Topical Preparations for the Treatment of Mild-to-moderate Acne Vulgaris

Systematic Review and Network Meta-analysis

B. Stuart; E. Maund; C. Wilcox; K. Sridharan; G. Sivaramakrishnan; C. Regas; D. Newell; I. Soulsby; K.F. Tang; A.Y. Finlay; H.C. Bucher; P. Little; A.M. Layton; M. Santer


The British Journal of Dermatology. 2021;185(3):512-525. 

In This Article


Study Selection and Network Structure

We identified 3717 references and, after removing duplicates, 2236 were screened by two reviewers for eligibility. We obtained 329 full texts and identified 133 eligible full texts reporting on 82 trials. An updated search in June 2020 identified a further 23 full texts, nine of which were eligible. We excluded 54 full texts, comprising 5126 participants, because the outcomes of interest could not be extracted. Of the trials identified by the original and updated searches, 81 full texts reporting on 40 trials including a total of 18 089 participants provided outcome data for meta-analysis (Figure 1).[25–62]

Figure 1.

PRISMA flow diagram.

Figure 2 shows network plots for direct evidence between treatments. In all analyses, the main comparator was vehicle. For all outcomes, the most common treatment studied was BPO compared with vehicle, followed by adapalene and adapalene + BPO compared with vehicle. Fewer trials compared clindamycin + tretinoin, erythromycin + zinc or tretinoin, tretinoin alone or azelaic acid with any other treatment.

Figure 2.

Network plots of direct evidence. BPO, benzoyl peroxide.

Trial Characteristics and Risk of Bias

Key trial characteristics and risk of bias are detailed in Table S1 and Figure S1 and Figure S2 (see Supporting Information). The mean sample size was 454 participants (SD 524). The average age was 19·77 years (SD 3·13) and 57·7% of participants were female. Overall, 50% of recruited participants were from North America, 29% were from Europe, 24% were from Asia, 5% were from South America and 3% were from Australia, but the ethnicity of these populations was poorly reported. Pharmaceutical companies sponsored 54% of trials and a further 38% did not report the funder.

Most trials had an unclear risk of bias for at least one domain owing to poor reporting and none had low risk of bias across all domains. While blinding of participants was generally well described in trials that included a vehicle, many trials were unclear in their description of the blinding of trial personnel. All trials were randomized, but the generation of the randomization sequence was poorly described in 30 trials.

Trial results

Table S2 out the pooled network analysis results and confidence ratings for all treatment comparisons. Figure 3 sets out all the pooled network comparisons relative to vehicle. Below, we consider the outcomes from the review for which sufficient data were available for network analysis. All treatment rankings and associated probabilities are set out in Table S3, Table S4, Table S5 and Table S6 (see Supporting Information).

Figure 3.

All treatments compared with vehicle (pooled network estimates). BPO, benzoyl peroxide; Clin, clindamycin; Tret, tretinoin; Eryth, Erythromycin.

Patient Global Assessment of Improvement

The proportion of participants who rated their acne as 'improved or much improved' was reported in 11 trials that included 6947 participants. Figure 3 shows that all treatments were significantly more effective than vehicle.

Table 1 sets out direct (no shading) and pooled (in grey) ORs and 95% confidence intervals (CIs) for comparisons. Compared with vehicle, adapalene + BPO had an OR of 3·65 (95% CI 2·58–5·15; moderate confidence) and network comparisons suggest that this treatment was significantly more effective than all other included treatments apart from clindamycin + BPO (OR 1·22, 95% CI 0·81–1·85; low confidence). Clindamycin + BPO was significantly more effective than BPO (OR 1·54, 95% CI 1·14–2·08; low confidence) or clindamycin alone (OR 1·91, 95% CI 1·36–2·68; moderate confidence).

Adverse Events

The withdrawal of participants from the trial or participants stopping the trial medication was reported in 35 trials of 16 735 participants. Results are set out in Table 2 and the rankings suggest that the lowest odds of withdrawal were in participants who used clindamycin. Clindamycin was associated with significantly lower odds of withdrawal than clindamycin + BPO (OR 2·17, 95% CI 1·25–3·70; very low confidence), BPO (OR 2·38, 95% CI 1·20–4·76; moderate confidence) or adapalene + BPO. The highest odds of withdrawal/discontinuation were for adapalene + BPO (OR 4·35, 95% CI 2·13–9·09; moderate confidence). Participants using adapalene + BPO had an OR of 2·56 (95% CI 1·41–4·76; moderate confidence) compared with adapalene alone, suggesting that the odds of withdrawal/discontinuation were three times higher with combination treatment than adapalene alone. Similarly, participants using adapalene + BPO had an OR of 2·22 (95% CI 0·94–5·26; moderate confidence) compared with those using tretinoin, and an OR of 1·85 (95% CI 1·08–3·13; moderate confidence) compared with those using BPO alone. However, the number of participants who withdrew owing to adverse events was low for all treatments (Table 3).

Total Lesion Counts

Mean change in total lesion counts was reported in 24 trials of 11 717 participants (Table 4). The largest change was observed in those using adapalene + BPO with a difference of 20·96 lesions (95% CI −25·02 to −16·90; moderate confidence) compared with vehicle. Network comparisons suggest significant improvements with adapalene + BPO compared with all other treatments apart from erythromycin + tretinoin, where the CIs were very wide and confidence was very low. Compared with the second ranked treatment, clindamycin + BPO, there were −8·27 (95% CI −13·02 to −3·52; very low confidence) fewer lesions with adapalene + BPO. Clindamycin + BPO and BPO alone were more effective than clindamycin alone with low and moderate confidence, respectively.

Investigator's Global Assessment

There were 14 trials of 13 342 participants that evaluated improvement in the IGA to 'clear' or 'almost clear' (Table 5). All treatments were significantly more effective than vehicle apart from tretinoin (OR 0·83, 95% CI 0·46–1·52; low confidence). Adapalene + BPO was significantly more effective than all treatments apart from clindamycin + BPO, with an OR of improvement of 3·83 (95% CI 2·40–6·10; moderate confidence) compared with vehicle. Based on the pooled network estimate, adapalene + BPO was approximately twice as likely to lead to improvement than either BPO or adapalene, with low and moderate confidence, respectively.

Other Outcomes and Sensitivity Analyses

There was insufficient data to undertake meta-analyses or network analyses for quality of life, patient satisfaction, C. acnes resistance and sensitivity analyses of outcomes in the short or long term.


There was no evidence of global inconsistency. However, some analyses suggested local inconsistency between direct and indirect comparisons (Table S7, Table S8, Table S9 and Table S10 see Supporting Information). The number of trials where pairs of direct and indirect estimates could be compared was very low and in all instances CIs for estimates of differences were wide, but there was no evidence of systematic differences with respect to potential effect modifiers. Therefore, this apparent inconsistency may represent true differences between direct and indirect effects, with indirect estimates being more precise as they came from a network with larger trials.

Confidence in Evidence

The grading of the comparisons with CINeMA (Table S11, Table S12, Table S13 and Table S14; see Supporting Information) showed mainly low to very low confidence ratings. This was due to concerns about reporting bias resulting from the involvement of industry in a large number of small trials[23] and to concerns about within-study bias owing to poor reporting of the randomization and blinding procedures noted above. There were few concerns about transitivity (indirectness). Owing to the strict inclusion criteria, most trials included a homogeneous population of interest. There was also evidence of heterogeneity and imprecision, usually related to the low numbers of trials available for some comparisons in the network.