Management options for mild to moderate acne – pairwise comparisons

National Guideline Alliance (UK)

Management options for mild to moderate acne – pairwise comparisons

Acne vulgaris: management

Evidence review E2

NICE Guideline, No. 198

Authors

National Guideline Alliance (UK).

London: National Institute for Health and Care Excellence (NICE); 2021 Jun.

ISBN-13: 978-1-4731-4147-6

Summary of review questions covered in this report

A single review protocol and literature search was used to identify randomised trials of treatments for acne vulgaris to address 9 review questions covering topical or oral pharmacological treatments and physical treatments, shown below. Outcomes were prioritised for either pairwise or network meta-analysis (NMA) and the evidence was divided according to the severity of acne into mild to moderate and moderate to severe categories. NMA was employed to assess comparative efficacy, acceptability and tolerability of treatments, which are outcomes commonly reported in the literature for the majority of treatments. Pairwise meta-analysis was used to synthesise outcomes for which evidence was more limited across treatments or was treatment-specific. The evidence was then summarised in four separate reviews covering the treatment of:

mild to moderate acne (NMA)
mild to moderate acne (pairwise meta-analysis)
moderate to severe acne (NMA)
moderate to severe acne (pairwise meta-analysis)

This evidence review contains information on the pairwise meta-analyses conducted to assess treatments for people with mild to moderate acne vulgaris. NMA has been the main method of analysis to inform these questions (see evidence review E1). This review reports the associated pairwise meta-analysis for outcomes not covered in the NMA. Information on the NMAs and pairwise meta-analyses conducted to assess treatments for people with moderate to severe acne vulgaris are contained in the evidence reports F1 and F2, respectively.

What is the effectiveness of topical treatments individually or in combination in the treatment of acne vulgaris, for example:
- benzoyl peroxide
- antibiotics
- antiseptics
- retinoids and retinoid-like agents (for example, tretinoin, adapalene, trifarotene)
- azelaic acid
- nicotinamide
- combination of antibiotic and retinoid or retinoid-like agent
- combination of benzoyl peroxide and retinoid or retinoid-like agent
- combination of antibiotic and benzoyl peroxide?
What is the effectiveness of oral antibiotic treatments individually or in combination in the treatment of acne vulgaris, for example:
- tetracyclines (for example oxytetracycline, doxycycline, minocycline, tetracycline, lymecycline)
- macrolide antibiotics (for example, erythromycin and azithromycin)
- trimethoprim?
What is the effectiveness of an oral antibiotic with a topical agent compared to oral antibiotic alone in the treatment of acne vulgaris?
What is the optimal duration of antibiotic treatments (topical and systemic) for acne vulgaris?
What is the effectiveness of hormonal contraceptives in the treatment of acne vulgaris?
What is the effectiveness of spironolactone in the treatment of acne vulgaris?
What is the effectiveness of metformin in the treatment of acne vulgaris?
What is the effectiveness of oral isotretinoin in the treatment of acne vulgaris?
What is the effectiveness of physical treatments for acne vulgaris, for example
- comedone extraction
- chemical peels (for example, glycolic acid, lactic acid, salicylic acid)
- intralesional steroids
- light devices (for example, intense pulsed light, photopneumatic therapy and photodynamic therapy)?

Management options for mild to moderate acne – pairwise comparisons

Review question

What is the effectiveness and acceptability of interventions for the treatment of mild to moderate acne vulgaris (side effects and participant reported improvement)?

Introduction

Mild to moderate acne is very common with a wide range of treatment modalities available including over the counter products. Management options should be effective and acceptable to the individual, taking into consideration potential side effects and contraindications. This evidence review therefore aims to find the most effective treatment option for people with mild to moderate acne.

Summary of the protocol

Please see Table 1 for a summary of the Population, Intervention, Comparison and Outcome (PICO) characteristics of this review.

Table 1

Summary of the protocol.

For further details see the review protocol in appendix A.

Methods and process

This evidence review was developed using the methods and process described in Developing NICE guidelines: the manual. Methods specific to this review question are described in the review protocol in appendix A and the methods document (supplementary document 1).

Declarations of interest were recorded according to NICE’s conflicts of interest policy.

Clinical evidence

Included studies

Overall 62 studies were included in this pairwise review. These are divided into the following categories of interventions: topical non-retinoids and retinoids, own class topicals, topical antibiotics, topical antiseptics, topical acids, oral antibiotics and combinations with other topicals, oral hormonal contraceptives and hormone-modifying agents, oral isotretinoin and physical treatments.

Topical non-retinoids and retinoids

Eighteen parallel group design RCTs (Adhikary 2014, Babaeinejad 2013, Berger 2007a, Chalker 1987, Dubey 2016, Gollnick 2009, Guerra-Tapia 2012, Hughes 1992, Iftikhar 2009, Langner 2000, Marazzi 2002a, Shwetha 2014, Stinco 2007, Thiboutout 2006, Tirado-Sanchez 2013, Trifu 2011, Tu 2001, Webster 2001) reported side effects of topical retinoid treatments or topical treatment combinations including a retinoid treatment in people with mild to moderate acne. Skin irritation was reported by the vast majority of studies.

Four parallel group design RCTs (Babayeva 2011, Berger 2007a, Berger 2007b, Marazzi 2002a) mentioned participants reported improvement of acne.

Four studies were conducted in the USA (Berger 2007a, Berger 2007b, Chalker 1987, Webster 2001), 3 studies in India (Adhikary 2014, Dubey 2016, Shwetha 2014), 2 studies in the UK (Hughes 1992, Marazzi 2002a), 1 study in China (Tu 2001), Italy (Stinco 2007), Iran (Babaeinejad 2013), Pakistan (Iftikhar 2009), Poland (Langner 2000), Mexico (Tirado-Sanchez 2013), Romania (Trifu 2011), Spain (Guerra-Tapia 2012), Turkey (Babayeva 2011); 2 studies were collaborations studies from North America/Europe (Gollnick 2009) and North America (Thiboutout 2006).

Own class topicals

Four parallel group design RCTs (Charakida 2007, Hanstead 1985, Katsambas 1989, Pazoki-Toroudi 2010) reported skin irritation as a side effect of treatment with Acnicare, topical azelaic acid and topical fucidic acid.

One study was conducted in Denmark (Hanstead 1985), Greece (Katsambas 1989), Iran (Pazoki-Toroudi 2010) and the UK (Charakida 2007).

Topical antibiotics

Fourteen parallel group design RCTs (Alirezai 2005, Carey 1996, Cunliffe 2002b, Eichenfield 2016, Hajheydari 2011, Jain 1998, Khanna 1990, Leyden 1987, Pazoki-Toroudi 2010, Pazoki-Toroudi 2011, Schaller 2016, Shalita 2005, Stein Gold 2016, Xu 2016) reported skin irritation as a side effect of treatment with topical antibiotics. Carey 1996 and Pazoki-Toroudi 2010 also mentioned participant reported improvement of acne.

Three studies were conducted in Iran (Hajheydari 2011, Pazoki-Toroudi 2010, Pazoki-Toroudi 2011) and the USA (Leyden 1987, Shalita 2005, Stein Gold 2016), 2 studies in India (Jain 1998, Khanna 1990), 1 study in Canada (Carey 1996), China (Xu 2016), Germany (Schaller 2016) and the UK (Cunliffe 2002b); 2 studies were collaboration studies from Europe (Alirezai 2005) and North America (Eichenfield 2016).

Topical antiseptics

Five parallel group design RCTs (Gollnick 2009, Hughes 1992, Milani 2003, Smith 1980b, Stoughton 1987) reported skin irritation as a side effects of treatment with topical antiseptics in people with mild to moderate acne.

Two studies were conducted in the USA (Smith 1980b-USA, Stoughton 1987), 1 in Italy (Milani 2003) and in the UK (Hughes 1992); 1 study was a collaboration study from Europe/North America (Gollnick 2009).

Topical acids

One parallel group design RCT (Boutli 2003) reported skin irritation and light sensitivity as side effects of treatment with topical acids. Three parallel group RCTs (Akarsu 2012, Poli 2005, Shalita 1981) mentioned participant reported improvement of acne.

One study was conducted in Greece (Boutli 2003), France (Poli 2005), Turkey (Akarsu 2012) and the USA (Shalita 1981).

Oral antibiotics and combinations with other topicals

Four parallel group design RCTs (Bleeker 1983, Maleszka 2011, Ozolins 2004, Rassai 2013) reported side effects of treatment with oral antibiotics or oral antibiotics in combination with topical antibiotics in people with mild to moderate acne. Ozolins 2004 and Rassai 2013 also mentioned participant reported improvement of acne.

One study was conducted in Iran (Rassai 2013), Poland (Maleszka 2011), Sweden (Bleeker 1983) and the UK (Ozolins 2004).

Oral hormonal contraceptives and hormone-modifying agents

Seven parallel group design RCTs (Alora Palli 2013, Jaisamrarn 2014, Jaisamrarn 2018, Leyden 2002, Palombo-Kinne 2009, Plewig 2009, Thorneycroft 2004) reported side effects of treatment with oral hormonal contraceptives and hormone-modifying agents in women with mild to moderate acne. Most often reported side effects were breast tenderness, breakthrough bleeding and neurological side effects. Plewig 2009 also mentioned participant reported improvement of acne.

Two studies were conducted in the USA (Alora Palli 2013, Leyden 2002), 2 studies in Thailand (Jaisamrarn 2014, Jaisamrarn 2018) and 1 study in Germany (Thorneycroft 2004); 2 studies were collaboration studies from Europe (Palombo-Kinne 2009-Europe, Plewig 2009).

Oral isotretinoin

One parallel group design RCT (Rademaker 2014, New Zealand) reported mucosal/cutaneous changes as a side effect of treatment with oral isotretinoin in people with mild to moderate acne.

Physical treatments

Chemical peels

Three parallel group design RCT (Dayal 2017, Dayal 2020, Sarkar 2019) reported side effects of treatments with chemical peels in people with mild to moderate acne. The most often reported side effects were erythema and changes in pigmentation. All 3 studies were conducted in India.

Energy based treatments (light/laser)

Three parallel group design RCTs (Papageorgiou 2000a, Ragab 2014, Seaton 2003) reported side effects of energy based treatments in people with mild to moderate acne. Most often reported side effects were skin irritation and erythema. Ragab 2014 also mentioned participant reported improvement of acne.

Two studies were conducted in the UK (Papageorgiou 2000a, Seaton 2003) and 1 study in Egypt (Ragab 2014).

See the literature search strategy in appendix B and study selection flow chart in appendix C.

Excluded studies

Studies not included in this review with reasons for their exclusion are provided in appendix K.

Summary of included studies

Summaries of the studies that were included in this review are presented in Table 2. The evidence table in appendix D lists all relevant outcomes including those extracted for the network meta-analysis (clinician reported improvement, discontinuation due for any reason and discontinuation due to adverse events). Only the relevant outcomes for the pairwise analysis are listed below.

Table 2

Summary of included studies.

See the full evidence tables in appendix D and the forest plots in appendix E.

Quality assessment of included studies in the evidence review

See the evidence profiles in appendix F.

Economic evidence

Included studies

A single economic search was undertaken for all topics included in the scope of this guideline but no economic studies were identified which were applicable to this review question. See the literature search strategy in appendix B and economic study selection flow chart in appendix G.

Excluded studies

Economic studies not included in this review are listed, and reasons for their exclusion are provided in appendix K.

Economic model

The economic model associated with these review questions was based on the NMA results (see evidence report E1).

The committee’s discussion of the evidence

The pairwise analysis was supplementary to the network meta-analysis so evidence from both of these were discussed when recommendations were drafted. For the discussion of the evidence that supported the recommendations see evidence report E1.

Recommendations supported by this evidence review

Evidence review underpinning recommendations 1.5.1, 1.5.2 and 1.5.5 to 1.5.14 (excluding 1.5.6 which is underpinned by evidence report L, 1.5.10 and bullet points 2 and 3 of recommendation 1.5.12 which are underpinned by evidence report F1) and 3 research recommendations on the effectiveness of chemical peels, the effectiveness of physical modalities and the effectiveness of hormone-modifying agents. Other evidence supporting these recommendations as well as the committee’s discussion of the evidence can be found in the evidence review on mild to moderate acne network meta-analysis (evidence report E1).

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Stein Gold 2016
Stein Gold, L. F., Jarratt, M. T., Bucko, A. D., Grekin, S. K., Berlin, J. M., Bukhalo, M., Weiss, J. S., Berk, D. R., Chang-Lin, J. E., Lin, V., et al. Efficacy and Safety of Once-Daily Dapsone Gel, 7.5% for Treatment of Adolescents and Adults with Acne Vulgaris: first of Two Identically Designed, Large, Multicenter, Randomized, Vehicle-controlled Trials. Journal of Drugs in Dermatology, 2016, 15(5):553–61 [PubMed: 27168264]
Stinco 2007
Stinco, G., Bragadin, G., Trotter, D., Pillon, B., Patrone, P.Relationship between sebostatic activity, tolerability and efficacy of three topical drugs to treat mild to moderate acne. Journal of the European Academy of Dermatology and Venereology, 2007, 21(3):320–5 [PubMed: 17309452]
Stoughton 1987
Stoughton, R. B., Leyden, J. J.Efficacy of 4 percent chlorhexidine gluconate skin cleanser in the treatment of acne vulgaris. Cutis, 1987, 39(6):551–3 [PubMed: 2956067]
Thiboutot 2006
Thiboutot, D., Pariser, D. M., Egan, N., Flores, J., HerndonJ. H.Jr, Kanof, N. B., Kempers, S. E., Maddin, S., Poulin, Y. P., Wilson, D. C., Hwa, J., Liu, Y., Graeber, M.Adapalene Study Group. Adapalene gel 0.3% for the treatment of acne vulgaris: a multicenter, randomized, double-blind, controlled, phase III trial. Journal of the American Academy of Dermatolology, 2006, 54(2):242–50 [PubMed: 16443054]
Thorneycroft 2004
Thorneycroft, I. H., Gollnick, H., Schellschmidt, I.Superiority of a combined contraceptive containing drospirenone to a triphasic preparation containing norgestimate in acne treatment. Cutis, 2004, 74(2):123–30 [PubMed: 15379365]
Tirado-Sanchez 2013
Tirado-Sanchez, A., Espindola, Y. S., Ponce-Olivera, R. M., Bonifaz, A.Efficacy and safety of adapalene gel 0.1% and 0.3% and tretinoin gel 0.05% for acne vulgaris: Results of a single-center, randomized, double-blinded, placebo-controlled clinical trial on Mexican patients (skin type III-IV). Journal of Cosmetic Dermatology, 2013, 12(2):103–7 [PubMed: 23725303]
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Appendices

Appendix H. Economic evidence tables

Economic evidence tables for review question: What is the effectiveness and acceptability of interventions for the treatment of mild to moderate acne (side effects and participant reported improvement)?

No economic evidence was identified which was applicable to this review question.

Appendix I. Economic evidence profiles

Economic model for review question: What is the effectiveness and acceptability of interventions for the treatment of mild to moderate acne (side effects and participant reported improvement)?

The economic model associated with this review question was based on the NMA results. So for the economic evidence profile see evidence report E1.

Appendix J. Economic analysis

Economic analysis for review question: What is the effectiveness and acceptability of interventions for the treatment of mild to moderate acne (side effects and participant reported improvement)?

The economic model associated with this review question was based on the NMA results. So for the economic analysis see evidence report E1.

Appendix K. Excluded studies

Excluded clinical and economic studies for review question: What is the effectiveness and acceptability of interventions for the treatment of mild to moderate acne (side effects and participant reported improvement)?

Clinical studies

Download PDF (1.5M)

Economic studies and studies reporting utility data

Download PDF (195K)

Appendix L. Research recommendations

Research recommendations for review question: What is the effectiveness and acceptability of interventions for the treatment of mild to moderate acne (side effects and participant reported improvement)?

For research recommendations associated with this review question see appendix L in evidence report E1.

Final

Evidence review underpinning recommendations 1.5.1, 1.5.2 and 1.5.5 to 1.5.14 (excluding 1.5.6 which is underpinned by evidence review L, 1.5.10 and bullet points 2 and 3 of recommendation 1.5.12 which are underpinned by evidence review F1 and 3 research recommendations in the NICE guideline - see evidence review E1 for the committee’s discussion of the evidence)

These evidence reviews were developed by the National Guideline Alliance which is a part of the Royal College of Obstetricians and Gynaecologists

Disclaimer: The recommendations in this guideline represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, professionals are expected to take this guideline fully into account, alongside the individual needs, preferences and values of their patients or service users. The recommendations in this guideline are not mandatory and the guideline does not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or their carer or guardian.

Local commissioners and/or providers have a responsibility to enable the guideline to be applied when individual health professionals and their patients or service users wish to use it. They should do so in the context of local and national priorities for funding and developing services, and in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Nothing in this guideline should be interpreted in a way that would be inconsistent with compliance with those duties.

NICE guidelines cover health and care in England. Decisions on how they apply in other UK countries are made by ministers in the Welsh Government, Scottish Government, and Northern Ireland Executive. All NICE guidance is subject to regular review and may be updated or withdrawn.

Bookshelf ID: NBK573046PMID: 34424623

Table 1Summary of the protocol

Population	People with acne vulgaris, of all ages who have mild to moderate acne
Intervention	Interventions will be categorised into the following classes (and, if relevant, subclasses): ➢ TOPICAL TREATMENTS Abrasive/cleaning agents Aluminium oxide [own class] Anthelmintics Cysticide (praziquantel) [own class] Class of avermectins: ivermectin Antibacterials Class of triclocarban and triclozan Antibiotics Class of sulphones (dapsone) Fucidic acid (sodium fusidate) [own class] Class of lincosamides (for example clindamycin) Class of macrolides (for example clarithromycin, erythromycin with zinc acetate dihydrate) Class of nitroimidazoles (metronidazole) Class of carboxylic acids (mupirocin) Class of penicillins Sub-class of natural (for example almecillin) Sub-class of aminopenicillins (for example ampicillin) Sub-class of β-lactamase-resistant (for example methicillin) Sub-class of carboxypenicillins (for example ticarcillin) Sub-class of ureidopenicillins (for example azlocillin) Sub-class of other penicillins (mecillinam, pivmecillinam hydrochloride) Class of pleuromutilins (for example retapamulin) Antiseptics Benzoyl peroxide (trade: Acnecide, Brevoxyl, Panoxyl) [own class] Chlorhexidine gluconate (trade: Acnemed, Cepton) or digluconate [own class] Dicarboxylic acids Azelaic acid [own class] Vitamin B3 Nicotinamide (niacinamide) [own class] Retinoids or retinoid-like agents Class of retinoids or retinoid-like agents (adapalene, isotretinoin, retinol, tazarotene, tretinoin, trifarotene) Combined interventions Benzoyl peroxide & potassium hydroxyguinoline sulfate [own class] Class of benzoyl peroxide & retinoid (benzoyl peroxide + adapalene) Class of benzoyl peroxide & lincosamide (benzoyl peroxide + clindamycin) Class of lincosamides & retinoid (clindamycin + tretinoin) Class of macrolides & retinoid (erythomycin + retinoid) [topical] Germolene (phenol 1.2% + chlorhexidine diculconate [own class] ➢ ORAL ANTIBIOTICS Class of carbapenems (for example imipenem, meropenem) Class of carbapenems with cilastatin (imipenem with cilastatin) Class of carbapenems with b lactamase inhibitor (meropenem with vaborbactam) Class of cephamycins/cephalosporins Sub-class of 1^st-generation (for example cefadroxil) Sub-class of 2^nd-generation (for example cefaclore) Sub-class of 3^rd-generation (for example cefdinir) Sub-class of 4^th-generation (for example cefozopran) Sub-class of 5^th-generation (for example ceftolozane) Class of cephamycins/cephalosporins with β-lactamase inhibitor (for example ceftraroline or ceftazidime with avibactam, cefoperazone with sulbactam, ceftolozane with tazobactam) Class of sulphones (dapsone) Fucidic acid (sodium fusidate) [own class] Class of lincosamides (for example clindamycin) Class of macrolides (for example clarithromycin, erythromycin) Class of monobactams (aztreonam) Class of monobactams with β-lactamase inhibitor (aztreonam with avibactam) Class of penicillins Sub-class of natural (for example almecillin) Sub-class of aminopenicillins (for example ampicillin) Sub-class of β-lactamase-resistant (for example methicillin) Sub-class of carboxypenicillins (for example ticarcillin) Sub-class of ureidopenicillins (for example azlocillin) Sub-class of other penicillins (mecillinam, pivmecillinam hydrochloride) Class of penicillin with β-lactamase inhibitor (for example co-amoxiclav [amoxicillin with clavulanic acid], piperacillin with tazobactam, ticaricillin with clavulanic acid, sultamicillin [ampicillin with sulbactam]) Class of penicillin with flucloxacilin (co-fluampicil [ampicillin + flucloxacilin]) Class of pleuromutilins (for example retapamulin) Class of quinolones Sub-class of 1^st-generation (for example rosoxacin) Sub-class of 2^nd-generation (for example ofloxacin) Sub-class of 3^rd-generation (for example temafloxacin) Sub-class of 4^th-generation (for example sitafloxacin) Class of tetracyclines (for example doxycycline, oxytetracycline) Trimethoprim [own class] Co-trimoxazole (trimethoprim-sulfamethoxazole; TMP-SMX) [own class] ➢ TOPICAL TREATMENTS COMBINED WITH ORAL ANTIBIOTICS ➢ ORAL HORMONAL CONTRACEPTIVES AND HORMONE-MODIFYING AGENTS Co-cyprindiol (ethinylestradiol + cyproterone acetate) [own class of combined oral contraceptive] Class of combined oral contraceptives Sub-class of 2^nd generation (oestrogen, for example ethinylestradiol or estradiol or mestranol combined with levonorgestrel or norethisterone) Sub-class of 3^rd generation (oestrogen, for example ethinylestradiol combined with desogestrel or gestodene or norgestimate) Sub-class of 4^th generation (oestrogen, for example ethinylestradiol or estradiol combined with dienogest or drospirenone or nomegestrol acetate) Monophasic and phasic combined oral contraceptives containing the same hormones will be analysed as separate interventions within their sub-class. Class of progestogen-only oral contraceptives Sub-class of 1^st generation (for example medroxyprogesterone acetate) Sub-class of 2^nd generation (for example levonorgestrel, norethisterone/norethindrone) Sub-class of 3^rd generation (for example desogestrel, norgestimate, gestodene) Sub-class of 4^th generation (for example dienogest, drospirenone, nomegestrol acetate) Class of selective aldosterone receptor antagonists (for example spironolactone alone or combined with furosemide or hydroflumethiazide [co-flumactone], eplerenone, canrenone) Class of 5α-reductase inhibitors (dutasteride, finasteride, tamsulosin with dutasteride) Class of other non-steroidal anti-androgens (for example abiraterone acetate, apalutamide, bicalutamide, cyproterone acetate, clormadinone acetate, enzalutamide, flutamide) Metformin [own class] ➢ ORAL ISOTRETINOIN Class of oral retinoid and total cumulative dose ≥ 120mg/kg (single course) Sub-class of daily dosing (dose ≥0.5mg/kg/day or <0.5mg/kg/day) Sub-class of alternate day dosing (dose ≥0.5mg/kg/day or <0.5mg/kg/day) Sub-class of less frequent or other dosing (dose ≥0.5mg/kg/day or <0.5mg/kg/day) Class of oral retinoid and total cumulative dose < 120mg/kg (single course) Sub-class of daily dosing (dose ≥0.5mg/kg/day or <0.5mg/kg/day) Sub-class of alternate day dosing (dose ≥0.5mg/kg/day or <0.5mg/kg/day) Sub-class of less frequent or other dosing (dose ≥0.5mg/kg/day or <0.5mg/kg/day) ➢ PHYSICAL TREATMENTS Class of chemical peels Sub-class of superficial peels Sub-class of moderate peels Sub-class of deep peels for example amino fruit acid, glycolic acid, Jessner’s peel, lactic acid, salicylic acid, trichloroacetic acid [TCA]; these will be categorised into different sub-classes as reported in the included studies, according to the concentration of their active ingredient and treatment duration. Comedone extraction [own class] Class of photothermal therapy (for example fractional erbium glass laser) Class of photochemical therapy (for example blue or red light and their combination) Class of photochemical and photothermal therapy (for example potassium titanyul phosphate laser, Intense Pulsed Light [IPL], Pulsed Dye Laser) Class of photodynamic therapy (for example 5-aminolevuliniv acid [ALA], liposomal methylene blue gel, methylaminolevulinate [MAL]) Smoothbeam™ laser [own class] Photopneumatic therapy (for example intense pulsed light + vacuum) Radiofrequency (for example fractional microneedling, bipolar)
Comparison	No treatment Waiting list Pill placebo Other active intervention Sham physical treatment
Outcomes	Important Specific short-term side effects for comparisons of treatments within the same class or those that involve an inactive arm topical non-retinoid treatments: – skin irritation topical retinoid treatments: – skin irritation – light sensitivity oral antibiotics: – skin irritation – gastrointestinal – thrush/candidiasis oral hormonal contraceptives and hormone-modifying agents: – breast tenderness – neurological – sexual dysfunction – hepatobillary effects – mood disturbance – breakthrough bleeding oral isotretinoin: – mucosal / cutaneous changes (for example new chelitis) – change in mood – new psychiatric diagnosis – suicidality physical treatments: – chemical peels: - skin irritation - skin redness (erythema) - changes in pigmentation - infection of treated area – energy based treatments (light/laser): - skin irritation - skin redness (erythema) - changes in pigmentation Participant reported improvement

Table 2Summary of included studies

Study

Population

Interventions

Outcomes

Adhikary 2014

Country: India

Study type: RCT

N=200

Sex: mixed

Number randomised: arm 1: n=100

Number randomised: arm 2: n=100

Inclusion details: Age at least 10 years, grade I to grade II acne vulgaris of face, on the Indian grading scale.

Intervention: arm 1: topical Isotretinoin gel 0.05 % once daily at night and topical Clindamycin phosphate 1% lotion in the morning

Intervention: arm 2: Adapalene 0.1 % gel once daily at night and topical Clindamycin phosphate 1% lotion in the morning.

Skin irritation

Akarsu 2012

Country: Turkey

Study type: RCT

N=50

Sex: mixed

Number randomised: arm 1: n=25

Number randomised: arm 2: n=25

Inclusion details: Mild to moderate AV, between the ages of 18 and 35 years, and with between 10–50 IL and 10–100 NIL above the mandibular line at baseline.

Intervention: arm 1: SAL 3% + CLIND-topical 1% + BPO-topical 5%

Intervention: arm 2: CLIND-topical 1% + BPO-topical 5%

Participant reported improvement

Alirezai 2005

Country: Europe

Study type: RCT

N=592

Sex: mixed

Number randomised: arm 1: n=265

Number randomised: arm 2: n=261

Number randomised: arm 3: n=66

Inclusion details: At least age 12, acne vulgaris on face (severity grade of 2 to 5 on the Leeds revised scale), and 15–50 inflammatory facial lesions.

Intervention: arm 1: CLIND-topical 1% gel

Intervention: arm 2: CLIND-topical 1% topical solution

Intervention: arm 3: Vehicle gel

Skin irritation

Alora Palli 2013

Country: United States

Study type: RCT

N=30

Sex: female

Number randomised: arm 1: n=16

Number randomised: arm 2: n=14

Inclusion details: Female, age 18 to 45 years, who achieved spontaneous menarche, desired contraception and had a diagnosis of truncal acne of 10 to 50 inflammatory lesions on the back and chest combined with not more than 5 nodules.

Intervention: arm 1: EE-oral 0.02 mg + DROS-oral 3mg od

Intervention: arm 2: PLC-oral

Neurological side effects
Change in mood
Breakthrough bleeding

Babaeinejad 2013

Country: Iran

Study type: RCT

N=60

Sex: mixed

Number randomised: arm 1: n=30

Number randomised: arm 2: n=30

Inclusion details: Mild acne vulgaris (Evaluator Global Severity Score, EGSS, of 2).

Intervention: arm 1: BPO 2.5% gel

Intervention: arm 2: ADAP 0.1% gel

Skin irritation

Babayeva 2011

Country: Turkey

Study type: RCT

N=46

Sex: mixed

Number randomised: arm 1: n=23

Number randomised: arm 2: n=23

Inclusion details: 18 and 35 years of age, with 10–50 inflammatory lesions and 10–100 non-Inflammatory lesions above the mandibular line at baseline.

Intervention: arm 1: SAL 3% + CLIND-topical 1%

Intervention: arm 2: TRET-topical 0.05% + CLIND-topical 1%

Participant reported improvement

Berger 2007a

Country: United States

Study type: RCT

N=156

Sex: mixed

Number randomised: arm 1: n=78

Number randomised: arm 2: n=78

Inclusion details: Ages 12 to 40 years, in good health, with mild to moderate acne vulgaris defined as 20 to 150 total facial lesions. Of these lesions, 10 to 100 were to be comedones (open and closed), and 10 to 50 were to be inflammatory lesions (papules and pustules). No more than 2 were to be nodules (defined as deep inflammatory lesions of 1 cm or greater).

Intervention: arm 1: TRET-topical 0.04%

Intervention: arm 2: TRET-topical 0.1%

Skin irritation
Light sensitivity
Participant reported improvement

Berger 2007b

Country: United States

Study type: RCT

N=178

Sex: mixed

Number randomised: arm 1: n=88

Number randomised: arm 2: n=90

Inclusion details: 19 and 45 years of age with mild to moderate acne vulgaris - between 15 and 80 total facial lesions that consisted of 10 to 40 inflammatory lesions and no more than 2 nodules.

Intervention: arm 1: TRET-topical 0.04%

Intervention: arm 2: Vehicle gel

Participant reported improvement

Bleeker 1983

Country: Sweden

Study type: RCT

N=40

Sex: mixed

Number randomised: arm 1: n=20

Number randomised: arm 2: n=20

Inclusion details: Mild to moderate papulopustular acne.

Intervention: arm 1: Erythromycin stearate capsules 500mg b.d.

Intervention: arm 2: Erythromycin base capsules 500mg b.d.

GI side effects

Boutli 2003

Country: Greece

Study type: RCT

N=37

Sex: mixed

Number randomised: arm 1: n=19

Number randomised: arm 2: n=18

Inclusion details: Age 13–25, moderate acne (grade 11, Pilsbury and Kligman), 20–50 comedones and 20–40 papulopustules.

Intervention: arm 1: Topical benzoil peroxide 5% gel

Intervention: arm 2: Topical Nisal cream (chloroxylenol 0.5% + salicylic acid 2%)

Skin irritation
Light sensitivity

Carey 1996

Country: Canada

Study type: RCT

N=499

Sex: mixed

Number randomised: arm 1: n=249

Number randomised: arm 2: n=250

Inclusion details: Under 25 years, 15 - 75 inflamed lesions on the face.

Intervention: arm 1: Topical fucidic acid 2%

Intervention: arm 2: Topical erythromycin 2%

Skin irritation
Participant reported improvement

Chalker 1987

Country: United States

Study type: RCT

N=313

Sex: mixed

Number randomised: arm 1: n=156

Number randomised: arm 2: n=157

Inclusion details: Acne vulgaris with a minimum of 12 inflammatory lesions and 12 noninflammatory lesions and a maximum of 3 facial nodulocystic lesions, aged 13–30.

Intervention: arm 1: Topical ISO 0.05% gel b.d.

Intervention: arm 2: Vehicle b.d.

Skin irritation

Charakida 2007

Country: United Kingdom

Study type: RCT

N=40

Sex: mixed

Number randomised: arm 1: n=20

Number randomised: arm 2: n=20

Inclusion details: Participants aged between 16 and 45 years with mild to moderate facial inflammatory acne defined as the presence of at least 10 acne papules or pustules between the brow and jaw line and an acne severity score of between 2 and 7 on the Leeds revised acne grading system.

Intervention: arm 1: ACNICARE (triethyl citrate + ethyl linoleate) topical b.d.

Intervention: arm 2: Vehicle topical b.d.

Skin irritation

Cunliffe 2002b

Country: United Kingdom

Study type: RCT

N=79

Sex: mixed

Number randomised: arm 1: n=40

Number randomised: arm 2: n=39

Inclusion details: Acne vulgaris, aged 13 to 30. Baseline or screening P acnes counts on facial skin (cheek or forehead) had to be at least 104 colony-forming units (CFUs) per square centimetre, of which no more than 104 CFU/cm 2 could be erythromycin or clindamycin resistant. Eligible patients also had to have 15 to 100 inflammatory lesions, 15 to 100 comedones, and <2 nodules/cysts on the face. Sexually active female patients were required to use contraception for 28 days before the start and for the duration of the study.

Intervention: arm 1: topical clindamycin 1% / BPO 5% gel b.d.

Intervention: arm 2: topical clindamycin 1%

Skin irritation

Dayal 2017

Country: India

Study type: RCT

N=40

Sex: mixed

Number randomised: arm 1: n=20

Number randomised: arm 2: n=20

Inclusion details: Mild-to-moderate (grade I and grade II) facial acne vulgaris, graded using a system taking into account the predominant lesions present: Grade 1 (mild): comedones, occasional papules. Grade 2 (moderate): papules, comedones, few pustules. Grade 3 (severe): predominant pustules, nodules, abscesses. Grade 4 (cystic): mainly cysts, abscesses, widespread scarring.

Intervention: arm 1: salicylic acid 30%

Intervention: arm 2: Jessner’s peel

Skin redness
Pigment changes

Dayal 2020

Country: India

Study type: RCT

N=50

Sex: mixed

Number randomised: arm 1: n=25

Number randomised: arm 2: n=25

Inclusion details: Mild-to-moderate (grade I and grade II) facial acne vulgaris on the Vaishampayan grading system.

Intervention: arm 1: 30% salicylic acid peel

Intervention: arm 2: 45% mandelic acid peel

Skin redness
Pigment changes

Dubey 2016

Country: India

Study type: RCT

N=100

Sex: mixed

Number randomised: arm 1: n=50

Number randomised: arm 2: n=50

Inclusion details: Male and non-pregnant participants aged between 12 and 30 years. Participants with mild to moderate acne vulgaris; based on simple acne grading scale (grade 1 to grade 4). Participants with only comedones as noninflammatory lesions, and papules and pustules as inflammatory lesions were included in the study (mild to moderate acne vulgaris- grades 1 and 2).

Intervention: arm 1: adapalene (0.1%) o.d.

Intervention: arm 2: benzoyl peroxide (2.5%) clindamycin (1%) combination o.d.

Skin irritation

Eichenfield 2016

Country: North America

Study type: RCT

N=2238

Sex: mixed

Number randomised: arm 1: n=1118

Number randomised: arm 2: n=1120

Inclusion details: At least 12 years of age, with a diagnosis of acne, with 20–50 facial inflammatory lesions (papules and pustules) and 30–100 facial noninflammatory lesions (open and closed comedones), and with an acne grade of 3 (indicating moderate severity) on the Global Acne Assessment Score (GAAS) at screening and at baseline.

Intervention: arm 1: Topical dapsone 7.5% gel o.d.

Intervention: arm 2: Topical vehicle o.d.

Skin irritation

Gollnick 2009

Country: North America/Europe

Study type: RCT

N=1670

Sex: mixed

Number randomised: arm 1: n=419

Number randomised: arm 2: n=418

Number randomised: arm 3: n=415

Number randomised: arm 4: n=418

Inclusion details: 12 years of age or older with acne vulgaris, having on the face 20–50 inflammatory lesions, 30–100 noninflammatory lesions and an Investigator’s Global Assessment (IGA) score of 3, corresponding to moderate acne.

Intervention: arm 1: Adapalene 0.1%–BPO 2.5% fixed combination topical gel o.d.

Intervention: arm 2: Adapalene 0.1% topical gel o.d.

Intervention: arm 3: BPO 2.5% topical gel o.d.

Intervention: arm 4: Vehicle topical o.d.

Skin irritation

Guerra-Tapia 2012

Country: Spain

Study type: RCT

N=168

Sex: mixed

Number randomised: arm 1: n=83

Number randomised: arm 2: n=85

Inclusion details: Aged 12 to 39 years, with = 15 inflammatory lesions and/ or non-inflammatory lesions but = 3 nodulocystic lesions and an acne grade of = 2.0 and < 7.0 on the Leeds Revised Acne Grading System.

Intervention: arm 1: topical BPO % + CLIND 1% o.d.

Intervention: arm 2: Adapalene 0.1% topical gel o.d.

Skin irritation

Hajheydari 2011

Country: Iran

Study type: RCT

N=96

Sex: mixed

Number randomised: arm 1: n=32

Number randomised: arm 2: n=32

Number randomised: arm 3: n=32

Inclusion details: Aged 12–28 years with mild to moderate acne vulgaris.

Intervention: arm 1: Topical azithromycin 2% b.d.

Intervention: arm 2: Topical erythromycin 2% b.d.

Intervention: arm 3: Topical clindamycin 2% b.d.

Skin irritation

Hanstead 1985

Country: Denmark

Study type: RCT

N=79

Sex: mixed

Number randomised: arm 1: n=40

Number randomised: arm 2: n=39

Inclusion details: Mild to moderate acne vulgaris.

Intervention: arm 1: Topical fucidin cream 2%

Intervention: arm 2: Topical placebo cream

Skin irritation

Hughes 1992

Country: United Kingdom

Study type: RCT

N=77

Sex: mixed

Number randomised: arm 1: n=25

Number randomised: arm 2: n=26

Number randomised: arm 3: n=26

Inclusion details: 15–100 inflamed and/or 15–100 non-inflamed lesions but no more than three nodulocystic lesions on the face.

Intervention: arm 1: Topical isotretinoin 0.05% b.d.

Intervention: arm 2: Topical BPO 5% b.d.

Intervention: arm 3: Vehicle b.d.

Skin irritation

Iftikhar 2009

Country: Pakistan

Study type: RCT

N=200

Sex: mixed

Number randomised: arm 1: na, n=100 completed

Number randomised: arm 2: na, n=100 completed

Inclusion details: More than 13 years of age, with mild to moderate acne (comedones, papulopustules and few nodules with no scarring) and free of intercurrent illness.

Intervention: arm 1: 0.1% ADAP topical o.d.

Intervention: arm 2: 4% BPO topical o.d.

Skin irritation

Jain 1998

Country: India

Study type: RCT

N=40

Sex: Mixed

Number randomised: arm 1: n=20

Number randomised: arm 2: n=20

Inclusion details: Moderately severe acne, with lesions on the face.

Intervention: arm 1: 5% benzoyl peroxide topical and 1% metronidazole gel o.d.

Intervention: arm 2: 5% benzoyl peroxide topical and 1% clindamycin gel o.d.

Skin irritation

Jaisamrarn 2014

Country: Thailand

Study type: RCT

N=201

Sex: female

Number randomised: arm 1: n=100

Number randomised: arm 2: n=101

Inclusion details: Healthy females aged between 18 and 45 years with mild to moderate acne vulgaris - defined as having no more than 5 comedones or papules and no pustule while moderate acne vulgaris was defined as 6–15 comedones or papules and/or a maximum of three pustules.

Intervention: arm 1: triphasic EE/NGM treatment at the dosage of 0.035/0.18, 0.035/0.215 and 0.035/0.25mg on days 1–7, 8–14 and 15–21, respectively, and took inactive tablets for 7 days before starting the next treatment cycle

Intervention: arm 2: biphasic EE/DSG treatment at the dosage of 0.04/0.025 and 0.03/0.125mg on days 1–7 and 8–22 of each cycle, respectively, and discontinued treatment for 6 days before starting the next treatment cycle.

Breast tenderness
Neurological side effects
Breakthrough bleeding

Jaisamrarn 2018

Country: Thailand

Study type: RCT

N=180

Sex: female

Number randomised: arm 1: n=90

Number randomised: arm 2: n=90

Inclusion details: Healthy women between the ages of 18 to 45 years with mild to moderate acne vulgaris and who had dysmenorrhea of any degree of severity. Mild acne vulgaris was defined as having comedones as the main type of acne lesion with < 10 papules and pustules. Moderate acne was defined as having 10–40 papules and pustules, 10–40 comedones, and/or mild truncal disease.

Intervention: arm 1: EE/CMA at the dosage of 30 mcg/2 mg once daily; treatment was for 21 consecutive days, starting on the first day of the menstruation, followed by 7 days of medication free before starting the next cycle of treatment.

Intervention: arm 2: received EE/DRSP at the dosage of 30 mcg/3 mg once daily; treatment was for 21 consecutive days, starting on the first day of the menstruation, followed by 7 days of medication free before starting the next cycle of treatment.

Breast tenderness
Neurological side effects
Breakthrough bleeding

Katsambas 1989; Trial 1

Country: Greece

Study type: RCT

N=92

Sex: mixed

Number randomised: arm 1: n=43

Number randomised: arm 2: n=49

Inclusion details: Papulo-pustular acne (degree II/III of Plewig-Kligmann).

Intervention: arm 1: 20% azelaic acid cream

Intervention: arm 2: vehicle

Skin irritation

Khanna 1990

Country: India

Study type: RCT

N=26

Sex: Mixed

Number randomised: arm 1: na, n=12 completed

Number randomised: arm 2: na, n=14 completed

Inclusion details: Moderately severe acne - defined as the presence, on the face (above the jawline) of the subject, of 5–15 inflammatory lesions (IN) but no more than 5 nodulocystic lesions and / or more than 50 non-inflammatory (NI) acne lesions.

Intervention: arm 1: topical clindamycin hydrochloride 1% twice a day

Intervention: arm 2: hydro-alcoholic vehicle twice a day

Skin irritation

Langner 2000

Country: Poland

Study type: RCT

N=127

Sex: Mixed

Number randomised: arm 1: n=43

Number randomised: arm 2: n=42

Number randomised: arm 3: n=42

Inclusion details: Acne vulgaris of the face (15–100 inflammatory lesions and/or 15–100 non-inflammatory lesions, but not more than three nodulocystic lesions).

Intervention: arm 1: isotretinoin 0.05%w/w cream formulated with standard sunscreen

Intervention: arm 2: isotretinoin (0.10%w/w) cream formulated with standard sunscreen

Intervention: arm 3: placebo vehicle sunscreen cream

Skin irritation

Leyden 1987

Country: United States

Study type: RCT

N=109

Sex: Mixed

Number randomised: arm 1: n=55

Number randomised: arm 2: n=54

Inclusion details: At least 14 years of age and had to have a minimum of ten but no more than sixty facial papules and pustules, and no more than six facial nodular cystic lesions.

Intervention: arm 1: 2% erythromycin gel

Intervention: arm 2: clindamycin phosphate 1 % solution

Skin irritation

Leyden 2002

Country: United States

Study type: RCT

N=371

Sex: Female

Number randomised: arm 1: n=185

Number randomised: arm 2: n=186

Inclusion details: Healthy women, at least 14 years of age, with regular menstrual cycles and moderate facial acne. Moderate facial acne was defined as a total facial count of 6 to 200 noninflammatory comedones, 10 to 75 inflammatory lesions (papules and pustules), and 5 or fewer nodules. Also required a normal Papanicolaou test result within the past 6 months or a low-grade abnormal Papanicolaou test result under medical evaluation, a negative pregnancy test result, and agreement to use a nonhormonal method of contraception if at risk for pregnancy.

Intervention: arm 1: tablets containing 20g of EE and 100g of LNG in a 28-day blister pack with 21 days of active medication followed by 7 days of placebo

Intervention: arm 2: Placebo oral

Breakthrough bleeding

Maleszka 2011

Country: Poland

Study type: RCT

N=240

Sex: mixed

Number randomised: arm 1: n=120

Number randomised: arm 2: n=120

Inclusion details: 14 years or older with a clinical diagnosis of moderate acne vulgaris.

Intervention: arm 1: Azithromycin 500mg o.d. for 3 days in the first week, followed by 500-mg tablets weekly to complete 10 weeks of treatment.

Intervention: arm 2: Doxycycline (Hiramicin) 100-mg capsules twice a day on the first day of the treatment, followed by doxycycline 100-mg capsules once a day during 12 weeks of treatment.

GI side effects

Marazzi 2002a

Country: United Kingdom

Study type: RCT

N=188

Sex: Mixed

Number randomised: arm 1: n=95

Number randomised: arm 2: n=93

Inclusion details: Facial acne vulgaris having 15–100 inflammatory lesions and/or 15–100 non-inflammatory lesions, but not more than three nodulocystic lesions.

Intervention: arm 1: gel containing isotretinoin 0.1%w/w and erythromycin 4.0%w/w in a vehicle of butylated hydroxytoluene, hydroxypropylcellulose and ethanol

Intervention: arm 2: comparator gel contained benzoyl peroxide 5.0%w/w and erythromycin 3.0%w/w

Skin irritation
Participant reported improvement

Milani 2003

Country: Italy

Study type: RCT

N=60

Sex: Mixed

Number randomised: arm 1: n=30

Number randomised: arm 2: n=30

Inclusion details: 15–35 years with mild to moderate acne vulgaris, defined as at least 10 inflammatory lesions and 10 non-inflamatory lesions, and no more than two nodulo-cystic lesions.

Intervention: arm 1: Hydrogen peroxide gel (Crystacide 1%)

Intervention: arm 2: Benzoyl peroxide gel (PanOxyl 4%)

Skin irritation

Ozolins 2004

Country: United Kingdom

Study type: RCT

N=649

Sex: mixed

Number randomised: arm 1: n=131

Number randomised: arm 2: n=130

Number randomised: arm 3: n=130

Number randomised: arm 4: n=127

Number randomised: arm 5: n=131

Inclusion details: Mild to moderate acne vulgaris (acne grade 3·0 or less) and at least 15 inflamed and 15 non-inflamed lesions on the face.

Intervention: arm 1: OXYTETRA-oral 500mg b.d. + PLC-topical

Intervention: arm 2: MINO-oral 100mg + PLC-topical

Intervention: arm 3: BPO- topical 5% + PLC-oral

Intervention: arm 4: Combined formulation of BPO- topical 5%/ERYTH-topical 3%+ PLC-oral

Intervention: arm 5: BPO-topical 5% + ERYTH-topical 2% + PLC-oral

Skin irritation
GI side effects
Participant reported improvement

Palombo-Kinne 2009

Country: Europe

Study type: RCT

N=1338

Sex: female

Number randomised: arm 1: n=530

Number randomised: arm 2: n=541

Number randomised: arm 3: n=267

Inclusion details: Female patients between 16 and 45 years old with mild to moderate papulopustular acne and without contraindications to COC use. Mild to moderate facial papulopustular acne was defined as 10–50 comedones (non-inflammatory lesions), 10–50 papules and pustules together (inflammatory lesions) and not more than three small nodules (inflammatory lesions); a normal Papanicolaou test result within the past 6 months; use of a non-hormonal method of contraception for sexually active patients.

Intervention: arm 1: EE-oral 0.030mg + DNG-oral 2mg

Intervention: arm 2: CPA-oral (2mg) + EE-oral (0.035mg)

Intervention: arm 3: PLC-oral

Breast tenderness
Neurological side effects
Breakthrough bleeding

Papageorgiou 2000a

Country: United Kingdom

Study type: RCT

N=107

Sex: mixed

Number randomised: arm 1: n=27

Number randomised: arm 2: n=30

Number randomised: arm 3: n=25

Number randomised: arm 4: n=25

Inclusion details: Mild to moderate acne, age ranging from 14 to 50 years, otherwise healthy.

Intervention: arm 1: BLU-PT 415nm

Intervention: arm 2: BR-LED 415 and 660nm

Intervention: arm 3: White light control

Intervention: arm 4: BPO-topical 5%

Skin irritation

Pazoki-Toroudi 2010

Country: Iran

Study type: RCT

N=126

Sex: mixed

Number randomised: arm 1: na, n=35 completed

Number randomised: arm 2: na, n=31 completed

Number randomised: arm 3: na, n=40 completed

Number randomised: arm 4: n=20

Inclusion details: Age between 14 and 40 years, mild-to-moderate forms of acne vulgaris with at least 10 inflammatory lesions on the face (with a maximum of three nodules).

Intervention: arm 1: Azelaic acid 5% gel

Intervention: arm 2: Erythromycin 2% gel

Intervention: arm 3: Azelaic acid 5% + Erythromycin 2% gel

Intervention: arm 4: Placebo

Skin irritation
Participant reported improvement

Pazoki-Toroudi 2011

Country: Iran

Study type: RCT

N=150

Sex: mixed

Number randomised: arm 1: n=50

Number randomised: arm 2: n=50

Number randomised: arm 3: n=50

Inclusion details: Age between 14 and 40 years, mild-to-moderate forms of acne vulgaris with at least 10 inflammatory lesions on the face .

Intervention: arm 1: Azelaic acid 5% gel

Intervention: arm 2: Clindamycin 2% gel

Intervention: arm 3: Azelaic acid + Clindamycin gel

Skin irritation

Plewig 2009

Country: Europe

Study type: RCT

N=377

Sex: women

Number randomised: arm 1: n=251

Number randomised: arm 2: n=126

Inclusion details: Women with moderate papulopustular acne of the face (8– 75 papules and/or pustules) aged between 18 and 40 years (smokers up to 30 years).

Intervention: arm 1: Ethinyl estradiol 0.03mg + chlormadinone acetate 2mg

Intervention: arm 2: Placebo

Breast tenderness
Neurological side effects
Change in mood
Breakthrough bleeding
Participant reported improvement

Poli 2005

Country: France

Study type: RCT

N=81

Sex: mixed

Number randomised: arm 1: n=42

Number randomised: arm 2: n=39

Inclusion details: Greasy or normal or combination skin type, with phototypes II–IV, presenting with inflammatory (7–15 lesions) and retentional (15–30 lesions) mild to moderate acne vulgaris.

Intervention: arm 1: Diacneal (0.1% retinaldehyde and 6% glycolic acid)

Intervention: arm 2: Vehicle

Participant reported improvement

Rademaker 2014

Country: New Zealand

Study type: RCT

N=58

Sex: mixed

Number randomised: arm 1: n=29

Number randomised: arm 2: n=29

Inclusion details: 25–55 years of age, with low-grade adult acne - defined as three or more acne lesions/month on the face, for at least the last 3 months.

Intervention: arm 1: 5mg isotretinoin once daily

Intervention: arm 2: No treatment for 16 weeks

Mucosal or cutaneous changes

Ragab 2014

Country: Egypt

Study type: RCT

N=25

Sex: mixed

Number randomised: arm 1: n=15

Number randomised: arm 2: n=10

Inclusion details: Participants aged 14 years or over. Participants with mild to moderate acne vulgaris; determined by Evaluator Global Severity score.Score of 2 or 3 on scale before treatment.

Intervention: arm 1: PDT using 5-aminolevulinic acid (ALA) with intense pulsed light (IPL)

Intervention: arm 2: IPL alone

Skin redness
Pigment changes
Participant reported improvement

Rassai 2013

Country: Iran

Study type: RCT

N=144

Sex: mixed

Number randomised: arm 1: na, n=74 completed

Number randomised: arm 2: na, n=74 completed

Inclusion details: Inflammatory acne vulgaris, at least 20 comedones, or with nodules or cysts disregarding the number of comedones.

Intervention: arm 1: 500mg azithromycin/day, 3 days a week + oral levamisole 150mg/day, 2 days a week

Intervention: arm 2: 500mg azithromycin/day, 3 days a week

Skin irritation
GI side effects
Participant reported improvement

Sarkar 2019

Country: India

Study type: RCT

N=45

Sex: mixed

Number randomised: arm 1: n=15

Number randomised: arm 2: n=15

Number randomised: arm 3: n=15

Inclusion details: Patients with acne (grade 1 and 2) with postacne hyperpigmentation. Patients aged >12 years.

Intervention: arm 1: 35% glycolic acid peel

Intervention: arm 2: 20% salicylic acid-10% mandelic acid

Intervention: arm 3: Phytic acid

Skin redness

Schaller 2016

Country: Germany

Study type: RCT

N=217

Sex: mixed

Number randomised: arm 1: n=108

Number randomised: arm 2: n=109

Inclusion details: 12–45 years old, having facial acne vulgaris (defined as having 17–60 inflammatory lesions [papules and pustules], =1 facial nodular cystic lesion, 20–125 non-inflammatory facial lesions and an Investigator’s Static Global Assessment [ISGA] score of ‘mild’ or ‘moderate’).

Intervention: arm 1: Benzoyl peroxide 3% + clindamycin 1% QD

Intervention: arm 2: Azelaic acid 20% BID

Skin irritation

Seaton 2003

Country: United Kingdom

Study type: RCT

N=41

Sex: mixed

Number randomised: arm 1: n=31

Number randomised: arm 2: n=10

Inclusion details: Aged between 18 and 45 years with mild-to-moderate facial inflammatory acne defined as the presence of at least ten acne papules or pustules between the brow and jawline and an acne severity score of between 2 and 7 on the Leeds revised acne grading system.

Intervention: arm 1: Pulsed dye laser

Intervention: arm 2: Sham laser

Skin redness
Skin irritation

Shalita 1981

Country: United States

Study type: RCT

N=49

Sex: mixed

Number randomised: arm 1: n=25

Number randomised: arm 2: n=24

Inclusion details: Teenagers (12 to 20) with mild to moderate acne vulgaris, classed by Pillsbury, Shelly and Kligman grades I or II, with at least fifteen comedones and no more than ten inflammatory lesions.

Intervention: arm 1: 0.5% salicylic acid (Stri-Dex medicated pads)

Intervention: arm 2: Placebo

Participant reported improvement

Shalita 2005

Country: United States

Study type: RCT

N=1026

Sex: mixed

Number randomised: arm 1: n=386

Number randomised: arm 2: n=127

Number randomised: arm 3: n=385

Number randomised: arm 4: n=128

Inclusion details: 12 years of age or older with mild to moderate facial acne vulgaris and an Investigator’s Static Global Assessment (ISGA) score of 2 or greater at baseline. Also a minimum of 17 but no more than 40 facial inflammatory lesions, including nasal lesions, and a minimum of 20, but no more than 150 facial non-inflammatory lesions, excluding nasal lesions.

Intervention: arm 1: Clindamycin foam o.d.

Intervention: arm 2: Vehicle foam o.d.

Intervention: arm 3: Clindamycin gel 1% o.d.

Intervention: arm 4: Vehicle gel o.d.

Skin irritation

Shwetha 2014

Country: India

Study type: RCT

N=120

Sex: mixed

Number randomised: arm 1: n=60

Number randomised: arm 2: n=60

Inclusion details: Mild to moderate acne on face as per Indian Acne Alliance Grading for Severity of acne, aged between 12 to 25 years.

Intervention: arm 1: topical 1% clindamycin + 0.1% adapalene

Intervention: arm 2: topical 1% clindamycin + 2.5 % benzoyl peroxide

Skin irritation

Smith 1980b

Country: United States

Study type: RCT

N=59

Sex: mixed

Number randomised: arm 1: n=29

Number randomised: arm 2: n=30

Inclusion details: At least ten inflammatory papules and/or pustules and no more than three nodulocystic lesions on the face, otherwise in good health.

Intervention: arm 1: 20% Benzoyl-peroxide b.d.

Intervention: arm 2: Vehicle b.d.

Skin irritation

Stein Gold 2016

Country: United States

Study type: RCT

N=2102

Sex: mixed.

Number randomised: arm 1: 1044

Number randomised: arm 2: 1058

Inclusion details: Moderate acne, with 20 to 50 inflammatory lesions (papules and pustules) and 30 to 100 noninflammatory lesions (open and closed comedones) on the face. Patients were also required to have an acne grade of 3 (indicating moderate acne) on the Global Acne Assessment Score. Males and females.

Intervention: arm 1: Dapsone gel 7.5%.

Intervention: arm 2: Vehicle

Skin irritation

Stinco 2007

Country: Italy

Study type: RCT

N=65

Sex: mixed

Number randomised: arm 1: n=25

Number randomised: arm 2: n=20

Number randomised: arm 3: n=20

Inclusion details: Mild or moderate comedonic or papulopustular acne, localized on the face. each patient had a minimum of 20 facial non-inflammatory lesions (open and closed comedones) and 10 inflamed lesions. Also required to be in good health and have not received any oral or topical anti-acne therapy in the 8 weeks prior the study.

Intervention: arm 1: Azelaic acid o.d.

Intervention: arm 2: Benzoyl peroxide o.d.

Intervention: arm 3: Adapalene o.d.

Skin irritation

Stoughton 1987

Country: United States

Study type: RCT

N=110

Sex: mixed

Number randomised: arm 1: n=55

Number randomised: arm 2: n=55

Inclusion details: Helathy participants aged between 12 and 35 years and with a minimum of 10 erythematous facial papules and pustules.

Intervention: arm 1: Chlorhexidine gluconate skin solution

Intervention: arm 2: vehicle

Skin irritation

Thiboutot 2006

Country: North America

Study type: RCT

N=653

Sex: mixed

Number randomised: arm 1: n=261

Number randomised: arm 2: n=258

Number randomised: arm 3: n=134

Inclusion details: Participants 12 years or older, with 20 to 100 noninflammatory facial lesions, 20 to 50 inflammatory facial lesions, and no nodules or cysts; specified washout periods were required for participants taking certain topical and systemic treatments.

Intervention: arm 1: Adapalene 0.1% gel

Intervention: arm 2: Adapalene 0.3% gel

Intervention: arm 2: Vehicle

Skin irritation

Thorneycroft 2004

Country: Germany

Study type: RCT

N=1154

Sex: female

Number randomised: arm 1: n=568

Number randomised: arm 2: n=586

Inclusion details: Otherwise healthy female subjects ranging in age from 15 to 40 years without contraindications for combined oral contraceptive use with mild to moderate acne vulgaris, having 6 to 100 comedones (noninflammatory lesions), 10 to 50 papules or pustules together, and not more than 5 nodules on the face (inflammatory lesions). Normal gynecologic examination and cervical smear within the last 6 months; negative pregnancy test; 3 spontaneous withdrawal bleedings following delivery, abortion, or lactation; and avoidance of comedogenic cosmetics or sunscreens, sex hormone preparations, and antiacne therapy.

Intervention: arm 1: 30micrograms ethinyl estradiol + 3milligrams drospirenone

Intervention: arm 2: 35micrograms ethinyl estradiol + 0.18, 0.215, 0.25 mg norgestimate

Breast tenderness
Neurological side effects

Tirado-Sanchez 2013

Country: Mexico

Study type: RCT

N=171

Sex: mixed

Number randomised: arm 1: n=43

Number randomised: arm 2: n=43

Number randomised: arm 3: n=45

Number randomised: arm 4: n=40

Inclusion details: 18 years or older with at least ten noninflammatory acne lesions and <30 inflammatory lesions on the entire face. Patients with childbearing potential were required to use birth control and to have a negative pregnancy test result at the beginning of the study.

Intervention: arm 1: Adapalene 0.1% gel

Intervention: arm 2: Adapalene 0,3% gel

Intervention: arm 3: Tretinoin 0.05% gel

Intervention: arm 4: Placebo gel

Skin irritation

Trifu 2011

Country: Romania

Study type: RCT

N=47

Sex: men

Number randomised: arm 1: n=32

Number randomised: arm 2: n=15

Inclusion details: White-skinned men with acne vulgaris of the face of mild-to-moderate severity, with a score of 2 or 3 on IGA, and with TLC between 20 and 100, and ILC between 10 and 50.

Intervention: arm 1: Tretinoin 0.05% cream

Intervention: arm 2: Vehicle

Skin irritation

Tu 2001

Country: China

Study type: RCT

N=150

Sex: mixed

Number randomised: arm 1: n=75

Number randomised: arm 2: n=75

Inclusion details: Grade II–III acne vulgaris

Intervention: arm 1: Adapalene gel 0.1%

Intervention: arm 2: Tretinoin gel 0.025%

Skin irritation

Webster 2001

Country: United States

Study type: RCT

N=143

Sex: Mixed

Number randomised: arm 1: n=72

Number randomised: arm 2: n=71

Inclusion details: At least 12 years old with mild to moderate facial acne vulgaris, defined as 10 to 60 facial inflammatory lesions, 10 to 200 facial noninflammatory lesions, and no more than 2 facial nodular cystic lesions (none more than 5mm in diameter).

Intervention: arm 1: once-daily application of tazarotene 0.1% gel

Intervention: arm 2: tretinoin 0.025% gel

Skin irritation

Xu 2016

Country: China

Study type: RCT

N=1016

Sex: Mixed

Number randomised: arm 1: n=500

Number randomised: arm 2: n=516

Inclusion details: Aged 12–45 years (inclusive) diagnosed with mild to moderate acne, with at least 17, but not more than 60 facial inflammatory lesions (papules plus pustules), at least 20 but not more than 125 facial non-inflammatory lesions (open and closed comedones), no more than 1 facial nodular lesion with no cystic lesions, and who had a baseline Investigator’s Static Global Assessment (ISGA) score of 2 or 3.

Intervention: arm 1: topical clindamycin 1%/benzoyl peroxide 5% once-daily gel

Intervention: arm 2: clindamycin 1% twice-daily gel

Skin irritation

: Abbreviations: AZE + SAL peel: azelaic acid and salicylic acid peel; 1319-LSR: 1319 nm laser photochemical therapy; 589-LSR: 589 nm laser photochemical therapy; 5ALA: 5-aminolevulinic acid withunspecified light source; 5ALA-IPL-PDT: 5 aminolevulinic acid using intense pulsed light; 5ALA-KTP-PDT: 5-aminolevulinic acid using KTP (potassium titanyl phosphate) laser; 5ALA-PDL-PDT: 5-aminolevulinic acid using pulsed dye laser; 5ALA-RED-PDT: 5-aminolevulinic acid using red light; 5ARI: 5-alpha-reductase inhibitors; ACTINAC: Actinac (4% chloramphenicol, 4% hydrocortisone acetate, 2.4% butoxyethyl nicotinate, 2.4% allantoin, 32% precipitated sulphur); ADAP + BPO: adapalene + benzoyl peroxide; ADAP: adapalene; AFA peel: amino fruit acid (available in creams, pads, lotions); AZE: azelaic acid; AZITH:azithromycin; BIFON: bifonazole; BiRF: bipolar radiofrequency; BLU-PT: blue light emitting diode therapy (LED) photochemical therapy; BPO + CLIND: benzoyl peroxide 5%/clindamycin 1%; BPO: benzoyl peroxide; BR-LED: blue + red light; BUTEN: butenifine; CD271: CD 271 alcoholic gel; CHLOR: chlorhexidine gluconate/digluconate; CIPRO: ciprofloxacine; CLIND: clindamycin; CLIND + TRET: clindamycin 1% + tretioin 0.025%; CLIND+ ZINC: clindamycin with zinc acetatedihydrate; CMA: chlormadinone acetate; CO2: fractional CO2 laser; CPA + EE: co-cyprindiol (ethinylestradiol with cyproterone acetate); CPA: cyproterone acetate; DAPS: dapsone; DEM: demeclocycline; DOXY: doxycycline; DRSP: drospirenone; EE + DNG: estradiol (valerate) + dienogest; EE + DROS: ethinylestradiol + drospirenone; EE + LNG: ethinylestradiol+levonorgestrel; EE: ethinylestradiol; EE+DSGethinylestradiol+ desogestrel; EE+NGM: ethinylestradiol+norgestimate; ERYTH + ZINC: erythromycin with zinc acetate dihydrate; ERYTH:erythromycin; FCA: fucidic acid (sodium fusidate); FMR: fractional microneedling radiofrequency; GLY peel: glycolic acid; GOLDMP: gold microparticles; HPS: hydrogen peroxide; IPL: intense pulsed light; IPL+VAC: intense pulsed light + vacuum; IRL: near infrared light; ISO<120.Alt<0.5: isotretinoin ≥0.5mg/kg/every other day total cumulative dose < 120mg/kg; ISO<120.Alt≥0.5: isotretinoin <0.5mg/kg/every other day total cumulative dose < 120mg/kg; ISO<120.Daily<0.5: isotretinoin ≥0.5mg/kg/day total cumulative dose < 120mg/kg; ISO<120.Daily≥0.5: isotretinoin<0.5mg/kg/day total cumulative dose < 120mg/kg; ISO<120.Other<0.5: isotretinoin≥0.5mg/kg/less frequently total cumulative dose < 120mg/kg; ISO<120.Other≥0.5: isotretinoin<0.5mg/kg/less frequently total cumulative dose < 120mg/kg; ISO≥120.Alt<0.5: isotretinoin≥0.5mg/kg/every other day total cumulative dose >= 120mg/kg; ISO≥120.Alt≥0.5: isotretinoin<0.5mg/kg/every other day total cumulative dose >= 120mg/kg; ISO≥120.Daily<0.5: ISOisotretinoin ≥0.5mg/kg/day total cumulative dose >= 120mg/kg; ISO≥120.Daily≥0.5: isotretinoin<0.5mg/kg/day total cumulative dose >= 120mg/kg; ISO≥120.Other<0.5: isotretinoin≥0.5mg/kg/less frequently total cumulative dose >= 120mg/kg; ISO≥120.Other≥0.5: isotretinoin<0.5mg/kg/less frequently total cumulative dose >= 120mg/kg; ISO: isotretinoin; JES peel: Jessner’s peel; KTP: potassium titanyl phosphate laser; LEVA: levamisole; LNG: levonorgestrel; LYME: lymecycline; MAL with occlusion: methyl aminolevulinate ; MAL without occlusion: methylaminolevulinate ; MAL-DL-PDT: methyl aminolevulinate using daylight; MAL-IPL-PDT: methyl aminolevulinate using intense pulsed light; MAL-KTP-PDT: methyl aminolevulinate using potassium titanyl phosphate (KTP) laser; MAL-RED-PDT: methyl aminolevulinate using red light; MD: microdermabrasion; METF: metformin; MET: metronidazole; MICO: miconazole nitrate; MINO: minocycline; MOT:motretinide; n: number of participants randomised/completed to/in each trial arm; NAD:nadifloxacin; NAFL: fractional erbiumglass laser; NBUVB: nearband ultraviolet light; Nd:YAG: long-pulse neodymium-doped yttrium aluminum garnet laser; NELS: Nels Cream (chloroxylenol + zinc oxide); NICO: nicotinamide (NIACINAMID); no!no!: no!no! skin device (broad spectrum light of 450–2000nm, 6 J/cm-2); NOR + EE:norethisterone + ethinylestradiol; OXYTETRA: oxytetracycline; PBBL: pneumatic broadband light therapy; PDL: pulsed dye laser; PLC: placebo; PLC-physical: sham physical treatment; PRED:prednisolone; PYA peel: pyruvic acid; RED: red light; RETINOL: retinol (vitamin A); ROXI: roxithromycin; SAL peel: salicylic acid; SARE:sarecyclin; SOS: superoxidised solution (an electrochemically processed aqueous solution manufactured from pure water and sodium chloride); SPIRO: spironolactone; TAZ:tazarotene; TCA peel: trichloroaecetic acid; TETRA: tetracycline;TRET: tretinoin (retin A, all-trans reinoic acid); TRIC: triclozan;; ZINCG: zinc gluconate.

Management options for mild to moderate acne – pairwise comparisons

Authors

Summary of review questions covered in this report

Management options for mild to moderate acne – pairwise comparisons

Review question

Introduction

Summary of the protocol

Table 1

Methods and process

Clinical evidence

Included studies

Topical non-retinoids and retinoids

Own class topicals

Topical antibiotics

Topical antiseptics

Topical acids

Oral antibiotics and combinations with other topicals

Oral hormonal contraceptives and hormone-modifying agents

Oral isotretinoin

Physical treatments

Chemical peels

Energy based treatments (light/laser)

Excluded studies

Summary of included studies

Table 2

Quality assessment of included studies in the evidence review

Economic evidence

Included studies

Excluded studies

Economic model

The committee’s discussion of the evidence

Recommendations supported by this evidence review

References

Appendices

Appendix A. Review protocol

Appendix B. Literature search strategies

Appendix C. Clinical evidence study selection

Appendix D. Evidence tables

Appendix E. Forest plots

Appendix F. GRADE tables

Appendix G. Economic evidence study selection

Appendix H. Economic evidence tables

Economic evidence tables for review question: What is the effectiveness and acceptability of interventions for the treatment of mild to moderate acne (side effects and participant reported improvement)?

Appendix I. Economic evidence profiles

Economic model for review question: What is the effectiveness and acceptability of interventions for the treatment of mild to moderate acne (side effects and participant reported improvement)?

Appendix J. Economic analysis

Economic analysis for review question: What is the effectiveness and acceptability of interventions for the treatment of mild to moderate acne (side effects and participant reported improvement)?

Appendix K. Excluded studies

Excluded clinical and economic studies for review question: What is the effectiveness and acceptability of interventions for the treatment of mild to moderate acne (side effects and participant reported improvement)?

Clinical studies

Economic studies and studies reporting utility data

Appendix L. Research recommendations

Research recommendations for review question: What is the effectiveness and acceptability of interventions for the treatment of mild to moderate acne (side effects and participant reported improvement)?

Table 1Summary of the protocol

Table 2Summary of included studies