Interventions for rosacea

Esther J van Zuuren; Mark A Graber; Sally Hollis; Maria MMC Chaudhry; Aditya K Gupta

doi:10.1002/14651858.CD003262.pub2

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Figure 1

Rosacea

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Analysis 1.2

Comparison 1 Topical metronidazole versus placebo, Outcome 2 Self‐assessed improvement of rosacea.

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Analysis 1.3

Comparison 1 Topical metronidazole versus placebo, Outcome 3 Physician's global evaluation of improvement (WMD).

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Analysis 1.4

Comparison 1 Topical metronidazole versus placebo, Outcome 4 Physician's global evaluation of improvement (OR).

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Analysis 1.8

Comparison 1 Topical metronidazole versus placebo, Outcome 8 Drop‐out rate.

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Analysis 1.9

Comparison 1 Topical metronidazole versus placebo, Outcome 9 Adverse events.

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Study	Interventions	Author's conclusions	Summary outcome	Comment	Notes
Barnhorst 1996	Lid hygiene plus warm compresses plus metronidazole 0.75% gel BID versus lid hygiene plus warm compresses	Metronidazole gel may be safe and effective for rosacea of the eyelids (blepharitis).	Eye and eyelid grading pre‐post mean (SD) 1.5 (1.7) versus 1.0 (1.7). (Authors report significant improvement in treatment group but not in control group p = 0.022 versus p = 0.10 [inappropriate analysis]. No direct comparison reported). Eye pre‐post mean (SD) 0.4 (1.0) versus 0.3 (0.9). Eyelid pre‐post mean (SD) 1.1 (0.9) versus 0.7 (0.8).	Small group (13 participants), within‐patient comparison. Not much data. Participant not blinded. Data skewed.	BID = twice a day N = number SD = standard deviation QD = once daily
Bitar 1990	Metronidazole cream 1% BID versus placebo cream BID	Metronidazole cream is effective and well tolerated in the treatment of rosacea.	Facial erythrosis, no significant difference. Sites of rosacea forehead, 58% versus 26%, other sites 25% versus 10%. N papules 4.5 (4.24) versus 6.5 (4.95). N of pustules 1.5 (1.41) versus 3.4 (4.94). Erythema and telangiectasia, no statistical difference.	Data on papules and pustules are skewed.
Bjerke 1989b	Metronidazole cream 1% BID versus placebo cream BID	Statistically significant difference in reduction of papules, pustules, erythema and overall assessment in favour of metronidazole.	Lesion count reduction 78% versus 48%, reduction of papules 75% versus 43%, reduction of pustules 100% vs 81%.	No SDs were given.
Bleicher 1987	Metronidazole 0.75% BID versus placebo BID	Topical metronidazole is safe and effective for moderate to severe rosacea.	Self‐assessment of improvement, 28/37 versus 4/37 (p < 0.0001). Physician's global evaluation of improvement, 29/37 versus 1/37 (p < 0.0001). Decrease in lesion counts, 65.1 versus 14.9%. Reduction in erythema, 0.8 versus 0.3 (erythema rating 0 to 3, higher is worse).	No SDs were given. Within‐patient comparison.
Breneman 1998	Metronidazole 1% QD versus placebo	Topical metronidazole was significantly better than placebo in reduction of the lesions, erythema and the physician's global rosacea scores.	Decrease in lesion count 8 versus 3.	No SDs were given.
Dahl 1998	Metronidazole 0.75% BID versus placebo BID	Topical metronidazole maintains remission of moderate to severe rosacea.	Lesion count 3.3 versus 5.5, relapse rate 23% versus 42%, free of lesions 53% versus 32%. Erythema (74% had no or mild erythema versus 55%), telangiectasia (no significant difference or effect) and dryness were also assessed.	No SDs were given. N of adverse events unclear.
Jorizzo 1998	Metronidazole 1% QD versus metronidazole BID versus placebo QD versus placebo BID.	Twice‐daily dosing seems as effective as once‐daily dosing of metronidazole 1%. However, a greater vehicle effect occurs with twice‐daily dosing.	Decrease in lesion count 58% versus 58% versus 30% versus 40%. Physician's global evaluation of improvement 79% versus 72% versus 39% versus 45% Adverse events 1 versus 2 versus 1 versus 1. Drop‐outs 0?	Unclear how many participants started in each group, no SDs, drop‐out rate unclear. Data seem very skewed. Drop‐out rate of 0 is very unlikely in a group of 277 participants.
Nielsen 1983a	Metronidazole 1% QD versus placebo QD	Topical metronidazole proved to be more effective than placebo.	Papules count 8.6 versus 16.6 and pustules count 0.3 versus 0.8. Erythema 2.5 versus 3.1.	No SDs were given.

Analysis 1.10

Comparison 1 Topical metronidazole versus placebo, Outcome 10 Data that can not be presented graphically in MetaView.

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Analysis 2.2

Comparison 2 Topical azelaic cream versus placebo, Outcome 2 Self‐assessed improvement of rosacea.

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Analysis 2.4

Comparison 2 Topical azelaic cream versus placebo, Outcome 4 Physician's global evaluation of improvement.

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Analysis 2.8

Comparison 2 Topical azelaic cream versus placebo, Outcome 8 Drop‐out rate.

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Analysis 2.9

Comparison 2 Topical azelaic cream versus placebo, Outcome 9 Adverse events.

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Study	Intervention	Author's conclusions	Summary outcome	Comment	Notes
Bjerke 1999	Azelaic cream 20% BID versus placebo BID	Azelaic acid 20% cream is effective and well‐tolerated in papulopustular rosacea.	Decrease in lesions 73.4% versus 50.6%, in erythema 47.9% versus 37.9%, in telangiectasia 22.3% versus 23.5%.	No SDs.	BID = twice a day N = number SD = standard deviation
Carmichael 1993	Azelaic cream 20% BID versus placebo BID Within‐patient comparison	Azelaic acid 20% cream is effective for rosacea.	16/33 participants experienced improvement in the azelaic cream treated side versus only 1/33 in the placebo treated side. Physician's global evaluation: 30/33 improved versus 11/33. Papule count 2.5 (2.87) versus 6.3 (4.6), pustule count 0.0 (0.17) versus 0.4 (0.57). Adverse events 24/33 versus 19/33. Drop‐outs 0.	Data are skewed.

Analysis 2.10

Comparison 2 Topical azelaic cream versus placebo, Outcome 10 Data that can not be presented graphically in MetaView.

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Analysis 3.8

Comparison 3 Clarithromycin and omeprazole versus placebo, Outcome 8 Drop‐out rate.

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Analysis 3.9

Comparison 3 Clarithromycin and omeprazole versus placebo, Outcome 9 Adverse events.

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Study	Interventions	Author's conclusions	Summary outcome	Comment	Notes
Bamford 1999	Clarithromycin 500 mg TID and omeprazole 40 mg QD versus placebo	No difference between treatment and placebo group.	N of pustules (SD) 6.2 (8.3) versus 12.6 (19.3). Total score (SD) 6.3 (2.5) versus 7.9 (4.9)	Data on pustules quite skewed. Data on total score very skewed.	N = number SD = standard deviation TID = three times a day QD = once daily

Analysis 3.10

Comparison 3 Clarithromycin and omeprazole versus placebo, Outcome 10 Data that can not be presented graphically in MetaView.

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Analysis 4.2

Comparison 4 Rilmenidine versus placebo, Outcome 2 Self‐assessed improvement of rosacea.

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Analysis 4.4

Comparison 4 Rilmenidine versus placebo, Outcome 4 Physician's global evaluation of improvement.

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Analysis 4.8

Comparison 4 Rilmenidine versus placebo, Outcome 8 Drop‐out rate.

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Analysis 4.9

Comparison 4 Rilmenidine versus placebo, Outcome 9 Adverse events.

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Study	Intervention	Author's conclusion	Summary outcome	Comment	Notes
Grosshans 1997	Rilmenidine 1 mg QD versus placebo tablets	Rilmenidine is not efficient in reducing the number of lesions in rosacea, but could reduce the flushes.	N of participants with at least 50% decrease in lesion count 69.2% versus 57.1%. Decrease in lesion count 1 versus 2 Decrease in flushes ‐13 versus ‐5.	No SDs.	N = number SD = standard deviation QD = once daily

Analysis 4.10

Comparison 4 Rilmenidine versus placebo, Outcome 10 Data that can not be presented graphically in MetaView.

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Analysis 5.4

Comparison 5 Benzoyl peroxide acetone versus placebo, Outcome 4 Physician's global evaluation of improvement.

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Analysis 5.8

Comparison 5 Benzoyl peroxide acetone versus placebo, Outcome 8 Drop‐out rate.

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Analysis 5.9

Comparison 5 Benzoyl peroxide acetone versus placebo, Outcome 9 Adverse events.

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Study	Intervention	Author's conclusion	Summary outcome	Comment	Notes
Montes 1983	Benzoyl peroxide acetone gel 5% QD versus placebo	Benzoyl peroxide is superior to placebo and has a remarkable ability to clear the lesions.	Overall response 2.69 versus 3.71, papule score 0.89 versus 1.91, pustule score 0.46 versus 1.31 in favour of benzoyl peroxide.	Unclear how many participants started, only first 4 weeks included.	SD = standard deviation QD = once daily

Analysis 5.10

Comparison 5 Benzoyl peroxide acetone versus placebo, Outcome 10 Data that can not be presented graphically in MetaView.

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Study	Intervention	Author's conclusion	Summary outcome	Comment	Notes
Sauder 1997	Sodium sulfacetamide 10% and sulfur 5% BID versus placebo BID	Sodium sulfacetamide 10% and sulfur 5% is effective in reducing lesions and erythema in rosacea and well tolerated.	Self‐assessed improvement in rosacea severity 90% versus 58%. Physician's evaluation of improvement 98% versus 68%, participants and physicians 7 point improvement score both p < 0.001 using non‐parametric test. Lesion count reduction (SEM) 78% (4.5) versus 36% (8.9). p < 0.001 using non‐parametric test.	Unclear how many participants started in each group. Large SDs (when calculated from SEM), data skewed.	BID = twice a day SD = standard deviation

Analysis 6.10

Comparison 6 Sodium sulfacetamide 10% and sulfur 5% lotion versus placebo, Outcome 10 Data that can not be presented graphically in MetaView.

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Analysis 7.2

Comparison 7 Oral Tetracycline versus placebo, Outcome 2 Self‐assessed improvement of rosacea.

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Analysis 7.4

Comparison 7 Oral Tetracycline versus placebo, Outcome 4 Physician's global evaluation of improvement.

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Analysis 7.9

Comparison 7 Oral Tetracycline versus placebo, Outcome 9 Adverse events.

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Study	Intervention	Author's conclusions	Summary outcome	Comment	Notes
Bartholomew 1982	Oxytetracycline 250 mg BID versus placebo BID	Systemic oxytetracycline is useful and safe for ocular rosacea and rosacea of the face.	N of remissions 11/17 versus 5/18. Drop‐out rate 2/35 (at least 1 placebo), adverse events 2 (at least 1 placebo). Relapses generally occurred 2 to 3 weeks after stopping oxytetracycline. Repeated courses achieved remissions of 3 to 6 months.	Only few data were presented. Data on drop‐out rate and adverse events not completely clear.	BID = twice a day N = number SD = standard deviation TID = three times a day
Marks 1971	Tetracycline 250 mg for 1 week TID and then BID versus placebo	Tetracycline is significantly better than placebo for rosacea.	Lesion count post treatment 4.60 (6.20) versus 16.63 (12.81). N improved > 50% 17 versus 4. Drop‐outs unclear.	Large SDs, data skewed. In this study there was a third comparator (ampicillin).
Sneddon 1966	Tetracycline 250 mg BID versus placebo BID	Tetracycline is significantly more effective than placebo in controlling rosacea.	Assessable improvement after 1 month 78% versus 45%. Drop‐out rates unclear in total 7. Adverse events unclear.

Analysis 7.10

Comparison 7 Oral Tetracycline versus placebo, Outcome 10 Data that can not be presented graphically in MetaView.

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Analysis 8.2

Comparison 8 Ampicillin versus placebo, Outcome 2 Self‐assessed improvement of rosacea.

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Analysis 8.4

Comparison 8 Ampicillin versus placebo, Outcome 4 Physician's global evaluation of improvement.

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Analysis 8.9

Comparison 8 Ampicillin versus placebo, Outcome 9 Adverse events.

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Study	Intervention	Author's conclusions	Summary outcome	Comment	Notes
Marks 1971	Ampicillin? versus placebo	Ampicillin is effective for rosacea.	Lesion count post treatment 9.53 (8.79) versus 16.63 (12.81) N improved greater than 50% 9 versus 4. Drop‐out rate unclear.	Large SDs, data skewed. In this study there was a third comparator (tetracycline).	N = number SD = standard deviation

Analysis 8.10

Comparison 8 Ampicillin versus placebo, Outcome 10 Data that can not be presented graphically in MetaView.

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Analysis 9.4

Comparison 9 Oral metronidazole and topical hydrocortisone 1% cream versus oral placebo and hydrocortisone 1% cream, Outcome 4 Physician's global evaluation of improvement.

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Analysis 9.8

Comparison 9 Oral metronidazole and topical hydrocortisone 1% cream versus oral placebo and hydrocortisone 1% cream, Outcome 8 Drop‐out rate.

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Analysis 9.9

Comparison 9 Oral metronidazole and topical hydrocortisone 1% cream versus oral placebo and hydrocortisone 1% cream, Outcome 9 Adverse events.

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Study	Intervention	Author's conclusion	Summary outcome	Comment	Notes
Maddin 1999	Azelaic acid cream 20% BID versus metronidazole 0.75% BID	Azelaic acid is an effective and safe alternative to metronidazole for rosacea with the added benefit of increased participant satisfaction	Decrease in lesion count 78.5% versus 69.4%. Papule count 2.30 (3.35) versus 3.24 (3.79), pustule count 0.14 (0.70) versus 0.24 (1.08). Physician's global evaluation of improvement 2.7 (1) versus 3.1 (1), p = 0.05 (rating 1 to 6, higher indicates worse, data extracted from figure). Participants' rate of improvement 1.87 (0.76) versus 2.33 (0.95). Willingness to use again 92% versus 66% Adverse events 1/40 versus 0/40.	Large SDs, so skewed data 3 participants withdrew.	BID = twice a day N = number SD = standard deviation

Analysis 10.10

Comparison 10 Topical azelaic cream versus topical metronidazole, Outcome 10 Data that can not be presented graphically in MetaView.

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Analysis 11.3

Comparison 11 Oral metronidazole versus oral oxytetracycline, Outcome 3 Patients and physician's global evaluation of improvement.

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Analysis 11.8

Comparison 11 Oral metronidazole versus oral oxytetracycline, Outcome 8 Drop‐out rate.

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Analysis 12.2

Comparison 12 Topical metronidazole cream versus oral tetracycline, Outcome 2 Self‐assessed improvement of rosacea.

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Analysis 12.4

Comparison 12 Topical metronidazole cream versus oral tetracycline, Outcome 4 Physcian's global evaluation of improvement.

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Analysis 12.8

Comparison 12 Topical metronidazole cream versus oral tetracycline, Outcome 8 Drop‐out rate.

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Analysis 12.9

Comparison 12 Topical metronidazole cream versus oral tetracycline, Outcome 9 Adverse events.

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Study	Intervention	Author's conclusion	Summary outcome	Comment	Notes
Veien 1986	Metronidazole 1% cream and placebo tablet BID versus tetracycline tablet 250 mg and placebo cream BID	There is no statistical difference in effectiveness between metronidazole and tetracycline treatment.	Median number of lesions after 8 weeks 11.1 versus 0 Percentage of no improvement of erythema after 8 weeks 11.1 versus 12.5.	Tetracyclines had a more rapid onset on lesions. Drop‐out rate 1, but unclear in which group.	BID = twice a day N = number SD = standard deviation

Analysis 12.10

Comparison 12 Topical metronidazole cream versus oral tetracycline, Outcome 10 Data that can not be presented graphically in MetaView.

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Analysis 13.2

Comparison 13 Oral tetracycline versus ampicillin, Outcome 2 Self‐assessed improvement of rosacea.

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Analysis 13.4

Comparison 13 Oral tetracycline versus ampicillin, Outcome 4 Physician's global evaluation of improvement.

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Analysis 13.9

Comparison 13 Oral tetracycline versus ampicillin, Outcome 9 Adverse events.

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Study	Intervention	Author's conclusions	Summary outcome	Comment	Notes
Marks 1971	Tetracycline TID 250 mg for 1 week and then BID versus ampicillin?	Tetracycline and ampicillin have comparative effectiveness for treatment of rosacea.	Lesion count post treatment 4.60 (6.20) versus 9.53 (8.79). N improved greater than 50% is 17 versus 9. Drop‐outs unclear.	Large SD, data skewed. In this study there was a third comparator.	BID = twice a day N = number SD = standard deviation TID = three times a day

Analysis 13.10

Comparison 13 Oral tetracycline versus ampicillin, Outcome 10 Data that can not be presented graphically in MetaView.

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Table 1. The Cochrane Skin Group Specialised Trials Register (March 2002)

Search Strategy

((ACNE AND ROSACEA) OR (ROSACEA) OR RHINOPHYMA OR ROZACEA OR FLUSHING OR (GRANULOMATOUS AND ROSACEA) OR (LUPUS AND MILIARIS AND DISSEMINATA AND FACEI) OR COUPEROSE OR (MOYBITTAN* AND DISEAS*) OR (ROSACEA AND FULMINANS) OR (PYODERMA AND FACIALE)) AND (ANTIBIOTIC* OR TETRACYCLIN* OR DOXYCYCLIN* OR MINOCYCLIN* OR PERMETHRIN* OR BENZOYLPEROXID* OR ((ORAL AND ANTICONCEPTIV*) OR (ORAL AND CONTRACEPTIV*)) OR DIANE‐35 OR ERYTHROMYCIN* OR SULFUR OR SULPHUR OR (AZELAIC AND ACID) OR (*TRETINOIN AND CREAM) OR SPIRONOLACTONE OR LASER OR CORTICOSTEROID* OR METRONIDAZOL* OR ZINC OR MASSAGE) AND THERAPY

Table 1. The Cochrane Skin Group Specialised Trials Register (March 2002)

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Table 2. The Cochrane Central Register of Controlled Trials (CENTRAL) (March 2002)

Search Strategy

((ACNE and ROSACEA) or ROSACE*)
ACNE‐ROSACEA*:ME
((((ANTIBIOTIC* or TETRACYCLIN*) or DOXYCYCLIN*) or MINOCYCLIN*) or PERMETHRIN*)

((BENZOYLPEROXID* or (ORAL and ANTICONCEPTIV*)) OR (ORAL AND CONTRACEPTIV*))
((((DIANE‐35 or ERYTHROMYCIN*) or SULFUR) or SULPHUR) OR (AZELAIC and ACID))
((((* and CREAM) or SPIRONOLACTONE) OR LASER) OR CORTICOSTEROID*)
METRONIDAZOL*
THERAPY
((((#3 or #4) or #5) or #6) or #7)

(((((#3 or #4) or #5) or #6) or #7) or #8)
(#1 or #2)
(#11 and #9)
(#11 and #10)
(#11 and #10)
(#11 and #10)
(((RHINOPHYMA or ROZACEA) or FLUSHING) OR (GRANULOMATOUS and ROSACEA))
(((LUPUS and (MILIARIS and (DISSEMINATA and FACEI))) or COUPEROSE) OR (MOYBITTAN* AND DISEASE*))
((ROSACEA and FULMINANS) or (PYODERMA and FACIALE))
((ZINC or SURGERY) or MASSAGE)
((#16 or #17) or #18)
(#11 or #20)
(#9 or #19)
((#21 and #22) and #8)
(#22 or #8)
(#24 and #21)

Table 2. The Cochrane Central Register of Controlled Trials (CENTRAL) (March 2002)

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Table 3. MEDLINE (from 1966 to March 2002)

Search Strategy

A. search strategy to locate RCTs
search terms for Pubmed, as given in the Cochrane Handbook (Clarke 2003), appendix 5b.3
B. Search strategy to locate rosacea
("acne rosacea"[MeSH Terms] OR rosacea[Text Word] OR "rhinophyma"[MeSH Terms] OR rhinophyma[Text Word] OR rozacea[All Fields] OR "flushing"[MeSH Terms] OR flushing[Text Word] OR (facial[All Fields] AND ("telangiectasis"[MeSH Terms] OR telangiectasia[Text Word]) OR (facial[All Fields] AND ("erythema"[MeSH Terms] OR erythema[Text Word]) OR (facial[All Fields] AND (edema[Text Word] OR oedema[Text Word] OR "edema"[MeSH Terms])))

C. Search strategy to locate the interventions
("therapy"[MeSH Subheading] OR "therapeutics"[MeSH Terms] OR therapy[Text Word] OR treatment[Text Word] OR "drug therapy"[MeSH Subheading] OR "drug therapy"[MeSH Terms] OR drug therapy[Text Word] OR "surgery"[MeSH Subheading] OR "surgery"[MeSH Terms] OR surgery[Text Word] OR "antibiotics"[MeSH Terms] OR antibiotic*[Text Word] OR "tetracyclines"[MeSH Terms] OR "tetracycline"[MeSH Terms] OR tetracyclin*[Text Word] OR "doxycycline"[MeSH Terms] OR doxycyclin*[Text Word] OR "minocycline"[MeSH Terms] OR minocyclin*[Text Word] OR "permethrin"[MeSH Terms] OR permethrin*[Text Word] OR "benzoyl peroxide"[MeSH Terms] OR benzoyl peroxid*[Text Word] OR "contraceptives, oral"[MeSH Terms] OR oral contraceptiv*[Text Word] OR "diane 35"[All Fields] OR erythromycin[MeSH Terms] OR erythromycin*[tw] OR sulfur[Text Word] OR sulphur[Text Word] OR "sulfur"[MeSH Terms] OR "azelaic acid"[Substance Name] OR azelaic acid[Text Word] OR "tretinoin"[MeSH Terms] OR tretinoin[Text Word] OR "isotretinoin"[MeSH Terms] OR isotretinoin[Text Word] OR "lasers"[MeSH Terms] OR laser[Text Word] OR lasers[tw] OR "spironolactone"[MeSH Terms] OR spironolacton*[Text Word] OR "adrenal cortex hormones"[MeSH Terms] OR corticosteroid*[Text Word] OR "metronidazole"[MeSH Terms] OR metronidazole[Text Word] OR "zinc"[MeSH Terms] OR zinc[Text Word] OR "massage"[MeSH Terms] OR massage[Text Word])

Combined search strategy A+B+C
(Randomized Controlled Trial[pt] OR Controlled Clinical Trial[pt] OR randomized controlled trials[mesh terms] OR random allocation[mesh terms] OR double‐blind method[mesh terms] OR single‐blind method[mesh terms] OR clinical trial[pt] OR clinical trials[Mesh Terms] OR "clinical trial"[tw] OR ((singl*[tw] OR doubl*[tw] OR trebl*[tw] OR tripl*[tw]) AND (mask*[tw] OR blind*[tw])) OR (placebos[mesh terms] OR placebo*[tw] OR random*[tw] OR research design[MeSH:NoExp] OR comparative study[mesh terms] OR evaluation studies[mesh terms] OR follow‐up studies[mesh terms] OR prospective studies[mesh terms] OR control*[tw] OR prospectiv*[tw] OR volunteer*[tw]) NOT (animal[MeSH Terms] NOT human[MeSH Terms])) AND ("acne rosacea"[MeSH Terms] OR rosacea[Text Word] OR "rhinophyma"[MeSH Terms] OR rhinophyma[Text Word] OR rozacea[All Fields] OR "flushing"[MeSH Terms] OR flushing[Text Word] OR (facial[All Fields] AND ("telangiectasis"[MeSH Terms] OR telangiectasia[Text Word]) OR (facial[All Fields] AND ("erythema"[MeSH Terms] OR erythema[Text Word]) OR (facial[All Fields] AND (edema[Text Word] OR oedema[Text Word] OR "edema"[MeSH Terms])) ) AND ("therapy"[MeSH Subheading] OR "therapeutics"[MeSH Terms] OR therapy[Text Word] OR treatment[Text Word] OR "drug therapy"[MeSH Subheading] OR "drug therapy"[MeSH Terms] OR drug therapy[Text Word] OR "surgery"[MeSH Subheading] OR "surgery"[MeSH Terms] OR surgery[Text Word] OR "antibiotics"[MeSH Terms] OR antibiotic*[Text Word] OR "tetracyclines"[MeSH Terms] OR "tetracycline"[MeSH Terms] OR tetracyclin*[Text Word] OR "doxycycline"[MeSH Terms] OR doxycyclin*[Text Word] OR "minocycline"[MeSH Terms] OR minocyclin*[Text Word] OR "permethrin"[MeSH Terms] OR permethrin*[Text Word] OR "benzoyl peroxide"[MeSH Terms] OR benzoyl peroxid*[Text Word] OR "contraceptives, oral"[MeSH Terms] OR oral contraceptiv*[Text Word] OR "diane 35"[All Fields] OR erythromycin[MeSH Terms] OR erythromycin*[tw] OR sulfur[Text Word] OR sulphur[Text Word] OR "sulfur"[MeSH Terms] OR "azelaic acid"[Substance Name] OR azelaic acid[Text Word] OR "tretinoin"[MeSH Terms] OR tretinoin[Text Word] OR "isotretinoin"[MeSH Terms] OR isotretinoin[Text Word] OR "lasers"[MeSH Terms] OR laser[Text Word] OR lasers[tw] OR "spironolactone"[MeSH Terms] OR spironolacton*[Text Word] OR "adrenal cortex hormones"[MeSH Terms] OR corticosteroid*[Text Word] OR "metronidazole"[MeSH Terms] OR metronidazole[Text Word] OR "zinc"[MeSH Terms] OR zinc[Text Word] OR "massage"[MeSH Terms] OR massage[Text Word])
Limited to Adult 19+ AND Entry Date 1966 thru march 2002

Table 3. MEDLINE (from 1966 to March 2002)

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Table 4. EMBASE (from 1980 to March 2002)

Search strategy

1 rosacea.mp. or exp ROSACEA
2 Randomized Controlled Trial
3 exp therapy
4 (treatment or treated).mp. [mp=title, abstract, subject headings, drugtrade name, original title, device manufacturer, drug manufacturer name]
5 therapy.mp. [mp=title, abstract, subject headings, drug trade name,original title, device manufacturer, drug manufacturer name]
6 antibiotics.mp. [mp=title, abstract, subject headings, drug tradename, original title, device manufacturer, drug manufacturer name]
7 exp Antibiotic Agent
8 antibiotic.mp. [mp=title, abstract, subject headings, drug trade name,original title, device manufacturer, drug manufacturer name]
9 lasers.mp. or exp Laser
10 laser.mp. [mp=title, abstract, subject headings, drug trade name,original title, device manufacturer, drug manufacturer name]
11 oral contraceptives.mp. or exp Oral Contraceptive Agent
12 oral contraceptive.mp. [mp=title, abstract, subject headings, drugtrade name, original title, device manufacturer, drug manufacturer name]
13 isotretinoin.mp. or exp ISOTRETINOIN
14 tretinoin.mp. or exp Retinoic Acid
15 azelaic acid.mp. or exp Azelaic Acid
16 3 or 4 or 5 or 6 or 6 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15
17 1 and 16
18 (randomized controlled trial$ or rct).mp. [mp=title, abstract,subject headings, drug trade name, original title, device manufacturer, drugmanufacturer name]
19 18 or 2
20 17 and 19
21 from 20 keep 1‐22

Table 4. EMBASE (from 1980 to March 2002)

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Table 5. Biosis (from 1970 to March 2002)

Search Strategy

1(rosacea or rozacea).mp.[mp=title, keywords, heading words, registry words, abstracts, biosystematic codes/super taxa, title, book title, original language book title, title, orinal language book title, biosystematic codes/super taxa, subject headings, heading words]
2 clinical trial.mp. [mp=title, keywords, heading words, registry words, abstracts, biosystematic codes/super taxa, title, book title, original language book title, title, orinal language book title, biosystematic codes/super taxa, subject headings, heading words]
3 randomi$.mp.[mp=title, keywords, heading words, registry words, abstracts, biosystematic codes/super taxa, title, book title, original language book title, title, orinal language book title, biosystematic codes/super taxa, subject headings, heading words]
4 1 and 2 and 3
5 double blind.mp.[mp=title, keywords, heading words, registry words, abstracts, biosystematic codes/super taxa, title, book title, original language book title, title, orinal language book title, biosystematic codes/super taxa, subject headings, heading words]
6 1 and 5
7 6 not 4
8 from 7 keep 5,8,10‐13, 15,17‐19
9 from 8 keep 1

Table 5. Biosis (from 1970 to March 2002)

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Table 6. Science Citation Index (from 1988 to March 2002)

Search Strategy

rosacea AND (therap* or treatment or treated or antibiotic* or laser or lasers or isotretinoin or tretinoin or azelaic acid or oral contraceptive*) AND (random* or rct)

Table 6. Science Citation Index (from 1988 to March 2002)

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Table 7. Pharmaceutical companies contacted

Name	Response	Additional	Comment
Roche	Yes	No
ASTA Medica	Yes	No
Merck	Yes	No
Dumex‐Alpharma	Yes	No
Galderma	Yes	No
AHP Pharma	No	No
Yamanouchi	No	No
Dermik Laboratories	No	No

Table 7. Pharmaceutical companies contacted

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Table 8. Clinicians and researchers contacted

Name	Response	Additional	Comment
F.C. Powell	Yes	No
National Rosacea Society	No	No
A. Rebora	No	No
T. Jansen	No	No
W.J. Cunliffe	No	No
D.M. Thiboutot	No	No
G Plewig	No	No
J.K. Wilkin	No	No
J.L. Jorizzo	Yes	No

Table 8. Clinicians and researchers contacted

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Comparison 1. Topical metronidazole versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Quality of life ‐ no data available	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2 Self‐assessed improvement of rosacea Show forest plot	2	174	Odds Ratio (M‐H, Fixed, 95% CI)	5.96 [2.95, 12.06]

3 Physician's global evaluation of improvement (WMD) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

4 Physician's global evaluation of improvement (OR) Show forest plot	3	313	Odds Ratio (M‐H, Fixed, 95% CI)	7.01 [3.56, 13.81]

8 Drop‐out rate Show forest plot	5	523	Odds Ratio (M‐H, Random, 95% CI)	0.81 [0.25, 2.64]

9 Adverse events Show forest plot	4	433	Odds Ratio (M‐H, Fixed, 95% CI)	1.11 [0.54, 2.27]

10 Data that can not be presented graphically in MetaView Show forest plot			Other data	No numeric data

Comparison 1. Topical metronidazole versus placebo

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Comparison 2. Topical azelaic cream versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Quality of life ‐ no data available	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2 Self‐assessed improvement of rosacea Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

4 Physician's global evaluation of improvement Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

8 Drop‐out rate Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

9 Adverse events Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

10 Data that can not be presented graphically in MetaView Show forest plot			Other data	No numeric data

Comparison 2. Topical azelaic cream versus placebo

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Comparison 3. Clarithromycin and omeprazole versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Quality of life ‐ no data available	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2 Self‐assessed improvement of rosacea ‐ no data available	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
8 Drop‐out rate Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

9 Adverse events Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

10 Data that can not be presented graphically in MetaView Show forest plot			Other data	No numeric data

Comparison 3. Clarithromycin and omeprazole versus placebo

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Comparison 4. Rilmenidine versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Quality of life ‐ no data available	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2 Self‐assessed improvement of rosacea Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

4 Physician's global evaluation of improvement Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

8 Drop‐out rate Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

9 Adverse events Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

10 Data that can not be presented graphically in MetaView Show forest plot			Other data	No numeric data

Comparison 4. Rilmenidine versus placebo

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Comparison 5. Benzoyl peroxide acetone versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Quality of life ‐ no data available	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2 Self‐assessed improvement of rosacea ‐ no data available	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
4 Physician's global evaluation of improvement Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

8 Drop‐out rate Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

9 Adverse events Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

10 Data that can not be presented graphically in MetaView Show forest plot			Other data	No numeric data

Comparison 5. Benzoyl peroxide acetone versus placebo

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Comparison 6. Sodium sulfacetamide 10% and sulfur 5% lotion versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Quality of life ‐ no data available	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2 Self‐assessed improvement of rosacea ‐ no data available	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
10 Data that can not be presented graphically in MetaView Show forest plot			Other data	No numeric data

Comparison 6. Sodium sulfacetamide 10% and sulfur 5% lotion versus placebo

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Comparison 7. Oral Tetracycline versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Quality of life ‐ no data available	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2 Self‐assessed improvement of rosacea Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

4 Physician's global evaluation of improvement Show forest plot	3	152	Odds Ratio (M‐H, Fixed, 95% CI)	6.06 [2.96, 12.42]

9 Adverse events Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

10 Data that can not be presented graphically in MetaView Show forest plot			Other data	No numeric data

Comparison 7. Oral Tetracycline versus placebo

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Comparison 8. Ampicillin versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Quality of life ‐ no data available	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2 Self‐assessed improvement of rosacea Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

4 Physician's global evaluation of improvement Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

9 Adverse events Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

10 Data that can not be presented graphically in MetaView Show forest plot			Other data	No numeric data

Comparison 8. Ampicillin versus placebo

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Comparison 9. Oral metronidazole and topical hydrocortisone 1% cream versus oral placebo and hydrocortisone 1% cream

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Quality of life ‐ no data available	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2 Self‐assessed improvement of rosacea ‐ no data available	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
4 Physician's global evaluation of improvement Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

8 Drop‐out rate Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

9 Adverse events Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 9. Oral metronidazole and topical hydrocortisone 1% cream versus oral placebo and hydrocortisone 1% cream

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Comparison 10. Topical azelaic cream versus topical metronidazole

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Quality of life ‐ no data available	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2 Self‐assessed improvement of rosacea ‐ no data available	0		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
10 Data that can not be presented graphically in MetaView Show forest plot			Other data	No numeric data

Comparison 10. Topical azelaic cream versus topical metronidazole

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Comparison 11. Oral metronidazole versus oral oxytetracycline

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Quality of life ‐ no data available	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2 Self‐assessed improvement of rosacea ‐ no data available	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
3 Patients and physician's global evaluation of improvement Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

8 Drop‐out rate Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 11. Oral metronidazole versus oral oxytetracycline

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Comparison 12. Topical metronidazole cream versus oral tetracycline

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Quality of life ‐ no data available	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2 Self‐assessed improvement of rosacea Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

4 Physcian's global evaluation of improvement Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

8 Drop‐out rate Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

9 Adverse events Show forest plot	1	51	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

10 Data that can not be presented graphically in MetaView Show forest plot			Other data	No numeric data

Comparison 12. Topical metronidazole cream versus oral tetracycline

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Comparison 13. Oral tetracycline versus ampicillin

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Quality of life ‐ no data available	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2 Self‐assessed improvement of rosacea Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

4 Physician's global evaluation of improvement Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

9 Adverse events Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

10 Data that can not be presented graphically in MetaView Show forest plot			Other data	No numeric data

Comparison 13. Oral tetracycline versus ampicillin

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