopic dermatitis (AD) in children and adults. J Am Acad Dermatol. 2016;75:494-503.e6.
- Bhatia N, Stein Gold L, Kircik LH, et al. Two multicenter, randomized, double-blind, parallel group comparison studies of a novel foam formulation of halobetasol propionate, 0.05% vs its vehicle in adult subjects with plaque psoriasis. J Drugs Dermatol. 2019;18:790-796.
- Temple R, Ellenberg SS. Placebo-controlled trials and active-control trials in the evaluation of new treatments. part 1: ethical and scientific issues. Ann Intern Med. 2000;133:455-463.
- Aitken M, Kleinrock M. Medicine Use and Spending in the U.S.: A Review of 2018 and Outlook to 2023. IQVIA Institute for Human Data Science. https://www.iqvia.com/insights/the-iqvia-institute/reports/medicine-use-and-spending-in-the-us-a-review-of-2018-and-outlook-to-2023. Published May 9, 2019. Accessed August 15, 2020.
- Olfson M, Marcus SC. Decline in placebo-controlled trial results suggests new directions for comparative effectiveness research. Health Aff Proj Hope. 2019;32:1116-1125.
- Thiboutot D, Zaenglein A, Weiss J, et al. An aqueous gel fixed combination of clindamycin phosphate 1.2% and benzoyl peroxide 2.5% for the once-daily treatment of moderate to severe acne vulgaris: assessment of efficacy and safety in 2813 patients. J Am Acad Dermatol. 2008;59:792-800.
- Eichenfield LF, Lain T, Frankel EH, et al. Efficacy and safety of once-daily dapsone gel, 7.5% for treatment of adolescents and adults with acne vulgaris: second of two identically designed, large, multicenter, randomized, vehicle-controlled trials. J Drugs Dermatol. 2016;15:962-969.
- Allergan. 2017 Form 10-K. https://www.abbvie.com/content/dam/abbvie-dotcom/uploads/PDFs/allergan/allergan-annual-report-form-10K-123117.pdf. Accessed August 19, 2020.
- Paller AS, Tom WL, Lebwohl MG, et al. Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of atopic dermatitis (AD) in children and adults. J Am Acad Dermatol. 2016;75:494-503.e6.
- Bhatia N, Stein Gold L, Kircik LH, et al. Two multicenter, randomized, double-blind, parallel group comparison studies of a novel foam formulation of halobetasol propionate, 0.05% vs its vehicle in adult subjects with plaque psoriasis. J Drugs Dermatol. 2019;18:790-796.
- Temple R, Ellenberg SS. Placebo-controlled trials and active-control trials in the evaluation of new treatments. part 1: ethical and scientific issues. Ann Intern Med. 2000;133:455-463.
Practice Points
- When evaluating a new treatment, it is important to consider not only whether it is effective but also whether it provides additional value compared to existing treatment options.
- Encouraging active comparator trials will provide clinicians and patients with important data to guide decision-making regarding the most appropriate treatment options.
Post-acne nasal papules described in a series of patients
, but researchers believe the condition could be an underrecognized problem, affecting patients with skin of color in particular, according to the authors of a case series published in Pediatric Dermatology.
Jorge Roman, MD, and coauthors in the department of dermatology at New York (N.Y.) University identified 20 patients with a history of acne who had nasal papules, in a retrospective review of electronic medical records at NYU over 1 year (April 2018 to April 2019). The presentation ranged from “a few, small skin-colored papules to large, dome-shaped papulonodules, to more extensive rhinophymatous-like” changes with some patients having papular lesions on the chin in addition to the nose, they wrote in the report.
These papules greatly resembled angiofibromas, but appear to be a sequela of acne, according to the authors. In five patients who had biopsies, the results showed “a dome-shaped proliferation of spindle and stellate-shaped cells with thickened collagen bundles and dilated thin-walled blood vessels,” the authors wrote. “The histopathological findings of these nasal papules were indistinguishable from those of a conventional angiofibroma.”
In addition, the patients did not have evidence of underlying genetic conditions that could explain the angiofibroma-like lesions. “Although acne has not previously been implicated in the development of angiofibromas, based on the data available for our patients, it seems extremely unlikely that the lesions would be related to anything else,” Dr. Roman, a dermatology resident at New York University, said in an interview.
He said he first recognized the nasal papules in clinic as a first-year resident, but was surprised to find a lack of information on the condition. “Dermatology has a name for just about every skin disease imaginable, so I found it very odd when I couldn’t find much describing this condition,” he said. “There was a large disparity between what we were seeing in clinic and what was reported in the literature.”
Nearly all the patients were Hispanic (17 of 20) and adolescent males (17 patients), with a median age of 16 years at the time of presentation. There were two Black patients and one Asian patient. Race and ethnicity were not mentioned in two previous reports describing papular acne scarring, but Dr. Roman and colleagues noted that in their clinic, the condition appeared to affect adolescent patients with skin of color predominantly.
Reasons why nasal papules may be underreported are unclear, Dr. Roman noted. One possible explanation is lower use of dermatologic care among patients with skin of color. “Interestingly, previous research has shown that racial minorities are lower utilizers of dermatologic care. It is possible that the patient demographic most afflicted by this condition face significant barriers when seeking care,” he said.
Due to a low level of awareness of acne-related nasal papules, “clinicians may not recognize it as an acne-related scarring process. This is significant, as early recognition and treatment can prevent the development or progression of these potentially disfiguring sequelae,” Dr. Roman said.
Although the results are from a small case series at a single center, Dr. Roman said this condition may be more prevalent than realized. “Having been raised in a predominately Latino community in Texas, I can easily recall seeing people with these papules growing up. I don’t think it would be surprising for dermatologists reading our paper to say, ‘I’ve seen this in clinic before,’ ” he said.
Regarding treatment, there is an ongoing investigation into what treatments are effective for the acne-related nasal papules. “Physical treatment modalities such as ablative laser or surgical removal seem to be the most efficacious,” Dr. Roman said. “In the future, a prospective clinical study will help to better define the prevalence and risk factors for the condition,” he said.
He and coauthors reported no conflicts of interest. No funding source was listed.
SOURCE: Roman J et al. Pediatr Dermatol. 2020 Aug 7. doi: 10.1111/pde.14319.
, but researchers believe the condition could be an underrecognized problem, affecting patients with skin of color in particular, according to the authors of a case series published in Pediatric Dermatology.
Jorge Roman, MD, and coauthors in the department of dermatology at New York (N.Y.) University identified 20 patients with a history of acne who had nasal papules, in a retrospective review of electronic medical records at NYU over 1 year (April 2018 to April 2019). The presentation ranged from “a few, small skin-colored papules to large, dome-shaped papulonodules, to more extensive rhinophymatous-like” changes with some patients having papular lesions on the chin in addition to the nose, they wrote in the report.
These papules greatly resembled angiofibromas, but appear to be a sequela of acne, according to the authors. In five patients who had biopsies, the results showed “a dome-shaped proliferation of spindle and stellate-shaped cells with thickened collagen bundles and dilated thin-walled blood vessels,” the authors wrote. “The histopathological findings of these nasal papules were indistinguishable from those of a conventional angiofibroma.”
In addition, the patients did not have evidence of underlying genetic conditions that could explain the angiofibroma-like lesions. “Although acne has not previously been implicated in the development of angiofibromas, based on the data available for our patients, it seems extremely unlikely that the lesions would be related to anything else,” Dr. Roman, a dermatology resident at New York University, said in an interview.
He said he first recognized the nasal papules in clinic as a first-year resident, but was surprised to find a lack of information on the condition. “Dermatology has a name for just about every skin disease imaginable, so I found it very odd when I couldn’t find much describing this condition,” he said. “There was a large disparity between what we were seeing in clinic and what was reported in the literature.”
Nearly all the patients were Hispanic (17 of 20) and adolescent males (17 patients), with a median age of 16 years at the time of presentation. There were two Black patients and one Asian patient. Race and ethnicity were not mentioned in two previous reports describing papular acne scarring, but Dr. Roman and colleagues noted that in their clinic, the condition appeared to affect adolescent patients with skin of color predominantly.
Reasons why nasal papules may be underreported are unclear, Dr. Roman noted. One possible explanation is lower use of dermatologic care among patients with skin of color. “Interestingly, previous research has shown that racial minorities are lower utilizers of dermatologic care. It is possible that the patient demographic most afflicted by this condition face significant barriers when seeking care,” he said.
Due to a low level of awareness of acne-related nasal papules, “clinicians may not recognize it as an acne-related scarring process. This is significant, as early recognition and treatment can prevent the development or progression of these potentially disfiguring sequelae,” Dr. Roman said.
Although the results are from a small case series at a single center, Dr. Roman said this condition may be more prevalent than realized. “Having been raised in a predominately Latino community in Texas, I can easily recall seeing people with these papules growing up. I don’t think it would be surprising for dermatologists reading our paper to say, ‘I’ve seen this in clinic before,’ ” he said.
Regarding treatment, there is an ongoing investigation into what treatments are effective for the acne-related nasal papules. “Physical treatment modalities such as ablative laser or surgical removal seem to be the most efficacious,” Dr. Roman said. “In the future, a prospective clinical study will help to better define the prevalence and risk factors for the condition,” he said.
He and coauthors reported no conflicts of interest. No funding source was listed.
SOURCE: Roman J et al. Pediatr Dermatol. 2020 Aug 7. doi: 10.1111/pde.14319.
, but researchers believe the condition could be an underrecognized problem, affecting patients with skin of color in particular, according to the authors of a case series published in Pediatric Dermatology.
Jorge Roman, MD, and coauthors in the department of dermatology at New York (N.Y.) University identified 20 patients with a history of acne who had nasal papules, in a retrospective review of electronic medical records at NYU over 1 year (April 2018 to April 2019). The presentation ranged from “a few, small skin-colored papules to large, dome-shaped papulonodules, to more extensive rhinophymatous-like” changes with some patients having papular lesions on the chin in addition to the nose, they wrote in the report.
These papules greatly resembled angiofibromas, but appear to be a sequela of acne, according to the authors. In five patients who had biopsies, the results showed “a dome-shaped proliferation of spindle and stellate-shaped cells with thickened collagen bundles and dilated thin-walled blood vessels,” the authors wrote. “The histopathological findings of these nasal papules were indistinguishable from those of a conventional angiofibroma.”
In addition, the patients did not have evidence of underlying genetic conditions that could explain the angiofibroma-like lesions. “Although acne has not previously been implicated in the development of angiofibromas, based on the data available for our patients, it seems extremely unlikely that the lesions would be related to anything else,” Dr. Roman, a dermatology resident at New York University, said in an interview.
He said he first recognized the nasal papules in clinic as a first-year resident, but was surprised to find a lack of information on the condition. “Dermatology has a name for just about every skin disease imaginable, so I found it very odd when I couldn’t find much describing this condition,” he said. “There was a large disparity between what we were seeing in clinic and what was reported in the literature.”
Nearly all the patients were Hispanic (17 of 20) and adolescent males (17 patients), with a median age of 16 years at the time of presentation. There were two Black patients and one Asian patient. Race and ethnicity were not mentioned in two previous reports describing papular acne scarring, but Dr. Roman and colleagues noted that in their clinic, the condition appeared to affect adolescent patients with skin of color predominantly.
Reasons why nasal papules may be underreported are unclear, Dr. Roman noted. One possible explanation is lower use of dermatologic care among patients with skin of color. “Interestingly, previous research has shown that racial minorities are lower utilizers of dermatologic care. It is possible that the patient demographic most afflicted by this condition face significant barriers when seeking care,” he said.
Due to a low level of awareness of acne-related nasal papules, “clinicians may not recognize it as an acne-related scarring process. This is significant, as early recognition and treatment can prevent the development or progression of these potentially disfiguring sequelae,” Dr. Roman said.
Although the results are from a small case series at a single center, Dr. Roman said this condition may be more prevalent than realized. “Having been raised in a predominately Latino community in Texas, I can easily recall seeing people with these papules growing up. I don’t think it would be surprising for dermatologists reading our paper to say, ‘I’ve seen this in clinic before,’ ” he said.
Regarding treatment, there is an ongoing investigation into what treatments are effective for the acne-related nasal papules. “Physical treatment modalities such as ablative laser or surgical removal seem to be the most efficacious,” Dr. Roman said. “In the future, a prospective clinical study will help to better define the prevalence and risk factors for the condition,” he said.
He and coauthors reported no conflicts of interest. No funding source was listed.
SOURCE: Roman J et al. Pediatr Dermatol. 2020 Aug 7. doi: 10.1111/pde.14319.
FROM PEDIATRIC DERMATOLOGY
FDA approves topical antiandrogen for acne
Clascoterone is a topical androgen receptor inhibitor indicated for treatment of acne vulgaris in patients aged 12 years and older, according to the labeling from manufacturer Cassiopea. Clascoterone, which will be marketed as Winlevi, targets the androgen hormones that contribute to acne by inhibiting serum production and inflammation, according to a company press release.
“Although clascoterone’s exact mechanism of action is unknown, laboratory studies suggest clascoterone competes with androgens, specifically dihydrotestosterone, for binding to the androgen receptors within the sebaceous gland and hair follicles,” according to the release.
Approval was based in part on a pair of phase 3, double-blind, vehicle-controlled, 12-week, randomized trials including 1,440 patients aged 9 years and older with moderate to severe facial acne. The findings were published in April, in JAMA Dermatology .
Participants were randomized to twice-daily application of clascoterone or a control vehicle; treatment success was defined as having an Investigator’s Global Assessment score of 0 (clear) or 1 (almost clear), as well as at least a 2-grade improvement from baseline, and absolute change in noninflammatory and inflammatory lesion counts at week 12.
At 12 weeks, treatment success rates were 18.4% and 20.3% among those on clascoterone, compared with 9% and 6.5%, respectively, among controls. There were also significant reductions in noninflammatory and inflammatory lesions from baseline at 12 weeks, compared with controls.
In the studies, treatment was well tolerated, with a safety profile similar to safety in controls. Adverse events thought to be related to clascoterone in the studies (a total of 13) included application-site pain; erythema; oropharyngeal pain; hypersensitivity, dryness, or hypertrichosis at the application site; eye irritation; headache; and hair color changes. “Clascoterone targets androgen receptors at the site of application and is quickly metabolized to an inactive form, thus limiting systemic activity,” the authors of the study wrote.
Clascoterone is expected to be available in the United States in early 2021, according to the manufacturer.
Clascoterone is a topical androgen receptor inhibitor indicated for treatment of acne vulgaris in patients aged 12 years and older, according to the labeling from manufacturer Cassiopea. Clascoterone, which will be marketed as Winlevi, targets the androgen hormones that contribute to acne by inhibiting serum production and inflammation, according to a company press release.
“Although clascoterone’s exact mechanism of action is unknown, laboratory studies suggest clascoterone competes with androgens, specifically dihydrotestosterone, for binding to the androgen receptors within the sebaceous gland and hair follicles,” according to the release.
Approval was based in part on a pair of phase 3, double-blind, vehicle-controlled, 12-week, randomized trials including 1,440 patients aged 9 years and older with moderate to severe facial acne. The findings were published in April, in JAMA Dermatology .
Participants were randomized to twice-daily application of clascoterone or a control vehicle; treatment success was defined as having an Investigator’s Global Assessment score of 0 (clear) or 1 (almost clear), as well as at least a 2-grade improvement from baseline, and absolute change in noninflammatory and inflammatory lesion counts at week 12.
At 12 weeks, treatment success rates were 18.4% and 20.3% among those on clascoterone, compared with 9% and 6.5%, respectively, among controls. There were also significant reductions in noninflammatory and inflammatory lesions from baseline at 12 weeks, compared with controls.
In the studies, treatment was well tolerated, with a safety profile similar to safety in controls. Adverse events thought to be related to clascoterone in the studies (a total of 13) included application-site pain; erythema; oropharyngeal pain; hypersensitivity, dryness, or hypertrichosis at the application site; eye irritation; headache; and hair color changes. “Clascoterone targets androgen receptors at the site of application and is quickly metabolized to an inactive form, thus limiting systemic activity,” the authors of the study wrote.
Clascoterone is expected to be available in the United States in early 2021, according to the manufacturer.
Clascoterone is a topical androgen receptor inhibitor indicated for treatment of acne vulgaris in patients aged 12 years and older, according to the labeling from manufacturer Cassiopea. Clascoterone, which will be marketed as Winlevi, targets the androgen hormones that contribute to acne by inhibiting serum production and inflammation, according to a company press release.
“Although clascoterone’s exact mechanism of action is unknown, laboratory studies suggest clascoterone competes with androgens, specifically dihydrotestosterone, for binding to the androgen receptors within the sebaceous gland and hair follicles,” according to the release.
Approval was based in part on a pair of phase 3, double-blind, vehicle-controlled, 12-week, randomized trials including 1,440 patients aged 9 years and older with moderate to severe facial acne. The findings were published in April, in JAMA Dermatology .
Participants were randomized to twice-daily application of clascoterone or a control vehicle; treatment success was defined as having an Investigator’s Global Assessment score of 0 (clear) or 1 (almost clear), as well as at least a 2-grade improvement from baseline, and absolute change in noninflammatory and inflammatory lesion counts at week 12.
At 12 weeks, treatment success rates were 18.4% and 20.3% among those on clascoterone, compared with 9% and 6.5%, respectively, among controls. There were also significant reductions in noninflammatory and inflammatory lesions from baseline at 12 weeks, compared with controls.
In the studies, treatment was well tolerated, with a safety profile similar to safety in controls. Adverse events thought to be related to clascoterone in the studies (a total of 13) included application-site pain; erythema; oropharyngeal pain; hypersensitivity, dryness, or hypertrichosis at the application site; eye irritation; headache; and hair color changes. “Clascoterone targets androgen receptors at the site of application and is quickly metabolized to an inactive form, thus limiting systemic activity,” the authors of the study wrote.
Clascoterone is expected to be available in the United States in early 2021, according to the manufacturer.
Variations in Preference for Topical Vehicles Among Demographic Groups
Topical medication is a mainstay in the treatment of dermatologic conditions. Adherence to medication regimens can be challenging in patients requiring long-term topical treatment, and nonadherence is multifactorial. A major modifiable contributing factor is patient dissatisfaction with the vehicle used. Medications often have options for different topical preparations. Therefore, it is important to consider patient preference when prescribing topical treatments to maximize adherence, ensure patient satisfaction, and optimize outcomes.
We hypothesized that notable differences exist among demographic groups regarding preference for topical vehicles. Little research has been conducted to delineate trends. This study aimed to identify variations in preference for creams, lotions, and ointments by age, gender, and ethnicity.
Methods
Data were collected through surveys distributed to all patients seen at the Truman Medical Center University Health Dermatology Clinic in Kansas City, Missouri, between September 2018 and June 2019. The study was approved by the University of Missouri Kansas City institutional review board. An estimated response rate of 95% was achieved. Each patient was informed that the survey was voluntary and anonymous, and declining to complete the survey had no effect on the care provided. Each patient completed only 1 survey and returned it to a collection box before departing from clinic.
In the survey, patients provided demographic information, including age, gender, and ethnicity. Age groups included patients younger than 40 years, 40 to 60 years, and older than 60 years. Gender groups included male and female. Ethnicity included white, black, Hispanic/Latino, and Asian/Pacific Islander or other. Patients then chose 1 of 3 options for topical vehicle preference: cream, lotion, or ointment. Each of these options was accompanied by a brief description of the vehicle, a photograph, and examples of common commercial products to aid in decision-making. The expected values were calculated based on a probability distribution under the assumption that variables have no association. Therefore, the discrepancy between the expected value and the observed value was used to describe the significance of the association between variables.
Data were analyzed using χ2 tests with the aid of a statistician. P<.05 was considered statistically significant.
Results
A total of 404 surveys were collected and recorded. Data showed statistically significant trends in each demographic parameter.
Age
First, we analyzed differences in preference based on age (Table 1). Of 404 patients, 163 were younger than 40 years, 171 were aged 40 to 60 years, and 70 were older than 60 years. Patients younger than 40 years preferred lotion (68 vs 46.0 expected). Patients aged 40 to 60 years showed preference for cream (83 vs 76.6 expected) and ointment (56 vs 46.1 expected). Patients older than 60 years preferred cream (41 vs 31.4 expected). These findings were statistically significant (P<.0001).
Gender
Next, we evaluated variations based on gender (Table 2). Of 404 patients, 254 were female and 150 were male. Females preferred cream (127 vs 113.8 expected). Males exhibited preference for lotion (50 vs 42.3 expected) and ointment (46 vs 40.5 expected). Differences between genders were statistically significant (P=.023).
Ethnicity
We then analyzed preferences based on ethnicity (Table 3). Of 404 patients, 30 were Hispanic/Latino, 26 were Asian/Pacific Islander or other, 227 were white, and 121 were black. Hispanic/Latino patients showed equivocal findings, aligning with expected counts. Asian/Pacific Islander or other patients exhibited slight preferences for cream (14 vs 11.6 expected) and lotion (10 vs 7.3 expected). White patients preferred cream (119 vs 101.7 expected) and lotion (82 vs 64.1 expected). Black patients showed strong preference for ointment (72 vs 32.6 expected). Differences in preferences based on ethnicity were statistically significant (P<.0001).
Comment
Topical medication is a mainstay of dermatologic therapy. Many topical preparations (or vehicles) exist, including ointments, creams, lotions, gels, solutions, and foams. Vehicle type not only influences bioavailability of the prepared medication but also has a notable impact on adherence and subsequent efficacy of the topical therapy.
Medication adherence is especially challenging in dermatology, as topical medications play a central role in treatment. Compliance with the medication regimen is paramount in treatment efficacy.1 In dermatology, adherence with oral medications is higher than it is for topical medications2; various factors contribute to this difference. Compliance may decline with topical treatment due to time-consuming application, misunderstanding about the disease or the treatment regimen, frequency of administration, dissatisfaction with efficacy or appearance, and other variables.3
Other factors have been found to be important to topical medication adherence; younger age, female gender, marriage, employment, nonsmoking, nondrinking, and higher cognitive ability were associated with higher topical medication adherence.4 Our study focused on one factor: identification of demographic-specific preferences that might have implications on adherence within the studied demographic groups.
It is known that individual preferences exist when patients are choosing a topical preparation. However, a PubMed search of articles indexed for MEDLINE using the terms topical, vehicle, preparation, adherence, and preference revealed few studies that examined the preference for topical vehicle by age, gender, or ethnicity.
Existing studies have examined preferences for topical preparations based on specific disease states; this literature, albeit limited, demonstrates that preferences for topical product formulations vary among acne, atopic dermatitis, and plaque psoriasis patients.5 Other studies focus on specific patient populations or medications. For example, one study found that preference for corticosteroid vehicles among psoriasis patients was highly variable and choice of vehicle was critical to adherence.6 Another study highlighted differences in vehicle choice between younger and older age groups with psoriasis.7
Given the limited data overall, it was our goal to determine if any patterns of preference existed by age, gender, or ethnicity, regardless of disease state or indication for topical product. Importantly, over-the-counter products—cosmetic or otherwise—were not differentiated from prescribed topical medications. Our survey elucidated significant differences in preference by age, gender, and ethnicity.
Notable Findings
Regarding age, patients younger than 40 years preferred lotion, patients aged 40 to 60 years preferred cream, and patients older than 60 years preferred cream. Analysis based on gender showed that females preferred cream, and males preferred lotion and ointment. Analysis based on ethnicity most notably demonstrated a strong preference for ointment in black patients while showing preference for cream in white patients.
Potential Biases and Pitfalls
Limitations of this study included the small Hispanic/Latino and Asian/Pacific Islander populations surveyed, possible misunderstanding of the survey by respondents, and the potential for surveys being filled out twice by the same patient. Future surveys could be conducted over a longer period to increase the total sample size and to better characterize less-represented populations, such as Hispanic and Asian patients. To avoid repeat participation, the first question of the survey asked patients to indicate if they had previously completed the survey and instructed patients who had to return the repeat survey to the front desk.
To limit other errors, our survey included concise accessible descriptions of each preparation along with clear representative photographs and examples of common brands. Still, it is possible that some mistakes could have been made while patients filled out the survey based on comprehension deficits, oversight, or other reasons. It also is possible that preference might vary individually depending on the indication of the topical product—cosmetic or therapeutic—or even by anatomic site of application. Neither of these considerations was assessed specifically in our survey.
Conclusion
Our hope is that this study helps practitioners better anticipate topical preferences among patients with the ultimate goal of increasing medication adherence and patient outcomes. Nevertheless, although these general trends can provide helpful guidance, we acknowledge that individual preferences vary, and care should always be patient centered.
Acknowledgment
We thank An-Lin Cheng, PhD (Kansas City, Missouri), for assistance with the statistical analysis.
- Kircik LH. Vehicles always matter. J Drugs Dermatol. 2019;18:s99.
- Furue M, Onozuka D, Takeuchi S, et al. Poor adherence to oral andtopical medication in 3096 dermatological patients as assessed by the Morisky Medication Adherence Scale-8. Br J Dermatol. 2015;172:272-275.
- Tan X, Feldman SR, Chang, J, et al. Topical drug delivery systems in dermatology: a review of patient adherence issues. Expert Opin Drug Deliv. 2012;9:1263-1271.
- Ahn CS, Culp L, Huang WW, et al. Adherence in dermatology. J Dermatolog Treat. 2017;28:94-103.
- Eastman WJ, Malahias S, Delconte J, et al. Assessing attributes of topical vehicles for the treatment of acne, atopic dermatitis, and plaque psoriasis. Cutis. 2014;94:46-53.
- Felix K, Unrue E, Inyang M, et al. Patients preferences for different corticosteroid vehicles are highly variable. J Dermatolog Treat. 2019;31:147-151.
- Hong C-H, Papp KA, Lophaven KW, et al. Patients with psoriasis have different preferences for topical therapy, highlighting the importance of individualized treatment approaches: randomized phase IIIb PSO-INSIGHTFUL study. J Eur Acad Dermatol Venereol. 2017;31:1876-1883.
Topical medication is a mainstay in the treatment of dermatologic conditions. Adherence to medication regimens can be challenging in patients requiring long-term topical treatment, and nonadherence is multifactorial. A major modifiable contributing factor is patient dissatisfaction with the vehicle used. Medications often have options for different topical preparations. Therefore, it is important to consider patient preference when prescribing topical treatments to maximize adherence, ensure patient satisfaction, and optimize outcomes.
We hypothesized that notable differences exist among demographic groups regarding preference for topical vehicles. Little research has been conducted to delineate trends. This study aimed to identify variations in preference for creams, lotions, and ointments by age, gender, and ethnicity.
Methods
Data were collected through surveys distributed to all patients seen at the Truman Medical Center University Health Dermatology Clinic in Kansas City, Missouri, between September 2018 and June 2019. The study was approved by the University of Missouri Kansas City institutional review board. An estimated response rate of 95% was achieved. Each patient was informed that the survey was voluntary and anonymous, and declining to complete the survey had no effect on the care provided. Each patient completed only 1 survey and returned it to a collection box before departing from clinic.
In the survey, patients provided demographic information, including age, gender, and ethnicity. Age groups included patients younger than 40 years, 40 to 60 years, and older than 60 years. Gender groups included male and female. Ethnicity included white, black, Hispanic/Latino, and Asian/Pacific Islander or other. Patients then chose 1 of 3 options for topical vehicle preference: cream, lotion, or ointment. Each of these options was accompanied by a brief description of the vehicle, a photograph, and examples of common commercial products to aid in decision-making. The expected values were calculated based on a probability distribution under the assumption that variables have no association. Therefore, the discrepancy between the expected value and the observed value was used to describe the significance of the association between variables.
Data were analyzed using χ2 tests with the aid of a statistician. P<.05 was considered statistically significant.
Results
A total of 404 surveys were collected and recorded. Data showed statistically significant trends in each demographic parameter.
Age
First, we analyzed differences in preference based on age (Table 1). Of 404 patients, 163 were younger than 40 years, 171 were aged 40 to 60 years, and 70 were older than 60 years. Patients younger than 40 years preferred lotion (68 vs 46.0 expected). Patients aged 40 to 60 years showed preference for cream (83 vs 76.6 expected) and ointment (56 vs 46.1 expected). Patients older than 60 years preferred cream (41 vs 31.4 expected). These findings were statistically significant (P<.0001).
Gender
Next, we evaluated variations based on gender (Table 2). Of 404 patients, 254 were female and 150 were male. Females preferred cream (127 vs 113.8 expected). Males exhibited preference for lotion (50 vs 42.3 expected) and ointment (46 vs 40.5 expected). Differences between genders were statistically significant (P=.023).
Ethnicity
We then analyzed preferences based on ethnicity (Table 3). Of 404 patients, 30 were Hispanic/Latino, 26 were Asian/Pacific Islander or other, 227 were white, and 121 were black. Hispanic/Latino patients showed equivocal findings, aligning with expected counts. Asian/Pacific Islander or other patients exhibited slight preferences for cream (14 vs 11.6 expected) and lotion (10 vs 7.3 expected). White patients preferred cream (119 vs 101.7 expected) and lotion (82 vs 64.1 expected). Black patients showed strong preference for ointment (72 vs 32.6 expected). Differences in preferences based on ethnicity were statistically significant (P<.0001).
Comment
Topical medication is a mainstay of dermatologic therapy. Many topical preparations (or vehicles) exist, including ointments, creams, lotions, gels, solutions, and foams. Vehicle type not only influences bioavailability of the prepared medication but also has a notable impact on adherence and subsequent efficacy of the topical therapy.
Medication adherence is especially challenging in dermatology, as topical medications play a central role in treatment. Compliance with the medication regimen is paramount in treatment efficacy.1 In dermatology, adherence with oral medications is higher than it is for topical medications2; various factors contribute to this difference. Compliance may decline with topical treatment due to time-consuming application, misunderstanding about the disease or the treatment regimen, frequency of administration, dissatisfaction with efficacy or appearance, and other variables.3
Other factors have been found to be important to topical medication adherence; younger age, female gender, marriage, employment, nonsmoking, nondrinking, and higher cognitive ability were associated with higher topical medication adherence.4 Our study focused on one factor: identification of demographic-specific preferences that might have implications on adherence within the studied demographic groups.
It is known that individual preferences exist when patients are choosing a topical preparation. However, a PubMed search of articles indexed for MEDLINE using the terms topical, vehicle, preparation, adherence, and preference revealed few studies that examined the preference for topical vehicle by age, gender, or ethnicity.
Existing studies have examined preferences for topical preparations based on specific disease states; this literature, albeit limited, demonstrates that preferences for topical product formulations vary among acne, atopic dermatitis, and plaque psoriasis patients.5 Other studies focus on specific patient populations or medications. For example, one study found that preference for corticosteroid vehicles among psoriasis patients was highly variable and choice of vehicle was critical to adherence.6 Another study highlighted differences in vehicle choice between younger and older age groups with psoriasis.7
Given the limited data overall, it was our goal to determine if any patterns of preference existed by age, gender, or ethnicity, regardless of disease state or indication for topical product. Importantly, over-the-counter products—cosmetic or otherwise—were not differentiated from prescribed topical medications. Our survey elucidated significant differences in preference by age, gender, and ethnicity.
Notable Findings
Regarding age, patients younger than 40 years preferred lotion, patients aged 40 to 60 years preferred cream, and patients older than 60 years preferred cream. Analysis based on gender showed that females preferred cream, and males preferred lotion and ointment. Analysis based on ethnicity most notably demonstrated a strong preference for ointment in black patients while showing preference for cream in white patients.
Potential Biases and Pitfalls
Limitations of this study included the small Hispanic/Latino and Asian/Pacific Islander populations surveyed, possible misunderstanding of the survey by respondents, and the potential for surveys being filled out twice by the same patient. Future surveys could be conducted over a longer period to increase the total sample size and to better characterize less-represented populations, such as Hispanic and Asian patients. To avoid repeat participation, the first question of the survey asked patients to indicate if they had previously completed the survey and instructed patients who had to return the repeat survey to the front desk.
To limit other errors, our survey included concise accessible descriptions of each preparation along with clear representative photographs and examples of common brands. Still, it is possible that some mistakes could have been made while patients filled out the survey based on comprehension deficits, oversight, or other reasons. It also is possible that preference might vary individually depending on the indication of the topical product—cosmetic or therapeutic—or even by anatomic site of application. Neither of these considerations was assessed specifically in our survey.
Conclusion
Our hope is that this study helps practitioners better anticipate topical preferences among patients with the ultimate goal of increasing medication adherence and patient outcomes. Nevertheless, although these general trends can provide helpful guidance, we acknowledge that individual preferences vary, and care should always be patient centered.
Acknowledgment
We thank An-Lin Cheng, PhD (Kansas City, Missouri), for assistance with the statistical analysis.
Topical medication is a mainstay in the treatment of dermatologic conditions. Adherence to medication regimens can be challenging in patients requiring long-term topical treatment, and nonadherence is multifactorial. A major modifiable contributing factor is patient dissatisfaction with the vehicle used. Medications often have options for different topical preparations. Therefore, it is important to consider patient preference when prescribing topical treatments to maximize adherence, ensure patient satisfaction, and optimize outcomes.
We hypothesized that notable differences exist among demographic groups regarding preference for topical vehicles. Little research has been conducted to delineate trends. This study aimed to identify variations in preference for creams, lotions, and ointments by age, gender, and ethnicity.
Methods
Data were collected through surveys distributed to all patients seen at the Truman Medical Center University Health Dermatology Clinic in Kansas City, Missouri, between September 2018 and June 2019. The study was approved by the University of Missouri Kansas City institutional review board. An estimated response rate of 95% was achieved. Each patient was informed that the survey was voluntary and anonymous, and declining to complete the survey had no effect on the care provided. Each patient completed only 1 survey and returned it to a collection box before departing from clinic.
In the survey, patients provided demographic information, including age, gender, and ethnicity. Age groups included patients younger than 40 years, 40 to 60 years, and older than 60 years. Gender groups included male and female. Ethnicity included white, black, Hispanic/Latino, and Asian/Pacific Islander or other. Patients then chose 1 of 3 options for topical vehicle preference: cream, lotion, or ointment. Each of these options was accompanied by a brief description of the vehicle, a photograph, and examples of common commercial products to aid in decision-making. The expected values were calculated based on a probability distribution under the assumption that variables have no association. Therefore, the discrepancy between the expected value and the observed value was used to describe the significance of the association between variables.
Data were analyzed using χ2 tests with the aid of a statistician. P<.05 was considered statistically significant.
Results
A total of 404 surveys were collected and recorded. Data showed statistically significant trends in each demographic parameter.
Age
First, we analyzed differences in preference based on age (Table 1). Of 404 patients, 163 were younger than 40 years, 171 were aged 40 to 60 years, and 70 were older than 60 years. Patients younger than 40 years preferred lotion (68 vs 46.0 expected). Patients aged 40 to 60 years showed preference for cream (83 vs 76.6 expected) and ointment (56 vs 46.1 expected). Patients older than 60 years preferred cream (41 vs 31.4 expected). These findings were statistically significant (P<.0001).
Gender
Next, we evaluated variations based on gender (Table 2). Of 404 patients, 254 were female and 150 were male. Females preferred cream (127 vs 113.8 expected). Males exhibited preference for lotion (50 vs 42.3 expected) and ointment (46 vs 40.5 expected). Differences between genders were statistically significant (P=.023).
Ethnicity
We then analyzed preferences based on ethnicity (Table 3). Of 404 patients, 30 were Hispanic/Latino, 26 were Asian/Pacific Islander or other, 227 were white, and 121 were black. Hispanic/Latino patients showed equivocal findings, aligning with expected counts. Asian/Pacific Islander or other patients exhibited slight preferences for cream (14 vs 11.6 expected) and lotion (10 vs 7.3 expected). White patients preferred cream (119 vs 101.7 expected) and lotion (82 vs 64.1 expected). Black patients showed strong preference for ointment (72 vs 32.6 expected). Differences in preferences based on ethnicity were statistically significant (P<.0001).
Comment
Topical medication is a mainstay of dermatologic therapy. Many topical preparations (or vehicles) exist, including ointments, creams, lotions, gels, solutions, and foams. Vehicle type not only influences bioavailability of the prepared medication but also has a notable impact on adherence and subsequent efficacy of the topical therapy.
Medication adherence is especially challenging in dermatology, as topical medications play a central role in treatment. Compliance with the medication regimen is paramount in treatment efficacy.1 In dermatology, adherence with oral medications is higher than it is for topical medications2; various factors contribute to this difference. Compliance may decline with topical treatment due to time-consuming application, misunderstanding about the disease or the treatment regimen, frequency of administration, dissatisfaction with efficacy or appearance, and other variables.3
Other factors have been found to be important to topical medication adherence; younger age, female gender, marriage, employment, nonsmoking, nondrinking, and higher cognitive ability were associated with higher topical medication adherence.4 Our study focused on one factor: identification of demographic-specific preferences that might have implications on adherence within the studied demographic groups.
It is known that individual preferences exist when patients are choosing a topical preparation. However, a PubMed search of articles indexed for MEDLINE using the terms topical, vehicle, preparation, adherence, and preference revealed few studies that examined the preference for topical vehicle by age, gender, or ethnicity.
Existing studies have examined preferences for topical preparations based on specific disease states; this literature, albeit limited, demonstrates that preferences for topical product formulations vary among acne, atopic dermatitis, and plaque psoriasis patients.5 Other studies focus on specific patient populations or medications. For example, one study found that preference for corticosteroid vehicles among psoriasis patients was highly variable and choice of vehicle was critical to adherence.6 Another study highlighted differences in vehicle choice between younger and older age groups with psoriasis.7
Given the limited data overall, it was our goal to determine if any patterns of preference existed by age, gender, or ethnicity, regardless of disease state or indication for topical product. Importantly, over-the-counter products—cosmetic or otherwise—were not differentiated from prescribed topical medications. Our survey elucidated significant differences in preference by age, gender, and ethnicity.
Notable Findings
Regarding age, patients younger than 40 years preferred lotion, patients aged 40 to 60 years preferred cream, and patients older than 60 years preferred cream. Analysis based on gender showed that females preferred cream, and males preferred lotion and ointment. Analysis based on ethnicity most notably demonstrated a strong preference for ointment in black patients while showing preference for cream in white patients.
Potential Biases and Pitfalls
Limitations of this study included the small Hispanic/Latino and Asian/Pacific Islander populations surveyed, possible misunderstanding of the survey by respondents, and the potential for surveys being filled out twice by the same patient. Future surveys could be conducted over a longer period to increase the total sample size and to better characterize less-represented populations, such as Hispanic and Asian patients. To avoid repeat participation, the first question of the survey asked patients to indicate if they had previously completed the survey and instructed patients who had to return the repeat survey to the front desk.
To limit other errors, our survey included concise accessible descriptions of each preparation along with clear representative photographs and examples of common brands. Still, it is possible that some mistakes could have been made while patients filled out the survey based on comprehension deficits, oversight, or other reasons. It also is possible that preference might vary individually depending on the indication of the topical product—cosmetic or therapeutic—or even by anatomic site of application. Neither of these considerations was assessed specifically in our survey.
Conclusion
Our hope is that this study helps practitioners better anticipate topical preferences among patients with the ultimate goal of increasing medication adherence and patient outcomes. Nevertheless, although these general trends can provide helpful guidance, we acknowledge that individual preferences vary, and care should always be patient centered.
Acknowledgment
We thank An-Lin Cheng, PhD (Kansas City, Missouri), for assistance with the statistical analysis.
- Kircik LH. Vehicles always matter. J Drugs Dermatol. 2019;18:s99.
- Furue M, Onozuka D, Takeuchi S, et al. Poor adherence to oral andtopical medication in 3096 dermatological patients as assessed by the Morisky Medication Adherence Scale-8. Br J Dermatol. 2015;172:272-275.
- Tan X, Feldman SR, Chang, J, et al. Topical drug delivery systems in dermatology: a review of patient adherence issues. Expert Opin Drug Deliv. 2012;9:1263-1271.
- Ahn CS, Culp L, Huang WW, et al. Adherence in dermatology. J Dermatolog Treat. 2017;28:94-103.
- Eastman WJ, Malahias S, Delconte J, et al. Assessing attributes of topical vehicles for the treatment of acne, atopic dermatitis, and plaque psoriasis. Cutis. 2014;94:46-53.
- Felix K, Unrue E, Inyang M, et al. Patients preferences for different corticosteroid vehicles are highly variable. J Dermatolog Treat. 2019;31:147-151.
- Hong C-H, Papp KA, Lophaven KW, et al. Patients with psoriasis have different preferences for topical therapy, highlighting the importance of individualized treatment approaches: randomized phase IIIb PSO-INSIGHTFUL study. J Eur Acad Dermatol Venereol. 2017;31:1876-1883.
- Kircik LH. Vehicles always matter. J Drugs Dermatol. 2019;18:s99.
- Furue M, Onozuka D, Takeuchi S, et al. Poor adherence to oral andtopical medication in 3096 dermatological patients as assessed by the Morisky Medication Adherence Scale-8. Br J Dermatol. 2015;172:272-275.
- Tan X, Feldman SR, Chang, J, et al. Topical drug delivery systems in dermatology: a review of patient adherence issues. Expert Opin Drug Deliv. 2012;9:1263-1271.
- Ahn CS, Culp L, Huang WW, et al. Adherence in dermatology. J Dermatolog Treat. 2017;28:94-103.
- Eastman WJ, Malahias S, Delconte J, et al. Assessing attributes of topical vehicles for the treatment of acne, atopic dermatitis, and plaque psoriasis. Cutis. 2014;94:46-53.
- Felix K, Unrue E, Inyang M, et al. Patients preferences for different corticosteroid vehicles are highly variable. J Dermatolog Treat. 2019;31:147-151.
- Hong C-H, Papp KA, Lophaven KW, et al. Patients with psoriasis have different preferences for topical therapy, highlighting the importance of individualized treatment approaches: randomized phase IIIb PSO-INSIGHTFUL study. J Eur Acad Dermatol Venereol. 2017;31:1876-1883.
Practice Points
- Variations exist in preference for topical vehicles by age group, gender, and ethnicity.
- Identifying and utilizing preferred treatment options can help maximize patient outcomes.
Tolerability of Tretinoin Lotion 0.05% for Moderate to Severe Acne Vulgaris: A Post Hoc Analysis in a Black Population
Acne vulgaris (acne) is the most common dermatologic condition in black patients.1,2 However, among outpatient visits, racial disparities exist in both the likelihood of seeing a dermatologist and being treated.3 Black patients are less likely to visit a dermatologist or receive any acne medication. Acne in black skin is frequently associated with postinflammatory hyperpigmentation (PIH), an important consideration in treatment choice and maintenance.
There is a paucity of clinical studies that specifically evaluate acne treatment in this patient population. An 8-week, vehicle-controlled study with tretinoin cream 0.025% in 27 black patients with acne reported notable decreases in papules, pustules, and hyperpigmented macules in 83% of patients treated with tretinoin compared to only 13% receiving vehicle.4 However, irritation and inflammation were problematic. An open-label study of adapalene gel 0.1% in 65 black South Africans also demonstrated significant improvement in inflammatory and noninflammatory lesions and PIH (P<.01), with seemingly better tolerability.5,6 A meta-analysis of 5 randomized studies from the United States and Europe (N=655) compared the efficacy and safety of adapalene gel 0.1% in black (n=46) and white patients.7 There was no significant difference in percentage reduction in comedonal (44%) or total (42%) lesion counts. The percentage reduction in inflammatory lesion counts (53%) was significantly greater in black patients (P=.012). Tolerability also was better; black patients experienced significantly less erythema and scaling (P<.001 and P=.026, respectively), though erythema can be underestimated in darker skin tones because of the masking effects of melanin.5,7 Dryness was more common, though a smaller percentage of black patients reported moderate or severe dryness compared to white patients (7% vs 18%).7
Black patients also are less likely to receive combination therapy, and again clinical data are limited.3 A more recent subgroup analysis evaluated the safety and efficacy of adapalene 0.1%–benzoyl peroxide 2.5% gel in black patients with moderate acne from 3 studies (n=238 out of a total of 3855 patients).8 Similar results were obtained as in the overall study populations, with 64.3% and 48.5% reductions in inflammatory and noninflammatory lesion counts, respectively, at week 12. The most common treatment-related adverse event (AE) in both treatment groups was dry skin (11.3%).8
Extensive clinical data in a predominantly white population have shown that topical retinoids (eg, tretinoin, adapalene, tazarotene) are highly effective in treating acne, and they are recommended as the cornerstone of topical therapy.9 However, there is a common perception that they are primarily effective in comedonal acne10 and that their use is associated with notable cutaneous irritation.11,12 Several attempts have been made to alleviate the tolerability issue using novel delivery systems. A new lotion formulation of tretinoin recently was developed and leveraged polymeric emulsion technology with the aim to improve both efficacy and tolerability of tretinoin. Herein, we performed a post hoc analysis of 2 large phase 3 clinical studies13 in patients with moderate or severe acne treated with tretinoin lotion 0.05% to evaluate its safety and tolerability in a black population.
METHODS
Study Design
We conducted a post hoc analysis of 2 identical multicenter, randomized, double-blind, vehicle-controlled, parallel-group clinical studies13 in black patients with moderate or severe acne. Protocols received approval from the appropriate institutional review board for each center before patient enrollment, and the studies were conducted in accordance with the Declaration of Helsinki and Good Clinical Practice as well as in compliance with local regulatory requirements. All patients were informed of the study details and provided written consent before entering the studies.
Patients were enrolled with an evaluator global severity score (EGSS) of 3 (moderate) or 4 (severe). Participants were randomized (1:1) to receive tretinoin lotion 0.05% or vehicle applied to the face once daily for 12 weeks.
Study Population
Eligible patients for the post hoc analysis included male and female patients with black skin who were 9 years and older and presented with 20 to 40 inflammatory lesions (papules, pustules, and nodules), 20 to 100 noninflammatory lesions (open and closed comedones), and 2 or fewer nodules. A washout period of up to 1 month was required for patients who previously used prescription and over-the-counter acne treatments, and a washout period of 6 months was required for systemic retinoids.
Safety Evaluation
Cutaneous safety (erythema and scaling) and tolerability (itching, burning, and stinging) were evaluated on a 4-point scale (0=none; 3=severe). Severity of hypopigmentation and hyperpigmentation also was assessed using this 4-point scale. The investigator assessed erythema and scaling at the time of each study visit. Reports of itching, burning, and stinging were solicited from participants and recorded as an average score of their symptoms during the period since the prior visit.
Adverse events were evaluated throughout and summarized by treatment group, severity, and relationship to study medication.
Statistical Analysis
The safety analysis set comprised all randomized patients who were presumed to have used the study drug at least once and who provided at least 1 postbaseline evaluation. All AEs occurring during the studies were recorded and coded using the Medical Dictionary for Regulatory Activities version 18.0. Treatment group comparisons were made by tabulating the frequency of participants reporting 1 or more AEs during the study.
Cutaneous safety (scaling, erythema, hypopigmentation, and hyperpigmentation) and tolerability (itching, burning, and stinging) scores were presented by treatment group with descriptive statistics at baseline and weeks 4, 8, and 12. Frequencies and percentages for each outcome category were included in the statistics.
RESULTS
Baseline Characteristics
A total of 308 patients were included in the post hoc analysis. Overall, 257 (83.4%) patients completed the studies, including 138 (83.6%) patients receiving tretinoin lotion 0.05% and 119 (83.2%) receiving vehicle (Figure 1). Completion rates were similar in the female and male subgroups (83.3% and 83.8%, respectively). The most common reasons for study discontinuations were lost to follow-up (n=32; 10.4%) or participant request (n=13; 4.2%) and were similar irrespective of treatment or sex. There were no study discontinuations due to AEs.
Demographic data (Table) were similar across the 2 treatment arms. The mean age (standard deviation [SD]) of the participants was 22.1 (8.35) years (range, 9–58 years). Participants were predominantly female (209/308 [67.9%]) and tended to be a little older than the males (mean age, 23.6 vs 18.8 years).
There were no noticeable differences between treatment groups regarding baseline lesion counts or EGSS. At baseline, the mean number (SD) of inflammatory and noninflammatory lesions was 25.2 (4.87) and 41.1 (16.55), respectively. At baseline, 286 (92.9%) participants had moderate acne (EGSS=3). A higher proportion of male participants (10.1%) had severe acne (EGSS=4) at baseline compared to female participants (5.7%).
At baseline, the mean score (SD) for scaling, erythema, itching, burning, and stinging in those participants that were subsequently treated with tretinoin lotion 0.05% was 0.2 (0.42), 0.4 (0.68), 0.3 (0.60), 0.1 (0.28), and 0.1 (0.32), respectively (where 1=mild)(Figure 2). There were no differences in mean baseline scores between active and vehicle treatment groups for hyperpigmentation (0.8 each) and hypopigmentation (0.1 each) in the active and vehicle treatment groups. Mean baseline scores were slightly higher in the female participants (0.9) compared to male participants (0.6). Baseline moderate or severe hyperpigmentation was reported in 23.2% and 3.2% of participants, respectively, who were subsequently treated with tretinoin lotion 0.05%, which also was more commonly reported in female participants (33/105 [31.5%]) than male participants (8/50 [16.0%]).
Safety
Treatment-Related AEs
More participants treated with tretinoin lotion 0.05% reported treatment-emergent AEs (TEAEs) compared to vehicle (35 vs 18). The majority of participants reporting TEAEs were female (24 of 35). There were 2 (1.3%) serious AEs with tretinoin lotion 0.05% (both female), and 1 female participant (0.6%) discontinued the study drug because of a TEAE (eTable).
Overall, there were 12 (7.7%) treatment-related AEs; all were mild (n=10) or moderate (n=2). Treatment-related AEs reported by more than 1% of participants treated with tretinoin lotion 0.05% included application-site pain (n=4; 2.6%), dryness (n=4; 2.6%), irritation (n=2; 1.3%), exfoliation (n=2; 1.3%), or erythema (n=2; 1.3%). The majority of treatment-related AEs (10/12) were reported in the female subgroup. Although application-site pain (3.4%) and dryness (3.8%) were more commonly reported in the white population (unpublished data, Ortho Dermatologics) in the 2 studies, differences between the 2 racial groups were not significant.
Cutaneous Safety and Tolerability
Erythema and scaling were recorded by the investigator. Mild to moderate erythema was noted in 31% of participants at baseline, with 21% reporting mild to moderate scaling. Both improved over the study period following treatment with tretinoin lotion 0.05%, with 79% of participants having no erythema and 88% having no scaling by week 12. Mean scores for erythema and scaling remained less than 0.5 throughout the study (1=mild). There were slight transient increases in the mean baseline score for scaling (from 0.2 to 0.3) at week 4 in the active treatment group. By week 12, mean scores were half those reported at baseline (Figure 2).
Severity of itching, burning, and stinging was reported by participants. Overall, 23% reported mild to moderate itching at baseline. Only 7 participants (5%) reported any itching by week 12 in the tretinoin lotion 0.05% group. Reports of burning and stinging were both rare and mild at baseline. Mean scores for itching, burning, and stinging at baseline for those participants who were subsequently treated with tretinoin lotion 0.05% were 0.3, 0.1, and 0.1, respectively (1=mild). Itching severity reduced progressively with treatment. There were slight transient increases in mean scores for burning (from 0.1 to 0.2) and stinging (from 0.1 to 0.2) at week 4, returning to baseline levels or below by week 12.
Hyperpigmentation and Hypopigmentation
There was a progressive improvement in baseline hyperpigmentation severity in participants treated with tretinoin lotion 0.05%; mean scores reduced from 0.8 at baseline to 0.6 by week 12 (Figure 3), with a similar improvement in both sexes (Figure 4). Moderate to severe hyperpigmentation was reported in 24 (17.3%) participants by week 12 compared to 41 (26.4%) at baseline; the majority (n=21) were female at week 12. Moderate to severe hyperpigmentation was reported in 24 (19.7%) participants treated with vehicle at week 12.
Hypopigmentation at baseline was rare and mild, and again most common in female patients. There was no increase in hypopigmentation over the course of the study.
COMMENT
Topical retinoids (eg, tretinoin, adapalene, tazarotene) are recommended as the cornerstone of topical acne treatment, with safety and efficacy well documented in large pivotal trials.14 However, data in black patients are lacking. Acne is the most common dermatologic condition in these patients, and yet investigation into this important population is limited to small study populations or subgroup analyses.
Tretinoin lotion 0.05% is a novel topical treatment for moderate to severe acne that leverages polymeric emulsion technology. The development rationale was to provide a tretinoin formulation with improved efficacy and tolerability, features that could be especially suited to black patients with acne.
In our post hoc analysis of black patients with acne, tretinoin lotion 0.05% generally was considered safe and well tolerated. The most commonly reported treatment-related AEs were of low incidence and included application-site reactions and skin-related events attributed to the known properties of tretinoin. Most noteworthy was the extremely low irritation potential of this novel tretinoin formulation. Treatment-related AEs generally were mild, and interestingly, the majority occurred in female patients. The incidence of the most common treatment-related AEs—application-site dryness (2.6%) and application-site pain (2.6%)—was lower than that reported in the white populations in the 2 studies (3.8% and 3.4%, respectively).(unpublished data, Ortho Dermatologics), though the differences were not significant (P=.625 and P=.799).
Approximately one-quarter of participants had mild to moderate erythema, scaling, itching, and stinging at baseline. All of these cutaneous symptoms improved with treatment. There were slight transient increases in scaling and stinging at week 4, with stinging more noticeable in the female population. There were no noticeable changes in mild to moderate burning during the study.
Postinflammatory hyperpigmentation is an important consideration in black patients with acne. It can arise from either acne-induced inflammation or injury. It can be of greater concern to the patient than the acne itself and often is the main reason black patients seek a dermatologist consultation. In a survey of adult female acne, nonwhite women experienced substantially more PIH than white women. In addition, clearance of PIH was most important for these nonwhite women (42% vs 8% for white women), whereas lesion clearance was the most important aspect for white women (58% vs 32% for nonwhite women).15 Erring on the side of increased tolerability is appropriate in black patients with acne, given that any irritant reactions can lead to pigmentary alterations—hyperpigmentation or hypopigmentation—that can cause considerable patient anxiety. The psychologic impact of PIH can be devastating, and an ideal acne treatment in these patients would be one that is effective against both PIH and acne. Tretinoin cream 0.1% monotherapy has been shown to be effective in reducing PIH.16 Postinflammatory hyperpigmentation lesions and normal skin were assessed by clinical and colorimetric evaluations and by analysis of biopsy specimens. Although facial PIH lesions in the 24 tretinoin-treated patients were significantly lighter after 40 weeks of treatment compared to vehicle in this study (P<.001), overall improvement was first noted after 4 weeks (P=.009). Normal skin also was minimally lightened by tretinoin; however, exuberant local skin reactions, including peeling, developed in 50% of patients. Mild to moderate PIH was present in the majority of tretinoin-treated patients at baseline in our post hoc analysis, severe in 3.2% of cases, and both more common and severe in females. Mean scores reduced over the 12-week study period, from 0.6 to 0.4 in male patients and 0.9 to 0.7 in female patients. Hypopigmentation was rare and mild at baseline and did not increase over the course of the study. A pilot study with a cream formulation of tazarotene in patients with acne from darker racial groups showed the retinoid to be effective in treating PIH following 18 weeks of once-daily application.17 Further longer-term studies on treating PIH with tretinoin lotion 0.05% are warranted given its tolerability profile.
CONCLUSION
This novel tretinoin lotion 0.05% formulation is a safe and well-tolerated topical treatment for moderate to severe comedonal and inflammatory acne in black patients. Tretinoin lotion 0.05% does not appear to induce PIH and may afford an effective, well-tolerated, dual-treatment option.
Acknowledgments
We thank Brian Bulley, MSc (Konic Limited, United Kingdom), for medical writing support. Ortho Dermatologics funded Konic’s activities pertaining to this manuscript.
- Halder RM, Grimes PE, McLaurin CI, et al. Incidence of common dermatoses in a predominantly black dermatologic practice. Cutis. 1983;32:388,390.
- Taylor SC, Cook-Bolden F, Rahman Z, et al. Acne vulgaris in skin of color. J Am Acad Dermatol. 2002;46(suppl 2):S98-S106.
- Rogers AT, Semenov YR, Kwatra SG, et al. Racial disparities in the management of acne: evidence from the National Ambulatory Medial Care Survey, 2005-2014. J Dermatolog Treat. 2018;29:287-289.
- Halder RM. The role of retinoids in the management of cutaneous conditions in blacks. J Am Acad Dermatol. 1998;39(suppl 2):S98-S103.
- Jacyk WK. Adapalene in the treatment of African patients. J Eur Acad Dermatol Venereol. 2001;15(suppl 3):37-42.
- Jacyk WK, Mpofu P. Adapalene gel 0.1% for topical treatment of acne vulgaris in African patients. Cutis. 2001;68(suppl 4):48-54.
- Czernielewski J, Poncet M, Mizzi F. Efficacy and cutaneous safety of adapalene in black patients versus white patients with acne vulgaris. Cutis. 2002;70:243-248.
- Alexis AF, Johnson LA, Kerrouche N, et al. A subgroup analysis to evaluate the efficacy and safety of adapalene-benzoyl peroxide topical gel in black subjects with moderate acne. J Drugs Dermatol. 2014;13:170-174.
- Leyden JJ, Shalita A, Thiboutot D, et al. Topical retinoids in inflammatory acne: a retrospective, investigator-blinded, vehicle-controlled, photographic assessment. Clin Ther. 2005;27:216-224.
- Zaenglein AL, Pathy AL, Schlosser BJ, et al. Guidelines of care for the management of acne vulgaris. J Am Acad Dermatol. 2016;74:945-973.
- Culp L, Moradi Tuchayi S, Alinia H, et al. Tolerability of topical retinoids: are there clinically meaningful differences among topical retinoids?J Cutan Med Surg. 2015;19:530-538.
- Kircik LH. Evaluating tretinoin formulations in the treatment of acne. J Drugs Dermatol. 2014;13:466-470.
- Tyring SK, Kircik LH, Pariser DM, et al. Novel tretinoin 0.05% lotion for the once-daily treatment of moderate-to-severe acne vulgaris: assessment of efficacy and safety in patients aged 9 years and older. J Drugs Dermatol. 2018;17:1084-1091.
- Leyden J, Stein-Gold l, Weiss J. Why topical retionoids are the mainstay of therapy for acne. Dermatol Ther (Heidelb) 2017;7:293-304.
- Callender VD, Alexis AF, Daniels SR, et al. Racial differences in clinical characteristics, perceptions and behaviors, and psychosocial impact of adult female acne. J Clin Aesthet Dermatol. 2014;7:19-31.
- Bulengo-Ransby SM, Griffiths CE, Kimbrough-Green CK, et al. Topical tretinoin (retinoic acid) therapy for hyperpigmented lesions caused by inflammation of the skin in black patients. N Engl J Med. 1993;328:1438-1443.
- Grimes P, Callender V. Tazarotene cream for postinflammatory hyperpigmentation and acne vulgaris in darker skin: a double-blind, randomized, vehicle-controlled study. Cutis. 2006;77:45-50.
Acne vulgaris (acne) is the most common dermatologic condition in black patients.1,2 However, among outpatient visits, racial disparities exist in both the likelihood of seeing a dermatologist and being treated.3 Black patients are less likely to visit a dermatologist or receive any acne medication. Acne in black skin is frequently associated with postinflammatory hyperpigmentation (PIH), an important consideration in treatment choice and maintenance.
There is a paucity of clinical studies that specifically evaluate acne treatment in this patient population. An 8-week, vehicle-controlled study with tretinoin cream 0.025% in 27 black patients with acne reported notable decreases in papules, pustules, and hyperpigmented macules in 83% of patients treated with tretinoin compared to only 13% receiving vehicle.4 However, irritation and inflammation were problematic. An open-label study of adapalene gel 0.1% in 65 black South Africans also demonstrated significant improvement in inflammatory and noninflammatory lesions and PIH (P<.01), with seemingly better tolerability.5,6 A meta-analysis of 5 randomized studies from the United States and Europe (N=655) compared the efficacy and safety of adapalene gel 0.1% in black (n=46) and white patients.7 There was no significant difference in percentage reduction in comedonal (44%) or total (42%) lesion counts. The percentage reduction in inflammatory lesion counts (53%) was significantly greater in black patients (P=.012). Tolerability also was better; black patients experienced significantly less erythema and scaling (P<.001 and P=.026, respectively), though erythema can be underestimated in darker skin tones because of the masking effects of melanin.5,7 Dryness was more common, though a smaller percentage of black patients reported moderate or severe dryness compared to white patients (7% vs 18%).7
Black patients also are less likely to receive combination therapy, and again clinical data are limited.3 A more recent subgroup analysis evaluated the safety and efficacy of adapalene 0.1%–benzoyl peroxide 2.5% gel in black patients with moderate acne from 3 studies (n=238 out of a total of 3855 patients).8 Similar results were obtained as in the overall study populations, with 64.3% and 48.5% reductions in inflammatory and noninflammatory lesion counts, respectively, at week 12. The most common treatment-related adverse event (AE) in both treatment groups was dry skin (11.3%).8
Extensive clinical data in a predominantly white population have shown that topical retinoids (eg, tretinoin, adapalene, tazarotene) are highly effective in treating acne, and they are recommended as the cornerstone of topical therapy.9 However, there is a common perception that they are primarily effective in comedonal acne10 and that their use is associated with notable cutaneous irritation.11,12 Several attempts have been made to alleviate the tolerability issue using novel delivery systems. A new lotion formulation of tretinoin recently was developed and leveraged polymeric emulsion technology with the aim to improve both efficacy and tolerability of tretinoin. Herein, we performed a post hoc analysis of 2 large phase 3 clinical studies13 in patients with moderate or severe acne treated with tretinoin lotion 0.05% to evaluate its safety and tolerability in a black population.
METHODS
Study Design
We conducted a post hoc analysis of 2 identical multicenter, randomized, double-blind, vehicle-controlled, parallel-group clinical studies13 in black patients with moderate or severe acne. Protocols received approval from the appropriate institutional review board for each center before patient enrollment, and the studies were conducted in accordance with the Declaration of Helsinki and Good Clinical Practice as well as in compliance with local regulatory requirements. All patients were informed of the study details and provided written consent before entering the studies.
Patients were enrolled with an evaluator global severity score (EGSS) of 3 (moderate) or 4 (severe). Participants were randomized (1:1) to receive tretinoin lotion 0.05% or vehicle applied to the face once daily for 12 weeks.
Study Population
Eligible patients for the post hoc analysis included male and female patients with black skin who were 9 years and older and presented with 20 to 40 inflammatory lesions (papules, pustules, and nodules), 20 to 100 noninflammatory lesions (open and closed comedones), and 2 or fewer nodules. A washout period of up to 1 month was required for patients who previously used prescription and over-the-counter acne treatments, and a washout period of 6 months was required for systemic retinoids.
Safety Evaluation
Cutaneous safety (erythema and scaling) and tolerability (itching, burning, and stinging) were evaluated on a 4-point scale (0=none; 3=severe). Severity of hypopigmentation and hyperpigmentation also was assessed using this 4-point scale. The investigator assessed erythema and scaling at the time of each study visit. Reports of itching, burning, and stinging were solicited from participants and recorded as an average score of their symptoms during the period since the prior visit.
Adverse events were evaluated throughout and summarized by treatment group, severity, and relationship to study medication.
Statistical Analysis
The safety analysis set comprised all randomized patients who were presumed to have used the study drug at least once and who provided at least 1 postbaseline evaluation. All AEs occurring during the studies were recorded and coded using the Medical Dictionary for Regulatory Activities version 18.0. Treatment group comparisons were made by tabulating the frequency of participants reporting 1 or more AEs during the study.
Cutaneous safety (scaling, erythema, hypopigmentation, and hyperpigmentation) and tolerability (itching, burning, and stinging) scores were presented by treatment group with descriptive statistics at baseline and weeks 4, 8, and 12. Frequencies and percentages for each outcome category were included in the statistics.
RESULTS
Baseline Characteristics
A total of 308 patients were included in the post hoc analysis. Overall, 257 (83.4%) patients completed the studies, including 138 (83.6%) patients receiving tretinoin lotion 0.05% and 119 (83.2%) receiving vehicle (Figure 1). Completion rates were similar in the female and male subgroups (83.3% and 83.8%, respectively). The most common reasons for study discontinuations were lost to follow-up (n=32; 10.4%) or participant request (n=13; 4.2%) and were similar irrespective of treatment or sex. There were no study discontinuations due to AEs.
Demographic data (Table) were similar across the 2 treatment arms. The mean age (standard deviation [SD]) of the participants was 22.1 (8.35) years (range, 9–58 years). Participants were predominantly female (209/308 [67.9%]) and tended to be a little older than the males (mean age, 23.6 vs 18.8 years).
There were no noticeable differences between treatment groups regarding baseline lesion counts or EGSS. At baseline, the mean number (SD) of inflammatory and noninflammatory lesions was 25.2 (4.87) and 41.1 (16.55), respectively. At baseline, 286 (92.9%) participants had moderate acne (EGSS=3). A higher proportion of male participants (10.1%) had severe acne (EGSS=4) at baseline compared to female participants (5.7%).
At baseline, the mean score (SD) for scaling, erythema, itching, burning, and stinging in those participants that were subsequently treated with tretinoin lotion 0.05% was 0.2 (0.42), 0.4 (0.68), 0.3 (0.60), 0.1 (0.28), and 0.1 (0.32), respectively (where 1=mild)(Figure 2). There were no differences in mean baseline scores between active and vehicle treatment groups for hyperpigmentation (0.8 each) and hypopigmentation (0.1 each) in the active and vehicle treatment groups. Mean baseline scores were slightly higher in the female participants (0.9) compared to male participants (0.6). Baseline moderate or severe hyperpigmentation was reported in 23.2% and 3.2% of participants, respectively, who were subsequently treated with tretinoin lotion 0.05%, which also was more commonly reported in female participants (33/105 [31.5%]) than male participants (8/50 [16.0%]).
Safety
Treatment-Related AEs
More participants treated with tretinoin lotion 0.05% reported treatment-emergent AEs (TEAEs) compared to vehicle (35 vs 18). The majority of participants reporting TEAEs were female (24 of 35). There were 2 (1.3%) serious AEs with tretinoin lotion 0.05% (both female), and 1 female participant (0.6%) discontinued the study drug because of a TEAE (eTable).
Overall, there were 12 (7.7%) treatment-related AEs; all were mild (n=10) or moderate (n=2). Treatment-related AEs reported by more than 1% of participants treated with tretinoin lotion 0.05% included application-site pain (n=4; 2.6%), dryness (n=4; 2.6%), irritation (n=2; 1.3%), exfoliation (n=2; 1.3%), or erythema (n=2; 1.3%). The majority of treatment-related AEs (10/12) were reported in the female subgroup. Although application-site pain (3.4%) and dryness (3.8%) were more commonly reported in the white population (unpublished data, Ortho Dermatologics) in the 2 studies, differences between the 2 racial groups were not significant.
Cutaneous Safety and Tolerability
Erythema and scaling were recorded by the investigator. Mild to moderate erythema was noted in 31% of participants at baseline, with 21% reporting mild to moderate scaling. Both improved over the study period following treatment with tretinoin lotion 0.05%, with 79% of participants having no erythema and 88% having no scaling by week 12. Mean scores for erythema and scaling remained less than 0.5 throughout the study (1=mild). There were slight transient increases in the mean baseline score for scaling (from 0.2 to 0.3) at week 4 in the active treatment group. By week 12, mean scores were half those reported at baseline (Figure 2).
Severity of itching, burning, and stinging was reported by participants. Overall, 23% reported mild to moderate itching at baseline. Only 7 participants (5%) reported any itching by week 12 in the tretinoin lotion 0.05% group. Reports of burning and stinging were both rare and mild at baseline. Mean scores for itching, burning, and stinging at baseline for those participants who were subsequently treated with tretinoin lotion 0.05% were 0.3, 0.1, and 0.1, respectively (1=mild). Itching severity reduced progressively with treatment. There were slight transient increases in mean scores for burning (from 0.1 to 0.2) and stinging (from 0.1 to 0.2) at week 4, returning to baseline levels or below by week 12.
Hyperpigmentation and Hypopigmentation
There was a progressive improvement in baseline hyperpigmentation severity in participants treated with tretinoin lotion 0.05%; mean scores reduced from 0.8 at baseline to 0.6 by week 12 (Figure 3), with a similar improvement in both sexes (Figure 4). Moderate to severe hyperpigmentation was reported in 24 (17.3%) participants by week 12 compared to 41 (26.4%) at baseline; the majority (n=21) were female at week 12. Moderate to severe hyperpigmentation was reported in 24 (19.7%) participants treated with vehicle at week 12.
Hypopigmentation at baseline was rare and mild, and again most common in female patients. There was no increase in hypopigmentation over the course of the study.
COMMENT
Topical retinoids (eg, tretinoin, adapalene, tazarotene) are recommended as the cornerstone of topical acne treatment, with safety and efficacy well documented in large pivotal trials.14 However, data in black patients are lacking. Acne is the most common dermatologic condition in these patients, and yet investigation into this important population is limited to small study populations or subgroup analyses.
Tretinoin lotion 0.05% is a novel topical treatment for moderate to severe acne that leverages polymeric emulsion technology. The development rationale was to provide a tretinoin formulation with improved efficacy and tolerability, features that could be especially suited to black patients with acne.
In our post hoc analysis of black patients with acne, tretinoin lotion 0.05% generally was considered safe and well tolerated. The most commonly reported treatment-related AEs were of low incidence and included application-site reactions and skin-related events attributed to the known properties of tretinoin. Most noteworthy was the extremely low irritation potential of this novel tretinoin formulation. Treatment-related AEs generally were mild, and interestingly, the majority occurred in female patients. The incidence of the most common treatment-related AEs—application-site dryness (2.6%) and application-site pain (2.6%)—was lower than that reported in the white populations in the 2 studies (3.8% and 3.4%, respectively).(unpublished data, Ortho Dermatologics), though the differences were not significant (P=.625 and P=.799).
Approximately one-quarter of participants had mild to moderate erythema, scaling, itching, and stinging at baseline. All of these cutaneous symptoms improved with treatment. There were slight transient increases in scaling and stinging at week 4, with stinging more noticeable in the female population. There were no noticeable changes in mild to moderate burning during the study.
Postinflammatory hyperpigmentation is an important consideration in black patients with acne. It can arise from either acne-induced inflammation or injury. It can be of greater concern to the patient than the acne itself and often is the main reason black patients seek a dermatologist consultation. In a survey of adult female acne, nonwhite women experienced substantially more PIH than white women. In addition, clearance of PIH was most important for these nonwhite women (42% vs 8% for white women), whereas lesion clearance was the most important aspect for white women (58% vs 32% for nonwhite women).15 Erring on the side of increased tolerability is appropriate in black patients with acne, given that any irritant reactions can lead to pigmentary alterations—hyperpigmentation or hypopigmentation—that can cause considerable patient anxiety. The psychologic impact of PIH can be devastating, and an ideal acne treatment in these patients would be one that is effective against both PIH and acne. Tretinoin cream 0.1% monotherapy has been shown to be effective in reducing PIH.16 Postinflammatory hyperpigmentation lesions and normal skin were assessed by clinical and colorimetric evaluations and by analysis of biopsy specimens. Although facial PIH lesions in the 24 tretinoin-treated patients were significantly lighter after 40 weeks of treatment compared to vehicle in this study (P<.001), overall improvement was first noted after 4 weeks (P=.009). Normal skin also was minimally lightened by tretinoin; however, exuberant local skin reactions, including peeling, developed in 50% of patients. Mild to moderate PIH was present in the majority of tretinoin-treated patients at baseline in our post hoc analysis, severe in 3.2% of cases, and both more common and severe in females. Mean scores reduced over the 12-week study period, from 0.6 to 0.4 in male patients and 0.9 to 0.7 in female patients. Hypopigmentation was rare and mild at baseline and did not increase over the course of the study. A pilot study with a cream formulation of tazarotene in patients with acne from darker racial groups showed the retinoid to be effective in treating PIH following 18 weeks of once-daily application.17 Further longer-term studies on treating PIH with tretinoin lotion 0.05% are warranted given its tolerability profile.
CONCLUSION
This novel tretinoin lotion 0.05% formulation is a safe and well-tolerated topical treatment for moderate to severe comedonal and inflammatory acne in black patients. Tretinoin lotion 0.05% does not appear to induce PIH and may afford an effective, well-tolerated, dual-treatment option.
Acknowledgments
We thank Brian Bulley, MSc (Konic Limited, United Kingdom), for medical writing support. Ortho Dermatologics funded Konic’s activities pertaining to this manuscript.
Acne vulgaris (acne) is the most common dermatologic condition in black patients.1,2 However, among outpatient visits, racial disparities exist in both the likelihood of seeing a dermatologist and being treated.3 Black patients are less likely to visit a dermatologist or receive any acne medication. Acne in black skin is frequently associated with postinflammatory hyperpigmentation (PIH), an important consideration in treatment choice and maintenance.
There is a paucity of clinical studies that specifically evaluate acne treatment in this patient population. An 8-week, vehicle-controlled study with tretinoin cream 0.025% in 27 black patients with acne reported notable decreases in papules, pustules, and hyperpigmented macules in 83% of patients treated with tretinoin compared to only 13% receiving vehicle.4 However, irritation and inflammation were problematic. An open-label study of adapalene gel 0.1% in 65 black South Africans also demonstrated significant improvement in inflammatory and noninflammatory lesions and PIH (P<.01), with seemingly better tolerability.5,6 A meta-analysis of 5 randomized studies from the United States and Europe (N=655) compared the efficacy and safety of adapalene gel 0.1% in black (n=46) and white patients.7 There was no significant difference in percentage reduction in comedonal (44%) or total (42%) lesion counts. The percentage reduction in inflammatory lesion counts (53%) was significantly greater in black patients (P=.012). Tolerability also was better; black patients experienced significantly less erythema and scaling (P<.001 and P=.026, respectively), though erythema can be underestimated in darker skin tones because of the masking effects of melanin.5,7 Dryness was more common, though a smaller percentage of black patients reported moderate or severe dryness compared to white patients (7% vs 18%).7
Black patients also are less likely to receive combination therapy, and again clinical data are limited.3 A more recent subgroup analysis evaluated the safety and efficacy of adapalene 0.1%–benzoyl peroxide 2.5% gel in black patients with moderate acne from 3 studies (n=238 out of a total of 3855 patients).8 Similar results were obtained as in the overall study populations, with 64.3% and 48.5% reductions in inflammatory and noninflammatory lesion counts, respectively, at week 12. The most common treatment-related adverse event (AE) in both treatment groups was dry skin (11.3%).8
Extensive clinical data in a predominantly white population have shown that topical retinoids (eg, tretinoin, adapalene, tazarotene) are highly effective in treating acne, and they are recommended as the cornerstone of topical therapy.9 However, there is a common perception that they are primarily effective in comedonal acne10 and that their use is associated with notable cutaneous irritation.11,12 Several attempts have been made to alleviate the tolerability issue using novel delivery systems. A new lotion formulation of tretinoin recently was developed and leveraged polymeric emulsion technology with the aim to improve both efficacy and tolerability of tretinoin. Herein, we performed a post hoc analysis of 2 large phase 3 clinical studies13 in patients with moderate or severe acne treated with tretinoin lotion 0.05% to evaluate its safety and tolerability in a black population.
METHODS
Study Design
We conducted a post hoc analysis of 2 identical multicenter, randomized, double-blind, vehicle-controlled, parallel-group clinical studies13 in black patients with moderate or severe acne. Protocols received approval from the appropriate institutional review board for each center before patient enrollment, and the studies were conducted in accordance with the Declaration of Helsinki and Good Clinical Practice as well as in compliance with local regulatory requirements. All patients were informed of the study details and provided written consent before entering the studies.
Patients were enrolled with an evaluator global severity score (EGSS) of 3 (moderate) or 4 (severe). Participants were randomized (1:1) to receive tretinoin lotion 0.05% or vehicle applied to the face once daily for 12 weeks.
Study Population
Eligible patients for the post hoc analysis included male and female patients with black skin who were 9 years and older and presented with 20 to 40 inflammatory lesions (papules, pustules, and nodules), 20 to 100 noninflammatory lesions (open and closed comedones), and 2 or fewer nodules. A washout period of up to 1 month was required for patients who previously used prescription and over-the-counter acne treatments, and a washout period of 6 months was required for systemic retinoids.
Safety Evaluation
Cutaneous safety (erythema and scaling) and tolerability (itching, burning, and stinging) were evaluated on a 4-point scale (0=none; 3=severe). Severity of hypopigmentation and hyperpigmentation also was assessed using this 4-point scale. The investigator assessed erythema and scaling at the time of each study visit. Reports of itching, burning, and stinging were solicited from participants and recorded as an average score of their symptoms during the period since the prior visit.
Adverse events were evaluated throughout and summarized by treatment group, severity, and relationship to study medication.
Statistical Analysis
The safety analysis set comprised all randomized patients who were presumed to have used the study drug at least once and who provided at least 1 postbaseline evaluation. All AEs occurring during the studies were recorded and coded using the Medical Dictionary for Regulatory Activities version 18.0. Treatment group comparisons were made by tabulating the frequency of participants reporting 1 or more AEs during the study.
Cutaneous safety (scaling, erythema, hypopigmentation, and hyperpigmentation) and tolerability (itching, burning, and stinging) scores were presented by treatment group with descriptive statistics at baseline and weeks 4, 8, and 12. Frequencies and percentages for each outcome category were included in the statistics.
RESULTS
Baseline Characteristics
A total of 308 patients were included in the post hoc analysis. Overall, 257 (83.4%) patients completed the studies, including 138 (83.6%) patients receiving tretinoin lotion 0.05% and 119 (83.2%) receiving vehicle (Figure 1). Completion rates were similar in the female and male subgroups (83.3% and 83.8%, respectively). The most common reasons for study discontinuations were lost to follow-up (n=32; 10.4%) or participant request (n=13; 4.2%) and were similar irrespective of treatment or sex. There were no study discontinuations due to AEs.
Demographic data (Table) were similar across the 2 treatment arms. The mean age (standard deviation [SD]) of the participants was 22.1 (8.35) years (range, 9–58 years). Participants were predominantly female (209/308 [67.9%]) and tended to be a little older than the males (mean age, 23.6 vs 18.8 years).
There were no noticeable differences between treatment groups regarding baseline lesion counts or EGSS. At baseline, the mean number (SD) of inflammatory and noninflammatory lesions was 25.2 (4.87) and 41.1 (16.55), respectively. At baseline, 286 (92.9%) participants had moderate acne (EGSS=3). A higher proportion of male participants (10.1%) had severe acne (EGSS=4) at baseline compared to female participants (5.7%).
At baseline, the mean score (SD) for scaling, erythema, itching, burning, and stinging in those participants that were subsequently treated with tretinoin lotion 0.05% was 0.2 (0.42), 0.4 (0.68), 0.3 (0.60), 0.1 (0.28), and 0.1 (0.32), respectively (where 1=mild)(Figure 2). There were no differences in mean baseline scores between active and vehicle treatment groups for hyperpigmentation (0.8 each) and hypopigmentation (0.1 each) in the active and vehicle treatment groups. Mean baseline scores were slightly higher in the female participants (0.9) compared to male participants (0.6). Baseline moderate or severe hyperpigmentation was reported in 23.2% and 3.2% of participants, respectively, who were subsequently treated with tretinoin lotion 0.05%, which also was more commonly reported in female participants (33/105 [31.5%]) than male participants (8/50 [16.0%]).
Safety
Treatment-Related AEs
More participants treated with tretinoin lotion 0.05% reported treatment-emergent AEs (TEAEs) compared to vehicle (35 vs 18). The majority of participants reporting TEAEs were female (24 of 35). There were 2 (1.3%) serious AEs with tretinoin lotion 0.05% (both female), and 1 female participant (0.6%) discontinued the study drug because of a TEAE (eTable).
Overall, there were 12 (7.7%) treatment-related AEs; all were mild (n=10) or moderate (n=2). Treatment-related AEs reported by more than 1% of participants treated with tretinoin lotion 0.05% included application-site pain (n=4; 2.6%), dryness (n=4; 2.6%), irritation (n=2; 1.3%), exfoliation (n=2; 1.3%), or erythema (n=2; 1.3%). The majority of treatment-related AEs (10/12) were reported in the female subgroup. Although application-site pain (3.4%) and dryness (3.8%) were more commonly reported in the white population (unpublished data, Ortho Dermatologics) in the 2 studies, differences between the 2 racial groups were not significant.
Cutaneous Safety and Tolerability
Erythema and scaling were recorded by the investigator. Mild to moderate erythema was noted in 31% of participants at baseline, with 21% reporting mild to moderate scaling. Both improved over the study period following treatment with tretinoin lotion 0.05%, with 79% of participants having no erythema and 88% having no scaling by week 12. Mean scores for erythema and scaling remained less than 0.5 throughout the study (1=mild). There were slight transient increases in the mean baseline score for scaling (from 0.2 to 0.3) at week 4 in the active treatment group. By week 12, mean scores were half those reported at baseline (Figure 2).
Severity of itching, burning, and stinging was reported by participants. Overall, 23% reported mild to moderate itching at baseline. Only 7 participants (5%) reported any itching by week 12 in the tretinoin lotion 0.05% group. Reports of burning and stinging were both rare and mild at baseline. Mean scores for itching, burning, and stinging at baseline for those participants who were subsequently treated with tretinoin lotion 0.05% were 0.3, 0.1, and 0.1, respectively (1=mild). Itching severity reduced progressively with treatment. There were slight transient increases in mean scores for burning (from 0.1 to 0.2) and stinging (from 0.1 to 0.2) at week 4, returning to baseline levels or below by week 12.
Hyperpigmentation and Hypopigmentation
There was a progressive improvement in baseline hyperpigmentation severity in participants treated with tretinoin lotion 0.05%; mean scores reduced from 0.8 at baseline to 0.6 by week 12 (Figure 3), with a similar improvement in both sexes (Figure 4). Moderate to severe hyperpigmentation was reported in 24 (17.3%) participants by week 12 compared to 41 (26.4%) at baseline; the majority (n=21) were female at week 12. Moderate to severe hyperpigmentation was reported in 24 (19.7%) participants treated with vehicle at week 12.
Hypopigmentation at baseline was rare and mild, and again most common in female patients. There was no increase in hypopigmentation over the course of the study.
COMMENT
Topical retinoids (eg, tretinoin, adapalene, tazarotene) are recommended as the cornerstone of topical acne treatment, with safety and efficacy well documented in large pivotal trials.14 However, data in black patients are lacking. Acne is the most common dermatologic condition in these patients, and yet investigation into this important population is limited to small study populations or subgroup analyses.
Tretinoin lotion 0.05% is a novel topical treatment for moderate to severe acne that leverages polymeric emulsion technology. The development rationale was to provide a tretinoin formulation with improved efficacy and tolerability, features that could be especially suited to black patients with acne.
In our post hoc analysis of black patients with acne, tretinoin lotion 0.05% generally was considered safe and well tolerated. The most commonly reported treatment-related AEs were of low incidence and included application-site reactions and skin-related events attributed to the known properties of tretinoin. Most noteworthy was the extremely low irritation potential of this novel tretinoin formulation. Treatment-related AEs generally were mild, and interestingly, the majority occurred in female patients. The incidence of the most common treatment-related AEs—application-site dryness (2.6%) and application-site pain (2.6%)—was lower than that reported in the white populations in the 2 studies (3.8% and 3.4%, respectively).(unpublished data, Ortho Dermatologics), though the differences were not significant (P=.625 and P=.799).
Approximately one-quarter of participants had mild to moderate erythema, scaling, itching, and stinging at baseline. All of these cutaneous symptoms improved with treatment. There were slight transient increases in scaling and stinging at week 4, with stinging more noticeable in the female population. There were no noticeable changes in mild to moderate burning during the study.
Postinflammatory hyperpigmentation is an important consideration in black patients with acne. It can arise from either acne-induced inflammation or injury. It can be of greater concern to the patient than the acne itself and often is the main reason black patients seek a dermatologist consultation. In a survey of adult female acne, nonwhite women experienced substantially more PIH than white women. In addition, clearance of PIH was most important for these nonwhite women (42% vs 8% for white women), whereas lesion clearance was the most important aspect for white women (58% vs 32% for nonwhite women).15 Erring on the side of increased tolerability is appropriate in black patients with acne, given that any irritant reactions can lead to pigmentary alterations—hyperpigmentation or hypopigmentation—that can cause considerable patient anxiety. The psychologic impact of PIH can be devastating, and an ideal acne treatment in these patients would be one that is effective against both PIH and acne. Tretinoin cream 0.1% monotherapy has been shown to be effective in reducing PIH.16 Postinflammatory hyperpigmentation lesions and normal skin were assessed by clinical and colorimetric evaluations and by analysis of biopsy specimens. Although facial PIH lesions in the 24 tretinoin-treated patients were significantly lighter after 40 weeks of treatment compared to vehicle in this study (P<.001), overall improvement was first noted after 4 weeks (P=.009). Normal skin also was minimally lightened by tretinoin; however, exuberant local skin reactions, including peeling, developed in 50% of patients. Mild to moderate PIH was present in the majority of tretinoin-treated patients at baseline in our post hoc analysis, severe in 3.2% of cases, and both more common and severe in females. Mean scores reduced over the 12-week study period, from 0.6 to 0.4 in male patients and 0.9 to 0.7 in female patients. Hypopigmentation was rare and mild at baseline and did not increase over the course of the study. A pilot study with a cream formulation of tazarotene in patients with acne from darker racial groups showed the retinoid to be effective in treating PIH following 18 weeks of once-daily application.17 Further longer-term studies on treating PIH with tretinoin lotion 0.05% are warranted given its tolerability profile.
CONCLUSION
This novel tretinoin lotion 0.05% formulation is a safe and well-tolerated topical treatment for moderate to severe comedonal and inflammatory acne in black patients. Tretinoin lotion 0.05% does not appear to induce PIH and may afford an effective, well-tolerated, dual-treatment option.
Acknowledgments
We thank Brian Bulley, MSc (Konic Limited, United Kingdom), for medical writing support. Ortho Dermatologics funded Konic’s activities pertaining to this manuscript.
- Halder RM, Grimes PE, McLaurin CI, et al. Incidence of common dermatoses in a predominantly black dermatologic practice. Cutis. 1983;32:388,390.
- Taylor SC, Cook-Bolden F, Rahman Z, et al. Acne vulgaris in skin of color. J Am Acad Dermatol. 2002;46(suppl 2):S98-S106.
- Rogers AT, Semenov YR, Kwatra SG, et al. Racial disparities in the management of acne: evidence from the National Ambulatory Medial Care Survey, 2005-2014. J Dermatolog Treat. 2018;29:287-289.
- Halder RM. The role of retinoids in the management of cutaneous conditions in blacks. J Am Acad Dermatol. 1998;39(suppl 2):S98-S103.
- Jacyk WK. Adapalene in the treatment of African patients. J Eur Acad Dermatol Venereol. 2001;15(suppl 3):37-42.
- Jacyk WK, Mpofu P. Adapalene gel 0.1% for topical treatment of acne vulgaris in African patients. Cutis. 2001;68(suppl 4):48-54.
- Czernielewski J, Poncet M, Mizzi F. Efficacy and cutaneous safety of adapalene in black patients versus white patients with acne vulgaris. Cutis. 2002;70:243-248.
- Alexis AF, Johnson LA, Kerrouche N, et al. A subgroup analysis to evaluate the efficacy and safety of adapalene-benzoyl peroxide topical gel in black subjects with moderate acne. J Drugs Dermatol. 2014;13:170-174.
- Leyden JJ, Shalita A, Thiboutot D, et al. Topical retinoids in inflammatory acne: a retrospective, investigator-blinded, vehicle-controlled, photographic assessment. Clin Ther. 2005;27:216-224.
- Zaenglein AL, Pathy AL, Schlosser BJ, et al. Guidelines of care for the management of acne vulgaris. J Am Acad Dermatol. 2016;74:945-973.
- Culp L, Moradi Tuchayi S, Alinia H, et al. Tolerability of topical retinoids: are there clinically meaningful differences among topical retinoids?J Cutan Med Surg. 2015;19:530-538.
- Kircik LH. Evaluating tretinoin formulations in the treatment of acne. J Drugs Dermatol. 2014;13:466-470.
- Tyring SK, Kircik LH, Pariser DM, et al. Novel tretinoin 0.05% lotion for the once-daily treatment of moderate-to-severe acne vulgaris: assessment of efficacy and safety in patients aged 9 years and older. J Drugs Dermatol. 2018;17:1084-1091.
- Leyden J, Stein-Gold l, Weiss J. Why topical retionoids are the mainstay of therapy for acne. Dermatol Ther (Heidelb) 2017;7:293-304.
- Callender VD, Alexis AF, Daniels SR, et al. Racial differences in clinical characteristics, perceptions and behaviors, and psychosocial impact of adult female acne. J Clin Aesthet Dermatol. 2014;7:19-31.
- Bulengo-Ransby SM, Griffiths CE, Kimbrough-Green CK, et al. Topical tretinoin (retinoic acid) therapy for hyperpigmented lesions caused by inflammation of the skin in black patients. N Engl J Med. 1993;328:1438-1443.
- Grimes P, Callender V. Tazarotene cream for postinflammatory hyperpigmentation and acne vulgaris in darker skin: a double-blind, randomized, vehicle-controlled study. Cutis. 2006;77:45-50.
- Halder RM, Grimes PE, McLaurin CI, et al. Incidence of common dermatoses in a predominantly black dermatologic practice. Cutis. 1983;32:388,390.
- Taylor SC, Cook-Bolden F, Rahman Z, et al. Acne vulgaris in skin of color. J Am Acad Dermatol. 2002;46(suppl 2):S98-S106.
- Rogers AT, Semenov YR, Kwatra SG, et al. Racial disparities in the management of acne: evidence from the National Ambulatory Medial Care Survey, 2005-2014. J Dermatolog Treat. 2018;29:287-289.
- Halder RM. The role of retinoids in the management of cutaneous conditions in blacks. J Am Acad Dermatol. 1998;39(suppl 2):S98-S103.
- Jacyk WK. Adapalene in the treatment of African patients. J Eur Acad Dermatol Venereol. 2001;15(suppl 3):37-42.
- Jacyk WK, Mpofu P. Adapalene gel 0.1% for topical treatment of acne vulgaris in African patients. Cutis. 2001;68(suppl 4):48-54.
- Czernielewski J, Poncet M, Mizzi F. Efficacy and cutaneous safety of adapalene in black patients versus white patients with acne vulgaris. Cutis. 2002;70:243-248.
- Alexis AF, Johnson LA, Kerrouche N, et al. A subgroup analysis to evaluate the efficacy and safety of adapalene-benzoyl peroxide topical gel in black subjects with moderate acne. J Drugs Dermatol. 2014;13:170-174.
- Leyden JJ, Shalita A, Thiboutot D, et al. Topical retinoids in inflammatory acne: a retrospective, investigator-blinded, vehicle-controlled, photographic assessment. Clin Ther. 2005;27:216-224.
- Zaenglein AL, Pathy AL, Schlosser BJ, et al. Guidelines of care for the management of acne vulgaris. J Am Acad Dermatol. 2016;74:945-973.
- Culp L, Moradi Tuchayi S, Alinia H, et al. Tolerability of topical retinoids: are there clinically meaningful differences among topical retinoids?J Cutan Med Surg. 2015;19:530-538.
- Kircik LH. Evaluating tretinoin formulations in the treatment of acne. J Drugs Dermatol. 2014;13:466-470.
- Tyring SK, Kircik LH, Pariser DM, et al. Novel tretinoin 0.05% lotion for the once-daily treatment of moderate-to-severe acne vulgaris: assessment of efficacy and safety in patients aged 9 years and older. J Drugs Dermatol. 2018;17:1084-1091.
- Leyden J, Stein-Gold l, Weiss J. Why topical retionoids are the mainstay of therapy for acne. Dermatol Ther (Heidelb) 2017;7:293-304.
- Callender VD, Alexis AF, Daniels SR, et al. Racial differences in clinical characteristics, perceptions and behaviors, and psychosocial impact of adult female acne. J Clin Aesthet Dermatol. 2014;7:19-31.
- Bulengo-Ransby SM, Griffiths CE, Kimbrough-Green CK, et al. Topical tretinoin (retinoic acid) therapy for hyperpigmented lesions caused by inflammation of the skin in black patients. N Engl J Med. 1993;328:1438-1443.
- Grimes P, Callender V. Tazarotene cream for postinflammatory hyperpigmentation and acne vulgaris in darker skin: a double-blind, randomized, vehicle-controlled study. Cutis. 2006;77:45-50.
Practice Points
- Acne vulgaris is the most common dermatologic disorder seen in black patients, though data on treatment effects is lacking.
- Postinflammatory hyperpigmentation (PIH) frequently coexists with acne, and retinoids are known to treat both.
- Tretinoin lotion 0.05% is effective in treating both inflammatory and noninflammatory lesions in black patients with acne and reducing PIH without the irritant contact dermatitis seen with other retinoid formulations.
Fighting Acne for the Fighting Forces
Acne treatment presents unique challenges in the active-duty military population. Lesions on the face may interfere with proper fit and seal of protective masks and helmets, while those involving the shoulders or back may cause considerable discomfort beneath safety restraints, parachute harnesses, or flak jackets. Therefore, untreated acne may limit servicemembers from performing their assigned duties. Treatments themselves also may be limiting; for instance, aircrew members who are taking oral doxycycline, tetracycline, or erythromycin may be grounded (ie, temporarily removed from duty) during and after therapy to monitor for side effects. Minocycline is considered unacceptable for aviators and is completely restricted for use due to risk for central nervous system side effects. Isotretinoin is restricted in aircrew members, submariners, and divers. If initiated, isotretinoin requires grounding for the entire duration of therapy and up to 3 months following treatment. Normalization of triglyceride levels and slit-lamp ocular examination also must take place prior to return to full duty, which may lead to additional grounding time. Well-established topical and oral treatments not impacting military duty are omitted from this review.
Antibiotics
Minocycline
Minocycline carries a small risk for development of systemic lupus erythematosus and other autoimmune treatment-emergent adverse effects. It has known gastrointestinal tract side effects, and long-term use also can lead to bluish discoloration of the skin.1 Systemic minocycline is restricted in aircrew members due to its risk for central nervous system side effects, including light-headedness, dizziness, and vertigo.2-5
A topical formulation of minocycline recently was developed and approved by the US Food and Drug Administration as a means to reduce systemic adverse effects. This 4% minocycline foam has thus far been safe and well tolerated, with adverse events reported in less than 1% of study participants.1,6 In addition, topical minocycline was shown in a recent phase 3 study to notably reduce inflammatory lesion counts when compared to control vehicles at as early as 3 weeks.7 Topical minocycline may emerge as a viable treatment option for active-duty servicemembers in the future.
Doxycycline
Doxycycline is not medically disqualifying. Even so, it may still necessitate grounding for a period of time while monitoring for side effects.4 Doxycycline can lead to photosensitivity, which could be difficult to tolerate for active-duty personnel training in sunny climates. Fortunately, uniform regulations and personal protective equipment requirements provide cover for most of the body surfaces aside from the face, which is protected by various forms of covers. If the patient tolerates the medication well without considerable side effects, he/she may be returned to full duty, making doxycycline an acceptable alternative to minocycline in the military population.
Sarecycline
This novel compound is a tetracycline-class antibiotic with a narrower spectrum of activity, with reduced activity against enteric gram-negative bacteria. It has shown efficacy in reducing inflammatory and noninflammatory acne lesions, including lesions on the face, back, and chest. Common adverse side effects are nausea, headache, nasopharyngitis, and vomiting. Vestibular and phototoxic adverse effects were reported in less than 1% of patients.1,8 The US Food and Drug Administration approved sarecycline as a once-daily oral formulation for moderate to severe acne vulgaris, the first new antibiotic to be approved for the disease in the last 40 years. Sarecycline is not mentioned in any US military guidelines with regard to medical readiness and duty status; however, given its lack of vestibular side effects and narrower activity spectrum, it may become another acceptable treatment option in the military population.
Isotretinoin
Isotretinoin is well established as an excellent treatment of acne and stands alone as the only currently available medication that alters the disease course and prevents relapse in many patients. Nearly all patients on isotretinoin experience considerable mucocutaneous dryness, and up to 25% of patients on high-dose isotretinoin develop myalgia.9 Isotretinoin causes serious retinoid embryopathy, requiring all patients to be enrolled in the iPLEDGE program (https://www.ipledgeprogram.com/iPledgeUI/home.u) and to use 2 methods of contraception during treatment. Although it is uncommon to have notable elevations in lipids and transaminases during treatment with isotretinoin, routine laboratory monitoring generally is performed until the patient reaches steady dosing.
Isotretinoin is not permitted for use in active aircrew members, submariners, or divers. Servicemembers pursuing isotretinoin therapy are removed from their duty and are nondeployable for the entirety of their treatment course and several months after completion.4,5
Photodynamic Therapy
Aminolevulinic acid and photodynamic therapy (ALA-PDT) has been successfully used in the management of acne.10 In addition to inducing selective damage to sebaceous glands, it has been proposed that PDT also destroys Propionibacterium acnes and reduces keratinocyte shedding and immunologic changes that play key roles in the development of acne.10
A recent randomized controlled trial comparing the efficacy of ALA-PDT vs adapalene gel plus oral doxycycline for treatment of moderate acne included 46 patients with moderate inflammatory acne.10 Twenty-three participants received 2 sessions (spaced 2 weeks apart) of 20% ALA incubated for 90 minutes before red light irradiation with a fluence of 37 J/cm2, and the other 23 received 100 mg/d of oral doxycycline plus adapalene gel 0.1%. By 6-week follow-up, there was a significantly higher reduction in total lesions within the PDT group (P=.038), which was sustained at the secondary 12-week follow-up (P=.026). There was a 79% total reduction of lesions in the ALA-PDT group vs 67% in the doxycycline plus adapalene group.10
Although some studies have shown promise for PDT as an emerging treatment option for acne, further research is needed. A 2016 systematic review of the related literature determined that although 20% ALA-PDT with red light was more effective than lower concentrations of ALA and also more effective than ALA-PDT with blue light—which offered no additional benefit when compared with blue light alone—high-quality evidence on the use of PDT for acne is lacking overall.11 At the time of the review, there was little certainty as to the usefulness of ALA-PDT with red or blue light as a standard treatment for individuals with moderate to severe acne. A 2019 review by Marson and Baldwin12 echoed this sentiment, recommending more stringently designed studies to elucidate the true role of PDT as a monotherapy or adjunctive treatment of acne.
Pulsed Dye Laser
Pulsed dye laser (PDL) was first shown to be a potential therapy for acne by Seaton et al,13 who conducted a small-scale, randomized, controlled trial with 41 patients, each assigned to either a single PDL treatment or a sham treatment. Patients were re-evaluated at 12 weeks, measuring acne severity by the Leeds revised acne grading system and taking total lesion counts. Acne severity (P=.007) and total lesion counts (P=.023) were significantly improved in the treatment group, with a 53% reduction in total lesion count following a single PDL treatment.13
In 2007, a Spanish study described use of PDL every 4 weeks for a total of 12 weeks in 36 patients with mild to moderate acne. Using lesion counts as their primary outcome measure, the investigators found results similar to those from Seaton et al,13 with a 57% decrease in active lesions.14 Others still have found similar outcomes. A 2009 study of 45 patients with mild to moderate acne compared patients treated with PDL every 2 weeks for 12 weeks to patients receiving either topical therapy or chemical peels with 25% trichloroacetic acid. At 12 weeks, they noted the best results were in the PDL group.15
Karsai et al16 compared PDL as an adjuvant treatment of acne to proven treatment with clindamycin plus benzoyl peroxide gel. Eighty patients were randomized to topical therapy plus PDL or topical therapy alone and were followed at 2 and 4 weeks after the initial treatment. Although both groups showed improvement as measured by inflammatory lesion count and dermatology life quality index, there was no statistically significant difference noted between groups.16
Case Report
A 24-year-old active-duty male servicemember was referred to the dermatology department for evaluation of treatment-resistant nodulocystic scarring acne. Prior to his arrival to dermatology, he had completed 2 weeks of isotretinoin before discontinuation due to notable mood alteration. Following the isotretinoin, he was then switched to doxycycline 100 mg twice daily, which he trialed for 3 months. Even on the antibiotic, the patient continued to develop new pustules and cysts, prompting referral to dermatology for additional treatment options (Figure, A). All of the previous topical and oral medications had been discontinued at the current presentation.
The patient received 3 treatments with the 595-nm PDL (spot size, 10 mm; fluence, 7 J/cm2; pulse width, 6 milliseconds) spaced 4 weeks apart. At each treatment, fewer than 10 total inflammatory lesions were treated, including inflammatory papules, pustules, and nodules. Nodular lesions were treated with 2 pulses. After each treatment, the patient reported that all treated lesions resolved within 2 days (Figure, B). Subsequent treated lesions all occurred at previously uninvolved sites.
Final Thoughts
Antibiotic resistance is a known and growing problem throughout the medical community. In 2013, the US Centers for Disease Control and Prevention reported that dermatologists prescribe more antibiotics than any other specialty.17 Aside from antibiotic stewardship, systemic antibiotics come with various considerations when selecting ideal acne treatment regimens in military populations, as they are either medically disqualifying or lead to temporary grounding status. Numerous guidelines on acne have recommended limiting the use of antibiotics, instead pursuing alternative therapies such as spironolactone, oral contraceptives, or isotretinoin.9,18 Both spironolactone and oral contraceptives work well via antiandrogenic and antisebogenic properties; however, these therapies are limited to female patients only, who make up a minority of patients in the active-duty military setting. Isotretinoin is highly effective in the treatment of acne, but it requires grounding for the entirety of treatment and for months afterward, which comes at great personal and financial costs to servicemembers and their commanders due to limited-duty status and inability to deploy.
Given the operational constraints with isotretinoin and the continual rise of antibiotic resistance, PDL appears to be a safe and effective alternative therapy for acne. In our case, the patient had complete resolution of active inflammatory lesions after each of his treatments. He had no adverse effects and tolerated the treatments well. We report this case here to highlight the use of PDL as an effective therapy for spot treatment in patients limited by personal or operational constraints and as a means to reduce antibiotic use in the face of a growing tide of antibiotic resistance.
- Kircik LH. What’s new in the management of acne vulgaris. Cutis. 2019;104:48-52.
- US Department of the Army. Standards of medical fitness. https://armypubs.army.mil/epubs/DR_pubs/DR_a/pdf/web/ARN8673_AR40_501_FINAL_WEB.pdf. Published June 27, 2019. Accessed June 23, 2020.
- US Department of the Air Force. Medical examinations and standards. http://aangfs.com/wp-content/uploads/2012/10/AFI-48-123-Medical-Examination-Standards.pdf. Published January 29, 2013. Accessed June 23, 2020.
- US Navy Aeromedical Reference and Waiver Guide. Navy Medicine website. https://www.med.navy.mil/sites/nmotc/nami/arwg/Documents/WaiverGuide/Complete_Waiver_Guide.pdf. Published September 4, 2019. Accessed June 17, 2020.
- Burke KR, Larrymore DC, Cho S. Treatment considerations for US military members with skin disease. Cutis. 2019:103:329-332.
- Gold LS, Dhawan S, Weiss J, et al. A novel topical minocycline foam for the treatment of moderate-to-severe acne vulgaris: results of 2 randomized, double-blind, phase 3 studies. J Am Acad Dermatol. 2019;30:168-177.
- Raoof J, Hooper D, Moore A, et al. FMX101 4% topical minocycline foam for the treatment of moderate to severe acne vulgaris: efficacy and safety from a phase 3 randomized, double-blind, vehicle-controlled study. Poster presented at: 2018 Fall Clinical Dermatology Conference; October 18-21, 2018; Las Vegas, NV.
- Moore A, Green LJ, Bruce S, et al. Once-daily oral sarecycline 1.5 mg/kg/day is effective for moderate to severe acne vulgaris; results from two identically designed, phase 3, randomized, double-blind clinical trials. J Drugs Dermatol. 2018;17:987-996.
- Barbieri JS, Spaccarelli N, Margolis DJ, et al. Approaches to limit systemic antibiotic use in acne: systemic alternatives, emerging topical therapies, dietary modification, and laser and light-based treatments.J Am Acad Dermatol. 2019;80:538-549.
- Nicklas C, Rubio R, Cardenas C, et al. Comparison of efficacy of aminolaevulinic acid photodynamic therapy vs. adapalene gel plus oral doxycycline for treatment of moderate acne vulgaris—a simple, blind, randomized, and controlled trial. Photodermatol Photoimmunol Photomed. 2019;35:3-10.
- Barbaric J, Abbott R, Posadzki P, et al. Light therapies for acne [published online September 27, 2016]. Cochrane Database Syst Rev. doi:10.1002/14651858.CD007917.pub2.
- Marson JW, Baldwin HE. New concepts, concerns, and creations in acne. Dermatol Clin. 2019;37:1-9.
- Seaton ED, Charakida A, Mouser PE, et al. Pulsed-dye laser treatment for inflammatory acne vulgaris: randomised controlled trial. Lancet Lond Engl. 2003;362:1347-1352.
- Harto A, Garcia-Morales I, Belmar P, et al. Pulsed dye laser treatment of acne. study of clinical efficacy and mechanism of action. Actas Dermosifiliogr. 2007;98:415-419.
- Leheta TM. Role of the 585-nm pulsed dye laser in the treatment of acne in comparison with other topical therapeutic modalities. J Cosmet Laser Ther Off Publ Eur Soc Laser Dermatol. 2009;11:118-124.
- Karsai S, Schmitt L, Raulin C. The pulsed-dye laser as an adjuvant treatment modality in acne vulgaris: a randomized controlled single-blinded trial. Br J Dermatol. 2010;163:395-401.
- Centers for Disease Control and Prevention. Outpatient antibiotic prescriptions—United States. annual report 2013.https://www.cdc.gov/antibiotic-use/community/pdfs/Annual-ReportSummary_2013.pdf. Accessed June 23, 2020.
- Zaenglein AL, Pathy AL, Schlosser BJ, et al. Guidelines of care for the management of acne vulgaris. J Am Acad Dermatol. 2016;74:945-973.e33.
Acne treatment presents unique challenges in the active-duty military population. Lesions on the face may interfere with proper fit and seal of protective masks and helmets, while those involving the shoulders or back may cause considerable discomfort beneath safety restraints, parachute harnesses, or flak jackets. Therefore, untreated acne may limit servicemembers from performing their assigned duties. Treatments themselves also may be limiting; for instance, aircrew members who are taking oral doxycycline, tetracycline, or erythromycin may be grounded (ie, temporarily removed from duty) during and after therapy to monitor for side effects. Minocycline is considered unacceptable for aviators and is completely restricted for use due to risk for central nervous system side effects. Isotretinoin is restricted in aircrew members, submariners, and divers. If initiated, isotretinoin requires grounding for the entire duration of therapy and up to 3 months following treatment. Normalization of triglyceride levels and slit-lamp ocular examination also must take place prior to return to full duty, which may lead to additional grounding time. Well-established topical and oral treatments not impacting military duty are omitted from this review.
Antibiotics
Minocycline
Minocycline carries a small risk for development of systemic lupus erythematosus and other autoimmune treatment-emergent adverse effects. It has known gastrointestinal tract side effects, and long-term use also can lead to bluish discoloration of the skin.1 Systemic minocycline is restricted in aircrew members due to its risk for central nervous system side effects, including light-headedness, dizziness, and vertigo.2-5
A topical formulation of minocycline recently was developed and approved by the US Food and Drug Administration as a means to reduce systemic adverse effects. This 4% minocycline foam has thus far been safe and well tolerated, with adverse events reported in less than 1% of study participants.1,6 In addition, topical minocycline was shown in a recent phase 3 study to notably reduce inflammatory lesion counts when compared to control vehicles at as early as 3 weeks.7 Topical minocycline may emerge as a viable treatment option for active-duty servicemembers in the future.
Doxycycline
Doxycycline is not medically disqualifying. Even so, it may still necessitate grounding for a period of time while monitoring for side effects.4 Doxycycline can lead to photosensitivity, which could be difficult to tolerate for active-duty personnel training in sunny climates. Fortunately, uniform regulations and personal protective equipment requirements provide cover for most of the body surfaces aside from the face, which is protected by various forms of covers. If the patient tolerates the medication well without considerable side effects, he/she may be returned to full duty, making doxycycline an acceptable alternative to minocycline in the military population.
Sarecycline
This novel compound is a tetracycline-class antibiotic with a narrower spectrum of activity, with reduced activity against enteric gram-negative bacteria. It has shown efficacy in reducing inflammatory and noninflammatory acne lesions, including lesions on the face, back, and chest. Common adverse side effects are nausea, headache, nasopharyngitis, and vomiting. Vestibular and phototoxic adverse effects were reported in less than 1% of patients.1,8 The US Food and Drug Administration approved sarecycline as a once-daily oral formulation for moderate to severe acne vulgaris, the first new antibiotic to be approved for the disease in the last 40 years. Sarecycline is not mentioned in any US military guidelines with regard to medical readiness and duty status; however, given its lack of vestibular side effects and narrower activity spectrum, it may become another acceptable treatment option in the military population.
Isotretinoin
Isotretinoin is well established as an excellent treatment of acne and stands alone as the only currently available medication that alters the disease course and prevents relapse in many patients. Nearly all patients on isotretinoin experience considerable mucocutaneous dryness, and up to 25% of patients on high-dose isotretinoin develop myalgia.9 Isotretinoin causes serious retinoid embryopathy, requiring all patients to be enrolled in the iPLEDGE program (https://www.ipledgeprogram.com/iPledgeUI/home.u) and to use 2 methods of contraception during treatment. Although it is uncommon to have notable elevations in lipids and transaminases during treatment with isotretinoin, routine laboratory monitoring generally is performed until the patient reaches steady dosing.
Isotretinoin is not permitted for use in active aircrew members, submariners, or divers. Servicemembers pursuing isotretinoin therapy are removed from their duty and are nondeployable for the entirety of their treatment course and several months after completion.4,5
Photodynamic Therapy
Aminolevulinic acid and photodynamic therapy (ALA-PDT) has been successfully used in the management of acne.10 In addition to inducing selective damage to sebaceous glands, it has been proposed that PDT also destroys Propionibacterium acnes and reduces keratinocyte shedding and immunologic changes that play key roles in the development of acne.10
A recent randomized controlled trial comparing the efficacy of ALA-PDT vs adapalene gel plus oral doxycycline for treatment of moderate acne included 46 patients with moderate inflammatory acne.10 Twenty-three participants received 2 sessions (spaced 2 weeks apart) of 20% ALA incubated for 90 minutes before red light irradiation with a fluence of 37 J/cm2, and the other 23 received 100 mg/d of oral doxycycline plus adapalene gel 0.1%. By 6-week follow-up, there was a significantly higher reduction in total lesions within the PDT group (P=.038), which was sustained at the secondary 12-week follow-up (P=.026). There was a 79% total reduction of lesions in the ALA-PDT group vs 67% in the doxycycline plus adapalene group.10
Although some studies have shown promise for PDT as an emerging treatment option for acne, further research is needed. A 2016 systematic review of the related literature determined that although 20% ALA-PDT with red light was more effective than lower concentrations of ALA and also more effective than ALA-PDT with blue light—which offered no additional benefit when compared with blue light alone—high-quality evidence on the use of PDT for acne is lacking overall.11 At the time of the review, there was little certainty as to the usefulness of ALA-PDT with red or blue light as a standard treatment for individuals with moderate to severe acne. A 2019 review by Marson and Baldwin12 echoed this sentiment, recommending more stringently designed studies to elucidate the true role of PDT as a monotherapy or adjunctive treatment of acne.
Pulsed Dye Laser
Pulsed dye laser (PDL) was first shown to be a potential therapy for acne by Seaton et al,13 who conducted a small-scale, randomized, controlled trial with 41 patients, each assigned to either a single PDL treatment or a sham treatment. Patients were re-evaluated at 12 weeks, measuring acne severity by the Leeds revised acne grading system and taking total lesion counts. Acne severity (P=.007) and total lesion counts (P=.023) were significantly improved in the treatment group, with a 53% reduction in total lesion count following a single PDL treatment.13
In 2007, a Spanish study described use of PDL every 4 weeks for a total of 12 weeks in 36 patients with mild to moderate acne. Using lesion counts as their primary outcome measure, the investigators found results similar to those from Seaton et al,13 with a 57% decrease in active lesions.14 Others still have found similar outcomes. A 2009 study of 45 patients with mild to moderate acne compared patients treated with PDL every 2 weeks for 12 weeks to patients receiving either topical therapy or chemical peels with 25% trichloroacetic acid. At 12 weeks, they noted the best results were in the PDL group.15
Karsai et al16 compared PDL as an adjuvant treatment of acne to proven treatment with clindamycin plus benzoyl peroxide gel. Eighty patients were randomized to topical therapy plus PDL or topical therapy alone and were followed at 2 and 4 weeks after the initial treatment. Although both groups showed improvement as measured by inflammatory lesion count and dermatology life quality index, there was no statistically significant difference noted between groups.16
Case Report
A 24-year-old active-duty male servicemember was referred to the dermatology department for evaluation of treatment-resistant nodulocystic scarring acne. Prior to his arrival to dermatology, he had completed 2 weeks of isotretinoin before discontinuation due to notable mood alteration. Following the isotretinoin, he was then switched to doxycycline 100 mg twice daily, which he trialed for 3 months. Even on the antibiotic, the patient continued to develop new pustules and cysts, prompting referral to dermatology for additional treatment options (Figure, A). All of the previous topical and oral medications had been discontinued at the current presentation.
The patient received 3 treatments with the 595-nm PDL (spot size, 10 mm; fluence, 7 J/cm2; pulse width, 6 milliseconds) spaced 4 weeks apart. At each treatment, fewer than 10 total inflammatory lesions were treated, including inflammatory papules, pustules, and nodules. Nodular lesions were treated with 2 pulses. After each treatment, the patient reported that all treated lesions resolved within 2 days (Figure, B). Subsequent treated lesions all occurred at previously uninvolved sites.
Final Thoughts
Antibiotic resistance is a known and growing problem throughout the medical community. In 2013, the US Centers for Disease Control and Prevention reported that dermatologists prescribe more antibiotics than any other specialty.17 Aside from antibiotic stewardship, systemic antibiotics come with various considerations when selecting ideal acne treatment regimens in military populations, as they are either medically disqualifying or lead to temporary grounding status. Numerous guidelines on acne have recommended limiting the use of antibiotics, instead pursuing alternative therapies such as spironolactone, oral contraceptives, or isotretinoin.9,18 Both spironolactone and oral contraceptives work well via antiandrogenic and antisebogenic properties; however, these therapies are limited to female patients only, who make up a minority of patients in the active-duty military setting. Isotretinoin is highly effective in the treatment of acne, but it requires grounding for the entirety of treatment and for months afterward, which comes at great personal and financial costs to servicemembers and their commanders due to limited-duty status and inability to deploy.
Given the operational constraints with isotretinoin and the continual rise of antibiotic resistance, PDL appears to be a safe and effective alternative therapy for acne. In our case, the patient had complete resolution of active inflammatory lesions after each of his treatments. He had no adverse effects and tolerated the treatments well. We report this case here to highlight the use of PDL as an effective therapy for spot treatment in patients limited by personal or operational constraints and as a means to reduce antibiotic use in the face of a growing tide of antibiotic resistance.
Acne treatment presents unique challenges in the active-duty military population. Lesions on the face may interfere with proper fit and seal of protective masks and helmets, while those involving the shoulders or back may cause considerable discomfort beneath safety restraints, parachute harnesses, or flak jackets. Therefore, untreated acne may limit servicemembers from performing their assigned duties. Treatments themselves also may be limiting; for instance, aircrew members who are taking oral doxycycline, tetracycline, or erythromycin may be grounded (ie, temporarily removed from duty) during and after therapy to monitor for side effects. Minocycline is considered unacceptable for aviators and is completely restricted for use due to risk for central nervous system side effects. Isotretinoin is restricted in aircrew members, submariners, and divers. If initiated, isotretinoin requires grounding for the entire duration of therapy and up to 3 months following treatment. Normalization of triglyceride levels and slit-lamp ocular examination also must take place prior to return to full duty, which may lead to additional grounding time. Well-established topical and oral treatments not impacting military duty are omitted from this review.
Antibiotics
Minocycline
Minocycline carries a small risk for development of systemic lupus erythematosus and other autoimmune treatment-emergent adverse effects. It has known gastrointestinal tract side effects, and long-term use also can lead to bluish discoloration of the skin.1 Systemic minocycline is restricted in aircrew members due to its risk for central nervous system side effects, including light-headedness, dizziness, and vertigo.2-5
A topical formulation of minocycline recently was developed and approved by the US Food and Drug Administration as a means to reduce systemic adverse effects. This 4% minocycline foam has thus far been safe and well tolerated, with adverse events reported in less than 1% of study participants.1,6 In addition, topical minocycline was shown in a recent phase 3 study to notably reduce inflammatory lesion counts when compared to control vehicles at as early as 3 weeks.7 Topical minocycline may emerge as a viable treatment option for active-duty servicemembers in the future.
Doxycycline
Doxycycline is not medically disqualifying. Even so, it may still necessitate grounding for a period of time while monitoring for side effects.4 Doxycycline can lead to photosensitivity, which could be difficult to tolerate for active-duty personnel training in sunny climates. Fortunately, uniform regulations and personal protective equipment requirements provide cover for most of the body surfaces aside from the face, which is protected by various forms of covers. If the patient tolerates the medication well without considerable side effects, he/she may be returned to full duty, making doxycycline an acceptable alternative to minocycline in the military population.
Sarecycline
This novel compound is a tetracycline-class antibiotic with a narrower spectrum of activity, with reduced activity against enteric gram-negative bacteria. It has shown efficacy in reducing inflammatory and noninflammatory acne lesions, including lesions on the face, back, and chest. Common adverse side effects are nausea, headache, nasopharyngitis, and vomiting. Vestibular and phototoxic adverse effects were reported in less than 1% of patients.1,8 The US Food and Drug Administration approved sarecycline as a once-daily oral formulation for moderate to severe acne vulgaris, the first new antibiotic to be approved for the disease in the last 40 years. Sarecycline is not mentioned in any US military guidelines with regard to medical readiness and duty status; however, given its lack of vestibular side effects and narrower activity spectrum, it may become another acceptable treatment option in the military population.
Isotretinoin
Isotretinoin is well established as an excellent treatment of acne and stands alone as the only currently available medication that alters the disease course and prevents relapse in many patients. Nearly all patients on isotretinoin experience considerable mucocutaneous dryness, and up to 25% of patients on high-dose isotretinoin develop myalgia.9 Isotretinoin causes serious retinoid embryopathy, requiring all patients to be enrolled in the iPLEDGE program (https://www.ipledgeprogram.com/iPledgeUI/home.u) and to use 2 methods of contraception during treatment. Although it is uncommon to have notable elevations in lipids and transaminases during treatment with isotretinoin, routine laboratory monitoring generally is performed until the patient reaches steady dosing.
Isotretinoin is not permitted for use in active aircrew members, submariners, or divers. Servicemembers pursuing isotretinoin therapy are removed from their duty and are nondeployable for the entirety of their treatment course and several months after completion.4,5
Photodynamic Therapy
Aminolevulinic acid and photodynamic therapy (ALA-PDT) has been successfully used in the management of acne.10 In addition to inducing selective damage to sebaceous glands, it has been proposed that PDT also destroys Propionibacterium acnes and reduces keratinocyte shedding and immunologic changes that play key roles in the development of acne.10
A recent randomized controlled trial comparing the efficacy of ALA-PDT vs adapalene gel plus oral doxycycline for treatment of moderate acne included 46 patients with moderate inflammatory acne.10 Twenty-three participants received 2 sessions (spaced 2 weeks apart) of 20% ALA incubated for 90 minutes before red light irradiation with a fluence of 37 J/cm2, and the other 23 received 100 mg/d of oral doxycycline plus adapalene gel 0.1%. By 6-week follow-up, there was a significantly higher reduction in total lesions within the PDT group (P=.038), which was sustained at the secondary 12-week follow-up (P=.026). There was a 79% total reduction of lesions in the ALA-PDT group vs 67% in the doxycycline plus adapalene group.10
Although some studies have shown promise for PDT as an emerging treatment option for acne, further research is needed. A 2016 systematic review of the related literature determined that although 20% ALA-PDT with red light was more effective than lower concentrations of ALA and also more effective than ALA-PDT with blue light—which offered no additional benefit when compared with blue light alone—high-quality evidence on the use of PDT for acne is lacking overall.11 At the time of the review, there was little certainty as to the usefulness of ALA-PDT with red or blue light as a standard treatment for individuals with moderate to severe acne. A 2019 review by Marson and Baldwin12 echoed this sentiment, recommending more stringently designed studies to elucidate the true role of PDT as a monotherapy or adjunctive treatment of acne.
Pulsed Dye Laser
Pulsed dye laser (PDL) was first shown to be a potential therapy for acne by Seaton et al,13 who conducted a small-scale, randomized, controlled trial with 41 patients, each assigned to either a single PDL treatment or a sham treatment. Patients were re-evaluated at 12 weeks, measuring acne severity by the Leeds revised acne grading system and taking total lesion counts. Acne severity (P=.007) and total lesion counts (P=.023) were significantly improved in the treatment group, with a 53% reduction in total lesion count following a single PDL treatment.13
In 2007, a Spanish study described use of PDL every 4 weeks for a total of 12 weeks in 36 patients with mild to moderate acne. Using lesion counts as their primary outcome measure, the investigators found results similar to those from Seaton et al,13 with a 57% decrease in active lesions.14 Others still have found similar outcomes. A 2009 study of 45 patients with mild to moderate acne compared patients treated with PDL every 2 weeks for 12 weeks to patients receiving either topical therapy or chemical peels with 25% trichloroacetic acid. At 12 weeks, they noted the best results were in the PDL group.15
Karsai et al16 compared PDL as an adjuvant treatment of acne to proven treatment with clindamycin plus benzoyl peroxide gel. Eighty patients were randomized to topical therapy plus PDL or topical therapy alone and were followed at 2 and 4 weeks after the initial treatment. Although both groups showed improvement as measured by inflammatory lesion count and dermatology life quality index, there was no statistically significant difference noted between groups.16
Case Report
A 24-year-old active-duty male servicemember was referred to the dermatology department for evaluation of treatment-resistant nodulocystic scarring acne. Prior to his arrival to dermatology, he had completed 2 weeks of isotretinoin before discontinuation due to notable mood alteration. Following the isotretinoin, he was then switched to doxycycline 100 mg twice daily, which he trialed for 3 months. Even on the antibiotic, the patient continued to develop new pustules and cysts, prompting referral to dermatology for additional treatment options (Figure, A). All of the previous topical and oral medications had been discontinued at the current presentation.
The patient received 3 treatments with the 595-nm PDL (spot size, 10 mm; fluence, 7 J/cm2; pulse width, 6 milliseconds) spaced 4 weeks apart. At each treatment, fewer than 10 total inflammatory lesions were treated, including inflammatory papules, pustules, and nodules. Nodular lesions were treated with 2 pulses. After each treatment, the patient reported that all treated lesions resolved within 2 days (Figure, B). Subsequent treated lesions all occurred at previously uninvolved sites.
Final Thoughts
Antibiotic resistance is a known and growing problem throughout the medical community. In 2013, the US Centers for Disease Control and Prevention reported that dermatologists prescribe more antibiotics than any other specialty.17 Aside from antibiotic stewardship, systemic antibiotics come with various considerations when selecting ideal acne treatment regimens in military populations, as they are either medically disqualifying or lead to temporary grounding status. Numerous guidelines on acne have recommended limiting the use of antibiotics, instead pursuing alternative therapies such as spironolactone, oral contraceptives, or isotretinoin.9,18 Both spironolactone and oral contraceptives work well via antiandrogenic and antisebogenic properties; however, these therapies are limited to female patients only, who make up a minority of patients in the active-duty military setting. Isotretinoin is highly effective in the treatment of acne, but it requires grounding for the entirety of treatment and for months afterward, which comes at great personal and financial costs to servicemembers and their commanders due to limited-duty status and inability to deploy.
Given the operational constraints with isotretinoin and the continual rise of antibiotic resistance, PDL appears to be a safe and effective alternative therapy for acne. In our case, the patient had complete resolution of active inflammatory lesions after each of his treatments. He had no adverse effects and tolerated the treatments well. We report this case here to highlight the use of PDL as an effective therapy for spot treatment in patients limited by personal or operational constraints and as a means to reduce antibiotic use in the face of a growing tide of antibiotic resistance.
- Kircik LH. What’s new in the management of acne vulgaris. Cutis. 2019;104:48-52.
- US Department of the Army. Standards of medical fitness. https://armypubs.army.mil/epubs/DR_pubs/DR_a/pdf/web/ARN8673_AR40_501_FINAL_WEB.pdf. Published June 27, 2019. Accessed June 23, 2020.
- US Department of the Air Force. Medical examinations and standards. http://aangfs.com/wp-content/uploads/2012/10/AFI-48-123-Medical-Examination-Standards.pdf. Published January 29, 2013. Accessed June 23, 2020.
- US Navy Aeromedical Reference and Waiver Guide. Navy Medicine website. https://www.med.navy.mil/sites/nmotc/nami/arwg/Documents/WaiverGuide/Complete_Waiver_Guide.pdf. Published September 4, 2019. Accessed June 17, 2020.
- Burke KR, Larrymore DC, Cho S. Treatment considerations for US military members with skin disease. Cutis. 2019:103:329-332.
- Gold LS, Dhawan S, Weiss J, et al. A novel topical minocycline foam for the treatment of moderate-to-severe acne vulgaris: results of 2 randomized, double-blind, phase 3 studies. J Am Acad Dermatol. 2019;30:168-177.
- Raoof J, Hooper D, Moore A, et al. FMX101 4% topical minocycline foam for the treatment of moderate to severe acne vulgaris: efficacy and safety from a phase 3 randomized, double-blind, vehicle-controlled study. Poster presented at: 2018 Fall Clinical Dermatology Conference; October 18-21, 2018; Las Vegas, NV.
- Moore A, Green LJ, Bruce S, et al. Once-daily oral sarecycline 1.5 mg/kg/day is effective for moderate to severe acne vulgaris; results from two identically designed, phase 3, randomized, double-blind clinical trials. J Drugs Dermatol. 2018;17:987-996.
- Barbieri JS, Spaccarelli N, Margolis DJ, et al. Approaches to limit systemic antibiotic use in acne: systemic alternatives, emerging topical therapies, dietary modification, and laser and light-based treatments.J Am Acad Dermatol. 2019;80:538-549.
- Nicklas C, Rubio R, Cardenas C, et al. Comparison of efficacy of aminolaevulinic acid photodynamic therapy vs. adapalene gel plus oral doxycycline for treatment of moderate acne vulgaris—a simple, blind, randomized, and controlled trial. Photodermatol Photoimmunol Photomed. 2019;35:3-10.
- Barbaric J, Abbott R, Posadzki P, et al. Light therapies for acne [published online September 27, 2016]. Cochrane Database Syst Rev. doi:10.1002/14651858.CD007917.pub2.
- Marson JW, Baldwin HE. New concepts, concerns, and creations in acne. Dermatol Clin. 2019;37:1-9.
- Seaton ED, Charakida A, Mouser PE, et al. Pulsed-dye laser treatment for inflammatory acne vulgaris: randomised controlled trial. Lancet Lond Engl. 2003;362:1347-1352.
- Harto A, Garcia-Morales I, Belmar P, et al. Pulsed dye laser treatment of acne. study of clinical efficacy and mechanism of action. Actas Dermosifiliogr. 2007;98:415-419.
- Leheta TM. Role of the 585-nm pulsed dye laser in the treatment of acne in comparison with other topical therapeutic modalities. J Cosmet Laser Ther Off Publ Eur Soc Laser Dermatol. 2009;11:118-124.
- Karsai S, Schmitt L, Raulin C. The pulsed-dye laser as an adjuvant treatment modality in acne vulgaris: a randomized controlled single-blinded trial. Br J Dermatol. 2010;163:395-401.
- Centers for Disease Control and Prevention. Outpatient antibiotic prescriptions—United States. annual report 2013.https://www.cdc.gov/antibiotic-use/community/pdfs/Annual-ReportSummary_2013.pdf. Accessed June 23, 2020.
- Zaenglein AL, Pathy AL, Schlosser BJ, et al. Guidelines of care for the management of acne vulgaris. J Am Acad Dermatol. 2016;74:945-973.e33.
- Kircik LH. What’s new in the management of acne vulgaris. Cutis. 2019;104:48-52.
- US Department of the Army. Standards of medical fitness. https://armypubs.army.mil/epubs/DR_pubs/DR_a/pdf/web/ARN8673_AR40_501_FINAL_WEB.pdf. Published June 27, 2019. Accessed June 23, 2020.
- US Department of the Air Force. Medical examinations and standards. http://aangfs.com/wp-content/uploads/2012/10/AFI-48-123-Medical-Examination-Standards.pdf. Published January 29, 2013. Accessed June 23, 2020.
- US Navy Aeromedical Reference and Waiver Guide. Navy Medicine website. https://www.med.navy.mil/sites/nmotc/nami/arwg/Documents/WaiverGuide/Complete_Waiver_Guide.pdf. Published September 4, 2019. Accessed June 17, 2020.
- Burke KR, Larrymore DC, Cho S. Treatment considerations for US military members with skin disease. Cutis. 2019:103:329-332.
- Gold LS, Dhawan S, Weiss J, et al. A novel topical minocycline foam for the treatment of moderate-to-severe acne vulgaris: results of 2 randomized, double-blind, phase 3 studies. J Am Acad Dermatol. 2019;30:168-177.
- Raoof J, Hooper D, Moore A, et al. FMX101 4% topical minocycline foam for the treatment of moderate to severe acne vulgaris: efficacy and safety from a phase 3 randomized, double-blind, vehicle-controlled study. Poster presented at: 2018 Fall Clinical Dermatology Conference; October 18-21, 2018; Las Vegas, NV.
- Moore A, Green LJ, Bruce S, et al. Once-daily oral sarecycline 1.5 mg/kg/day is effective for moderate to severe acne vulgaris; results from two identically designed, phase 3, randomized, double-blind clinical trials. J Drugs Dermatol. 2018;17:987-996.
- Barbieri JS, Spaccarelli N, Margolis DJ, et al. Approaches to limit systemic antibiotic use in acne: systemic alternatives, emerging topical therapies, dietary modification, and laser and light-based treatments.J Am Acad Dermatol. 2019;80:538-549.
- Nicklas C, Rubio R, Cardenas C, et al. Comparison of efficacy of aminolaevulinic acid photodynamic therapy vs. adapalene gel plus oral doxycycline for treatment of moderate acne vulgaris—a simple, blind, randomized, and controlled trial. Photodermatol Photoimmunol Photomed. 2019;35:3-10.
- Barbaric J, Abbott R, Posadzki P, et al. Light therapies for acne [published online September 27, 2016]. Cochrane Database Syst Rev. doi:10.1002/14651858.CD007917.pub2.
- Marson JW, Baldwin HE. New concepts, concerns, and creations in acne. Dermatol Clin. 2019;37:1-9.
- Seaton ED, Charakida A, Mouser PE, et al. Pulsed-dye laser treatment for inflammatory acne vulgaris: randomised controlled trial. Lancet Lond Engl. 2003;362:1347-1352.
- Harto A, Garcia-Morales I, Belmar P, et al. Pulsed dye laser treatment of acne. study of clinical efficacy and mechanism of action. Actas Dermosifiliogr. 2007;98:415-419.
- Leheta TM. Role of the 585-nm pulsed dye laser in the treatment of acne in comparison with other topical therapeutic modalities. J Cosmet Laser Ther Off Publ Eur Soc Laser Dermatol. 2009;11:118-124.
- Karsai S, Schmitt L, Raulin C. The pulsed-dye laser as an adjuvant treatment modality in acne vulgaris: a randomized controlled single-blinded trial. Br J Dermatol. 2010;163:395-401.
- Centers for Disease Control and Prevention. Outpatient antibiotic prescriptions—United States. annual report 2013.https://www.cdc.gov/antibiotic-use/community/pdfs/Annual-ReportSummary_2013.pdf. Accessed June 23, 2020.
- Zaenglein AL, Pathy AL, Schlosser BJ, et al. Guidelines of care for the management of acne vulgaris. J Am Acad Dermatol. 2016;74:945-973.e33.
Practice Points
- Acne is a common disease that may cause considerable physical and psychological morbidity. Numerous therapies are available, each with their respective risks and benefits.
- Military servicemembers face unique challenges in the management of acne due to operational and medical readiness considerations.
- Less conventional treatments such as photodynamic therapy and pulsed dye laser may be available to military servicemembers.
- Pulsed dye laser is an effective alternative treatment of acne, especially in an age of growing antibiotic resistance.
Why Is It That the Biggest Resistance With Fighting the Battle Against Bacterial Resistance Seems to Fall on Dermatology Clinicians?
This discussion focuses on antibiotic resistance in acne therapy but also includes general principles related to this subject. “Seeing is believing” is a concept we have all heard many times, and we generally can all agree with and relate to what this is saying to us. However, it is harder to get a consensus of agreement on concepts that are happening beneath the surface but are not visibly apparent. Antibiotic resistance is a concept that falls into this latter category, especially in acne treatment. Many clinicians are not convinced antibiotic resistance is clinically relevant, exclaiming “I just do not see it in my practice.” The problem is—especially in the case of acne where oral tetracycline agents commonly are prescribed—how does the clinician “see” antibiotic resistance? Clinicians do not obtain bacterial cultures or perform sensitivity testing as they might do when evaluating a suspected cutaneous infection such as folliculitis, an inflamed postsurgical wound, a purulent leg ulcer, or an abscess. Additionally, if the selected therapy is not as effective as anticipated, it may be attributed to the patient needing another type of treatment or something “stronger,” or maybe they are not fully compliant. In fact, a very possible reason for inadequate therapeutic response may be that the predominant Cutibacterium acnes strains in a particular case are proinflammatory, and many of the strains are not highly sensitive to the chosen antibiotic.1
In the United States, antibiotic resistance in C acnes is most prevalent with erythromycin, followed by clindamycin, tetracycline, doxycycline, and minocycline, respectively.2 The relative patterns of antibiotic resistance in specific geographic regions correlate with the magnitude of specific antibiotic use, and that consistent reduction in use of a given antibiotic in a community can reverse the prevalence of resistance to that antibiotic progressively over time.3 Combination therapy approaches to mitigate emergence of resistant bacteria during acne treatment with an exit plan explained up-front with the patient are important to reduce prolonged use or repeated cycles of antibiotic use and in some cases to circumvent antibiotic use and incorporate a different therapeutic approach.1-3 Interestingly, in a retrospective chart review of acne patients who were eventually treated with oral isotretinoin at dermatology practices within a major university health system, approximately two-thirds received oral antibiotics for 6 months or longer and one-third for 1 year or longer.4 It is easy for all of us to have good intentions; however, in reality it is not always easy, practical, or in the best interest of the patient to stringently enforce recommendations that are determined not to be the best option at that time. Patients get a vote, too, as long as they are fully informed of benefits vs risks.
The concern about emergence of less-sensitive bacteria during acne antibiotic treatment is not limited to discussion of C acnes resistance. Use of both oral and topical antibiotics creates “ecologic mischief,” which is the emergence of less-sensitive strains of other bacteria exposed to the antibiotic—both commensal and opportunistic—especially at anatomic sites such as the skin, nasopharyngeal region, and gastrointestinal and genitourinary tracts.5-7 Application of topical erythromycin to the face can induce erythromycin-resistant bacteria such as staphylococci on the face as well as at remote sites such as the nares (nasal vestibule) and the back.6 Antibiotics used to treat acne, predominantly oral tetracyclines, showed positive oropharyngeal cultures for Streptococcus pyogenes in 33% (13/39) of treated patients; among these positive cultures, 85% (11/13) were resistant to at least one tetracycline antibiotic.7 Importantly, the streptococcal colonization of the oropharynx in individuals taking an oral antibiotic for acne may not induce a clinically apparent pharyngitis in that individual, but that person can carry and spread that streptococcal pathogen to others. In either case, the dermatology clinician, even if he/she suspects the connection related to antibiotic selection pressure and resistance, would not “see” the antibiotic resistance, as the individuals who develop a “sore throat” or strep throat do not seek care for this problem through a dermatology office.
The first formally organized and independent group in dermatology to address antibiotic use and resistance issues was the Scientific Panel on Antibiotic Use in Dermatology, which I put together in 2004 with James J. Leyden, MD (Philadelphia, Pennsylvania) and Guy F. Webster, MD (Hockessin, Delaware), and was comprised mostly of interested dermatologists with contributions from microbiologists and infectious disease specialists. A series of meetings, publications, and presentations have emerged from this group, which now falls under the auspices of the American Acne & Rosacea Society. Through the efforts of these organizations and other groups and companies with a strong interest in combating antibiotic resistance, we continue to see slow but steady progress in enlightening dermatology clinicians to think about if and when antibiotic therapy is needed and for how long. The subject of when antibiotics are not necessary also has been addressed, including both oral and topical antibiotics in many common scenarios encountered in dermatology practice.8 Examples include incision and drainage of an inflamed epidermal cyst without antibiotic therapy and use of white petrolatum instead of a topical antibiotic after most dermatologic procedures such as biopsies, tangential procedures, and closures after excisional procedures. Overall, the potential for topical antibiotics containing bacitracin and/or neomycin to induce allergic contact dermatitis is higher than the risk for postoperative wound infection. A major reason to avoid facilitating the emergence of antibiotic-resistant bacteria is that these organisms are efficient in packaging their resistance genes along with those from other bacteria, thus creating multidrug-resistant bacterial strains. This situation creates bigger challenges with trying to select effective therapies.
A cross-sectional analysis of antibiotics prescribed by dermatologists from January 1, 2008, to December 31, 2016, performed via a large commercial prescription claims database showed that among almost 1 million courses of oral antibiotics prescribed by approximately 12,000 unique dermatology prescribers, overall antibiotic prescribing decreased 36.6%, reflecting a drop of 1.23 courses per 100 visits, with much of the reduction occurring among extended antibiotic courses for acne and rosacea.9 Dermatology clinicians appear to be increasing their consideration of treatment alternatives such as oral spironolactone in adult female patients or earlier transition to oral isotretinoin therapy before starting another cycle with the same or a different oral antibiotic. Some have increased the use of physical device therapies. Importantly, we do not want to throw out the baby with the bathwater. Oral antibiotics remain important agents for treatment of moderate to severe inflammatory acne and in rosacea when subantibiotic-dose doxycycline is not accessible or is not effective after an adequate trial of therapy. Last but not least, a full-court press with an optimal topical regimen is the foundation of acne therapy, as monotherapy with an oral antibiotic for acne is considered dermatologic heresy and for good reason.
- Del Rosso JQ, Leyden JJ. Status report on antibiotic resistance: implications for the dermatologist. Dermatol Clin. 2007;25:127-132.
- Leyden JJ, Del Rosso JQ, Webster GF. Clinical considerations in the treatment of acne vulgaris and other inflammatory skin disorders: a status report. Dermatol Clin. 2009;27:1-15.
- Del Rosso JQ, Zeichner JA. The clinical relevance of antibiotic resistance: thirteen principles that every dermatologist needs to consider when prescribing antibiotic therapy. Dermatol Clin. 2016;34:167-173.
- Nagler AR, Milam EC, Orlow SJ. The use of oral antibiotics before isotretinoin therapy in patients with acne. J Am Acad Dermatol. 2016;74:273-279.
- Del Rosso JQ, Kim GK. Topical antibiotics: therapeutic value or ecologic mischief? Dermatol Ther. 2009;22:398-406.
- Bowe WP, Leyden JJ. Clinical implications of antibiotic resistance: risk of systemic infection from Staphylococcus and Streptococcus. In: Shalita AR, Del Rosso JQ, Webster GF, eds. Acne Vulgaris. London, England: Informa Healthcare; 2011:125-133.
- Levy RM, Huang EY, Roling D, et al. Effect of antibiotics on the oropharyngeal flora in patients with acne. Arch Dermatol. 2003;139:467-471.
- Hirschmann JV. When antibiotics are unnecessary. Dermatol Clin. 2009;27:75-83.
- Barbieri JS, Bhate K, Hartnett KP, et al. Trends in oral antibiotic prescription in dermatology, 2008 to 2016. JAMA Dermatol. 2019;155:290-297.
This discussion focuses on antibiotic resistance in acne therapy but also includes general principles related to this subject. “Seeing is believing” is a concept we have all heard many times, and we generally can all agree with and relate to what this is saying to us. However, it is harder to get a consensus of agreement on concepts that are happening beneath the surface but are not visibly apparent. Antibiotic resistance is a concept that falls into this latter category, especially in acne treatment. Many clinicians are not convinced antibiotic resistance is clinically relevant, exclaiming “I just do not see it in my practice.” The problem is—especially in the case of acne where oral tetracycline agents commonly are prescribed—how does the clinician “see” antibiotic resistance? Clinicians do not obtain bacterial cultures or perform sensitivity testing as they might do when evaluating a suspected cutaneous infection such as folliculitis, an inflamed postsurgical wound, a purulent leg ulcer, or an abscess. Additionally, if the selected therapy is not as effective as anticipated, it may be attributed to the patient needing another type of treatment or something “stronger,” or maybe they are not fully compliant. In fact, a very possible reason for inadequate therapeutic response may be that the predominant Cutibacterium acnes strains in a particular case are proinflammatory, and many of the strains are not highly sensitive to the chosen antibiotic.1
In the United States, antibiotic resistance in C acnes is most prevalent with erythromycin, followed by clindamycin, tetracycline, doxycycline, and minocycline, respectively.2 The relative patterns of antibiotic resistance in specific geographic regions correlate with the magnitude of specific antibiotic use, and that consistent reduction in use of a given antibiotic in a community can reverse the prevalence of resistance to that antibiotic progressively over time.3 Combination therapy approaches to mitigate emergence of resistant bacteria during acne treatment with an exit plan explained up-front with the patient are important to reduce prolonged use or repeated cycles of antibiotic use and in some cases to circumvent antibiotic use and incorporate a different therapeutic approach.1-3 Interestingly, in a retrospective chart review of acne patients who were eventually treated with oral isotretinoin at dermatology practices within a major university health system, approximately two-thirds received oral antibiotics for 6 months or longer and one-third for 1 year or longer.4 It is easy for all of us to have good intentions; however, in reality it is not always easy, practical, or in the best interest of the patient to stringently enforce recommendations that are determined not to be the best option at that time. Patients get a vote, too, as long as they are fully informed of benefits vs risks.
The concern about emergence of less-sensitive bacteria during acne antibiotic treatment is not limited to discussion of C acnes resistance. Use of both oral and topical antibiotics creates “ecologic mischief,” which is the emergence of less-sensitive strains of other bacteria exposed to the antibiotic—both commensal and opportunistic—especially at anatomic sites such as the skin, nasopharyngeal region, and gastrointestinal and genitourinary tracts.5-7 Application of topical erythromycin to the face can induce erythromycin-resistant bacteria such as staphylococci on the face as well as at remote sites such as the nares (nasal vestibule) and the back.6 Antibiotics used to treat acne, predominantly oral tetracyclines, showed positive oropharyngeal cultures for Streptococcus pyogenes in 33% (13/39) of treated patients; among these positive cultures, 85% (11/13) were resistant to at least one tetracycline antibiotic.7 Importantly, the streptococcal colonization of the oropharynx in individuals taking an oral antibiotic for acne may not induce a clinically apparent pharyngitis in that individual, but that person can carry and spread that streptococcal pathogen to others. In either case, the dermatology clinician, even if he/she suspects the connection related to antibiotic selection pressure and resistance, would not “see” the antibiotic resistance, as the individuals who develop a “sore throat” or strep throat do not seek care for this problem through a dermatology office.
The first formally organized and independent group in dermatology to address antibiotic use and resistance issues was the Scientific Panel on Antibiotic Use in Dermatology, which I put together in 2004 with James J. Leyden, MD (Philadelphia, Pennsylvania) and Guy F. Webster, MD (Hockessin, Delaware), and was comprised mostly of interested dermatologists with contributions from microbiologists and infectious disease specialists. A series of meetings, publications, and presentations have emerged from this group, which now falls under the auspices of the American Acne & Rosacea Society. Through the efforts of these organizations and other groups and companies with a strong interest in combating antibiotic resistance, we continue to see slow but steady progress in enlightening dermatology clinicians to think about if and when antibiotic therapy is needed and for how long. The subject of when antibiotics are not necessary also has been addressed, including both oral and topical antibiotics in many common scenarios encountered in dermatology practice.8 Examples include incision and drainage of an inflamed epidermal cyst without antibiotic therapy and use of white petrolatum instead of a topical antibiotic after most dermatologic procedures such as biopsies, tangential procedures, and closures after excisional procedures. Overall, the potential for topical antibiotics containing bacitracin and/or neomycin to induce allergic contact dermatitis is higher than the risk for postoperative wound infection. A major reason to avoid facilitating the emergence of antibiotic-resistant bacteria is that these organisms are efficient in packaging their resistance genes along with those from other bacteria, thus creating multidrug-resistant bacterial strains. This situation creates bigger challenges with trying to select effective therapies.
A cross-sectional analysis of antibiotics prescribed by dermatologists from January 1, 2008, to December 31, 2016, performed via a large commercial prescription claims database showed that among almost 1 million courses of oral antibiotics prescribed by approximately 12,000 unique dermatology prescribers, overall antibiotic prescribing decreased 36.6%, reflecting a drop of 1.23 courses per 100 visits, with much of the reduction occurring among extended antibiotic courses for acne and rosacea.9 Dermatology clinicians appear to be increasing their consideration of treatment alternatives such as oral spironolactone in adult female patients or earlier transition to oral isotretinoin therapy before starting another cycle with the same or a different oral antibiotic. Some have increased the use of physical device therapies. Importantly, we do not want to throw out the baby with the bathwater. Oral antibiotics remain important agents for treatment of moderate to severe inflammatory acne and in rosacea when subantibiotic-dose doxycycline is not accessible or is not effective after an adequate trial of therapy. Last but not least, a full-court press with an optimal topical regimen is the foundation of acne therapy, as monotherapy with an oral antibiotic for acne is considered dermatologic heresy and for good reason.
This discussion focuses on antibiotic resistance in acne therapy but also includes general principles related to this subject. “Seeing is believing” is a concept we have all heard many times, and we generally can all agree with and relate to what this is saying to us. However, it is harder to get a consensus of agreement on concepts that are happening beneath the surface but are not visibly apparent. Antibiotic resistance is a concept that falls into this latter category, especially in acne treatment. Many clinicians are not convinced antibiotic resistance is clinically relevant, exclaiming “I just do not see it in my practice.” The problem is—especially in the case of acne where oral tetracycline agents commonly are prescribed—how does the clinician “see” antibiotic resistance? Clinicians do not obtain bacterial cultures or perform sensitivity testing as they might do when evaluating a suspected cutaneous infection such as folliculitis, an inflamed postsurgical wound, a purulent leg ulcer, or an abscess. Additionally, if the selected therapy is not as effective as anticipated, it may be attributed to the patient needing another type of treatment or something “stronger,” or maybe they are not fully compliant. In fact, a very possible reason for inadequate therapeutic response may be that the predominant Cutibacterium acnes strains in a particular case are proinflammatory, and many of the strains are not highly sensitive to the chosen antibiotic.1
In the United States, antibiotic resistance in C acnes is most prevalent with erythromycin, followed by clindamycin, tetracycline, doxycycline, and minocycline, respectively.2 The relative patterns of antibiotic resistance in specific geographic regions correlate with the magnitude of specific antibiotic use, and that consistent reduction in use of a given antibiotic in a community can reverse the prevalence of resistance to that antibiotic progressively over time.3 Combination therapy approaches to mitigate emergence of resistant bacteria during acne treatment with an exit plan explained up-front with the patient are important to reduce prolonged use or repeated cycles of antibiotic use and in some cases to circumvent antibiotic use and incorporate a different therapeutic approach.1-3 Interestingly, in a retrospective chart review of acne patients who were eventually treated with oral isotretinoin at dermatology practices within a major university health system, approximately two-thirds received oral antibiotics for 6 months or longer and one-third for 1 year or longer.4 It is easy for all of us to have good intentions; however, in reality it is not always easy, practical, or in the best interest of the patient to stringently enforce recommendations that are determined not to be the best option at that time. Patients get a vote, too, as long as they are fully informed of benefits vs risks.
The concern about emergence of less-sensitive bacteria during acne antibiotic treatment is not limited to discussion of C acnes resistance. Use of both oral and topical antibiotics creates “ecologic mischief,” which is the emergence of less-sensitive strains of other bacteria exposed to the antibiotic—both commensal and opportunistic—especially at anatomic sites such as the skin, nasopharyngeal region, and gastrointestinal and genitourinary tracts.5-7 Application of topical erythromycin to the face can induce erythromycin-resistant bacteria such as staphylococci on the face as well as at remote sites such as the nares (nasal vestibule) and the back.6 Antibiotics used to treat acne, predominantly oral tetracyclines, showed positive oropharyngeal cultures for Streptococcus pyogenes in 33% (13/39) of treated patients; among these positive cultures, 85% (11/13) were resistant to at least one tetracycline antibiotic.7 Importantly, the streptococcal colonization of the oropharynx in individuals taking an oral antibiotic for acne may not induce a clinically apparent pharyngitis in that individual, but that person can carry and spread that streptococcal pathogen to others. In either case, the dermatology clinician, even if he/she suspects the connection related to antibiotic selection pressure and resistance, would not “see” the antibiotic resistance, as the individuals who develop a “sore throat” or strep throat do not seek care for this problem through a dermatology office.
The first formally organized and independent group in dermatology to address antibiotic use and resistance issues was the Scientific Panel on Antibiotic Use in Dermatology, which I put together in 2004 with James J. Leyden, MD (Philadelphia, Pennsylvania) and Guy F. Webster, MD (Hockessin, Delaware), and was comprised mostly of interested dermatologists with contributions from microbiologists and infectious disease specialists. A series of meetings, publications, and presentations have emerged from this group, which now falls under the auspices of the American Acne & Rosacea Society. Through the efforts of these organizations and other groups and companies with a strong interest in combating antibiotic resistance, we continue to see slow but steady progress in enlightening dermatology clinicians to think about if and when antibiotic therapy is needed and for how long. The subject of when antibiotics are not necessary also has been addressed, including both oral and topical antibiotics in many common scenarios encountered in dermatology practice.8 Examples include incision and drainage of an inflamed epidermal cyst without antibiotic therapy and use of white petrolatum instead of a topical antibiotic after most dermatologic procedures such as biopsies, tangential procedures, and closures after excisional procedures. Overall, the potential for topical antibiotics containing bacitracin and/or neomycin to induce allergic contact dermatitis is higher than the risk for postoperative wound infection. A major reason to avoid facilitating the emergence of antibiotic-resistant bacteria is that these organisms are efficient in packaging their resistance genes along with those from other bacteria, thus creating multidrug-resistant bacterial strains. This situation creates bigger challenges with trying to select effective therapies.
A cross-sectional analysis of antibiotics prescribed by dermatologists from January 1, 2008, to December 31, 2016, performed via a large commercial prescription claims database showed that among almost 1 million courses of oral antibiotics prescribed by approximately 12,000 unique dermatology prescribers, overall antibiotic prescribing decreased 36.6%, reflecting a drop of 1.23 courses per 100 visits, with much of the reduction occurring among extended antibiotic courses for acne and rosacea.9 Dermatology clinicians appear to be increasing their consideration of treatment alternatives such as oral spironolactone in adult female patients or earlier transition to oral isotretinoin therapy before starting another cycle with the same or a different oral antibiotic. Some have increased the use of physical device therapies. Importantly, we do not want to throw out the baby with the bathwater. Oral antibiotics remain important agents for treatment of moderate to severe inflammatory acne and in rosacea when subantibiotic-dose doxycycline is not accessible or is not effective after an adequate trial of therapy. Last but not least, a full-court press with an optimal topical regimen is the foundation of acne therapy, as monotherapy with an oral antibiotic for acne is considered dermatologic heresy and for good reason.
- Del Rosso JQ, Leyden JJ. Status report on antibiotic resistance: implications for the dermatologist. Dermatol Clin. 2007;25:127-132.
- Leyden JJ, Del Rosso JQ, Webster GF. Clinical considerations in the treatment of acne vulgaris and other inflammatory skin disorders: a status report. Dermatol Clin. 2009;27:1-15.
- Del Rosso JQ, Zeichner JA. The clinical relevance of antibiotic resistance: thirteen principles that every dermatologist needs to consider when prescribing antibiotic therapy. Dermatol Clin. 2016;34:167-173.
- Nagler AR, Milam EC, Orlow SJ. The use of oral antibiotics before isotretinoin therapy in patients with acne. J Am Acad Dermatol. 2016;74:273-279.
- Del Rosso JQ, Kim GK. Topical antibiotics: therapeutic value or ecologic mischief? Dermatol Ther. 2009;22:398-406.
- Bowe WP, Leyden JJ. Clinical implications of antibiotic resistance: risk of systemic infection from Staphylococcus and Streptococcus. In: Shalita AR, Del Rosso JQ, Webster GF, eds. Acne Vulgaris. London, England: Informa Healthcare; 2011:125-133.
- Levy RM, Huang EY, Roling D, et al. Effect of antibiotics on the oropharyngeal flora in patients with acne. Arch Dermatol. 2003;139:467-471.
- Hirschmann JV. When antibiotics are unnecessary. Dermatol Clin. 2009;27:75-83.
- Barbieri JS, Bhate K, Hartnett KP, et al. Trends in oral antibiotic prescription in dermatology, 2008 to 2016. JAMA Dermatol. 2019;155:290-297.
- Del Rosso JQ, Leyden JJ. Status report on antibiotic resistance: implications for the dermatologist. Dermatol Clin. 2007;25:127-132.
- Leyden JJ, Del Rosso JQ, Webster GF. Clinical considerations in the treatment of acne vulgaris and other inflammatory skin disorders: a status report. Dermatol Clin. 2009;27:1-15.
- Del Rosso JQ, Zeichner JA. The clinical relevance of antibiotic resistance: thirteen principles that every dermatologist needs to consider when prescribing antibiotic therapy. Dermatol Clin. 2016;34:167-173.
- Nagler AR, Milam EC, Orlow SJ. The use of oral antibiotics before isotretinoin therapy in patients with acne. J Am Acad Dermatol. 2016;74:273-279.
- Del Rosso JQ, Kim GK. Topical antibiotics: therapeutic value or ecologic mischief? Dermatol Ther. 2009;22:398-406.
- Bowe WP, Leyden JJ. Clinical implications of antibiotic resistance: risk of systemic infection from Staphylococcus and Streptococcus. In: Shalita AR, Del Rosso JQ, Webster GF, eds. Acne Vulgaris. London, England: Informa Healthcare; 2011:125-133.
- Levy RM, Huang EY, Roling D, et al. Effect of antibiotics on the oropharyngeal flora in patients with acne. Arch Dermatol. 2003;139:467-471.
- Hirschmann JV. When antibiotics are unnecessary. Dermatol Clin. 2009;27:75-83.
- Barbieri JS, Bhate K, Hartnett KP, et al. Trends in oral antibiotic prescription in dermatology, 2008 to 2016. JAMA Dermatol. 2019;155:290-297.
