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Doi:10.1016/j.jaad.2006.04.084

Systematic review of rosacea treatments Esther J. van Zuuren, MD,a Aditya K. Gupta, MD, PhD, FRCP(C),b,c Melissa D. Gover, BSc,c Mark Graber, MD,d and Sally Hollis, MSce Leiden, The Netherlands; Toronto and London, Ontario, Canada; Iowa City, Iowa; and Lancaster, United Kingdom Background: Rosacea is a common chronic skin and ocular condition. It is unclear which treatmentsare most effective. We have conducted a Cochrane review of rosacea therapies.This article is a distillationof that work.
Objective: We sought to assess the evidence for the efficacy and safety of rosacea therapies.
Methods: Multiple databases were systematically searched. Randomized controlled trials in people withmoderate to severe rosacea were included. Study selection, assessment of methodologic quality, dataextraction, and analysis were carried out by two independent researchers.
Results: In all, 29 studies met inclusion criteria. Topical metronidazole is more effective than placebo(odds ratio 5.96, 95% confidence interval 2.95-12.06). Azelaic acid is more effective than placebo (oddsratio 2.45, 95% confidence interval 1.82-3.28). Firm conclusions could not be drawn about other therapies.
Limitations: The quality of the studies was generally poor.
Conclusions: There is evidence that topical metronidazole and azelaic acid are effective. There is someevidence that oral metronidazole and tetracycline are effective. More well-designed, randomized controlledtrials are required to provide better evidence of the efficacy and safety of other rosacea therapies. ( J AmAcad Dermatol 2007;56:107-15.) by recurrent episodes of facial flushing, ery-thema, papules, pustules, and telangiectasia confidence interval in a symmetrical, facial distribution.Several well- RCT: randomized controlled trial defined types of rosacea are described includingerythematotelangiectatic rosacea, papulopustularrosacea, phymatous rosacea, ocular rosacea, and can develop without involvement of other areas of the variant granulomatous rosacOcular rosacea the skin and may wax and wane.Rosacea usuallypresents in the second or third decade of life andhas a prevalence of up to 10%.It is especially com- From the Department of Dermatology B1-Q, Leiden University mon in fair-skinned people of Celtic and northern Medical Centera; Division of Dermatology, Department of European heritage, with women more often affected Medicine, Sunnybrook and Women's College Health Sciences than However, men will more often progress Center and the University of Torontob; Mediprobe Research Inc, to the later stages.
Londonc; Emergency Medicine and Family Medicine, Universityof Iowa College of Medicined; and University of Lancaster.e Traditionally, rosacea has been managed with a Funding sources: None.
treatment tailored to the specific symptoms pre- Conflicts of interest: None identified.
sented.A brief overview of these therapies is This manuscript is based on an earlier publication by van Zuuren presented in Other treatments tried et al,copyright Cochrane Library, reproduced with permission.
include facial massage (for edema), spironolactone, Reprint requests: Esther J. van Zuuren, MD, Department of Derma- tology B1-Q, Leiden University Medical Center, PO Box 9600, beta-blockers, dapsone, oral contraceptives, ben- 2300 RC Leiden, The Netherlands. zoyl peroxide, bifonazole cream, and treatment of Helicobacter pyloriUnfortunately, many of Published online November 10, 2006.
these remain poorly studied. This review was per- 0190-9622/$32.00ª 2007 by the American Academy of Dermatology, Inc.
formed to systematically evaluate rosacea treatments including the potential impact of nonpharmacologic J AM ACAD DERMATOL 108 van Zuuren et al Table I. Rosacea therapi Topical therapies Metronidazole (0.75%, 1%) Clindamycin lotionPermethrin 5% creamTretinoin creamSulfacetamide 10%/sulfur 5%Azelaic acid (15% gel, 20% cream) Proposed therapies TacrolimusTopical NADH Possible side effects candidal vaginitis,reduction in oralcontraceptiveefficacy Discontinue oral treatment once sufficient efficacy noted Maintenance therapy with topical medications intense pulsedlight Oral isotretinoin 13-cis-retinoic acid Possible side effects persistent rosacea include: dry sensitive monitoring of liver skin, dry mucosae, dry eyes, pruritis, dermatitis, myalgia, enzymes, cholesteroland triglycerideelevation abnormalities forwomen who becomepregnant Oral hypotensives Low-dose isotretinoin Laser therapySurgical MetronidazoleFusidic acid gel NADH, reduced form of ß-nicotinamide adenine dinucleotide.
agents such as foods (eg, spicy food), certain cos- of rosacea. As rosacea can cause shame, embarrass- metics, and sunscreens.
ment, low self-esteem, anxiety, lack of confidence, Unfortunately, there is no universally accepted and depression, our primary outcome was the clinical definition of rosacea, and there are no patients' self-assessment of rosacea, and their per- standard validated tools for assessing the severity ception of their quality of life.
J AM ACAD DERMATOL van Zuuren et al 109 VOLUME 56, NUMBER 1 Table II. Criteria used to assess the methodologic quality of randomized controlled trialsfor rosacea therapies Quality assessment criteria: Was the randomization procedure used appropriate? Was the allocation concealment adequate? Was an intention-to-treat analysis used? Were health workers and study personnel blind to treatment? Were participants blind to treatment?Aside from the intervention, were groups treated equally? Was the study duration fixed/adequate (at least 4 weeks)?Were number and timing of assessment points fixed? Was there an acceptable description or definition of rosacea? Was the site of evaluation recorded? y Were concomitant medications permitted and recorded? Was previous oral and topical rosacea therapy stopped a minimum of 4 weeks before the initial assessment?Were the therapeutic interventions adequately described?Were adequate details about how to use/take the medication given to all participants? Was the dropout rate less than 5%? Modifiedand used with permission.
*All these criteria must be ‘‘yes'' to be high quality.
yStudy must not allow concomitant medications that might change outcome.
criteria were considered high quality, whereas stud- A systematic review of randomized controlled ies meeting some, but not all, were generally classi- trials (RCTs) was performed according to a prespe- fied as intermediate. Studies classified as low quality were excluded from analysis. Supporting methodol-ogy descriptions for each criterion had to be present Search strategies in the published text to merit the grading. Details of Two reviewers performed independent searches eligible trials were extracted and summarized using of the following 6 electronic databases: The structured data collection forms.
Cochrane Skin Group Specialized Trials Register(February 2005), The Cochrane Central Register of Controlled Trials (February 2005), MEDLINE (1966- The primary outcome measures included impact February 2005), EMBASE (1980-February 2005), on quality of life and participant-assessed changes in Biosis (1970-March 2002), and Science Citation rosacea severity. Secondary outcome measures were Index (1988-February 2005). In addition, the refer- physician-assessed changes in rosacea severity, phy- ence lists of all identified RCTs and key review sician's global evaluation (improvement defined articles were searched. Attempts were made to as $ 50% change), lesion counts (treatment success obtain details of unpublished and ongoing RCTs defined as [50% reduction), time needed for and grey literature through correspondence with improvement, and duration of remission. Other authors and pharmaceutical companies.
outcomes included dropout rates and incidence ofadverse events.
Selection criteria We considered all RCTs evaluating any type of intervention used to treat rosacea. Study participants Quantitative pooling was performed using odds had to be older than 19 years with moderate to severe ratio (OR) for categorical measures or weighted rosacea as assessed by a physician. Two reviewers mean differences for continuous measures. Where independently assessed these articles for eligibility.
study results were heterogeneous, the reasons for Any disagreement was resolved by discussion.
this were explored (eg, treatment or participantfactors) and a random effects model was used to Study design quality assessment reflect the increased uncertainty. Investigation of and data extraction the robustness of the conclusions according to the Study design was assessed by two reviewers as methodologic quality of the contributing studies was per the criteria in . Studies meeting all the not practical because there were only a few studies J AM ACAD DERMATOL 110 van Zuuren et al contributing to each comparison; study quality was within these therapeutic categories, making compar- considered qualitatively when drawing conclusions.
isons and pooling of data was problematic because Some studies used a split-face, within-patient of heterogeneous study designs, skewed data, miss- design, where two interventions were allocated ing variability, and differences in comparators or randomly to the left and right side of the face.
dosing regimens. Only data on outcome measures Where possible, a conditional OR (based on the from trials on topical metronidazole, topical azelaic discordant cases only) was calculated; this can be acid, and oral tetracycline could be pooled. Most interpreted in the same way as the ORs from parallel studies used numbers of papules or pustules as an group studies.However, the paired data necessary outcome measure rather than a more clinically rel- for this were sometimes unavailable, in which case evant measure, such as participant assessment of marginal ORs (based on the overall rates for each appearance. Below is a summary of the most impor- treatment) were calculated and reported. These tant conclusions. For details and full reporting of the marginal ORs should be interpreted cautiously, be- data, please refer to the complete Cochrane review cause they differ from conditional ORs when there as published in the Cochrane Li is correlation between the outcomes of the twotreatments.
METRONIDAZOLETopical metronidazole versus placebo Nine trials assessed the efficacy of topical metro- Description of studies and methodologic nidazole versus placebo.The quality of included studies treatment period ranged from 8 to 9 weeks in each Searches identified 71 possible RCTs. A total of 29 trial, except for that of Dahl et al,which was 6 RCTs were included.Breneman et aland months. Three studies addressed self-assessed im- Leyden et aldescribed different outcome measures provement of rosacea severitOnly data from of the same study and Thiboutot et alreported two studiescould be pooled , A) and there two RCTs in one publication. Most of the participants was clear evidence that metronidazole was more in the included studies had papulopustular rosacea effective than placebo. Bleicher et alconfirmed and were between 40 and 50 years old; only two these data (OR 7.0; 95% confidence interval [CI] addressed ocular rosacea. Of the 71 2.5-20.0). Data on physician's global evaluation studies, 41 were excluded because allocation con- concerning improvement were similar to the pa- cealment was inadequate, the study was not blinded, tient-assessed measures in favor of metronidazole the dropout rate was more than 10%, or other (OR 7.01; 95% CI 3.56-13.81).The other stud- major methodologic or because ies showed comparable they were awaiting assessment.Of the 29 Most of the adverse events mentioned were mild, included studies, 8 were classified as high qual- including pruritus, skin irritation, and dry skin. There ity.The remaining 21 trials were were no significant differences in the number of of intermediate quaIn only 14 adverse events between groups.
of the 29 trialswas thereadequate blinding of treatment allocation. Blindingof outcome assessment was demonstrated in all Topical azelaic acid versus topical except two studies.Intention-to-treat analysis was used in 17 of the 29 trials.
There was no statistically significant difference in For 14 studies the variability (SD or SE) of contin- the patient self-assessment between topical azelaic uous measurements were completely or partially acid and topical metronidazole.However, phy- lacking, making these data unusable in a meta- sicians rated the azelaic acid group more improved (OR 1.84; 95% CI 1.10-3.09).The number ofadverse events was lower in the metronidazole group (OR 4.56; 95% CI 2.07-1However, the severity of adverse events in both groups was reported as mild to moderate and mostly transient.
oral antibiotics (8 Topical metronidazole versus oral trials),topical benzoyl peroxide com- bined with topical antibiotics (2 and other In two 8-week studiesno statistically signifi- therapies (4 Five trials included com- cant treatment difference was seen between metro- parisons in more than one category.Even nidazole cream and (oxy)-tetracycline.

J AM ACAD DERMATOL van Zuuren et al 111 VOLUME 56, NUMBER 1 Fig 1. Meta-analytic comparisons of participant-assessed improvement between topicalmetronidazole and placebo (A), oral tetracycline and placebo (B), and topical azelaic acidand placebo (C). Modifiedand used with permission. CI, Confidence interval; OR, odds ratio.
Metronidazole plus sunscreen (sun protection factor 15) versus Oral metronidazole versus oral A poorly designed study favored metronidazole In one study, oral metronidazole and oral oxytet- plus sunscreen over place racycline were not statistically different at 12 weeksby both physician and patient assessment.Noadverse events were reported in either group.
Topical metronidazole versus topicalpermethrin versus placebo Koc¸ak et alinvestigated the efficacy and safety Tetracycline versus placebo One trialcompared oral oxytetracycline with Permethrin was inferior to topical metronidazole placebo, and in two oral tetracycline was because it showed no effect on pustules.
compared with placebo. These are both (older)tetracyclines with a similar molecular structure andthe same pharmacokinetic and pharmacodynamic Benzoyl peroxide 5%/erythromycin 3% gel profile and so the results were pooled. Study dura- versus metronidazole gel tion ranged from 4 to 6 weeks. Bartholomew et No significant difference was shown between addressed treatment efficacy in ocular rosacea.
the two therapies in 4 weeks (OR 0.92; 95% CI There was insufficient evidence of any advantage of tetracycline over placebo according to patients' J AM ACAD DERMATOL 112 van Zuuren et al Table III. Data to be included in future rosacea studies Well-designed RCT with reporting the Proper description of randomization procedure and allocation concealmentData presented with appropriate summaries and analysis (including variability)The number of participants who started in and dropped out from each groupOutcomes primarily based on: patient's opinion of treatment efficacy, quality of life, and patient-assessmentPhysician's opinion, reflected by global evaluation, lesion counts, and assessment of telangiectasiaUse of intention-to-treat analysis RCT, Randomized controlled trial.
Modifiedand used with permission.
assessment (B).However, the dropout rate The mean scores at 12 weeks for physician's global was unclear and the data were skewed with large assessment were 1.85 (marked to definite improve- variability. By physician assessment, tetracyclines are ment) versus 2.96 for placebo (minimal improve- far more effective than placebo in the treatment ment) (authors state P = .0026).
of rosacea (OR 6.06; 95% CI 2.96-12.42). Repeated The data showed large variability and some data courses of treatment with the same dose achieved were missing. Most data were skewed. Treatment- lasting remission 3 to 6 months after stopping related adverse events included site burning and itching, both well-known side effects of benzoylperoxiThe same study using photographic Clarithromycin and omeprazole assessments as outcomes came to similar same These data were skewed with large variability and, thus, it is impossible to draw conclusions about Benzoyl peroxide acetone versus placebo At 4 weeks, benzoyl peroxide showed an im- provement on the physician's global evaluation Azelaic acid versus placebo score compared with placebo (OR 3.17; 95% CI Four trials compared azelaic acid with pla- 1.08-9.31).The other measurements were also in The treatment period ranged from 9 favor of benzoyl peroxide (P .05). Irritation and to 12 weeks. Three studiesshowed a clear burning were frequently reported in both groups.
improvement in the azelaic acid group as rated by Oral metronidazole and topical both physicians and patients , C ). A split-face, hydrocortisone 1% cream versus oral placebo and topical hydrocortisone 1% cream (marginal OR 30.1; P .0003).
The physicians considered 10 of 14 participants The data on lesion counts did not include varia- treated with oral metronidazole improved versus bility and the data in the study by Carmichael et al only 2 of 13 participants on placebo (OR 13.75; 95% were skewed.
CI 2.05-92.04).Only limited data were given in this More side effects were reported in the azelaic group (11.5%) versus the placebo group (5.7%) (OR1.61; 95% CI 0.89-2.92)The same holds true for Rilmenidine versus placebo the study of Carmichael et alSide effects were Both the patients and the physicians believed that considered mild and transient with burning, stinging, there was no significant difference between rilmeni- and irritation being reported most frequently.
dine and placebo; neither treatment was BENZOYL PEROXIDE WITH ANTIBIOTICS Sodium sulfacetamide/sulfur versus placebo Benzoyl peroxide 5%/clindamycin 1% gel The percentage of participants who considered themselves improved was 90% in the sodium sulfa- The mean scores at 12 weeks for patient's global cetamide 10%/sulfur 5% group versus 58% in the assessment in the study of Breneman et alwere placebo group (authors state P The phy- 1.54 (much to slightly better) in the benzoyl peroxide sicians shared this opinion. Adverse events were and clindamycin group versus 2.50 (slightly better to reported in 38% versus 29%, respectively. Applica- same) in the placebo group (authors state P = .0002).
tion site reactions such as dryness, erythema, and J AM ACAD DERMATOL van Zuuren et al 113 VOLUME 56, NUMBER 1 Table IV. Questions for which evidence is lacking in the literature 1. What is the efficacy and safety of commonly used treatments for rosacea (eg, tetracycline, minocycline, doxycycline, isotretinoin, and laser therapy)? 2. What is the efficacy and safety of treatments for ocular rosacea?3. Is there any efficacy of dietary measures and/or sun-protective measures in the treatment of rosacea?4. What is the efficacy and safety of benzoyl peroxide alone or in combination with topical antibiotics for rosacea?5. Is permethrin effective and safe for rosacea treatment? Studies to answer these questions should meet the criteria mentioned in pruritus were the most commonly reported adverse the study with permethrin.Both benzoyl peroxide events. It was unclear how many participants started and permethrin are well-known drugs and further in each group or how improvement was defined, and investigation in the treatment of rosacea may be for continuous measurements the variability was large and the data No studies could be included addressing dietary or sun-protective measures; however, two studies did combine treatment with a sun protection fac- There were significant limitations in the quality of tor.Although not really substantiated, most peo- evidence available for most treatments. Although the ple with rosacea are given the advice to avoid trigger clinical design of the included studies was in theory factors, (eg, spicy foods, alcohol, and sunlight).
adequate, closer examination revealed that the qual- Only two trials could be included on treatment ity of reported data was often low. of ocular rosacea,even though almost 60% summarize recommendations for future rosacea of people with rosacea have ocular involve- studiesIt should be noted that although split-face ment.Although often mild, the ocular pre- studies can be efficient, they are subject to potential sentation can be both severe and debilitating. There biases. Contamination may occur if active cream was insufficient evidence for the efficacy of topical is accidentally transferred onto the placebo side.
metronidazole.Oral oxytetracycline seems to be Furthermore, a treatment may have systemic effects, effective for ocular although only the beneficial or harmful, which will affect both sides.
opinion of the physician was reported.
Our principal outcome measure, quality of life, A very interesting treatment seems to be low-dose was not assessed in any of the studies and only a few doxycycline (20 mg twice a day),which is a studies assessed the participant's own opinion. It is subantimicrobial dose that reduces inflammation.
interesting to note that the investigators were more Other potential advantages of this treatment include satisfied at the end of the study than the partici- lessening the risks of Propionibacterium acne's re- pantFor other diseases it is often the reverse.
sistance to tetracyclines and lowering the incidence This may have implications for clinicians, as a of tetracycline-induced adverse events. Unfortu- patient's perception of a lack of sufficient efficacy nately, even though they are commonly used to treat can impact compliance and may lead to the use of rosacea, no RCTs evaluating doxycycline, minocy- alternative therapies. Topical metronidazole and cline, isotretinoin, or laser therapy could be included azelaic acid appear to be effective and safe for in this review (most often because of inadequate short-term use, with the rate of adverse events in study design). There is an urgent need for better the placebo groups being similar to the active treat- quality, adequately designed RCTs on the commonly ment groups. With regard to tetracycline, only 3 used treatments for rosacea.
could be included in this review, onlyone of which assessed the opinion of the partici- pants; however, this study failed to detect any 1. van Zuuren EJ, Graber MA, Hollis S, Chaudhry M, Gupta AK, difference from placebo. It is possible that in this Gover M. Interventions for rosacea. The Cochrane Database ofSystematic Reviews. 2005; issue 3. Available at: case the study duration of 6 weeks was too short.
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