Abstract

Background

Acne is an inflammatory disorder with a high global burden. It is common in adolescents and primarily affects sebaceous gland‐rich areas. The clinical benefit of the topical acne treatments azelaic acid, salicylic acid, nicotinamide, sulphur, zinc, and alpha‐hydroxy acid is unclear.

Objectives

To assess the effects of topical treatments (azelaic acid, salicylic acid, nicotinamide, zinc, alpha‐hydroxy acid, and sulphur) for acne.

Search methods

We searched the following databases up to May 2019: the Cochrane Skin Group Specialised Register, CENTRAL, MEDLINE, Embase, and LILACS. We also searched five trials registers.

Selection criteria

Clinical randomised controlled trials of the six topical treatments compared with other topical treatments, placebo, or no treatment in people with acne.

Data collection and analysis

We used standard methodological procedures expected by Cochrane. Key outcomes included participants' global self‐assessment of acne improvement (PGA), withdrawal for any reason, minor adverse events (assessed as total number of participants who experienced at least one minor adverse event), and quality of life.

Main results

We included 49 trials (3880 reported participants) set in clinics, hospitals, research centres, and university settings in Europe, Asia, and the USA.

The vast majority of participants had mild to moderate acne, were aged between 12 to 30 years (range: 10 to 45 years), and were female. Treatment lasted over eight weeks in 59% of the studies. Study duration ranged from three months to three years.

We assessed 26 studies as being at high risk of bias in at least one domain, but most domains were at low or unclear risk of bias.

We grouped outcome assessment into short‐term (less than or equal to 4 weeks), medium‐term (from 5 to 8 weeks), and long‐term treatment (more than 8 weeks). The following results were measured at the end of treatment, which was mainly long‐term for the PGA outcome and mixed length (medium‐term mainly) for minor adverse events.

Azelaic acid

In terms of treatment response (PGA), azelaic acid is probably less effective than benzoyl peroxide (risk ratio (RR) 0.82, 95% confidence interval (CI) 0.72 to 0.95; 1 study, 351 participants), but there is probably little or no difference when comparing azelaic acid to tretinoin (RR 0.94, 95% CI 0.78 to 1.14; 1 study, 289 participants) (both moderate‐quality evidence). There may be little or no difference in PGA when comparing azelaic acid to clindamycin (RR 1.13, 95% CI 0.92 to 1.38; 1 study, 229 participants; low‐quality evidence), but we are uncertain whether there is a difference between azelaic acid and adapalene (1 study, 55 participants; very low‐quality evidence).

Low‐quality evidence indicates there may be no differences in rates of withdrawal for any reason when comparing azelaic acid with benzoyl peroxide (RR 0.88, 95% CI 0.60 to 1.29; 1 study, 351 participants), clindamycin (RR 1.30, 95% CI 0.48 to 3.56; 2 studies, 329 participants), or tretinoin (RR 0.66, 95% CI 0.29 to 1.47; 2 studies, 309 participants), but we are uncertain whether there is a difference between azelaic acid and adapalene (1 study, 55 participants; very low‐quality evidence).

In terms of total minor adverse events, we are uncertain if there is a difference between azelaic acid compared to adapalene (1 study; 55 participants) or benzoyl peroxide (1 study, 30 participants) (both very low‐quality evidence). There may be no difference when comparing azelaic acid to clindamycin (RR 1.50, 95% CI 0.67 to 3.35; 1 study, 100 participants; low‐quality evidence). Total minor adverse events were not reported in the comparison of azelaic acid versus tretinoin, but individual application site reactions were reported, such as scaling.

Salicylic acid

For PGA, there may be little or no difference between salicylic acid and tretinoin (RR 1.00, 95% CI 0.92 to 1.09; 1 study, 46 participants; low‐quality evidence); we are not certain whether there is a difference between salicylic acid and pyruvic acid (1 study, 86 participants; very low‐quality evidence); and PGA was not measured in the comparison of salicylic acid versus benzoyl peroxide.

There may be no difference between groups in withdrawals when comparing salicylic acid and pyruvic acid (RR 0.89, 95% CI 0.53 to 1.50; 1 study, 86 participants); when salicylic acid was compared to tretinoin, neither group had withdrawals (both based on low‐quality evidence (2 studies, 74 participants)). We are uncertain whether there is a difference in withdrawals between salicylic acid and benzoyl peroxide (1 study, 41 participants; very low‐quality evidence).

For total minor adverse events, we are uncertain if there is any difference between salicylic acid and benzoyl peroxide (1 study, 41 participants) or tretinoin (2 studies, 74 participants) (both very low‐quality evidence). This outcome was not reported for salicylic acid versus pyruvic acid, but individual application site reactions were reported, such as scaling and redness.

Nicotinamide

Four studies evaluated nicotinamide against clindamycin or erythromycin, but none measured PGA. Low‐quality evidence showed there may be no difference in withdrawals between nicotinamide and clindamycin (RR 1.12, 95% CI 0.49 to 2.60; 3 studies, 216 participants) or erythromycin (RR 1.40, 95% CI 0.46 to 4.22; 1 study, 158 participants), or in total minor adverse events between nicotinamide and clindamycin (RR 1.20, 95% CI 0.73 to 1.99; 3 studies, 216 participants; low‐quality evidence). Total minor adverse events were not reported in the nicotinamide versus erythromycin comparison.

Alpha‐hydroxy (fruit) acid

There may be no difference in PGA when comparing glycolic acid peel to salicylic‐mandelic acid peel (RR 1.06, 95% CI 0.88 to 1.26; 1 study, 40 participants; low‐quality evidence), and we are uncertain if there is a difference in total minor adverse events due to very low‐quality evidence (1 study, 44 participants). Neither group had withdrawals (2 studies, 84 participants; low‐quality evidence).

Authors' conclusions

Compared to benzoyl peroxide, azelaic acid probably leads to a worse treatment response, measured using PGA. When compared to tretinoin, azelaic acid probably makes little or no difference to treatment response. For other comparisons and outcomes the quality of evidence was low or very low.

Risk of bias and imprecision limit our confidence in the evidence. We encourage the comparison of more methodologically robust head‐to‐head trials against commonly used active drugs.

Author(s)

Haibo Liu, Haiyan Yu, Jun Xia, Ling Liu, Guan J Liu, Hong Sang, Frank Peinemann

Abstract

Plain language summary

Topical azelaic acid, salicylic acid, nicotinamide, sulphur, zinc, and fruit acid (alpha‐hydroxy acid) for acne

Background

Acne vulgaris ('acne') is a costly and common skin disorder in which hair follicles become blocked. Acne affects up to 85% of adolescents and young adults. Topical retinoids (treatment derived from vitamin A) and antimicrobials (treatment that kills micro‐organisms such as bacteria) are common treatments. Other topical medications are also used, but there are concerns about their efficacy and safety.

Review question

This Cochrane Review aimed to assess the effects of six topical treatments (azelaic acid, salicylic acid, nicotinamide, sulphur, zinc, and alpha‐hydroxy acid (organic acids found in food, sometimes known as fruit acid) on people with acne when compared with an inactive substance (placebo), no treatment, or other topical treatments. The evidence is current to May 2019.

Study characteristics

We included 49 trials (3880 reported participants). At least one study assessed each eligible treatment.

Most trial participants were female, aged between 12 and 30 years, with mild to moderate acne. Nearly 60% of the trials treated participants for longer than eight weeks. Study duration ranged from three months to three years.

Nine trials reported pharmaceutical support. The studies were mainly conducted in Europe, Asia, and the USA, in clinics, hospitals, research centres, and universities.

Key results

The following results were measured at the end of treatment, which was mainly long term (more than 8 weeks) for the outcome 'Participants' global self‐assessment of acne improvement' (PGA) and mixed in length, but mainly medium term (from 5 to 8 weeks), for 'Total number of participants who experienced at least one minor side effect'.

Azelaic acid probably leads to worse PGA when compared to benzoyl peroxide, but when compared to tretinoin, there is probably little or no difference (both moderate‐quality evidence). When comparing azelaic acid to clindamycin, there may be little or no difference in PGA (low‐quality evidence), but we are uncertain whether azelaic acid reduces PGA compared to adapalene (very low‐quality evidence).

In terms of participant withdrawal (for any reason), there may be no difference when azelaic acid is compared with benzoyl peroxide, clindamycin, and tretinoin (all low‐quality evidence). We are uncertain whether azelaic acid reduces withdrawals when compared to adapalene (very low‐quality evidence).

We are uncertain whether azelaic acid has fewer total minor adverse events when compared to adapalene or benzoyl peroxide (very‐low quality evidence). When comparing azelaic acid to clindamycin, there may be no difference in total adverse events (low‐quality evidence). The studies that compared azelaic acid with tretinoin only reported individual side effects (e.g. scaling).

We are uncertain if there is a difference between salicylic acid and pyruvic acid on PGA score (very low‐quality evidence). There may be little or no difference between salicylic acid and tretinoin in PGA (low‐quality evidence). No study comparing salicylic acid with benzoyl peroxide assessed PGA. There may be no difference in withdrawals when comparing salicylic acid and pyruvic acid; there were no withdrawals when salicylic acid was compared to tretinoin (both low‐quality evidence). We are uncertain if there is a difference in withdrawals between salicylic acid and benzoyl peroxide (very low‐quality evidence).

We are uncertain whether salicylic acid reduces total minor adverse events when compared to benzoyl peroxide or tretinoin (very low‐quality evidence). For salicylic acid compared with pyruvic acid only individual application site reactions were reported (e.g. scaling and redness).

None of the four studies assessing nicotinamide (compared to clindamycin or erythromycin) assessed PGA. Nicotinamide may make no difference to withdrawals when compared to clindamycin or erythromycin, and may make no difference to total minor adverse events when compared to clindamycin (both low‐quality evidence); however, no studies comparing nicotinamide with erythromycin looked at total minor adverse events.

Glycolic acid peels may make no difference to PGA when compared to salicylic‐mandelic acid peels (low‐quality evidence), we are uncertain of the effect on total minor adverse events (very low‐quality evidence), and there were no withdrawals (low‐quality evidence).

Quality of the evidence

Our evidence quality was mixed for the PGA outcome (very low to moderate), mainly low quality for withdrawals, and very low quality for total minor side effects. We had some concerns with the small size of the studies and how they were conducted.

Author(s)

Haibo Liu, Haiyan Yu, Jun Xia, Ling Liu, Guan J Liu, Hong Sang, Frank Peinemann

Reviewer's Conclusions

Authors' conclusions 

Implications for practice 

Presently, clinicians often choose topical retinoids and antimicrobials as the first choice of treatment for mild and moderate acne (Akhavan 2003; Titus 2012; Well 2013). The data in this review show there is no high‐quality evidence to determine the effects of the topical treatments azelaic acid, salicylic acid, nicotinamide, sulphur, zinc, and alpha‐hydroxy acid over the commonly used topical drugs. In some cases, the comparative studies suggest no difference between these topical treatments and commonly used retinoids or antimicrobials, but we cannot draw definitive conclusions due to very low‐ to low‐quality evidence. The limited number of trials and other issues (e.g. inadequate reporting) make it hard to obtain high‐quality evidence.

We cannot draw conclusions about the effect of the following comparisons on the outcome 'participants' global self‐assessment of acne improvement', as the quality of evidence is very low or the outcome was not reported.

• Azelaic acid compared to adapalene
• Salicylic acid compared to pyruvic acid
• Salicylic acid compared to benzoyl peroxide
• Nicotinamide compared to clindamycin
• Nicotinamide compared to erythromycin

In terms of treatment response (participants' global self‐assessment of acne improvement; PGA), azelaic acid is probably less effective than benzoyl peroxide (moderate‐quality evidence), and there may be little or no difference in PGA when comparing azelaic acid to clindamycin (low‐quality evidence). There is probably little or no difference when comparing azelaic acid to tretinoin (moderate‐quality evidence). There may be little or no difference in PGA between salicylic acid and tretinoin (low‐quality evidence). There may be no difference in PGA when comparing glycolic acid peel to salicylic‐mandelic acid peel (low‐quality evidence).

We cannot draw conclusions about the effect of the following comparisons on the outcome 'withdrawal for any reason', as the quality of evidence is very low or the outcome was not reported.

• Azelaic acid compared to adapalene
• Salicylic acid compared to benzoyl peroxide

Based on low‐quality evidence, there may be no differences in rates of withdrawal for any reason when comparing the following.

• Azelaic acid with benzoyl peroxide, clindamycin, or tretinoin
• Salicylic acid with pyruvic acid
• Nicotinamide with clindamycin or erythromycin

There were no withdrawals in the comparisons of salicylic acid versus tretinoin and glycolic acid versus salicylic‐mandelic acid.

We cannot draw conclusions about the effect of the following comparisons on minor adverse events, assessed as total number of participants who experienced at least one minor adverse event, as the quality of evidence is very low or the outcome was not reported.

• Azelaic acid compared to adapalene
• Azelaic acid compared to benzoyl peroxide
• Azelaic acid compared to tretinoin
• Salicylic acid compared to benzoyl peroxide
• Salicylic acid with pyruvic acid
• Salicylic acid was compared to tretinoin
• Nicotinamide compared to erythromycin
• Glycolic acid (alpha‐hydroxy acid) compared to salicylic‐mandelic acid (peel)

There may be no difference in minor adverse events when comparing azelaic acid to clindamycin.

The adverse events caused by these treatments included mainly application site reactions such as erythema, scaling, dry skin, burning, peeling, and itching, and the risk of specific adverse events (e.g. erythema) was mostly similar between treatment groups.

We do not have sufficient evidence to determine the efficacy and safety of sulphur, zinc, and gluconolactone, which are no longer used in clinical practice.

In the absence of high‐quality evidence for these treatments, clinical decisions may continue to be guided by clinical experiences and patients' preferences.

Implications for research 

There is a need for further head‐to‐head comparisons of the topical treatments azelaic acid, salicylic acid, nicotinamide, and glycolic acid with commonly used active drugs (topical retinoids and antimicrobials). Moreover, trials comparing these topical treatments with vehicle/placebo or no treatment are also required. This will confirm their efficacy for treating mild to moderate acne.

Randomised trials with a parallel or cross‐over design are necessary. With respect to cross‐over trials, study authors should report the outcome data as previously suggested (Elbourne 2002). Study authors should clearly report the severity of illness. Participants irrespective of age, severity, or gender need to be included. Study authors should clearly report the co‐interventions in each treatment arm. A long‐term treatment duration (over 8 weeks) for future trials is suggested. We do not recommend trials authors measure the drug efficacy in the post‐treatment follow‐up period as these topical medications most probably have no long‐lasting effect after withdrawal of therapy.

The variability in conducting and reporting of trials significantly hampered combining study results for meta‐analysis. We recommend standardisation of outcome reporting in future trials. The trial authors should use a standardised scale (e.g. measured by a four‐point scale: excellent, good, fair, and poor) to measure participants' global self‐assessment of acne improvement, and the authors should provide a clear description of how the outcome was measured. Study authors should also report the number of withdrawals from the trial and the reasons for withdrawals. In addition, development of a standardised scale for physicians' global evaluation of acne improvement is necessary, and the report of number of participants would be better. We recommend study authors report the total number of participants who experienced at least one adverse event, but not report adverse events as count data. It would also be useful if study authors presented the total number of participants who experienced individual side effects, e.g. redness. Assessment of quality of life using a validated instrument (e.g. Acne‐Specific Quality of Life Questionnaire; Acne‐QoL) is highly desirable. Adherence to recommendations from the Cochrane Skin ‐ Core Outcome Set Initiative would improve and standardise outcome measurement (CS‐COUSIN 2019).

Unfortunately, the study authors often presented inadequate data or information, for example, randomisation was not clearly described, allocation concealment was not reported, it was unclear who was blinded, results were presented in figures with no raw data, standard deviations (SDs) were not mentioned and could not be obtained in any way, and exact P values were not reported. Furthermore, 11/49 studies had high attrition bias; therefore, efforts should be made to ensure participants remain in the study. We have to acknowledge that many included studies in this review predate the CONSORT recommendations (Begg 1996; Moher 2001), but future studies should ensure they adhere to the CONSORT recommendations on trials to guarantee the full availability of all data. Many of our analyses were limited to single study data. These studies had small sample sizes; hence, we downgraded the majority of our evidence for imprecision. Future studies should ensure a sample size calculation is used. We could not assess publication bias because of the limited number of studies in each comparison.

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