Rosacea

NEW YORK – A middle-aged patient with Fitzpatrick type V skin comes to the office with a 10-year history of “breakouts” on her face. When asked about topical treatments, she reports that “everything burns or stings,” and says she just has very sensitive skin. What could this be?

[email protected]

On Twitter @karioakes

NEW YORK – A middle-aged patient with Fitzpatrick type V skin comes to the office with a 10-year history of “breakouts” on her face. When asked about topical treatments, she reports that “everything burns or stings,” and says she just has very sensitive skin. What could this be?

[email protected]

On Twitter @karioakes

NEW YORK – A middle-aged patient with Fitzpatrick type V skin comes to the office with a 10-year history of “breakouts” on her face. When asked about topical treatments, she reports that “everything burns or stings,” and says she just has very sensitive skin. What could this be?

[email protected]

On Twitter @karioakes

What do your patients need to know?

Vascular instability associated with rosacea is exacerbated by triggers such as sunlight, hot drinks, spicy foods, stress, and rapid changing weather, which make patients flush and blush, increase the appearance of telangiectasia, and disrupt the normal skin barrier. Because the patients feel on fire, an anti-inflammatory approach is indicated. The regimen I recommend includes mild cleansers, barrier repair creams and supplements, antioxidants (topical and oral), and sun protection, all without parabens and harsh chemicals. I always recommend a product that I dispense at the office and another one of similar effectiveness that can be found over-the-counter.

What are your go-to treatments?

Cleansing is indispensable to maintain the normal flow in and out of the skin. I recommend mild cleansers without potentially sensitizing agents such as propylene glycol or parabens. It also should have calming agents (eg, fruit extracts) that remove the contaminants from the skin surface without stripping the important layers of lipids that constitute the barrier of the skin as well as ingredients (eg, prebiotics) that promote the healthy skin biome. Selenium in thermal spring water has free radical scavenging and anti-inflammatory properties as well as protection against heavy metals.

After cleansing, I recommend a product to repair, maintain, and improve the barrier of the skin. A healthy skin barrier has an equal ratio of cholesterol, ceramides, and free fatty acids, the building blocks of the skin. In a barrier repair cream I look for ingredients that stop and prevent damaging inflammation, improve the skin's natural ability to repair and heal (eg, niacinamide), and protect against environmental insults. It should contain petrolatum and/or dimethicone to form a protective barrier on the skin to seal in moisture.

Oral niacinamide should be taken as a photoprotective agent. Oral supplementation (500 mg twice daily) is effective in reducing skin cancer. Because UV light is a trigger factor, oral photoprotection is recommended.

Topical antioxidants also are important. Free radical formation has been documented even in photoprotected skin. These free radicals have been implicated in skin cancer development and metalloproteinase production and are triggers of rosacea. As a result, I advise my patients to apply topical encapsulated vitamin C every night. The encapsulated form prevents oxidation of the product before application. In addition, I recommend oral vitamin C (1 g daily) and vitamin E (400 U daily).

For sun protection I recommend sunblocks with titanium dioxide and zinc oxide for total UVA and UVB protection. If the patient has a darker skin type, sun protection should contain iron oxide. Chemical agents can cause irritation, photocontact dermatitis, and exacerbation of rosacea symptoms. Daily application of sun protection with reapplication every 2 hours is reinforced. 

What holistic therapies do you recommend?

Stress reduction activities, including yoga, relaxation, massages, and meditation, can help. Oral consumption of trigger factors is discouraged. Antioxidant green tea is recommended instead of caffeinated beverages. 

Suggested Readings 

Baldwin HE, Bathia ND, Friedman A, et al. The role of cutaneous microbiota harmony in maintaining functional skin barrier. J Drugs Dermatol. 2017;16:12-18.

Celerier P, Richard A, Litoux P, et al. Modulatory effects of selenium and strontium salts on keratinocyte-derived inflammatory cytokines. Arch Dermatol Res. 1995;287:680-682.

Chen AC, Martin AJ, Choy B, et al. A phase 3 randomized trial of nicotinamide for skin cancer chemoprevention. N Engl J Med. 2015;373:1618-1626.

Jones D. Reactive oxygen species and rosacea. Cutis. 2004;74(suppl 3):17-20.

What do your patients need to know?

Vascular instability associated with rosacea is exacerbated by triggers such as sunlight, hot drinks, spicy foods, stress, and rapid changing weather, which make patients flush and blush, increase the appearance of telangiectasia, and disrupt the normal skin barrier. Because the patients feel on fire, an anti-inflammatory approach is indicated. The regimen I recommend includes mild cleansers, barrier repair creams and supplements, antioxidants (topical and oral), and sun protection, all without parabens and harsh chemicals. I always recommend a product that I dispense at the office and another one of similar effectiveness that can be found over-the-counter.

What are your go-to treatments?

Cleansing is indispensable to maintain the normal flow in and out of the skin. I recommend mild cleansers without potentially sensitizing agents such as propylene glycol or parabens. It also should have calming agents (eg, fruit extracts) that remove the contaminants from the skin surface without stripping the important layers of lipids that constitute the barrier of the skin as well as ingredients (eg, prebiotics) that promote the healthy skin biome. Selenium in thermal spring water has free radical scavenging and anti-inflammatory properties as well as protection against heavy metals.

After cleansing, I recommend a product to repair, maintain, and improve the barrier of the skin. A healthy skin barrier has an equal ratio of cholesterol, ceramides, and free fatty acids, the building blocks of the skin. In a barrier repair cream I look for ingredients that stop and prevent damaging inflammation, improve the skin's natural ability to repair and heal (eg, niacinamide), and protect against environmental insults. It should contain petrolatum and/or dimethicone to form a protective barrier on the skin to seal in moisture.

Oral niacinamide should be taken as a photoprotective agent. Oral supplementation (500 mg twice daily) is effective in reducing skin cancer. Because UV light is a trigger factor, oral photoprotection is recommended.

Topical antioxidants also are important. Free radical formation has been documented even in photoprotected skin. These free radicals have been implicated in skin cancer development and metalloproteinase production and are triggers of rosacea. As a result, I advise my patients to apply topical encapsulated vitamin C every night. The encapsulated form prevents oxidation of the product before application. In addition, I recommend oral vitamin C (1 g daily) and vitamin E (400 U daily).

For sun protection I recommend sunblocks with titanium dioxide and zinc oxide for total UVA and UVB protection. If the patient has a darker skin type, sun protection should contain iron oxide. Chemical agents can cause irritation, photocontact dermatitis, and exacerbation of rosacea symptoms. Daily application of sun protection with reapplication every 2 hours is reinforced. 

What holistic therapies do you recommend?

Stress reduction activities, including yoga, relaxation, massages, and meditation, can help. Oral consumption of trigger factors is discouraged. Antioxidant green tea is recommended instead of caffeinated beverages. 

Suggested Readings 

Baldwin HE, Bathia ND, Friedman A, et al. The role of cutaneous microbiota harmony in maintaining functional skin barrier. J Drugs Dermatol. 2017;16:12-18.

Celerier P, Richard A, Litoux P, et al. Modulatory effects of selenium and strontium salts on keratinocyte-derived inflammatory cytokines. Arch Dermatol Res. 1995;287:680-682.

Chen AC, Martin AJ, Choy B, et al. A phase 3 randomized trial of nicotinamide for skin cancer chemoprevention. N Engl J Med. 2015;373:1618-1626.

Jones D. Reactive oxygen species and rosacea. Cutis. 2004;74(suppl 3):17-20.

What do your patients need to know?

Vascular instability associated with rosacea is exacerbated by triggers such as sunlight, hot drinks, spicy foods, stress, and rapid changing weather, which make patients flush and blush, increase the appearance of telangiectasia, and disrupt the normal skin barrier. Because the patients feel on fire, an anti-inflammatory approach is indicated. The regimen I recommend includes mild cleansers, barrier repair creams and supplements, antioxidants (topical and oral), and sun protection, all without parabens and harsh chemicals. I always recommend a product that I dispense at the office and another one of similar effectiveness that can be found over-the-counter.

What are your go-to treatments?

Cleansing is indispensable to maintain the normal flow in and out of the skin. I recommend mild cleansers without potentially sensitizing agents such as propylene glycol or parabens. It also should have calming agents (eg, fruit extracts) that remove the contaminants from the skin surface without stripping the important layers of lipids that constitute the barrier of the skin as well as ingredients (eg, prebiotics) that promote the healthy skin biome. Selenium in thermal spring water has free radical scavenging and anti-inflammatory properties as well as protection against heavy metals.

After cleansing, I recommend a product to repair, maintain, and improve the barrier of the skin. A healthy skin barrier has an equal ratio of cholesterol, ceramides, and free fatty acids, the building blocks of the skin. In a barrier repair cream I look for ingredients that stop and prevent damaging inflammation, improve the skin's natural ability to repair and heal (eg, niacinamide), and protect against environmental insults. It should contain petrolatum and/or dimethicone to form a protective barrier on the skin to seal in moisture.

Oral niacinamide should be taken as a photoprotective agent. Oral supplementation (500 mg twice daily) is effective in reducing skin cancer. Because UV light is a trigger factor, oral photoprotection is recommended.

Topical antioxidants also are important. Free radical formation has been documented even in photoprotected skin. These free radicals have been implicated in skin cancer development and metalloproteinase production and are triggers of rosacea. As a result, I advise my patients to apply topical encapsulated vitamin C every night. The encapsulated form prevents oxidation of the product before application. In addition, I recommend oral vitamin C (1 g daily) and vitamin E (400 U daily).

For sun protection I recommend sunblocks with titanium dioxide and zinc oxide for total UVA and UVB protection. If the patient has a darker skin type, sun protection should contain iron oxide. Chemical agents can cause irritation, photocontact dermatitis, and exacerbation of rosacea symptoms. Daily application of sun protection with reapplication every 2 hours is reinforced. 

What holistic therapies do you recommend?

Stress reduction activities, including yoga, relaxation, massages, and meditation, can help. Oral consumption of trigger factors is discouraged. Antioxidant green tea is recommended instead of caffeinated beverages. 

Suggested Readings 

Baldwin HE, Bathia ND, Friedman A, et al. The role of cutaneous microbiota harmony in maintaining functional skin barrier. J Drugs Dermatol. 2017;16:12-18.

Celerier P, Richard A, Litoux P, et al. Modulatory effects of selenium and strontium salts on keratinocyte-derived inflammatory cytokines. Arch Dermatol Res. 1995;287:680-682.

Chen AC, Martin AJ, Choy B, et al. A phase 3 randomized trial of nicotinamide for skin cancer chemoprevention. N Engl J Med. 2015;373:1618-1626.

Jones D. Reactive oxygen species and rosacea. Cutis. 2004;74(suppl 3):17-20.

Rosacea is a chronic inflammatory skin disease characterized by central facial erythema with or without intermittent papules and pustules (described as the inflammatory lesions of rosacea). Although twice-daily clindamycin 1% solution or gel has been used in the treatment of acne, few studies have investigated the use of clindamycin in rosacea.^1,2 In one study comparing twice-daily clindamycin lotion 1% with oral tetracycline in 43 rosacea patients, clindamycin was found to be superior in the eradication of pustules.³ A combination therapy of clindamycin 1% and benzoyl peroxide 5% was found to be more effective than the vehicle in inflammatory lesions and erythema of rosacea in a 12-week randomized controlled trial; however, a definitive advantage over US Food and Drug Administration-approved topical agents used to treat papulopustular rosacea was not established.^4,5 Two further studies evaluated clindamycin phosphate 1.2%-tretinoin 0.025% combination gel in the treatment of rosacea, but only 1 showed any effect on papulopustular lesions.^6-8 The objective of the studies reported here was to evaluate the efficacy and safety of clindamycin in the treatment of patients with moderate to severe rosacea.

Methods

Study Design

Two multicenter (study A, 20 centers; study B, 10 centers), randomized, investigator-blinded, vehicle-controlled studies were conducted in the United States between 1999 and 2002 in accordance with the Declaration of Helsinki, International Conference on Harmonisation Good Clinical Practice guidelines, and local regulatory requirements. The studies were reviewed and approved by the respective institutional review boards, and all participants provided written informed consent.

In study A, moderate to severe rosacea patients with erythema, telangiectasia, and at least 8 inflammatory lesions were randomized to receive clindamycin cream 1% or vehicle cream once (in the evening) or twice daily (in the morning and evening) or clindamycin cream 0.3% once daily (in the evening) for 12 weeks (1:1:1:1:1 ratio). All study treatments were supplied in identical tubes with blinded labels.

In study B, patients with moderate to severe rosacea and at least 8 inflammatory lesions were randomized in a 1:1 ratio with instructions to apply clindamycin gel 1% or vehicle gel to the affected areas twice daily (morning and evening) for 12 weeks.

Efficacy Evaluation

Evaluations were performed at baseline and weeks 2, 4, 8, and 12 on the intention-to-treat population with the last observation carried forward.

Efficacy assessments in both studies included inflammatory lesion counts (papules and pustules) of 5 facial regions--forehead, chin, nose, right cheek, left cheek--counted separately and then combined to give the total inflammatory lesion count (both studies), as well as improvement in the investigator global rosacea severity score (0=none/clear; 1=mild, detectable erythema with ≤7 papules/pustules; 2=moderate, prominent erythema with ≥8 papules/pustules; 3=severe, intense erythema with ≥10 to <50 papules/pustules; 3.5 [study A] or 4 [study B]=very severe, intense erythema with >50 papules/pustules). In study B, the proportion of participants dichotomized to success (a score of 0 [none/clear] or 1 [mild/almost clear]) or failure (a score of ≥2) on the 5-point investigator global rosacea severity scale at week 12 was evaluated. In study A, investigator global improvement assessment at week 12, based on photographs taken at baseline, was graded on a 7-point scale (from -1 [worse], 0 [no change], and 1 [minimal improvement] to 5 [clear]). In both studies, erythema severity was graded on a 7-point scale in increments of 0.5 (from 0=no erythema to 3.5=very severe redness, very intense redness). Skin irritation also was graded as none, mild, moderate, or severe. 

Safety Evaluation

Safety was assessed by the incidence of adverse events (AEs).

Statistical Analysis

Studies were powered assuming 60% reduction in inflammatory lesion counts with active and 40% with vehicle, based on historical data from a prior study with metronidazole cream 0.75% versus vehicle; 64 participants were required in each treatment group to detect this effect using a 2-sided t test (&#945;=.017). Pairwise comparisons (clindamycin vs respective vehicle) were performed using the Cochran-Mantel-Haenszel test for combined lesion count percentage change.

Results

Participant Disposition and Baseline Characteristics

Overall, a total of 629 participants were randomized across both studies. In study A, a total of 416 participants were randomized into 5 treatment arms, with 369 participants (88.7%) completing the study; 47 (11.3%) participants discontinued study A, mainly due to participant request (19/47 [40.4%]) or lost to follow-up (11/47 [23.4%]). In study B, a total of 213 participants were randomized to receive either clindamycin gel 1% (n=109 [51.2%]) twice daily or vehicle gel (n=104 [48.8%]) twice daily, with 193 participants (90.6%) completing the study; 20 (9.4%) participants discontinued study B, mainly due to participant request (6/20 [30%]) or lost to follow-up (4/20 [20%]). Participants in studies A and B were similar in demographics and baseline disease characteristics (Table). The majority of participants were white females. 

Efficacy

No statistically significant difference was observed in all pairwise comparisons (clindamycin cream twice daily vs vehicle twice daily, clindamycin cream once daily vs vehicle once daily, clindamycin gel vs vehicle gel) for the primary end point of mean percentage change from baseline in inflammatory lesion counts at week 12 (Figure 1; P>.5 for all pairwise comparisons). 

At week 12, the proportion of participants in study B deemed as a success (none/clear or mild/almost clear [investigator global rosacea severity score of 0 or 1]) in the clindamycin gel 1% and vehicle gel groups were 45% versus 38%, respectively (P=.347) (Figure 2). 

For the secondary end point of mean investigator global rosacea severity assessment at week 12 (study A), there were no significant differences between the active and vehicle control groups (P>.5 for all pairwise comparisons)(Figure 3). Also, the proportion of participants with at least a moderate investigator global improvement assessment from baseline to week 12 ranged from 45% for clindamycin cream 1% twice daily to 56% for clindamycin cream 0.3% cream once daily and from 45% for vehicle cream once daily to 51% for vehicle cream twice daily (P>.5 for all pairwise comparisons).

There were no significant differences in the mean total erythema severity scores at week 12 for clindamycin cream 1% twice daily versus vehicle cream twice daily (6.3 vs 6.0; P>.5), clindamycin cream 1% once daily versus vehicle cream once daily (6.2 vs 6.0; P>.5), clindamycin cream 0.3% once daily versus vehicle cream once daily (5.9 vs 6.0; P>.5), and clindamycin gel 1% twice daily versus vehicle gel twice daily (6.7 vs 6.2; P>.5). 

There were no relevant differences between any of the clindamycin cream groups and their respective vehicle group at week 12 for skin irritation, including desquamation, edema, dryness, pruritus, and stinging/burning.

Safety

In study A, the majority of AEs in all 5 treatment arms were nondermatologic, mild in intensity, and not considered to be related to the study treatment by the investigator. Overall, 12 participants had AEs considered by the investigator as possibly or probably related to the study treatment: 4.9% in the clindamycin cream 1% twice daily group, 4.6% in the clindamycin cream 1% once daily group, 3.7% in the vehicle cream twice daily group, 1.2% in the clindamycin cream 0.3% once daily group, and 0% in the vehicle cream once daily group. Two treatment-related AEs led to treatment discontinuation, including dermatitis in 1 participant from the clindamycin cream 1% once daily group and contact dermatitis in 1 participant from the clindamycin cream 1% twice daily group.

Comment

No evidence of increased efficacy over the respective vehicles was observed with clindamycin cream or gel, whatever the regimen, in the treatment of rosacea patients in either of these well-designed and well-powered, blinded studies. Slight improvements in the various efficacy criteria were observed, even in the vehicle groups, highlighting the importance of using a good basic skin care regimen in the management of rosacea.⁹ In contrast to our observations of lack of efficacy in the treatment of rosacea, clinical efficacy of clindamycin has been demonstrated in acne,^10-12 albeit with low efficacy for clindamycin monotherapy.¹³ It is noteworthy that oral or topical antibiotics are no longer recommended as monotherapy for acne to prevent and minimize antibiotic resistance and to preserve the therapeutic value of antibiotics.¹⁴

Acne and rosacea are both chronic inflammatory disorders of the skin associated with papules and pustules, and they share some common inflammatory patterns.^15-19 Furthermore, the intrinsic anti-inflammatory activity of clindamycin in addition to its antibiotic effects has been suggested by some authors as the main reason for treating acne with clindamycin.²⁰ However, the relative contributions of antibacterial and/or anti-inflammatory properties remain to be fully elucidated, and evidence for direct anti-inflammatory effects of clindamycin remains heterogeneous.^21,22 Several pathophysiological factors have been implicated in acne, including hormonal effects, abnormal keratinocyte function, increased sebum production, and microbial components (eg, hypercolonization of the skin follicles by Propionibacterium acnes).^23,24 The antibiotic activity of clindamycin against P acnes may be the key factor responsible for the clinical effects in acne.^25,26 Although clindamycin may have anti-inflammatory effects in acne via a different inflammatory pathway not shared by rosacea, a purely antibiotic mechanism of action of clindamycin also could explain why we observed no evidence of efficacy in the treatment of rosacea, as no causative bacterial component has been clearly demonstrated in rosacea.²⁷

Conclusion

In these studies, clindamycin cream 0.3% once daily, clindamycin cream 1% once or twice daily, and clindamycin gel 1% twice daily were all well tolerated; however, they were no more effective than the vehicles in the treatment of moderate to severe rosacea.  

Acknowledgment

The authors would like to thank Helen Simpson, PhD, of Galderma R&D (Sophia Antipolis, France), for editorial and medical writing assistance.

Rosacea is a chronic inflammatory skin disease characterized by central facial erythema with or without intermittent papules and pustules (described as the inflammatory lesions of rosacea). Although twice-daily clindamycin 1% solution or gel has been used in the treatment of acne, few studies have investigated the use of clindamycin in rosacea.^1,2 In one study comparing twice-daily clindamycin lotion 1% with oral tetracycline in 43 rosacea patients, clindamycin was found to be superior in the eradication of pustules.³ A combination therapy of clindamycin 1% and benzoyl peroxide 5% was found to be more effective than the vehicle in inflammatory lesions and erythema of rosacea in a 12-week randomized controlled trial; however, a definitive advantage over US Food and Drug Administration-approved topical agents used to treat papulopustular rosacea was not established.^4,5 Two further studies evaluated clindamycin phosphate 1.2%-tretinoin 0.025% combination gel in the treatment of rosacea, but only 1 showed any effect on papulopustular lesions.^6-8 The objective of the studies reported here was to evaluate the efficacy and safety of clindamycin in the treatment of patients with moderate to severe rosacea.

Methods

Study Design

Two multicenter (study A, 20 centers; study B, 10 centers), randomized, investigator-blinded, vehicle-controlled studies were conducted in the United States between 1999 and 2002 in accordance with the Declaration of Helsinki, International Conference on Harmonisation Good Clinical Practice guidelines, and local regulatory requirements. The studies were reviewed and approved by the respective institutional review boards, and all participants provided written informed consent.

In study A, moderate to severe rosacea patients with erythema, telangiectasia, and at least 8 inflammatory lesions were randomized to receive clindamycin cream 1% or vehicle cream once (in the evening) or twice daily (in the morning and evening) or clindamycin cream 0.3% once daily (in the evening) for 12 weeks (1:1:1:1:1 ratio). All study treatments were supplied in identical tubes with blinded labels.

In study B, patients with moderate to severe rosacea and at least 8 inflammatory lesions were randomized in a 1:1 ratio with instructions to apply clindamycin gel 1% or vehicle gel to the affected areas twice daily (morning and evening) for 12 weeks.

Efficacy Evaluation

Evaluations were performed at baseline and weeks 2, 4, 8, and 12 on the intention-to-treat population with the last observation carried forward.

Efficacy assessments in both studies included inflammatory lesion counts (papules and pustules) of 5 facial regions--forehead, chin, nose, right cheek, left cheek--counted separately and then combined to give the total inflammatory lesion count (both studies), as well as improvement in the investigator global rosacea severity score (0=none/clear; 1=mild, detectable erythema with ≤7 papules/pustules; 2=moderate, prominent erythema with ≥8 papules/pustules; 3=severe, intense erythema with ≥10 to <50 papules/pustules; 3.5 [study A] or 4 [study B]=very severe, intense erythema with >50 papules/pustules). In study B, the proportion of participants dichotomized to success (a score of 0 [none/clear] or 1 [mild/almost clear]) or failure (a score of ≥2) on the 5-point investigator global rosacea severity scale at week 12 was evaluated. In study A, investigator global improvement assessment at week 12, based on photographs taken at baseline, was graded on a 7-point scale (from -1 [worse], 0 [no change], and 1 [minimal improvement] to 5 [clear]). In both studies, erythema severity was graded on a 7-point scale in increments of 0.5 (from 0=no erythema to 3.5=very severe redness, very intense redness). Skin irritation also was graded as none, mild, moderate, or severe. 

Safety Evaluation

Safety was assessed by the incidence of adverse events (AEs).

Statistical Analysis

Studies were powered assuming 60% reduction in inflammatory lesion counts with active and 40% with vehicle, based on historical data from a prior study with metronidazole cream 0.75% versus vehicle; 64 participants were required in each treatment group to detect this effect using a 2-sided t test (&#945;=.017). Pairwise comparisons (clindamycin vs respective vehicle) were performed using the Cochran-Mantel-Haenszel test for combined lesion count percentage change.

Results

Participant Disposition and Baseline Characteristics

Overall, a total of 629 participants were randomized across both studies. In study A, a total of 416 participants were randomized into 5 treatment arms, with 369 participants (88.7%) completing the study; 47 (11.3%) participants discontinued study A, mainly due to participant request (19/47 [40.4%]) or lost to follow-up (11/47 [23.4%]). In study B, a total of 213 participants were randomized to receive either clindamycin gel 1% (n=109 [51.2%]) twice daily or vehicle gel (n=104 [48.8%]) twice daily, with 193 participants (90.6%) completing the study; 20 (9.4%) participants discontinued study B, mainly due to participant request (6/20 [30%]) or lost to follow-up (4/20 [20%]). Participants in studies A and B were similar in demographics and baseline disease characteristics (Table). The majority of participants were white females. 

Efficacy

No statistically significant difference was observed in all pairwise comparisons (clindamycin cream twice daily vs vehicle twice daily, clindamycin cream once daily vs vehicle once daily, clindamycin gel vs vehicle gel) for the primary end point of mean percentage change from baseline in inflammatory lesion counts at week 12 (Figure 1; P>.5 for all pairwise comparisons). 

At week 12, the proportion of participants in study B deemed as a success (none/clear or mild/almost clear [investigator global rosacea severity score of 0 or 1]) in the clindamycin gel 1% and vehicle gel groups were 45% versus 38%, respectively (P=.347) (Figure 2). 

For the secondary end point of mean investigator global rosacea severity assessment at week 12 (study A), there were no significant differences between the active and vehicle control groups (P>.5 for all pairwise comparisons)(Figure 3). Also, the proportion of participants with at least a moderate investigator global improvement assessment from baseline to week 12 ranged from 45% for clindamycin cream 1% twice daily to 56% for clindamycin cream 0.3% cream once daily and from 45% for vehicle cream once daily to 51% for vehicle cream twice daily (P>.5 for all pairwise comparisons).

There were no significant differences in the mean total erythema severity scores at week 12 for clindamycin cream 1% twice daily versus vehicle cream twice daily (6.3 vs 6.0; P>.5), clindamycin cream 1% once daily versus vehicle cream once daily (6.2 vs 6.0; P>.5), clindamycin cream 0.3% once daily versus vehicle cream once daily (5.9 vs 6.0; P>.5), and clindamycin gel 1% twice daily versus vehicle gel twice daily (6.7 vs 6.2; P>.5). 

There were no relevant differences between any of the clindamycin cream groups and their respective vehicle group at week 12 for skin irritation, including desquamation, edema, dryness, pruritus, and stinging/burning.

Safety

In study A, the majority of AEs in all 5 treatment arms were nondermatologic, mild in intensity, and not considered to be related to the study treatment by the investigator. Overall, 12 participants had AEs considered by the investigator as possibly or probably related to the study treatment: 4.9% in the clindamycin cream 1% twice daily group, 4.6% in the clindamycin cream 1% once daily group, 3.7% in the vehicle cream twice daily group, 1.2% in the clindamycin cream 0.3% once daily group, and 0% in the vehicle cream once daily group. Two treatment-related AEs led to treatment discontinuation, including dermatitis in 1 participant from the clindamycin cream 1% once daily group and contact dermatitis in 1 participant from the clindamycin cream 1% twice daily group.

Comment

No evidence of increased efficacy over the respective vehicles was observed with clindamycin cream or gel, whatever the regimen, in the treatment of rosacea patients in either of these well-designed and well-powered, blinded studies. Slight improvements in the various efficacy criteria were observed, even in the vehicle groups, highlighting the importance of using a good basic skin care regimen in the management of rosacea.⁹ In contrast to our observations of lack of efficacy in the treatment of rosacea, clinical efficacy of clindamycin has been demonstrated in acne,^10-12 albeit with low efficacy for clindamycin monotherapy.¹³ It is noteworthy that oral or topical antibiotics are no longer recommended as monotherapy for acne to prevent and minimize antibiotic resistance and to preserve the therapeutic value of antibiotics.¹⁴

Acne and rosacea are both chronic inflammatory disorders of the skin associated with papules and pustules, and they share some common inflammatory patterns.^15-19 Furthermore, the intrinsic anti-inflammatory activity of clindamycin in addition to its antibiotic effects has been suggested by some authors as the main reason for treating acne with clindamycin.²⁰ However, the relative contributions of antibacterial and/or anti-inflammatory properties remain to be fully elucidated, and evidence for direct anti-inflammatory effects of clindamycin remains heterogeneous.^21,22 Several pathophysiological factors have been implicated in acne, including hormonal effects, abnormal keratinocyte function, increased sebum production, and microbial components (eg, hypercolonization of the skin follicles by Propionibacterium acnes).^23,24 The antibiotic activity of clindamycin against P acnes may be the key factor responsible for the clinical effects in acne.^25,26 Although clindamycin may have anti-inflammatory effects in acne via a different inflammatory pathway not shared by rosacea, a purely antibiotic mechanism of action of clindamycin also could explain why we observed no evidence of efficacy in the treatment of rosacea, as no causative bacterial component has been clearly demonstrated in rosacea.²⁷

Conclusion

In these studies, clindamycin cream 0.3% once daily, clindamycin cream 1% once or twice daily, and clindamycin gel 1% twice daily were all well tolerated; however, they were no more effective than the vehicles in the treatment of moderate to severe rosacea.  

Acknowledgment

The authors would like to thank Helen Simpson, PhD, of Galderma R&D (Sophia Antipolis, France), for editorial and medical writing assistance.

Rosacea is a chronic inflammatory skin disease characterized by central facial erythema with or without intermittent papules and pustules (described as the inflammatory lesions of rosacea). Although twice-daily clindamycin 1% solution or gel has been used in the treatment of acne, few studies have investigated the use of clindamycin in rosacea.^1,2 In one study comparing twice-daily clindamycin lotion 1% with oral tetracycline in 43 rosacea patients, clindamycin was found to be superior in the eradication of pustules.³ A combination therapy of clindamycin 1% and benzoyl peroxide 5% was found to be more effective than the vehicle in inflammatory lesions and erythema of rosacea in a 12-week randomized controlled trial; however, a definitive advantage over US Food and Drug Administration-approved topical agents used to treat papulopustular rosacea was not established.^4,5 Two further studies evaluated clindamycin phosphate 1.2%-tretinoin 0.025% combination gel in the treatment of rosacea, but only 1 showed any effect on papulopustular lesions.^6-8 The objective of the studies reported here was to evaluate the efficacy and safety of clindamycin in the treatment of patients with moderate to severe rosacea.

Methods

Study Design

Two multicenter (study A, 20 centers; study B, 10 centers), randomized, investigator-blinded, vehicle-controlled studies were conducted in the United States between 1999 and 2002 in accordance with the Declaration of Helsinki, International Conference on Harmonisation Good Clinical Practice guidelines, and local regulatory requirements. The studies were reviewed and approved by the respective institutional review boards, and all participants provided written informed consent.

In study A, moderate to severe rosacea patients with erythema, telangiectasia, and at least 8 inflammatory lesions were randomized to receive clindamycin cream 1% or vehicle cream once (in the evening) or twice daily (in the morning and evening) or clindamycin cream 0.3% once daily (in the evening) for 12 weeks (1:1:1:1:1 ratio). All study treatments were supplied in identical tubes with blinded labels.

In study B, patients with moderate to severe rosacea and at least 8 inflammatory lesions were randomized in a 1:1 ratio with instructions to apply clindamycin gel 1% or vehicle gel to the affected areas twice daily (morning and evening) for 12 weeks.

Efficacy Evaluation

Evaluations were performed at baseline and weeks 2, 4, 8, and 12 on the intention-to-treat population with the last observation carried forward.

Efficacy assessments in both studies included inflammatory lesion counts (papules and pustules) of 5 facial regions--forehead, chin, nose, right cheek, left cheek--counted separately and then combined to give the total inflammatory lesion count (both studies), as well as improvement in the investigator global rosacea severity score (0=none/clear; 1=mild, detectable erythema with ≤7 papules/pustules; 2=moderate, prominent erythema with ≥8 papules/pustules; 3=severe, intense erythema with ≥10 to <50 papules/pustules; 3.5 [study A] or 4 [study B]=very severe, intense erythema with >50 papules/pustules). In study B, the proportion of participants dichotomized to success (a score of 0 [none/clear] or 1 [mild/almost clear]) or failure (a score of ≥2) on the 5-point investigator global rosacea severity scale at week 12 was evaluated. In study A, investigator global improvement assessment at week 12, based on photographs taken at baseline, was graded on a 7-point scale (from -1 [worse], 0 [no change], and 1 [minimal improvement] to 5 [clear]). In both studies, erythema severity was graded on a 7-point scale in increments of 0.5 (from 0=no erythema to 3.5=very severe redness, very intense redness). Skin irritation also was graded as none, mild, moderate, or severe. 

Safety Evaluation

Safety was assessed by the incidence of adverse events (AEs).

Statistical Analysis

Studies were powered assuming 60% reduction in inflammatory lesion counts with active and 40% with vehicle, based on historical data from a prior study with metronidazole cream 0.75% versus vehicle; 64 participants were required in each treatment group to detect this effect using a 2-sided t test (&#945;=.017). Pairwise comparisons (clindamycin vs respective vehicle) were performed using the Cochran-Mantel-Haenszel test for combined lesion count percentage change.

Results

Participant Disposition and Baseline Characteristics

Overall, a total of 629 participants were randomized across both studies. In study A, a total of 416 participants were randomized into 5 treatment arms, with 369 participants (88.7%) completing the study; 47 (11.3%) participants discontinued study A, mainly due to participant request (19/47 [40.4%]) or lost to follow-up (11/47 [23.4%]). In study B, a total of 213 participants were randomized to receive either clindamycin gel 1% (n=109 [51.2%]) twice daily or vehicle gel (n=104 [48.8%]) twice daily, with 193 participants (90.6%) completing the study; 20 (9.4%) participants discontinued study B, mainly due to participant request (6/20 [30%]) or lost to follow-up (4/20 [20%]). Participants in studies A and B were similar in demographics and baseline disease characteristics (Table). The majority of participants were white females. 

Efficacy

No statistically significant difference was observed in all pairwise comparisons (clindamycin cream twice daily vs vehicle twice daily, clindamycin cream once daily vs vehicle once daily, clindamycin gel vs vehicle gel) for the primary end point of mean percentage change from baseline in inflammatory lesion counts at week 12 (Figure 1; P>.5 for all pairwise comparisons). 

At week 12, the proportion of participants in study B deemed as a success (none/clear or mild/almost clear [investigator global rosacea severity score of 0 or 1]) in the clindamycin gel 1% and vehicle gel groups were 45% versus 38%, respectively (P=.347) (Figure 2). 

For the secondary end point of mean investigator global rosacea severity assessment at week 12 (study A), there were no significant differences between the active and vehicle control groups (P>.5 for all pairwise comparisons)(Figure 3). Also, the proportion of participants with at least a moderate investigator global improvement assessment from baseline to week 12 ranged from 45% for clindamycin cream 1% twice daily to 56% for clindamycin cream 0.3% cream once daily and from 45% for vehicle cream once daily to 51% for vehicle cream twice daily (P>.5 for all pairwise comparisons).

There were no significant differences in the mean total erythema severity scores at week 12 for clindamycin cream 1% twice daily versus vehicle cream twice daily (6.3 vs 6.0; P>.5), clindamycin cream 1% once daily versus vehicle cream once daily (6.2 vs 6.0; P>.5), clindamycin cream 0.3% once daily versus vehicle cream once daily (5.9 vs 6.0; P>.5), and clindamycin gel 1% twice daily versus vehicle gel twice daily (6.7 vs 6.2; P>.5). 

There were no relevant differences between any of the clindamycin cream groups and their respective vehicle group at week 12 for skin irritation, including desquamation, edema, dryness, pruritus, and stinging/burning.

Safety

In study A, the majority of AEs in all 5 treatment arms were nondermatologic, mild in intensity, and not considered to be related to the study treatment by the investigator. Overall, 12 participants had AEs considered by the investigator as possibly or probably related to the study treatment: 4.9% in the clindamycin cream 1% twice daily group, 4.6% in the clindamycin cream 1% once daily group, 3.7% in the vehicle cream twice daily group, 1.2% in the clindamycin cream 0.3% once daily group, and 0% in the vehicle cream once daily group. Two treatment-related AEs led to treatment discontinuation, including dermatitis in 1 participant from the clindamycin cream 1% once daily group and contact dermatitis in 1 participant from the clindamycin cream 1% twice daily group.

Comment

No evidence of increased efficacy over the respective vehicles was observed with clindamycin cream or gel, whatever the regimen, in the treatment of rosacea patients in either of these well-designed and well-powered, blinded studies. Slight improvements in the various efficacy criteria were observed, even in the vehicle groups, highlighting the importance of using a good basic skin care regimen in the management of rosacea.⁹ In contrast to our observations of lack of efficacy in the treatment of rosacea, clinical efficacy of clindamycin has been demonstrated in acne,^10-12 albeit with low efficacy for clindamycin monotherapy.¹³ It is noteworthy that oral or topical antibiotics are no longer recommended as monotherapy for acne to prevent and minimize antibiotic resistance and to preserve the therapeutic value of antibiotics.¹⁴

Acne and rosacea are both chronic inflammatory disorders of the skin associated with papules and pustules, and they share some common inflammatory patterns.^15-19 Furthermore, the intrinsic anti-inflammatory activity of clindamycin in addition to its antibiotic effects has been suggested by some authors as the main reason for treating acne with clindamycin.²⁰ However, the relative contributions of antibacterial and/or anti-inflammatory properties remain to be fully elucidated, and evidence for direct anti-inflammatory effects of clindamycin remains heterogeneous.^21,22 Several pathophysiological factors have been implicated in acne, including hormonal effects, abnormal keratinocyte function, increased sebum production, and microbial components (eg, hypercolonization of the skin follicles by Propionibacterium acnes).^23,24 The antibiotic activity of clindamycin against P acnes may be the key factor responsible for the clinical effects in acne.^25,26 Although clindamycin may have anti-inflammatory effects in acne via a different inflammatory pathway not shared by rosacea, a purely antibiotic mechanism of action of clindamycin also could explain why we observed no evidence of efficacy in the treatment of rosacea, as no causative bacterial component has been clearly demonstrated in rosacea.²⁷

Conclusion

In these studies, clindamycin cream 0.3% once daily, clindamycin cream 1% once or twice daily, and clindamycin gel 1% twice daily were all well tolerated; however, they were no more effective than the vehicles in the treatment of moderate to severe rosacea.  

Acknowledgment

The authors would like to thank Helen Simpson, PhD, of Galderma R&D (Sophia Antipolis, France), for editorial and medical writing assistance.

To improve patient care and outcomes, leading dermatologists offered their recommendations on redness-reducing products. Consideration must be given to:

• Avène Antirougeurs FORT Relief Concentrate
  Pierre Fabre Dermo-Cosmetique USA
  “This formula has medical-grade ruscus extract to support microcirculation and soothe skin reactivity and redness, as well as soothing Avène Thermal Spring Water.” — Jeannette Graf, MD, New York, New York
   
• Eucerin Redness Relief
  Beiersdorf Inc
  “Eucerin’s Redness Relief product line has worked well for some of my patients.” — Gary Goldenberg, MD, New York, New York
   
• Redness Solutions Daily Protective Base Broad Spectrum SPF 15
  Clinique Laboratories, LLC
  “This oil-free makeup primer has a sheer green tint that camouflages redness while also protecting from UV rays.” — Shari Lipner, MD, PhD, New York, New York

Cutis invites readers to send us their recommendations. Athlete’s foot treatments, cleansing devices, and men’s products will be featured in upcoming editions of Cosmetic Corner. Please email your recommendation(s) to the Editorial Office.

Disclaimer: Opinions expressed herein do not necessarily reflect those of Cutis or Frontline Medical Communications Inc. and shall not be used for product endorsement purposes. Any reference made to a specific commercial product does not indicate or imply that Cutis or Frontline Medical Communications Inc. endorses, recommends, or favors the product mentioned. No guarantee is given to the effects of recommended products.

To improve patient care and outcomes, leading dermatologists offered their recommendations on redness-reducing products. Consideration must be given to:

• Avène Antirougeurs FORT Relief Concentrate
  Pierre Fabre Dermo-Cosmetique USA
  “This formula has medical-grade ruscus extract to support microcirculation and soothe skin reactivity and redness, as well as soothing Avène Thermal Spring Water.” — Jeannette Graf, MD, New York, New York
   
• Eucerin Redness Relief
  Beiersdorf Inc
  “Eucerin’s Redness Relief product line has worked well for some of my patients.” — Gary Goldenberg, MD, New York, New York
   
• Redness Solutions Daily Protective Base Broad Spectrum SPF 15
  Clinique Laboratories, LLC
  “This oil-free makeup primer has a sheer green tint that camouflages redness while also protecting from UV rays.” — Shari Lipner, MD, PhD, New York, New York

Cutis invites readers to send us their recommendations. Athlete’s foot treatments, cleansing devices, and men’s products will be featured in upcoming editions of Cosmetic Corner. Please email your recommendation(s) to the Editorial Office.

Disclaimer: Opinions expressed herein do not necessarily reflect those of Cutis or Frontline Medical Communications Inc. and shall not be used for product endorsement purposes. Any reference made to a specific commercial product does not indicate or imply that Cutis or Frontline Medical Communications Inc. endorses, recommends, or favors the product mentioned. No guarantee is given to the effects of recommended products.

To improve patient care and outcomes, leading dermatologists offered their recommendations on redness-reducing products. Consideration must be given to:

• Avène Antirougeurs FORT Relief Concentrate
  Pierre Fabre Dermo-Cosmetique USA
  “This formula has medical-grade ruscus extract to support microcirculation and soothe skin reactivity and redness, as well as soothing Avène Thermal Spring Water.” — Jeannette Graf, MD, New York, New York
   
• Eucerin Redness Relief
  Beiersdorf Inc
  “Eucerin’s Redness Relief product line has worked well for some of my patients.” — Gary Goldenberg, MD, New York, New York
   
• Redness Solutions Daily Protective Base Broad Spectrum SPF 15
  Clinique Laboratories, LLC
  “This oil-free makeup primer has a sheer green tint that camouflages redness while also protecting from UV rays.” — Shari Lipner, MD, PhD, New York, New York

Cutis invites readers to send us their recommendations. Athlete’s foot treatments, cleansing devices, and men’s products will be featured in upcoming editions of Cosmetic Corner. Please email your recommendation(s) to the Editorial Office.

Disclaimer: Opinions expressed herein do not necessarily reflect those of Cutis or Frontline Medical Communications Inc. and shall not be used for product endorsement purposes. Any reference made to a specific commercial product does not indicate or imply that Cutis or Frontline Medical Communications Inc. endorses, recommends, or favors the product mentioned. No guarantee is given to the effects of recommended products.

When tasked with outlining updated therapy regimens for rosacea, specific patient vignettes come to mind.

A 53-year-old male golfer presents with years of central facial flushing, prominent telangiectases, erythema, and scattered pink papules. He attempted various over-the-counter topical products indicated for acne, such as salicylic acid scrub and benzoyl peroxide cream, with no improvement and much irritation. Recently, his wife has been helping him apply redness-concealing makeup in the morning and over-the-counter hydrocortisone cream in the evening, which has been slightly helpful.

This patient’s rosacea could conceivably be labeled under the papulopustular rosacea subtype; however, the conventional categories are fluid with subtype overlap and imprecise diagnostic criteria. He also seemed to display features of the erythematotelangiectatic subtype, perhaps with underlying photodamage as well as steroid rebound erythema and/or atrophy.¹ Nevertheless, it is a common presentation, and certain baseline tenets should be applied. First, all steroid products and irritants (eg, benzoyl peroxide and salicylic acid ingredients, any scrub vehicle) should be discontinued. Education about avoidance of triggers (ie, sun, heat, spicy food, alcohol, stress is paramount. Because barrier inadequacy is a recent insight into rosacea pathogenesis, mild syndet- or lipid-free cleansers, daily sunscreen, and evening emollients dictate baseline skin care, as does meticulous situation-specific sun protection.^2,3 The papular component and immediate erythema in and around the papules can be managed topically (prior to sunscreen or emollient application) with metronidazole gel or cream up to twice daily, ivermectin cream once daily, or azelaic acid gel or foam up to twice daily. Oral doxycycline 40 mg (delayed release) on an empty stomach or 50 mg (immediate release) with food to avert antimicrobial dosing and antibiotic resistance also could be considered if topical therapy is inadequate or irritating, though gastrointestinal comorbidities with rosacea also should be delineated before initiating oral antibiotics.^4-6 (Management of this patient’s nonlesional fixed erythema, telangiectases, and flushing is discussed after the next vignette.)

What if a woman presented in a similar fashion as above, only without papules? Her family physician prescribed metronidazole gel twice daily for years with no improvement in flushing, redness, or telangiectases.

Background erythema in rosacea often is persistent with trigger-specific intensification, with or without episodic facial flushing; undoubtedly, these symptoms can be difficult to compartmentalize depending on the clarity of the patient’s history and frequency of clinic visits. The aforementioned baseline skin care and sun-protection regimen applies, and newer topical agents such as α-adrenergics (daily oxymetazoline cream or brimonidine gel) may be considered for persistent erythema; however, irritant potential and rebound erythema are common.^7-9 Topical therapies such as metronidazole gel, as in this case, are inadequate for persistent background erythema or flushing. Persistent erythema and telangiectases can be reduced with pulsed dye laser or intense pulsed light modalities, particularly following conservative management of acute inflammation.⁵ Episodic flushing is poorly controlled with the above tactics, but anecdotally, topical or oral α-adrenergics or oral nonselective beta-blockers could be considered; the latter is also applicable to migraine therapy, which is perhaps comorbid with rosacea.^5,10

A 35-year-old Hispanic woman states that the scalp, forehead, and cheeks have been flaky, pink, and pruritic for years. She saw several aestheticians for it and the admixed “acne” on the face, receiving salicylic acid chemical peels with no improvement and much dyspigmentation.

Although underreported, the commingling of rosacea with seborrheic dermatitis is common, perhaps with mutual Demodex mite overpopulation, assigning topical therapies to its management such as daily ivermectin cream or steroid-sparing pimecrolimus cream for inflammatory papules and scaly regions of the face and scalp.^11-13 Further, this case exemplifies the increasing incidence and awareness of rosacea in darker skin types, along with its postinflammatory pigmentary perturbations, which necessitate repeated education about barrier control and sun protection.¹⁴

A 72-year-old male farmer presents with his wife whoinsists that his nose has been increasing in size for years; she procures a prior driver’s license photograph as proof. She also notes that he has been snoring at night and having more trouble breathing while working outdoors. The patient had not noticed.

Phymatous rosacea may exist as an additional feature of any rosacea subtype or as a singular finding, presenting as actively inflamed, fibrotic/noninflamed, or both. Management, particularly if inflamed, involves baseline gentle skin care and sun protection, avoidance of rosacea triggers, and implementation of oral therapy such as doxycycline or isotretinoin. Many cases, particularly those with a fibrotic component, warrant surgical methods such as fractionated CO₂ laser or Shaw scalpel surgical sculpting. These cases frequently demonstrate varying degrees of airway compromise, validating surgery as a legitimate medical, not merely cosmetic, presentation.^5,15

Final Thoughts

The Table, constructed as a concise therapy compendium by the ROSacea COnsensus (ROSCO) international panel of dermatologists and ophthalmologists, outlines data-driven and expert experience-based therapies for rosacea.⁵ This panel asserts that phenotypical features, not rigid subtypes, oblige patient-specific treatment schema. Also, as these cases outline, an evolving understanding of rosacea’s multifaceted pathogenesis, assorted presentations, and frequent pitfalls in daily skin care and initial management require individualized care.

When tasked with outlining updated therapy regimens for rosacea, specific patient vignettes come to mind.

A 53-year-old male golfer presents with years of central facial flushing, prominent telangiectases, erythema, and scattered pink papules. He attempted various over-the-counter topical products indicated for acne, such as salicylic acid scrub and benzoyl peroxide cream, with no improvement and much irritation. Recently, his wife has been helping him apply redness-concealing makeup in the morning and over-the-counter hydrocortisone cream in the evening, which has been slightly helpful.

This patient’s rosacea could conceivably be labeled under the papulopustular rosacea subtype; however, the conventional categories are fluid with subtype overlap and imprecise diagnostic criteria. He also seemed to display features of the erythematotelangiectatic subtype, perhaps with underlying photodamage as well as steroid rebound erythema and/or atrophy.¹ Nevertheless, it is a common presentation, and certain baseline tenets should be applied. First, all steroid products and irritants (eg, benzoyl peroxide and salicylic acid ingredients, any scrub vehicle) should be discontinued. Education about avoidance of triggers (ie, sun, heat, spicy food, alcohol, stress is paramount. Because barrier inadequacy is a recent insight into rosacea pathogenesis, mild syndet- or lipid-free cleansers, daily sunscreen, and evening emollients dictate baseline skin care, as does meticulous situation-specific sun protection.^2,3 The papular component and immediate erythema in and around the papules can be managed topically (prior to sunscreen or emollient application) with metronidazole gel or cream up to twice daily, ivermectin cream once daily, or azelaic acid gel or foam up to twice daily. Oral doxycycline 40 mg (delayed release) on an empty stomach or 50 mg (immediate release) with food to avert antimicrobial dosing and antibiotic resistance also could be considered if topical therapy is inadequate or irritating, though gastrointestinal comorbidities with rosacea also should be delineated before initiating oral antibiotics.^4-6 (Management of this patient’s nonlesional fixed erythema, telangiectases, and flushing is discussed after the next vignette.)

What if a woman presented in a similar fashion as above, only without papules? Her family physician prescribed metronidazole gel twice daily for years with no improvement in flushing, redness, or telangiectases.

Background erythema in rosacea often is persistent with trigger-specific intensification, with or without episodic facial flushing; undoubtedly, these symptoms can be difficult to compartmentalize depending on the clarity of the patient’s history and frequency of clinic visits. The aforementioned baseline skin care and sun-protection regimen applies, and newer topical agents such as α-adrenergics (daily oxymetazoline cream or brimonidine gel) may be considered for persistent erythema; however, irritant potential and rebound erythema are common.^7-9 Topical therapies such as metronidazole gel, as in this case, are inadequate for persistent background erythema or flushing. Persistent erythema and telangiectases can be reduced with pulsed dye laser or intense pulsed light modalities, particularly following conservative management of acute inflammation.⁵ Episodic flushing is poorly controlled with the above tactics, but anecdotally, topical or oral α-adrenergics or oral nonselective beta-blockers could be considered; the latter is also applicable to migraine therapy, which is perhaps comorbid with rosacea.^5,10

A 35-year-old Hispanic woman states that the scalp, forehead, and cheeks have been flaky, pink, and pruritic for years. She saw several aestheticians for it and the admixed “acne” on the face, receiving salicylic acid chemical peels with no improvement and much dyspigmentation.

Although underreported, the commingling of rosacea with seborrheic dermatitis is common, perhaps with mutual Demodex mite overpopulation, assigning topical therapies to its management such as daily ivermectin cream or steroid-sparing pimecrolimus cream for inflammatory papules and scaly regions of the face and scalp.^11-13 Further, this case exemplifies the increasing incidence and awareness of rosacea in darker skin types, along with its postinflammatory pigmentary perturbations, which necessitate repeated education about barrier control and sun protection.¹⁴

A 72-year-old male farmer presents with his wife whoinsists that his nose has been increasing in size for years; she procures a prior driver’s license photograph as proof. She also notes that he has been snoring at night and having more trouble breathing while working outdoors. The patient had not noticed.

Phymatous rosacea may exist as an additional feature of any rosacea subtype or as a singular finding, presenting as actively inflamed, fibrotic/noninflamed, or both. Management, particularly if inflamed, involves baseline gentle skin care and sun protection, avoidance of rosacea triggers, and implementation of oral therapy such as doxycycline or isotretinoin. Many cases, particularly those with a fibrotic component, warrant surgical methods such as fractionated CO₂ laser or Shaw scalpel surgical sculpting. These cases frequently demonstrate varying degrees of airway compromise, validating surgery as a legitimate medical, not merely cosmetic, presentation.^5,15

Final Thoughts

The Table, constructed as a concise therapy compendium by the ROSacea COnsensus (ROSCO) international panel of dermatologists and ophthalmologists, outlines data-driven and expert experience-based therapies for rosacea.⁵ This panel asserts that phenotypical features, not rigid subtypes, oblige patient-specific treatment schema. Also, as these cases outline, an evolving understanding of rosacea’s multifaceted pathogenesis, assorted presentations, and frequent pitfalls in daily skin care and initial management require individualized care.

When tasked with outlining updated therapy regimens for rosacea, specific patient vignettes come to mind.

A 53-year-old male golfer presents with years of central facial flushing, prominent telangiectases, erythema, and scattered pink papules. He attempted various over-the-counter topical products indicated for acne, such as salicylic acid scrub and benzoyl peroxide cream, with no improvement and much irritation. Recently, his wife has been helping him apply redness-concealing makeup in the morning and over-the-counter hydrocortisone cream in the evening, which has been slightly helpful.

This patient’s rosacea could conceivably be labeled under the papulopustular rosacea subtype; however, the conventional categories are fluid with subtype overlap and imprecise diagnostic criteria. He also seemed to display features of the erythematotelangiectatic subtype, perhaps with underlying photodamage as well as steroid rebound erythema and/or atrophy.¹ Nevertheless, it is a common presentation, and certain baseline tenets should be applied. First, all steroid products and irritants (eg, benzoyl peroxide and salicylic acid ingredients, any scrub vehicle) should be discontinued. Education about avoidance of triggers (ie, sun, heat, spicy food, alcohol, stress is paramount. Because barrier inadequacy is a recent insight into rosacea pathogenesis, mild syndet- or lipid-free cleansers, daily sunscreen, and evening emollients dictate baseline skin care, as does meticulous situation-specific sun protection.^2,3 The papular component and immediate erythema in and around the papules can be managed topically (prior to sunscreen or emollient application) with metronidazole gel or cream up to twice daily, ivermectin cream once daily, or azelaic acid gel or foam up to twice daily. Oral doxycycline 40 mg (delayed release) on an empty stomach or 50 mg (immediate release) with food to avert antimicrobial dosing and antibiotic resistance also could be considered if topical therapy is inadequate or irritating, though gastrointestinal comorbidities with rosacea also should be delineated before initiating oral antibiotics.^4-6 (Management of this patient’s nonlesional fixed erythema, telangiectases, and flushing is discussed after the next vignette.)

What if a woman presented in a similar fashion as above, only without papules? Her family physician prescribed metronidazole gel twice daily for years with no improvement in flushing, redness, or telangiectases.

Background erythema in rosacea often is persistent with trigger-specific intensification, with or without episodic facial flushing; undoubtedly, these symptoms can be difficult to compartmentalize depending on the clarity of the patient’s history and frequency of clinic visits. The aforementioned baseline skin care and sun-protection regimen applies, and newer topical agents such as α-adrenergics (daily oxymetazoline cream or brimonidine gel) may be considered for persistent erythema; however, irritant potential and rebound erythema are common.^7-9 Topical therapies such as metronidazole gel, as in this case, are inadequate for persistent background erythema or flushing. Persistent erythema and telangiectases can be reduced with pulsed dye laser or intense pulsed light modalities, particularly following conservative management of acute inflammation.⁵ Episodic flushing is poorly controlled with the above tactics, but anecdotally, topical or oral α-adrenergics or oral nonselective beta-blockers could be considered; the latter is also applicable to migraine therapy, which is perhaps comorbid with rosacea.^5,10

A 35-year-old Hispanic woman states that the scalp, forehead, and cheeks have been flaky, pink, and pruritic for years. She saw several aestheticians for it and the admixed “acne” on the face, receiving salicylic acid chemical peels with no improvement and much dyspigmentation.

Although underreported, the commingling of rosacea with seborrheic dermatitis is common, perhaps with mutual Demodex mite overpopulation, assigning topical therapies to its management such as daily ivermectin cream or steroid-sparing pimecrolimus cream for inflammatory papules and scaly regions of the face and scalp.^11-13 Further, this case exemplifies the increasing incidence and awareness of rosacea in darker skin types, along with its postinflammatory pigmentary perturbations, which necessitate repeated education about barrier control and sun protection.¹⁴

A 72-year-old male farmer presents with his wife whoinsists that his nose has been increasing in size for years; she procures a prior driver’s license photograph as proof. She also notes that he has been snoring at night and having more trouble breathing while working outdoors. The patient had not noticed.

Phymatous rosacea may exist as an additional feature of any rosacea subtype or as a singular finding, presenting as actively inflamed, fibrotic/noninflamed, or both. Management, particularly if inflamed, involves baseline gentle skin care and sun protection, avoidance of rosacea triggers, and implementation of oral therapy such as doxycycline or isotretinoin. Many cases, particularly those with a fibrotic component, warrant surgical methods such as fractionated CO₂ laser or Shaw scalpel surgical sculpting. These cases frequently demonstrate varying degrees of airway compromise, validating surgery as a legitimate medical, not merely cosmetic, presentation.^5,15

Final Thoughts

The Table, constructed as a concise therapy compendium by the ROSacea COnsensus (ROSCO) international panel of dermatologists and ophthalmologists, outlines data-driven and expert experience-based therapies for rosacea.⁵ This panel asserts that phenotypical features, not rigid subtypes, oblige patient-specific treatment schema. Also, as these cases outline, an evolving understanding of rosacea’s multifaceted pathogenesis, assorted presentations, and frequent pitfalls in daily skin care and initial management require individualized care.

A partnership between ophthalmologists and dermatologists holds the potential to produce a better treatment for ocular rosacea, one of the few conditions that brings the two specialties together.

“Hopefully, the paradigm eventually shifts from treating symptoms and signs of ocular rosacea with oral antibiotics or reflexive referral to ophthalmology to approaching cutaneous treatment first,” said dermatologist Kara Capriotti, MD, who has been working with a team of ophthalmologists to develop a treatment that focuses on ocular rosacea as a “lid disease,” instead of as a primary ocular surface problem.

Rosacea.org

A partnership between ophthalmologists and dermatologists holds the potential to produce a better treatment for ocular rosacea, one of the few conditions that brings the two specialties together.

“Hopefully, the paradigm eventually shifts from treating symptoms and signs of ocular rosacea with oral antibiotics or reflexive referral to ophthalmology to approaching cutaneous treatment first,” said dermatologist Kara Capriotti, MD, who has been working with a team of ophthalmologists to develop a treatment that focuses on ocular rosacea as a “lid disease,” instead of as a primary ocular surface problem.

Rosacea.org

A partnership between ophthalmologists and dermatologists holds the potential to produce a better treatment for ocular rosacea, one of the few conditions that brings the two specialties together.

“Hopefully, the paradigm eventually shifts from treating symptoms and signs of ocular rosacea with oral antibiotics or reflexive referral to ophthalmology to approaching cutaneous treatment first,” said dermatologist Kara Capriotti, MD, who has been working with a team of ophthalmologists to develop a treatment that focuses on ocular rosacea as a “lid disease,” instead of as a primary ocular surface problem.

Rosacea.org

SYDNEY, AUSTRALIA – Treatment with topical tretinoin resulted in complete resolution of rosacea symptoms in a significant number of patients, in a small retrospective study presented at the annual meeting of the Australasian College of Dermatologists.

“As an intermediary step between topical antibiotics and oral isotretinoin, we propose that topical tretinoin may be effective in the management and reduction of rosacea symptoms,” Emily Forward, MD, of the University of Sydney, said at the meeting. There has been recent discussion regarding the use of low-dose isotretinoin in the treatment of rosacea, but safety with long-term use is an issue, she noted.

Bianca Nogrady/Frontline Medical News

SYDNEY, AUSTRALIA – Treatment with topical tretinoin resulted in complete resolution of rosacea symptoms in a significant number of patients, in a small retrospective study presented at the annual meeting of the Australasian College of Dermatologists.

“As an intermediary step between topical antibiotics and oral isotretinoin, we propose that topical tretinoin may be effective in the management and reduction of rosacea symptoms,” Emily Forward, MD, of the University of Sydney, said at the meeting. There has been recent discussion regarding the use of low-dose isotretinoin in the treatment of rosacea, but safety with long-term use is an issue, she noted.

Bianca Nogrady/Frontline Medical News

SYDNEY, AUSTRALIA – Treatment with topical tretinoin resulted in complete resolution of rosacea symptoms in a significant number of patients, in a small retrospective study presented at the annual meeting of the Australasian College of Dermatologists.

“As an intermediary step between topical antibiotics and oral isotretinoin, we propose that topical tretinoin may be effective in the management and reduction of rosacea symptoms,” Emily Forward, MD, of the University of Sydney, said at the meeting. There has been recent discussion regarding the use of low-dose isotretinoin in the treatment of rosacea, but safety with long-term use is an issue, she noted.

Bianca Nogrady/Frontline Medical News

ORLANDO – Botulinum toxin may have a place in treating psoriasis and rosacea.

There is not a huge body of literature supporting the use of neuromodulators for these conditions, but a smattering of case reports have shown positive results and some clinicians are exploring their off label use, Erin Gilbert, MD, said at the annual meeting of the American Academy of Dermatology.

Courtesy Dr. Erin Gilbert

[email protected]

On Twitter @alz_gal

ORLANDO – Botulinum toxin may have a place in treating psoriasis and rosacea.

There is not a huge body of literature supporting the use of neuromodulators for these conditions, but a smattering of case reports have shown positive results and some clinicians are exploring their off label use, Erin Gilbert, MD, said at the annual meeting of the American Academy of Dermatology.

Courtesy Dr. Erin Gilbert

[email protected]

On Twitter @alz_gal

ORLANDO – Botulinum toxin may have a place in treating psoriasis and rosacea.

There is not a huge body of literature supporting the use of neuromodulators for these conditions, but a smattering of case reports have shown positive results and some clinicians are exploring their off label use, Erin Gilbert, MD, said at the annual meeting of the American Academy of Dermatology.

Courtesy Dr. Erin Gilbert

[email protected]

On Twitter @alz_gal

PORTLAND, ORE. – Dermatologists have plenty of room to improve when it comes to choosing cost-effective medications for acne or rosacea, based on the results of a large retrospective analysis of Medicare claims data.

Patients with acne or rosacea consistently paid more for topical retinoids, topical antibiotics, and oral tetracyclines when the prescriber was a dermatologist instead of a family or internal medicine physician, Myron Zhang reported at the annual meeting of the Society for Investigative Dermatology.

PORTLAND, ORE. – Dermatologists have plenty of room to improve when it comes to choosing cost-effective medications for acne or rosacea, based on the results of a large retrospective analysis of Medicare claims data.

Patients with acne or rosacea consistently paid more for topical retinoids, topical antibiotics, and oral tetracyclines when the prescriber was a dermatologist instead of a family or internal medicine physician, Myron Zhang reported at the annual meeting of the Society for Investigative Dermatology.

PORTLAND, ORE. – Dermatologists have plenty of room to improve when it comes to choosing cost-effective medications for acne or rosacea, based on the results of a large retrospective analysis of Medicare claims data.

Patients with acne or rosacea consistently paid more for topical retinoids, topical antibiotics, and oral tetracyclines when the prescriber was a dermatologist instead of a family or internal medicine physician, Myron Zhang reported at the annual meeting of the Society for Investigative Dermatology.

MIAMI – Management of rosacea continues to challenge dermatologists and patients alike, although new advances and recent studies shine a light on promising new therapies to target this inflammatory skin condition.

Linda Stein Gold, MD, who directs dermatology clinical trials at the Henry Ford Hospital in Detroit, shared new information about the pathophysiology of rosacea and the controversial associations with cardiovascular disease and addressed the rosacea “genes versus environment” etiology question at the Orlando Dermatology Aesthetic and Clinical Conference.

Courtesy RegionalDerm.com

Cardiovascular comorbidities

“We’ve heard a lot about psoriasis and cardiovascular comorbidities, and we worry that other skin diseases may have similar associations,” Dr. Stein Gold said. New revelations in the pathogenesis of rosacea suggest a comparable association, she added, including findings related to matrix metalloproteinases (MMPs). MMPs have a key role in rosacea, for example, and are also important in the pathogenesis of cardiovascular disease, she noted. Several studies have confirmed this association as well as other links, including to Parkinson’s disease.

Although these studies support associations, more evidence is needed to prove any causal relationship between rosacea and other conditions where inflammation plays a prominent role, she added.

Translating findings into action

Given this emerging evidence, “what are we going to do about it?” Dr. Stein Gold asked attendees at the meeting. Research suggests tetracycline might be protective, she said, because this antibiotic can inhibit MMP activity. In a retrospective cohort study, investigators discovered rosacea patients on tetracycline therapy were at lower risk for developing vascular disease (J Invest Dermatol. 2014 Aug;134[8]:2267-9).

Nature or nurture?

Researchers and clinicians frequently debate the precise etiology of rosacea and whether the underlying causes are primarily genetic versus environmental. Investigators conducted a twin cohort study to find a more concrete answer, specifically looking at identical and fraternal twin pairs to determine how much genetics or environment likely contributes to factors on the National Rosacea Society grading system (JAMA Dermatol. 2015 Nov;151[11]:1213-9).

“The bottom line is it’s really about half and half – about half were associated with genetics, the other half with environment,” Dr. Stein Gold said.

No matter what the etiology, it’s important to diagnose and treat rosacea, Dr. Stein Gold said. Although patients tend to be middle-aged white women, the condition is not limited to this patient population, and “you have to think about it to diagnose it in skin of color,” she added.

Rosacea, which has a high emotional impact, presents an opportunity for dermatologists to improve quality of life, Dr. Stein Gold said. “When people walk around with papules and pustules, [other] people think there is something wrong with them.”

Dr. Stein Gold disclosed that she is a consultant, member of the advisory boards and speaker’s bureaus for, and receives research grants from Galderma, Leo, Novan, Valeant, Novartis, Celgene and Allergan. She is also a consultant, advisory board member, and receives research grants from Dermira and Foamix. She is a consultant to Sol-Gel, Promis, Anacor, and Medimetriks. She is on the advisory board for Promis.

MIAMI – Management of rosacea continues to challenge dermatologists and patients alike, although new advances and recent studies shine a light on promising new therapies to target this inflammatory skin condition.

Linda Stein Gold, MD, who directs dermatology clinical trials at the Henry Ford Hospital in Detroit, shared new information about the pathophysiology of rosacea and the controversial associations with cardiovascular disease and addressed the rosacea “genes versus environment” etiology question at the Orlando Dermatology Aesthetic and Clinical Conference.

Courtesy RegionalDerm.com

Cardiovascular comorbidities

“We’ve heard a lot about psoriasis and cardiovascular comorbidities, and we worry that other skin diseases may have similar associations,” Dr. Stein Gold said. New revelations in the pathogenesis of rosacea suggest a comparable association, she added, including findings related to matrix metalloproteinases (MMPs). MMPs have a key role in rosacea, for example, and are also important in the pathogenesis of cardiovascular disease, she noted. Several studies have confirmed this association as well as other links, including to Parkinson’s disease.

Although these studies support associations, more evidence is needed to prove any causal relationship between rosacea and other conditions where inflammation plays a prominent role, she added.

Translating findings into action

Given this emerging evidence, “what are we going to do about it?” Dr. Stein Gold asked attendees at the meeting. Research suggests tetracycline might be protective, she said, because this antibiotic can inhibit MMP activity. In a retrospective cohort study, investigators discovered rosacea patients on tetracycline therapy were at lower risk for developing vascular disease (J Invest Dermatol. 2014 Aug;134[8]:2267-9).

Nature or nurture?

Researchers and clinicians frequently debate the precise etiology of rosacea and whether the underlying causes are primarily genetic versus environmental. Investigators conducted a twin cohort study to find a more concrete answer, specifically looking at identical and fraternal twin pairs to determine how much genetics or environment likely contributes to factors on the National Rosacea Society grading system (JAMA Dermatol. 2015 Nov;151[11]:1213-9).

“The bottom line is it’s really about half and half – about half were associated with genetics, the other half with environment,” Dr. Stein Gold said.

No matter what the etiology, it’s important to diagnose and treat rosacea, Dr. Stein Gold said. Although patients tend to be middle-aged white women, the condition is not limited to this patient population, and “you have to think about it to diagnose it in skin of color,” she added.

Rosacea, which has a high emotional impact, presents an opportunity for dermatologists to improve quality of life, Dr. Stein Gold said. “When people walk around with papules and pustules, [other] people think there is something wrong with them.”

Dr. Stein Gold disclosed that she is a consultant, member of the advisory boards and speaker’s bureaus for, and receives research grants from Galderma, Leo, Novan, Valeant, Novartis, Celgene and Allergan. She is also a consultant, advisory board member, and receives research grants from Dermira and Foamix. She is a consultant to Sol-Gel, Promis, Anacor, and Medimetriks. She is on the advisory board for Promis.

MIAMI – Management of rosacea continues to challenge dermatologists and patients alike, although new advances and recent studies shine a light on promising new therapies to target this inflammatory skin condition.

Linda Stein Gold, MD, who directs dermatology clinical trials at the Henry Ford Hospital in Detroit, shared new information about the pathophysiology of rosacea and the controversial associations with cardiovascular disease and addressed the rosacea “genes versus environment” etiology question at the Orlando Dermatology Aesthetic and Clinical Conference.

Courtesy RegionalDerm.com

Cardiovascular comorbidities

“We’ve heard a lot about psoriasis and cardiovascular comorbidities, and we worry that other skin diseases may have similar associations,” Dr. Stein Gold said. New revelations in the pathogenesis of rosacea suggest a comparable association, she added, including findings related to matrix metalloproteinases (MMPs). MMPs have a key role in rosacea, for example, and are also important in the pathogenesis of cardiovascular disease, she noted. Several studies have confirmed this association as well as other links, including to Parkinson’s disease.

Although these studies support associations, more evidence is needed to prove any causal relationship between rosacea and other conditions where inflammation plays a prominent role, she added.

Translating findings into action

Given this emerging evidence, “what are we going to do about it?” Dr. Stein Gold asked attendees at the meeting. Research suggests tetracycline might be protective, she said, because this antibiotic can inhibit MMP activity. In a retrospective cohort study, investigators discovered rosacea patients on tetracycline therapy were at lower risk for developing vascular disease (J Invest Dermatol. 2014 Aug;134[8]:2267-9).

Nature or nurture?

Researchers and clinicians frequently debate the precise etiology of rosacea and whether the underlying causes are primarily genetic versus environmental. Investigators conducted a twin cohort study to find a more concrete answer, specifically looking at identical and fraternal twin pairs to determine how much genetics or environment likely contributes to factors on the National Rosacea Society grading system (JAMA Dermatol. 2015 Nov;151[11]:1213-9).

“The bottom line is it’s really about half and half – about half were associated with genetics, the other half with environment,” Dr. Stein Gold said.

No matter what the etiology, it’s important to diagnose and treat rosacea, Dr. Stein Gold said. Although patients tend to be middle-aged white women, the condition is not limited to this patient population, and “you have to think about it to diagnose it in skin of color,” she added.

Rosacea, which has a high emotional impact, presents an opportunity for dermatologists to improve quality of life, Dr. Stein Gold said. “When people walk around with papules and pustules, [other] people think there is something wrong with them.”

Dr. Stein Gold disclosed that she is a consultant, member of the advisory boards and speaker’s bureaus for, and receives research grants from Galderma, Leo, Novan, Valeant, Novartis, Celgene and Allergan. She is also a consultant, advisory board member, and receives research grants from Dermira and Foamix. She is a consultant to Sol-Gel, Promis, Anacor, and Medimetriks. She is on the advisory board for Promis.