Systematic review of rosacea treatments

doi:10.1016/j.jaad.2006.04.084

Journal of the American Academy of Dermatology

Volume 56, Issue 1, January 2007, Pages 107-115

https://doi.org/10.1016/j.jaad.2006.04.084 Get rights and content

Background

Rosacea is a common chronic skin and ocular condition. It is unclear which treatments are most effective. We have conducted a Cochrane review of rosacea therapies.¹ This article is a distillation of 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 with moderate to severe rosacea were included. Study selection, assessment of methodologic quality, data extraction, 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 (odds ratio 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 some evidence that oral metronidazole and tetracycline are effective. More well-designed, randomized controlled trials are required to provide better evidence of the efficacy and safety of other rosacea therapies.

Section snippets

Methods

A systematic review of randomized controlled trials (RCTs) was performed according to a prespecified protocol.¹

Description of studies and methodologic quality of included studies

Searches identified 71 possible RCTs. A total of 29 RCTs were included.21, 22, 23, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 Breneman et al³⁴ and Leyden et al⁵¹ described different outcome measures of the same study and Thiboutot et al⁴⁹ reported two RCTs in one publication. Most of the participants in the included studies had papulopustular rosacea and were between 40 and 50 years old; only two studies27, 28 addressed ocular rosacea.

Topical metronidazole versus placebo

Nine trials assessed the efficacy of topical metronidazole versus placebo.21, 27, 29, 30, 32, 33, 38, 39, 42 The treatment period ranged from 8 to 9 weeks in each trial, except for that of Dahl et al,²¹ which was 6 months. Three studies addressed self-assessed improvement of rosacea severity.30, 32, 42 Only data from two studies30, 42 could be pooled (Fig 1, A) and there was clear evidence that metronidazole was more effective than placebo. Bleicher et al³² confirmed these data (OR 7.0; 95%

Oral metronidazole versus oral oxytetracycline

In one study, oral metronidazole and oral oxytetracycline were not statistically different at 12 weeks by both physician and patient assessment.⁴⁵ No adverse events were reported in either group.

Tetracycline versus placebo

One trial²⁸ compared oral oxytetracycline with placebo, and in two trials40, 47 oral tetracycline was compared with placebo. These are both (older) tetracyclines with a similar molecular structure and the same pharmacokinetic and pharmacodynamic profile and so the results were pooled. Study duration

Azelaic acid versus placebo

Four trials compared azelaic acid with placebo.31, 35, 49 The treatment period ranged from 9 to 12 weeks. Three studies31, 49 showed a clear improvement in the azelaic acid group as rated by both physicians and patients (Fig 1, C). A split-face, within-patient study³⁵ confirmed these results (marginal OR 30.1; P < .0003).

The data on lesion counts did not include variability and the data in the study by Carmichael et al³⁵ were skewed.

More side effects were reported in the azelaic group (11.5%)

Benzoyl peroxide 5%/clindamycin 1% gel versus placebo

The mean scores at 12 weeks for patient's global assessment in the study of Breneman et al³⁴ were 1.54 (much to slightly better) in the benzoyl peroxide and clindamycin group versus 2.50 (slightly better to same) in the placebo group (authors state P = .0002). The mean scores at 12 weeks for physician's global assessment were 1.85 (marked to definite improvement) versus 2.96 for placebo (minimal improvement) (authors state P = .0026).

The data showed large variability and some data were missing.

Benzoyl peroxide acetone versus placebo

At 4 weeks, benzoyl peroxide showed an improvement on the physician's global evaluation score compared with placebo (OR 3.17; 95% CI 1.08-9.31).⁴¹ The other measurements were also in favor of benzoyl peroxide (P < .05). Irritation and burning were frequently reported in both groups.

Oral metronidazole and topical hydrocortisone 1% cream versus oral placebo and topical hydrocortisone 1% cream

The physicians considered 10 of 14 participants treated with oral metronidazole improved versus only 2 of 13 participants on placebo (OR 13.75; 95% CI 2.05-92.04).⁴⁴ Only limited data were given in this study.⁴⁴

Rilmenidine versus placebo

Both

Discussion

There were significant limitations in the quality of evidence available for most treatments. Although the clinical design of the included studies was in theory adequate, closer examination revealed that the quality of reported data was often low. Table III, Table IV summarize recommendations for future rosacea studies.⁸⁸ It should be noted that although split-face studies can be efficient, they are subject to potential biases. Contamination may occur if active cream is accidentally transferred

References (93)

G.H. Crawford et al.
Rosacea, I: etiology, pathogenesis, and subtype classification
J Am Acad Dermatol
(2004)
J. Wilkin et al.
Standard classification of rosacea: report of the National Rosacea Society expert committee on the classification and staging of rosacea
J Am Acad Dermatol
(2002)
J. Wilkin et al.
Standard grading system for rosacea: report of the National Rosacea Society expert committee on the classification and staging of rosacea
J Am Acad Dermatol
(2004)
J.Q. Del Rosso
The use of topical azelaic acid 15% gel or metronidazole 0.75% gel for the treatment of rosacea: evaluation of a single-site comparative trial subset
J Am Acad Dermatol
(2004)
S. Maddin
A comparison of topical azelaic acid 20% cream and topical metronidazole 0.75% cream in the treatment of patients with papulopustular rosacea
J Am Acad Dermatol
(1999)
M.T. Pelle et al.
Rosacea, II: therapy
J Am Acad Dermatol
(2004)
D.A. Barnhorst et al.
The efficacy of topical metronidazole in the treatment of ocular rosacea
Ophthalmology
(1996)
J.L. Jorizzo et al.
The efficacy of metronidazole 1% cream once daily compared with metronidazole 1% cream twice daily and their vehicles in rosacea: a double-blind clinical trial
J Am Acad Dermatol
(1998)
R. Marks et al.
Comparative effectiveness of tetracycline and ampicillin in rosacea: a controlled trial
Lancet
(1971)
R.J. Pye et al.
Treatment of rosacea by metronidazole
Lancet
(1976)

D. Thiboutot et al.

Efficacy and safety of azelaic acid (15%) gel as a new treatment for papulopustular rosacea: results from two vehicle-controlled, randomized phase III studies

J Am Acad Dermatol

(2003)

M.V. Dahl et al.

Once-daily topical metronidazole cream formulations in the treatment of the papules and pustules of rosacea

J Am Acad Dermatol

(2001)

B. Dreno et al.

Comparison of the clinical efficacy and safety of metronidazole 0.75% cream with metronidazole 0.75% gel in the treatment of rosacea. P373

J Eur Acad Dermatol Venereol

(1998)

J. Frucht-Pery et al.

Efficacy of doxycycline and tetracycline in ocular rosacea

Am J Ophthalmol

(1993)

P.G. Nielsen

The relapse rate for rosacea after treatment with either oral tetracycline or metronidazole cream

Br J Dermatol

(1983)

J.K. Wilkin

Effect of nadolol on flushing reactions in rosacea

J Am Acad Dermatol

(1989)

D.M. Thiboutot

Acne and rosacea: new and emerging therapies

Dermatol Clin

(2000)

E.J. van Zuuren et al.

Interventions for rosacea

The Cochrane Database of Systematic Reviews

(2005)

J.L. Michel et al.

Frequency, severity and treatment of ocular rosacea during cutaneous rosacea

Ann Dermatol Venereol

(2003)

M. Berg et al.

An epidemiological study of rosacea

Acta Derm Venereol

(1989)

T. Jansen et al.

Rosacea: classification and treatment

J R Soc Med

(1997)

A.M. Kligman

A personal critique on the state of knowledge of rosacea

Dermatology

(2004)

K. Landow

Unraveling the mystery of rosacea: keys to getting the red out

Postgrad Med

(2002)

J.B. Bikowski et al.

Rosacea: where are we now?

J Drugs Dermatol

(2004)

G.A. Ertl et al.

A comparison of the efficacy of topical tretinoin and low-dose oral isotretinoin in rosacea

Arch Dermatol

(1994)

E. Espagne et al.

Double-blind study versus excipient of 0.75% metronidazole gel in the treatment of rosacea

Ann Dermatol Venereol

(1993)

R.B. Odom

The subtypes of rosacea: implications for treatment

Cutis

(2004)

F.C. Powell

The histopathology of rosacea: 'where's the beef?'

Dermatology

(2004)

A. Rebora

Rosacea

J Invest Dermatol

(1987)

A. Shalita et al.

Mechanism-based selection of pharmacologic agents for rosacea

Cutis

(2004)

R.J. Signore

A pilot study of 5 percent permethrin cream versus 0.75 percent metronidazole gel in acne rosacea

Cutis

(1995)

J.K. Wilkin et al.

Treatment of rosacea: topical clindamycin versus oral tetracycline

Int J Dermatol

(1993)

J.E. Wolf

The role of topical metronidazole in the treatment of rosacea

Cutis

(2004)

M.V. Dahl et al.

Topical metronidazole maintains remissions of rosacea

Arch Dermatol

(1998)

P.G. Nielsen

A double-blind study of 1% metronidazole cream versus systemic oxytetracycline therapy for rosacea

Br J Dermatol

(1983)

F. Curtin et al.

Meta-analysis combining parallel and cross-over clinical trials, II: binary outcomes

Stat Med

(2002)

J.T. Bamford et al.

Effect of treatment of Helicobacter pylori infection on rosacea

Arch Dermatol

(1999)

R.S. Bartholomew et al.

Oxytetracycline in the treatment of ocular rosacea: a double-blind trial

Br J Ophthalmol

(1982)

A. Bitar et al.

A double-blind randomized study of metronidazole (Flagyl) 1% cream in the treatment of acne rosacea, a placebo controlled study

Drug Invest

(1990)

J. Bjerke et al.

Metronidazole (Elyzol) 1% cream vs. placebo cream in the treatment of rosacea

Clin Trials J

(1989)

R. Bjerke et al.

Double-blind comparison of azelaic acid 20% cream and its vehicle in treatment of papulo-pustular rosacea

Acta Derm Venereol

(1999)

P.A. Bleicher et al.

Topical metronidazole therapy for rosacea

Arch Dermatol

(1987)

D.L. Breneman et al.

A double-blind, multicenter clinical trial comparing efficacy of once-daily metronidazole 1 percent cream to vehicle in patients with rosacea

Cutis

(1998)

D. Breneman et al.

Double-blind, randomized, vehicle-controlled clinical trial of once-daily benzoyl peroxide/clindamycin topical gel in the treatment of patients with moderate to severe rosacea

Int J Dermatol

(2004)

A.J. Carmichael et al.

Topical azelaic acid in the treatment of rosacea

J Dermatol Treat

(1993)

B.E. Elewski et al.

A comparison of 15% azelaic acid gel and 0.75% metronidazole gel in the topical treatment of papulopustular rosacea: results of a randomized trial

Arch Dermatol

(2003)

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Funding sources: None.

Conflicts of interest: None identified.

This manuscript is based on an earlier publication by van Zuuren et al,¹ copyright Cochrane Library, reproduced with permission.

View full text

From the Cochrane LibrarySystematic review of rosacea treatments

Background

Objective

Methods

Results

Limitations

Conclusions

Section snippets

Methods

Description of studies and methodologic quality of included studies

Topical metronidazole versus placebo

Oral metronidazole versus oral oxytetracycline

Tetracycline versus placebo

Azelaic acid versus placebo

Benzoyl peroxide 5%/clindamycin 1% gel versus placebo

Benzoyl peroxide acetone versus placebo

Oral metronidazole and topical hydrocortisone 1% cream versus oral placebo and topical hydrocortisone 1% cream

Rilmenidine versus placebo

Discussion

J Am Acad Dermatol

J Am Acad Dermatol

J Am Acad Dermatol

J Am Acad Dermatol

J Am Acad Dermatol

J Am Acad Dermatol

Ophthalmology

J Am Acad Dermatol

Lancet

Lancet

J Am Acad Dermatol

J Am Acad Dermatol

J Eur Acad Dermatol Venereol

Am J Ophthalmol

Br J Dermatol

J Am Acad Dermatol

Dermatol Clin

Interventions for rosacea

The Cochrane Database of Systematic Reviews

Frequency, severity and treatment of ocular rosacea during cutaneous rosacea

Ann Dermatol Venereol

An epidemiological study of rosacea

Acta Derm Venereol

Rosacea: classification and treatment

J R Soc Med

A personal critique on the state of knowledge of rosacea

Dermatology

Unraveling the mystery of rosacea: keys to getting the red out

Postgrad Med

Rosacea: where are we now?

J Drugs Dermatol

A comparison of the efficacy of topical tretinoin and low-dose oral isotretinoin in rosacea

Arch Dermatol

Double-blind study versus excipient of 0.75% metronidazole gel in the treatment of rosacea

Ann Dermatol Venereol

The subtypes of rosacea: implications for treatment

Cutis

The histopathology of rosacea: 'where's the beef?'

Dermatology

Rosacea

J Invest Dermatol

Mechanism-based selection of pharmacologic agents for rosacea

Cutis

A pilot study of 5 percent permethrin cream versus 0.75 percent metronidazole gel in acne rosacea

Cutis

Treatment of rosacea: topical clindamycin versus oral tetracycline

Int J Dermatol

The role of topical metronidazole in the treatment of rosacea

Cutis

Topical metronidazole maintains remissions of rosacea

Arch Dermatol

A double-blind study of 1% metronidazole cream versus systemic oxytetracycline therapy for rosacea

Br J Dermatol

Meta-analysis combining parallel and cross-over clinical trials, II: binary outcomes

Stat Med

Effect of treatment of Helicobacter pylori infection on rosacea

Arch Dermatol

Oxytetracycline in the treatment of ocular rosacea: a double-blind trial

Br J Ophthalmol

A double-blind randomized study of metronidazole (Flagyl) 1% cream in the treatment of acne rosacea, a placebo controlled study

Drug Invest

From the Cochrane Library
Systematic review of rosacea treatments