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Rosacea
Evidence Levels: A Double-blind study B Clinical trial ≥ 20 subjects C Clinical trial < 20 subjects D Series ≥ 5 subjects E Anecdotal case reports
Courtesy of Jason Smith MD, Rome, Georgia
Rosacea is a common, chronic, heterogenous, inflammatory skin disease, seen most often in adults of both genders and all skin types. It predominantly involves the central face and is characterized by intermittent flares that present with transient findings (flushing, papules/pustules) and by persistence of some fixed clinical manifestations (telangiectasias, persistent facial erythema). Individuals who develop rosacea are innately affected by rosacea-prone skin that exhibits physiochemical and ultrastructural differences from normal facial skin. These include altered colocalization of cutaneous nerves and vessels, increase in perivascular mast cells, aberrant patterns of cutaneous receptor distribution and magnitude, altered gene expression patterns that appear to correlate with clinical features, aberrant response to environmental exposures (‘triggers’), increased serine protease activity, diminished antioxidant reserve (superoxide dismutase), augmented immunologic and inflammatory responses via the cathelicidin cascade and other pathways, and progressive alterations in superficial cutaneous vasculature. The collective effects of these changes observed within rosacea-prone skin are neurovascular dysregulation and augmented immune detection–response. These dominant pathophysiologic mechanisms correlate with specific clinical manifestations that lead to different phenotypic expressions among patients affected by rosacea, which may progress over time and directly impact upon management of individual cases of rosacea.
The most common presentations of cutaneous rosacea seen by clinicians in real-world practice are central facial erythema with or without papulopustular lesions. Patients may also present with phymatous changes, usually affecting the nose (rhinophyma) and/or ocular rosacea, often described by patients as sensations of dry eyes, grittiness, itchiness, and/or irritation. The latter may include blepharitis, conjunctivitis, and less commonly chalazion, hordeolum, and keratitis. Facial telangiectasias are characteristic visible signs of rosacea. Rosacea flares are associated with episodic facial vasodilation (flushing of rosacea), and papulopustular lesions in some patients, both which are transient clinical features that distinguish rosacea from chronic photodamage. Persistent erythema involving the central face is commonly observed between flares of rosacea, due to proliferation and fixed dilatation of superficial facial vasculature. Sensory symptoms of facial burning and/or stinging can accompany rosacea, especially during flares. Dry facial skin, sometimes with fine scaling, is often noted (‘rosacea dermatitis’) due to increased transepidermal water loss inherent to rosacea-affected skin, which is distinct from seborrheic dermatitis. Marked chronic facial edema, solitary plaque rosacea, granulomatous rosacea, and extrafacial rosacea are relatively uncommon clinical variants of the disease.
Management Strategy
Rosacea is diagnosed clinically, with a usual onset in early adulthood. Importantly, the clinical manifestations of rosacea vary among affected individuals, with central facial erythema and episodic flushing being the two most consistent diagnostic features. Papulopustular lesions are noted in some patients during flares. The presence and the intensity of individual manifestations of rosacea vary in affected individuals over time.
As both neurovascular dysregulation and augmented immune detection–response are integral components of rosacea-prone skin, avoidance of ‘triggers’ that can induce facial vasodilation (i.e., alcohol, spicy food, hot drinks, hot ambient temperature) is suggested, as is avoidance of common skin irritants. Consistent use of gentle skin care, moisturizer application, and photoprotection are integral components of cutaneous rosacea management. Cosmetic camouflage of the erythema and telangiectasia may be helpful for some patients. Papulopustular lesions can be effectively treated with specific ‘antiinflammatory’ topical or oral agents, either as monotherapy, or in combination, which are described later. Agents used to treat papulopustular lesions also reduce perilesional erythema; none have shown efficacy in reducing persistent facial erythema of rosacea (PFE; background vascular erythema), which is due to fixed dilation of superficial facial vasculature. With regard to using oral agents that can improve papulopustular rosacea, but can induce antibiotic resistance as an unwanted consequence, guidelines suggest that subantibiotic treatment is used initially if deemed to be indicated and if accessible. Use of topical corticosteroids of any potency for treatment of rosacea, although tempting due to initial benefit, is best avoided due to the high potential for ‘cutaneous steroid addiction’ characterized by a marked rosaceaform eruption and other persistent adverse effects. Persistent facial erythema can be treated with topical application of an α-adrenoreceptor agonist or with designated physical modalities, such as intense pulsed light or vascular lasers . The latter are more effectively utilized to treat telangiectasias, which are not responsive to available topical or oral agents used to treat rosacea. Flushing of rosacea, a major hallmark of a flare, is usually the most difficult manifestation to treat; however, the frequency and intensity of episodic flaring appear to be reduced by available medical therapies when used consistently. Ocular rosacea is often managed with emollient ophthalmic preparations (‘artificial tears’) and an oral tetracycline agent. Increased Demodex mite density may occur in some patients with cutaneous rosacea with or without papulopustular lesions, and in ocular rosacea, with the mites apparently serving as a trigger factor in some cases, or inducing a rosaceaform papulopustular facial eruption. Some reports have suggested that eradication of Helicobacter pylori infection with antibiotic therapy improves rosacea, although others refute these findings; this subject area remains controversial. The use of physical devices, such as laser and light-based therapies, is rapidly evolving with some guidance provided in available publications and consensus recommendations. Specific treatments are shown below in sections on papulopustular rosacea, erythematotelangiectatic rosacea, flushing, lymphedema, ocular rosacea, and rosacea fulminans. Treatments for rhinophyma and perioral dermatitis are described in separate chapters.
Specific Investigations
In selected cases
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Exclude carcinoid syndrome: history, physical examination, laboratory testing
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Exclude cutaneous lupus: history, serology, histology
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Exclude chronic photodamage: history, physical examination
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Exclude contact dermatitis: history, physical examination, patch testing
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Exclude seborrheic dermatitis: history, physical examination
Papulopustular Rosacea
Managing rosacea: a review of the use of metronidazole alone and in combination with oral antibiotics
Conde JF, Yelverton CB, Balkrishnan R, et al. J Drugs Dermatol. 2007; 6(5): 495–8.
The efficacy and safety of topical metronidazole used as monotherapy or in combination with oral antibiotic therapy was demonstrated in several studies for papulopustular rosacea. A variety of metronidazole 0.75% and 1% vehicle formulations are available (gel, cream, lotion) for once daily or twice daily use. Combination therapy induces a faster onset of inflammatory lesion reduction and perilesional erythema, especially in cases of greater severity.
Topical metronidazole maintains remissions of rosacea
Dahl MV, Katz HI, Krueger GG, et al. Arch Dermatol 1998; 134: 679–83.
Eighty-eight subjects who had responded to treatment with systemic tetracycline and topical metronidazole were randomized to receive 0.75% metronidazole gel or placebo gel for 6 months. In those using metronidazole, 23% developed a relapse of papulopustular lesions and 55% noted worsening of erythema, compared with 42% and 74% of subjects in the placebo group, respectively.
Azelaic acid in the treatment of papulopustular rosacea: a systematic review of randomized trials
Liu RH, Smith MK, Basta SA, et al. Arch Dermatol. 2006; 142(8): 1047–52.
This is a thorough analysis of randomized controlled studies of topical azelaic acid 15% gel and 20% cream with their vehicles, and with metronidazole gel. Topical azelaic acid is effective for papulopustular rosacea, evidenced by reduction in mean inflammatory lesion counts and perilesional erythema. Comparison with topical metronidazole showed azelaic acid to be at least equally effective, if not a better treatment option.
Cathelicidin, kallikrein-5, and serine protease activity is inhibited during treatment of rosacea with azelaic acid 15% gel
Coda AB, Hata T, Miller J, et al. J Am Acad Dermatol 2013; 69(4): 570–7.
Gene expression and protease activity were measured in a 16-week, prospective, multicenter study of patients with papulopustular rosacea treated with azelaic acid 15% gel. Murine and keratinocyte models have shown that azelaic acid downregulates kallikrein-5 and cathelicidin (LL37). This study performed in patients with papulopustular rosacea showed that azelaic acid downregulated kallikrein-5 and cathelicidin and identified rosacea subsets with high or low baseline serine protease activity. This supports apparent modes of action for topical azelaic acid in rosacea.
Impact of order of application of moisturizers on percutaneous absorption kinetics: evaluation of sequential application of moisturizer lotions and azelaic acid gel 15% using a human skin model
Del Rosso JQ, Lehman PA, Raney SG. Cutis 2009; 83(3): 119–24.
This study addressed a common clinical question about the preferred order of moisturizer application. Data were collected ex vivo using human skin and tested with three commonly used moisturizer lotions. The results showed that moisturizer application can be either before or after azelaic acid 15% gel with no significant change in the percutaneous absorption profile of azelaic acid, at least with the moisturizers that were tested.
Azelaic acid topical formulations: differentiation of 15% gel and 15% foam
Del Rosso, JQ. J Clin Aesthet Dermatol 2017; 10(3): 37–40.
Efficacy and safety with both formulations in papulopustular rosacea has been substantiated in randomized, controlled trials. Differences in vehicle technology and potential clinical impact on potential neurosensory skin tolerability reactions between the formulations are explained. The foam formulation appears to reduce the potential for neurosensory symptoms (i.e., stinging, burning) that may occur in a subset of patients after skin application compared to the gel. The importance of proper skin care in rosacea treatment is discussed.
Efficacy and safety of ivermectin 1% cream in treatment of papulopustular rosacea: results of two randomized, double-blind, vehicle controlled, pivotal studies
Stein L, Kircik L, Fowler J, et al. J Drugs Dermatol 2014; 13: 316–23.
Nearly 700 subjects were enrolled in each study; a high mean inflammatory lesion count (≈30) was present at baseline in all study arms. Treatments were applied once daily. At 12 weeks, assessments of ‘clear’ or ‘almost clear’ were noted in 38.4% and 40.1% of the ivermectin group and 11.6% and 18.8% of the vehicle group, respectively ( p <0.001). Skin tolerability was very favorable and systemic safety signals were noted.
Superiority of ivermectin 1% cream over metronidazole 0.75% cream in treating inflammatory lesions of rosacea: a randomized, investigator-blinded trial
Taieb A, Ortonne JP, Ruzicka T, et al. Br J Dermatol 2015; 172: 1103–10.
In a 16-week study ( n = 962), subjects applying ivermectin cream experienced an 83% reduction in inflammatory lesions (the primary end point), compared with a 74% reduction in the metronidazole group ( p <0.001). A longer duration of remission posttreatment (median 115 vs. 85 days) was noted in the ivermectin-treated study arm. Skin tolerability was highly favorable in both groups. The likelihood of achieving clear skin based on investigator assessment is higher with topical ivermectin, though both agents are effective and well tolerated.
Dual anti-inflammatory and anti-parasitic action of topical ivermectin 1% in papulopustular rosacea
Schaller M, Gonser L, Belge K, et al. J Eur Acad Dermatol Venereol 2017; 31(11): 1907–11.
In a pilot study ( n = 20), ivermectin 1% cream was used once daily for ≥12 weeks to treat papulopustular rosacea of at least moderate severity and a minimum Demodex density ≥15/cm 2 . Outcomes were evaluated clinically, by change in Demodex density, and via biomarker measurement. Both antiinflammatory and antiparasitic modes of action were shown. Mean Demodex density was significantly reduced at weeks 6 and 12 ( p <0.001). Biomarkers (i.e., IL8, LL37, TLR4) were markedly downregulated. Clear or almost clear skin by investigator global assessment was achieved in 80% of subjects.
Minocycline 1.5% foam for the treatment of moderate to severe papulopustular rosacea: results of 2 phase 3, randomized, clinical trials
Stein Gold LS, Del Rosso JQ, Kircik L, et al. J Am Acad Dermatol 2020; 82(5): 1166–73.
Two double-blind, randomized, 12-week, multicenter studies completed in subjects treated once daily with minocycline 1.5% foam ( n = 1009) or vehicle foam ( n = 513) evaluated efficacy, tolerability, and safety. Minocycline 1.5% foam showed significantly greater reductions in papulopustular lesions ( p = .0031; p <.0001) and higher rates of treatment success ( p = 0.0273; p = .0077) than vehicle. Skin tolerability was favorable in both study arms. No serious treatment-related adverse events were noted; no major systemic side effects reported to occur with oral minocycline were observed.
Two randomized phase III clinical trials evaluating anti-inflammatory dose doxycycline (40-mg doxycycline, USP capsules, modified release) administered once daily for treatment of rosacea
Del Rosso JQ, Webster GF, Jackson M, et al. J Am Acad Dermatol 2007; 56: 791–802.
Doxycycline 40 mg modified-release capsule once daily used as monotherapy vs. placebo was proven to be effective and well tolerated for papulopustular rosacea in two large-scale phase III studies. This dosing formulation mitigates antibiotic resistance by avoiding bacterial selection pressure. Cases of phototoxicity were not observed, and no reports of vaginal candidiasis were noted among actively treated females ( n = 185).
Comparison of anti-inflammatory dose doxycycline versus doxycycline 100 mg in the treatment of rosacea
Del Rosso JQ, Schlessinger J, Werschler P. J Drugs Dermatol. 2008; 7(6): 573–6.
In this randomized, double-blind, head-to-head, 16-week trial, subjects ( n = 91) received subantibiotic-dose doxycycline 40 mg daily or antibiotic-dose doxycycline 100 mg daily. Efficacy was equivalent in both groups at all time points based on investigator global assessment and inflammatory lesion count reductions. Gastrointestinal side effects of nausea, vomiting, diarrhea, esophageal pain, and abdominal pain occurred only in the group treated with doxycycline 100 mg.
An open-label, community-based, 12-week assessment of the effectiveness and safety of monotherapy with doxycycline 40 mg (30-mg immediate-release and 10-mg delayed-release beads)
Webster GF. Cutis 2010; 86(5 Suppl): 7–15.
This report of a large phase 4 community-based (open), 12-week trial assessed outcomes with the 40-mg, once-daily, subantibiotic-dose doxycycline formulation used as monotherapy in adults with mild-to-severe papulopustular rosacea. The primary outcome measure was a change in investigator global assessment (IGA) score from baseline to week 12. Among the 826 monotherapy participants who completed the trial, approximately 75% of participants were clear or near clear by week 12. Adverse events that occurred in >1% included diarrhea (1.2%), nausea (1.3%), and headache (1.0%); fungal/yeast infections were noted in 0.4%. These data support the efficacy and safety of this formulation in this patient population.
Among participants who received subantibiotic-dose doxycycline as ‘add-on therapy’ to topical rosacea treatments that presented with persistent rosacea at baseline, therapeutic outcomes were very similar to these monotherapy results.
Efficacy of extended-release 45 mg oral minocycline and extended-release oral minocycline plus 15% azelaic acid in the treatment of acne rosacea
Jackson JM, Kircik LH, Lorenz DJ. J Drugs Dermatol 2013; 12(3): 292–8.
The use of an extended-release low-dose minocycline 45 mg tablet once daily, with or without topical azelaic acid, for the treatment of papulopustular rosacea is reported. This is an antibiotic-dose of minocycline; subantibiotic dosing with oral minocycline has not been established.
Minocycline is not as commonly used as doxycycline for treatment of rosacea, likely due to the potential for vertigo, need for chronic administration, cutaneous pigmentation changes with prolonged use, lack of a proven subantibiotic-dose/formulation, and rare association with drug hypersensitivity syndrome, autoimmune reactions such as hepatitis and systemic lupus-like syndrome, and higher potential for benign intracranial hypertension.
Treatment of rosacea: topical clindamycin versus oral tetracycline
Wilkin JK, DeWitt S. Int J Dermatol 1993; 32: 65–7.
A randomized, blinded 12-week trial compared topical clindamycin lotion twice daily with oral tetracycline ( n = 43). Efficacy outcomes were similar in both groups, although clindamycin was superior in pustule reduction.
Current published recommendations by multiple organized groups that discuss acne and rosacea management, and antibiotic therapy use, advise against monotherapy with topical clindamycin due to increased emergence of antibiotic-resistant bacterial strains. In the case of rosacea, there are several other approved topical therapy options available.
Randomized, phase 2, dose-ranging study in the treatment of rosacea with encapsulated benzoyl peroxide gel
Leyden JJ. J Drugs Dermatol 2014; 13(6): 685–8.
Once-daily application of encapsulated benzoyl peroxide 1% and 5% formulations were evaluated in a multicentered randomized, double-blind, vehicle-controlled, 12-week study in patients with predominantly moderate papulopustular rosacea ( n = 92). Both 1% and 5% encapsulated benzoyl peroxide gel were significantly superior to vehicle in reducing papulopustular lesions ( p = 0.01; p = 0.02); the 5% formulation was significantly superior to vehicle based on IGA ratings of achieving clear or almost clear ( p = 0.0013).
Double-blind, randomized, vehicle-randomized clinical trial of once-daily benzoyl peroxide/clindamycin topical gel in the treatment of patients with moderate to severe rosacea
Breneman D, Savin R, VandePol C, et al. Int J Dermatol 2004; 43: 381–7.
Use of 5% benzoyl peroxide/1% clindamycin gel once daily was shown to be effective ( n = 52). Mean percentage reduction in inflammatory lesions from baseline to the end of treatment was 71.3% in the benzoyl peroxide/clindamycin group and 19.3% in the vehicle group ( p = 0.0056). Application site reactions were noted in four of 26 patients in the benzoyl peroxide/clindamycin study group.
Oral use of azithromycin for treatment of acne rosacea
Fernandez-Obregon A. Arch Dermatol 2004; 140: 489–90.
Ten patients responded to azithromycin 250 mg/day for 3 days each week (Monday, Wednesday, and Friday) within 4 weeks. Ocular symptoms also improved. The long half-life of azithromycin supports intermittent administration.
Papulopustular rosacea: response to treatment with oral azithromycin
Lova Navarro M, Sánchez-Pedreño Guillen P, Victoria Martínez AM, et al. Actas Dermosifiliogr 2018; 109(6): 529–35.
This prospective pilot study evaluated oral azithromycin use after inadequate response to oral doxycycline and metronidazole gel ( n = 16). Fourteen patients showed complete or almost complete improvement (complete clearance of papules/pustules; marked reduction in perilesional erythema). The authors concluded that oral azithromycin could be effective for short-term and long-term treatment in refractory cases.
Caution with oral azithromycin is suggested in older patients and those with a history of cardiac disease.
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