Acne and Rosacea continue to be frustrating conditions to control for both patients and physicians. And while the issue of antibiotic resistant strains of Propionibacterium acnes hangs on the dermatological horizon like a dark cloud, there is a lot of good news regarding both of these conditions.
Ongoing research continues to reveal new data about acne and rosacea, data that should lead to more effective therapy options. New medications, new formulations of existing medications, new treatment approaches and even rosacea-targeting light therapies are available or may soon be available to treat these persistent conditions.
What’s New in Acne Treatment?
Of growing concern to dermatologists is the apparent increasing resistance to medications shown by strains of P. acnes. In the classic sense, resistance means that the dose needed to kill an organism exceeds the concentration that the drug can achieve in the compartment where the organism is living.
“Since the follicular concentration of a compound cannot be measured for technical reasons, other methods must be used to assess the relative resistance of P. acnes,” explains James J. Leyden, M.D., Professor Emeritus of Dermatology at the University of Pennsylvania School of Medicine. “One such method is to correlate outcomes in patients who have been demonstrated to have less sensitive — or more resistant — strains. In studies, these patients did not fare as well as those who have more sensitive strains.”
In one study, sub-groups of about 150 patients each were treated with various regimens. With a dosage of minocycline of 100 mg a day, there was a huge difference in clinical outcomes of at least moderate improvement, with the less sensitive groups showing the least improvement. And topical formulations of benzoyl peroxide, either alone or in combination with erythromycin, were as effective in this population as minocycline.
“There is no decreased sensitivity to benzoyl peroxide, so the idea that topical benzoyl peroxide could be as effective as minocycline is a reflection of this changing resistance to certain medications,” says Dr. Leyden.
A recent study showed that in patients who carry high numbers of less sensitive or “resistant” strains of P. acnes, isotretinoin substantially reduced, but not totally eradicated, these organisms.
“I think that as physicians, we all need to be aware of the issue of medication-resistant microbes and take steps to ensure that we are not over using antibiotic therapies, especially since we deal with chronic conditions,” explains Dr. Leyden.
Antibiotic Alternatives
While it approved dapsone gel 5% (Aczone) for the topical treatment of acne vulgaris, the FDA expressed concerns about glucose-6-phosphate dehydrogenase (G6PD) deficiency and patients must be screened for this. However, according to Dr. Leyden, in clinical trials involving about 30 patients with G6PD deficiency, topical dapsone had no effect on their hemoglobin.
“An ongoing study is looking at another cohort of patients who are G6PD deficient. If that study fails to demonstrate any clinical issues, then perhaps the FDA will agree that G6PD testing is not necessary before treating a patient with topical dapsone,” says Dr. Leyden. “This medication has been shown to have an in vivo anti-microbial effect. We know systemically it has a lot of anti-inflammatory effects and any potential anti-inflammatory effects topically would be useful in acne.”
Among topical retinoids, there’s a new, higher-strength adapalene 0.3%, which a study shows is well tolerated and more effective than the available 0.1% concentration (Differin). Dr. Leyden says that this new formulation is awaiting a decision by the FDA. Two topical combination formulations of tretinoin and clindamycin are also being evaluated by the FDA.
According to Dr. Leyden, a study involving therapy with a combination of doxycycline and topical adapalene showed at the end of the 12-week treatment that the combination was superior. The patients entered a 16-week maintenance period and were randomized for either topical adapalene or a vehicle. After 16 weeks, patients on topical adapalene showed a significantly better maintenance rate.
A second study, involving more intense inflammatory acne, evaluated the efficacy of three maintenance therapies (tazarotene, minocycline hydrochloride, and tazarotene plus minocycline) in sustaining improvement attained after therapy with topical tazarotene plus 20-mg minocycline. Those who reached the 75% improvement — about 80% of the patients — were randomized to
12 weeks of maintenance therapy with tazarotene gel plus placebo capsules, vehicle gel plus minocycline capsules, or tazarotene gel plus minocycline capsules.
“All three treatments were effective in sustaining improvements in acne. After 12 weeks of maintenance therapy, the mean reductions from baseline in non-inflammatory and inflammatory lesion count, respectively, were 60% and 54% for tazarotene, 52% and 66% for minocycline, and 64% and 66% for tazarotene plus minocycline,” says Dr. Leyden. At week 24, more than 80% of patients in each group had maintained at least 50% global improvement from baseline, and more than 50% had maintained at least 75% global improvement.
Controlling Inflammation
Controlling the inflammation that is a result of acne is a critical component in the overall treatment of the disease. According to Neal Bhatia, M.D., Assistant Clinical Professor at the University of Wisconsin, acne-related inflammation involves balances between cellular and humoral.
“It all has to do with the way the T-helper cell is activated. We have the TH1 profile, which is cellular and the TH2 profile, which is antibody mediated,” explains Dr. Bhatia. “With acne, there are high levels of interleukin 1, 12, and tumor necrosis factor, all of which impact inflammation. Interleukin 1 is the most critical of these because of the way it impacts inflammation cascades.”
P. acnes also interacts with toll-like receptor 2 (TLR-2) to release interleukin 1 promoting additional inflammation cascades. Topical retinoids work by inhibiting the expression of TLR-2, reducing the impact of P. acnes and significantly reducing the initial inflammatory cascades.
“P. acnes carries a lot of weapons for breaking down tissue, creating inflammation, and infecting adhesion molecules. The four basic mechanisms for what P. acnes does to inflammation are based on how it attacks our own system,” explains Dr. Bhatia. “It’s attracting lymphocytes, neutrophils, and some of the other carrier cells. It has a lot to do with activating complement to set the ball into motion, as well as using production of free fatty acids, which constantly promotes a fuel for the activity, in addition to stimulating TLR-2 expression.”
According to Dr. Bhatia, acne has its own inflammation component that affects fibrosis, impairs wound healing and leads to scarring. Also, P. acnes affects the TH1 cytokine response, which is known to be anti-fibrotic. Finally, there’s a high level of macrophages and dendritic cells compared to lymphocytes, resulting in additional scarring.
Anti-Inflammatory Drugs
Acne has its own immunomodulator category of drugs that also serve as anti-inflammatory drugs. Retinoids act as anti-inflammatory drugs by binding to a receptor in the nucleus, which then forms a negative feedback mechanism against a neurotransmitter called AP1. At that point, there’s blockage of the transcription that is necessary to promote cytokine release.
Topical antibiotics also have a mechanism against inflammation. According to Dr. Bhatia, there is a direct effect against P. acnes and also an indirect effect on the ability to promote comedogenesis. “Tetracyclines have several different mechanisms. Down-regulating cytokines and impacting nitric oxide are important for intracellular killing as well as for the way that neutrophils and some of the other lymphocyte markers are recruited,” explains Dr. Bhatia. “But again it’s separating that antibiotic effect as well as the effect on inflammation.”
Azelaic acid (Finacea) also has an anti-inflammation action. “Azelaic acid inhibits the generation of reactive oxygen species by neutrophils which reduces oxidative tissue injury at the sites of acne inflammation,” explains Dr. Bhatia.
Hormone Therapy
Androgens play a critical role in acne because they increase the size of the sebaceous gland and increase sebum production. The primary sources of androgen are the ovary, the adrenal gland under the influence of ACTH, and the skin. Studies show that people who lack functional androgen receptors do not make adult levels of sebum and do not develop acne. Reducing sebum production is the main goal of hormone therapy.
“We’re not certain of the clinical significance of the skin production of androgens because a lot is being made by the ovaries or testes. But, the skin is a large organ, so even if it’s involved in any respect in androgen metabolism, it could play a role in acne,” says Diane M. Thiboutot M.D., a Professor of Dermatology at the Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center. “It might be that women with acne may have greater local production of androgen in their skin that could in part account for the presence of acne. Many of our female patients with acne were found to have high levels of testosterone.”
According to Dr. Thiboutot, hormonal therapy is appropriate if there is excess androgen production by the adrenal gland or by the ovary. It’s also very useful as an adjunctive therapy in women with normal serum androgens, and in some cases it can be useful as an alternative to repeat courses of isotretinoin (Accutane, Amnesteem, Claravis, Sotret).
Typical hormonal therapy medications in the United States include oral contraceptives, glucocorticoids, and some androgen-receptor blockers. The androgen receptor blockers are oral spironolactone and cyproterone acetate, which is not available in the United States, and flutamide.
“Low-dose spironolactone works well in women with acne. Many patients who do very well with 25 mg a day or 25 mg twice daily, so it can be a very effective addition to treatment,” explains Dr. Thiboutot. “Unfortunately, topical spironolactone doesn’t affect sebum production.”
Agents that block adrenal production of androgens are oral contraceptives and low-dose glucocorticoids. “Most times we use prednisone at a low dose because there seems to be increased risk of adrenal suppression with dexamethasone,” says Dr. Thiboutot. “While we have patients on treatment with dexamethasone or prednisone for congenital adrenal hyperplasia, it’s important to know whether your therapy is actually reducing those androgens, so you may want to check the serum dehydroepiandrosterone sulfate (DHEAS) to see if you’re bringing that down into the normal range.”
Even on low-dose prednisone, adrenal suppression could still occur, so you may want to refer to an endocrinologist or an internist to have cortisol checked or to check adrenal function in general.
Oral Contraceptives
Oral contraceptives contain a low-dose of an estrogen and a progestin. Studies show that most oral contraceptives used to treat acne have similar effectiveness, around a 45% reduction in inflammatory lesions. However, a novel progestin has been introduced called drospirenone, which is a derivative of 17-spironolactone, and it is found in the Yasmin brand oral contraceptive, which contains about 30 µg of estrogen.
According to Dr. Thiboutot, a small trial for this contraceptive involving 128 women showed about a 60% lesion reduction over 9 months. Phase III trials for this therapy are in progress.
Many patients are concerned about the interaction between oral contraceptives and antibiotics. “The gut flora is needed to cleave estrogen from the conjugated estrogen in the oral contraceptives, and the risk of an interaction is greatest with tetracyclines,” says Dr. Thiboutot. “But the number of reports in the literature is actually small. However, I think that we should discuss this with our patients.”
New Rosacea Treatment
Despite widespread acceptance of their use in clinical practice for more than four decades, there has not been an abundance of controlled trials on the use of oral tetracycline agents for rosacea. A review of the literature by James Q. Del Rosso, D.O., a dermatologist in private practice in Las Vegas, uncovered only 155 total patients with rosacea treated in studies with antibiotic doses of oral tetracyclines.
“Our use of these agents is primarily based on clinical experience and the fact that we know they work. Also, overall, their safety profiles have been favorable,” says Dr. Del Rosso. “But we don’t have definitive evidence that P. acnes or any other bacterium is involved in the pathogenesis of rosacea.”
Dr. Del Rosso says a recent article in the Journal of the American Academy of Dermatology outlined a variety of different anti-inflammatory effects of tetracyclines. “Why look at anti-inflammatory effects in rosacea?” he asks. “It’s a chronic disease associated with inflammation, so we know we’re going to administer long-term therapy in many patients to sustain control, and an antibiotic effect is not proven to be needed. Anti-inflammatory activity appears to play a key role, however.”
What are the pharmacologic effects of tetracycline agents? “There’s a dose-related antibiotic effect. In order to reduce bacteria, a given drug must achieve certain inhibitory concentrations to exhibit antibiotic activity. Distinct from their dose-related antibiotic effect, there are a variety of anti-inflammatory mechanisms associated with tetracyclines. However, there is a dosage separation between anti-inflammatory and antibiotic activities that has been identified only with doxycycline,” explains Dr. Del Rosso.
Low-dose doxycycline (50 mg to 100 mg a day) is not synonymous with non-antibiotic effect, as even a single dose of 50 mg exerts antibiotic selection pressure for about 2 to 4 hours. High-dose doxycycline (150 to 200 mg a day) is at an antibiotic dose level. There is now an FDA-approved 40-mg controlled-release capsule formulation of doxycycline (Oracea) for the treatment of rosacea in adults, referred to specifically as anti-inflammatory dose doxycycline. This dose is anti-inflammatory without antibiotic activity, which removes any potential issues regarding emergence of antibiotic resistance, especially with long-term administration. A lack of antimicrobial activity has been confirmed based on pharmacokinetic data and microbiologic studies completed over durations of up to 18 months.
According to Dr. Del Rosso, two pivotal parallel studies were conducted to assess the efficacy of anti-inflammatory dose doxycycline in adults with moderate to severe rosacea.
In these Phase III 16-week trials, patients were treated with 40 mg doxycycline controlled-release once a day or placebo once a day. The primary efficacy parameter was a change in the total inflammatory lesion count from baseline to endpoint at week 16. In both studies, there was decreased inflammatory lesion counts in both the actively treated and placebo groups, but the reduction in lesions was much greater in the actively treated group with statistical significance observed in both trials.
No plateau effect was observed in actively treated patients in both studies, indicating continued improvements in lesion reduction throughout the entire 16 weeks of use. Additionally, both studies showed some reduction in erythema. In terms of safety, none of the study patients developed photosensitivity. Nor did any of the female patients treated with active drug in both trials (n=185) develop vaginal candidiasis, an observation consistent with the lack of antibiotic effect of anti-inflammatory dose doxycycline.
Phototherapy for Rosacea
According to Emil Tanghetti, M.D., Director of the Center for Dermatology and Laser Surgery in Sacramento, work continues on developing the phototherapy technologies and treatment approaches needed to identify and hit the correct targets to treat rosacea.
The challenges are in being able to penetrate deeply enough to hit the correct targets with the right energies and do so safely. Researchers are looking into better identifying the specific components of the condition, such as sebum and vascular components, that need to be targeted.
Ongoing research by Dr. Tanghetti and others continues to improve the technology and to apply the lessons learned from treating similar conditions with light sources. “Contradicting conventional wisdom, we found that multiple pulses with pulsed dye lasers actually penetrated deeper if we waited longer between pulses,” says Dr. Tanghetti. “Our testing also showed that using various wavelengths in combination allowed us to hit deeper lesions. We developed a prototype laser that shot a pulsed dye followed by an Nd:YAG.”
Dr. Tanghetti believes this technology offers promise and is confident that more effective and affordable phototherapies for rosacea are on the horizon.
A Growing Armamentarium
While acne and rosacea continue to be difficult to treat and control, we have many choices of treatment to help patients combat these conditions. We continue to learn more about acne and rosacea with ongoing research and are better learning how to treat the cause of these problems.
Acne and Rosacea continue to be frustrating conditions to control for both patients and physicians. And while the issue of antibiotic resistant strains of Propionibacterium acnes hangs on the dermatological horizon like a dark cloud, there is a lot of good news regarding both of these conditions.
Ongoing research continues to reveal new data about acne and rosacea, data that should lead to more effective therapy options. New medications, new formulations of existing medications, new treatment approaches and even rosacea-targeting light therapies are available or may soon be available to treat these persistent conditions.
What’s New in Acne Treatment?
Of growing concern to dermatologists is the apparent increasing resistance to medications shown by strains of P. acnes. In the classic sense, resistance means that the dose needed to kill an organism exceeds the concentration that the drug can achieve in the compartment where the organism is living.
“Since the follicular concentration of a compound cannot be measured for technical reasons, other methods must be used to assess the relative resistance of P. acnes,” explains James J. Leyden, M.D., Professor Emeritus of Dermatology at the University of Pennsylvania School of Medicine. “One such method is to correlate outcomes in patients who have been demonstrated to have less sensitive — or more resistant — strains. In studies, these patients did not fare as well as those who have more sensitive strains.”
In one study, sub-groups of about 150 patients each were treated with various regimens. With a dosage of minocycline of 100 mg a day, there was a huge difference in clinical outcomes of at least moderate improvement, with the less sensitive groups showing the least improvement. And topical formulations of benzoyl peroxide, either alone or in combination with erythromycin, were as effective in this population as minocycline.
“There is no decreased sensitivity to benzoyl peroxide, so the idea that topical benzoyl peroxide could be as effective as minocycline is a reflection of this changing resistance to certain medications,” says Dr. Leyden.
A recent study showed that in patients who carry high numbers of less sensitive or “resistant” strains of P. acnes, isotretinoin substantially reduced, but not totally eradicated, these organisms.
“I think that as physicians, we all need to be aware of the issue of medication-resistant microbes and take steps to ensure that we are not over using antibiotic therapies, especially since we deal with chronic conditions,” explains Dr. Leyden.
Antibiotic Alternatives
While it approved dapsone gel 5% (Aczone) for the topical treatment of acne vulgaris, the FDA expressed concerns about glucose-6-phosphate dehydrogenase (G6PD) deficiency and patients must be screened for this. However, according to Dr. Leyden, in clinical trials involving about 30 patients with G6PD deficiency, topical dapsone had no effect on their hemoglobin.
“An ongoing study is looking at another cohort of patients who are G6PD deficient. If that study fails to demonstrate any clinical issues, then perhaps the FDA will agree that G6PD testing is not necessary before treating a patient with topical dapsone,” says Dr. Leyden. “This medication has been shown to have an in vivo anti-microbial effect. We know systemically it has a lot of anti-inflammatory effects and any potential anti-inflammatory effects topically would be useful in acne.”
Among topical retinoids, there’s a new, higher-strength adapalene 0.3%, which a study shows is well tolerated and more effective than the available 0.1% concentration (Differin). Dr. Leyden says that this new formulation is awaiting a decision by the FDA. Two topical combination formulations of tretinoin and clindamycin are also being evaluated by the FDA.
According to Dr. Leyden, a study involving therapy with a combination of doxycycline and topical adapalene showed at the end of the 12-week treatment that the combination was superior. The patients entered a 16-week maintenance period and were randomized for either topical adapalene or a vehicle. After 16 weeks, patients on topical adapalene showed a significantly better maintenance rate.
A second study, involving more intense inflammatory acne, evaluated the efficacy of three maintenance therapies (tazarotene, minocycline hydrochloride, and tazarotene plus minocycline) in sustaining improvement attained after therapy with topical tazarotene plus 20-mg minocycline. Those who reached the 75% improvement — about 80% of the patients — were randomized to
12 weeks of maintenance therapy with tazarotene gel plus placebo capsules, vehicle gel plus minocycline capsules, or tazarotene gel plus minocycline capsules.
“All three treatments were effective in sustaining improvements in acne. After 12 weeks of maintenance therapy, the mean reductions from baseline in non-inflammatory and inflammatory lesion count, respectively, were 60% and 54% for tazarotene, 52% and 66% for minocycline, and 64% and 66% for tazarotene plus minocycline,” says Dr. Leyden. At week 24, more than 80% of patients in each group had maintained at least 50% global improvement from baseline, and more than 50% had maintained at least 75% global improvement.
Controlling Inflammation
Controlling the inflammation that is a result of acne is a critical component in the overall treatment of the disease. According to Neal Bhatia, M.D., Assistant Clinical Professor at the University of Wisconsin, acne-related inflammation involves balances between cellular and humoral.
“It all has to do with the way the T-helper cell is activated. We have the TH1 profile, which is cellular and the TH2 profile, which is antibody mediated,” explains Dr. Bhatia. “With acne, there are high levels of interleukin 1, 12, and tumor necrosis factor, all of which impact inflammation. Interleukin 1 is the most critical of these because of the way it impacts inflammation cascades.”
P. acnes also interacts with toll-like receptor 2 (TLR-2) to release interleukin 1 promoting additional inflammation cascades. Topical retinoids work by inhibiting the expression of TLR-2, reducing the impact of P. acnes and significantly reducing the initial inflammatory cascades.
“P. acnes carries a lot of weapons for breaking down tissue, creating inflammation, and infecting adhesion molecules. The four basic mechanisms for what P. acnes does to inflammation are based on how it attacks our own system,” explains Dr. Bhatia. “It’s attracting lymphocytes, neutrophils, and some of the other carrier cells. It has a lot to do with activating complement to set the ball into motion, as well as using production of free fatty acids, which constantly promotes a fuel for the activity, in addition to stimulating TLR-2 expression.”
According to Dr. Bhatia, acne has its own inflammation component that affects fibrosis, impairs wound healing and leads to scarring. Also, P. acnes affects the TH1 cytokine response, which is known to be anti-fibrotic. Finally, there’s a high level of macrophages and dendritic cells compared to lymphocytes, resulting in additional scarring.
Anti-Inflammatory Drugs
Acne has its own immunomodulator category of drugs that also serve as anti-inflammatory drugs. Retinoids act as anti-inflammatory drugs by binding to a receptor in the nucleus, which then forms a negative feedback mechanism against a neurotransmitter called AP1. At that point, there’s blockage of the transcription that is necessary to promote cytokine release.
Topical antibiotics also have a mechanism against inflammation. According to Dr. Bhatia, there is a direct effect against P. acnes and also an indirect effect on the ability to promote comedogenesis. “Tetracyclines have several different mechanisms. Down-regulating cytokines and impacting nitric oxide are important for intracellular killing as well as for the way that neutrophils and some of the other lymphocyte markers are recruited,” explains Dr. Bhatia. “But again it’s separating that antibiotic effect as well as the effect on inflammation.”
Azelaic acid (Finacea) also has an anti-inflammation action. “Azelaic acid inhibits the generation of reactive oxygen species by neutrophils which reduces oxidative tissue injury at the sites of acne inflammation,” explains Dr. Bhatia.
Hormone Therapy
Androgens play a critical role in acne because they increase the size of the sebaceous gland and increase sebum production. The primary sources of androgen are the ovary, the adrenal gland under the influence of ACTH, and the skin. Studies show that people who lack functional androgen receptors do not make adult levels of sebum and do not develop acne. Reducing sebum production is the main goal of hormone therapy.
“We’re not certain of the clinical significance of the skin production of androgens because a lot is being made by the ovaries or testes. But, the skin is a large organ, so even if it’s involved in any respect in androgen metabolism, it could play a role in acne,” says Diane M. Thiboutot M.D., a Professor of Dermatology at the Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center. “It might be that women with acne may have greater local production of androgen in their skin that could in part account for the presence of acne. Many of our female patients with acne were found to have high levels of testosterone.”
According to Dr. Thiboutot, hormonal therapy is appropriate if there is excess androgen production by the adrenal gland or by the ovary. It’s also very useful as an adjunctive therapy in women with normal serum androgens, and in some cases it can be useful as an alternative to repeat courses of isotretinoin (Accutane, Amnesteem, Claravis, Sotret).
Typical hormonal therapy medications in the United States include oral contraceptives, glucocorticoids, and some androgen-receptor blockers. The androgen receptor blockers are oral spironolactone and cyproterone acetate, which is not available in the United States, and flutamide.
“Low-dose spironolactone works well in women with acne. Many patients who do very well with 25 mg a day or 25 mg twice daily, so it can be a very effective addition to treatment,” explains Dr. Thiboutot. “Unfortunately, topical spironolactone doesn’t affect sebum production.”
Agents that block adrenal production of androgens are oral contraceptives and low-dose glucocorticoids. “Most times we use prednisone at a low dose because there seems to be increased risk of adrenal suppression with dexamethasone,” says Dr. Thiboutot. “While we have patients on treatment with dexamethasone or prednisone for congenital adrenal hyperplasia, it’s important to know whether your therapy is actually reducing those androgens, so you may want to check the serum dehydroepiandrosterone sulfate (DHEAS) to see if you’re bringing that down into the normal range.”
Even on low-dose prednisone, adrenal suppression could still occur, so you may want to refer to an endocrinologist or an internist to have cortisol checked or to check adrenal function in general.
Oral Contraceptives
Oral contraceptives contain a low-dose of an estrogen and a progestin. Studies show that most oral contraceptives used to treat acne have similar effectiveness, around a 45% reduction in inflammatory lesions. However, a novel progestin has been introduced called drospirenone, which is a derivative of 17-spironolactone, and it is found in the Yasmin brand oral contraceptive, which contains about 30 µg of estrogen.
According to Dr. Thiboutot, a small trial for this contraceptive involving 128 women showed about a 60% lesion reduction over 9 months. Phase III trials for this therapy are in progress.
Many patients are concerned about the interaction between oral contraceptives and antibiotics. “The gut flora is needed to cleave estrogen from the conjugated estrogen in the oral contraceptives, and the risk of an interaction is greatest with tetracyclines,” says Dr. Thiboutot. “But the number of reports in the literature is actually small. However, I think that we should discuss this with our patients.”
New Rosacea Treatment
Despite widespread acceptance of their use in clinical practice for more than four decades, there has not been an abundance of controlled trials on the use of oral tetracycline agents for rosacea. A review of the literature by James Q. Del Rosso, D.O., a dermatologist in private practice in Las Vegas, uncovered only 155 total patients with rosacea treated in studies with antibiotic doses of oral tetracyclines.
“Our use of these agents is primarily based on clinical experience and the fact that we know they work. Also, overall, their safety profiles have been favorable,” says Dr. Del Rosso. “But we don’t have definitive evidence that P. acnes or any other bacterium is involved in the pathogenesis of rosacea.”
Dr. Del Rosso says a recent article in the Journal of the American Academy of Dermatology outlined a variety of different anti-inflammatory effects of tetracyclines. “Why look at anti-inflammatory effects in rosacea?” he asks. “It’s a chronic disease associated with inflammation, so we know we’re going to administer long-term therapy in many patients to sustain control, and an antibiotic effect is not proven to be needed. Anti-inflammatory activity appears to play a key role, however.”
What are the pharmacologic effects of tetracycline agents? “There’s a dose-related antibiotic effect. In order to reduce bacteria, a given drug must achieve certain inhibitory concentrations to exhibit antibiotic activity. Distinct from their dose-related antibiotic effect, there are a variety of anti-inflammatory mechanisms associated with tetracyclines. However, there is a dosage separation between anti-inflammatory and antibiotic activities that has been identified only with doxycycline,” explains Dr. Del Rosso.
Low-dose doxycycline (50 mg to 100 mg a day) is not synonymous with non-antibiotic effect, as even a single dose of 50 mg exerts antibiotic selection pressure for about 2 to 4 hours. High-dose doxycycline (150 to 200 mg a day) is at an antibiotic dose level. There is now an FDA-approved 40-mg controlled-release capsule formulation of doxycycline (Oracea) for the treatment of rosacea in adults, referred to specifically as anti-inflammatory dose doxycycline. This dose is anti-inflammatory without antibiotic activity, which removes any potential issues regarding emergence of antibiotic resistance, especially with long-term administration. A lack of antimicrobial activity has been confirmed based on pharmacokinetic data and microbiologic studies completed over durations of up to 18 months.
According to Dr. Del Rosso, two pivotal parallel studies were conducted to assess the efficacy of anti-inflammatory dose doxycycline in adults with moderate to severe rosacea.
In these Phase III 16-week trials, patients were treated with 40 mg doxycycline controlled-release once a day or placebo once a day. The primary efficacy parameter was a change in the total inflammatory lesion count from baseline to endpoint at week 16. In both studies, there was decreased inflammatory lesion counts in both the actively treated and placebo groups, but the reduction in lesions was much greater in the actively treated group with statistical significance observed in both trials.
No plateau effect was observed in actively treated patients in both studies, indicating continued improvements in lesion reduction throughout the entire 16 weeks of use. Additionally, both studies showed some reduction in erythema. In terms of safety, none of the study patients developed photosensitivity. Nor did any of the female patients treated with active drug in both trials (n=185) develop vaginal candidiasis, an observation consistent with the lack of antibiotic effect of anti-inflammatory dose doxycycline.
Phototherapy for Rosacea
According to Emil Tanghetti, M.D., Director of the Center for Dermatology and Laser Surgery in Sacramento, work continues on developing the phototherapy technologies and treatment approaches needed to identify and hit the correct targets to treat rosacea.
The challenges are in being able to penetrate deeply enough to hit the correct targets with the right energies and do so safely. Researchers are looking into better identifying the specific components of the condition, such as sebum and vascular components, that need to be targeted.
Ongoing research by Dr. Tanghetti and others continues to improve the technology and to apply the lessons learned from treating similar conditions with light sources. “Contradicting conventional wisdom, we found that multiple pulses with pulsed dye lasers actually penetrated deeper if we waited longer between pulses,” says Dr. Tanghetti. “Our testing also showed that using various wavelengths in combination allowed us to hit deeper lesions. We developed a prototype laser that shot a pulsed dye followed by an Nd:YAG.”
Dr. Tanghetti believes this technology offers promise and is confident that more effective and affordable phototherapies for rosacea are on the horizon.
A Growing Armamentarium
While acne and rosacea continue to be difficult to treat and control, we have many choices of treatment to help patients combat these conditions. We continue to learn more about acne and rosacea with ongoing research and are better learning how to treat the cause of these problems.
Acne and Rosacea continue to be frustrating conditions to control for both patients and physicians. And while the issue of antibiotic resistant strains of Propionibacterium acnes hangs on the dermatological horizon like a dark cloud, there is a lot of good news regarding both of these conditions.
Ongoing research continues to reveal new data about acne and rosacea, data that should lead to more effective therapy options. New medications, new formulations of existing medications, new treatment approaches and even rosacea-targeting light therapies are available or may soon be available to treat these persistent conditions.
What’s New in Acne Treatment?
Of growing concern to dermatologists is the apparent increasing resistance to medications shown by strains of P. acnes. In the classic sense, resistance means that the dose needed to kill an organism exceeds the concentration that the drug can achieve in the compartment where the organism is living.
“Since the follicular concentration of a compound cannot be measured for technical reasons, other methods must be used to assess the relative resistance of P. acnes,” explains James J. Leyden, M.D., Professor Emeritus of Dermatology at the University of Pennsylvania School of Medicine. “One such method is to correlate outcomes in patients who have been demonstrated to have less sensitive — or more resistant — strains. In studies, these patients did not fare as well as those who have more sensitive strains.”
In one study, sub-groups of about 150 patients each were treated with various regimens. With a dosage of minocycline of 100 mg a day, there was a huge difference in clinical outcomes of at least moderate improvement, with the less sensitive groups showing the least improvement. And topical formulations of benzoyl peroxide, either alone or in combination with erythromycin, were as effective in this population as minocycline.
“There is no decreased sensitivity to benzoyl peroxide, so the idea that topical benzoyl peroxide could be as effective as minocycline is a reflection of this changing resistance to certain medications,” says Dr. Leyden.
A recent study showed that in patients who carry high numbers of less sensitive or “resistant” strains of P. acnes, isotretinoin substantially reduced, but not totally eradicated, these organisms.
“I think that as physicians, we all need to be aware of the issue of medication-resistant microbes and take steps to ensure that we are not over using antibiotic therapies, especially since we deal with chronic conditions,” explains Dr. Leyden.
Antibiotic Alternatives
While it approved dapsone gel 5% (Aczone) for the topical treatment of acne vulgaris, the FDA expressed concerns about glucose-6-phosphate dehydrogenase (G6PD) deficiency and patients must be screened for this. However, according to Dr. Leyden, in clinical trials involving about 30 patients with G6PD deficiency, topical dapsone had no effect on their hemoglobin.
“An ongoing study is looking at another cohort of patients who are G6PD deficient. If that study fails to demonstrate any clinical issues, then perhaps the FDA will agree that G6PD testing is not necessary before treating a patient with topical dapsone,” says Dr. Leyden. “This medication has been shown to have an in vivo anti-microbial effect. We know systemically it has a lot of anti-inflammatory effects and any potential anti-inflammatory effects topically would be useful in acne.”
Among topical retinoids, there’s a new, higher-strength adapalene 0.3%, which a study shows is well tolerated and more effective than the available 0.1% concentration (Differin). Dr. Leyden says that this new formulation is awaiting a decision by the FDA. Two topical combination formulations of tretinoin and clindamycin are also being evaluated by the FDA.
According to Dr. Leyden, a study involving therapy with a combination of doxycycline and topical adapalene showed at the end of the 12-week treatment that the combination was superior. The patients entered a 16-week maintenance period and were randomized for either topical adapalene or a vehicle. After 16 weeks, patients on topical adapalene showed a significantly better maintenance rate.
A second study, involving more intense inflammatory acne, evaluated the efficacy of three maintenance therapies (tazarotene, minocycline hydrochloride, and tazarotene plus minocycline) in sustaining improvement attained after therapy with topical tazarotene plus 20-mg minocycline. Those who reached the 75% improvement — about 80% of the patients — were randomized to
12 weeks of maintenance therapy with tazarotene gel plus placebo capsules, vehicle gel plus minocycline capsules, or tazarotene gel plus minocycline capsules.
“All three treatments were effective in sustaining improvements in acne. After 12 weeks of maintenance therapy, the mean reductions from baseline in non-inflammatory and inflammatory lesion count, respectively, were 60% and 54% for tazarotene, 52% and 66% for minocycline, and 64% and 66% for tazarotene plus minocycline,” says Dr. Leyden. At week 24, more than 80% of patients in each group had maintained at least 50% global improvement from baseline, and more than 50% had maintained at least 75% global improvement.
Controlling Inflammation
Controlling the inflammation that is a result of acne is a critical component in the overall treatment of the disease. According to Neal Bhatia, M.D., Assistant Clinical Professor at the University of Wisconsin, acne-related inflammation involves balances between cellular and humoral.
“It all has to do with the way the T-helper cell is activated. We have the TH1 profile, which is cellular and the TH2 profile, which is antibody mediated,” explains Dr. Bhatia. “With acne, there are high levels of interleukin 1, 12, and tumor necrosis factor, all of which impact inflammation. Interleukin 1 is the most critical of these because of the way it impacts inflammation cascades.”
P. acnes also interacts with toll-like receptor 2 (TLR-2) to release interleukin 1 promoting additional inflammation cascades. Topical retinoids work by inhibiting the expression of TLR-2, reducing the impact of P. acnes and significantly reducing the initial inflammatory cascades.
“P. acnes carries a lot of weapons for breaking down tissue, creating inflammation, and infecting adhesion molecules. The four basic mechanisms for what P. acnes does to inflammation are based on how it attacks our own system,” explains Dr. Bhatia. “It’s attracting lymphocytes, neutrophils, and some of the other carrier cells. It has a lot to do with activating complement to set the ball into motion, as well as using production of free fatty acids, which constantly promotes a fuel for the activity, in addition to stimulating TLR-2 expression.”
According to Dr. Bhatia, acne has its own inflammation component that affects fibrosis, impairs wound healing and leads to scarring. Also, P. acnes affects the TH1 cytokine response, which is known to be anti-fibrotic. Finally, there’s a high level of macrophages and dendritic cells compared to lymphocytes, resulting in additional scarring.
Anti-Inflammatory Drugs
Acne has its own immunomodulator category of drugs that also serve as anti-inflammatory drugs. Retinoids act as anti-inflammatory drugs by binding to a receptor in the nucleus, which then forms a negative feedback mechanism against a neurotransmitter called AP1. At that point, there’s blockage of the transcription that is necessary to promote cytokine release.
Topical antibiotics also have a mechanism against inflammation. According to Dr. Bhatia, there is a direct effect against P. acnes and also an indirect effect on the ability to promote comedogenesis. “Tetracyclines have several different mechanisms. Down-regulating cytokines and impacting nitric oxide are important for intracellular killing as well as for the way that neutrophils and some of the other lymphocyte markers are recruited,” explains Dr. Bhatia. “But again it’s separating that antibiotic effect as well as the effect on inflammation.”
Azelaic acid (Finacea) also has an anti-inflammation action. “Azelaic acid inhibits the generation of reactive oxygen species by neutrophils which reduces oxidative tissue injury at the sites of acne inflammation,” explains Dr. Bhatia.
Hormone Therapy
Androgens play a critical role in acne because they increase the size of the sebaceous gland and increase sebum production. The primary sources of androgen are the ovary, the adrenal gland under the influence of ACTH, and the skin. Studies show that people who lack functional androgen receptors do not make adult levels of sebum and do not develop acne. Reducing sebum production is the main goal of hormone therapy.
“We’re not certain of the clinical significance of the skin production of androgens because a lot is being made by the ovaries or testes. But, the skin is a large organ, so even if it’s involved in any respect in androgen metabolism, it could play a role in acne,” says Diane M. Thiboutot M.D., a Professor of Dermatology at the Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center. “It might be that women with acne may have greater local production of androgen in their skin that could in part account for the presence of acne. Many of our female patients with acne were found to have high levels of testosterone.”
According to Dr. Thiboutot, hormonal therapy is appropriate if there is excess androgen production by the adrenal gland or by the ovary. It’s also very useful as an adjunctive therapy in women with normal serum androgens, and in some cases it can be useful as an alternative to repeat courses of isotretinoin (Accutane, Amnesteem, Claravis, Sotret).
Typical hormonal therapy medications in the United States include oral contraceptives, glucocorticoids, and some androgen-receptor blockers. The androgen receptor blockers are oral spironolactone and cyproterone acetate, which is not available in the United States, and flutamide.
“Low-dose spironolactone works well in women with acne. Many patients who do very well with 25 mg a day or 25 mg twice daily, so it can be a very effective addition to treatment,” explains Dr. Thiboutot. “Unfortunately, topical spironolactone doesn’t affect sebum production.”
Agents that block adrenal production of androgens are oral contraceptives and low-dose glucocorticoids. “Most times we use prednisone at a low dose because there seems to be increased risk of adrenal suppression with dexamethasone,” says Dr. Thiboutot. “While we have patients on treatment with dexamethasone or prednisone for congenital adrenal hyperplasia, it’s important to know whether your therapy is actually reducing those androgens, so you may want to check the serum dehydroepiandrosterone sulfate (DHEAS) to see if you’re bringing that down into the normal range.”
Even on low-dose prednisone, adrenal suppression could still occur, so you may want to refer to an endocrinologist or an internist to have cortisol checked or to check adrenal function in general.
Oral Contraceptives
Oral contraceptives contain a low-dose of an estrogen and a progestin. Studies show that most oral contraceptives used to treat acne have similar effectiveness, around a 45% reduction in inflammatory lesions. However, a novel progestin has been introduced called drospirenone, which is a derivative of 17-spironolactone, and it is found in the Yasmin brand oral contraceptive, which contains about 30 µg of estrogen.
According to Dr. Thiboutot, a small trial for this contraceptive involving 128 women showed about a 60% lesion reduction over 9 months. Phase III trials for this therapy are in progress.
Many patients are concerned about the interaction between oral contraceptives and antibiotics. “The gut flora is needed to cleave estrogen from the conjugated estrogen in the oral contraceptives, and the risk of an interaction is greatest with tetracyclines,” says Dr. Thiboutot. “But the number of reports in the literature is actually small. However, I think that we should discuss this with our patients.”
New Rosacea Treatment
Despite widespread acceptance of their use in clinical practice for more than four decades, there has not been an abundance of controlled trials on the use of oral tetracycline agents for rosacea. A review of the literature by James Q. Del Rosso, D.O., a dermatologist in private practice in Las Vegas, uncovered only 155 total patients with rosacea treated in studies with antibiotic doses of oral tetracyclines.
“Our use of these agents is primarily based on clinical experience and the fact that we know they work. Also, overall, their safety profiles have been favorable,” says Dr. Del Rosso. “But we don’t have definitive evidence that P. acnes or any other bacterium is involved in the pathogenesis of rosacea.”
Dr. Del Rosso says a recent article in the Journal of the American Academy of Dermatology outlined a variety of different anti-inflammatory effects of tetracyclines. “Why look at anti-inflammatory effects in rosacea?” he asks. “It’s a chronic disease associated with inflammation, so we know we’re going to administer long-term therapy in many patients to sustain control, and an antibiotic effect is not proven to be needed. Anti-inflammatory activity appears to play a key role, however.”
What are the pharmacologic effects of tetracycline agents? “There’s a dose-related antibiotic effect. In order to reduce bacteria, a given drug must achieve certain inhibitory concentrations to exhibit antibiotic activity. Distinct from their dose-related antibiotic effect, there are a variety of anti-inflammatory mechanisms associated with tetracyclines. However, there is a dosage separation between anti-inflammatory and antibiotic activities that has been identified only with doxycycline,” explains Dr. Del Rosso.
Low-dose doxycycline (50 mg to 100 mg a day) is not synonymous with non-antibiotic effect, as even a single dose of 50 mg exerts antibiotic selection pressure for about 2 to 4 hours. High-dose doxycycline (150 to 200 mg a day) is at an antibiotic dose level. There is now an FDA-approved 40-mg controlled-release capsule formulation of doxycycline (Oracea) for the treatment of rosacea in adults, referred to specifically as anti-inflammatory dose doxycycline. This dose is anti-inflammatory without antibiotic activity, which removes any potential issues regarding emergence of antibiotic resistance, especially with long-term administration. A lack of antimicrobial activity has been confirmed based on pharmacokinetic data and microbiologic studies completed over durations of up to 18 months.
According to Dr. Del Rosso, two pivotal parallel studies were conducted to assess the efficacy of anti-inflammatory dose doxycycline in adults with moderate to severe rosacea.
In these Phase III 16-week trials, patients were treated with 40 mg doxycycline controlled-release once a day or placebo once a day. The primary efficacy parameter was a change in the total inflammatory lesion count from baseline to endpoint at week 16. In both studies, there was decreased inflammatory lesion counts in both the actively treated and placebo groups, but the reduction in lesions was much greater in the actively treated group with statistical significance observed in both trials.
No plateau effect was observed in actively treated patients in both studies, indicating continued improvements in lesion reduction throughout the entire 16 weeks of use. Additionally, both studies showed some reduction in erythema. In terms of safety, none of the study patients developed photosensitivity. Nor did any of the female patients treated with active drug in both trials (n=185) develop vaginal candidiasis, an observation consistent with the lack of antibiotic effect of anti-inflammatory dose doxycycline.
Phototherapy for Rosacea
According to Emil Tanghetti, M.D., Director of the Center for Dermatology and Laser Surgery in Sacramento, work continues on developing the phototherapy technologies and treatment approaches needed to identify and hit the correct targets to treat rosacea.
The challenges are in being able to penetrate deeply enough to hit the correct targets with the right energies and do so safely. Researchers are looking into better identifying the specific components of the condition, such as sebum and vascular components, that need to be targeted.
Ongoing research by Dr. Tanghetti and others continues to improve the technology and to apply the lessons learned from treating similar conditions with light sources. “Contradicting conventional wisdom, we found that multiple pulses with pulsed dye lasers actually penetrated deeper if we waited longer between pulses,” says Dr. Tanghetti. “Our testing also showed that using various wavelengths in combination allowed us to hit deeper lesions. We developed a prototype laser that shot a pulsed dye followed by an Nd:YAG.”
Dr. Tanghetti believes this technology offers promise and is confident that more effective and affordable phototherapies for rosacea are on the horizon.
A Growing Armamentarium
While acne and rosacea continue to be difficult to treat and control, we have many choices of treatment to help patients combat these conditions. We continue to learn more about acne and rosacea with ongoing research and are better learning how to treat the cause of these problems.
